CN104530045A - Pyrazolo[4,3-c]tetrahydropyridine c-Met kinase inhibitors as well as preparation method and application thereof - Google Patents

Pyrazolo[4,3-c]tetrahydropyridine c-Met kinase inhibitors as well as preparation method and application thereof Download PDF

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CN104530045A
CN104530045A CN201510024284.2A CN201510024284A CN104530045A CN 104530045 A CN104530045 A CN 104530045A CN 201510024284 A CN201510024284 A CN 201510024284A CN 104530045 A CN104530045 A CN 104530045A
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pyridine
pyrazolo
tetrahydrochysene
phenyl
arh
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胡诗合
陈亚东
陆涛
金乔梅
袁浩亮
庄津
胡亚宁
张立
王冰洋
赵爽
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China Pharmaceutical University
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China Pharmaceutical University
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

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Abstract

The invention relates to a kind of new compounds taking 4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine as the parent nucleus as well as a preparation method and medical uses thereof and particularly the use as a c-Met kinase inhibitor. The new compounds can be used independently or combined with at least one other medicine for treating the diseases regulated by protein kinase such as cancer.

Description

Pyrazolo [4,3-c] tetrahydropyridine class c-Met kinase inhibitor and its production and use
Invention field
The present invention relates to a class based on 4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine new compound, their preparation method and their medical use, particularly as the purposes of c-Met kinase inhibitor.This new compound composition can be used alone or with at least one other medicines coupling being used for the treatment of the disorders such as cancers regulated by protein kinase.
Background technology
Malignant tumour is one of major disease of serious threat human life, antitumor drug plays an important role in the clinical treatment of tumour, in recent years, along with the development of Protocols in Molecular Biology and on cellular and molecular level to the further understanding of Tumorigenesis, new drug development just develops from traditional cell toxicity medicament towards the new type antineoplastic medicine for link target multiple tumor development mechanism, wherein, for the suppression of tumour Signal Transduction path be the effective prevention means of Targeted cancer therapy.Protein tyrosine kinase (RTKs, receptor tyrosine kinases) play an important role in intracellular signal transduction pathway, it by extracellular signal transmission in cell, and through to physiological activities such as the propagation of the transduction regulatory tumour cell in downstream, differentiation, growth and apoptosis.The generation of RTKs and tumour develops closely related, and therefore, its family member has become the main flow target of antitumor drug research and development.
Receptor tyrosine kinase MET, i.e. hepatocyte growth factor receptor HGFR, belong to a Ge Zi family of receptor tyrosine kinase, this family also contains RON kinases.PHGF and discrete element SF are the natural high-affinity parts of MET.HGF/MET signal path is most important to the invasive growth in fetal development and neomorph in postpartum.For grownup, under normal circumstances, this path is only fully active in wound healing and tissue regeneration processes.But formed in tumour, in the process of invasive growth and transfer, cancer cells also can frequently activate HGF/MET path.HGF and/or MET unusual high levels in various solid knurl is expressed, as liver cancer, and mammary cancer, carcinoma of the pancreas, lung cancer, kidney, bladder cancer, ovarian cancer, brain tumor, prostate cancer and other cancers.The HGF/MET of overexpression is usually also relevant to metastatic phenotype and poor prognosis.In addition, the overactivity of HGF/MET signal transduction pathway can produce other tumor therapeuticing methods and hinder.In tumour cell microenvironment, the rise of HGF level can make patient produce resistance to other antitumor kinase inhibitor, shows HGF/MET inhibitor another vital role in cancer therapy.Correlative study shows that the overactivity of HGF/MET signal transduction pathway can make patient produce resistance to EGFR and BRAF kinase inhibitor.The exception of HGF/MET path and the generation of tumour, Infiltration and metastasis, and the generation of cancer therapy resistance is closely related, therefore the suppression of HGF/MET path has cancer therapy potentiality, has become one of leading target path in antitumor drug research and cancer therapy.Wherein, the non-c-Met kinases specific small molecule inhibitor (R)-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine of Pfizer successfully went on the market in 2011, and had good therapeutic action to nonsmall-cell lung cancer.
Summary of the invention
The present invention have studied on the basis in a large number with optionally c-Met micromolecular inhibitor, according to the crystal structure model of c-Met protein kinase, Computer-Aided Drug Design means are utilized to build structure activity relationship model and the medicine virtual screening model of c-Met inhibitor, design and synthesize a series of with 4 on this basis, 5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine is the compound of the brand new of parent nucleus, pharmacological tests shows: compound of the present invention has good c-Met kinase inhibiting activity.
Technical scheme of the present invention is as follows:
The compound of general formula (I) or its pharmacy acceptable salt:
Wherein X represents-CR 1r 2-,-SO 2-or-CO-, wherein R 1, R 2represent hydrogen, halogen, alkyl, aryl or Het independently of one another;
Y represents-NR 3cO-,-CONR 4-, wherein R 3, R 4represent hydrogen, alkyl, aryl or Het independently of one another;
Q 1represent alkyl, aryl or Het;
Q 2represent aryl or Het;
R represents hydrogen, hydroxyl, alkyl ,-CONR 5r 6,-CONR 5(CH 2) nnR 6,-CONR 5(CH 2) noR 6,-NR 5cOR 6,-NR 5r 6,-NR 5(CH 2) nnR 6,-NR 5(CH 2) noR 6,-CR 5r 6, aryl or Het, wherein n=1,2,3,4 or 5, R 5, R 6represent hydrogen, alkyl, aryl or Het independently of one another;
Alkyl is the straight or branched saturated hydrocarbyl with 1-6 carbon atom; Or for having the cyclic saturated hydrocarbon base of 3-6 carbon atom; Or for connecting the cyclic saturated hydrocarbon base with 3-6 carbon atom with the straight or branched saturated hydrocarbyl of 1-6 carbon atom;
Aryl is the carbocyclic ring being selected from phenyl, naphthyl, acenaphthenyl or tetralyl, it is optionally replaced by 1,2 or 3 substituting group separately, and each substituting group is independently selected from hydrogen, alkyl, cyano group, halogen, nitro, haloalkyl, hydroxyl, sulfydryl, alkoxyl group, alkylthio, alkoxyalkyl, aralkyl, alkyl diaryl, aryl or Het;
Het is the monocyclic heterocycles being selected from piperidyl, pyrryl, pyrazolyl, imidazolyl, furyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrimidyl, pyrazinyl or pyridazinyl; Or be selected from quinolyl, quinoxalinyl, indyl, benzimidazolyl-, benzoxazolyl, benzoisoxazole base, benzothiazolyl, benzisothiazole base, benzofuryl, benzothienyl, 2,3-dihydrobenzo [1,4] bicyclic heterocycle of dioxine base or benzo [1,3] dioxa cyclopentenyl; Each monocycle or bicyclic heterocycle are optionally replaced by 1,2 or 3 substituting group, and each substituting group is independently selected from halogen, haloalkyl, hydroxyl, alkyl or alkoxyl group;
Halogen is the substituting group being selected from fluorine, chlorine, bromine or iodine;
Another preferred version of the present invention is:
Wherein X represents-CR 1r 2-,-SO 2-or-CO-, wherein R 1, R 2represent hydrogen, alkyl independently of one another;
Y represents-NR 3cO-,-CONR 4-, wherein R 3, R 4represent hydrogen, alkyl independently of one another;
Q 1represent alkyl, aryl or Het;
Q 2represent aryl or Het;
R represents hydrogen, hydroxyl, alkyl ,-CONR 5r 6,-CONR 5(CH 2) nnR 6,-CONR 5(CH 2) noR 6,-NR 5cOR 6,-NR 5r 6,-NR 5(CH 2) nnR 6,-NR 5(CH 2) noR 6,-CR 5r 6, aryl or Het, wherein n=1,2,3,4 or 5, R 5, R 6represent hydrogen, alkyl, aryl or Het independently of one another;
Another preferred version of the present invention is:
Wherein X represents-SO 2-or-CO-;
Y represents-NR 3cO-,-CONR 4-, wherein R 3, R 4represent hydrogen, alkyl independently of one another;
Q 1represent alkyl, aryl or Het;
Q 2represent aryl or Het;
R represents hydrogen, hydroxyl, alkyl ,-CONR 5r 6,-CONR 5(CH 2) nn R 6,-CONR 5(CH 2) no R 6,-NR 5cOR 6,-NR 5r 6,-NR 5(CH 2) nnR 6,-NR 5(CH 2) noR 6,-CR 5r 6, aryl or Het, wherein n=1,2,3,4 or 5, R 5, R 6represent hydrogen, alkyl, aryl or Het independently of one another;
Another preferred version of the present invention is:
Wherein X represents-SO 2-or-CO-;
Y represents-NR 3cO-,-CONR 4-, wherein R 3, R 4represent hydrogen, alkyl independently of one another;
Q 1be selected from following aromatic ring, fragrant heterocycle, replace aromatic ring or replace fragrant heterocycle: phenyl, naphthyl, pyrryl, pyrazolyl, imidazolyl, furyl, thienyl, pyridyl, pyrimidyl, quinolyl, isoquinolyl, substituting group can be 1 ~ 3 alkylamino, nitro, cyano group, halogen or trifluoromethyl;
Q 2be selected from following aromatic ring, fragrant heterocycle, replace aromatic ring or replace fragrant heterocycle: phenyl, pyrazolyl, furyl, substituting group can be 1 ~ 3 alkylamino, nitro, cyano group, halogen or trifluoromethyl;
R represents hydrogen, hydroxyl, alkyl ,-NR 5cOR 6,-NR 5r 6,-NR 5(CH 2) nnR 6,-NR 5(CH 2) noR 6,-CR 5r 6, aryl or Het, wherein n=1,2,3,4 or 5, R 5, R 6represent hydrogen, alkyl, aryl or Het independently of one another;
Another preferred version of the present invention is:
Wherein X represents-SO 2-;
Y represents-NHCO-,-CONH-;
Q 1represent 2,6-dichlorophenyl;
Q 2be selected from following aromatic ring, fragrant heterocycle, replace aromatic ring or replace fragrant heterocycle: phenyl, pyrazolyl, furyl, substituting group can be 1 ~ 3 alkylamino, nitro, cyano group, halogen or trifluoromethyl;
R represents hydrogen, hydroxyl ,-COR 7,-NHR 8, wherein R 7represent hydrogen, hydroxyl, piperidyl, piperazinyl, N methyl piperazine base, Pyrrolidine base, morpholinyl, hydroxyethylamino, second diamino, the third diamino, fourth diamino, methoxy ethylamino, isopropylamino, piperidines amino, 4-hydroxy piperidine base, N-hydroxyethyl piperazine base, 3-hydroxymethyl piperidine base; R 8represent hydrogen, ethanoyl, 4-methyl piperidine base, 4-acetylpiperidinyl, 4-methanesulphonylpiperidine base, morpholine ethyl, THP trtrahydropyranyl;
According to the present invention, pharmacy acceptable salt comprises the acid salt that compound of Formula I and following acid are formed: hydrochloric acid, Hydrogen bromide, sulfuric acid, phosphoric acid, methylsulfonic acid, Phenylsulfonic acid, tosic acid, naphthene sulfonic acid, citric acid, tartrate, lactic acid, pyruvic acid, acetic acid, toxilic acid or succsinic acid, fumaric acid, Whitfield's ointment, phenylacetic acid, tussol.Comprise the acid salt of mineral alkali in addition, as: containing alkali metal cations, alkaline earth metal cation, ammonium cation salt.
The preferred following structural compounds of compound of general formula I:
3-(4-fluorophenyl)-5-(4-P-acetamido benzene sulfonyl base)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-1-1)
3-(4-fluorophenyl)-5-(3-nitrobenzenesulfonyl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-1-2)
3-(4-fluorophenyl)-5-(3-pyridine sulfonyl sulfonyl base)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-1-3)
3-(4-fluorophenyl)-5-(2,6-dichlorobenzene alkylsulfonyl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-1-4)
3-(4-fluorophenyl)-5-(2-naphthalene sulfonyl base)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-1-5)
3-(4-fluorophenyl)-5-(4-Methyl benzenesulfonyl base)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-1-6)
3-(4-fluorophenyl)-5-(8-quinoline alkylsulfonyl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-1-7)
3-(4-fluorophenyl)-5-(4-fluoro benzoyl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-1-8)
3-(3-acetylamino phenyl)-5-(3-nitrobenzenesulfonyl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-2-1)
3-(3-acetylamino phenyl)-5-(3-pyridine sulfonyl sulfonyl base)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-2-2)
3-(3-acetylamino phenyl)-5-(2,6-dichlorobenzene alkylsulfonyl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-2-3)
3-(3-acetylamino phenyl)-5-(2-naphthalene sulfonyl base)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-2-4)
3-(3-acetylamino phenyl)-5-(4-Methyl benzenesulfonyl base)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-2-5)
3-(3-acetylamino phenyl)-5-(8-quinoline alkylsulfonyl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-2-6)
3-(4-acetylamino phenyl)-5-(3-nitrobenzenesulfonyl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-2-7)
3-(4-acetylamino phenyl)-5-(3-pyridine sulfonyl sulfonyl base)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-2-8)
3-(4-acetylamino phenyl)-5-(2,6-dichlorobenzene alkylsulfonyl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-2-9)
3-(4-acetylamino phenyl)-5-(2-naphthalene sulfonyl base)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-2-10)
3-(4-acetylamino phenyl)-5-(4-Methyl benzenesulfonyl base)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-2-11)
3-(4-acetylamino phenyl)-5-(8-quinoline alkylsulfonyl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-2-12)
3-(4-(1-Acetylpiperidin-4-is amino) phenyl)-5-(3-nitrobenzenesulfonyl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-3-1)
3-(4-(1-Acetylpiperidin-4-is amino) phenyl)-5-(3-pyridine sulfonyl sulfonyl base)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-3-2)
3-(4-(1-Acetylpiperidin-4-is amino) phenyl)-5-(2,6-dichlorobenzene alkylsulfonyl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-3-3)
3-(4-(1-Acetylpiperidin-4-is amino) phenyl)-5-(2-naphthalene sulfonyl base)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-3-4)
3-(4-(1-Acetylpiperidin-4-is amino) phenyl)-5-(4-Methyl benzenesulfonyl base)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-3-5)
3-(4-(1-Acetylpiperidin-4-is amino) phenyl)-5-(8-quinoline alkylsulfonyl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-3-6)
3-(4-(1-Acetylpiperidin-4-is amino) phenyl)-5-(2-thiophen sulfuryl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-3-7)
3-(4-(1-methyl piperidine-4-is amino) phenyl)-5-(2,6-dichlorobenzene alkylsulfonyl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-3-8)
3-(4-(1-methyl piperidine-4-is amino) phenyl)-5-(2-thiophen sulfuryl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-3-9)
3-(4-(1-methyl piperidine-4-is amino) phenyl)-5-(3-pyridine sulfonyl sulfonyl base)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-3-10)
3-(4-(1-methyl piperidine-4-is amino) phenyl)-5-(8-quinoline alkylsulfonyl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-3-11)
3-(4-(1-methyl piperidine-4-is amino) phenyl)-5-(2-naphthalene sulfonyl base)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-3-12)
3-(4-(1-methanesulphonylpiperidine-4-is amino) phenyl)-5-(3-nitrobenzenesulfonyl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-3-13)
3-(4-(1-methanesulphonylpiperidine-4-is amino) phenyl)-5-(3-pyridine sulfonyl sulfonyl base)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-3-14)
3-(4-(1-methanesulphonylpiperidine-4 is amino) phenyl)-5-(2,6-dichlorobenzene alkylsulfonyl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-3-15)
3-(4-(1-methanesulphonylpiperidine-4-is amino) phenyl)-5-(2-naphthalene sulfonyl base)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-3-16)
3-(4-(1-methanesulphonylpiperidine-4-is amino) phenyl)-5-(4-Methyl benzenesulfonyl base)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-3-17)
3-(4-(1-methanesulphonylpiperidine-4-is amino) phenyl)-5-(8-quinoline alkylsulfonyl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-3-18)
3-(4-(1-methanesulphonylpiperidine-4-is amino) phenyl)-5-(2-thiophen sulfuryl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-3-19)
3-(4-(4-THP trtrahydropyranyl is amino) phenyl)-5-(8-quinoline alkylsulfonyl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-4-1)
3-(4-(4-THP trtrahydropyranyl is amino) phenyl)-5-(2-thiophen sulfuryl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-4-2)
3-(4-(morpholine ethylamino) phenyl)-5-(8-quinoline alkylsulfonyl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-5-1)
3-(2-furyl)-5-(8-quinoline alkylsulfonyl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-6-1)
3-(4-(1-piperidine formyl base) phenyl)-5-(2,6-dichlorobenzene alkylsulfonyl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-7-1)
3-(4-(1-piperazine formyl radical) phenyl)-5-(2,6-dichlorobenzene alkylsulfonyl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-7-2)
3-(4-(4-methyl isophthalic acid-piperazine formyl radical) phenyl)-5-(2,6-dichlorobenzene alkylsulfonyl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-7-3)
3-(4-(1-Pyrrolidine formyl radical) phenyl)-5-(2,6-dichlorobenzene alkylsulfonyl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-7-4)
3-(4-(1-morpholine methanoyl) phenyl)-5-(2,6-dichlorobenzene alkylsulfonyl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-7-5)
3-(4-(N-aminoethyl carbamyl) phenyl)-5-(2,6-dichlorobenzene alkylsulfonyl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-7-6)
3-(4-(N-aminopropyl carbamyl) phenyl)-5-(2,6-dichlorobenzene alkylsulfonyl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-7-7)
3-(4-(N-methoxyethyl carbamyl) phenyl)-5-(2,6-dichlorobenzene alkylsulfonyl)-4,5,6,7-tetrahydrochysene-1H-are than azoles also [4,3-c] pyridine (I-7-8)
3-(4-(N-sec.-propyl carbamyl) phenyl)-5-(2,6-dichlorobenzene alkylsulfonyl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-7-9)
3-(4-(N-ammonia butylcarbamoyl) phenyl)-5-(2,6-dichlorobenzene alkylsulfonyl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-7-10)
3-(4-(4-piperidyl carbamyl) phenyl)-5-(2,6-dichlorobenzene alkylsulfonyl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-7-11)
3-(4-(4-hydroxyl-1-piperidine formyl base) phenyl)-5-(2,6-dichlorobenzene alkylsulfonyl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-7-12)
3-(4-(4-hydroxyethyl-1-piperazine formyl radical) phenyl)-5-(2,6-dichlorobenzene alkylsulfonyl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-7-13)
3-(4-(3-methylol-1-piperidine formyl base) phenyl)-5-(2,6-dichlorobenzene alkylsulfonyl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-7-14)
3-(4-(1-piperazine formyl radical) phenyl)-5-(2,6-difluorophenylsulphonyl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-7-15)
3-(4-(4-methyl isophthalic acid-piperazine formyl radical) phenyl)-5-(2,6-difluorophenylsulphonyl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-7-16)
3-(4-(1-Pyrrolidine formyl radical) phenyl)-5-(2,6-difluorophenylsulphonyl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-7-17)
3-(4-(1-morpholine methanoyl) phenyl)-5-(2,6-difluorophenylsulphonyl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-7-18)
3-(4-hydroxymethyl phenyl)-5-(2,6-dichlorobenzene alkylsulfonyl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-8-1)
3-(4-(piperidines-4-is amino) phenyl)-5-(2-chlorobenzenesulfonyl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-8-2)
3-(N-(4-(1-methanesulphonylpiperidine-4-is amino) phenyl) carbamyl)-5-(2,6-dichlorobenzene alkylsulfonyl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-9-1)
3-(N-(4-(1-methyl piperidine-4-is amino) phenyl) carbamyl)-5-(2,6-dichlorobenzene alkylsulfonyl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-9-2)
3-(N-(4-(1-methyl piperidine-4-is amino) phenyl) carbamyl)-5-(3-nitrobenzenesulfonyl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-9-3)
3-(N-(4-(1-methyl piperidine-4-is amino) phenyl) carbamyl)-5-(3-cyanophenylsulfonyl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-9-4)
3-(N-(4-(1-methyl piperidine-4-is amino) phenyl) carbamyl)-5-(3-tnBuoromethyl-benzenesulfonyl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-9-5)
3-(N-(4-(1-methyl piperidine-4-is amino) phenyl) carbamyl)-5-(2,3-dichlorobenzene alkylsulfonyl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-9-6)
3-(N-(4-(4-piperidines is amino) phenyl) carbamyl)-5-(2-chlorobenzenesulfonyl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-9-7)
3-(N-(4-(4-piperidines is amino) phenyl) carbamyl)-5-(3-cyanophenylsulfonyl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-9-8)
3-(N-(4-(4-piperidines is amino) phenyl) carbamyl)-5-(3-tnBuoromethyl-benzenesulfonyl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-9-9)
3-(N-(4-(4-tetrahydropyrans is amino) phenyl) carbamyl)-5-(2,6-dichlorobenzene alkylsulfonyl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-9-10)
3-(N-(4-(hydroxyl kharophen) phenyl) carbamyl)-5-(2,6-dichlorobenzene alkylsulfonyl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-9-11)
3-(N-(4-(hydroxyl kharophen) phenyl) carbamyl)-5-(2,3-dichlorobenzene alkylsulfonyl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-9-12)
3-(N-(4-(hydroxyl kharophen) phenyl) carbamyl)-5-(3-nitrobenzenesulfonyl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-9-13)
3-(N-(4-(hydroxyl kharophen) phenyl) carbamyl)-5-(3-cyanophenylsulfonyl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-9-14)
3-(N-(4-(hydroxyl kharophen) phenyl) carbamyl)-5-(3-tnBuoromethyl-benzenesulfonyl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-9-15)
3-(N-(4-(1-Acetylpiperidin-4-is amino) phenyl) carbamyl)-5-(2,6-dichlorobenzene alkylsulfonyl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-9-16)
3-(N-(4-(1-Acetylpiperidin-4-is amino) phenyl) carbamyl)-5-(3-tnBuoromethyl-benzenesulfonyl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-9-17)
3-(N-(4-(1-methylpiperazine base) phenyl) carbamyl)-5-(2,6-dichlorobenzene alkylsulfonyl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-9-18)
3-(N-(4-(N-hydroxyethylcarbamoyl) phenyl) carbamyl)-5-(2,6-dichlorobenzene alkylsulfonyl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-9-19)
3-(N-(4-(4-methyl isophthalic acid-piperazine formyl radical) phenyl) carbamyl)-5-(2,6-dichlorobenzene alkylsulfonyl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-9-20)
3-(N-(4-(3-methylol-1-piperidine formyl base) phenyl) carbamyl)-5-(2,6-dichlorobenzene alkylsulfonyl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-9-21)
3-(N-(4-(4-hydroxyl-1-piperidine formyl base) phenyl) carbamyl)-5-(2,6-dichlorobenzene alkylsulfonyl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-9-22)
3-(N-(4-(1-piperazine formyl radical) phenyl) carbamyl)-5-(2,6-dichlorobenzene alkylsulfonyl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-9-23)
(S)-(+)-3-(N-(4-(1-(2-pyrrolidinomethyl) Pyrrolidine formyl radical) phenyl) carbamyl)-5-(2; 6-dichlorobenzene alkylsulfonyl)-4; 5; 6; 7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-9-24)
3-(N-(4-(4-methylol-1-piperidine formyl base) phenyl) carbamyl)-5-(2,6-dichlorobenzene alkylsulfonyl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-9-25)
3-(N-(4-(N-aminopropyl carbamyl) phenyl) carbamyl)-5-(2,6-dichlorobenzene alkylsulfonyl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-9-26)
3-(N-(4-(N-methoxycarbonyl propyl carbamyl) phenyl) carbamyl)-5-(2,6-dichlorobenzene alkylsulfonyl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-9-27)
3-(1-methyl-4-pyrazoles formamido group)-5-(2,6-dichlorobenzene alkylsulfonyl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-10-1)
3-(4-(1-piperidin-4-yl) pyrazolyl)-5-(2; 6-dichlorobenzene alkylsulfonyl)-4,5,6; preparation method is as follows for 7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-11-1) part of compounds of the present invention:
Method one:
Method two:
Method three:
Method four:
Method five:
Method six:
Method seven:
Method eight:
Method nine:
The compounds of this invention can prepare by above-mentioned or similar above-mentioned preparation method, and the difference according to substituent difference and substituting group position selects corresponding raw material.
Pharmacology test result shows, the compound of general formula I and pharmacy acceptable salt thereof are to having excellent inhibit activities, and therefore, compound of Formula I and pharmacy acceptable salt thereof may be used for treating the clinical disease relevant with c-Met.The described disease relevant with c-Met can be nonsmall-cell lung cancer, liver cancer, Papillary Renal Cell Carcinoma, cancer of the stomach, esophagus cancer, glioblastoma, incidence squamous cell, kidney, acute leukemia, prostate cancer, thyroid carcinoma, skin carcinoma, colorectal carcinoma, carcinoma of the pancreas, ovarian cancer, mammary cancer, myelodysplastic syndrome or mesothelioma etc.
Here is partial pharmacologic test and result:
(1) the c-Met inhibit activities of target compound measures
Synthesized compound FRET (fluorescence resonance energy transfer) (FRET) method measures the inhibit activities to c-Met, and compares with positive control drug, filters out active compound preferably.C-Met is by purifying or directly buy test kit acquisition.
Concrete grammar: use after c-Met kinase dilution liquid is diluted to suitable concn.Containing c-Met, peptide substrate, HEPES (pH7.5), BRIJ-35, MgCl in kinase reaction mixture 2and EDTA.C-Met phospho-peptide substrate is used as 100% phosphorylation contrast, does not add ATP and is used as 0% phosphorylation contrast.After reacting 1h under room temperature, in reaction system, add the Development Reagent A of appropriateness dilution.Continue reaction 1h under room temperature, add Stop Reagent stopped reaction.Excitation wavelength 400nm, determined wavelength is the fluorescence intensity of 445nm (coumarin) and 520nm (fluorescein) simultaneously.By formulae discovery test-compound inhibiting rate.
(2) anti tumor activity in vitro of target compound measures
Measure breast carcinoma cell strain MDA231 with mtt assay, Gastric cancer line, stomach cancer cell line BSG823, malignant myeloid cell lines K562, breast carcinoma cell strain MCF7, resistance breast carcinoma cell strain MCF7, Leukemic cell strains NB4, hepatoma cell strain HEPG2, umbilical vein vascular endothelial cells strain HUVEC, lung cancer cell types, colon cancer cell line HCT116, maxicell lung cancer cell line H460, liver cancer cell SMMC7721, the restraining effect of the tumor cell lines such as lung carcinoma cell H1299.
Mtt assay utilizes the desaturase that in viable cell plastosome, existence is relevant to NADP that ectogenic MTT can be made to be reduced into the bluish voilet crystallisate (Formazan) of insoluble, and is deposited in cell, and dead cell is without this function.Use the purple crystal thing in dimethyl sulfoxide (DMSO) (DMSO) or three liquid (10%SDS-5% isopropylcarbinol-0.01mol/L HCL) dissolved cell again, measure its its amount of viable cell of OD value indirect reaction with enzyme-linked immunosorbent assay instrument at 570nm wavelength place.
Concrete grammar: be inoculated in 96 well culture plates by certain cell concentration by the tumour cell that will carry out testing being in cell log vegetative period, add sieved sample (can directly add after suspension cell fishplate bar) after cultivating 24h, cell is at 37 DEG C, 5%CO 2continue cultivation under condition after 48 hours, add MTT and continue cultivation 4 hours, dissolving crystallized with DMSO, detect under microplate reader.
3), following table is external C-Met kinase activity and the cancer cell in vitro active testing result of part of compounds:
(in table, compound numbers corresponds to compound numbers above)
Pharmacology test result shows, the compounds of this invention has good c-Met inhibit activities, and there is good Anti-tumor angiogenesis, can be used for the clinical disease prevented or treatment is relevant with c-Met inhibitor, these diseases can be: nonsmall-cell lung cancer, liver cancer, Papillary Renal Cell Carcinoma, cancer of the stomach, esophagus cancer, glioblastoma, incidence squamous cell, kidney, acute leukemia, prostate cancer, thyroid carcinoma, skin carcinoma, colorectal carcinoma, carcinoma of the pancreas, ovarian cancer, mammary cancer, myelodysplastic syndrome or mesothelioma etc.
Embodiment
Fusing point b shape melting point tube measures, and medium is methyl-silicone oil, and thermometer does not correct; IR spectrum Nicolet Impact 410 type determination of infrared spectroscopy, KBr compressing tablet; 1hNMR JEOL FX90Q type fourier transform NMR instrument, BRUKERACF-300 type nuclear magnetic resonance analyser and BRUKER AM-500 type nuclear magnetic resonance analyser complete (in TMS mark); MS Nicolet2000 type Fourier transform mass spectrometer and MAT-212 type mass spectrograph measure; Microwave reaction CEM Discover single mold microwave instrument.
Embodiment 1
1-tertbutyloxycarbonyl-4-morpholinyl-1,2,5,6-tetrahydropyridine (Y-1)
N-tertbutyloxycarbonyl-4-piperidone 10.0g (50mmol) is added in the mono-neck bottle of 250mL, morpholine 0.50g (5.7mmol), tosic acid (catalyst), dry toluene 120mL, back flow reaction is spent the night, and reaction solution becomes reddish-brown from faint yellow, stopped reaction, be cooled to room temperature, the reddish-brown oily matter 15.2g that reaction solution directly concentrates, non-purifying directly carries out next step reaction.
Embodiment 2
1-tertbutyloxycarbonyl-3-(4-fluoro benzoyl)-4-piperidone (Y-2)
Y-115.0g (56mmo1) is added, anhydrous CH in the mono-neck bottle of 250mL 2cl 280mL, under being placed in ice bath, adds triethylamine 8.5g (84mmol), is slowly added dropwise to the anhydrous CH to fluorobenzoyl chloride 14.0g (86mmol) under ice bath state 2cl 2solution 60mL (solution colour is along with dropping constantly intensification), react 2h at 0 DEG C, be warming up to 25 DEG C of reaction 4h, in reaction solution, add 100mL water, adjust PH to 6, react 0.5h at 25 DEG C with the 5%HCl aqueous solution, TLC detects has novel substance to produce.Reaction solution stratification, separates organic layer, aqueous phase CH 2cl 2extract 3 times (40mL × 3), merge organic phase, with anhydrous magnesium sulfate drying, suction filtration, column chromatography (PE: EA=5: 1) after filtrate is concentrated, obtains dark red oil 7.2g, yield 39%, MS m/z:320.2 [M-H] -.
Embodiment 3
3-(4-fluorophenyl)-5-tertbutyloxycarbonyl-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (Y-3)
Hydrazine hydrochloride 4.0g (60mmol) is added in the mono-neck bottle of 250mL, sodium acetate 5.0g (60mmol), dehydrated alcohol 120mL, be warming up to 70 DEG C of reaction 1h, filtered while hot, filtrate is transferred to the mono-neck bottle of 250mL, add Y-27.0g (20mmol), be warming up to 70 DEG C of reaction 1h (reaction solution becomes muddy by clarification), be cooled to room temperature reaction 5h (reaction solution separates out a large amount of yellow solid), TLC detects raw material and disappears.Stopped reaction, reaction solution suction filtration, filter cake absolute ethanol washing, dry, obtain faint yellow solid 4.5g, yield 62%, MS m/z:316.1 [M-H] -.
Embodiment 4
3-(4-fluorophenyl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (Y-4)
Y-3200mg (0.63mmol) is added, anhydrous CH in the mono-neck bottle of 100mL 2cl 220mL, is placed in ice bath, is added dropwise to trifluoroacetic acid 2mL (27mmol), and ice bath reaction 30min, dislocation room temperature reaction 1h, TLC detect raw material and disappear.Revolve desolventizing, enriched material column chromatography (CH 2cl 2: MeOH=20: 1), obtain yellow solid 150mg, yield 77%, MS m/z:218.2 [M+H] +.
Embodiment 5
3-(4-fluorophenyl)-5-(4-P-acetamido benzene sulfonyl base)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-1-1)
Y-4100mg (0.4mmol) is added in the mono-neck bottle of 100mL, anhydrous THF10mL, triethylamine 60mg (0.6mmol) is added dropwise under ice bath, stir 10min, the anhydrous THF solution of slow dropping 4-acetylsulphanilyl chloride 103mg (0.44mmol), react 1h under ice bath, TLC detects raw material and disappears.Elimination salt precipitates, column chromatography (CH after filtrate is concentrated 2cl 2: MeOH=30: 1), obtain white powdery solid 70mg, yield 42%, MS m/z:415.2 [M+H] +.
1H-NMR(300MHz，DMSO-d 6)δ(ppm)：12.91and 12.61(s，1H，tautomers)，9.89(s，1H，-NH-)，7.76-7.77(m，4H，ArH)，7.42-7.49(m，4H，ArH)，4.43(s，2H，-CH 2-)，3.49(m，2H，-CH 2-)，2.73(m，2H，-CH 2-)，2.01(s，3H，-COCH 3).
Embodiment 6
3-(4-fluorophenyl)-5-(3-nitrobenzenesulfonyl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-1-2)
Preparation method is similar to the preparation of I-1-1, yellow powder solid 50mg, yield 31%, MS m/z:403.3 [M+H] +.
1H-NMR(300MHz，DMSO-d 6)δ(ppm)：12.80(s，1H，tautomers)，8.80(s，1H，ArH)，8.42-8.49(m，2H，ArH)，8.28(m，1H，ArH)，7.71-7.76(m，2H，ArH)，7.49-7.52(m，2H，ArH)，4.74(s，2H，-CH2-)，3.74(m，2H，-CH2-)，2.89(m，2H，-CH2-).
Embodiment 7
3-(4-fluorophenyl)-5-(3-pyridine sulfonyl sulfonyl base)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-1-3)
Preparation method is similar to the preparation of I-1-1, faint yellow powdery solid 32mg, yield 22%, MS m/z:359.2 [M+H] +.
1H-NMR(300MHz，DMSO-d 6)δ(ppm)：12.96(s，1H，tautomers)，9.07(s，1H，ArH)，8.87(m，1H，ArH)，8.30(m，1H，ArH)，7.64-7.67(m，3H，ArH)，7.50-7.54(m，2H，ArH)，4.40(s，2H，-CH 2-)，3.47(m，2H，-CH 2-)，2.75(m，2H，-CH 2-).
Embodiment 8
3-(4-fluorophenyl)-5-(2,6-dichlorobenzene alkylsulfonyl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-1-4)
Preparation method is similar to the preparation of I-1-1, white powdery solid 42mg, yield 24%, MS m/z:427.3 [M+H] +.
1H-NMR(300MHz，DMSO-d 6)δ(ppm)：12.93(s，1H，tautomers)，7.67-7.70(m，4H，ArH)，7.57-7.60(m，1H，ArH)，7.46-7.51(m，2H，ArH)，4.62(s，2H，-CH 2-)，3.69(m，2H，-CH 2-)，2.73(m，2H，-CH 2-).
Embodiment 9
3-(4-fluorophenyl)-5-(2-naphthalene sulfonyl base)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-1-5)
Preparation method is similar to the preparation of I-1-1, white powdery solid 60mg, yield 37%, MS m/z:408.2 [M+H] +.
1H-NMR(300MHz，DMSO-d 6)δ(ppm)：8.58(s，1H，ArH)，8.21(d，1H，J＝7.6Hz，ArH)，8.13(d，1H，J＝1.8Hz，ArH)，8.05(d，1H，J＝7.8Hz，ArH)，7.84(dd，1H，J＝8.6Hz，J＝1.8Hz，ArH)，7.57-7.75(m，4H，ArH)，7.29(m，2H，ArH)，4.43(s，2H，-CH 2-)，3.49(m，2H，-CH 2-)，2.73(m，2H，-CH 2-).
Embodiment 10
3-(4-fluorophenyl)-5-(4-Methyl benzenesulfonyl base)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-1-6)
Preparation method is similar to the preparation of I-1-1, white powdery solid 55mg, yield 37%, MS m/z:372.2 [M+H] +.
1H-NMR(300MHz，DMSO-d 6)δ(ppm)：12.92(s，1H，tautomers)，7.76-7.78(m，4H，ArH)，7.42-7.48(m，4H，ArH)，4.28(s，2H，-CH 2-)，3.48(m，2H，-CH 2-)，2.73(m，2H，-CH 2-)，2.39(s，3H，ArCH 3).
Embodiment 11
3-(4-fluorophenyl)-5-(8-quinoline alkylsulfonyl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-1-7)
Preparation method is similar to the preparation of I-1-1, white powdery solid 100mg, yield 61%, MS m/z:409.2 [M+H] +.
1H-NMR(300MHz，DMSO-d 6)δ(ppm)：12.80(s，1H，tautomers)，8.58(m，1H，ArH)，8.43-8.50(m，2H，ArH)，8.28(d，1H，J＝7.2Hz，ArH)，7.59-7.78(m，4H，ArH)，7.48(m，2H，ArH)，4.75(s，2H，-CH 2-)，3.74(m，2H，-CH 2-)，3.02(m，2H，-CH2-).
Embodiment 12
3-(4-fluorophenyl)-5-(4-fluoro benzoyl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-1-8)
Preparation method is similar to the preparation of I-1-1, white powdery solid 80mg, yield 59%, MS m/z:340.2 [M+H] +.
1H-NMR(300MHz，DMSO-d 6)δ(ppm)：12.92(s，1H，tautomers)，7.86-7.88(m，4H，ArH)，7.40-7.44(m，4H，ArH)，4.25(s，2H，-CH 2-)，3.48(m，2H，-CH 2-)，2.70(m，2H，-CH 2-).
Embodiment 13
1-tertbutyloxycarbonyl-3-(4-nitro benzoyl)-4-piperidone (Z-1)
Y-115.0g (56mmol) is added, anhydrous CH in the mono-neck bottle of 250mL 2cl 280mL, under being placed in ice bath, adds triethylamine 8.5g (84mmol), is slowly added dropwise to the anhydrous CH of paranitrobenzoyl chloride 16.0 (86mmol) under ice bath state 2cl 2solution 60mL (solution colour is along with dropping constantly intensification), react 2h at 0 DEG C, be warming up to 25 DEG C of reaction 4h, in reaction solution, add 100mL water, adjust PH to 6, react 0.5h at 25 DEG C with the 5%HCl aqueous solution, TLC detects has novel substance to produce.Reaction solution stratification, separates organic layer, aqueous phase CH 2cl 2extract 3 times (40mL × 3), merge organic phase, with anhydrous magnesium sulfate drying, suction filtration, column chromatography (PE: EA=5: 1) after filtrate is concentrated, obtains dark red oil 7.2g, yield 37%, MS m/z:347.2 [M-H] -.
Embodiment 14
3-(4-nitrophenyl)-5-tertbutyloxycarbonyl-4,5,6,7-tetrahydrochysene-1H-[pyrazolo [4,3-c] pyridine (Z-2)
Hydrazine hydrochloride 4.0g (60mmol) is added in the mono-neck bottle of 250mL, sodium acetate 5.0g (60mmol), dehydrated alcohol 120mL, be warming up to 70 DEG C of reaction 1h, filtered while hot, filtrate is transferred to the mono-neck bottle of 250mL, add Z-17.0g (20mmol), be warming up to 70 DEG C of reaction 1h (reaction solution becomes muddy by clarification), be cooled to room temperature reaction 5h (reaction solution separates out a large amount of yellow solid), TLC detects raw material and disappears.Stopped reaction, suction filtration, filter cake absolute ethanol washing, dry, obtain faint yellow solid 4.3g, yield 62%, mp:225-226 DEG C, MS m/z:343.1 [M-H] -.
Embodiment 15
3-(4-aminophenyl)-5-tertbutyloxycarbonyl-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (Z-3)
In the mono-neck bottle of 100mL, add Z-21.0g (2.9mmol), use 50mL dissolve with methanol, then add 10%Pd/C 100mg, in airtight atmosphere of hydrogen, 30 DEG C of reactions are spent the night, and TLC detects raw material and disappears.Suction filtration, column chromatography (PE: EA=3: 1) after filtrate is concentrated, obtains yellow solid 750mg, yield 82%, mp:188-189 DEG C, MS m/z:315.2 [M+H] +.
Embodiment 16
3-(4-acetylamino phenyl)-5-tertbutyloxycarbonyl-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (Z-4)
Z-3500mg (1.6mmol) is added in the mono-neck bottle of 100mL, add anhydrous THF 40mL, triethylamine 193mg (1.9mmol) is added under ice bath, 15min is stirred at 0 DEG C, slowly be added dropwise to the anhydrous THF solution 5mL of Acetyl Chloride 98Min., 0 DEG C of reaction 2h, TLC detect raw material and disappear.Stopped reaction, elimination salt precipitates, and column chromatography (PE: EA=1: 1) after filtrate is concentrated, obtains faint yellow solid 210mg, yield 37%, mp:261-262 DEG C, MS m/z:357.3 [M+H] +.
Embodiment 17
3-(4-acetylamino phenyl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (Z-5)
Z-4200mg (0.56mmol) is added, anhydrous CH in the mono-neck bottle of 100mL 2cl 220mL, is placed in ice bath, is added dropwise to trifluoroacetic acid 2mL (27mmol), and ice bath reaction 30min, dislocation room temperature reaction 1h, TLC detect raw material and disappear.Revolve desolventizing, enriched material column chromatography (CH 2cl 2: MeOH=20: 1), obtain yellow solid 150mg, yield 77%, mp:266-267 DEG C, MS m/z:257.2 [M+H] +.
Embodiment 18
3-(4-acetylamino phenyl)-5-(3-nitrobenzenesulfonyl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-2-7)
Z-5100mg (0.4mmol) is added in the mono-neck bottle of 100mL, anhydrous THF10mL, triethylamine 60mg (0.6mmol) is added dropwise under ice bath, stir 10min, the anhydrous THF solution of slow dropping 3-nitrobenzene sulfonyl chloride 95mg (0.44mmol), react 1h under ice bath, TLC detects raw material and disappears.Elimination salt precipitates, column chromatography (CH after filtrate is concentrated 2cl 2: MeOH=30: 1), obtain dark yellow solid 40mg, yield 31%, MS m/z:442.2 [M+H] +.
1H-NMR(300MHz，DMSO-d 6)δ(ppm)：12.80(s，1H，tautomers)，10.09(s，1H，-NH-)，8.80(s，1H，ArH)，8.42-8.49(m，2H，ArH)，8.28(m，1H，ArH)，7.72-7.76(m，2H，ArH)，749-53(m，2H，ArH)，4.74(s，2H，-CH 2-)，3.74(m，2H，-CH 2-)，2.89(m，2H，-CH 2-)，2.07(s，3H，-COCH 3).
Embodiment 19
3-(3-acetylamino phenyl)-5-(3-nitrobenzenesulfonyl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-2-1)
Preparation method is similar to the preparation of I-2-7, obtains dark yellow solid 40mg, yield 31%, MS m/z:442.2 [M+H] +.
1H-NMR(300MHz，DMSO-d 6)δ(ppm)：12.80(s，1H，tautomers)，10.02(s，1H，-NH-)，8.80(s，1H，ArH)，8.45-8.55(m，2H，ArH)，8.28(m，1H，ArH)，7.91-8.01(m，2H，ArH)，7.22-7.48(m，2H，ArH)，4.40(s，2H，-CH 2-)，3.58(m，2H，-CH 2-)，2.78(m，2H，-CH 2-)，2.08(s，3H，-COCH 3).
Embodiment 20
3-(3-acetylamino phenyl)-5-(3-pyridine sulfonyl sulfonyl base)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-2-2)
Preparation method is similar to the preparation of I-2-7, faint yellow powdery solid 50mg, yield 31%, MS m/z:398.2 [M+H] +.
1H-NMR(300MHz，DMSO-d 6)δ(ppm)：12.03(s，1H，tautomers)，10.03(s，1H，-NH-)，9.02(s，1H，ArH)，8.86(m，1H，ArH)，8.28(m，1H，ArH)，7.93(m，1H，ArH)，7.65(m，1H，ArH)，7.49(m，1H，ArH)，7.24-7.26(m，2H，ArH)，4.42(s，2H，-CH 2-)，3.50(m，2H，-CH 2-)，2.74(m，2H，-CH 2-)，2.09(s，3H，-COCH 3).
Embodiment 21
3-(3-acetylamino phenyl)-5-(2-naphthalene sulfonyl base)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-2-4)
Preparation method is similar to the preparation of I-2-7, white powdery solid 66mg, yield 47%, MS m/z:447.3 [M+H] +.
1H-NMR(300MHz，DMSO-d 6)δ(ppm)：12.65(s，1H，tautomers)，10.10(s，1H，-NH-)，8.60(s，1H，ArH)，8.23(d，1H，J＝7.4Hz，ArH)，8.13(d，1H，J＝8.7Hz，ArH)，8.05(m，1H，ArH)，7.86-7.89(m，2H，ArH)，7.70-7.73(m，2H，ArH)，7.20-7.48(m，3H，ArH)，4.41(s，2H，-CH 2-)，3.48(m，2H，-CH 2-)，2.74(m，2H，-CH 2-)，1.99(s，3H，-COCH 3).
Embodiment 22
3-(3-acetylamino phenyl)-5-(8-quinoline alkylsulfonyl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-2-6)
Preparation method is similar to the preparation of I-2-7, white powdery solid 95mg, yield 53%, MS m/z:448.2 [M+H] +.
1H-NMR(300MHz，DMSO-d 6)δ(ppm)：12.80(s，1H，tautomers)，10.05(s，1H，-NH-)，8.82(d，1H，J＝2.6Hz，ArH)，8.43-8.50(m，2H，ArH)，8.28(d，1H，J＝7.2Hz，ArH)，7.59-7.78(m，4H，ArH)，7.48(m，2H，ArH)，4.78(s，2H，-CH 2-)，3.75(m，2H，-CH 2-)，3.16(m，2H，-CH 2-)，2.08(s，3H，-COCH 3).
Embodiment 23
3-(4-acetylamino phenyl)-5-(3-pyridine sulfonyl sulfonyl base)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-2-8)
Preparation method is similar to the preparation of I-2-7, faint yellow powdery solid 60mg, yield 38%, MS m/z:398.2 [M+H] +.
1H-NMR(300MHz，DMSO-d 6)δ(ppm)：12.94(s，1H，tautomers)，10.07(s，1H，-NH-)，9.05(s，1H，ArH)，8.86(m，1H，ArH)，8.30(m，1H，ArH)，7.64-7.67(m，3H，ArH)，7.52(m，2H，ArH)，4.41(s，2H，-CH 2-)，3.47(m，2H，-CH 2-)，2.73(m，2H，-CH 2-)，2.07(s，3H，-COCH 3).
Embodiment 24
3-(4-acetylamino phenyl)-5-(2,6-dichlorobenzene alkylsulfonyl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-2-9)
Preparation method is similar to the preparation of I-2-7, white powdery solid 35mg, yield 19%, MS m/z:465.0 [M+H] +.
1H-NMR(300MHz，DMSO-d 6)δ(ppm)：12.93(s，1H，tautomers)，10.01(s，1H，-NH-)，7.66-7.69(m，4H，ArH)，7.57-7.60(m，1H，ArH)，7.46-7.51(m，2H，ArH)，4.62(s，2H，-CH 2-)，3.69(m，2H，-CH 2-)，2.73(m，2H，-CH 2-)，2.06(s，3H，-COCH 3).
Embodiment 25
3-(4-acetylamino phenyl)-5-(2-naphthalene sulfonyl base)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-2-10)
Preparation method is similar to the preparation of I-2-7, white powdery solid 88mg, yield 49%, MS m/z:447.3 [M+H] +.
1H-NMR(300MHz，DMSO-d 6)δ(ppm)：10.00(s，1H，-NH-)，8.58(s，1H，ArH)，8.21(d，1H，J＝7.4Hz，ArH)，8.13(d，1H，J＝8.6Hz，ArH)，8.05(d，1H，J＝7.8Hz，ArH)，7.86(dd，1H，J＝8.6Hz，J＝1.6Hz，ArH)，7.68-7.75(m，4H，ArH)，7.48(m，2H，ArH)，4.41(s，2H，-CH 2-)，3.48(m，2H，-CH 2-)，2.73(m，2H，-CH 2-)，2.07(s，3H，-COCH 3).
Embodiment 26
3-(4-acetylamino phenyl)-5-(4-Methyl benzenesulfonyl base)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-2-11)
Preparation method is similar to the preparation of I-2-7, white powdery solid 80mg, yield 49%, MS m/z:411.2 [M+H] +.
1H-NMR(300MHz，DMSO-d 6)δ(ppm)：12.91(s，1H，tautomers)，10.11(s，1H，-NH-)，7.76-7.77(m，4H，ArH)，7.42-7.49(m，4H，ArH)，4.28(s，2H，-CH 2-)，3.48(m，2H，-CH 2-)，2.73(m，2H，-CH 2-)，2.39(s，3H，ArCH 3)，2.07(s，3H，-COCH 3).
Embodiment 27
3-(4-acetylamino phenyl)-5-(8-quinoline alkylsulfonyl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-2-12)
Preparation method is similar to the preparation of I-2-7, white powdery solid 110mg, yield 62%, MS m/z:448.2 [M+H] +.
1H-NMR(300MHz，DMSO-d 6)δ(ppm)：12.80(s，1H，tautomers)，10.06(s，1H，-NH-)，8.58(d，1H，J＝2.6Hz，ArH)，8.43-8.50(m，2H，ArH)，8.28(d，1H，J＝7.2Hz，ArH)，7.59-7.78(m，4H，ArH)，7.46-7.49(m，2H，ArH)，4.75(s，2H，-CH 2-)，3.74(m，2H，-CH 2-)，3.02(m，2H，-CH 2-)，2.07(s，3H，-COCH 3).
Embodiment 28
3-(4-(1-methyl piperidine 4 is amino) phenyl)-5-tertbutyloxycarbonyl-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (Z-6)
Z-3400mg (1.20mmol) is added, 1-methyl-4-piperidone 180mg (1.44mmol), 100mLClCH in 250mL three-necked bottle 2cH 2cl, passes into nitrogen, adds trifluoroacetic acid 0.8mL (10.0mmol), react 30min under room temperature in nitrogen atmosphere, adds NaBH (OAc) 3410mg (1.44mmol), room temperature reaction 2h, TLC detect raw material and disappear.Add 150mL water, use CH 2cl 2extract 3 times (20mL × 3), organic phase anhydrous magnesium sulfate drying, suction filtration, column chromatography (CH after filtrate is concentrated 2cl 2: MeOH=20: 1), obtain yellow solid 390mg, yield 75%, MS m/z:412.2 [M+H] +.
Embodiment 29
3-(4-(1-methyl piperidine-4 is amino) phenyl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridines (Z-7)
Z-6 300mg (0.73mmol) is added, anhydrous CH in the mono-neck bottle of 100mL 2cl 240mL, is placed in ice bath, is added dropwise to trifluoroacetic acid 1.5mL (20mmol), and ice bath reaction 1h, dislocation room temperature reaction 1h, TLC detect raw material and disappear.Revolve desolventizing, enriched material column chromatography (CH 2cl 2: MeOH=10: 1), obtain yellow solid 210mg, yield 93%, MS m/z:311.2 [M+H] +.
Embodiment 30
3-(4-(1-methyl piperidine-4 is amino) phenyl)-5-(2,6-dichlorobenzene alkylsulfonyl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-3-8)
Z-7100mg (0.3mmol) is added in the mono-neck bottle of 100mL, anhydrous THF10mL, triethylamine 50mg (0.45mmol) is added dropwise under ice bath, stir 10min, slow dropping 2, the anhydrous THF solution of 6-two chloro phenylsulfonyl chloride 87mg (0.33mmol), reacts 1h under ice bath, and TLC detects raw material and disappears.Elimination salt precipitates, column chromatography (CH after filtrate is concentrated 2cl 2: MeOH=20: 1), obtain faint yellow solid 10mg, yield 6%, MS m/z:520.1 [M+H] +.
1H-NMR(300MHz，DMSO-d 6)δ(ppm)：12.50(s，1H，pyrazole)，7.67-7.70(m，2H，ArH)，7.58(m，1H，ArH)，7.25(d，2H，J＝8.5Hz，ArH)，6.65(d，2H，J＝8.6Hz，ArH)，5.80(s，1H，-NH-)，4.57(s，2H，-CH 2-)，3.67(m，2H，-CH 2)，2.93(m，2H，piperdine)，2.71(m，2H，-CH 2-)，2.35(m，3H，-CH 3)，2.28(m，1H，piperdine)，1.96(m，2H，piperdine)，1.46(m，2H，piperdine)，1.12(m，2H，piperdine).
Embodiment 31
3-(4-(1-Acetylpiperidin-4 is amino) phenyl)-5-(3-nitrobenzenesulfonyl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-3-1)
Preparation method is similar to the preparation of I-3-8, obtains light red solid 30mg, yield 19%, MS m/z:525.2 [M+H] +.
1H-NMR(300MHz，DMSO-d 6)δ(ppm)：8.52(m，1H，ArH)，8.49(s，1H，ArH)，8.30(m，1H，ArH)，7.90(t，1H，J＝8.0Hz，ArH)，7.25(d，2H，J＝8.4Hz，ArH)，6.68(d，2H，J＝8.5Hz，ArH)，5.80(s，1H，-NH-)，4.38(s，2H，-CH 2-)，4.25(m，1H，piperdine)，3.78(m，1H，piperdine)，3.40(m，2H，-CH2-)，3.40(m，1H，piperdine)，3.15(m，1H，piperdine)，2.83(m，1H，piperdine)，2.69(m，2H，-CH 2-)，2.01(s，3H，-COCH 3)，1.95(m，2H，piperdine)，1.24(m，2H，piperdine).
Embodiment 32
3-(4-(1-Acetylpiperidin-4 is amino) phenyl)-5-(3-pyridine sulfonyl sulfonyl base)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-3-2)
Preparation method is similar to the preparation of I-3-8, white powdery solid 40mg, yield 28%, MS m/z:481.3 [M+H] +.
1H-NMR(300MHz，DMSO-d 6)δ(ppm)：12.57(s，1H，pyrazole)，9.02(m，1H，ArH)，8.86(m，1H，ArH)，8.27(m，1H，ArH)，7.66(m，1H，ArH)，7.27(d，2H，ArH)，6.68(d，2H，ArH)，5.79(s，1H，-NH-)，4.35(s，2H，-CH 2-)，4.25(m，1H，piperdine)，3.79(m，1H，piperdine)，3.47(m，2H，-CH 2-)，3.47(m，1H，piperdine)，3.16(m，1H，piperdine)，2.80(m，1H，piperdine)，2.71(m，2H，-CH 2-)，2.01(s，3H，-COCH 3)，1.92(m，2H，piperdine)，1.25(m，2H，piperdine).
Embodiment 33
3-(4-(1-Acetylpiperidin-4 is amino) phenyl)-5-(2,6-dichlorobenzene alkylsulfonyl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-3-3)
Preparation method is similar to the preparation of I-3-8, yellow powder solid 60mg, yield 37%, MS m/z:548.1 [M+H] +.
1H-NMR(300MHz，DMSO-d 6)δ(ppm)：12.60(s，1H，pyrazole)，7.67-7.69(m，2H，ArH)，7.58(m，1H，ArH)，7.25-7.27(m，2H，ArH)，6.66-6.68(m，2H，ArH)，5.79(br，1H，-NH-)，4.57(s，2H，-CH 2-)，4.23(m，1H，piperdine)，3.76(m，1H，piperdine)，3.66(m，2H，-CH2-)，3.51(m，1H，piperdine)，3.11(m，1H，piperdine)，2.82(m，1H，piperdine)，2.72(m，2H，-CH 2-)，2.00(s，3H，-COCH 3)，1.90(m，2H，piperdine)，1.30(m，2H，piperdine).
Embodiment 34
3-(4-(1-Acetylpiperidin-4 is amino) phenyl)-5-(2-naphthalene sulfonyl base)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-3-4)
Preparation method is similar to the preparation of I-3-8, grey powdery solid 27mg, yield 17%, MS m/z:530.2 [M+H] +.
1H-NMR(300MHz，DMSO-d 6)δ(ppm)：12.59(s，1H，pyrazole)，8.59(s，1H，ArH)，8.22(m，1H，ArH)，8.10(m，1H，ArH)，8.05(m，1H，ArH)，7.68-7.74(m，2H，ArH)，7.25(d，2H，J＝8.4Hz，ArH)，6.68(d，2H，J＝8.5Hz，ArH)，5.79(s，1H，-NH-)，4.33(s，2H，-CH 2-)，4.24(m，1H，piperdine)，3.80(m，1H，piperdine)，3.48(m，2H，-CH 2-)，3.48(m，1H，piperdine)，3.11(m，1H，piperdine)，2.83(m，1H，piperdine)，2.70(m，2H，-CH 2-)，2.01(s，3H，-COCH 3)，1.92(m，2H，piperdine)，1.28(m，2H，piperdine).
Embodiment 35
3-(4-(1-Acetylpiperidin-4 is amino) phenyl)-5-(4-Methyl benzenesulfonyl base)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-3-5)
Preparation method is similar to the preparation of I-3-8, white powdery solid 40mg, yield 28%, MS m/z:494.1 [M+H] +.
1H-NMR(300MHz，DMSO-d 6)δ(ppm)：12.64(s，1H，pyrazole)，7.73(d，2H，ArH)，7.43(d，2H，ArH)，7.25(d，2H，J＝7.6Hz，ArH)，6.68(d，2H，J＝8.5Hz，ArH)，5.82(br，1H，-NH-)，4.24(s，2H，-CH 2-)，3.78(m，1H，piperdine)，3.50(m，1H，piperdine)，3.05(m，1H，piperdine)，3.02(m，2H，-CH2-)，2.84(m，1H，piperdine)，2.72(m，1H，piperdine)，2.72(m，2H，-CH 2-)，2.01(s，3H，-COCH 3)，1.98(m，2H，piperdine)，1.33(m，2H，piperdine).
Embodiment 36
3-(4-(1-Acetylpiperidin-4 is amino) phenyl)-5-(8-quinoline alkylsulfonyl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-3-6)
Preparation method is similar to the preparation of I-3-8, yellow powder solid 27mg, yield 17%, MS m/z:531.2 [M+H] +.
1H-NMR(300MHz，DMSO-d 6)δ(ppm)：12.45(s，1H，pyrazole)，8.85(m，1H，ArH)，8.50(m，1H，ArH)，8.42(m，1H，ArH)，8.28(m，1H，ArH)，7.76(t，1H，J＝7.8Hz，ArH)，7.62(m，1H，ArH)，7.25(d，2H，J＝8.3Hz，ArH)，6.69(d，2H，J＝8.5Hz，ArH)，5.78(br，1H，-NH-)，4.67(s，2H，-CH 2-)，4.24(m，1H，piperdine)，3.79(m，1H，piperdine)，3.73(m，2H，-CH 2-)，3.33(m，1H，piperdine)，3.17(m，1H，piperdine)，3.08(m，2H，-CH 2-)，2.78(m，1H，piperdine)，2.01(s，3H，-COCH 3)，1.90(m，2H，piperdine)，1.23(m，2H，piperdine).
Embodiment 37
3-(4-(1-Acetylpiperidin-4 is amino) phenyl)-5-(2-thiophen sulfuryl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-3-7)
Preparation method is similar to the preparation of I-3-8, grey powdery solid 10mg, yield 7%, MS m/z:486.2 [M+H] +.
1H-NMR(300MHz，DMSO-d 6)δ(ppm)：8.02(m，1H，ArH)，7.76(m，1H，ArH)，7.27(m，1H，ArH)，7.25(d，2H，J＝8.4Hz，ArH)，6.68(d，2H，J＝8.5Hz，ArH)，5.80(br，1H，-NH-)，4.28(s，2H，-CH 2-)，4.22(m，1H，piperdine)，3.79(m，1H，piperdine)，3.50(m，2H，-CH 2-)，3.18(m，1H，piperdine)，3.10(m，1H，piperdine)，2.78(m，1H，piperdine)，2.74(m，2H，-CH 2-).2.01(s，3H，-COCH 3)，1.89(m，2H，piperdine)，1.29(m，2H，piperdine).
Embodiment 38
3-(4-(1-methyl piperidine-4-is amino) phenyl)-5-(2-thiophen sulfuryl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-3-9)
Preparation method is similar to the preparation of I-3-8, grey powdery solid 45mg, yield 31%, MS m/z:458.2 [M+H] +.
1H-NMR(300MHz，DMSO-d 6)δ(ppm)：12.71(s，1H，tautomers)，8.03(m，1H，ArH)，7.76(m，1H，ArH)，7.27(m，1H，ArH)，7.25-7.27(m，2H，ArH)，6.67-7.68(m，2H，ArH)，6.05(br，1H，-NH-)，4.29(s，2H，-CH 2-)，3.44(m，2H，-CH 2-)，3.36(m，2H，-CH 2-)，3.08(m，2H，piperdine)，2.75(m，3H，-CH 3)，2.75(m，1H，piperdine)，2.13(m，2H，piperdine)，1.70(m，2H，piperdine)，1.12(m，2H，piperdine).
Embodiment 39
3-(4-(1-methyl piperidine-4 is amino) phenyl)-5-(3-pyridine sulfonyl sulfonyl base)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-3-10)
Preparation method is similar to the preparation of I-3-8, yellow powder solid 30mg, yield 21%, MS m/z:453.2 [M+H] +.
1H-NMR(300MHz，DMSO-d 6)δ(ppm)：12.66(s，1H，pyrazole)，9.01(m，1H，ArH)，8.86(m，1H，ArH)，8.26(m，1H，ArH)，7.65(m，1H，ArH)，7.27(d，2H，J＝8.0Hz，ArH)，6.68(d，2H，J＝8.5Hz，ArH)，5.91(br，1H，-NH-)，4.60(s，2H，-CH 2-)，3.45(m，2H，-CH 2-)，3.34((m，2H，-CH 2-)，3.04(m，2H，piperdine)，2.70(m，3H，-CH 3)，2.70(m，1H，piperdine)，2.05(m，2H，piperdine)，1.62(m，2H，piperdine)，1.17(m，2H，piperdine).
Embodiment 40
3-(4-(1-methyl piperidine-4 is amino) phenyl)-5-(8-quinoline alkylsulfonyl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-3-11)
Preparation method is similar to the preparation of I-3-8, yellow powder solid 15mg, yield 9%, MS m/z:503.1 [M+H] +.
1H-NMR(300MHz，DMSO-d 6)δ(ppm)：8.84(m，1H，ArH)，8.50(m，1H，ArH)，8.47(m，1H，ArH)，8.28(m，1H，ArH)，7.75(t，1H，J＝7.7Hz，ArH)，7.62(m，1H，ArH)，7.24(d，2H，J＝8.4Hz，ArH)，6.68(d，2H，J＝8.5Hz，ArH)，5.78(s，1H，-NH-)，4.67(s，2H，-CH 2-)，3.72(m，2H，-CH 2-)，2.95((m，2H，-CH 2-)，2.95(m，2H，piperdine)，2.39(m，3H，-CH 3)，2.37(m，1H，piperdine)，1.97(m，2H，piperdine)，1.48(m，2H，piperdine)，1.17(m，2H，piperdine).
Embodiment 41
3-(4-(1-methyl piperidine-4 is amino) phenyl)-5-(2-naphthalene sulfonyl base)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-3-12)
Preparation method is similar to the preparation of I-3-8, white look powdery solid 35mg, yield 22%, MS m/z:502.3 [M+H] +.
1H-NMR(300MHz，DMSO-d 6)δ(ppm)：12.50(s，1H，pyrazole)，8.56(s，1H，ArH)，8.21(m，1H，ArH)，8.13(m，1H，ArH)，8.06(m，1H，ArH)，7.84(m，1H，ArH)，7.66-7.73(m，2H，ArH)，7.26(d，2H，J＝8.4Hz，ArH)，6.68(d，2H，J＝8.5Hz，ArH)，5.92(br，1H，-NH-)，4.36(s，2H，-CH 2-)，3.46(m，2H，-CH 2-)，2.87((m，2H，-CH 2-)，2.71(m，2H，piperdine)，2.60(m，3H，-CH 3)，2.30(m，1H，piperdine)，2.03(m，2H，piperdine)，1.63(m，2H，piperdine)，1.20(m，2H，piperdine).
Embodiment 42
3-(4-(1-methanesulphonylpiperidine-4-is amino) phenyl)-5-(3-nitrobenzenesulfonyl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-3-13)
Preparation method is similar to the preparation of I-3-8, obtains light red solid 30mg, yield 18%, MS m/z:561.2 [M+H] +.
1H-NMR(300MHz，DMSO-d 6)δ(ppm)：8.51(m，1H，ArH)，8.40(s，1H，ArH)，8.25(m，1H，ArH)，7.85(t，1H，J＝8.0Hz，ArH)，7.30(d，2H，J＝8.4Hz，ArH)，6.68(d，2H，J＝8.5Hz，ArH)，5.80(s，1H，-NH-)，4.37(s，2H，-CH 2-)，4.10(m，1H，piperdine)，3.77(m，2H，-CH 2-)，3.55(m，2H，piperdine)，3.20(m，2H，piperdine)，2.95(m，2H，-CH 2-)，2.85(s，3H，-SO 2CH 3)，1.95(m，2H，piperdine)，1.45(m，2H，piperdine).
Embodiment 43
3-(4-(1-methanesulphonylpiperidine-4-is amino) phenyl)-5-(3-pyridine sulfonyl sulfonyl base)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-3-14)
Preparation method is similar to the preparation of I-3-8, white powdery solid 40mg, yield 26%, MS m/z:517.3 [M+H] +.
1H-NMR(300MHz，DMSO-d 6)δ(ppm)：12.58(s，1H，pyrazole)，9.00(m，1H，ArH)，8.88(m，1H，ArH)，8.25(m，1H，ArH)，7.67(m，1H，ArH)，7.27(d，2H，J＝8.4Hz，ArH)，6.68(d，2H，J＝8.5Hz，ArH)，5.79(br，1H，-NH-)，4.38(s，2H，-CH 2-)，4.11(m，1H，piperdine)，3.76(m，2H，-CH 2-)，3.55(m，2H，piperdine)，3.20(m，2H，piperdine)，2.95(m，2H，-CH 2-)，2.84(s，3H，-SO 2CH 3)，1.99(m，2H，piperdine)，1.60(m，2H，piperdine).
Embodiment 44
3-(4-(1-methanesulphonylpiperidine-4 is amino) phenyl)-5-(2,6-dichlorobenzene alkylsulfonyl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-3-15)
Preparation method is similar to the preparation of I-3-8, white powdery solid 55mg, yield 31%, MS m/z:584.1 [M+H] +.
1H-NMR(300MHz，DMSO-d 6)δ(ppm)：12.60(s，1H，pyrazole)，7.67-7.69(m，2H，ArH)，7.58(m，1H，ArH)，7.26(d，2H，J＝8.4Hz，ArH)，6.68(d，2H，J＝8.5Hz，ArH)，5.79(s，1H，-NH-)，4.38(s，2H，-CH 2-)，4.14(m，1H，piperdine)，3.77(m，2H，-CH 2-)，3.52(m，2H，piperdine)，3.22(m，2H，piperdine)，3.00(m，2H，-CH 2-)，2.87(s，3H，-SO 2CH 3)，2.01(m，2H，piperdine)，1.7(m，2H，piperdine).
Embodiment 45
3-(4-(1-methanesulphonylpiperidine-4-is amino) phenyl)-5-(2-naphthalene sulfonyl base)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-3-16)
Preparation method is similar to the preparation of I-3-8, grey powdery solid 87mg, yield 51%, MS m/z:566.2 [M+H] +.
1H-NMR(300MHz，DMSO-d 6)δ(ppm)：12.59(s，1H，pyrazole)，8.59(s，1H，ArH)，8.22(m，1H，ArH)，8.11(m，1H，ArH)，8.07(m，1H，ArH)，7.68-7.74(m，2H，ArH)，7.25(d，2H，J＝8.4Hz，ArH)，6.68(d，2H，J＝8.5Hz，ArH)，5.79(br，1H，-NH-)，4.35(s，2H，-CH 2-)，4.12(m，1H，piperdine)，3.75(m，2H，-CH 2-)，3.55(m，2H，piperdine)，3.20(m，2H，piperdine)，3.01(m，2H，-CH 2-)，2.86(s，3H，-SO 2CH 3)，2.01(m，2H，piperdine)，1.85(m，2H，piperdine).
Embodiment 46
3-(4-(1-methanesulphonylpiperidine-4-is amino) phenyl)-5-(4-Methyl benzenesulfonyl base)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-3-17)
Preparation method is similar to the preparation of I-3-8, white powdery solid 70mg, yield 44%, MS m/z:530.1 [M+H] +.
1H-NMR(300MHz，DMSO-d 6)δ(ppm)：12.64(s，1H，pyrazole)，7.73(d，2H，ArH)，7.43-7.44(m，2H，ArH)，7.25(d，2H，J＝8.4Hz，ArH)，6.68(d，2H，J＝8.5Hz，ArH)，5.82(br，1H，-NH-)，4.35(s，2H，-CH 2-)，4.11(m，1H，piperdine)，3.76(m，2H，-CH 2-)，3.56(m，2H，piperdine)，3.20(m，2H，piperdine)，3.01(m，2H，-CH 2-).2.86(s，3H，-SO 2CH 3)，1.99(m，2H，piperdine)，1.85(m，2H，piperdine).
Embodiment 47
3-(4-(1-methanesulphonylpiperidine-4-is amino) phenyl)-5-(8-quinoline alkylsulfonyl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-3-18)
Preparation method is similar to the preparation of I-3-8, white powdery solid 105mg, yield 62%, MS m/z:567.2 [M+H] +.
1H-NMR(300MHz，DMSO-d 6)δ(ppm)：12.45(s，1H，pyrazole)，8.85(m，1H，ArH)，8.50(m，1H，ArH)，8.42(m，1H，ArH)，8.28(m，1H，ArH)，7.76(t，1H，J＝7.8Hz，ArH)，7.62(m，1H，ArH)，7.25(d，2H，J＝8.4Hz，ArH)，6.69(d，2H，J＝8.5Hz，ArH)，5.78(br，1H，-NH-)，4.51(s，2H，-CH 2-)，4.09(m，1H，piperdine)，3.78(m，2H，-CH 2-)，3.56(m，2H，piperdine)，3.21(m，2H，piperdine)，3.05(m，2H，-CH 2-).2.91(s，3H，-SO 2CH 3)，1.99(m，2H，piperdine)，1.80(m，2H，piperdine).
Embodiment 48
3-(4-(1-methanesulphonylpiperidine-4-is amino) phenyl)-5-(2-thiophen sulfuryl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-3-19)
Preparation method is similar to the preparation of I-3-8, grey powdery solid 10mg, yield 6%, MS m/z:522.2 [M+H] +. 1H-NMR(300MHz，DMSO-d 6)δ(ppm)：8.02(m，1H，ArH)，7.76(m，1H，ArH)，7.27(m，1H，ArH)，7.25(d，2H，J＝8.4Hz，ArH)，6.68(d，2H，J＝8.5Hz，ArH)，5.80(br，1H，-NH-)，4.51(s，2H，-CH 2-)，4.07(m，1H，piperdine)，3.77(m，2H，-CH 2-)，3.57(m，2H，piperdine)，3.23(m，2H，piperdine)，3.04(m，2H，-CH 2-).2.91(s，3H，-SO 2CH 3)，1.97(m，2H，piperdine)，1.82(m，2H，piperdine).
Embodiment 49
3-(4-(4-THP trtrahydropyranyl is amino) phenyl)-5-(8-quinoline alkylsulfonyl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-4-1)
Preparation method is similar to the preparation of I-3-8, white powdery solid 78mg, yield 53%, MS m/z:490.2 [M+H] +.
1H-NMR(300MHz，DMSO-d 6)δ(ppm)：8.87(m，1H，ArH)，8.51(m，1H，ArH)，8.43(m，1H，ArH)，8.27(m，1H，ArH)，7.77(t，1H，J＝7.8Hz，ArH)，7.61(m，1H，ArH)，7.25(d，2H，J＝8.4Hz，ArH)，6.69(d，2H，J＝8.5Hz，ArH)，5.78(br，1H，-NH-)，4.68(s，2H，-CH 2-)，4.11(m，4H，tetrahydropyran)，3.88(m，2H，-CH 2-)，3.72(m，1H，tetrahydropyran)，3.40(m，2H，-CH 2-)，1.90(m，2H，tetrahydropyran)，1.41(m，2H，tetrahydropyran).
Embodiment 50
3-(4-(4-THP trtrahydropyranyl is amino) phenyl)-5-(2-thiophen sulfuryl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-4-2)
Preparation method is similar to the preparation of I-3-8, grey powdery solid 11mg, yield 8%, MS m/z:445.2 [M+H] +.
1H-NMR(300MHz，DMSO-d 6)δ(ppm)：8.02(m，1H，ArH)，7.76(m，1H，ArH)，7.27(m，1H，ArH)，7.25(d，2H，J＝8.4Hz，ArH)，6.68(d，2H，J＝8.5Hz，ArH)，5.80(br，1H，-NH-)，4.67(s，2H，-CH 2-)，4.13(m，4H，tetrahydropyran)，3.81(m，2H，-CH 2-)，3.69(m，1H，tetrahydropyran)，3.42(m，2H，-CH 2-)，1.95(m，2H，tetrahydropyran)，1.58(m，2H，tetrahydropyran).
Embodiment 51
3-(4-(morpholine ethylamino) phenyl)-5-tertbutyloxycarbonyl-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (Z-8)
Z-3 100mg (0.3mmol) is added in the mono-neck bottle of 100mL, dry DMF 10mL, cesium carbonate 310mg (0.9mmol) is added dropwise under room temperature, stir 30min, add 4-(2-chloroethyl) morpholine 57mg (0.36mmol) and potassiumiodide 106mg (0.6mmol) respectively, be warming up to 90 DEG C of reactions 2h, TLC and detect raw material disappearance.Reaction solution adds water, extraction into ethyl acetate 3 times, organic phase anhydrous magnesium sulfate drying, suction filtration, column chromatography (CH after concentrated 2cl 2: MeOH=50: 1), obtain pale yellow oil 100mg, yield 78%, MS m/z:428.2 [M+H] +.
Embodiment 52
3-(4-(morpholine ethylamino) phenyl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridines (Z-9)
Z-8 300mg (0.7mmol) is added, anhydrous CH in the mono-neck bottle of 100mL 2cl 240mL, is placed in ice bath, is added dropwise to trifluoroacetic acid 1.5mL (20mmol), and ice bath reaction 1h, dislocation room temperature reaction 1h, TLC detect raw material and disappear.Revolve desolventizing, enriched material column chromatography (CH 2cl 2: MeOH=20: 1), obtain yellow solid 200mg, yield 87%, MS m/z:328.2 [M+H] +.
Embodiment 53
3-(4-(morpholine ethylamino) phenyl)-5-(8-quinoline alkylsulfonyl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-5-1)
Z-9 100mg (0.3mmol) is added in the mono-neck bottle of 100mL, anhydrous THF10mL, triethylamine 50mg (0.45mmol) is added dropwise under ice bath, stir 10min, the anhydrous THF solution of slow dropping 8-quinoline sulfuryl chloride 75mg (0.33mmol), react 1h under ice bath, TLC detects raw material and disappears.Elimination salt precipitates, and column chromatography (CH2Cl2: MeOH=30: 1) after filtrate is concentrated, obtains yellow powder solid 27mg, yield 17%, MS m/z:519.2 [M+H] +.
1H-NMR(300MHz，DMSO-d 6)δ(ppm)：8.87(m，1H，ArH)，8.51(m，1H，ArH)，8.43(m，1H，ArH)，8.27(m，1H，ArH)，7.77(t，1H，J＝7.8Hz，ArH)，7.61(m，1H，ArH)，7.25(d，2H，J＝8.4Hz，ArH)，6.69(d，2H，J＝8.5Hz，ArH)，4.75(s，2H，-CH 2-)，3.75(m，4H，morpholine)，3.69(m，2H，-CH 2-)，3.45(m，2H，-CH 2-)，3.25(m，4H，morpholine)，2.82(m，2H，-CH 2-)，275(m，2H，-CH 2-).
Embodiment 54
1-tertbutyloxycarbonyl-3-(2-furancarbonyl)-4-piperidone (Z-10)
Y-1 15.0g (56mmol) is added, anhydrous CH in the mono-neck bottle of 250mL 2cl 280mL, under being placed in ice bath, adds triethylamine 8.5g (84mmol), is slowly added dropwise to the anhydrous CH of 2 furoyl chloride 11.2g (86mmol) under ice bath state 2cl 2solution 50mL (solution colour is along with dropping constantly intensification), react 2h at 0 DEG C, be warming up to 25 DEG C of reaction 5h, in reaction solution, add 100mL water, adjust PH to 6, react 0.5h at 25 DEG C with the 5%HCl aqueous solution, TLC detects has novel substance to produce.Reaction solution stratification, separates organic layer, aqueous phase CH 2cl 2extract 3 times (50mL × 3), merge organic phase, with anhydrous magnesium sulfate drying, suction filtration, column chromatography (PE: EA=5: 1) after filtrate is concentrated, obtains white oil thing 6.0g, yield 37%, MS m/z:292.2 [M-H] -.
Embodiment 55
3-(2-furyl)-5-tertbutyloxycarbonyl-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (Z-11)
Hydrazine hydrochloride 0.4g (6mmol) is added in the mono-neck bottle of 100mL, sodium acetate 0.5g (6mmol), dehydrated alcohol 15mL, be warming up to 70 DEG C of reaction 1h, filtered while hot, filtrate is transferred to the mono-neck bottle of 100mL, add Z-10 0.6g (2mmol), be warming up to 70 DEG C of reaction 1h (reaction solution becomes muddy by clarification), be cooled to room temperature reaction 5h, TLC detects raw material and disappears.Stopped reaction, reaction solution suction filtration, filter cake absolute ethanol washing, dry, obtain white solid 0.4g, yield 69%, MS m/z:288.1 [M-H] -.
Embodiment 56
3-(2-furyl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (Z-12)
Z-11 400mg (1.4mmol) is added, anhydrous CH in the mono-neck bottle of 100mL 2cl 220mL, is placed in ice bath, is added dropwise to trifluoroacetic acid 2mL (27mmol), and ice bath reaction 30min, dislocation room temperature reaction 1h, TLC detect raw material and disappear.Revolve desolventizing, enriched material column chromatography (CH 2cl 2: MeOH=20: 1), obtain white solid 200mg, yield 76%, MS m/z:190.2 [M+H] +.
Embodiment 57
3-(2-furyl)-5-(8-quinoline alkylsulfonyl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-6-1)
Z-12 100mg (0.5mmol) is added in the mono-neck bottle of 100mL, anhydrous THF10mL, triethylamine 150mg (1.5mmol) is added dropwise under ice bath, stir 10min, the anhydrous THF solution of slow dropping 8-quinoline sulfuryl chloride 125mg (0.55mmol), react 1h under ice bath, TLC detects raw material and disappears.Elimination salt precipitates, column chromatography (CH2Cl2: MeOH=30: 1) after filtrate is concentrated, yellow powder solid 27mg, yield 17%, MS m/z:381.2 [M+H] +.
1H-NMR(300MHz，DMSO-d 6)δ(ppm)：8.87(m，1H，ArH)，8.51(m，1H，ArH)，8.43(m，1H，ArH)，8.27(m，1H，ArH)，7.77(t，1H，J＝7.8Hz，ArH)，7.61(m，1H，ArH)，7.20-7.26(m，2H，ArH)，6.67-7.02(m，1H，ArH).
Embodiment 58
1-tertbutyloxycarbonyl-3-(4-methoxycarbonyl benzoyl)-4-piperidone (Z-13)
Y-1 12.0g (45mmol) is added, anhydrous CH in the mono-neck bottle of 250mL 2cl 280mL, under being placed in ice bath, adds triethylamine 7.0g (68mmol), is slowly added dropwise to the anhydrous CH of 4-chloroformyl methyl benzoate 12.0g (68mmol) under ice bath state 2cl 2solution 50mL (solution colour is along with dropping constantly intensification), react 2h at 0 DEG C, be warming up to 25 DEG C of reaction 5h, in reaction solution, add 100mL water, adjust PH to 6, react 0.5h at 25 DEG C with the 5%HCl aqueous solution, TLC detects has novel substance to produce.Reaction solution stratification, separates organic layer, aqueous phase CH 2cl 2extract 3 times (50mL × 3), merge organic phase, with anhydrous magnesium sulfate drying, suction filtration, column chromatography (PE: EA=5: 1) after filtrate is concentrated, obtains white solid 6.0g, yield 38%, MS m/z:360.2 [M-H] -.
Embodiment 59
3-(4-methoxycarbonyl phenyl)-5-tertbutyloxycarbonyl-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (Z-14)
Hydrazine hydrochloride 0.3g (4.5mmol) is added in the mono-neck bottle of 100mL, sodium acetate 0.4g (4.5mmol), dehydrated alcohol 15mL, be warming up to 70 DEG C of reaction 1h, filtered while hot, filtrate is transferred to the mono-neck bottle of 100mL, add Z-13 1.0g (3mmol), be warming up to 70 DEG C of reaction 1h (reaction solution becomes muddy by clarification), be cooled to room temperature reaction 5h, TLC detects raw material and disappears.Stopped reaction, reaction solution suction filtration, filter cake absolute ethanol washing, dry, obtain white solid 0.5g, yield 51%, MS m/z:356.1 [M-H] -.
1H-NMR(300MHz，DMSO-d 6)δ(ppm)：12.80(s，1H，pyrazole)，8.03(d，2H，J＝7.9Hz，ArH)，7.76(m，2H，ArH)，4.62(s，2H，-CH 2-)，3.87(s，3H，-CH 3)，3.65(m，2H，-CH 2-)，3.17(m，4H，piperidine)，2.71(m，2H，-CH 2-)，1.42(s，9H，-CH 3×3).
Embodiment 60
3-(4-methoxycarbonyl phenyl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (Z-15)
Z-14 300mg (0.8mmol) is added, anhydrous CH in the mono-neck bottle of 100mL 2cl 220mL, is placed in ice bath, is added dropwise to trifluoroacetic acid 2mL (27mmol), and ice bath reaction 30min, dislocation room temperature reaction 1h, TLC detect raw material and disappear.Revolve desolventizing, enriched material column chromatography (CH 2cl 2: MeOH=20: 1), obtain white solid 180mg, yield 82%, MS m/z:258.2 [M+H] +.
1H-NMR(300MHz，DMSO-d 6)δ(ppm)：8.02(d，2H，J＝8.4Hz，ArH)，7.73(d，2H，J＝8.4Hz，ArH)，4.18(s，2H，-CH 2-)，3.95(s，3H，-CH 3)，3.43(m，2H，-CH 2-)，2.77(m，2H，-CH 2-).
Embodiment 61
3-(4-methoxycarbonyl phenyl)-5-(2,6-dichlorobenzene alkylsulfonyl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (Z-16)
Z-15 100mg (0.4mmol) is added in the mono-neck bottle of 100mL, anhydrous THF10mL, triethylamine 120mg (1.2mmol) is added dropwise under ice bath, stir 10min, slow dropping 2, the anhydrous THF solution of 6-two chloro phenylsulfonyl chloride 112mg (0.44mmol), reacts 1h under ice bath, and TLC detects raw material and disappears.Elimination salt precipitates, column chromatography (CH2Cl2: MeOH=30: 1) after filtrate is concentrated, yellow powder solid 120mg, yield 65%, MS m/z:467.2 [M+H] +.
Embodiment 62
3-(4-carboxyl phenyl)-5-(2,6-dichlorobenzene alkylsulfonyl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (Z-17)
In the mono-neck bottle of 100mL, add Z-16 300mg (0.6mmol), dehydrated alcohol 30mL, add NaOH solid 80mg (1.8mmol), back flow reaction 5h, TLC detect raw material and disappear.Stopped reaction, cooling, revolves desolventizing, obtains yellow solid.Be dissolved in water, 4mol/L aqueous hydrochloric acid adjusts PH to 6, and extraction into ethyl acetate 3 times, anhydrous magnesium sulfate drying, suction filtration concentrates moral yellow solid 200mg, yield 74%, MS m/z:453.2 [M+H] +.
Embodiment 63
3-(4-(1-piperidine formyl base) phenyl)-5-(2,6-dichlorobenzene alkylsulfonyl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-7-1)
Z-17 100mg (0.2mmol) is added in the mono-neck bottle of 100mL, dry DMF 10mL, TFFH90mg (0.3mmol) and DIEA 90mg (0.6mmol) is added respectively under room temperature, room temperature reaction 15min, add piperidines 92mg (0.3mmol), room temperature reaction 2h, TLC detect raw material and disappear.Stopped reaction, adds water, extraction into ethyl acetate 3 times, and organic phase saturated NaCl solution washing 3 times, anhydrous magnesium sulfate drying, suction filtration, revolves desolventizing, enriched material column chromatography (CH 2cl 2: MeOH=30: 1), obtain white solid 35mg yield 6%, MS m/z:520.1 [M+H] +.
1H-NMR(300MHz，DMSO-d 6)δ(ppm)：12.70(s，1H，pyrazole)，7.74-7.77(m，2H，ArH)，7.50-7.54(m，2H，ArH)，7.41-7.47(m，1H，ArH)，6.73-6.77(m，2H，ArH)，4.65(s，2H，-CH 2-)，3.67(m，2H，-CH 2-)，3.17(m，4H，piperidine)，2.78(m，2H，-CH 2-)，1.55-1.57(m，6H，piperdine).
Embodiment 64
3-(4-(1-piperazine formyl radical) phenyl)-5-(2,6-dichlorobenzene alkylsulfonyl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-7-2)
Preparation method is similar to the preparation of I-7-1, obtains white solid 30mg, yield 29%, MS m/z:521.1 [M+H] +.
1H-NMR(300MHz，DMSO-d 6)δ(ppm)：12.80(s，1H，pyrazole)，7.78-7.80(m，2H，ArH)，7.60-7.65(m，2H，ArH)，7.42-7.49(m，1H，ArH)，6.73-6.77(m，2H，ArH)，4.66(s，2H，-CH 2-)，3.67(m，2H，-CH 2-)，3.17(m，4H，piperidine)，2.75(m，2H，-CH 2-)，2.37(m，4H，piperdine)，2.01(br，1H，-NH-).
Embodiment 65
3-(4-(4-methyl isophthalic acid-piperazine formyl radical) phenyl)-5-(2,6-dichlorobenzene alkylsulfonyl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-7-3)
Preparation method is similar to the preparation of I-7-1, obtains white solid 45mg, yield 43%, MS m/z:535.1 [M+H] +. 1H-NMR(300MHz，DMSO-d 6)δ(ppm)：12.70(s，1H，pyrazole)，7.57-7.67(m，2H，ArH)，7.49(m，1H，ArH)，7.47-7.49(m，2H，ArH)，7.19-7.20(m，2H，ArH)，4.65(s，2H，-CH 2-)，3.65(m，2H，-CH 2-)，3.17(m，4H，piperdine)，3.06(s，3H，-CH 3)，2.73(m，2H，-CH 2-)，2.27(m，4H，piperdine).
Embodiment 66
3-(4-(1-Pyrrolidine formyl radical) phenyl)-5-(2,6-dichlorobenzene alkylsulfonyl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-7-4)
Preparation method is similar to the preparation of I-7-1, obtains white solid 35mg, yield 35%, MS m/z:506.2 [M+H] +.
1H-NMR(300MHz，DMSO-d 6)δ(ppm)：12.80(s，1H，tautomers)，7.58-7.67(m，2H，ArH)，7.51(m，1H，ArH)，7.46-7.48(m，2H，ArH)，7.19-7.20(m，2H，ArH)，4.66(s，2H，-CH 2-)，3.74(m，2H，-CH 2-)，3.55(m，4H，pyrrolidine)，2.75(m，2H，-CH 2-)，1.84(m，4H，pyrrolidine).
Embodiment 67
3-(4-(1-morpholine methanoyl) phenyl)-5-(2,6-dichlorobenzene alkylsulfonyl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-7-5)
Preparation method is similar to the preparation of I-7-1, obtains white solid 40mg, yield 39%, MS m/z:522.2 [M+H] +.
1H-NMR(300MHz，DMSO-d 6)δ(ppm)：12.82and 13.09(s，1H，tautomers)，，7.77-7.81(m，2H，ArH)，7.70(m，1H，ArH)，7.58-7.64(m，3H，ArH)，7.20(m，1H，ArH)，4.75(s，2H，-CH 2-)，3.75(m，4H，morpholine)，3.69(m，2H，-CH 2-)，3.48(m，4H，morpholine)，2.82(m，2H，-CH 2-).
Embodiment 68
3-(4-(N-aminoethyl carbamyl) phenyl)-5-(2,6-dichlorobenzene alkylsulfonyl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-7-6)
Preparation method is similar to the preparation of I-7-1, obtains white solid 33mg, yield 32%, MS m/z:496.2 [M+H] +.
1H-NMR(300MHz，DMSO-d 6)δ(ppm)：8.80(s，1H，-NH-)，7.98-8.08(m，3H，ArH)，7.59-7.70(m，4H，ArH)，4.68(s，2H，-CH 2-)，4.39(br，1H，-NH 2)，3.75(m，2H，-CH 2-)，3.55(m，2H，-CH 2-)，3.05(m，2H，-CH 2-)，2.75(m，2H，-CH 2-).
Embodiment 69
3-(4-(N-aminopropyl carbamyl) phenyl)-5-(2,6-dichlorobenzene alkylsulfonyl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-7-7)
Preparation method is similar to the preparation of I-7-1, obtains white solid 25mg, yield 25%, MS m/z:509.1 [M+H] +.
1H-NMR(300MHz，DMSO-d 6)δ(ppm)：8.70(s，1H，-NH-)，7.93(d，2H，J＝8.3Hz，ArH)，7.59-7.70(m，5H，ArH)，4.68(s，2H，-CH 2-)，4.39(br，1H，-NH 2)，3.71(m，2H，-CH 2-)，3.34(m，2H，-CH 2-)，2.74(m，2H，-CH 2-)，2.46(m，2H，-CH 2-)，1.74(m，2H，-CH 2-).
Embodiment 70
3-(4-(N-methoxyethyl carbamyl) phenyl)-5-(2,6-dichlorobenzene alkylsulfonyl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-7-8)
Preparation method is similar to the preparation of I-7-1, obtains white solid 35mg, yield 34%, MS m/z:510.3 [M+H] +.
1H-NMR(300MHz，DMSO-d 6)δ(ppm)：12.80(s，1H，tautomers)，8.53(s，1H，-NH-)，7.92(m，2H，ArH)，7.55-7.69(m，5H，ArH)，4.64(s，2H，-CH 2-)，4.39(br，1H，-NH-)，3.70(m，2H，-CH 2-)，3.45(m，2H，-CH 2-)，3.28(s，3H，-OCH 3)，3.17(m，2H，-CH 2-)，2.77(m，2H，-CH 2-).
Embodiment 71
3-(4-(N-sec.-propyl carbamyl) phenyl)-5-(2,6-dichlorobenzene alkylsulfonyl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-7-9)
Preparation method is similar to the preparation of I-7-1, obtains white solid 41mg, yield 40%, MS m/z:494.2 [M+H] +.
1H-NMR(300MHz，DMSO-d 6)δ(ppm)：12.88(s，1H，tautomers)，8.25(s，1H，-NH-)，7.91(m，2H，ArH)，7.56-7.69(m，5H，ArH)，4.67(s，2H，-CH 2-)，4.39(br，1H，-NH-)，3.71(m，2H，-CH 2-)，3.16(m，1H，-CH-)，3.28(s，3H，-OCH 3)，2.77(m，2H，-CH 2-)，1.17(m，6H，-CH 3×2).
Embodiment 72
3-(4-(N-ammonia butylcarbamoyl) phenyl)-5-(2,6-dichlorobenzene alkylsulfonyl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-7-10)
Preparation method is similar to the preparation of I-7-1, obtains white solid 32mg, yield 31%, MS m/z:522.2 [M+H] +.
1H-NMR(300MHz，DMSO-d 6)δ(ppm)：8.57(s，1H，-NH-)，7.92(d，2H，ArH)，7.56-7.70(m，5H，ArH)，4.67(s，2H，-CH 2-)，4.10(br，1H，-NH-)，3.66(m，2H，-CH 2-)，3.30(m，2H，-CH 2-)，2.77(m，2H，-CH 2-)，2.44(m，2H，-CH 2-)，1.57(m，2H，-CH 2-)，0.96(m，2H，-CH 2-).
Embodiment 73
3-(4-(4-piperidyl carbamyl) phenyl)-5-(2,6-dichlorobenzene alkylsulfonyl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-7-11)
Preparation method is similar to the preparation of I-7-1, obtains white solid 47mg, yield 44%, MS m/z:535.2 [M+H] +.
1H-NMR(300MHz，DMSO-d 6)δ(ppm)：8.29(s，1H，-NH-)，7.92(d，2H，J＝8.2Hz，ArH)，7.58-7.70(m，5H，ArH)，4.67(s，2H，-CH 2-)，4.29(s，2H，-CH 2-)，3.86(m，1H，piperdine)，3.83(m，2H，piperdine)，3.72(m，2H，-CH 2-)，2.97(m，2H，piperdine)，2.78(m，2H，-CH 2-)，1.77(m，2H，piperdine)，1.46(m，2H，piperdine).
Embodiment 74
3-(4-(4-hydroxyl-1-piperidine formyl base) phenyl)-5-(2,6-dichlorobenzene alkylsulfonyl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-7-12)
Preparation method is similar to the preparation of I-7-1, obtains white solid 37mg, yield 35%, MS m/z:536.2 [M+H] +.
1H-NMR(300MHz，DMSO-d 6)δ(ppm)：8.30(s，1H，-NH-)，7.91(m，2H，ArH)，7.57-7.70(m，5H，ArH)，4.78(s，1H，-OH)，4.62(s，2H，-CH 2-)，3.66(m，2H，-CH 2-)，3.46(m，4H，piperdine)，2.80(m，2H，-CH 2-)，1.78(m，2H，piperdine)，1.35(m，2H，piperdine).
Embodiment 75
3-(4-(4-hydroxyethyl-1-piperazine formyl radical) phenyl)-5-(2,6-dichlorobenzene alkylsulfonyl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-7-13)
Preparation method is similar to the preparation of I-7-1, obtains white solid 49mg, yield 44%, MS m/z:565.2 [M+H] +.
1H-NMR(300MHz，DMSO-d 6)δ(ppm)：8.28(s，1H，-NH-)，7.91(m，2H，ArH)，7.55-7.69(m，5H，ArH)，4.78(s，1H，-OH)，4.62(s，2H，-CH 2-)，4.01(m，2H，-CH 2O-)，3.66(m，2H，-CH 2-)，3.45(m，4H，piperdine)，2.80(m，2H，-CH 2-)，2.55(m，4H，piperdine)，2.45(m，2H，-CH 2-).
Embodiment 76
3-(4-(3-methylol-1-piperidine formyl base) phenyl)-5-(2,6-dichlorobenzene alkylsulfonyl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-7-14)
Preparation method is similar to the preparation of I-7-1, obtains white solid 51mg, yield 43%, MS m/z:593.2 [M+H] +.
1H-NMR(300MHz，DMSO-d 6)δ(ppm)：8.29(s，1H，-NH-)，7.90(m，2H，ArH)，7.56-7.69(m，5H，ArH)，4.68(s，2H，-CH 2-)，4.60(s，1H，-OH)，4.15(m，2H，-CH 2O-)，3.75(m，2H，-CH 2-)，3.22(m，4H，piperdine)，2.87(m，2H，-CH 2-)，1.77(m，2H，piperdine)，1.50(m，1H，piperdine)，1.25(m，2H，piperdine).
Embodiment 77
3-(4-(1-piperazine formyl radical) phenyl)-5-(2,6-difluorophenylsulphonyl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-7-15)
Preparation method is similar to the preparation of I-7-1, obtains white solid 40mg, yield 41%, MS m/z:488.3 [M+H] +.
1H-NMR(300MHz，DMSO-d 6)δ(ppm)：12.99(s，1H，pyrazole)，7.75-7.76(m，2H，ArH)，7.57-7.60(m，2H，ArH)，7.41-7.43(m，1H，ArH)，6.68-6.70(m，2H，ArH)，4.66(s，2H，-CH 2-)，3.77(m，2H，-CH 2-)，3.14(m，4H，piperidine)，2.73(m，2H，-CH 2-)，2.35(m，4H，piperdine)，2.01(s，1H，-NH-).
Embodiment 78
3-(4-(4-methyl isophthalic acid-piperazine formyl radical) phenyl)-5-(2,6-difluorophenylsulphonyl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-7-16)
Preparation method is similar to the preparation of I-7-1, obtains white solid 35mg, yield 34%, MS m/z:502.1 [M+H] +.
1H-NMR(300MHz，DMSO-d 6)δ(ppm)：12.70(s，1H，pyrazole)，7.40-7.70(m，5H，ArH)，6.75(d，2H，J＝8.5Hz，ArH)，4.54(s，2H，-CH 2-)，3.59(m，2H，-CH2)，3.15(m，4H，piperdine)，3.06(s，3H，-CH 3)，2.75(m，2H，-CH 2-)，2.25(m，4H，piperdine).
Embodiment 79
3-(4-(1-Pyrrolidine formyl radical) phenyl)-5-(2,6-difluorophenylsulphonyl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-7-17)
Preparation method is similar to the preparation of I-7-1, obtains white solid 25mg, yield 27%, MS m/z:473.2 [M+H] +.
1H-NMR(300MHz，DMSO-d 6)δ(ppm)：12.78(s，1H，tautomers)，，7.50-7.60(m，4H，ArH)，7.41-7.46(m，1H，ArH)，6.75(d，2H，J＝8.5Hz，ArH)，4.54(s，2H，-CH 2-)，3.76(m，2H，-CH 2-)，3.55(m，4H，pyrrolidine)，2.72(m，2H，-CH 2-)，1.88(m，4H，pyrrolidine).
Embodiment 80
3-(4-(1-morpholine methanoyl) phenyl)-5-(2,6-difluorophenylsulphonyl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-7-18)
Preparation method is similar to the preparation of I-7-1, obtains white solid 31mg, yield 32%, MS m/z:489.2 [M+H] +.
1H-NMR(300MHz，DMSO-d 6)δ(ppm)：12.85(s，1H，tautomers)，7.75-7.79(m，2H，ArH)，7.65(m，1H，ArH)，7.52-7.60(m，3H，ArH)，，7.10(m，1H，ArH)，4.70(s，2H，-CH 2-)，3.69(m，4H，morpholine)，3.68(m，2H，-CH 2-)，3.48(m，4H，morpholine)，2.82(m，2H，-CH 2-).
Embodiment 81
1-tertbutyloxycarbonyl-3-ethoxycarbonyl formyl radical-4-piperidone (Z-18)
NaH 1.8g (75mmol) is added respectively in the mono-neck bottle of 250mL, oxalic acid diethyl ester 5.5g (37mmol) and anhydrous THF70mL, be warming up to 80 DEG C, the anhydrous THF solution 30mL of N-Boc-piperidone 5.0g (25mmol) is slowly added dropwise under reflux state, back flow reaction 12h (solution colour is brown), stopped reaction, cooling, by in reaction solution impouring 200mL frozen water, 1mol/L aqueous hydrochloric acid adjusts PH to 6, aqueous phase is extracted with ethyl acetate 3 times (80mL × 3), merge organic phase, with anhydrous magnesium sulfate drying, suction filtration, filtrate is concentrated obtains brown oil 4.5g, yield 79%, MS m/z:228.2 [M-H] -.
Embodiment 82
3-ethoxycarbonyl-5-tertbutyloxycarbonyl-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (Z-19)
Hydrazine hydrochloride 0.5g (6mmol) is added in the mono-neck bottle of 100mL, sodium acetate 0.7g (7.5mmol), dehydrated alcohol 30mL, be warming up to 70 DEG C of reaction 1h, filtered while hot, filtrate is transferred to the mono-neck bottle of 100mL, add Z-18 1.0g (3mmol), be warming up to 70 DEG C of reaction 1h, be cooled to room temperature reaction 5h, TLC detects raw material and disappears.Stopped reaction, reaction solution evaporating column chromatography (CH 2cl 2: MeOH=30: 1) obtain white solid 0.5g, yield 56%, MS m/z:294.1 [M-H] -.
Embodiment 83
3-carboxyl-5-tertbutyloxycarbonyl-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (Z-20)
In the mono-neck bottle of 100mL, add Z-19 400mg (1.3mmol), dehydrated alcohol 30mL, add NaOH solid 163mg (3.9mmol), back flow reaction 7h, TLC detect raw material and disappear.Stopped reaction, cooling, revolves desolventizing, obtains yellow solid.Be dissolved in water, 4mol/L aqueous hydrochloric acid adjusts PH to 6, and extraction into ethyl acetate 3 times, anhydrous magnesium sulfate drying, suction filtration concentrates moral yellow solid 210mg, yield 61%, MS m/z:268.2 [M+H] +.
Embodiment 84
3-(N-(4-aminophenyl) carbamyl)-5-tertbutyloxycarbonyl-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (Z-21)
Z-20 100mg (0.4mmol) is added in the mono-neck bottle of 100mL, dry DMF 10mL, EDCI120mg (0.6mmol) and HOBT 82mg (0.6mmol) is added respectively under room temperature, room temperature reaction 15min, add Ursol D 44mg (0.4mmol), room temperature reaction 2h, TLC detect raw material and disappear.Stopped reaction, adds water, extraction into ethyl acetate 3 times, and organic phase saturated NaCl solution washing 3 times, anhydrous magnesium sulfate drying, suction filtration, revolves desolventizing, enriched material column chromatography (CH 2cl 2: MeOH=30: 1), obtain white solid 85mg yield 60%, MS m/z:358.1 [M+H] +.
Embodiment 85
3-(N-(4-(1-methyl piperidine-4-is amino) phenyl) carbamyl)-5-tertbutyloxycarbonyl-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (Z-22)
Z-21 400mg (1.20mmol) is added, 1-methyl-4-piperidone 180mg (1.44mmol), 100mL ClCH in 250mL three-necked bottle 2cH 2cl, passes into nitrogen, adds trifluoroacetic acid 0.8mL (10.0mmol), react 30min under room temperature in nitrogen atmosphere, adds NaBH (OAc) 3410mg (1.44mmol), room temperature reaction 2h, TLC detect raw material and disappear.Add 150mL water, use CH 2cl 2extract 3 times (20mL × 3), organic phase anhydrous magnesium sulfate drying, suction filtration, column chromatography (CH after filtrate is concentrated 2cl 2: MeOH=15: 1), obtain yellow solid 430mg, yield 79%, MS m/z:455.2 [M+H] +.
Embodiment 86
3-(N-(4-(1-methyl piperidine-4-is amino) phenyl) carbamyl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridines (Z-23)
Z-22 300mg (0.66mmol) is added, anhydrous CH in the mono-neck bottle of 100mL 2cl 240mL, is placed in ice bath, is added dropwise to trifluoroacetic acid 1.5mL (20mmol), and ice bath reaction 1h, dislocation room temperature reaction 1h, TLC detect raw material and disappear.Revolve desolventizing, enriched material column chromatography (CH 2cl 2: MeOH=10: 1), obtain yellow solid 200mg, yield 86%, MS m/z:354.2 [M+H] +.
Embodiment 87
3-(N-(4-(1-methyl piperidine-4-is amino) phenyl) carbamyl)-5-(2,6-dichlorobenzene alkylsulfonyl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-9-2)
Z-23 100mg (0.3mmol) is added in the mono-neck bottle of 100mL, anhydrous THF10mL, triethylamine 50mg (0.45mmol) is added dropwise under ice bath, stir 10min, slow dropping 2, the anhydrous THF solution of 6-two chloro phenylsulfonyl chloride 87mg (0.33mmol), reacts 1h under ice bath, and TLC detects raw material and disappears.Elimination salt precipitates, and column chromatography (CH2Cl2: MeOH=20: 1) after filtrate is concentrated, obtains faint yellow solid 45mg, yield 29%, MS m/z:520.1 [M+H] +.
Embodiment 88
3-(N-(4-(1-methanesulphonylpiperidine-4-is amino) phenyl) carbamyl)-5-(2,6-dichlorobenzene alkylsulfonyl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-9-1)
Preparation method is similar to the preparation of I-9-2, obtains white solid 62mg, yield 33%, MS m/z:628.2 [M+H] +.
1H-NMR(300MHz，DMSO-d 6)δ(ppm)：13.20(s，1H，pyrazole)，10.68(s，1H，-NH-)，7.67-7.74(m，2H，ArH)，7.56-7.63(m，1H，ArH)，7.41-7.49(m，2H，ArH)，6.52-6.59(m，2H，ArH)，4.59(s，2H，-CH 2-)，3.68(m，2H，-CH 2-)，3.54(s，3H，-SO 2CH 3)，2.86(m，4H，piperdine)，2.78(m，2H，-CH 2-)，2.00(m，1H，piperdine)，1.96(m，2H，piperdine)，1.40(m，2H，piperdine).
Embodiment 89
3-(N-(4-(1-methyl piperidine-4-is amino) phenyl) carbamyl)-5-(3-nitrobenzenesulfonyl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-9-3)
Preparation method is similar to the preparation of I-9-2, obtains white solid 45mg, yield 28%, MS m/z:540.3 [M+H] +.
1H-NMR(300MHz，DMSO-d 6)δ(ppm)：13.20(s，1H，pyrazole)，10.34(s，1H，-NH-)，8.52(m，1H，ArH)，8.43(s，1H，ArH)，7.25(d，1H，J＝8.0Hz，ArH)，7.93(t，1H，J＝8.0Hz，ArH)，7.58-7.70(m，2H，ArH)，6.80-7.11(m，2H，ArH)，4.42(s，2H，-CH2-)，3.52(m，2H，-CH 2-)，3.50(m，2H，piperdine)，3.26(m，1H，piperdine)，3.02(m，2H，piperdine)，2.77(m，2H，-CH 2-)，2.72(s，3H，-NCH 3)，2.10(m，2H，piperdine)，1.80(m，2H，piperdine).
Embodiment 90
3-(N-(4-(1-methyl piperidine-4-is amino) phenyl) carbamyl)-5-(3-cyanophenylsulfonyl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-9-4)
Preparation method is similar to the preparation of I-9-2, obtains white solid 52mg, yield 33%, MS m/z:520.3 [M+H] +.
1H-NMR(300MHz，DMSO-d 6)δ(ppm)：13.20(s，1H，pyrazole)，10.17(s，1H，-NH-)，8.31(s，1H，ArH)，8.12-8.20(m，2H，ArH)，7.81-7.92(m，3H，ArH)，6.99-7.20(m，2H，ArH)，4.38(s，2H，-CH 2-)，3.49(m，2H，-CH 2-)，3.44(m，2H，piperdine)，3.26(m，1H，piperdine)，3.00(m，2H，piperdine)，2.78(m，2H，-CH 2-)，2.70(s，3H，-NCH 3)，2.12(m，2H，piperdine)，1.90(m，2H，piperdine).
Embodiment 91
3-(N-(4-(1-methyl piperidine-4-is amino) phenyl) carbamyl)-5-(3-tnBuoromethyl-benzenesulfonyl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-9-5)
Preparation method is similar to the preparation of I-9-2, obtains white solid 43mg, yield 26%, MS m/z:563.2 [M+H] +.
1H-NMR(300MHz，DMSO-d 6)δ(ppm)：13.20(s，1H，pyrazole)，10.27(s，1H，-NH-)，8.09-8.16(m，2H，ArH)，8.01(s，1H，ArH)，7.88(t，1H，J＝7.7Hz，ArH)，7.60-7.69(m，2H，ArH)，6.75-6.95(m，2H，ArH)，4.40(s，2H，-CH 2-)，3.52(m，2H，-CH 2-)，3.44(m，2H，piperdine)，3.39(m，1H，piperdine)，3.05(m，2H，piperdine)，2.73(m，2H，-CH 2-)，2.71(s，3H，-NCH 3)，2.02(m，2H，piperdine)，1.80(m，2H，piperdine).
Embodiment 92
3-(N-(4-(1-methyl piperidine-4-is amino) phenyl) carbamyl)-5-(2,3-dichlorobenzene alkylsulfonyl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-9-6)
Preparation method is similar to the preparation of I-9-2, obtains white solid 55mg, yield 33%, MS m/z:564.2 [M+H] +.
1H-NMR(300MHz，DMSO-d 6)δ(ppm)：13.20(s，1H，pyrazole)，10.06(s，1H，-NH-)，8.06(d，1H，J＝7.8Hz，ArH)，7.98(d，1H，J＝8.0Hz，ArH)，7.58-7.71(m，3H，ArH)，6.80-7.11(m，2H，ArH)，4.55(s，2H，-CH 2-)，3.67(m，2H，-CH 2-)，3.45(m，2H，piperdine)，3.27(m，1H，piperdine)，2.96(m，2H，piperdine)，2.77(m，2H，-CH 2-)，2.71(s，3H，-NCH 3)，2.11(m，2H，piperdine)，1.90(m，2H，piperdine).
Embodiment 93
3-(N-(4-(4-piperidines is amino) phenyl) carbamyl)-5-(2-chlorobenzenesulfonyl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-9-7)
Preparation method is similar to the preparation of I-9-2, obtains white solid 67mg, yield 43%, MS m/z:516.2 [M+H] +.
1H-NMR(300MHz，DMSO-d 6)δ(ppm)：13.20(s，1H，pyrazole)，9.58(s，1H，-NH-)，7.06-7.09(m，1H，ArH)，7.78-7.82(m，1H，ArH)，7.61-7.70(m，2H，ArH)，7.42(d，2H，J＝8.7Hz，ArH)，6.53(d，2H，J＝8.7Hz，ArH)，5.20(s，1H，-NH-)，4.50(s，2H，-CH 2-)，4.28(s，1H，-NH-)，3.63(m，1H，piperdine)，3.53(m，2H，-CH 2-)，3.32(m，2H，piperdine)，2.97(m，2H，piperdine)，2.75(m，2H，-CH 2-)，1.86(m，2H，piperdine)，1.30(m，2H，piperdine).
Embodiment 94
3-(N-(4-(4-piperidines is amino) phenyl) carbamyl)-5-(3-cyanophenylsulfonyl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-9-8)
Preparation method is similar to the preparation of I-9-2, obtains white solid 78mg, yield 51%, MS m/z:506.3 [M+H] +.
1H-NMR(300MHz，DMSO-d 6)δ(ppm)：13.20(s，1H，pyrazole)，10.17(s，1H，-NH-)，8.31(s，1H，ArH)，8.12-8.20(m，2H，ArH)，7.81-7.92(m，3H，ArH)，6.99-7.20(m，2H，ArH)，4.42(s，2H，-CH 2-)，3.65(m，1H，piperdine)，3.53(m，2H，-CH 2-)，3.32(m，2H，piperdine)，2.92(m，2H，piperdine)，2.76(m，2H，-CH 2-)，2.08(m，2H，piperdine)，1.88(m，2H，piperdine).
Embodiment 95
3-(N-(4-(4-piperidines is amino) phenyl) carbamyl)-5-(3-tnBuoromethyl-benzenesulfonyl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-9-9)
Preparation method is similar to the preparation of I-9-2, obtains white solid 67mg, yield 41%, MS m/z:549.2 [M+H] +.
1H-NMR(300MHz，DMSO-d 6)δ(ppm)：13.20(s，1H，pyrazole)，10.22(s，1H，-NH-)，9.14(s，1H，ArH)，8.89(s，1H，ArH)，8.11-8.17(m，2H，ArH)，8.01(s，1H，ArH)，7.86-7.91(m，2H，ArH)，7.10-7.30(m，1H，ArH)，4.42(s，2H，-CH 2-)，3.65(m，1H，piperdine)，3.53(m，2H，-CH 2-)，3.32(m，2H，piperdine)，2.92(m，2H，piperdine)，2.76(m，2H，-CH 2-)，2.08(m，2H，piperdine)，1.88(m，2H，piperdine).
Embodiment 96
3-(N-(4-(4-tetrahydropyrans is amino) phenyl) carbamyl)-5-(2,6-dichlorobenzene alkylsulfonyl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-9-10)
Preparation method is similar to the preparation of I-9-2, obtains white solid 56mg, yield 34%, MS m/z:551.1 [M+H] +.
1H-NMR(300MHz，DMSO-d 6)δ(ppm)：13.17(s，1H，pyrazole)，9.63(s，1H，-NH-)，7.69-7.70(m，2H，ArH)，7.56-7.61(m，1H，ArH)，7.46(d，2H，J＝8.4Hz，ArH)，6.56(d，2H，J＝8.4Hz，ArH)，5.30(br，1H，-NH-)，4.59(s，2H，-CH 2-)，3.88(m，2H，morpholine)，3.69(m，2H，-CH 2-)，3.39(m，1H，morpholine)，3.36(m，2H，morpholine)，2.78(m，2H，-CH 2-)，1.86(m，2H，piperdine)，1.40(m，2H，piperdine).
Embodiment 97
3-(N-(4-(hydroxyl kharophen) phenyl) carbamyl)-5-(2,6-dichlorobenzene alkylsulfonyl)-4,5,6,7-tetrahydrochysene-1H-pyrrole also [4,3-c] pyridine (I-9-11)
Preparation method is similar to the preparation of I-9-2, obtains white solid 66mg, yield 42%, MS m/z:525.2 [M+H] +.
1H-NMR(300MHz，DMSO-d 6)δ(ppm)：13.25(s，1H，pyrazole)，9.99(s，1H，-NH-)，9.59(s，1H，-NH-)，7.68-7.74(m，4H，ArH)，7.56-7.63(m，3H，ArH)，5.63(br，1H，-OH)，4.61(s，2H，-CH 2-)，3.97(s，2H，-CH 2OH)，3.70(m，2H，-CH 2-)，2.80(m，2H，-CH 2-).
Embodiment 98
3-(N-(4-(hydroxyl kharophen) phenyl) carbamyl)-5-(2,3-dichlorobenzene alkylsulfonyl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-9-12)
Preparation method is similar to the preparation of I-9-2, obtains white solid 45mg, yield 29%, MS m/z:525.3 [M+H] +.
1H-NMR(300MHz，DMSO-d 6)δ(ppm)：13.20(s，1H，pyrazole)，10.06(m，1H，-NH-)，9.60(s，1H，-NH-)，8.06(d，1H，J＝7.8Hz，ArH)，7.98(d，1H，J＝8.0Hz，ArH)，7.58-7.71(m，2H，ArH)，6.80-7.11(m，3H，ArH)，4.55(s，2H，-CH 2-)，3.97(s，2H，-CH 2OH)，3.67(m，2H，-CH 2-)，2.76(m，2H，-CH 2-).
Embodiment 99
3-(N-(4-(hydroxyl kharophen) phenyl) carbamyl)-5-(3-nitrobenzenesulfonyl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-9-13)
Preparation method is similar to the preparation of I-9-2, obtains white solid 48mg, yield 32%, MS m/z:501.1 [M+H] +.
1H-NMR(300MHz，DMSO-d 6)δ(ppm)：13.21(s，1H，pyrazole)，10.05(s，1H，-NH-)，9.62(s，1H，-NH-)，8.52(m，1H，ArH)，8.44(s，1H，ArH)，7.26(d，1H，J＝7.8Hz，ArH)，7.92(t，1H，J＝8.0Hz，ArH)，7.72(d，1H，J＝8.9Hz，ArH)，7.63(d，1H，J＝8.7Hz，ArH)，4.42(s，2H，-CH 2-)，4.00(s，2H，-CH 2OH)，3.52(m，2H，-CH 2-)，2.75(m，2H，-CH 2-).
Embodiment 100
3-(N-(4-(hydroxyl kharophen) phenyl) carbamyl)-5-(3-cyanophenylsulfonyl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-9-14)
Preparation method is similar to the preparation of I-9-2, obtains white solid 53mg, yield 37%, MS m/z:481.2 [M+H] +.
1H-NMR(300MHz，DMSO-d 6)δ(ppm)：13.22(s，1H，pyrazole)，10.01(s，1H，-NH-)，9.62(s，1H，-NH-)，8.31(s，1H，ArH)，8.12-8.19(m，2H，ArH)，7.83(t，1H，J＝8.0Hz，ArH)，7.62(d，2H，J＝8.9Hz，ArH)，7.50(d，2H，J＝7.9Hz，ArH)，4.38(s，2H，-CH 2-)，3.97(s，2H，-CH 2OH)，3.49(m，2H，-CH 2-)，2.75(m，2H，-CH 2-).
Embodiment 101
3-(N-(4-(hydroxyl kharophen) phenyl) carbamyl)-5-(3-tnBuoromethyl-benzenesulfonyl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-9-15)
Preparation method is similar to the preparation of I-9-2, obtains white solid 59mg, yield 38%, MS m/z:524.2 [M+H] +.
1H-NMR(300MHz，DMSO-d 6)δ(ppm)：13.19(s，1H，pyrazole)，10.04(m，1H，-NH-)，9.62(s，1H，-NH-)，8.11-8.16(m，2H，ArH)，8.08(s，1H，ArH)，7.86(m，1H，ArH)，7.70-7.74(m，2H，ArH)，7.61-7.64(m，2H，ArH)，4.41(s，2H，-CH 2-)，3.97(s，2H，-CH 2OH)，3.52(m，2H，-CH 2-)，2.76(m，2H，-CH 2-).
Embodiment 102
3-(N-(4-(1-Acetylpiperidin-4-is amino) phenyl) carbamyl)-5-(2,6-dichlorobenzene alkylsulfonyl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-9-16)
Preparation method is similar to the preparation of I-9-2, obtains white solid 66mg, yield 37%, MS m/z:592.2 [M+H] +.
1H-NMR(300MHz，DMSO-d 6)δ(ppm)：13.25(s，1H，pyrazole)，9.59(s，1H，-NH-)，7.68-7.74(m，4H，ArH)，7.56-7.63(m，3H，ArH)，5.79(br，1H，-NH-)，4.57(s，2H，-CH 2-)，4.23(m，1H，piperdine)，3.76(m，1H，piperdine)，3.66(m，2H，-CH2-)，3.51(m，1H，piperdine)，3.11(m，1H，piperdine)，2.82(m，1H，piperdine)，2.72(m，2H，-CH 2-).2.00(s，3H，-COCH 3)，1.90(m，2H，piperdine)，1.30(m，2H，piperdine).
Embodiment 103
3-(N-(4-(1-Acetylpiperidin-4-is amino) phenyl) carbamyl)-5-(3-tnBuoromethyl-benzenesulfonyl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-9-17)
Preparation method is similar to the preparation of I-9-2, obtains white solid 56mg, yield 32%, MS m/z:591.1 [M+H] +.
1H-NMR(300MHz，DMSO-d 6)δ(ppm)：13.03(s，1H，pyrazole)，10.48(m，1H，-NH-)，8.11-8.16(m，2H，ArH)，8.08(s，1H，ArH)，7.86(m，1H，ArH)，7.70-7.74(m，2H，ArH)，7.61-7.64(m，2H，ArH)，4.35(s，2H，-CH 2-)，4.25(m，1H，piperdine)，3.79(m，1H，piperdine)，3.47(m，2H，-CH 2-)，3.47(m，1H，piperdine)，3.16(m，1H，piperdine)，2.80(m，1H，piperdine)，2.71(m，2H，-CH 2-).2.01(s，3H，-COCH 3)，1.92(m，2H，piperdine)，1.25(m，2H，piperdine).
Embodiment 104
3-(N-(4-(1-methylpiperazine base) phenyl) carbamyl)-5-(2,6-dichlorobenzene alkylsulfonyl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-9-18)
Preparation method is similar to the preparation of I-9-2, obtains white solid 72mg, yield 43%, MS m/z:564.2 [M+H] +.
1H-NMR(300MHz，DMSO-d 6)δ(ppm)：13.44(s，1H，pyrazole)，9.80(m，1H，-NH-)，7.67-7.70(m，2H，ArH)，7.56-7.63(m，3H，ArH)，6.86-6.89(m，1H，ArH)，4.60(s，2H，-CH 2-)，3.68(m，2H，-CH 2-)，3.16(s，3H，-NCH 3-)，3.08(m，4H，piperdine)，2.79(m，2H，-CH 2-)，2.46(m，4H，piperdine).
Embodiment 105
3-(N-(4-carbethoxy phenyl) carbamyl)-5-tertbutyloxycarbonyl-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (Z-24)
Z-20100mg (0.4mmol) is added in the mono-neck bottle of 100mL, dry DMF 10mL, EDCI120mg (0.6mmol) and HOBT 82mg (0.6mmol) is added respectively under room temperature, room temperature reaction 15min, add Benzocaine 66mg (0.4mmol), room temperature reaction 2h, TLC detect raw material and disappear.Stopped reaction, adds water, extraction into ethyl acetate 3 times, organic phase saturated NaCl solution washing 3 times, anhydrous magnesium sulfate drying, suction filtration, revolves desolventizing, enriched material column chromatography (PE: EA=3: 1), obtains white solid 80mg yield 48%, MS m/z:415.1 [M+H] +.
Embodiment 106
3-(N-(4-carbethoxy phenyl) carbamyl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridines (Z-25)
Z-24300mg (0.72mmol) is added, anhydrous CH in the mono-neck bottle of 100mL 2cl 240mL, is placed in ice bath, is added dropwise to trifluoroacetic acid 1.5mL (20mmol), and ice bath reaction 1h, dislocation room temperature reaction 1h, TLC detect raw material and disappear.Revolve desolventizing, enriched material column chromatography (CH 2cl 2: MeOH=10: 1), obtain yellow solid 190mg, yield 88%, MS m/z:315.2 [M+H] +.
Embodiment 107
3-(N-(4-carbethoxy phenyl) carbamyl)-5-(2,6-dichlorobenzene alkylsulfonyl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (Z-26)
Z-25100mg (0.3mmol) is added in the mono-neck bottle of 100mL, anhydrous THF10mL, triethylamine 50mg (0.45mmol) is added dropwise under ice bath, stir 10min, slow dropping 2, the anhydrous THF solution of 6-two chloro phenylsulfonyl chloride 87mg (0.33mmol), reacts 1h under ice bath, and TLC detects raw material and disappears.Elimination salt precipitates, column chromatography (CH after filtrate is concentrated 2cl 2: MeOH=20: 1), obtain faint yellow solid 55mg, yield 35%, MS m/z:524.1 [M+H] +.
Embodiment 108
3-(N-(4-carboxyl phenyl) carbamyl)-5-(2,6-dichlorobenzene alkylsulfonyl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (Z-27)
In the mono-neck bottle of 100mL, add Z-26400mg (0.76mmol), dehydrated alcohol 30mL, add NaOH solid 92mg (2.3mmol), back flow reaction 7h, TLC detect raw material and disappear.Stopped reaction, cooling, revolves desolventizing, obtains yellow solid.Be dissolved in water, 4mol/L aqueous hydrochloric acid adjusts PH to 6, and extraction into ethyl acetate 3 times, anhydrous magnesium sulfate drying, suction filtration concentrates moral yellow solid 260mg, yield 69%, MS m/z:496.2 [M+H] +.
Embodiment 109
3-(N-(4-(N-hydroxyethylcarbamoyl) phenyl) carbamyl)-5-(2,6-dichlorobenzene alkylsulfonyl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-9-19)
Z-27100mg (0.2mmol) is added in the mono-neck bottle of 100mL, dry DMF 10mL, TFFH90mg (0.3mmol) and DIEA 90mg (0.6mmol) is added respectively under room temperature, room temperature reaction 15min, add thanomin 19mg (0.3mmol), room temperature reaction 2h, TLC detect raw material and disappear.Stopped reaction, adds water, extraction into ethyl acetate 3 times, and organic phase saturated NaCl solution washing 3 times, anhydrous magnesium sulfate drying, suction filtration, revolves desolventizing, enriched material column chromatography (CH 2cl 2: MeOH=30: 1), obtain white solid 35mg yield 34%, MS m/z:520.1 [M+H] +.
Embodiment 110
3-(N-(4-(4-methyl isophthalic acid-piperazine formyl radical) phenyl) carbamyl)-5-(2,6-dichlorobenzene alkylsulfonyl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-9-20)
Preparation method is similar to the preparation of I-9-19, obtains white solid 72mg, yield 63%, MS m/z:577.2 [M+H] +.
1H-NMR(300MHz，DMSO-d 6)δ(ppm)：13.31(s，1H，tautomers)，10.28(m，1H，-NH-)，7.90(d，2H，J＝8.4Hz，ArH)，7.68-7.70(m，1H，ArH)，7.49-7.55(m，1H，ArH)，7.39(d，2H，J＝8.4Hz，ArH)，7.18-7.22(m，1 H，ArH)，4.62(s，2H，-CH 2-)，3.68(m，2H，-CH 2-)，3.68(m，4H，piperdine)，3.20(s，3H，-NCH 3-)，2.81(m，4H，piperdine)，2.75(m，2H，-CH 2-).
Embodiment 111
3-(N-(4-(3-methylol-1-piperidine formyl base) phenyl) carbamyl)-5-(2,6-dichlorobenzene alkylsulfonyl) 4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-9-21)
Preparation method is similar to the preparation of I-9-19, obtains white solid 56mg, yield 47%, MS m/z:593.2 [M+H] +.
1H-NMR(300MHz，DMSO-d 6)δ(ppm)：13.31(s，1H，tautomers)，10.31(m，1H，-NH-)，7.95(s，1H，ArH)，7.92(s，1H，ArH)，7.76(m，1H，ArH)，7.74(s，1H，ArH)，7.62-7.66(m，1H，ArH)，7.40(s，1H，ArH)，7.37(s，1H，ArH)，4.68(s，2H，-CH 2-)，4.60(s，1H，-OH)，4.15(m，2H，-CH 2O-)，3.75(m，2H，-CH 2-)，3.22(m，4H，piperdine)，2.87(m，2H，-CH 2-)，1.77(m，2H，piperdine)，1.50(m，1H，piperdine)，1.25(m，2H，piperdine).
Embodiment 112
3-(N-(4-(4-hydroxyl-1-piperidine formyl base) phenyl) carbamyl)-5-(2,6-dichlorobenzene alkylsulfonyl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-9-22)
Preparation method is similar to the preparation of I-9-19, obtains white solid 55mg, yield 47%, MS m/z:588.3 [M+H] +.
1H-NMR(300MHz，DMSO-d 6)δ(ppm)：13.34(s，1H，tautomers)，10.25(m，1H，-NH-)，7.89(s，1H，ArH)，7.86(s，1H，ArH)，7.77(m，1H，ArH)，7.68(s，1H，ArH)，7.59-7.62(m，1H，ArH)，7.35(s，1H，ArH)，7.32(s，1H，ArH)，4.78(s，1H，-OH)，4.62(s，2H，-CH 2-)，3.66(m，2H，-CH 2-)，3.46(m，4H，piperdine)，2.80(m，2H，-CH 2-)，1.78(m，2H，piperdine)，1.35(m，2H，piperdine).
Embodiment 113
3-(N-(4-(1-piperazine formyl radical) phenyl) carbamyl)-5-(2,6-dichlorobenzene alkylsulfonyl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-9-23)
Preparation method is similar to the preparation of I-9-19, obtains white solid 45mg, yield 40%, MS m/z:564.2 [M+H] +.
1H-NMR(300MHz，DMSO-d 6)δ(ppm)：13.19(s，1H，pyrazole)，9.80(m，1H，-NH-)，7.67-7.70(m，2H，ArH)，7.56-7.64(m，3H，ArH)，6.86-6.89(m，2H，ArH)，4.60(s，2H，-CH 2-)，3.69(m，2H，-CH 2-)，3.68(m，4H，piperdine)，3.06(m，4H，piperdine)，2.75(m，2H，-CH 2-).
Embodiment 114
(S)-(+)-3-(N-(4-(1-(2-pyrrolidinomethyl) Pyrrolidine formyl radical) phenyl) carbamyl)-5-(2; 6-dichlorobenzene alkylsulfonyl)-4; 5; 6; 7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-9-24)
Preparation method is similar to the preparation of I-9-19, obtains white solid 56mg, yield 44%, MS m/z:632.2 [M+H] +.
1H-NMR(300MHz，DMSO-d 6)δ(ppm)：13.44(s，1H，pyrazole)，10.21(m，1H，-NH-)，7.90-7.93(m，2H，ArH)，7.68-7.71(m，3H，ArH)，7.53-7.62(m，2H，ArH)，4.62(s，2H，-CH 2-)，3.70(m，2H，-CH 2-)，3.62(m，2H，pyrrolidine)，3.42(m，2H，pyrrolidine)，3.16(m，2H，-CH 2-)，3.05(m，4H，pyrrolidine)，3.06(m，4H，piperdine)，2.81(m，2H，-CH 2-)，1.90(m，6H，piperdine)，1.77(m，1H，piperdine).
Embodiment 115
3-(N-(4-(4-methylol-1-piperidine formyl base) phenyl) carbamyl)-5-(2,6-dichlorobenzene alkylsulfonyl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-9-25)
Preparation method is similar to the preparation of I-9-19, obtains white solid 57mg, yield 47%, MS m/z:593.3 [M+H] +.
1H-NMR(300MHz，DMSO-d 6)δ(ppm)：13.44(s，1H，pyrazole)，10.25(m，1H，-NH-)，7.86-7.89(m，2H，ArH)，7.68-7.71(m，2H，ArH)，7.57-7.60(m，1H，ArH)，7.31-7.34(m，2H，ArH)，4.62(s，2H，-CH 2-)，4.49(s，1H，-OH)，3.70(m，2H，-CH2-)，2.29(m，2H，-CH 2O-)，3.16(m，4H，piperdine)，2.80(m，2H，-CH 2-)，1.00-1.40(m，5H，piperdine).
Embodiment 116
3-(N-(4-(N-aminopropyl carbamyl) phenyl) carbamyl)-5-(2,6-dichlorobenzene alkylsulfonyl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-9-26)
Preparation method is similar to the preparation of I-9-19, obtains white solid 41mg, yield 37%, MS m/z:552.2 [M+H] +.
1H-NMR(300MHz，DMSO-d 6)δ(ppm)：13.44(s，1H，pyrazole)，10.26(m，1H，-NH-)，7.86-7.88(m，2H，ArH)，7.68-7.70(m，2H，ArH)，7.57-7.60(m，1H，ArH)，7.31-7.34(m，2H，ArH)，4.68(s，2H，-CH 2-)，4.39(br，2H，-NH 2)，3.71(m，2H，-CH 2-)，3.34(m，2H，-CH 2-)，2.74(m，2H，-CH 2-)，2.46(m，2H，-CH 2-)，1.74(m，2H，-CH 2-).
Embodiment 117
3-(N-(4-(N-methoxycarbonyl propyl carbamyl) phenyl) carbamyl)-5-(2,6-dichlorobenzene alkylsulfonyl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-9-27)
Preparation method is similar to the preparation of I-9-19, obtains white solid 43mg, yield 38%, MS m/z:567.2 [M+H] +.
1H-NMR(300MHz，DMSO-d 6)δ(ppm)：13.44(s，1H，pyrazole)，10.28(m，1H，-NH-)，8.42(m，1H，-NH-)，7.86-7.88(m，2H，ArH)，7.68-7.70(m，2H，ArH)，7.57-7.60(m，1H，ArH)，7.31-7.34(m，2H，ArH)，4.63(s，2H，-CH 2-)，3.70(m，2H，-CH 2-)，3.37(s，3H，-OCH 3)，3.36(m，2H，-CH 2O-)，3.30(m，2H，-CH 2-)，2.81(m，2H，-CH 2-)，1.75(m，2H，-CH 2-).
Embodiment 118
N-third cyano group-N-tertbutyloxycarbonyl-alanine ethyl ester (Z-29)
Alanine ethyl ester hydrochloride 14.0g (91mmol) is added respectively in the mono-neck bottle of 250mL, NaOH 3.8g (95mmol) and methyl alcohol 150mL, be warming up to 70 DEG C, slowly be added dropwise to propylene cyanogen 6.4g (120mmol), back flow reaction 4h, stopped reaction, be cooled to room temperature, slowly be added dropwise to Boc acid anhydrides 18.0g (82mmol), room temperature reaction 3h, suction filtration, filtrate concentrates, acetic acid ethyl dissolution, organic phase washes 3 times, with anhydrous magnesium sulfate drying, suction filtration, filtrate is concentrated obtains colorless oil 9.5g, yield 63%, MS m/z:269.2 [M-H] -.
Embodiment 119
1-tertbutyloxycarbonyl-3-cyano group-4-piperidone (Z-30)
NaH 0.5g (20mmol) and dry toluene 70mL is added respectively in the mono-neck bottle of 250mL, be warming up to 120 DEG C, the anhydrous toluene solution 30mL of Z-29 4.0g (15mmol) is slowly added dropwise under reflux state, (solution colour is brown to back flow reaction 12h, separate out solid gradually), stopped reaction, cooling, by in reaction solution impouring 200mL frozen water, reaction 30min, leave standstill, separate aqueous phase, aqueous phase petroleum ether extraction 2 times, PH to 6 adjusted by aqueous phase acetic acid, extraction into ethyl acetate 3 times (80mL × 3), merge organic phase, with anhydrous magnesium sulfate drying, suction filtration, filtrate is concentrated obtains yellow oil 2.0g, yield 61%, MS m/z:223.2 [M-H] -.
Embodiment 120
3-amino-5-tertbutyloxycarbonyl-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (Z-31)
Hydrazine hydrochloride 0.5g (6.0mmol) is added in the mono-neck bottle of 100mL, sodium acetate 0.6g (6.0mmol), dehydrated alcohol 30mL, be warming up to 70 DEG C of reaction 1h, filtered while hot, filtrate is transferred to the mono-neck bottle of 100mL, add Z-30 1.0g (4.5mmol), be warming up to 70 DEG C of reaction 1h, be cooled to room temperature reaction 5h, TLC detects raw material and disappears.Stopped reaction, reaction solution evaporating column chromatography (CH 2cl 2: MeOH=20: 1) obtain red solid 0.4g, yield 40%, MS m/z:237.1 [M-H] -.
Embodiment 121
1-ethoxycarbonyl-3-amino-5-tertbutyloxycarbonyl-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (Z-32)
Z-31 0.5g (1.8mmol) and anhydrous THF 30mL is added respectively in 100mL mono-neck bottle, the anhydrous THF solution 10mL of Vinyl chloroformate 0.3g (1.8mmol) is slowly added dropwise at 0 DEG C, 0 DEG C of reaction 2h, is warming up to room temperature reaction 2h, and TLC detects raw material and disappears.Stopped reaction, suction filtration, filtrate is concentrated obtains white solid 0.3g through column chromatography (PE: EA=3: 1), yield 54%, MSm/z:309.2 [M-H] -.
Embodiment 122
1-ethoxycarbonyl-3-iodo-5-tertbutyloxycarbonyl-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (Z-33)
Elemental iodine 0.2g (0.72mmol) and anhydrous CH is added respectively in 100mL mono-neck bottle 2cl 220mL, is slowly added dropwise to Isopentyl nitrite 0.15g (1.2mmol) under room temperature, reaction 10min, is slowly added dropwise to the anhydrous CH of Z-32 0.2g (0.6mmol) 2cl 2solution 10mL, is warming up to 28 DEG C of reactions 1h, TLC and detects raw material disappearance.Stopped reaction, reaction solution adds saturated aqueous sodium thiosulfate, CH 2cl 2extract 3 times (10mL × 3), merge organic phase, with anhydrous magnesium sulfate drying, suction filtration, filtrate is concentrated obtains white solid 0.05g through column chromatography (PE: EA=10: 1), yield 20%, MS m/z:421.2 [M+H] +.
Embodiment 123
The iodo-5-of 1-ethoxycarbonyl-3-(2,6-dichlorobenzene alkylsulfonyl-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (Z-34)
Z-33 50mg (0.1mmol) is added, anhydrous CH in the mono-neck bottle of 100mL 2cl 240mL, is placed in ice bath, is added dropwise to trifluoroacetic acid 1mL (20mmol), and ice bath reaction 1h, dislocation room temperature reaction 1h, TLC detect raw material and disappear.Revolve desolventizing, enriched material column chromatography (PE: EA=1: 1), obtains yellow solid 45mg, stand-by.
Above-mentioned yellow solid 45mg (0.1mmol) is added in 100mL mono-neck bottle, anhydrous THF10mL, triethylamine 30mg (0.3mmol) is added dropwise under ice bath, stir 10min, slow dropping 2, the anhydrous THF solution of 6-two chloro phenylsulfonyl chloride 30mg (0.11mmol), reacts 1h under ice bath, and TLC detects raw material and disappears.Elimination salt precipitates, and column chromatography (PE: EA=10: 1) after filtrate is concentrated, obtains faint yellow solid 20mg, yield 38%, MS m/z:531.1 [M+H] +.
Embodiment 124
3-(1-methyl-4-pyrazoles formamido group)-5-(2,6-dichlorobenzene alkylsulfonyl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-10-1)
Preparation method is similar to the preparation of Z-21, obtains white solid 30mg, yield 46%, MS m/z:455.2 [M+H] +.
1H-NMR(300MHz，DMSO-d 6)δ(ppm)：13.19(s，1H，pyrazole)，9.80(m，1H，-NH-)，8.54(m，2H，ArH)，7.67-7.70(m，3H，ArH)，4.60(s，2H，-CH 2-)，3.69(m，2H，-CH 2-)，2.85(s，3H，-CH 3)，2.75(m，2H，-CH 2-).
Embodiment 125
3-(4-(1-piperidin-4-yl) pyrazolyl)-5-(2,6-dichlorobenzene alkylsulfonyl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-11-1)
Z-34 64mg (0.1mmol), 1-(1-t-butoxycarbonylpiperidin-4-base) pyrazoles-4-boric acid pinacol ester 55mg (0.12mmol), cesium carbonate 120mg (0.3mmol), dioxane and pure water (dioxane: pure water=10: 1) 5mL is added respectively in 100mL three-necked bottle, under nitrogen atmosphere, add Pd (dppf) Cl 24mg (0.004mmol), is warming up to 80 DEG C of reactions 4h, TLC and detects raw material disappearance.Suction filtration, column chromatography (CH after filtrate is concentrated 2cl 2: MeOH=30: 1), obtain yellow oil 20mg, then slough through trifluoroacetic acid and protect to obtain brown solid 6mg, yield 12%, MS m/z:482.2 [M+H] +.
1H-NMR(300MHz，DMSO-d 6)δ(ppm)：13.44(s，1H，pyrazole)，8.68-8.72(m，2H，ArH)，7.86-7.88(m，3H，ArH)，4.63(s，2H，-CH 2-)，3.70(m，2H，-CH 2-)，3.45(s，3H，-CH 3)，2.81(m，2H，-CH 2-).4.42(s，2H，-CH 2-)，3.65(m，1H，piperdine)，3.53(m，2H，-CH 2-)，3.32(m，2H，piperdine)，2.92(m，2H，piperdine)，2.76(m，2H，-CH 2-)，2.08(m，2H，piperdine)，1.88(m，2H，piperdine).

Claims (8)

1. the compound of general formula (I) or its pharmacy acceptable salt:
Wherein X represents-CR 1r2-,-SO 2-or-CO-, wherein R 1, R 2represent hydrogen, halogen, alkyl, aryl or Het independently of one another;
Y represents-NR 3cO-,-CONR 4-, wherein R 3, R 4represent hydrogen, alkyl, aryl or Het independently of one another;
Q 1represent alkyl, aryl or Het;
Q 2represent aryl or Het;
R represents hydrogen, hydroxyl, alkyl ,-CONR 5r 6,-CONR 5(CH 2) nnR 6,-CONR 5(CH 2) noR 6,-NR 5cOR 6,-NR 5r 6,-NR 5(CH 2) nnR 6,-NR 5(CH 2) noR 6,-CR 5r 6, aryl or Het, wherein n=1,2,3,4 or 5, R 5, R 6represent hydrogen, alkyl, aryl or Het independently of one another;
Alkyl is the straight or branched saturated hydrocarbyl with 1-6 carbon atom; Or for having the cyclic saturated hydrocarbon base of 3-6 carbon atom; Or for connecting the cyclic saturated hydrocarbon base with 3-6 carbon atom with the straight or branched saturated hydrocarbyl of 1-6 carbon atom;
Aryl is the carbocyclic ring being selected from phenyl, naphthyl, acenaphthenyl or tetralyl, it is optionally replaced by 1,2 or 3 substituting group separately, and each substituting group is independently selected from hydrogen, alkyl, cyano group, halogen, nitro, haloalkyl, hydroxyl, sulfydryl, alkoxyl group, alkylthio, alkoxyalkyl, aralkyl, alkyl diaryl, aryl or Het;
Het is the monocyclic heterocycles being selected from piperidyl, pyrryl, pyrazolyl, imidazolyl, furyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrimidyl, pyrazinyl or pyridazinyl; Or be selected from quinolyl, quinoxalinyl, indyl, benzimidazolyl-, benzoxazolyl, benzoisoxazole base, benzothiazolyl, benzisothiazole base, benzofuryl, benzothienyl, 2,3-dihydrobenzo [1,4] bicyclic heterocycle of dioxine base or benzo [1,3] dioxa cyclopentenyl; Each monocycle or bicyclic heterocycle are optionally replaced by 1,2 or 3 substituting group, and each substituting group is independently selected from halogen, haloalkyl, hydroxyl, alkyl or alkoxyl group;
Halogen is the substituting group being selected from fluorine, chlorine, bromine or iodine.
2. the compound of claim 1, is characterized in that:
Wherein X represents-SO 2-or-CO-;
Y represents-NR 3cO-,-CONR 4-, wherein R 3, R4 represents hydrogen, alkyl independently of one another;
Q 1represent alkyl, aryl or Het;
Q 2represent aryl or Het;
R represents hydrogen, hydroxyl, alkyl ,-CONR 5r 6,-CONR 5(CH 2) nn R 6,-CONR 5(CH 2) no R 6,-NR 5cOR 6,-NR 5r 6,-NR 5(CH 2) nnR 6,-NR 5(CH2) noR 6,-CR 5r 6, aryl or Het, wherein n=1,2,3,4 or 5, R 5, R 6represent hydrogen, alkyl, aryl or Het independently of one another.
3. the compound of claim 2, is characterized in that:
Wherein X represents-SO 2-or-CO-;
Y represents-NR 3cO-,-CONR 4-, wherein R 3, R 4represent hydrogen, alkyl independently of one another;
Q 1be selected from following aromatic ring, fragrant heterocycle, replace aromatic ring or replace fragrant heterocycle: phenyl, naphthyl, pyrryl, pyrazolyl, imidazolyl, furyl, thienyl, pyridyl, pyrimidyl, quinolyl, isoquinolyl, substituting group can be 1 ~ 3 alkylamino, nitro, cyano group, halogen or trifluoromethyl;
Q 2be selected from following aromatic ring, fragrant heterocycle, replace aromatic ring or replace fragrant heterocycle: phenyl, pyrazolyl, furyl, substituting group can be 1 ~ 3 alkylamino, nitro, cyano group, halogen or trifluoromethyl;
R represents hydrogen, hydroxyl, alkyl ,-NR 5cOR6 ,-NR 5r 6,-NR 5(CH 2) nnR 6,-NR 5(CH 2) noR 6,-CR 5r 6, aryl or Het, wherein n=1,2,3,4 or 5, R 5, R 6represent hydrogen, alkyl, aryl or Het independently of one another.
4. the compound of claim 3, is characterized in that:
Wherein X represents-SO 2-;
Y represents-NHCO-,-CONH-;
Q 1represent 2,6-trichlorophenyl;
Q 2be selected from following aromatic ring, fragrant heterocycle, replace aromatic ring or replace fragrant heterocycle: phenyl, pyrazolyl, furyl, substituting group can be 1 ~ 3 alkylamino, nitro, cyano group, halogen or trifluoromethyl;
R represents hydrogen, hydroxyl ,-COR 7,-NHR 8, wherein R 7represent hydrogen, hydroxyl, piperidyl, piperazinyl, N methyl piperazine base, Pyrrolidine base, morpholinyl, hydroxyethylamino, second diamino, the third diamino, fourth diamino, methoxy ethylamino, isopropylamino, piperidines amino, 4-hydroxy piperidine base, N-hydroxyethyl piperazine base, 3-hydroxymethyl piperidine base; R 8represent hydrogen, ethanoyl, 4-methyl piperidine base, 4-acetylpiperidinyl, 4-methanesulphonylpiperidine base, morpholine ethyl, THP trtrahydropyranyl.
5. the compound of claim 1, it is characterized in that following compound:
3-(4-fluorophenyl)-5-(4-P-acetamido benzene sulfonyl base)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-1-1)
3-(4-fluorophenyl)-5-(3-nitrobenzenesulfonyl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-1-2)
3-(4-fluorophenyl)-5-(3-pyridine sulfonyl sulfonyl base)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-1-3)
3-(4-fluorophenyl)-5-(2,6-dichlorobenzene alkylsulfonyl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-1-4)
3-(4-fluorophenyl)-5-(2-naphthalene sulfonyl base)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-1-5)
3-(4-fluorophenyl)-5-(4-Methyl benzenesulfonyl base)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-1-6)
3-(4-fluorophenyl)-5-(8-quinoline alkylsulfonyl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-1-7)
3-(4-fluorophenyl)-5-(4-fluoro benzoyl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-1-8)
3-(3-acetylamino phenyl)-5-(3-nitrobenzenesulfonyl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-2-1)
3-(3-acetylamino phenyl)-5-(3-pyridine sulfonyl sulfonyl base)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-2-2)
3-(3-acetylamino phenyl)-5-(2,6-dichlorobenzene alkylsulfonyl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-2-3)
3-(3-acetylamino phenyl)-5-(2-naphthalene sulfonyl base) 4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-2-4)
3-(3-acetylamino phenyl)-5-(4-Methyl benzenesulfonyl base)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-2-5)
3-(3-acetylamino phenyl)-5-(8-quinoline alkylsulfonyl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-2-6)
3-(4-acetylamino phenyl)-5-(3-nitrobenzenesulfonyl) 4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-2-7)
3-(4-acetylamino phenyl)-5-(3-pyridine sulfonyl sulfonyl base)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-2-8)
3-(4-acetylamino phenyl)-5-(2,6-dichlorobenzene alkylsulfonyl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-2-9)
3-(4-acetylamino phenyl)-5-(2-naphthalene sulfonyl base)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-2-10)
3-(4-acetylamino phenyl)-5-(4-Methyl benzenesulfonyl base)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-2-11)
3-(4-acetylamino phenyl)-5-(8-quinoline alkylsulfonyl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-2-12)
3-(4-(1-Acetylpiperidin-4-is amino) phenyl)-5-(3-nitrobenzenesulfonyl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-3-1)
3-(4-(1-Acetylpiperidin-4-is amino) phenyl)-5-(3-pyridine sulfonyl sulfonyl base)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-3-2)
3-(4-(1-Acetylpiperidin-4-is amino) phenyl)-5-(2,6-dichlorobenzene alkylsulfonyl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-3-3)
3-(4-(1-Acetylpiperidin-4-is amino) phenyl)-5-(2-naphthalene sulfonyl base)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-3-4)
3-(4-(1-Acetylpiperidin-4-is amino) phenyl)-5-(4-Methyl benzenesulfonyl base)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-3-5)
3-(4-(1-Acetylpiperidin-4-is amino) phenyl)-5-(8-quinoline alkylsulfonyl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-3-6)
3-(4-(1-Acetylpiperidin-4-is amino) phenyl)-5-(2-thiophen sulfuryl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-3-7)
3-(4-(1-methyl piperidine-4-is amino) phenyl)-5-(2,6-dichlorobenzene alkylsulfonyl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-3-8)
3-(4-(1-methyl piperidine-4-is amino) phenyl)-5-(2-thiophen sulfuryl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-3-9)
3-(4-(1-methyl piperidine-4-is amino) phenyl)-5-(3-pyridine sulfonyl sulfonyl base)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-3-10)
3-(4-(1-methyl piperidine-4-is amino) phenyl)-5-(8-quinoline alkylsulfonyl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-3-11)
3-(4-(1-methyl piperidine-4-is amino) phenyl)-5-(2-naphthalene sulfonyl base)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-3-12)
3-(4-(1-methanesulphonylpiperidine-4-is amino) phenyl)-5-(3-nitrobenzenesulfonyl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-3-13)
3-(4-(1-methanesulphonylpiperidine-4-is amino) phenyl)-5-(3-pyridine sulfonyl sulfonyl base)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-3-14)
3-(4-(1-methanesulphonylpiperidine-4 is amino) phenyl)-5-(2,6-dichlorobenzene alkylsulfonyl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-3-15)
3-(4-(1-methanesulphonylpiperidine-4-is amino) phenyl)-5-(2-naphthalene sulfonyl base)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-3-16)
3-(4-(1-methanesulphonylpiperidine-4-is amino) phenyl)-5-(4-Methyl benzenesulfonyl base)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-3-17)
3-(4-(1-methanesulphonylpiperidine-4-is amino) phenyl)-5-(8-quinoline alkylsulfonyl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-3-18)
3-(4-(1-methanesulphonylpiperidine-4-is amino) phenyl)-5-(2-thiophen sulfuryl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-3-19)
3-(4-(4-THP trtrahydropyranyl is amino) phenyl)-5-(8-quinoline alkylsulfonyl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-4-1)
3-(4-(4-THP trtrahydropyranyl is amino) phenyl)-5-(2-thiophen sulfuryl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-4-2)
3-(4-(morpholine ethylamino) phenyl)-5-(8-quinoline alkylsulfonyl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-5-1)
3-(2-furyl)-5-(8-quinoline alkylsulfonyl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-6-1)
3-(4-(1-piperidine formyl base) phenyl)-5-(2,6-dichlorobenzene alkylsulfonyl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-7-1)
3-(4-(1-piperazine formyl radical) phenyl)-5-(2,6-dichlorobenzene alkylsulfonyl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-7-2)
3-(4-(4-methyl isophthalic acid-piperazine formyl radical) phenyl)-5-(2,6-dichlorobenzene alkylsulfonyl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-7-3)
3-(4-(1-Pyrrolidine formyl radical) phenyl)-5-(2,6-dichlorobenzene alkylsulfonyl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-7-4)
3-(4-(1-morpholine methanoyl) phenyl)-5-(2,6-dichlorobenzene alkylsulfonyl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-7-5)
3-(4-(N-aminoethyl carbamyl) phenyl)-5-(2,6-dichlorobenzene alkylsulfonyl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-7-6)
3-(4-(N-aminopropyl carbamyl) phenyl)-5-(2,6-dichlorobenzene alkylsulfonyl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-7-7)
3-(4-(N-methoxyethyl carbamyl) phenyl)-5-(2,6-dichlorobenzene alkylsulfonyl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-7-8)
3-(4-(N-sec.-propyl carbamyl) phenyl)-5-(2,6-dichlorobenzene alkylsulfonyl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-7-9)
3-(4-(N-ammonia butylcarbamoyl) phenyl)-5-(2,6-dichlorobenzene alkylsulfonyl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-7-10)
3-(4-(4-piperidyl carbamyl) phenyl)-5-(2,6-dichlorobenzene alkylsulfonyl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-7-11)
3-(4-(4-hydroxyl-1-piperidine formyl base) phenyl)-5-(2,6-dichlorobenzene alkylsulfonyl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-7-12)
3-(4-(4-hydroxyethyl-1-piperazine formyl radical) phenyl)-5-(2,6-dichlorobenzene alkylsulfonyl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-7-13)
3-(4-(3-methylol-1-piperidine formyl base) phenyl)-5-(2,6-dichlorobenzene alkylsulfonyl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-7-14)
3-(4-(1-piperazine formyl radical) phenyl)-5-(2,6-difluorophenylsulphonyl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-7-15)
3-(4-(4-methyl isophthalic acid-piperazine formyl radical) phenyl)-5-(2,6-difluorophenylsulphonyl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-7-16)
3-(4-(1-Pyrrolidine formyl radical) phenyl)-5-(2,6-difluorophenylsulphonyl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-7-17)
3-(4-(1-morpholine methanoyl) phenyl)-5-(2,6-difluorophenylsulphonyl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-7-18)
3-(4-hydroxymethyl phenyl)-5-(2,6-dichlorobenzene alkylsulfonyl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-8-1)
3-(4-(piperidines-4-is amino) phenyl)-5-(2-chlorobenzenesulfonyl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-8-2)
3-(N-(4-(1-methanesulphonylpiperidine-4-is amino) phenyl) carbamyl)-5-(2,6-dichlorobenzene alkylsulfonyl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-9-1)
3-(N-(4-(1-methyl piperidine-4-is amino) phenyl) carbamyl)-5-(2,6-dichlorobenzene alkylsulfonyl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-9-2)
3-(N-(4-(1-methyl piperidine-4-is amino) phenyl) carbamyl)-5-(3-nitrobenzenesulfonyl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-9-3)
3-(N-(4-(1-methyl piperidine-4-is amino) phenyl) carbamyl)-5-(3-cyanophenylsulfonyl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-9-4)
3-(N-(4-(1-methyl piperidine-4-is amino) phenyl) carbamyl)-5-(3-tnBuoromethyl-benzenesulfonyl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-9-5)
3-(N-(4-(1-methyl piperidine-4-is amino) phenyl) carbamyl)-5-(2,3-dichlorobenzene alkylsulfonyl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-9-6)
3-(N-(4-(4-piperidines is amino) phenyl) carbamyl)-5-(2-chlorobenzenesulfonyl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-9-7)
3-(N-(4-(4-piperidines is amino) phenyl) carbamyl)-5-(3-cyanophenylsulfonyl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-9-8)
3-(N-(4-(4-piperidines is amino) phenyl) carbamyl)-5-(3-tnBuoromethyl-benzenesulfonyl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-9-9)
3-(N-(4-(4-tetrahydropyrans is amino) phenyl) carbamyl)-5-(2,6-dichlorobenzene alkylsulfonyl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-9-10)
3-(N-(4-(hydroxyl kharophen) phenyl) carbamyl)-5-(2,6-dichlorobenzene alkylsulfonyl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-9-11)
3-(N-(4-(hydroxyl kharophen) phenyl) carbamyl)-5-(2,3-dichlorobenzene alkylsulfonyl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-9-12)
3-(N-(4-(hydroxyl kharophen) phenyl) carbamyl)-5-(3-nitrobenzenesulfonyl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-9-13)
3-(N-(4-(hydroxyl kharophen) phenyl) carbamyl)-5-(3-cyanophenylsulfonyl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-9-14)
3-(N-(4-(hydroxyl kharophen) phenyl) carbamyl)-5-(3-tnBuoromethyl-benzenesulfonyl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-9-15)
3-(N-(4-(1-Acetylpiperidin-4-is amino) phenyl) carbamyl)-5-(2,6-dichlorobenzene alkylsulfonyl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-9-16)
3-(N-(4-(1-Acetylpiperidin-4-is amino) phenyl) carbamyl)-5-(3-tnBuoromethyl-benzenesulfonyl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-9-17)
3-(N-(4-(1-methylpiperazine base) phenyl) carbamyl)-5-(2,6-dichlorobenzene alkylsulfonyl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-9-18)
3-(N-(4-(N-hydroxyethylcarbamoyl) phenyl) carbamyl)-5-(2,6-dichlorobenzene alkylsulfonyl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-9-19)
3-(N-(4-(4-methyl isophthalic acid-piperazine formyl radical) phenyl) carbamyl)-5-(2,6-dichlorobenzene alkylsulfonyl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-9-20)
3-(N-(4-(3-methylol-1-piperidine formyl base) phenyl) carbamyl)-5-(2,6-dichlorobenzene alkylsulfonyl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-9-21)
3-(N-(4-(4-hydroxyl-1-piperidine formyl base) phenyl) carbamyl)-5-(2,6-dichlorobenzene alkylsulfonyl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-9-22)
3-(N-(4-(1-piperazine formyl radical) phenyl) carbamyl)-5-(2,6-dichlorobenzene alkylsulfonyl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-9-23)
(S)-(+)-3-(N-(4-(1-(2-pyrrolidinomethyl) Pyrrolidine formyl radical) phenyl) carbamyl)-5-(2; 6-dichlorobenzene alkylsulfonyl)-4; 5; 6; 7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-9-24)
3-(N-(4-(4-methylol-1-piperidine formyl base) phenyl) carbamyl)-5-(2,6-dichlorobenzene alkylsulfonyl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-9-25)
3-(N-(4-(N-aminopropyl carbamyl) phenyl) carbamyl)-5-(2,6-dichlorobenzene alkylsulfonyl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-9-26)
3-(N-(4-(N-methoxycarbonyl propyl carbamyl) phenyl) carbamyl)-5-(2,6-dichlorobenzene alkylsulfonyl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-9-27)
3-(1-methyl-4-pyrazoles formamido group)-5-(2,6-dichlorobenzene alkylsulfonyl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-10-1)
3-(4-(1-piperidin-4-yl) pyrazolyl)-5-(2,6-dichlorobenzene alkylsulfonyl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [4,3-c] pyridine (I-11-1).
6. the compound of any one of claim 1-5 or its pharmacy acceptable salt, wherein pharmacy acceptable salt comprises the acid salt that compound of Formula I and following acid are formed:: hydrochloric acid, Hydrogen bromide, sulfuric acid, phosphoric acid, methylsulfonic acid, Phenylsulfonic acid, tosic acid, naphthene sulfonic acid, citric acid, tartrate, lactic acid, pyruvic acid, acetic acid, toxilic acid or succsinic acid, fumaric acid, Whitfield's ointment, phenylacetic acid, tussol.Comprise the acid salt of mineral alkali in addition, as: containing alkali metal cations, alkaline earth metal cation, ammonium cation salt.
7. the compound of general formula I according to claim 1 or its pharmacy acceptable salt purposes in the medicine for the preparation of prevention or the treatment disease relevant with c-Met kinase inhibitor.
8. purposes according to claim 7, the described disease relevant with c-Met kinases can be nonsmall-cell lung cancer, liver cancer, Papillary Renal Cell Carcinoma, cancer of the stomach, esophagus cancer, glioblastoma, incidence squamous cell, kidney, acute leukemia, prostate cancer, thyroid carcinoma, skin carcinoma, colorectal carcinoma, carcinoma of the pancreas, ovarian cancer, mammary cancer, myelodysplastic syndrome or mesothelioma etc.
CN201510024284.2A 2015-01-14 2015-01-14 Pyrazolo[4,3-c]tetrahydropyridine c-Met kinase inhibitors as well as preparation method and application thereof Pending CN104530045A (en)

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