CN108117551A - Substitute (1H- pyrazoles [3,4-b] pyridine) carbamide compounds and its anticancer usage - Google Patents

Substitute (1H- pyrazoles [3,4-b] pyridine) carbamide compounds and its anticancer usage Download PDF

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CN108117551A
CN108117551A CN201611073936.2A CN201611073936A CN108117551A CN 108117551 A CN108117551 A CN 108117551A CN 201611073936 A CN201611073936 A CN 201611073936A CN 108117551 A CN108117551 A CN 108117551A
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phenyl
urea
methyl
pyridin
pyrazolos
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CN108117551B (en
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李剑
鲁彦丽
毛斐
朱进
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East China University of Science and Technology
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East China University of Science and Technology
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    • C—CHEMISTRY; METALLURGY
    • 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 present invention provides a kind of substitution (1H pyrazoles [3,4 b] pyridine) carbamide compounds and its anticancer usages.Specifically, the present invention provides compound of formula I and its pharmaceutically acceptable salt, wherein, the definition of each group is as noted in the discussion.The present invention compound of formula I can inhibit with the relevant receptor tyrosine kinase of tumorigenesis (including c Kit, PDGFR α and VEGFR2), for the treatment of tumour.

Description

Substitute (1H- pyrazoles [3,4-b] pyridine) carbamide compounds and its anticancer usage
Technical field
The present invention relates to pharmaceutical chemistry and pharmacotherapeutics field, relate more specifically to substitute (1H- pyrazoles [3,4-b] pyrrole Pyridine) carbamide compounds and its anticancer usage.
Background technology
Cancer (malignant tumour) is one of Chronic Non-Communicable Diseases of serious threat human health, it has also become increasingly serious Global public health problem.Statistics indicate that, China's pathogenesis of cancer number increasingly increases, and cancer morbidity is at present according to statistics 285.91/10 ten thousand, the death rate for 180.54/10 ten thousand, and, it is contemplated that within coming few decades, China's cancer morbidity, the death rate To continue that ascendant trend is presented.Therefore, for malignant tumour, it is very urgent to develop strong and effective therapy.With point The continuous development of sub- pharmacology, molecular weight tumor illustrates gradual sharpening to tumour essence；Meanwhile drug, genetic engineering, The extensive use of the advanced technologies such as combinatorial chemistry, extensive quick screening, accelerates and the potent exploitation of new type antineoplastic medicine. At present, the focus of antitumor drug research and development is being transferred to the new antitumoral medicine of targeting too many levels effect from cytotoxic drug Come on object, such as had begun for the antitumor drug of key gene, regulatory molecule and cell receptor Mutiple Targets from laboratory Into clinic.Molecular targeted therapy method has orientation, the advantage of positioning, with making drug selectivity with target tissue in cell or Asia It reacts on cellular level, allows medicament to controllably be distributed, and continue in target area slowly to discharge drug, it is possible to reduce Dosage improves therapeutic effect, reduces toxicity, is the effective way of whole world treatment of cancer.
In recent ten years, have more than ten anti-tumor drugs targetings to be successfully applied in clinic, and kinases is most important Molecular targeted therapy, at present whole world drug grind or exploration project in it is about 1/3rd related to kinases.It takes the lead in Into clinical tyrosine-kinase enzyme inhibitor, protein tyrosine kinase (protein tyrosine kinase, PTK) is most The most common growth factor receptors of tumour, participates in the adjusting of normal cell, signal transfers and development, also with the increasing of tumour cell Grow, break up, migrate it is closely related with apoptosis, by inhibit its activity can tumoricidal signal transfer, selective depression Tumour cell and influence is had no on normal cell.C-KIT is typical type III receptor tyrosine kinase, is ATP competitiveness kinases One kind plays a very important role in the occurrence and development and invasion and attack, migration and relapsing course in tumour, is current tumour point One of popular target of sub- targeted therapy, inhibitor also become the hot spot of antitumor drug research and development.
C-KIT (also known as CD117) is to find for 1987, is the one kind encoded by retrovirus proto-oncogene c-KIT Transmembrane receptor protein with tyrosine kinase activity, with platelet derived growth factor receptor (PDGFR), macrophage colony - 1 receptor of stimulating factor (CSF-1R) and Fms samples tyrosine kinase receptor 3 (FLT3) collectively constitute type III receptor tyrosine kinase Superfamily plays a very important role during tumor development.There is 30 multiple functions to obtain for c-KIT kinases Property (gain-of-function, GOF) mutant form is the receptor of stem cell factor (stemcell factor, SCF).Its quilt After stem cell factor activation, dimer is formed, causes the cross-film phosphorylation of Tyr568 and Tyr570 in JMD, so as to change The three-dimensional structure of JMD weakens its interaction with kinase active site, that is, weakens the self-inhibiting effect of kinases, cause kinases Area's phosphorylation, and then downstream signaling molecule is raised, downstream signaling pathway is finally activated, adjusts growth and the multiplication of cell.At present It is known that in gastrointestinal stromal tumor (gastrointestinal stromal tumor, GIST), acute myeloblastic leukemia (AML), there are the abnormal activation states of c-KIT receptors in the kinds of tumors tissue such as lung cancer.This is mostly derived from c-KIT mutation and leads Cause its overexpression and continuation activation.The Functional mutations of C-KIT genes occur mainly in extracellular domain (extron 8,9), born of the same parents (exons 1 7) extrons 9 mutation rate in A-loop areas is 3~21% in interior JMD (exons 1 1) and kinase domain, Codon 501~503 is occurred mainly in, main Types are to be repeatedly inserted into.The mutation rate of exons 11 is between 20~92%, collection In between codon 550~599, mutation type includes：Point mutation, deletion mutation, insertion mutation, substitute mutation, frame shift it is prominent Become etc.；The mutational site of exons 13 is mainly codon 642, and mutation rate is 0.8~4.1%.It is worth noting that：It is different The common c-KIT mutational sites of tumour have differences.Such as：In GIST, mutation occurs mainly in exons 11 (such as V560D), In acute myelocytic leukemia (AML) cell, the mutation of c-KIT activated forms occurs mainly in exons 17, such as D816V/H/Y. And it studies and shows in GIST, there are the mutation of c-KIT activated forms there are about 80%.
In addition, angiogenesis is considered playing an important role in the generation in tumour, development, invasion and attack and transfer process. On the one hand, blood vessel be generated as nutriment and oxygen enter tumor tissues, metabolite is transported histocyte outside establish Material base；On the other hand, for tumor cell migration to target organ, its continued growth is promoted to provide transport way.At present, grind Studying carefully the discovery factor related with Tumor Angiongesis has more than 30 to plant, such as platelet derived growth factor (PDGF), blood vessel endothelium life The long factor (VEGF), the fibroblast factor (FGF), angiostatin etc., wherein PDGF, which can raise pericyte, stimulates tumour blood Pipe generates, moreover it is possible to which induction of vascular endothelial cell, the multiplication of smooth muscle cell and tumour cell and migration promote connective tissue interstitial Generation, provide good support for newborn blood vessel, direct effect played to tumor vessel.The study found that more Kind intra-tumor has the participation of PDGFR signal transductions, wherein 7~12% find there is PDGFR- α intragenic mutations, mutable site collection In in extron 18 (II kinases area), 12 (nearly film control regions) and 14 (kinases areas), and PDGFRa mutant is mostly in low danger, It is common with stomach GIST.Further investigations have shown that the signal cascade access that VEGF/VEGFR-2 is mediated can be with modulating vascular Multiplication, migration, survival and the change of permeability of endothelial cell promote the new life of blood vessel.Fibroblast growth factor acceptor (FGFR) combined with FGFs, a variety of reactions of target cell can be triggered, played and close in the generation of tumour and the generation of blood vessel The effect of key.
Therefore, Mutiple Targets (c-KIT, PDGFR, VEGFR and FGFR) target tumor is developed to occur, develop associated signal paths Medicine expection can generate better antitumous effect, in particular for the antitumous effect of gastrointestinal stromal tumor.
The content of the invention
It is an object of the present invention to provide a kind of substitution (1H- pyrazoles [3,4-b] pyridine) carbamide compounds, structures General formula is such as shown in (I) or its pharmaceutically acceptable salt；
It is also another object of the present invention to provide as c-KIT and PDGFR-a double inhibitors substitution (1H- pyrazoles [3, 4-b] pyridine) carbamide compounds are preventing or are treating the relevant tumor disease of tyrosine kinase receptor inhibitor (between such as gastrointestinal tract Matter knurl) in terms of application.
In the first aspect of the present invention, compound shown in a kind of Formulas I or its pharmaceutically acceptable salt are provided,
Wherein,
X is O or S；
R1For C1~C4Straight or branched alkyl or C1~C4Linear chain or branch chain halogenated alkyl；
R2For substituted or unsubstituted C1~C6Straight or branched alkyl, substituted or unsubstituted C3~C8Cycloalkyl, substitution Or unsubstituted C6~C10Aryl, substituted or unsubstituted 4-10 unit's heteroaryls；
Wherein, the substitution refers to 1-3 substituent groups selected from the group below：Halogen, hydroxyl, nitro, cyano, C1-C4Alkane Base, C1-C4Halogenated alkyl, C1-C4Alkoxy ,-NRaRb, 4-10 unit's heteroaryls, 4-8 membered heterocycloalkyls, C6~C10Aryl；
And the C in above-mentioned substituent group6~C10Aryl can be not necessarily further by 1-3 selected from halogen, hydroxyl, nitre Base, cyano, C1-C6Alkyl, C1-C4Halogenated alkyl, C1-C4Substituent group substitution in alkoxy；
And the C in above-mentioned substituent group1-C4Alkyl can be not necessarily further by 1-3 selected from halogen, hydroxyl, nitro, cyanogen Substituent group substitution in base ,-NRaRb；
Ra and Rb are each independently H and C1-C4Alkyl；
The 4-10 unit's heteroaryls and 4-8 membered heterocycloalkyls are miscellaneous in N, O and S containing 1-3 independently Atom；
And the halogen is fluorine, chlorine, bromine or iodine.
In another preference, the R1For C1~C4Straight or branched alkyl or C1~C4Linear chain or branch chain perfluor alkane Base, it is preferred that the R1The methyl substituted for methyl or perfluor.
In another preference, compound shown in the Formulas I has one or more features selected from the group below：
(a) C described in1~C6Straight or branched alkyl is selected from：Ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, uncle Butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isobutyl group, new butyl；
(b) C3~C8Cycloalkyl is selected from：Cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, suberyl, cyclooctyl；
(c) C described in6~C10Aryl is selected from：Phenyl, naphthalene, dihydro indenyl, it is preferred that the C6~C10Aryl selects From：Phenyl, 2,3- dihydro -1H- indenes -2- bases, naphthalene -1- bases, naphthalene -2- bases；
(d) the 4-10 unit's heteroaryls described in are selected from：Pyrazolyl, pyridyl group, quinolyl, furyl, thienyl, it is preferred that The 4-10 unit's heteroaryls are selected from：1H- pyrazoles -5- bases, pyridine -2- bases, pyridin-3-yl, pyridin-4-yl, quinoline -3- bases, Furans -2- bases, thiophene -2- bases；
(e) the 4-8 membered heterocycloalkyls described in are selected from：Piperidyl, morpholinyl, piperazinyl (4- methyl piperazines base), pyrrolidines Base, THP trtrahydropyranyl, it is preferred that the 4-8 membered heterocycloalkyls are selected from：2- piperidin-1-yls, 2- morpholine -4- bases, morpholine -4- Base, 4- methylpiperazine-1-yls.
In another preference, the Heterocyclylalkyl is saturated heterocyclic alkyl.
In another preference, the Ra and Rb is identical.
In another preference, the Ra and Rb are simultaneously methyl or ethyl.
In another preference, the substituted C1~C6Straight or branched alkyl has Formula II structure,
Wherein, R3For 5-6 unit's heteroaryls, 5-6 membered heterocycloalkyls, C6~C10Aryl；
And the C6~C10Aryl can be not necessarily further by 1-3 selected from halogen, C1-C6Alkyl, C1-C4Alcoxyl Substituent group substitution in base；
The 5-6 unit's heteroaryls and 5-6 membered heterocycloalkyls contain the 1-3 miscellaneous originals in N, O and S independently Son；
Also, n is the integer between 1~4.
In another preference, the 5-6 unit's heteroaryls are selected from：Pyrazolyl, pyridyl group, furyl, thienyl, preferably Ground, the 4-10 unit's heteroaryls are selected from：1H- pyrazoles -5- bases, pyridine -2- bases, pyridin-3-yl, pyridin-4-yl, furans -2- Base, thiophene -2- bases.
In another preference, the 5-6 membered heterocycloalkyls are selected from：Piperidyl, morpholinyl, piperazinyl (4- methyl piperazines Piperazine base), pyrrolidinyl, THP trtrahydropyranyl, it is preferred that the 5-6 membered heterocycloalkyls are selected from：2- piperidin-1-yls, 2- morpholines- 4- bases, morpholine -4- bases, 4- methylpiperazine-1-yls.
In another preference, the R3For furyl, thienyl, pyridyl group, piperidyl, morpholinyl or phenyl, and The phenyl can be not necessarily further by 1-3 selected from halogen, C1-C6Alkyl, C1-C4Substituent group substitution in alkoxy.
In another preference, the R3For furans -2- bases, thiophene -2- bases, pyridin-4-yl, 2- piperidin-1-yls, 2- Morpholine -4- bases, phenyl (unsubstituted phenyl), 2- aminomethyl phenyls, 4- aminomethyl phenyls, 2- fluorophenyls, 2- chlorphenyls, 2,6- difluoros Phenyl, 4- fluorophenyls, 4- chlorphenyls or 4,5- Dimethoxyphenyls.
In another preference, the substituted C1~C6Straight or branched alkyl has formula III structure,
Wherein, R4For C1-C2Alkyl, and n is the integer between 1~3.
In another preference, the R4For methyl or ethyl.
In another preference, the substituted C6~C10Aryl for substitution phenyl and with formula IV structure,
Wherein, R5For hydrogen or C1~C4Alkyl；R6For 5-6 membered heterocycloalkyls orWherein, 5-6 members Heterocyclylalkyl can be not necessarily further by 1-3 selected from halogen, C1-C4Substituent group substitution in alkyl；And R4For C1-C2Alkane Base, and n is the integer between 0~3.
In another preference, the R6For 4- methyl piperazines base, morpholinyl orAnd R4For C1-C2 Alkyl, and n is the integer between 0~3.
In another preference, the R6For 4- methylpiperazine-1-yls, morpholine -4- bases orAnd R4 For C1-C2Alkyl, and n is the integer between 0~3.
In another preference, the Formula II structure is selected from：Furans -2- ylmethyls, thiophene -2- ylmethyls, pyridine -4- Ylmethyl, 2- piperidin-1-yls ethyl, 2- morpholine -4- bases ethyl, benzyl, phenethyl, phenylpropyl, benzene butyl, 2- methylbenzyls, 4- methylbenzyls, 2- luorobenzyls, 2- chlorobenzyls, 2,6- difluorobenzyls, 4- fluorobenzene ethyl, 4- chlorobenzene ethyls, 4,5- dimethoxys Phenethyl.
In another preference, the formula III structure is selected from：2- dimethylaminoethyls, 2- diethyllaminoethyls, 2- bis- Methylaminopropyl, 2- lignocaine propyl.
In another preference, the formula IV structure is selected from：2- (4- methylpiperazine-1-yls) phenyl, 3- (4- methyl piperazines Piperazine -1- bases) phenyl, 4- (4- methylpiperazine-1-yls) phenyl, 2- (morpholine -4- bases) phenyl, 2- methyl -4- (4- methyl piperazines - 1- yls) phenyl, 3- methyl -4- (4- methylpiperazine-1-yls) phenyl, 5- methyl -2- (4- methylpiperazine-1-yls) phenyl, 3- first Base -4- (morpholine -4- bases) phenyl, 5- methyl -2- (morpholine -4- bases) phenyl, (4- dimethylamino) phenyl, (3- dimethylamino) benzene Base, (4- diethylin) phenyl, (3- diethylin) phenyl, (4- dimethylamino) benzyl, (3- dimethylamino) benzyl, (4- bis- Ethylamino-) benzyl, (3- diethylin) benzyl.
In another preference, the R2It is selected from the group：
Ethyl, n-propyl, normal-butyl, isobutyl group, tertiary butyl, n-pentyl, n-hexyl, cyclopropyl, cyclobutyl, cyclopenta, Cyclobutyl, 1H- pyrazoles -5- bases, pyridine -2- bases, pyridin-3-yl, quinoline -3- bases, 2,3- dihydro -1H- indenes -2- bases, naphthalene -1- Base, naphthalene -2- bases, furans -2- ylmethyls, thiophene -2- ylmethyls, pyridin-4-yl methyl, 2- piperidin-1-yls ethyl, 2- morpholines - 4- bases ethyl, benzyl, phenethyl, phenylpropyl, benzene butyl, 2- methylbenzyls, 4- methylbenzyls, 2- luorobenzyls, 2- chlorobenzyls, 2, 6- difluorobenzyls, 4- fluorobenzene ethyl, 4- chlorobenzene ethyls, 4,5- Dimethoxyphenethyls, 2- dimethylaminoethyls, 2- lignocaines Ethyl, 2- dimethylamino-propyls, 2- lignocaines propyl, 2- (4- methylpiperazine-1-yls) phenyl, 3- (4- methyl piperazines -1- Base) phenyl, 4- (4- methylpiperazine-1-yls) phenyl, 2- (morpholine -4- bases) phenyl, 2- methyl -4- (4- methylpiperazine-1-yls) Phenyl, 3- methyl -4- (4- methylpiperazine-1-yls) phenyl, 5- methyl -2- (4- methylpiperazine-1-yls) phenyl, 3- methyl -4- (morpholine -4- bases) phenyl, 5- methyl -2- (morpholine -4- bases) phenyl, (4- dimethylamino) phenyl, (3- dimethylamino) phenyl, (4- diethylin) phenyl, (3- diethylin) phenyl, (4- dimethylamino) benzyl, (3- dimethylamino) benzyl, (4- diethylamine Base) benzyl, (3- diethylin) benzyl.
In another preference, the compound of formula I is selected from the group：
N- ethyls-N '-(4- (3- methyl-1 H- pyrazolos [3,4-b] pyridin-4-yl) phenyl) urea, N- propyl-N '-(4- (3- methyl-1 H- pyrazolos [3,4-b] pyridin-4-yl) phenyl) urea, N- butyl-N '-(4- (3- methyl-1 H- pyrazolos [3,4- B] pyridin-4-yl) phenyl) urea, N- isobutyl groups-N '-(4- (3- methyl-1 H- pyrazolos [3,4-b] pyridin-4-yl) phenyl) urea, N- tertiary butyls-N '-(4- (3- methyl-1 H- pyrazolos [3,4-b] pyridin-4-yl) phenyl) urea, N- n-pentyls-N '-(4- (3- first Base -1H- pyrazolos [3,4-b] pyridin-4-yl) phenyl) urea, N- n-hexyls-N '-(4- (3- methyl-1 H- pyrazolos [3,4-b] Pyridin-4-yl) phenyl) urea, N- n-hexyls-N '-(4- (3- Trifluoromethyl-1 H- pyrazolos [3,4-b] pyridin-4-yl) phenyl) Urea, N- cyclohexyl-N '-(4- (3- methyl-1 H- pyrazolos [3,4-b] pyridin-4-yl) phenyl) urea, N- cyclopropyl-N '-(4- (3- methyl-1 H- pyrazolos [3,4-b] pyridin-4-yl) phenyl) urea, N- cyclobutyl-N '-(4- (3- methyl-1 H- pyrazolos [3, 4-b] pyridin-4-yl) phenyl) urea, N- cyclopenta-N '-(4- (3- methyl-1 H- pyrazolos [3,4-b] pyridin-4-yl) phenyl) Urea, N- (pyridin-3-yl)-N '-(4- (3- methyl-1 H- pyrazolos [3,4-b] pyridin-4-yl) phenyl) urea, N- (pyridine -2- Base)-N '-(4- (3- methyl-1 H- pyrazolos [3,4-b] pyridin-4-yl) phenyl) urea, N- (1H- pyrazoles -5- bases)-N '-(4- (3- methyl-1 H- pyrazolos [3,4-b] pyridin-4-yl) phenyl) urea, N- (naphthalene -2- bases)-N '-(4- (3- methyl-1 H- pyrazolos [3,4-b] pyridin-4-yl) phenyl) urea, N- (2,3- dihydro -1H- indenes -2- bases)-N '-(4- (3- methyl-1 H- pyrazolos [3,4- B] pyridin-4-yl) phenyl) urea, N- (quinoline -3- bases)-N '-(4- (3- methyl-1 H- pyrazolos [3,4-b] pyridin-4-yl) benzene Base) urea, N- (thiophene -2- ylmethyls)-N '-(4- (3- methyl-1 H- pyrazolos [3,4-b] pyridin-4-yl) phenyl) urea, N- (furans Mutter -2- ylmethyls)-N '-(4- (3- methyl-1 H- pyrazolos [3,4-b] pyridin-4-yl) phenyl) urea, N- (pyridin-4-yl first Base)-N '-(4- (3- methyl-1 H- pyrazolos [3,4-b] pyridin-4-yl) phenyl) urea, N- (2- piperidin-1-yls ethyl)-N '- (4- (3- Trifluoromethyl-1 H- pyrazolos [3,4-b] pyridin-4-yl) phenyl) urea, N- (2- morpholine -4- bases ethyl)-N '-(4- (3- Trifluoromethyl-1 H- pyrazolos [3,4-b] pyridin-4-yl) phenyl) urea, N- (2- morpholine -4- bases ethyl)-N '-(4- (3- first Base -1H- pyrazolos [3,4-b] pyridin-4-yl) phenyl) urea, N- benzyls-N '-(4- (3- methyl-1 H- pyrazolos [3,4-b] pyrroles Pyridine -4- bases) phenyl) urea, N- (3- methylbenzyls)-N '-(4- (3- methyl-1 H- pyrazolos [3,4-b] pyridin-4-yl) phenyl) Urea, N- (4- fluorobenzene ethyl)-N '-(4- (3- methyl-1 H- pyrazolos [3,4-b] pyridin-4-yl) phenyl) urea, N- (3,4- diformazans Oxygroup phenethyl)-N '-(4- (3- methyl-1 H- pyrazolos [3,4-b] pyridin-4-yl) phenyl) urea, N- (2- chlorobenzyls)-N '- (4- (3- methyl-1 H- pyrazolos [3,4-b] pyridin-4-yl) phenyl) urea, N- (4- methylbenzyls)-N '-(4- (3- methyl-1s H- Pyrazolo [3,4-b] pyridin-4-yl) phenyl) urea, N- (4- chlorobenzene ethyls)-N '-(4- (3- methyl-1 H- pyrazolos [3,4-b] Pyridin-4-yl) phenyl) urea, N- (2- luorobenzyls)-N '-(4- (3- methyl-1 H- pyrazolos [3,4-b] pyridin-4-yl) phenyl) Urea, N- (4- phenyl butyls)-N '-(4- (3- methyl-1 H- pyrazolos [3,4-b] pyridin-4-yl) phenyl) urea, N- (3- phenyl third Base)-N '-(4- (3- methyl-1 H- pyrazolos [3,4-b] pyridin-4-yl) phenyl) urea, N- (2,6- difluorobenzyls)-N '-(4- (3- methyl-1 H- pyrazolos [3,4-b] pyridin-4-yl) phenyl) urea, N- (2- phenylethyls)-N '-(4- (3- methyl-1 H- pyrroles Azoles simultaneously [3,4-b] pyridin-4-yl) phenyl) urea, N- (2- phenethyls)-N '-(4- (3- Trifluoromethyl-1 H- pyrazolos [3,4-b] Pyridin-4-yl) phenyl) urea, N- (3- phenylpropyls)-N '-(4- (3- Trifluoromethyl-1 H- pyrazolos [3,4-b] pyridin-4-yl) benzene Base) urea, N- (4- chlorobenzene ethyls)-N '-(4- (3- Trifluoromethyl-1 H- pyrazolos [3,4-b] pyridin-4-yl) phenyl) urea, N- (2- dimethylaminoethyls)-N '-(4- (3- Trifluoromethyl-1 H- pyrazolos [3,4-b] pyridin-4-yl) phenyl) urea, N- (2- bis- Ethylaminoethyl)-N '-(4- (3- Trifluoromethyl-1 H- pyrazolos [3,4-b] pyridin-4-yl) phenyl) urea, N- (3- dimethylaminos Propyl)-N '-(4- (3- Trifluoromethyl-1 H- pyrazolos [3,4-b] pyridin-4-yl) phenyl) urea, N- (3- lignocaines propyl)- N '-(4- (3- Trifluoromethyl-1 H- pyrazolos [3,4-b] pyridin-4-yl) phenyl) urea, N- (2- dimethylaminoethyls)-N '-(4- (3- methyl-1 H- pyrazolos [3,4-b] pyridin-4-yl) phenyl) urea, N- (4- (4- methylpiperazine-1-yls) phenyl)-N '-(4- (3- Trifluoromethyl-1 H- pyrazolos [3,4-b] pyridin-4-yl) phenyl) thiocarbamide, N- (4- (4- methylpiperazine-1-yls) phenyl)- N '-(4- (3- Trifluoromethyl-1 H- pyrazolos [3,4-b] pyridin-4-yl) phenyl) urea, N- (2- methyl -4- (4- methyl piperazines - 1- yls) phenyl)-N '-(4- (3- Trifluoromethyl-1 H- pyrazolos [3,4-b] pyridin-4-yl) phenyl) urea, N- (3- methyl -4- (4- methylpiperazine-1-yls) phenyl)-N '-(4- (3- Trifluoromethyl-1 H- pyrazolos [3,4-b] pyridin-4-yl) phenyl) urea, N- (3- (4- methylpiperazine-1-yls) phenyl)-N '-(4- (3- Trifluoromethyl-1 H- pyrazolos [3,4-b] pyridin-4-yl) phenyl) Urea, N- (2- (4- methylpiperazine-1-yls) phenyl)-N '-(4- (3- Trifluoromethyl-1 H- pyrazolos [3,4-b] pyridin-4-yl) benzene Base) urea, N- (5- methyl -2- (4- methylpiperazine-1-yls) phenyl)-N '-(4- (3- Trifluoromethyl-1 H- pyrazolos [3,4-b] pyrroles Pyridine -4- bases) phenyl) urea, N- (3- methyl -4- (morpholine -4- bases) phenyl)-N '-(4- (3- Trifluoromethyl-1 H- pyrazolos [3,4- B] pyridin-4-yl) phenyl) urea, N- (2- (morpholine -4- bases) phenyl)-N '-(4- (3- Trifluoromethyl-1 H- pyrazolos [3,4-b] Pyridin-4-yl) phenyl) urea, N- (5- methyl -2- (morpholine -4- bases) phenyl)-N '-(4- (3- methyl-1 H- pyrazolos [3,4-b] Pyridin-4-yl) phenyl) urea, N- (2- methyl -4- (4- methylpiperazine-1-yls) phenyl)-N '-(4- (3- methyl-1 H- pyrazolos [3,4-b] pyridin-4-yl) phenyl) urea, N- (3- methyl -4- (4- methylpiperazine-1-yls) phenyl)-N '-(4- (3- methyl-1s H- Pyrazolo [3,4-b] pyridin-4-yl) phenyl) urea, N- (3- (4- methylpiperazine-1-yls) phenyl)-N '-(4- (3- methyl-1s H- Pyrazolo [3,4-b] pyridin-4-yl) phenyl) urea, N- (2- (4- methylpiperazine-1-yls) phenyl)-N '-(4- (3- methyl-1s H- Pyrazolo [3,4-b] pyridin-4-yl) phenyl) urea, N- (5- methyl -2- (4- methylpiperazine-1-yls) phenyl)-N '-(4- (3- first Base -1H- pyrazolos [3,4-b] pyridin-4-yl) phenyl) urea, N- (3- methyl -4- (morpholine -4- bases) phenyl)-N '-(4- (3- first Base -1H- pyrazolos [3,4-b] pyridin-4-yl) phenyl) urea, N- (2- (morpholine -4- bases) phenyl)-N '-(4- (3- methyl-1s H- Pyrazolo [3,4-b] pyridin-4-yl) phenyl) urea, N- (5- methyl -2- (morpholine -4- bases) phenyl)-N '-(4- (3- methyl-1s H- Pyrazolo [3,4-b] pyridin-4-yl) phenyl) urea, N- ((4- diethylin) phenyl)-N '-(4- (3- Trifluoromethyl-1 H- pyrazoles And [3,4-b] pyridin-4-yl) phenyl) urea, N- ((3- diethylin) phenyl)-N '-(4- (3- Trifluoromethyl-1 H- pyrazolos [3,4-b] pyridin-4-yl) phenyl) urea, N- ((3- dimethylamino) phenyl)-N '-(4- (3- Trifluoromethyl-1 H- pyrazolos [3, 4-b] pyridin-4-yl) phenyl) urea, N- (4- ((dimethylamino) methyl) phenyl)-N '-(4- (3- Trifluoromethyl-1 H- pyrazolos [3,4-b] pyridin-4-yl) phenyl) urea, N- (4- ((diethylin) methyl) phenyl)-N '-(4- (3- Trifluoromethyl-1 H- pyrazoles And [3,4-b] pyridin-4-yl) phenyl) urea, N- (3- ((dimethylamino) methyl) phenyl)-N '-(4- (3- Trifluoromethyl-1 H- pyrroles Azoles simultaneously [3,4-b] pyridin-4-yl) phenyl) urea, N- (3- ((diethylin) methyl) phenyl)-N '-(4- (3- Trifluoromethyl-1s H- Pyrazolo [3,4-b] pyridin-4-yl) phenyl) urea, N- ((4- dimethylamino) phenyl)-N '-(4- (3- Trifluoromethyl-1 H- pyrazoles And [3,4-b] pyridin-4-yl) phenyl) urea, N- ((4- diethylin) phenyl)-N '-(4- (3- methyl-1 H- pyrazolos [3,4- B] pyridin-4-yl) phenyl) urea, N- ((3- diethylin) phenyl)-N '-(4- (3- methyl-1 H- pyrazolos [3,4-b] pyridine- 4- yls) phenyl) urea, N- ((3- dimethylamino) phenyl)-N '-(4- (3- methyl-1 H- pyrazolos [3,4-b] pyridin-4-yl) benzene Base) urea, N- (4- ((dimethylamino) methyl) phenyl)-N '-(4- (3- methyl-1 H- pyrazolos [3,4-b] pyridin-4-yl) benzene Base) urea, N- (4- ((diethylin) methyl) phenyl)-N '-(4- (3- methyl-1 H- pyrazolos [3,4-b] pyridin-4-yl) benzene Base) urea, N- (3- ((dimethylamino) methyl) phenyl)-N '-(4- (3- methyl-1 H- pyrazolos [3,4-b] pyridin-4-yl) benzene Base) urea, N- ((4- dimethylamino) phenyl)-N '-(4- (3- methyl-1 H- pyrazolos [3,4-b] pyridin-4-yl) phenyl) urea.
In another preference, the X is O and R1For methyl.
In another preference, the R2For 4-10 unit's heteroaryls or phenyl, wherein the phenyl can further by Halogen, C1~C4Alkyl ,-NRaRb, 4-8 membered heterocycloalkyls, and the Ra and Rb is simultaneously methyl or ethyl.
In another preference, the R2The C substituted for 4-10 unit's heteroaryls or phenyl1~C6Alkyl, wherein, it is described Phenyl not necessarily can further be optionally substituted by halogen.
In another preference, the compound of formula I is selected from the group：
In the second aspect of the present invention, a kind of pharmaceutical composition is provided, the pharmaceutical composition includes：
(a) compound shown in the Formulas I described in the first aspect present invention of therapeutically effective amount or its is pharmaceutically acceptable Salt and optional (b) pharmaceutically acceptable carrier.
In another preference, 0.001-99wt% is contained in described pharmaceutical composition, preferably 0.1-90wt%, more preferably Compound shown in the Formulas I of ground 1-80wt% or its pharmaceutically acceptable salt, are based on the total weight of the composition.
In another preference, the dosage form of the pharmaceutical composition is peroral dosage form or injection.
In another preference, the pharmaceutical composition is used to inhibit tumour cell or treatment tumour.
In another preference, the tumour is selected from the group：Gastrointestinal stromal tumor, acute myeloblastic leukemia, lung cancer, Melanoma, acute myelocytic leukemia or its combination.
In another preference, the tumour cell includes the tumour that c-KIT and PDGFR α are wild type and saltant type Cell.
In another preference, the tumour cell is selected from the group：BaF3 cells, GIST-T1 cells, GIST-882 are thin Born of the same parents, MOLM14, MV4-11 or its combination.
In another preference, the BaF3 cells are selected from the group：BaF3 cells, c-KIT-BaF3 cells, c-KIT- A829P-BaF3 cells, c-KIT-L576P-BaF3 cells, c-KIT-C674S-BaF3 cells, c-KIT-D816H-BaF3 are thin Born of the same parents, c-KIT-D816V-BaF3 cells, c-KIT-T670I-BaF3 cells, c-KIT-V559D-T670I-BaF3 cells, c- KIT-V654A-BaF3 cells, c-KIT-N822K-BaF3 cells, c-KIT-V559D-BaF3 cells, c-KIT-V559D- V654A-BaF3 cells, PDGFR α-BaF3 cells, PDGFR α-T674I-BaF3 cells, FLT3-BaF3 cells and FLT3- ITD-BaF3 cells.
In another preference, the pharmaceutical composition is Mutiple Targets receptor tyrosine kinase inhibitor class pharmaceutical composition Object.
In another preference, the pharmaceutical composition can be used for inhibiting receptor tyrosine kinase.
In another preference, the receptor tyrosine kinase is type III receptor tyrosine kinase.
In another preference, the receptor tyrosine kinase is selected from the group：C-KIT, PDGFR α, VEGFR2 or its group It closes.
In another preference, the pharmaceutical composition can be applied and can also applied in vitro in vivo.
In the third aspect of the present invention, compound shown in the Formulas I described in a kind of first aspect present invention or its medicine are provided The purposes of acceptable salt on is used to prepare (i) and inhibits tumour cell or treat the pharmaceutical composition of tumour, (ii) receptor junket Histidine kinase inhibitor.
In the fourth aspect of the present invention, a kind of external method for inhibiting receptor tyrosine kinase is provided, including step：
(a) by compound shown in receptor tyrosine kinase and Formulas I described in first aspect present invention or its can pharmaceutically connect The salt received is contacted, so as to inhibit the activity of receptor tyrosine kinase.
In another preference, in step (a), by compound shown in the Formulas I described in first aspect present invention or its medicine Acceptable salt is added in cell culture system on, so that it is contacted with receptor tyrosine kinase.
In another preference, the cell is normal cell or tumour cell.
In another preference, the cell is mammalian cell.
In another preference, the cell is people's cell.
In another preference, the method is non-therapeutic and nondiagnostic.
In the fifth aspect of the present invention, provide it is a kind of treat oncology tools, including step：This is applied to the object of needs Compound shown in Formulas I described in invention first aspect or its pharmaceutically acceptable salt.
In another preference, the object includes people and non-human mammal.
It is to be understood that within the scope of the present invention, above-mentioned each technical characteristic of the invention and have in below (eg embodiment) It can be combined with each other between each technical characteristic of body description, so as to form new or preferred technical solution.As space is limited, exist This no longer tires out one by one states.
Description of the drawings
Fig. 1 shows that rat single dose intravenous gives individual and average blood concentration-time curve (IV-2mg/ after IA-41 Kg, n=3).
Fig. 2 shows each group average mice body weight change curve in embodiment 94.
Fig. 3 shows in embodiment 94 that each group mouse is averaged relative body weight change curve.
Fig. 4 shows each group mouse tumor volume change graph in embodiment 94.
Fig. 5 shows each group mouse relative tumour volume change curve in embodiment 94.
Fig. 6 shows each group mouse GIST-T1 mouse I in embodiment 94A- 41 test of pesticide effectiveness tumour photos.
Fig. 7 shows the knurl weight figure of each group mouse tumor in embodiment 94.
Fig. 8 shows compound IA- 41 test of pesticide effectiveness HE, Ki67, Tunel are dyed
Specific embodiment
The present inventor by extensively and in depth study, be surprised to find that for the first time compound of formula I can significantly inhibit with The activity of the relevant receptor tyrosine kinase of tumorigenesis (including c-KIT, PDGFR- α and VEGFR-2).Experiment shows Compound of formula I all has three kinds of kinases inhibitory activity, particularly especially bright to the inhibitory activity of c-KIT and PDGFR- α receptors It is aobvious.Meanwhile in cellular level research, an optimal kinase activity compound of the invention is to the wild type of c-KIT and PDGFR-a Stronger anti-proliferative capacity is shown with various mutations type cell line and Gao Xuan is shown to 8 kinds of real tumor cell lines Selecting property and effective antiproliferative activity particularly show gastrointestinal stromal tumor (GIST) cell line efficient antiproliferative effect Fruit.In pharmacokinetics and hERG researchs, which shows acceptable dynamic characteristic and good medication Security.In subsequent GIST-T1 animals drug effect model test, which also shows preferable antitumor multiplication effect Fruit.Therefore, the compounds of this invention can be used as multiple receptor tyrosine kinases inhibitor, and selectivity is developed for gastrointestinal stromal tumor Into more anti-tumor drugs targetings.
Term
Term " C1-C6Alkyl " refers to the straight or branched alkyl with 1-6 carbon atom, such as methyl, ethyl, propyl, different Propyl, butyl, isobutyl group, sec-butyl, tertiary butyl or similar group.
Term " C1-C4Alkoxy " refers to the straight or branched alkoxyl with 1-4 carbon atom, such as methoxyl group, ethoxy Base, propoxyl group, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy or similar group.
Term " cycloalkyl " refers to monocyclic 3 to 8 yuan of full carbon, complete 5 yuan/6 yuan or 6 yuan/6 yuan fused rings of carbon or polycyclic condensed ring group Group, wherein one or more rings can contain one or more double bonds, but neither one ring has the pi-electron system of total conjugated System.Examples of cycloalkyl has cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, cyclohexadienyl, adamantyl, cycloheptyl alkyl, cycloheptyl Trialkenyl etc..
At least there are a heteroatomic saturations or unsaturation ring selected from the group below on term " Heterocyclylalkyl " finger ring skeleton： N, S, O or P, wherein one or more rings can contain one or more double bonds.Such as pyrrolidinyl, piperidyl, piperazinyl, Quinoline base or similar group.
Term " aromatic ring " refers to the aromatic ring of the pi-electron system with conjugation, including isocyclic aryl, heteroaryl.
Term " aryl " represents to include the hydrocarbyl portion of one or more aromatic rings.The example of aryl moiety includes phenyl (Ph), phenylene, naphthalene, naphthylene, pyrenyl, anthryl and phenanthryl.
Term " heteroaryl " refers to at least one hetero atom as annular atom, remaining annular atom is the aryl of carbon, miscellaneous original Attached bag includes oxygen, sulphur, nitrogen.The ring can be 5 yuan or 6 yuan or 7 yuan of rings.The example of heteroaryl groups includes but not limited to furans Base, furylidene, fluorenyl, pyrrole radicals, N- alkyl pyrrole radicals, thienyl, oxazolyl, imidazole radicals, thiazolyl, benzofuranyl, Benzothienyl, pyridyl group, pyrimidine radicals, quinazolyl, quinolyl, isoquinolyl and indyl.
Term " amino " expression-NH2、-NH-(C1-C6Alkyl) or-N (C1-C6Alkyl)2。
Term " halogen " refers to fluorine, chlorine, bromine, iodine.Term " halogenated " refer to fluoro, chloro, bromo, iodo 's.
Herein, except part is illustrated, alkyl as described herein, cycloalkyl, Heterocyclylalkyl, aryl and heteroaryl are same When including substituted and unsubstituted part.In addition, cycloalkyl, Heterocyclylalkyl, aryl and heteroaryl can also condense mutually.
Except part is illustrated, term " substitution " refers to one or more hydrogen atoms on group by substituent group selected from the group below Substitution：C1-C10Alkyl, C3-C10Cycloalkyl, C1-C10Alkoxy, halogen, hydroxyl, carboxyl (- COOH), C1-C10Aldehyde radical, C2-C10 Acyl group, C2-C10Ester group, amino, phenyl；The phenyl includes unsubstituted phenyl or the substituted benzene with 1-3 substituent group Base, the substituent group are selected from：Halogen, C1-C10Alkyl, cyano, OH, nitro, C3-C10Cycloalkyl, C1-C10Alkoxy, amino.
Except illustrating part, among all compounds of the invention, each asymmetric carbon atom can be optionally R configurations or S configurations or the mixture of R configurations and S configurations.
Compound of formula I
As used herein, term " the compounds of this invention ", " compound shown in Formulas I " and " substitution (1H- pyrazoles [3,4-b] pyrrole Pyridine) carbamide compounds " it is used interchangeably, refer both to the compound with structure shown in Formulas I described in first aspect present invention.
The compounds of this invention can contain asymmetric or chiral centre, therefore can exist with different stereoisomeric forms in any ratio. All stereoisomeric forms in any ratio of the compounds of this invention include but not limited to diastereoisomer, enantiomter and resistance and turn isomery Body and their mixture (such as racemic mixture), are included within the scope of the present invention.
The compounds of this invention can also exist with different tautomeric forms, and all these forms are included in model of the present invention In enclosing.Term " tautomer " or " tautomeric form " refer to that the structure of the different-energy mutually converted via low energy barrier is different Structure body.
The compounds of this invention can be with nonsolvated forms and containing pharmaceutically acceptable solvent (such as water, ethyl alcohol etc.) Solvation form exists, and the compound of the present invention includes solvated and unsolvated form.
The compounds of this invention has basic group, therefore can be formed with inorganic acid or organic acid " pharmaceutically acceptable Salt " including pharmaceutically acceptable acid addition salts, by using inorganic acid or the free alkali of organic acid treatment the compounds of this invention, can obtain Pharmaceutically acceptable salt, the inorganic acid such as hydrochloric acid, hydrobromic acid, phosphoric acid and sulfuric acid, the organic acid such as ascorbic acid, Niacin, citric acid, tartaric acid, lactic acid, maleic acid, malonic acid, fumaric acid, oxalic acid, malic acid, glycolic, succinic acid, propionic acid, Acetic acid, methanesulfonic acid, trifluoromethanesulfonic acid, benzene sulfonic acid, p-methyl benzenesulfonic acid etc..
The present invention is also covered by the compounds of this invention through isotope marks, except one or more atoms are by atomic mass Or mass number was different from outside the fact that one of atomic mass common in nature or mass number atom is replaced, and was stated with this Person is identical.The isotope example in the compound of the present invention can be included, it is same including hydrogen, carbon, nitrogen, oxygen, phosphorus, sulphur, fluorine, iodine and chlorine Position element, respectively such as：2Hydrogen,3Hydrogen,11Carbon,13Carbon,14Carbon,13Nitrogen,15Nitrogen,15Oxygen,17Oxygen,18Oxygen,31Phosphorus,32Phosphorus,35Sulphur,18Fluorine,123 Iodine,125Iodine and36Chlorine.
Some isotope marks the compound of the present invention (such as with3H and14Those of C flag) for compound and/or Substrate tissue distribution assays.Particularly preferably it is tritiated (i.e.3H) and carbon-14 (i.e.14C) isotope, because they are easily prepared and inspection It surveys.Moreover, heavier isotope such as deuterium is (i.e.2H some as caused by larger metabolic stability control can be provided by) carrying out substitution Advantage (such as Half-life in vivo increases or volume requirements reduce) is treated, thus may be preferred in some cases.Positive electron Emit isotope, such as15O、13N、11C and18F studies for positron emission tomography (PET), to check substrate receptor Occupancy.The compound of the present invention of isotope marks can be generally followed similar to the institute in scheme and/or Examples below Disclosed method substitutes isotope-labeled reagent to prepare by using the reagent of isotope marks.
Compound according to the present invention has brand-new substitution (1H- pyrazoles [3,4-b] pyridine) ureas structure, and to it It carries out three kinds and closely related receptor tyrosine kinase is generated with tumor tissues (including c-KIT, PDGFR- α and VEGFR-2) Inhibitory activity is tested, and the antiproliferative activity test of the wild type and various mutations type cell line of c-KIT and PDGFR-a, 8 kinds really Tumor cell line inhibitory activity test and Pharmacokinetic Characteristics, hERG and the model experiment of animal drug effect test etc., respectively Kind Activity Results show that part of compounds of the present invention all has inhibitory activity to three kinds of kinases, particularly to c-KIT and PDGFR- The inhibitory activity of α receptors is especially apparent, and wherein the optimal compound of kinase inhibiting activity is to most of wild and mutation c-KIT There is inhibitory activity with PDGFR-a cell lines, and with good drug safety window, it is thin optionally to act on tumour Born of the same parents also show preferably antitumous effect in the animal pharmacophore model in later stage, new more further to design and develop from now on Multi-targeted receptor tyrosine kinase inhibitor series antineoplastic medicament is laid a good foundation.
In another aspect of this invention, the substitution (1H- pyrazoles [3,4-b] pyridine) with below formula (I) structure is provided Carbamide compounds：
In Formulas I：X is O or S；R1For C1~C4Straight or branched alkyl or C1~C4Linear chain or branch chain perfluoroalkyl；R2For C1 ~C6Straight or branched alkyl, C3~C6Cycloalkyl, C5~C6Aromatic heterocyclic, condensed ring or selected from following structure I I, III, IV：
Wherein, in Formula II, R3For C5~C6Aromatic heterocyclic, substituted or unsubstituted piperidines and morpholine ring group, substitution do not take For hexa-atomic aromatic ring yl, integers of the n between 1-4；
The substituent group of the substituted-phenyl is selected from：C1~C6Straight or branched alkyl, halogen, C1~C3Alkoxy, substituent group Number be 0~3 integer；
Wherein, in formula III, R4For C1~C2Alkyl, n are the integer between 1~3；
Wherein, in formula IV, R5For hydrogen or C1~C3Alkyl；R6For substituted or unsubstituted 4- methyl piperazines base or morpholine ring Base orN is the integer between 0~3.
First preferred embodiment of formula (I) compound of the present invention is compound (IA)：
R2For C1~C6Straight or branched alkyl, C3~C6Cycloalkyl, C5~C6Aromatic heterocyclic, condensed ring or selected from lower structure II、III、IV：
Wherein, in Formula II, R3For C5~C6Aromatic heterocyclic, substituted or unsubstituted piperidines and morpholine ring group, substitution do not take For hexa-atomic aromatic ring yl, integers of the n between 1-4；
The substituent group of the substituted-phenyl is selected from：C1~C6Straight or branched alkyl, halogen, C1~C3Alkoxy, substituent group Number be 0~3 integer；
Wherein, in formula III, R4For C1~C2Alkyl, n are the integer between 1~3；
Wherein, in formula IV, R5For hydrogen or C1~C3Alkyl；R6For substituted or unsubstituted 4- methyl piperazines base or morpholine ring Base orN is the integer between 0~3.
Second preferred embodiment of formula (I) compound of the present invention is compound (IB)：
X is O or S；R2For C1~C6Straight or branched alkyl, C3~C6Cycloalkyl, C5~C6Aromatic heterocyclic, condensed ring are selected from Following structure I I, III, IV：
Wherein, in Formula II, R3For C5~C6Aromatic heterocyclic, substituted or unsubstituted piperidines and morpholine ring group, substitution do not take For hexa-atomic aromatic ring yl, integers of the n between 1-4；
The substituent group of the substituted-phenyl is selected from：C1~C6Straight or branched alkyl, halogen, C1~C3Alkoxy, substituent group Number be 0~3 integer；
Wherein, in formula III, R4For C1~C2Alkyl, n are the integer between 1~3；
Wherein, in formula IV, R5For hydrogen or C1~C3Alkyl；R6For substituted or unsubstituted 4- methyl piperazines base or morpholine ring Base orN is the integer between 0~3.
Specifically, the compound of the present invention includes but not limited to compound selected from the group below：
Preparation method
The present invention also provides substitution (1H- pyrazoles [3,4-b] pyridine) carbamide compounds I of logical formula (I) structureA~IBAnd its The preparation method of intermediate V~XIV, specific synthetic method are as follows.
IASynthesis：
In formula, R2Meaning with it is described previously identical.
Specifically comprise the following steps：
1) by 3- methyl -5- amino -1H- pyrazoles, paranitrobenzaldehyde and 2,2- dimethyl-1,3-dioxane -4,6- Diketone is added in round-bottomed flask, is heated after being dissolved with n,N-Dimethylformamide under its boiling temperature until no CO2It releases Until.There is solid Precipitation in solution, suitable isopropanol is added in after being cooled to room temperature.It filters, solid N, N- bis- Ultrasound 15 minutes after methylformamide dissolving, then after filtering, obtain intermediate 3- methyl -4- (4- nitrobenzophenones) -4,5- dihydros - 1H- pyrazoles [3,4-b] pyridine -6 (7H) -one (intermediate V).
2) intermediate V is dissolved in dioxane, adds in 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone and N, O- double (three Methyl-monosilane base) trifluoroacetamide, it is refluxed overnight.It cools down after reaction, reaction solution is poured into suitable water, uses saturation NaHCO3Solution is tuned into alkalescence, and a large amount of solids are precipitated from solution.It filters, filter cake is dissolved with n,N-Dimethylformamide, ultrasound Continue to filter after 15 minutes, with ethyl acetate filter wash cake, filter cake dries to obtain intermediate 3- methyl -4- (4- nitrobenzophenones) -1H- pyrroles Azoles [3,4-b] pyridine -6 (7H) -one (intermediate VI).
3) intermediate VI is dissolved in suitable benzene phosphinylidyne dichloro, is reacted overnight at 110 DEG C.It cools down after reaction, System is poured into appropriate ice water, after stirring half an hour, is filtered, filter cake adds water molten with saturated sodium bicarbonate after stirring evenly Liquid is adjusted to alkalescent.It filters, filter cake dries to obtain the chloro- 3- methyl -4- of intermediate 6- (4- nitrobenzophenones) -6,7- dihydros -1H- Pyrazoles [3,4-b] pyridine (intermediate VII)
4) zinc powder, hydrazine hydrate, tetrahydrofuran mix in three-necked flask, under nitrogen protection, will be dissolved with intermediate VII's Tetrahydrofuran solution is at the uniform velocity added drop-wise in reaction system, finish rear back flow reaction 4 it is small when.It cools down, filters, filtrate after reaction With tetrahydrofuran extraction three times, vacuum distillation extraction liquid, residue obtain intermediate 4- (3- methyl-1 H- pyrroles through column chromatography for separation Azoles [3,4-b] pyridin-4-yl) aniline (intermediate VIII).
5) intermediate VIII is dissolved in suitable dimethyl sulfoxide (DMSO), adds in commercialization or homemade isocyanates chemical combination Object (R2- NCO), after adding triethylamine, room temperature reaction is overnight.After reaction, cool down, concentration, residue is through column chromatography point From obtaining compound N-R2- N '-[4- (3- methyl-1 H- pyrazoles [3,4-b] pyridin-4-yl) phenyl] urea (IA)。
IBSynthesis：
In formula, R2Meaning with it is described previously identical.
Specifically comprise the following steps：
1) sodium hydride is dissolved in suitable anhydrous tetrahydro furan, be heated to reflux, Trifluoroacetic Acid Ethyl Ester is then added dropwise With the tetrahydrofuran solution of the mixing of acetonitrile, 15h is reacted at 70 DEG C after adding.After reaction, it is cooled to room temperature, will reacts Liquid is poured into water, and is extracted with appropriate anhydrous ether, and it is 2 that water mutually adjusts PH with 2M hydrochloric acid solutions, is extracted again with anhydrous ether.Always Organic phase dried with anhydrous sodium sulfate, filter, filtrate decompression distillation, obtain 4,4,4- tri- fluoro- 3- carbonyls butyronitrile of crude product (in Mesosome IX)；
2) intermediate compound I X and hydrazine hydrate are mixed, methanesulfonic acid is slowly added dropwise, reacted overnight at 80 DEG C after adding.Reaction knot Shu Hou, vacuum distillation, residue ethyl acetate:N-hexane=1:1 dissolving, is stirred 5 minutes, is filtered, filtrate decompression distillation, warp Column chromatography for separation is crossed, obtains 3- trifluoromethyl -5- amino -1H- pyrazoles (intermediate X)；
3) paranitrobenzaldehyde is dissolved in ethyl alcohol, adds in 2,2- dimethyl-1,3-dioxane -4,6- diketone, 3h is reacted at 80 DEG C, adds the ethanol solution of intermediate X, after having solid precipitation, reacts half an hour.After reaction, it is cold But to room temperature, suitable isopropanol is added in.It filters, ultrasound 15 minutes after solid is dissolved with methanol, then filters, obtain intermediate 3- trifluoromethyls -4- (4- nitrobenzophenones) -4,5- dihydro-1 h-pyrazoles [3,4-b] pyridine -6 (7H) -one (intermediate X I).
4) intermediate X I is dissolved in chlorobenzene, adds in 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone and the double (front threes of N, O- Base silane base) trifluoroacetamide, it is refluxed overnight.It is cooled to room temperature after reaction, reaction solution is poured into suitable water, with full And NaHCO3Solution is tuned into alkalescence, and a large amount of solids are precipitated from solution.It filters, filter cake is washed with water, filter cake dries to obtain intermediate 3- trifluoromethyls -4- (4- nitrobenzophenones) -1H- pyrazoles [3,4-b] pyridine -6 (7H) -one (intermediate X II).
5) intermediate X II is dissolved in suitable benzene phosphinylidyne dichloro, is reacted overnight at 110 DEG C.It cools down after reaction, System is poured into appropriate ice water, after stirring half an hour, is filtered, filter cake adds water molten with saturated sodium bicarbonate after stirring evenly Liquid is adjusted to alkalescent.It filters, filter cake drying contact plate if there is starting material left, continuously adds phenylphosphonyl dichloride, according to initial conditions Reaction, up to intermediate X II, the reaction was complete, after post-processing again, obtains chloro- 3- trifluoromethyls -4- (the 4- nitrobenzenes of intermediate 6- Base) -6,7- dihydro-1 h-pyrazoles [3,4-b] pyridine (intermediate X III)
6) zinc powder, hydrazine hydrate, tetrahydrofuran mix in three-necked flask, under nitrogen protection, will be dissolved with intermediate X III Tetrahydrofuran solution be at the uniform velocity added drop-wise in reaction system, finish rear back flow reaction and stay overnight.It cools down, filters after reaction, filter Liquid is extracted three times with tetrahydrofuran, vacuum distillation extraction liquid, residue through column chromatography for separation, obtain intermediate 4- (3- trifluoromethyls- 1H- pyrazoles [3,4-b] pyridin-4-yl) aniline (intermediate X IV).
7) intermediate X IV is dissolved in suitable dimethyl sulfoxide (DMSO) or anhydrous THF, adds in commercialization or homemade isocyanic acid Ester type compound (R2- NCO), after adding triethylamine, room temperature reaction is overnight.After reaction, cool down, concentration, residue warp Column chromatography for separation obtains compound N-R2- N '-[4- (3- methyl-1 H- pyrazoles [3,4-b] pyridin-4-yl) phenyl] urea (IB)。
According to the introduction of above-mentioned preparation method, those of ordinary skill in the art are without creative work, you can obtain Formulas I institute Comprising all compounds.
Pharmaceutical composition and method of administration
In the present invention, the pharmaceutical composition can be directly used for disease treatment, for example, controlling for anti-tumor aspect It treats.When using pharmaceutical preparation of the present invention, other therapeutic agents, such as anti-tumor drug also can be used simultaneously.
The present invention provides a kind of pharmaceutical composition, the compounds of this invention and pharmaceutically may be used that it contains safe and effective amount The carrier or excipient of receiving.This kind of carrier includes (but being not limited to)：Brine, buffer solution, glucose, water, glycerine, ethyl alcohol, Pulvis, and combinations thereof.Pharmaceutical preparation should match with administering mode.
By taking pharmaceutical composition as an example, composition of the invention can be made into injection form, such as with physiological saline or contain There are glucose and the aqueous solution of other assistant agents to be prepared by conventional method.The pharmaceutical composition of such as tablet and capsule etc Object can be prepared by conventional method.Pharmaceutical composition such as injection, solution, tablet and capsule preferably aseptically manufacture. The pharmaceutical composition of the present invention can also be made into pulvis for Neulized inhalation.The dosage of active ingredient is therapeutically effective amount, example Such as the daily mg/kg weight of about 1 microgram/kg body weight-about 5.In addition, the compounds of this invention can also be together with other therapeutic agents It uses.
For the pharmaceutical composition of the present invention, required object (such as people and the inhuman food in one's mouth can be applied to by way of conventional Newborn animal).Representative method of application includes (but being not limited to)：Oral, injection, Neulized inhalation etc..
It is in mammal, the wherein safe and effective amount by the medicament administration of safe and effective amount during using pharmaceutical composition Typically at least about 10 micrograms/kg body weight, and in most cases it is no more than about 8 mg/kg weight, the preferably agent Amount is the mg/kg weight of about 10 micrograms/kg body weight-about 1.Certainly, specific dosage is also contemplated that administration route, patient health The factors such as situation, within the scope of these are all skilled practitioners technical ability.
Main advantages of the present invention include：
(a) the compound of the present invention can inhibit a variety of receptor tyrosine kinases (including c-Kit, PDGFR α and VEGFR2)。
(b) the compound of the present invention shows various tumor cell strains highly selective and effective antiproliferative activity.
(c) the compound of the present invention has good dynamic characteristic and drug safety.
(d) the compounds of this invention can effectively inhibit GIST-T1 tumour cells in vivo, and Tumor growth inhibition can reach 82.2%.
With reference to specific embodiment, the present invention is further explained.It is to be understood that these embodiments are merely to illustrate the present invention Rather than it limits the scope of the invention.The experimental method of actual conditions is not specified in the following example, usually according to conventional strip Part or according to the condition proposed by manufacturer.Unless otherwise stated, otherwise percentage and number are calculated by weight.
Embodiment 1
3- methyl -4- (4- nitrobenzophenones) -4,5- dihydro-1 h-pyrazoles [3,4-b] (7H) -one of pyridine -6 (intermediate V) It prepares
By 4.85 grams of 3- methyl -5- amino -1H- pyrazoles, 7.55 grams of paranitrobenzaldehydes and 7.2 grams of 2,2- dimethyl -1, 3- dioxane -4,6- diketone is put into 100 milliliters of round-bottomed flasks, after 20 milliliters of n,N-Dimethylformamide dissolving, Heating is reacted to no CO at 110 DEG C2Until releasing.There is solid Precipitation in solution after reacting 30 minutes, be cooled to room temperature 50 milliliters of isopropanol is added in afterwards.Filter, solid with n,N-Dimethylformamide ultrasound 15 minutes, after continue to take out Filter obtains title compound, 9.8 grams of white solids (intermediate V), yield 72% after solid drying.
1H-NMR(400MHz,DMSO-d6)δ:11.92 (s, 1H), 10.41 (s, 1H), 8.20 (d, J=8.7Hz, 2H), 7.45 (d, J=8.7Hz, 2H), 4.37 (t, J=6.3Hz, 1H), 2.88 (dd, J=15.9,7.3Hz, 1H), 2.58 (dd, J= 16.0,5.6Hz,1H),1.86(s,3H).
Embodiment 2
The preparation of 3- methyl -4- (4- nitrobenzophenones) -1H- pyrazoles [3,4-b] (7H) -one of pyridine -6 (intermediate VI)
14.9 grams of intermediate V are put into 250 milliliters of flasks, 100 milliliters of dioxane dissolvings is added in, then adds in 66 Double (trimethylsilyl) trifluoroacetamides of milliliter N, O-, add 15 grams of 2,3-Dichloro-5,6-dicyano-1,4-benzoquinones, return Flow through night.Reaction solution is poured into suitable quantity of water and with saturation NaHCO after reaction3Solution is tuned into alkalescence, and solid is from solution It is precipitated.Filter, filter cake successively washed with n,N-Dimethylformamide and ethyl acetate, dried at 40 DEG C of filter cake 11.3 grams yellowish Color solid (intermediate VI), yield 76%.
1H-NMR(400MHz,DMSO-d6)δ:13.00 (s, 1H), 11.78 (s, 1H), 8.33 (d, J=8.6Hz, 2H), 7.80 (d, J=8.6Hz, 2H), 6.00 (s, 1H), 2.01 (s, 3H)
Embodiment 3
The system of 6- chloro- 3- methyl -4- (4- nitrobenzophenones) -6,7- dihydro-1 h-pyrazoles [3,4-b] pyridine (intermediate VII) It is standby
5 grams of intermediate VI are put into 100 milliliters of flasks, 15 milliliters of benzene phosphinylidyne dichloro dissolvings is added in, is reacted at 110 DEG C Overnight.After reaction, treat that system cooling is poured into appropriate ice water, when stirring 1 is small, there are a large amount of solids to be precipitated.It filters, filter cake is used Saturated sodium bicarbonate solution is tuned into secondary suction filtration after alkalescent, and with a large amount of water wash filter cakes, 3.1 grams of sallow are dried to obtain at 40 DEG C Color solid (intermediate VII), yield are 58%.
1H-NMR(400MHz,DMSO-d6)δ:13.71 (s, 1H), 8.39 (d, J=8.7Hz, 2H), 7.90 (d, J= 8.7Hz,2H),7.25(s,1H),2.16(s,3H).
Embodiment 4
The preparation of 4- (3- methyl-1 H- pyrazoles [3,4-b] pyridin-4-yl) aniline (intermediate VIII)
By 25 grams of zinc powders, 70 milliliter of one hydrazine hydrate, 10 milliliters of tetrahydrofurans mix in 250 milliliters of three-necked flasks, in nitrogen Under protection, 70 milliliters of tetrahydrofuran solutions dissolved with 7 grams of intermediate VII are at the uniform velocity added drop-wise in reaction system, are flowed back after finishing React 4 it is small when.It filters after reaction, filtrate is extracted three times with tetrahydrofuran, vacuum distillation extraction liquid, residue eluant, eluent (tetrahydrofuran：Dichloromethane=1:3, v/v) through column chromatography for separation, 3.1 grams of white solid (intermediate VIII) is obtained, yield is 57%.
1H-NMR(400MHz,DMSO-d6)δ:13.20 (s, 1H), 8.38 (d, J=4.7Hz, 1H), 7.24 (d, J= 7.7Hz, 2H), 6.93 (d, J=4.7Hz, 1H), 6.69 (d, J=7.7Hz, 2H), 5.45 (s, 2H), 2.27 (s, 3H)
Embodiment 5
The preparation of tri- fluoro- 3- carbonyls butyronitrile (intermediate compound I X) of 4,4,4-
0.5 gram of sodium hydride is dissolved in 5ml anhydrous tetrahydro furans, is heated to reflux, obtains reaction system 1, then by 0.4 gram of second Nitrile is dissolved in 2ml anhydrous tetrahydro furans, adds in 1.2 grams of Trifluoroacetic Acid Ethyl Esters, mixed solution is added dropwise in reaction system 1, After adding 15h is reacted at 70 DEG C.After reaction, it is cooled to room temperature, reaction solution is poured into water, is extracted with appropriate anhydrous ether It takes, it is 2 that water mutually adjusts PH with 2M hydrochloric acid solutions, is extracted again with anhydrous ether.Total organic phase is dried with anhydrous sodium sulfate, mistake Filter, filtrate decompression distillation, obtains 4,4,4- tri- fluoro- 3- carbonyls butyronitrile (intermediate compound I X) of crude product.It is purple because the product boiling point is relatively low Without apparent fluorescence under outer, it is difficult to it monitors, is not further purified, therefore yield is calculated with same in next step, separately in feeding intake in next step, This step yield is reacted completely by Trifluoroacetic Acid Ethyl Ester, i.e., 100% calculates.
Embodiment 6
The preparation of 3- trifluoromethyl -5- amino -1H- pyrazoles (intermediate X)
1.16 grams of intermediate compound I X and 4.5ml hydrazine hydrates are mixed, 5.7ml methanesulfonic acids are added dropwise, are reacted after adding at 80 DEG C Overnight.After reaction, it is evaporated under reduced pressure, residue ethyl acetate:N-hexane=1:1 dissolving, is stirred 5 minutes, is filtered, filtrate Eluant, eluent (methanol is used in vacuum distillation after concentration:Dichloromethane=1:60, v/v) column chromatography for separation is carried out, obtains faint yellow oily Object 102 milligrams (intermediate Xs).Embodiment 5 and embodiment 6, two step total recoverys are 8%.
1H NMR(400MHz,DMSO-d6)δ:12.15(s,1H),5.53(s,1H),5.35(s,2H).
Embodiment 7
Intermediate 3- trifluoromethyls -4- (4- nitrobenzophenones) -4,5- dihydro-1 h-pyrazoles [3,4-b] pyridine -6 (7H) -one The preparation of (intermediate X I)
By 0.99 gram of paranitrobenzaldehyde and 0.95 gram of 50 milli of 2,2- dimethyl -1,3- dioxane -4,6- diketone input It rises in round-bottomed flask, after 20 milliliters of ethyl alcohol dissolving, reaction 3h is heated at 80 DEG C, adds the ethyl alcohol of 0.9 gram of intermediate X Solution (5ml).After having solid precipitation, half an hour is reacted.After reaction, it is cooled to room temperature, adds in 10ml isopropanols. It filters, ultrasound 15 minutes after solid is dissolved with methanol, then filters, title compound, 0.376 gram of pale yellow colored solid are obtained after solid drying Body (intermediate X I), yield 38%.
1H NMR(400MHz,DMSO-d6)δ：13.66 (s, 1H), 11.02 (s, 1H), 8.19 (d, J=8.8Hz, 2H), 7.36 (d, J=8.8Hz, 2H), 4.55 (t, J=5.6Hz, 1H), 3.19 (dd, J=5.6Hz, 2.8Hz, 1H), 2.56 (d, J= 2.8Hz,1H).
Embodiment 8
The system of 3- trifluoromethyls -4- (4- nitrobenzophenones) -1H- pyrazoles [3,4-b] (7H) -one of pyridine -6 (intermediate X II) It is standby
0.736 gram of intermediate X II is put into 50 milliliters of flasks, 15 milliliters of chlorobenzene dissolvings is added in, then adds in 2.7 millis N is risen, double (trimethylsilyl) trifluoroacetamides of O- add 0.975 gram of 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone, return Flow through night.Reaction solution is poured into suitable quantity of water and with saturation NaHCO after reaction3Solution is tuned into alkalescence, and solid is from solution It is precipitated.It filters, filter cake is washed with water, and 0.587 gram of faint yellow solid (intermediate X II), yield 80% are dried to obtain at 60 DEG C.
1H-NMR(400MHz,DMSO-d6)δ:14.15 (s, 1H), 12.09 (s, 1H), 8.28 (d, J=8.6Hz, 2H), 7.68 (d, J=8.6Hz, 2H), 6.46 (s, 1H)
Embodiment 9
6- chloro- 3- trifluoromethyls -4- (4- nitrobenzophenones) -6,7- dihydro-1 h-pyrazoles [3,4-b] pyridine (intermediate XIII preparation)
0.587 gram of intermediate X II is put into 100 milliliters of flasks, 10 milliliters of benzene phosphinylidyne dichloro dissolvings are added in, at 110 DEG C Lower reaction is overnight.After reaction, treat that system cooling is poured into appropriate ice water, when stirring 1 is small, there are a large amount of solids to be precipitated.It filters, Filter cake secondary suction filtration after being tuned into alkalescent with saturated sodium bicarbonate solution with a large amount of water wash filter cakes, is dried, point at 60 DEG C Plate, if also intermediate X II that the reaction was complete, repeats operation, last 300 milligrams of pale yellow solid (intermediates XIII), yield is 48%.
1H-NMR(400MHz,DMSO-d6)δ:14.96 (s, 1H), 8.32 (d, J=8.4Hz, 2H), 7.74 (d, J= 8.4Hz,2H),7.44(s,1H).
Embodiment 10
The preparation of 4- (3- methyl-1 H- pyrazoles [3,4-b] pyridin-4-yl) aniline (intermediate X IV)
By 342 milligrams of zinc powders, 2.6 milliliter of one hydrazine hydrate, 2 milliliters of tetrahydrofurans are mixed in 25 milliliters of three-necked flasks, in nitrogen Under gas shielded, 2 milliliters of tetrahydrofuran solutions dissolved with 200 milligrams of intermediate X III are at the uniform velocity added drop-wise in reaction system, are finished Back flow reaction is stayed overnight afterwards.It filters after reaction, filtrate is extracted three times with tetrahydrofuran, and vacuum distillation extraction liquid, residue is with washing De- agent (ethyl acetate：Petroleum ether=1:3, v/v) through column chromatography for separation, 90 milligrams of white solid (intermediate X IV), yield are obtained For 55%.
1H-NMR(400MHz,DMSO-d6)δ:14.61 (s, 1H), 8.60 (d, J=4.6Hz, 1H), 7.18 (dd, J= 4.6Hz, 8.2Hz, 3H), 6.66 (d, J=8.2Hz, 2H), 5.47 (s, 2H)
Embodiment 11
N- ethyls-N '-(4- (3- methyl-1 H- pyrazolos [3,4-b] pyridin-4-yl) phenyl) urea (compound IA- 1) It prepares
50 milligrams of 4- (3- methyl-1 H- pyrazoles [3,4-b] pyridin-4-yl) aniline (intermediate VIII) is dissolved in 1 milliliter two In methyl sulfoxide, 22 microlitres of ethyl isocyanates and 10 microlitres of triethylamines are added in, room temperature reaction is overnight.After reaction, Xiang Ti Suitable water is added in system, is extracted with ethyl acetate three times, anhydrous magnesium sulfate drying is filtered, and vacuum distillation, residue is through column layer Analysis separation (ethyl acetate:Petroleum ether=1:3, v/v) solid, obtained is washed again with ether, obtains title compound, 45 milligrams Yellow powder, yield are 69%.Mp：211-213℃；Purity：93%；
1H NMR(400MHz,CDCl3)δ:9.17 (s, 1H), 8.49 (d, J=4.8Hz, 2H), 7.30 (d, J=8.0Hz, 2H), 7.12 (d, J=4.7Hz, 1H), 6.83 (d, J=8.0Hz, 2H), 3.62 (q, 2H), 2.36 (s, 3H), 1.35 (t, J= 7.2Hz,3H)；HRMS(ESI)m/z calcd forC16H18N5O[M+H]+296.1511,found 296.1506.
Embodiment 12
N- propyl-N '-(4- (3- methyl-1 H- pyrazolos [3,4-b] pyridin-4-yl) phenyl) urea (compound IA- 2) It prepares
In addition to ethyl isocyanate is substituted for propylisocyanate, remaining required raw material, reagent and preparation method Same IA- 1, obtain title compound, 44 milligrams of yellow powder, yield 64%.Mp：208-210℃；Purity：92%；
1H NMR(400MHz,CDCl3)δ:9.15 (t, J=5.5Hz, 1H), 8.56 (d, J=4.9Hz, 1H), 7.28 (d, J =8.2Hz, 2H), 7.22 (d, J=5.0Hz, 1H), 6.72 (d, J=8.3Hz, 2H), 3.42-3.35 (t, 2H), 2.30 (s, 3H), 1.68-1.55 (m, 2H), 0.95 (t, J=7.4Hz, 3H)；HRMS(ESI)m/z calcd for C17H20N5O[M+H]+ 310.1668,found 310.1662.
Embodiment 13
N- butyl-N '-(4- (3- methyl-1 H- pyrazolos [3,4-b] pyridin-4-yl) phenyl) urea (compound IA- 3) It prepares
In addition to ethyl isocyanate is substituted for butyl isocyanate, remaining required raw material, reagent and preparation method Same IA- 1, obtain title compound, 62 milligrams of yellow powder, yield 72%.Mp：177-180℃；Purity：95%；
1H NMR(400MHz,CDCl3)δ:9.20 (s, 1H), 8.49 (d, J=4.8Hz), 7.27 (d, J=7.8Hz), 7.12 (d, J=4.8Hz), 6.81 (d, J=7.8Hz, 2H), 3.58 (dd, J=13.0,6.4Hz, 2H), 2.38 (s, 3H), 1.81-1.64 (m, 2H), 1.48 (m, 2H), 0.99 (t, J=7.3Hz)；HRMS(ESI)m/z calcd for C18H22N5O[M+ H]+324.1824,found 324.1819.
Embodiment 14
N- isobutyl groups-N '-(4- (3- methyl-1 H- pyrazolos [3,4-b] pyridin-4-yl) phenyl) urea (compound IA-4) Preparation
302 microlitres of isobutyl amines are dissolved in 2 milliliters of dimethyl sulfoxide (DMSO)s, add in 583 milligrams of carbonyl dimidazoles, room temperature reaction two After hour, without processing, it is (intermediate that 150 milligrams of 4- (3- methyl-1 H- pyrazoles [3,4-b] pyridin-4-yl) aniline are added in thereto Body VIII), 40 microlitres of triethylamines, room temperature reaction is overnight.After reaction, suitable water is added in into system, uses ethyl acetate Three times, anhydrous magnesium sulfate drying is filtered, and vacuum distillation, residue is through column chromatography for separation (methanol for extraction:Dichloromethane=1:30, V/v), 150 milligrams of title compound, yield 69% are obtained.Mp：262-265℃；Purity：96%；
1H NMR(400MHz,DMSO-d6)δ:13.30 (s, 1H), 8.64 (s, 1H), 8.44 (d, J=4.7Hz, 1H), 7.56 (d, J=8.5Hz, 2H), 7.43 (d, J=8.5Hz, 2H), 7.00 (d, J=4.7Hz, 1H), 6.27 (t, J=5.8Hz, 1H), 2.95 (t, J=6.2Hz, 2H), 2.23 (s, 3H), 1.71 (dt, J=13.5,6.6Hz, 1H), 0.89 (d, J=6.7Hz, 6H)；HRMS(ESI)m/z calcd for C18H22N5O[M+H]+324.1825,found 324.1819.
Embodiment 15
N- tertiary butyls-N '-(4- (3- methyl-1 H- pyrazolos [3,4-b] pyridin-4-yl) phenyl) urea (compound IA-5) Preparation
In addition to isobutyl amine is substituted for tert-butylamine, remaining required raw material, reagent and the same I of preparation methodA- 4, obtain title 120 milligrams of compound, yield 56%.Mp：244-251℃；Purity：100%；
1H NMR(400MHz,DMSO-d6)δ:13.30 (s, 1H), 8.47 (s, 1H), 8.44 (d, J=4.7Hz, 1H), 7.52 (d, J=8.5Hz, 2H), 7.42 (d, J=8.5Hz, 2H), 6.99 (d, J=4.7Hz, 1H), 6.08 (s, 1H), 2.23 (s,3H),1.31(s,9H)；HRMS(ESI)m/z calcd for C18H21N5NaO[M+Na]+346.1644,found 346.1638.
Embodiment 16
N- n-pentyls-N '-(4- (3- methyl-1 H- pyrazolos [3,4-b] pyridin-4-yl) phenyl) urea (compound IA-6) Preparation
In addition to isobutyl amine is substituted for n-amylamine, remaining required raw material, reagent and the same I of preparation methodA- 4, obtain title 150 milligrams of compound, yield 68%.Mp：233-236℃；Purity：98%；
1H NMR(400MHz,DMSO-d6)δ:13.31 (s, 1H), 8.64 (s, 1H), 8.45 (d, 1H, J=4.5Hz), 7.56 (d, J=8.3Hz, 2H), 7.43 (d, J=8.2Hz, 2H), 7.00 (d, J=4.6Hz, 1H), 6.22 (t, 1H), 3.10 (dd,2H),2.24(s,3H),1.45(m,2H),1.30(d,4H),0.89(t,3H)；HRMS(ESI)m/z calcd for C19H24N5O[M+H]+338.1981,found 338.1975.
Embodiment 17
N- n-hexyls-N '-(4- (3- methyl-1 H- pyrazolos [3,4-b] pyridin-4-yl) phenyl) urea (compound IA-7) Preparation
In addition to isobutyl amine is substituted for n-hexylamine, remaining required raw material, reagent and the same I of preparation methodA- 4, obtain title 120 milligrams of compound, yield 52%.Mp：213-215℃；Purity：98%；
1H NMR(400MHz,DMSO-d6)δ:13.30 (s, 1H, NH), 8.63 (s, 1H, NH), 8.44 (d, J=4.7Hz, 1H, ArH), 7.56 (d, J=8.5Hz, 2H, ArH), 7.42 (d, J=8.4Hz, 2H, ArH), 7.00 (d, J=4.7Hz, 1H, ), ArH 6.21 (t, J=5.5Hz, 1H, NH), 3.10 (dd, J=12.8,6.5Hz, 2H, CH2), 2.23 (s, 3H, CH3), 1.43 (d, J=6.5Hz, 2H, CH2), 1.29 (m, 6H, CH2), 0.88 (t, J=6.4Hz, 3H, CH3)；HRMS(ESI)m/z calcd for C20H25N5NaO[M+Na]+374.1957,found 374.1951.
Embodiment 18
N- cyclopropyl-N '-(4- (3- methyl-1 H- pyrazolos [3,4-b] pyridin-4-yl) phenyl) urea (compound IA-8) Preparation
In addition to isobutyl amine is substituted for cyclopropylamine, remaining required raw material, reagent and the same I of preparation methodA- 4, obtain title 130 milligrams of compound, yield 63%.Mp：247-250℃；Purity：97%；
1H NMR(400MHz,DMSO-d6)δ:13.30 (s, 1H), 8.53 (s, 1H), 8.45 (d, J=4.7Hz, 1H), 7.58 (d, J=8.5Hz, 2H), 7.43 (d, J=8.5Hz, 2H), 7.00 (d, J=4.7Hz, 1H), 6.49 (d, 1H), 2.60- 2.55 (m, 1H), 2.23 (s, 3H), 0.65 (q, J=6.7Hz, 2H), 0.46-0.39 (m, 2H)；HRMS(ESI)m/z calcd for C17H18N5O[M+H]+308.1511,found 308.1506.
Embodiment 19
N- cyclobutyl-N '-(4- (3- methyl-1 H- pyrazolos [3,4-b] pyridin-4-yl) phenyl) urea (compound IA-9) Preparation
In addition to isobutyl amine is replaced cyclic butylamine, remaining required raw material, reagent and the same I of preparation methodA- 4, obtain title 160 milligrams of compound, yield 67%.Mp：240-243℃；Purity：99%；
1H NMR(400MHz,DMSO-d6)δ:13.30 (s, 1H), 8.56 (s, 1H), 8.44 (d, J=4.7Hz, 1H), 7.55 (d, J=8.5Hz, 2H), 7.42 (d, J=8.4Hz, 2H, ArH), 7.00 (d, J=4.6Hz, 1H, ArH), 6.50 (d, J =8.1Hz, 1H, NH), 4.15 (dd, J=16.2,8.3Hz, 1H, CH), 2.23 (s, 3H, CH3), 2.19 (dd, 2H, CH2), 1.86 (dd, J=19.6,10.3Hz, 2H, CH2), 1.70-1.55 (m, 2H, CH2)；HRMS(ESI)m/z calcd for C18H20N5O[M+H]+322.1668,found 322.1662.
Embodiment 20
N- cyclopenta-N '-(4- (3- methyl-1 H- pyrazolos [3,4-b] pyridin-4-yl) phenyl) urea (compound IA-10) Preparation
In addition to isobutyl amine is substituted for cyclopentamine, remaining required raw material, reagent and the same I of preparation methodA- 4, obtain title 200 milligrams of compound, yield 89%.Mp：258-262℃；Purity：99%；
1H NMR(400MHz,DMSO-d6)δ:13.30 (s, 1H), 8.49 (s, 1H), 8.44 (d, J=4.7Hz, 1H), 7.55 (d, J=8.5Hz, 2H), 7.42 (d, J=8.5Hz, 2H), 7.00 (d, J=4.7Hz, 1H), 6.25 (d, J=7.2Hz, 1H), 3.96 (dq, J=13.5,6.7Hz, 1H), 2.23 (s, 3H), 1.85 (dt, J=12.2,6.0Hz, 2H), 1.62 (dd, J =16.4,5.9Hz, 2H), 1.56 (dd, J=14.2,7.2Hz, 2H), 1.39 (dt, J=12.2,6.3Hz, 2H)；HRMS (ESI)m/z calcd for C19H22N5O[M+H]+336.1824,found 336.1819.
Embodiment 21
N- cyclohexyl-N '-(4- (3- methyl-1 H- pyrazolos [3,4-b] pyridin-4-yl) phenyl) urea (compound IA-11) Preparation
In addition to ethyl isocyanate is substituted for cyclohexyl isocyanate, remaining required raw material, reagent and preparation side The same I of methodA- 1, obtain title compound, 40 milligrams of yellow powder, yield 52%.Mp：233-237℃；Purity：95%；
1H NMR(400MHz,DMSO-d6)δ:13.30 (s, 1H), 8.53 (s, 1H), 8.44 (d, J=4.6Hz, 1H), 7.54 (d, J=8.4Hz, 2H), 7.42 (d, J=8.4Hz, 2H), 7.00 (d, J=4.7Hz, 1H), 6.17 (d, J=7.8Hz, 1H), 3.54-3.41 (m, 1H), 2.23 (s, 3H), 1.82 (d, J=8.9Hz, 2H), 1.67 (d, J=12.8Hz, 2H), 1.55 (d, J=12.0Hz, 1H), 1.32 (dd, J=23.6,11.7Hz, 2H), 1.18 (dd, J=21.8,12.1Hz, 3H)；HRMS (ESI)m/z calcd for C20H24N5O[M+H]+390.1981,found 350.1975.
Embodiment 22
N- (furans -2- ylmethyls)-N '-(4- (3- methyl-1 H- pyrazolos [3,4-b] pyridin-4-yl) phenyl) urea (changes Close object IA- 12) preparation
In addition to isobutyl amine is substituted for 2- furylamines, remaining required raw material, reagent and the same I of preparation methodA- 4, it obtains 160 milligrams of title compound, yield 70%.Mp：232-234℃；Purity：100%；
1H NMR(400MHz,DMSO-d6)δ:13.31 (s, 1H), 8.77 (s, 1H), 8.45 (d, J=4.7Hz, 1H), 7.60 (s, 1H), 7.57 (d, J=8.5Hz, 2H), 7.44 (d, J=8.5Hz, 2H), 7.00 (d, J=4.7Hz, 1H), 6.65 (t, J=5.5Hz, 1H), 6.41 (s, 1H), 6.28 (s, 1H), 4.32 (d, J=5.6Hz, 2H), 2.23 (s, 3H)；HRMS (ESI)m/z calcd for C19H18N5O2[M+H]+348.1460,found 348.1455.
Embodiment 23
N- (thiophene -2- ylmethyls)-N '-(4- (3- methyl-1 H- pyrazolos [3,4-b] pyridin-4-yl) phenyl) urea (changes Close object IA- 13) preparation
In addition to isobutyl amine is substituted for 2-thenylaminine, remaining required raw material, reagent and the same I of preparation methodA- 4, it obtains 160 milligrams of title compound, yield 67%.Mp：233-235℃；Purity：100%；
1H NMR(400MHz,DMSO-d6)δ:13.31 (s, 1H), 8.81 (s, 1H), 8.45 (d, J=4.7Hz, 1H), 7.58 (d, J=8.5Hz, 2H), 7.44 (d, J=8.4Hz, 2H), 7.40 (d, J=4.8Hz, 1H), 7.04-6.94 (m, 3H), 6.77 (t, J=5.8Hz, 1H), 4.49 (d, J=5.8Hz, 2H), 2.23 (s, 3H)；HRMS(ESI)m/z calcd for C19H17N5NaOS[M+Na]+386.1052,found 386.1046.
Embodiment 24
N- (pyridin-4-yl methyl)-N '-(4- (3- methyl-1 H- pyrazolos [3,4-b] pyridin-4-yl) phenyl) urea (changes Close object IA- 14) preparation
In addition to isobutyl amine is substituted for 4- methylamino pyridines, remaining required raw material, reagent and the same I of preparation methodA- 4, Obtain 160 milligrams of title compound, yield 68%.Mp：218-222℃；Purity：97%；
1H NMR(400MHz,DMSO-d6)δ:13.31 (s, 1H), 8.97 (s, 1H), 8.52 (d, J=4.7Hz, 2H), 8.45 (d, J=4.7Hz, 1H), 7.59 (d, J=8.4Hz, 2H), 7.44 (d, J=8.4Hz, 2H), 7.32 (d, J=5.0Hz, 2H), 7.00 (d, J=4.6Hz, 1H), 6.85 (t, J=5.9Hz, 1H), 4.36 (d, J=5.9Hz, 2H), 2.23 (s, 3H)； HRMS(ESI)m/z calcd for C20H19N6O[M+H]+359.1620,found 359.1615.
Embodiment 25
N- benzyls-N '-(4- (3- methyl-1 H- pyrazolos [3,4-b] pyridin-4-yl) phenyl) urea (compound IA- 15) It prepares
In addition to ethyl isocyanate is substituted for benzyl isocyanate, remaining required raw material, reagent and preparation side The same I of methodA- 1, obtain title compound, 40 milligrams of yellow powder, yield 50%.Mp：91-97℃；Purity：93%；
1H NMR(400MHz,DMSO-d6)δ:9.56 (t, J=5.9Hz, 1H), 8.55 (d, J=5.0Hz, 1H), 7.37 (m, 4H), 7.27 (t, J=7.8Hz, 3H), 7.23 (d, J=5.0Hz, 1H), 6.71 (d, J=8.4Hz, 2H), 4.63 (d, J= 6.0Hz,2H),2.32(s,3H)；HRMS(ESI)m/z calcd for C21H20N5O[M+H]+358.1668,found 358.1662.
Embodiment 26
N- (3- methylbenzyls)-N '-(4- (3- methyl-1 H- pyrazolos [3,4-b] pyridin-4-yl) phenyl) urea (compound IA- 16) preparation
In addition to ethyl isocyanate is substituted for 3- methylbenzyl isocyanates, remaining required raw material, reagent and system The same I of Preparation MethodA- 1, obtain title compound, 50 milligrams of yellow powder, yield 60%.Mp：140-145℃；Purity：97%；
1H NMR(400MHz,DMSO-d6)δ:9.54 (t, J=6.0Hz, 1H), 8.55 (d, J=5.0Hz, 1H), 7.28 (d, J=8.4Hz, 2H), 7.25-7.16 (m, 4H), 7.08 (d, J=7.2Hz, 1H), 6.71 (d, J=8.4Hz, 2H), 4.59 (d, J=5.9Hz, 2H), 2.31 (d, J=6.1Hz, 3H), 2.29 (s, 3H)；HRMS(ESI)m/z calcd for C22H22N5O [M+H]+372.1824,found 372.1819.
Embodiment 27
N- (4- methylbenzyls)-N '-(4- (3- methyl-1 H- pyrazolos [3,4-b] pyridin-4-yl) phenyl) urea (compound IA- 17) preparation
In addition to isobutyl amine is substituted for methylbenzylamine, remaining required raw material, reagent and the same I of preparation methodA- 4, it obtains 170 milligrams of title compound, yield 69%.Mp：275-276℃；Purity：99%；
1H NMR(400MHz,DMSO-d6)δ:13.31 (s, 1H), 8.78 (s, 1H, NH), 8.45 (d, J=4.7Hz, 1H), 7.58 (d, J=8.5Hz, 2H), 7.44 (d, J=8.5Hz, 2H), 7.21 (d, J=7.9Hz, 2H), 7.15 (d, J=7.9Hz, 2H), 7.00 (d, J=4.7Hz, 1H), 6.66 (t, J=5.7Hz, 1H), 4.28 (d, J=5.8Hz, 2H), 2.29 (s, 3H), 2.23(s,3H)；HRMS(ESI)m/z calcd forC22H22N5O[M+H]+372.1824,found 372.1819.
Embodiment 28
N- (2- luorobenzyls)-N '-(4- (3- methyl-1 H- pyrazolos [3,4-b] pyridin-4-yl) phenyl) urea (compound IA- 18) preparation
In addition to isobutyl amine is substituted for adjacent fluorin benzyl amine, remaining required raw material, reagent and the same I of preparation methodA- 4, it must mark Inscribe 210 milligrams of compound, yield 84%.Mp：248-251℃；Purity：97%；
1H NMR(400MHz,DMSO-d6)δ:13.31 (s, 1H), 8.85 (s, 1H), 8.45 (d, J=4.7Hz, 1H), 7.57 (d, J=8.5Hz, 2H), 7.44 (d, J=8.5Hz, 2H), 7.40 (d, J=7.5Hz, 1H), 7.33 (dd, J=13.5, 6.8Hz, 1H), 7.20 (t, J=8.0Hz, 2H), 7.00 (d, J=4.7Hz, 1H), 6.73 (t, J=5.8Hz, 1H), 4.38 (d, J=5.8Hz, 2H), 2.23 (s, 3H)；HRMS(ESI)m/z calcd for C21H18FN5NaO[M+Na]+398.1393, found 398.1388.
Embodiment 29
N- (2- chlorobenzyls)-N '-(4- (3- methyl-1 H- pyrazolos [3,4-b] pyridin-4-yl) phenyl) urea (compound IA- 19) preparation
In addition to isobutyl amine is substituted for o-chlorine benzylamine, remaining required raw material, reagent and the same I of preparation methodA- 4, it must mark Inscribe 210 milligrams of compound, yield 79%.Mp：254-256℃；Purity：96%；
1H NMR(400MHz,DMSO-d6)δ:13.31 (s, 1H), 8.94 (s, 1H), 8.45 (d, J=4.7Hz, 1H), 7.58 (d, J=8.3Hz, 2H), 7.45 (m, 4H), 7.34 (dt, J=14.5,6.9Hz, 2H), 7.00 (d, J=4.7Hz, 1H), 6.77 (t, J=5.7Hz, 1H), 4.40 (d, J=5.7Hz, 2H), 2.23 (s, 3H)；HRMS(ESI)m/z calcd for C21H19ClN5O[M+H]+392.1278,found 392.1273.
Embodiment 30
N- (2,6- difluorobenzyls)-N '-(4- (3- methyl-1 H- pyrazolos [3,4-b] pyridin-4-yl) phenyl) urea (chemical combination Object IA- 20) preparation
Except isobutyl amine is substituted for outside 2,6- difluorobenzylamines, remaining required raw material, reagent and the same I of preparation methodA- 4, Obtain 200 milligrams of title compound, yield 77%.Mp：254-256℃；Purity：97%；
1H NMR(400MHz,DMSO-d6)δ:8.68 (s, 1H), 8.44 (d, J=4.7Hz, 1H), 7.54 (d, J= 8.5Hz, 2H), 7.40 (dd, 3H), 7.10 (dt, J=19.6,7.8Hz, 3H), 6.99 (d, J=4.7Hz, 1H), 6.70 (t, J =5.6Hz, 1H), 4.41 (d, J=5.6Hz, 2H), 2.22 (s, 3H)；HRMS(ESI)m/z calcd for C21H18F2N5O[M +H]+394.1479,found 394.1474.
Embodiment 31
N- (2- phenylethyls)-N '-(4- (3- methyl-1 H- pyrazolos [3,4-b] pyridin-4-yl) phenyl) urea (compound IA- 21) preparation
In addition to isobutyl amine is substituted for phenyl ethylamine, remaining required raw material, reagent and the same I of preparation methodA- 4, obtain title 200 milligrams of compound, yield 82%.Mp：221-224℃；Purity：99%；
1H NMR(400MHz,DMSO-d6)δ:13.31 (s, 1H), 8.73 (s, 1H), 8.45 (d, J=4.7Hz, 1H), 7.56 (d, J=8.5Hz, 2H), 7.43 (d, J=8.4Hz, 2H), 7.32 (d, J=7.4Hz, 2H), 7.24 (dd, J=18.6, 7.2Hz, 3H), 7.00 (d, J=4.7Hz, 1H), 6.22 (t, J=5.6Hz, 1H), 3.37 (t, 2H), 2.78 (t, J=7.1Hz, 2H),2.23(s,3H)；HRMS(ESI)m/z calcd for C22H22N5O[M+H]+372.1824,found 372.1819.
Embodiment 32
N- (4- fluorobenzene ethyl)-N '-(4- (3- methyl-1 H- pyrazolos [3,4-b] pyridin-4-yl) phenyl) urea (compound IA- 22) preparation
In addition to ethyl isocyanate to be substituted for 4- fluorobenzene ethyl isocyanates, remaining required raw material, reagent and system The same I of Preparation MethodA- 1,60 milligrams of title compound is obtained, yield is 23%.Mp：185-189 DEG C, purity：97%；
1H NMR(400MHz,CDCl3)δ:9.26 (s, 1H), 8.38 (d, J=4.9Hz, 1H), 7.26 (dd, J=8.3, 3.5Hz, 4H), 7.11 (d, J=4.9Hz, 1H), 6.99 (dd, J=16.8,8.3Hz, 2H), 6.81 (d, J=8.2Hz, 2H), 3.86-3.77 (t, 2H), 3.00 (t, J=6.9Hz, 2H), 2.36 (s, 3H)；HRMS(ESI)m/z calcd for C22H21FN5O[M+H]+390.1730,found 390.1725.
Embodiment 33
N- (4- chlorobenzene ethyls)-N '-(4- (3- methyl-1 H- pyrazolos [3,4-b] pyridin-4-yl) phenyl) urea (compound IA- 23) preparation
In addition to isobutyl amine is substituted for 4- chlorophenethylamines, remaining required raw material, reagent and the same I of preparation methodA- 4, it obtains 220 milligrams of title compound, yield 82%.Mp：244-247℃；Purity：99%；
1H NMR(400MHz,DMSO-d6)δ:13.30 (s, 1H), 8.71 (s, 1H), 8.45 (d, J=4.7Hz, 1H), 7.55 (d, J=8.5Hz, 2H), 7.43 (d, J=8.5Hz, 2H), 7.38 (d, J=8.3Hz, 2H), 7.29 (d, J=8.3Hz, 2H), 7.00 (d, J=4.7Hz, 1H), 6.21 (t, J=5.6Hz, 1H), 3.36 (t, 2H), 2.77 (t, J=7.0Hz, 2H), 2.23(s,3H)；HRMS(ESI)m/z calcd for C22H21ClN5O[M+H]+406.1435,found 406.1429.
Embodiment 34
N- (3,4- Dimethoxyphenethyls)-N '-(4- (3- methyl-1 H- pyrazolos [3,4-b] pyridin-4-yl) phenyl) Urea (compound IA- 24) preparation
Except ethyl isocyanate is substituted for outside 3,4- Dimethoxyphenethyl isocyanates, remaining required raw material, Reagent and the same I of preparation methodA- 1, obtain 50 milligrams of title compound, yield 18%.Mp：178-181℃；Purity：92%；
1H NMR(400MHz,CDCl3)δ:9.18 (t, J=5.4Hz, 1H), 8.48 (d, J=5.0Hz, 1H), 7.27 (d, J =8.3Hz, 2H), 7.22 (d, J=5.0Hz, 1H), 6.93-6.86 (m, 2H), 6.81 (d, J=7.9Hz, 1H), 6.71 (d, J =8.3Hz, 2H), 3.72 (s, 3H), 3.69 (s, 3H), 3.64 (dd, J=12.6,6.6Hz, 2H), 2.86 (t, J=6.9Hz, 2H),2.31(s,3H)；HRMS(ESI)m/z calcd for C24H26N5O3[M+H]+432.2036,found 432.2030.
Embodiment 35
N- (3- phenyl propyls)-N '-(4- (3- methyl-1 H- pyrazolos [3,4-b] pyridin-4-yl) phenyl) urea (compound IA- 25) preparation
In addition to isobutyl amine is substituted for amphetamine, remaining required raw material, reagent and preparation method are the same as embodiment IA- 4, Obtain 180 milligrams of title compound, yield 70%.Mp：223-225℃；Purity：98%；
1H NMR(400MHz,DMSO-d6)δ:13.31 (s, 1H), 8.68 (s, 1H), 8.45 (d, J=4.7Hz, 1H), 7.57 (d, J=8.5Hz, 2H), 7.43 (d, J=8.5Hz, 2H), 7.30 (t, J=7.4Hz, 2H), 7.23 (d, J=7.2Hz, 2H), 7.19 (t, J=7.1Hz, 1H), 7.00 (d, J=4.7Hz, 1H), 6.31 (t, J=5.5Hz, 1H), 3.13 (dd, J= 12.8,6.5Hz, 2H), 2.63 (t, J=7.6Hz, 2H), 2.24 (s, 3H), 1.83-1.67 (m, 2H)；HRMS(ESI)m/z calcd for C23H23N5NaO[M+Na]+408.1800,found 408.1795.
Embodiment 36
N- (4- phenyl butyls)-N '-(4- (3- methyl-1 H- pyrazolos [3,4-b] pyridin-4-yl) phenyl) urea (compound IA- 26) preparation
In addition to isobutyl amine is substituted for phentermine, remaining required raw material, reagent and the same I of preparation methodA- 4, obtain title 200 milligrams of compound, yield 75%.Mp：224-227℃；Purity：92%；
1H NMR(400MHz,DMSO-d6)δ:13.30 (s, 1H), 8.63 (s, 1H), 8.44 (d, J=4.6Hz, 1H), 7.55 (d, J=8.4Hz, 2H), 7.42 (d, J=8.3Hz, 2H), 7.28 (t, J=7.4Hz, 2H), 7.24-7.13 (m, 3H), 6.99 (d, J=4.6Hz, 1H), 6.24 (t, J=5.5Hz, 1H), 3.13 (dd, J=12.6,6.4Hz, 2H), 2.61 (t, J= 7.4Hz, 2H), 2.23 (s, 3H), 1.60 (dd, J=14.8,7.3Hz, 2H), 1.47 (dd, J=14.5,7.0Hz, 2H)；HRMS (ESI)m/z calcd for C24H25N5NaO[M+Na]+422.1957,found 422.1951.
Embodiment 37
N- (1H- pyrazoles -5- bases)-N '-(4- (3- methyl-1 H- pyrazolos [3,4-b] pyridin-4-yl) phenyl) urea (chemical combination Object IA- 27) preparation
In addition to isobutyl amine is substituted for 3- amino-pyrazols, remaining required raw material, reagent and the same I of preparation methodA- 4, it obtains 60 milligrams of title compound, yield 30%.Mp：260-263℃；Purity：99%；
1H NMR(400MHz,DMSO-d6)δ:13.33(s,1H),12.28(s,1H),9.26(s,1H),9.06(s,1H), 8.46 (d, J=4.7Hz, 1H), 7.63 (d, J=8.4Hz, 3H), 7.49 (d, J=8.5Hz, 2H), 7.03 (d, J=4.7Hz, 1H),6.29(s,1H),2.24(s,3H)；HRMS(ESI)m/z calcd for C17H15N7NaO[M+Na]+356.1236, found 356.1230.
Embodiment 38
N- (pyridin-3-yl)-N '-(4- (3- methyl-1 H- pyrazolos [3,4-b] pyridin-4-yl) phenyl) urea (compound IA- 28) preparation
In addition to isobutyl amine to be substituted for 3- pyridine amine, remaining required raw material, reagent and the same I of preparation methodA- 4, it must mark Inscribe 120 milligrams of compound, yield 52%.Mp：245-247℃；Purity：98%；
1H NMR(400MHz,DMSO-d6)δ:13.33 (s, 1H), 9.06 (s, 1H), 8.64 (s, 1H), 8.47 (d, J= 4.7Hz, 1H), 8.21 (d, J=4.1Hz, 1H), 7.97 (d, J=7.6Hz, 1H), 7.65 (d, J=8.5Hz, 2H), 7.51 (d, J=8.5Hz, 2H), 7.34 (dd, J=8.3,4.7Hz, 1H), 7.03 (d, J=4.7Hz, 1H), 6.66 (s, 1H), 2.25 (s, 3H)；HRMS(ESI)m/z calcd for C19H16N6NaO[M+Na]+367.1283,found 367.1278.
Embodiment 39
N- (pyridine -2- bases)-N '-(4- (3- methyl-1 H- pyrazolos [3,4-b] pyridin-4-yl) phenyl) urea (compound IA- 29) preparation
In addition to isobutyl amine to be substituted for 2- pyridine amine, remaining required raw material, reagent and the same I of preparation methodA- 4, it must mark Inscribe 46 milligrams of compound, yield 30%.Mp：244-248℃；Purity：96%；
1H NMR(400MHz,DMSO-d6)δ:13.32 (s, 1H), 10.74 (s, 1H), 9.53 (s, 1H), 8.46 (d, J= 4.7Hz, 1H), 8.30 (d, J=4.9Hz, 1H), 7.76 (t, J=7.8Hz, 1H), 7.70 (d, J=8.4Hz, 2H), 7.51 (t, J=8.0Hz, 3H), 7.02 (dd, J=8.1,4.0Hz, 2H), 2.23 (s, 3H)；HRMS(ESI)m/z calcd for C19H16N6NaO[M+Na]+367.1283,found 367.1278.
Embodiment 40
N- (2,3- dihydro -1H- indenes -2- bases)-N '-(4- (3- methyl-1 H- pyrazolos [3,4-b] pyridin-4-yl) phenyl) Urea (compound IA- 30) preparation
In addition to isobutyl amine to be substituted for 2- amino indenes, remaining required raw material, reagent and the same I of preparation methodA- 4, it obtains 50 milligrams of title compound, yield is 20%.Mp：249-251℃；Purity：96%；
1H NMR(400MHz,DMSO-d6)δ:13.30 (s, 1H), 8.55 (s, 1H), 8.44 (d, J=4.7Hz, 1H), 7.55 (d, J=8.5Hz, 2H), 7.43 (d, J=8.5Hz, 2H), 7.30-7.22 (m, 2H), 7.21-7.14 (m, 2H), 7.00 (d, J=4.7Hz, 1H), 6.55 (d, J=7.3Hz, 1H), 4.45 (m, 1H), 3.21 (dd, J=15.9,7.0Hz, 2H), 2.80 (dd, J=15.9,5.0Hz, 2H), 2.22 (d, J=5.9Hz, 3H)；HRMS(ESI)m/z calcd for C23H22N5O[M+H ]+384.1824,found 384.1819.
Embodiment 41
N- (naphthalene -2- bases)-N '-(4- (3- methyl-1 H- pyrazolos [3,4-b] pyridin-4-yl) phenyl) urea (compound IA- 31) preparation
In addition to isobutyl amine is substituted for 2- naphthylamines, remaining required raw material, reagent and the same I of preparation methodA- 4, it is marked 90 milligrams of compound is inscribed, yield is 34%.Mp：232-235℃；Purity：100%；
1H NMR(400MHz,DMSO-d6)δ:13.32 (s, 1H), 8.99 (d, J=5.5Hz, 2H), 8.47 (d, J= 4.7Hz, 1H), 8.14 (s, 1H), 7.89-7.78 (m, 3H), 7.68 (d, J=8.6Hz, 2H), 7.55-7.49 (m, 3H), 7.49-7.43 (m, 1H), 7.37 (t, J=7.5Hz, 1H), 7.04 (d, J=4.7Hz, 1H), 2.25 (d, J=8.6Hz, 3H)； HRMS(ESI)m/z calcd for C24H20N5O[M+1]+394.1668,found 394.1662.
Embodiment 42
N- (quinoline -3- bases)-N '-(4- (3- methyl-1 H- pyrazolos [3,4-b] pyridin-4-yl) phenyl) urea (compound IA- 32) preparation
In addition to isobutyl amine is substituted for 3- aminoquinolines, remaining required raw material, reagent and the same I of preparation methodA- 4, it obtains 80 milligrams of title compound, yield 30%.Mp：226-229℃；Purity：99%；
1H NMR(400MHz,DMSO-d6)δ:13.33 (s, 1H), 9.23 (s, 1H), 9.15 (s, 1H), 8.87 (d, J= 2.5Hz, 1H), 8.56 (d, J=2.3Hz, 1H), 8.47 (d, J=4.7Hz, 1H), 7.93 (dd, J=13.8,8.3Hz, 2H), 7.69 (d, J=8.5Hz, 2H), 7.64-7.55 (m, 2H), 7.53 (d, J=8.5Hz, 2H), 7.04 (d, J=4.7Hz, 1H), 2.26(s,3H)；HRMS(ESI)m/z calcd for C23H19N6O[M+H]+395.1620,found 395.1615.
Embodiment 43
N- (naphthalene -1- bases)-N '-(4- (3- methyl-1 H- pyrazolos [3,4-b] pyridin-4-yl) phenyl) urea (compound IA- 33) preparation
In addition to isobutyl amine is substituted for naphthalidine, remaining required raw material, reagent and the same I of preparation methodA- 4, obtain title 170 milligrams of compound, yield 69%.Mp：225-228℃；Purity：99%；
1H NMR(400MHz,DMSO-d6)δ:13.34 (s, 1H), 8.87 (s, 1H), 8.48 (d, J=4.6Hz, 1H), 8.15 (d, J=8.4Hz, 1H), 8.03 (d, J=7.5Hz, 1H), 7.96 (d, J=8.0Hz, 1H), 7.75-7.47 (m, 9H), 7.04 (d, J=4.6Hz, 1H), 2.26 (s, 3H)；HRMS(ESI)m/z calcd forC24H20N5O[M+H]+394.1668, found 394.1662.
Embodiment 44
N- (2- morpholine -4- bases ethyl)-N '-(4- (3- methyl-1 H- pyrazolos [3,4-b] pyridin-4-yl) phenyl) urea (IA- 34) preparation
395 microlitres of N- (2- amino-ethyls) morpholine is dissolved in 4.6 milliliters of n,N-Dimethylformamide, adds in 2.25 milliliters Pyridine obtains reaction system 1.452 microlitres of phenyl chloroformates are dissolved in 2 milliliters of tetrahydrofuran solutions, and under ice bath dropwise Add in reaction system 1.When normal-temperature reaction 3 is small, after reaction, suitable water is added in into system, is extracted with ethyl acetate three Secondary, saturated common salt washing, anhydrous magnesium sulfate drying is filtered, and concentration obtains residue.Residue is dissolved in 5 milliliters of dioxane In, add in 60 milligrams of 4- (3- methyl-1 H- pyrazoles [3,4-b] pyridin-4-yl) aniline (intermediate VIII) and 20 microlitres of 1- methyl Pyrrolidines, back flow reaction are overnight.After reaction, it is cooled to room temperature, is evaporated under reduced pressure, residue is through column chromatography for separation (methanol:Two Chloromethanes=1:15, v/v) title compound, is obtained, 45 milligrams of yellow solids, yield is 44%.Mp：98-101；Purity： 95%.
1H-NMR(400MHz,DMSO-d6)δ:13.30 (s, 1H), 8.88 (s, 1H), 8.45 (d, J=4.8Hz, 1H), 7.57 (d, J=8.4Hz, 2H), 7.43 (d, J=8.4Hz, 2H), 7.00 (d, J=4.8Hz, 1H), 6.18 (t, J=5.2Hz, 1H), 3.61 (brs, 4H), 3.55 (t, J=5.6Hz, 2H), 3.24 (q, J=11.6Hz, 5.6Hz, 2H), 2.41 (brs, 4H), 2.23(s,3H)；HRMS(ESI)m/z calcd for C20H25N6O2[M+H]+381.2034,found 381.2029.
Embodiment 45
N- (2- dimethylaminoethyls)-N '-(4- (3- methyl-1 H- pyrazolos [3,4-b] pyridin-4-yl) phenyl) urea (IA- 35) preparation
Except changing N- (2- amino-ethyls) morpholine into N, outside N- dimethyl-ethylenediamines, remaining required raw material, reagent and The same I of preparation methodA- 34, obtain 39 milligrams of title compound, yellow oil, yield 43%.Mp：54-56℃；Purity：99%；
1H-NMR(400MHz,DMSO-d6)δ::13.32 (s, 1H), 9.01 (s, 1H), 8.46 (d, J=4.8Hz, 1H), 7.56 (d, J=8.4Hz, 2H), 7.43 (d, J=8.4Hz, 2H), 7.00 (d, J=4.8Hz, 1H), 6.29 (t, J=5.6Hz, 1H), 3.24 (q, J=11.6Hz, 6.0Hz, 2H), 2.45 (t, J=6.0Hz, 2H), 2.27 (s, 6H), 2.24 (s, 3H)；HRMS (ESI)m/z calcd forC18H23N6O[M+H]+339.1928,found339.1927.
Embodiment 46
N- (2- methyl -4- (4- methylpiperazine-1-yls) phenyl)-N '-(4- (3- methyl-1 H- pyrazolos [3,4-b] pyrroles Pyridine -4- bases) phenyl) urea (IA- 36) preparation
1 gram of 5- fluorine-2-nitro methylbenzene and 1.783 grams of potassium carbonate are dissolved in 7 milliliters of dimethyl sulfoxide (DMSO)s, add in 1.072 millis It rises and is stirred overnight at N methyl piperazine, with 122 DEG C.After reaction, it is cooled to room temperature, suitable quantity of water is added in into system, uses second Acetoacetic ester extracts three times, saturated common salt washing, and anhydrous magnesium sulfate drying is filtered, and concentration obtains intermediate X V：1.2g.
1.2 grams of intermediate X V are dissolved in methanol, 120 milligrams of 10%Pd/C is added in, is passed through hydrogen, reacted at room temperature Night.After reaction, filter, concentration, residue is through column chromatography for separation (ethyl acetate:Petroleum ether=1:2, v/v) centre, is obtained Body XVI：0.935 gram.
In addition to changing N- (2- amino-ethyls) morpholine into intermediate X VI, remaining required raw material, reagent and preparation method Same IA- 34, title compound is obtained, 29 milligrams of pink solids, yield is 24%.Mp：263-264；Purity：95%.
1H-NMR(400MHz,DMSO-d6)δ::13.33 (s, 1H), 9.09 (s, 1H), 8.46 (d, J=4.8Hz, 1H), 7.86 (s, 1H), 7.62 (d, J=8.4Hz, 1H), 7.48 (d, J=8.4Hz, 3H), 7.02 (d, J=4.8Hz, 1H), 6.81 (s, 1H), 6.75 (d, J=8.8Hz, 1H), 3.07 (t, J=4.4Hz, 4H), 2.45 (t, J=4.4Hz, 4H), 2.25 (s, 3H),2.21(s,6H)；HRMS(ESI)m/z calcd for C26H30N7O[M+H]+456.2506,found 456.2504.
Embodiment 47
N- (3- methyl -4- (4- methylpiperazine-1-yls) phenyl)-N '-(4- (3- methyl-1 H- pyrazolos [3,4-b] pyrroles Pyridine -4- bases) phenyl) urea (IA- 37) preparation
In addition to 5- fluorine-2-nitro methylbenzenes to be changed into the fluoro- 5- nitrotoleunes of 2-, remaining required raw material, reagent and preparation The same I of methodA- 36, obtain 24 milligrams of title compound, Off-white solid, yield 20%.Mp：236-238；Purity：95%；
1H-NMR(400MHz,DMSO-d6)δ::13.34 (s, 1H), 8.87 (s, 1H), 8.58 (s, 1H), 8.46 (d, J= 4.8Hz, 1H), 7.62 (d, J=8.6Hz, 2H), 7.48 (d, J=8.6Hz, 2H), 7.27 (s, 1H), 7.24 (d, J=8.4Hz, 1H), 7.02 (d, J=4.8Hz, 1H), 6.97 (d, J=8.8Hz, 1H), 2.79 (t, J=4.4Hz, 4H), 2.45 (brs, 4H), 2.24(t,9H)；HRMS(ESI)m/z calcd for C26H30N7O[M+H]+456.2506,found 456.2506.
Embodiment 48
N- (3- (4- methylpiperazine-1-yls) phenyl)-N '-(4- (3- methyl-1 H- pyrazolos [3,4-b] pyridin-4-yl) Phenyl) urea (IA- 38) preparation
In addition to changing 5- fluorine-2-nitro methylbenzenes into 3- fluoronitrobenzenes, remaining required raw material, reagent and preparation method are same IA- 36, obtain 32 milligrams of title compound, yellow solid, yield 27%.Mp：108-109；Purity：95%；
1H-NMR(400MHz,DMSO-d6)δ:13.33 (s, 1H), 8.91 (s, 1H), 8.68 (s, 1H), 8.46 (d, J= 4.8Hz, 1H), 7.63 (d, J=8.4Hz, 3H), 7.49 (d, J=8.4Hz, 2H), 7.20 (s, 1H), 7.12 (t, J=8.0Hz, 1H), 7.02 (d, J=4.8Hz, 1H), 6.81 (d, J=7.6Hz, 1H), 6.59 (d, J=8.0Hz, 1H), 3.13 (brs, 4H), 2.50(brs,4H),2.25(d,6H)；HRMS(ESI)m/z calcd for C25H28N7O[M+H]+442.2350, found442.2348.
Embodiment 49
N- (2- (4- methylpiperazine-1-yls) phenyl)-N '-(4- (3- methyl-1 H- pyrazolos [3,4-b] pyridin-4-yl) Phenyl) urea (IA- 39) preparation
In addition to changing 5- fluorine-2-nitro methylbenzenes into 2- fluoronitrobenzenes, remaining required raw material, reagent and preparation method are same IA- 36, obtain 105 milligrams of title compound, white solid, yield 89%.Mp：253-253；Purity：99%；
1H-NMR(400MHz,DMSO-d6)δ:13.33 (s, 1H), 8.91 (s, 1H), 8.68 (s, 1H), 8.46 (d, J= 4.8Hz, 1H), 7.63 (d, J=8.4Hz, 3H), 7.49 (d, J=8.4Hz, 2H), 7.20 (s, 1H), 7.12 (t, J=8.0Hz, 1H), 7.02 (d, J=4.8Hz, 1H), 6.81 (d, J=7.6Hz, 1H), 6.59 (d, J=8.0Hz, 1H), 3.13 (brs, 4H), 2.50(brs,4H),2.25(d,6H)；HRMS(ESI)m/z calcd for C25H28N7O[M+H]+442.2350,found 442.2346.
Embodiment 50
N- (5- methyl -2- (4- methylpiperazine-1-yls) phenyl)-N '-(4- (3- methyl-1 H- pyrazolos [3,4-b] pyrroles Pyridine -4- bases) phenyl) urea (IA- 40) preparation
In addition to 5- fluorine-2-nitro methylbenzenes to be changed into the fluoro- 5- nitrotoleunes of 4-, remaining required raw material, reagent and preparation The same I of methodA- 36, obtain 23 milligrams of title compound, white solid, yield 19%.Mp：247-250；Purity：95%；
1H-NMR(400MHz,DMSO-d6)δ:13.33 (s, 1H), 9.81 (s, 1H), 8.47 (d, J=4.8Hz, 1H), 8.08 (s, 1H), 7.89 (s, 1H), 7.68 (d, J=8.4Hz, 2H), 7.50 (d, J=8.4Hz, 2H), 7.07 (d, J= 8.0Hz, 1H), 7.03 (d, J=4.8Hz, 1H), 6.79 (d, J=8.0Hz, 1H), 2.79 (t, J=4.0Hz, 4H), 2.64 (brs,4H),2.31(s,3H),2.25(s,6H)；HRMS(ESI)m/z calcd for C26H30N7O[M+H]+456.2506, found 456.2504.
Embodiment 51
N- (3- methyl -4- (morpholine -4- bases) phenyl)-N '-(4- (3- methyl-1 H- pyrazolos [3,4-b] pyridin-4-yl) Phenyl) urea (IA- 41) preparation
Except changing 5- fluorine-2-nitro methylbenzenes into 2- fluoro- 5- nitrotoleunes, N methyl piperazine is changed into outside morpholine, remaining Required raw material, reagent and the same I of preparation methodA- 36, title compound is obtained, 13 milligrams of white solids, yield is 11%.Mp： 253-255；Purity：90%.
1H-NMR(400MHz,DMSO-d6)δ:13.32 (s, 1H), 8.85 (s, 1H), 8.57 (s, 1H), 8.46 (d, J= 4.8Hz, 1H), 7.62 (d, J=8.4Hz, 2H), 7.48 (d, J=8.4Hz, 2H), 7.28 (s, 1H), 7.26 (d, J=8.4Hz, 1H), 7.03 (d, J=4.8Hz, 1H), 6.98 (d, J=8.4Hz, 1H), 3.73 (t, J=4.4Hz, 4H), 2.79 (t, J= 4.4Hz,4H),2.25(s,6H).；HRMS(ESI)m/z calcd for C25H27N6O2[M+H]+443.2190,found 443.2188.
Embodiment 52
N- (2- (morpholine -4- bases) phenyl)-N '-(4- (3- methyl-1 H- pyrazolos [3,4-b] pyridin-4-yl) phenyl) urea (IA- 42) preparation
Except changing 5- fluorine-2-nitro methylbenzenes into 2- fluoronitrobenzenes, N methyl piperazine is changed into outside morpholine, original needed for remaining Material, reagent and the same I of preparation methodA- 36, obtain 45 milligrams of title compound, Off-white solid, yield 39%.Mp：225-228℃； Purity：99%；
1H-NMR(400MHz,DMSO-d6)δ:13.33 (s, 1H), 9.76 (s, 1H), 8.47 (d, J=4.4Hz, 1H), 8.20 (s, 1H), 8.08 (d, J=8.0Hz, 1H), 7.68 (d, J=8.4Hz, 2H), 7.51 (d, J=8.4Hz, 2H), 7.20 (d, J=7.2Hz, 1H), 7.10 (t, J=7.2Hz, 1H), 7.03 (d, J=4.4Hz, 1H), 6.99 (d, J=8.0Hz, 1H), 3.87(brs,4H),2.83(brs,4H),2.25(s,3H).HRMS(ESI)m/z calcd for C24H25N6O2[M+H]+ 429.2034,found 429.2033.
Embodiment 53
N- (5- methyl -2- (morpholine -4- bases) phenyl)-N '-(4- (3- methyl-1 H- pyrazolos [3,4-b] pyridin-4-yl) Phenyl) urea (IA- 43) preparation
Except changing 5- fluorine-2-nitro methylbenzenes into 4- fluoro- 5- nitrotoleunes, N methyl piperazine is changed into outside morpholine, remaining Required raw material, reagent and the same I of preparation methodA- 36, obtain 57 milligrams of title compound, yellow solid, yield 48%.Mp：268- 270；Purity：98%；
1H-NMR(400MHz,DMSO-d6)δ:13.34 (s, 1H), 9.76 (s, 1H), 8.47 (d, J=4.4Hz, 1H), 8.19 (s, 1H), 7.94 (s, 1H), 7.68 (d, J=8.4Hz, 2H), 7.51 (d, J=8.4Hz, 2H), 7.09 (d, J= 8.0Hz, 1H), 7.03 (d, J=4.4Hz, 1H), 6.81 (d, J=8.0Hz, 1H), 3.86 (t, J=3.6Hz, 4H), 2.79 (t, J=3.6Hz, 4H), 2.26 (d, 6H)；HRMS(ESI)m/z calcd for C25H27N6O2[M+H]+443.2190,found 443.2188.
Embodiment 54
N- ((4- diethylin) phenyl)-N '-(4- (3- methyl-1 H- pyrazolos [3,4-b] pyridin-4-yl) phenyl) urea (IA- 44) preparation
Except changing 5- fluorine-2-nitro methylbenzenes into p-fluoronitrobenzene, N methyl piperazine is changed into outside diethylamine, needed for remaining Raw material, reagent and the same I of preparation methodA- 36, obtain 81 milligrams of title compound, sepia solid, yield 73%.Mp：242-246 ℃；Purity：95%；
1H-NMR(400MHz,DMSO-d6)δ:13.32 (s, 1H), 8.76 (s, 1H), 8.46 (d, J=4.8Hz, 1H), 8.33 (s, 1H), 7.63 (d, J=8.4Hz, 2H), 7.47 (d, J=8.4Hz, 2H), 7.25 (d, J=8.8Hz, 2H), 7.00 (d, J=4.8Hz, 1H), 6.64 (d, J=8.8Hz, 2H), 3.27 (q, J=6.8Hz, 4H), 2.26 (s, 3H), 1.07 (t, J= 6.8Hz,6H)；HRMS(ESI)m/z calcd for C24H27N6O[M+H]+415.2241,found 415.2238.
Embodiment 55
N- ((3- dimethylamino) phenyl)-N '-(4- (3- methyl-1 H- pyrazolos [3,4-b] pyridin-4-yl) phenyl) urea (IA- 45) preparation
7.2 milliliter of 40% formalin is placed on 2.56 milliliters of concentrated sulfuric acids under ice bath and is stirred, obtains system 1, between 2.4 grams The tetrahydrofuran of nitroaniline and 4.24 grams of sodium borohydrides (80 milliliters) solution is slowly added in system 1, and it is small that 2 are reacted under ice bath When, 1.92 grams of sodium hydroxides are added in, stir half an hour.After reaction, suitable quantity of water is added in into system, is extracted with ethyl acetate Three times, anhydrous sodium sulfate is dried, and is filtered, and vacuum distillation, residue is through column chromatography for separation (ethyl acetate:Petroleum ether=1:20, v/ V) 1.8 grams of intermediate are obtained
1.8 grams of intermediate X VII are dissolved in methanol, 900 milligrams of 10%Pd/C is added in, is passed through hydrogen, reacted at room temperature Night.After reaction, filter, concentration, residue is through column chromatography for separation (ethyl acetate:Petroleum ether=1:10, v/v) 1.3, are obtained Gram intermediate X VIII.
In addition to changing N- (2- amino-ethyls) morpholine into intermediate X VIII, remaining required raw material, reagent and preparation side The same I of methodA- 34, obtain 20 milligrams of title compound, faint yellow solid, yield 19%.Mp：226-228℃；Purity：98%；
1H-NMR(400MHz,DMSO-d6)δ:13.33 (s, 1H), 8.84 (s, 1H), 8.61 (s, 1H), 8.46 (d, J= 4.8Hz, 1H), 7.63 (d, J=8.4Hz, 2H), 7.49 (d, J=8.4Hz, 2H), 7.08 (t, J=8.0Hz, 1H), 7.03 (d, J=4.8Hz, 1H), 6.95 (s, 1H), 6.74 (d, J=8.0Hz, 1H), 6.38 (d, J=8.0Hz, 1H), 2.89 (s, 7H), 2.25(s,3H)；HRMS(ESI)m/z calcd for C22H23N6O[M+H]+387.1928,found 387.1925.
Embodiment 56
N- ((3- diethylin) phenyl)-N '-(4- (3- methyl-1 H- pyrazolos [3,4-b] pyridin-4-yl) phenyl) urea (IA- 46) preparation
In addition to 40% formalin is substituted for 40% acetaldehyde solution, remaining required raw material, reagent and preparation method Same IA- 45, obtain 29 milligrams of title compound, blue or green brown solid, yield 26%.Mp：125-128℃；Purity：97%；
1H-NMR(400MHz,DMSO-d6)δ:13.34 (s, 1H), 8.84 (s, 1H), 8.59 (s, 1H), 8.47 (d, J= 4.8Hz, 1H), 7.63 (d, J=8.4Hz, 2H), 7.49 (d, J=8.4Hz, 2H), 7.03 (t, J=4.8Hz, 8.4Hz, 2H), 6.92 (s, 1H), 6.63 (d, J=8.4Hz, 1H), 6.31 (d, J=8.4Hz, 1H), 3.31 (q, J=7.2Hz, 4H), 2.25 (s, 3H), 1.10 (t, J=7.2Hz, 6H)；HRMS(ESI)m/z calcd for C24H27N6O[M+H]+415.2241,found 415.2241.
Embodiment 57
N- (4- ((dimethylamino) methyl) phenyl)-N '-(4- (3- methyl-1 H- pyrazolos [3,4-b] pyridin-4-yl) benzene Base) urea (IA- 47) preparation
Except changing into 5- fluorine-2-nitro methylbenzenes to nitro benzyl chloride, N methyl piperazine is changed into outside dimethylamine, needed for remaining Raw material, reagent and the same I of preparation methodA- 36, obtain title compound, 100 milligrams of yellow solid, yield 93%.Mp：59-62℃； Purity：95%；
1H-NMR(400MHz,DMSO-d6)δ:13.34 (s, 1H), 8.96 (s, 1H), 8.80 (s, 1H), 8.47 (d, J= 4.8Hz, 1H), 7.64 (d, J=8.4Hz, H2), 7.49 (d, J=8.4Hz, 2H), 7.43 (d, J=8.4Hz, 2H), 7.20 (d, J=8.4Hz, 2H), 7.00 (t, J=4.8Hz, 1H), 3.34-3.33 (s, 2H), 2.25 (s, 3H), 2.13 (s, 6H)；HRMS (ESI)m/z calcd for C23H25N6O[M+H]+401.2084,found 401.2083.
Embodiment 58
N- (4- ((diethylin) methyl) phenyl)-N '-(4- (3- methyl-1 H- pyrazolos [3,4-b] pyridin-4-yl) benzene Base) urea (IA- 48) preparation
Except changing 5- fluorine-2-nitro methylbenzenes into nitro benzyl chloride, N methyl piperazine is changed into outside diethylamine, original needed for remaining Material, reagent and the same I of preparation methodA- 36, obtain title compound, 50 milligrams of yellow solid, yield 44%.Mp：123-125℃；It is pure Degree：97%；
1H-NMR(400MHz,DMSO-d6)δ:13.34 (s, 1H), 8.92 (s, 1H), 8.74 (s, 1H), 8.46 (d, J= 4.8Hz, 1H), 7.63 (d, J=8.4Hz, 2H), 7.49 (d, J=8.4Hz, 2H), 7.41 (d, J=7.6Hz, 2H), 7.23 (d, J=7.6Hz, 2H), 7.03 (d, J=4.8Hz, 1H), 3.46 (s, 2H), 2.44 (s, 4H), 2.25 (s, 3H), 0.98 (s, 6H)； HRMS(ESI)m/z calcd for C25H29N6O[M+H]+429.2397,found 429.2396.
Embodiment 59
N- (3- ((dimethylamino) methyl) phenyl)-N '-(4- (3- methyl-1 H- pyrazolos [3,4-b] pyridin-4-yl) benzene Base) urea (IA- 49) preparation
Except changing 5- fluorine-2-nitro methylbenzenes into a nitrobenzyl bromine, N methyl piperazine is changed into outside dimethylamine, needed for remaining Raw material, reagent and the same I of preparation methodA- 36, obtain title compound, 25 milligrams of yellow solid, yield 23%.Mp：185-186℃； Purity：90%；
1H-NMR(400MHz,DMSO-d6)δ:13.39 (s, 1H), 9.64 (s, 1H), 9.25 (s, 1H), 8.52 (d, J= 2.8Hz, 1H), 7.95 (d, J=7.6Hz, 1H), 7.73 (d, J=7.2Hz, 2H), 7.55 (d, J=7.2Hz, 2H), 7.31 (t, J=6.4Hz, 1H), 7.23 (d, J=6.4Hz, 1H), 7.08 (d, J=2.8Hz, 1H), 7.04 (t, J=6.4Hz, 1H), 3.50 (s,2H),2.30(s,3H),2.24(s,6H)；HRMS(ESI)m/z calcd for C23H25N6O[M+H]+401.2084, found 401.2082.
Embodiment 60
N- ((4- dimethylamino) phenyl)-N '-(4- (3- methyl-1 H- pyrazolos [3,4-b] pyridin-4-yl) phenyl) urea (IA- 50) preparation
Except changing 5- fluorine-2-nitro methylbenzenes into p-fluoronitrobenzene, N methyl piperazine is changed into outside dimethylamine, needed for remaining Raw material, reagent and the same I of preparation methodA- 36, obtain title compound, 10 milligrams of sepia solid, yield 10%.Mp：218-221 ℃；Purity：90%；
1H-NMR(400MHz,DMSO-d6)δ:13.33 (s, 1H), 8.78 (s, 1H), 8.46 (d, J=4.4Hz, 1H), 8.41 (s, 1H), 7.61 (d, J=8.4Hz, 2H), 7.48 (d, J=8.4Hz, 2H), 7.29 (d, J=8.8Hz, 2H), 7.02 (d, J=4.4Hz, 1H), 6.72 (d, J=8.8Hz, 2H), 2.82 (d, 6H), 2.23 (s, 3H)；HRMS(ESI)m/z calcd for C22H23N6O[M+H]+387.1928,found 387.1928.
Embodiment 61
N- n-pentyls-N '-(4- (3- Trifluoromethyl-1 H- pyrazolos [3,4-b] pyridin-4-yl) phenyl) urea (IB- 1) It prepares
Except isobutyl amine is replaced n-hexylamine, intermediate VIII is substituted for outside XIV, remaining required raw material, reagent and system The same I of Preparation MethodA- 4, title compound is obtained, 20 milligrams of white powders, yield is 20.Mp：215-216℃；Purity：99%；
1H NMR(400MHz,DMSO-d6)δ:14.73 (s, 1H), 8.66 (d, J=3.6Hz, 2H), 7.53 (d, J= 8.4Hz, 2H), 7.35 (d, J=8.4Hz, 2H), 7.24 (d, J=3.6Hz, 1H), 6.24 (t, J=5.4Hz, 1H), 3.10 (q, J=12.8,6.4Hz, 2H), 1.43 (m, 2H), 1.29 (m, 6H), 0.87 (t, J=6.8Hz, 3H) .HRMS (ESI) m/z calcd for C20H22N5OF3[M+H]+405.1776,found 405.1777.
Embodiment 62
N- (3- phenylpropyls)-N '-(4- (3- Trifluoromethyl-1 H- pyrazolos [3,4-b] pyridin-4-yl) phenyl) urea (IB- 2) preparation
Except isobutyl amine is substituted for phenyl ethylamine, intermediate VIII is substituted for outside XIV, remaining required raw material, reagent and The same I of preparation methodA- 4, obtain 27 milligrams of title compound, white solid, yield 25%.Mp：225-227℃；Purity：95%；
1H NMR(400MHz,DMSO-d6)δ:14.69 (s, 1H), 8.76 (s, 1H), 8.67 (d, J=4.8Hz, 1H), 7.54 (d, J=8.4Hz, 2H), 7.34 (dd, J=12.8,8.0Hz, 4H), 7.25 (m, 4H), 6.25 (t, J=5.6Hz, 1H), 2.78 (t, J=7.0Hz, 2H), 1.26 (m, 1H), 0.87 (brs, 1H) .HRMS (ESI) m/z calcd for C22H18N5OF3 [M+H]+425.1463,found 425.1465.
Embodiment 63
N- (3- phenylpropyls)-N '-(4- (3- Trifluoromethyl-1 H- pyrazolos [3,4-b] pyridin-4-yl) phenyl) urea (IB- 3) preparation
Except isobutyl amine is substituted for amphetamine, intermediate VIII is substituted for outside XIV, remaining required raw material, reagent and The same I of preparation methodA- 4, obtain title compound, 18 milligrams of white powder, yield 16%.Mp：212-214℃；Purity：100%；
1H NMR(400MHz,DMSO-d6)δ:14.71 (s, 1H), 8.70 (s, 1H), 8.67 (d, J=4.8Hz, 1H), 7.55 (d, J=8.4Hz, 2H), 7.36 (d, J=8.4Hz, 2H), 7.30 (t, J=7.4Hz, 2H), 7.24 (d, J=4.4Hz, 3H), 7.19 (t, J=7.2Hz, 1H), 6.33 (t, J=5.6Hz, 1H), 3.13 (dd, J=12.8,6.4Hz, 2H), 2.63 (t, J=7.6Hz, 2H), 1.76 (m, 2H) .HRMS (ESI) m/z calcd for C23H20N5OF3[M+H]+439.1620,found 439.1613.
Embodiment 64
N- (4- chlorobenzene ethyls)-N '-(4- (3- Trifluoromethyl-1 H- pyrazolos [3,4-b] pyridin-4-yl) phenyl) urea (IB- 4) preparation
Except isobutyl amine is substituted for 4- chlorophenethylamines, intermediate VIII is substituted for outside XIV, remaining required raw material, examination Agent and the same I of preparation methodA- 4, obtain title compound, 26 milligrams of pale yellow powder, yield 23%.Mp：228-232℃；Purity： 97%；
1H NMR(400MHz,DMSO-d6)δ:14.71 (s, 1H), 8.72 (s, 1H), 8.67 (d, J=4.8Hz, 1H), 7.53 (d, J=8.4Hz, 2H), 7.37 (dd, J=12.4,8.4Hz, 4H), 7.29 (d, J=8.0Hz, 2H), 7.24 (d, J= 4.8Hz, 1H), 6.23 (t, J=5.6Hz, 1H), 2.77 (t, J=6.8Hz, 2H), 1.24 (s, 1H), 0.84 (t, 1H) .HRMS (ESI)m/z calcd for C22H17N5OF3Na[M+Na]+482.0971,found 482.0973.
Embodiment 65
N- (2- dimethylaminoethyls)-N '-(4- (3- Trifluoromethyl-1 H- pyrazolos [3,4-b] pyridin-4-yl) phenyl) Urea (IB- 5) preparation
Except isobutyl amine is substituted for N, N- dimethyl-ethylenediamines, intermediate VIII is changed into outside intermediate X IV, remaining institute Need raw material, reagent and the same I of preparation methodA- 4, obtain 41 milligrams of title compound, Off-white solid, yield 42%.Mp：165-168 ℃；Purity：97%；
1H-NMR(400MHz,DMSO-d6)δ:8.93 (s, 1H), 8.67 (d, J=4.4Hz, 1H), 7.53 (d, J= 8.4Hz, 2H), 7.35 (d, J=8.4Hz, 2H), 7.24 (d, J=4.4Hz, 1H), 6.22 (t, J=5.2Hz, 1H), 3.22 (dd, J=11.6,6.0Hz, 2H), 2.39 (t, J=6.0Hz, 2H), 2.22 (s, 6H) .HRMS (ESI) m/z calcd for C18H20N6OF3[M+H]+393.1651,found 393.1651.
Embodiment 66
N- (2- diethyllaminoethyls)-N '-(4- (3- Trifluoromethyl-1 H- pyrazolos [3,4-b] pyridin-4-yl) phenyl) Urea (IB- 6) preparation
Except isobutyl amine is substituted for N, N- diethyl ethylenediamines, intermediate VIII is changed into outside intermediate X IV, remaining institute Need raw material, reagent and the same I of preparation methodA- 4, obtain title compound, 35 milligrams of off-white powder, yield 33%.Mp：128-132 ℃；Purity：97%；
1H-NMR(400MHz,DMSO-d6)δ:9.04 (s, 1H), 8.67 (d, J=4.4Hz, 1H), 7.55 (d, J= 8.4Hz, 2H), 7.35 (d, J=8.4Hz, 2H), 7.24 (d, J=4.4Hz, 1H), 6.29 (s, 1H), 3.24 (q, J=5.6Hz, 2H), 2.65 (s, 6H), 1.03 (t, J=7.2,8.9Hz, 6H) .HRMS (ESI) m/z calcd for C20H24N6OF3[M+H]+ 421.1964,found 421.1967.
Embodiment 67
N- (3- dimethylamino-propyls)-N '-(4- (3- Trifluoromethyl-1 H- pyrazolos [3,4-b] pyridin-4-yl) phenyl) Urea (IB- 7) preparation
Except isobutyl amine is substituted for 3- dimethylaminopropylamines, intermediate VIII is changed into outside intermediate X IV, needed for remaining Raw material, reagent and the same I of preparation methodA- 4, obtain title compound, 28 milligrams of pale yellow powder, yield 27%.Mp：186-189 ℃；Purity：96%；
1H-NMR(400MHz,DMSO-d6)δ:8.79 (s, 1H), 8.66 (d, J=4.8Hz, 1H), 7.54 (d, J= 8.4Hz, 2H), 7.35 (d, J=8.4Hz, 2H), 7.24 (d, J=4.8Hz, 1H), 6.33 (t, J=5.6Hz, 1H), 3.14 (dd, J=12.4,6.4Hz, 2H), 2.35 (t, J=6.0Hz, 2H), 2.21 (s, 6H), 1.61 (m, 2H) .HRMS (ESI) m/z calcd for C19H21N6OF3[M+H]+406.1729,found 406.1731.
Embodiment 68
N- (3- lignocaines propyl)-N '-(4- (3- Trifluoromethyl-1 H- pyrazolos [3,4-b] pyridin-4-yl) phenyl) Urea (IB- 8) preparation
Except isobutyl amine is substituted for 3 diethyl aminopropylamine, intermediate VIII is changed into outside intermediate X IV, needed for remaining Raw material, reagent and the same I of preparation methodA- 4, obtain title compound, 12 milligrams of off-white powder, yield 11%.Mp：217-220 ℃；Purity：99%；
1H-NMR(400MHz,DMSO-d6)δ:14.71 (s, 1H), 9.15 (s, 1H), 8.67 (d, J=4.4Hz, 1H), 7.55 (d, J=8.4Hz, 2H), 7.35 (d, J=8.4Hz, 2H), 7.24 (d, J=4.4Hz, 1H), 6.69 (s, 1H), 3.20 (q, J=11.6,6.0Hz, 2H), 3.06 (brs, 6H), 1.82 (brs, 2H), 1.21 (m, 6H) .HRMS (ESI) m/z calcd for C21H26N6OF3[M+H]+435.2120,found 435.2118.
Embodiment 69
N- (2- piperidin-1-yls ethyl)-N '-(4- (3- Trifluoromethyl-1 H- pyrazolos [3,4-b] pyridin-4-yl) phenyl) Urea (IB- 9) preparation
Except isobutyl amine is substituted for 1- (2- aminoethyls) piperidines, intermediate VIII is changed into outside intermediate X IV, remaining institute Need raw material, reagent and the same I of preparation methodA- 4, obtain title compound, 34 milligrams of pale yellow powder, yield 31%.Mp：120-122 ℃；Purity：93%；
1H-NMR(400MHz,DMSO-d6)δ:8.91 (s, 1H), 8.67 (d, J=4.4Hz, 1H), 7.54 (d, J= 8.4Hz, 2H), 7.35 (d, J=8.4Hz, 2H), 7.24 (d, J=4.4Hz, 1H), 6.17 (t, J=4.8Hz, 1H), 3.23 (dd, J=11.6,6.0Hz, 2H), 2.36 (t, 6H), 1.53 (m, 4H), 1.40 (m, 2H) .HRMS (ESI) m/z calcd for C21H24N6OF3[M+H]+433.1964,found 433.1963.
Embodiment 70
N- (2- morpholine -4- bases ethyl)-N '-(4- (3- Trifluoromethyl-1 H- pyrazolos [3,4-b] pyridin-4-yl) phenyl) Urea (IB- 10) preparation
Except isobutyl amine is substituted for N- (2- amino-ethyls) morpholine, intermediate VIII is changed into outside intermediate X IV, remaining Required raw material, reagent and the same I of preparation methodA- 4, obtain title compound, 35 milligrams of pale yellow powder, yield 32%.Mp：217- 219℃；Purity：96%；
1H-NMR(400MHz,DMSO-d6)δ:14.70 (s, 1H), 8.92 (s, 1H), 8.66 (d, J=4.8Hz, 1H), 7.54 (d, J=8.4Hz, 2H), 7.35 (d, J=8.4Hz, 2H), 7.24 (d, J=4.8Hz, 1H), 6.21 (t, J=5.2Hz, 1H), 3.61 (t, J=4.4Hz, 4H), 3.24 (dd, J=11.6,6.0Hz, 2H), 2.41 (t, 6H) .HRMS (ESI) m/z calcd for C20H22N6O2F3[M+H]+435.1756,found 435.1754.
Embodiment 71
N- (4- (4- methylpiperazine-1-yls) phenyl)-N '-(4- (3- Trifluoromethyl-1 H- pyrazolo [3,4-b] pyridines -4- Base) phenyl) urea (IB- 11) preparation
Except 5- fluorine-2-nitro methylbenzenes are substituted for 4- fluoronitrobenzenes, intermediate VIII is substituted for outside intermediate X IV, Remaining required raw material, reagent and the same I of preparation methodA- 36, obtain 37 milligrams of title compound, silver gray solid, yield 30%.Mp： 267-268℃；Purity：96%；
1H-NMR(400MHz,DMSO-d6)δ:14.73 (s, 1H), 8.83 (s, 1H), 8.68 (d, J=4.8Hz, 1H), 8.52 (s, 1H), 7.59 (d, J=8.4Hz, 2H), 7.40 (d, J=8.4Hz, 2H), 7.32 (d, J=8.8Hz, 2H), 7.26 (d, J=4.8Hz, 1H), 6.90 (d, J=8.8Hz, 2H), 3.06 (s, 4H), 2.44 (s, 4H), 2.24 (s, 3H) .HRMS (ESI)m/z calcd for C25H25N7OF3[M+H]+496.2073,found 496.2079.
Embodiment 72
N- (2- methyl -4- (4- methylpiperazine-1-yls) phenyl)-N '-(4- (3- Trifluoromethyl-1 H- pyrazolos [3,4-b] Pyridin-4-yl) phenyl) urea (IB- 12) preparation
In addition to intermediate VIII is substituted for intermediate X IV, remaining required raw material, reagent and the same I of preparation methodA- 36, obtain title compound, 22 milligrams of chocolate brown powder, yield 17%.Mp：250-253℃；Purity：91%；
1H-NMR(400MHz,DMSO-d6)δ:14.74 (s, 1H), 9.07 (s, 1H), 8.68 (d, J=4.4Hz, 1H), 7.86 (s, 1H), 7.59 (d, J=8.4Hz, 2H), 7.48 (d, J=8.8Hz, 1H), 7.40 (d, J=8.4Hz, 2H), 7.26 (d, J=4.4Hz, 1H), 6.81 (s, 1H), 6.76 (d, J=8.8Hz, 1H), 3.09 (s, 4H), 2.46 (s, 4H), 2.23 (d, 6H).HRMS(ESI)m/z calcd for C26H27N7OF3[M+H]+510.2229,found 510.2232.
Embodiment 73
N- (3- methyl -4- (4- methylpiperazine-1-yls) phenyl)-N '-(4- (3- Trifluoromethyl-1 H- pyrazolos [3,4-b] Pyridin-4-yl) phenyl) urea (IB- 13) preparation
Except 5- fluorine-2-nitro methylbenzenes are substituted for the fluoro- 5- nitrotoleunes of 2-, intermediate VIII is substituted for intermediate X IV Outside, remaining required raw material, reagent and the same I of preparation methodA- 36, obtain title compound, 69 milligrams of pale yellow powder, yield 54%.Mp：209-211℃；Purity：97%；
1H-NMR(400MHz,DMSO-d6)δ:14.73 (s, 1H), 8.87 (s, 1H), 8.68 (d, J=4.8Hz, 1H), 8.59 (s, 1H), 7.59 (d, J=8.4Hz, 2H), 7.40 (d, J=8.4Hz, 2H), 7.25 (m, 3H), 6.97 (d, J= 8.4Hz,1H),2.80(s,4H),2.44(s,4H),2.24(d,6H).HRMS(ESI)m/z calcd for C26H27N7OF3[M +H]+510.2229,found 510.2230.
Embodiment 74
N- (3- (4- methylpiperazine-1-yls) phenyl)-N '-(4- (3- Trifluoromethyl-1 H- pyrazolo [3,4-b] pyridines -4- Base) phenyl) urea (IB- 14) preparation
Except 5- fluorine-2-nitro methylbenzenes are substituted for 3- fluoronitrobenzenes, intermediate VIII is substituted for outside intermediate X IV, Remaining required raw material, reagent and the same I of preparation methodB- 11, obtain title compound, 57 milligrams of yellow powder, yield 46%.Mp： 229-231℃；Purity：95%；
1H-NMR(400MHz,DMSO-d6)δ:14.73 (s, 1H), 8.90 (s, 1H), 8.69 (d, J=4.8Hz, 2H), 7.60 (d, J=8.4Hz, 2H), 7.41 (d, J=8.4Hz, 2H), 7.27 (d, J=4.8Hz, 1H), 7.20 (s, 1H), 7.12 (t, J=8.0Hz, 1H), 6.82 (d, J=8.0Hz, 1H), 6.59 (d, J=8.0Hz, 1H), 3.12 (s, 4H), 2.48 (s, 4H),2.24(s,3H).HRMS(ESI)m/z calcd for C25H25N7OF3[M+H]+496.2073,found 496.2072..
Embodiment 75
N- (2- (4- methylpiperazine-1-yls) phenyl)-N '-(4- (3- Trifluoromethyl-1 H- pyrazolo [3,4-b] pyridines -4- Base) phenyl) urea (IB- 15) preparation
Except 5- fluorine-2-nitro methylbenzenes are substituted for 2- fluoronitrobenzenes, intermediate VIII is substituted for outside intermediate X IV, Remaining required raw material, reagent and the same I of preparation methodA- 36, obtain title compound, 40 milligrams of white powder, yield 32%.Mp： 283-286℃；Purity：98%；
1H-NMR(400MHz,DMSO-d6)δ:14.73 (s, 1H), 9.80 (s, 1H), 8.69 (d, J=4.4Hz, 1H), 8.09 (s, 1H), 8.03 (d, J=8.0Hz, 1H), 7.64 (d, J=8.0Hz, 2H), 7.43 (d, J=8.0Hz, 2H), 7.27 (d, J=4.4Hz, 1H), 7.19 (d, J=7.6Hz, 1H), 7.08 (t, J=8.0Hz, 1H), 6.99 (t, J=7.6Hz, 1H), 2.84(s,4H),2.63(s,4H),2.30(s,3H).HRMS(ESI)m/z calcd for C25H25N7OF3[M+H]+ 496.2073,found 496.2071.
Embodiment 76
N- (5- methyl -2- (4- methylpiperazine-1-yls) phenyl)-N '-(4- (3- Trifluoromethyl-1 H- pyrazolos [3,4-b] Pyridin-4-yl) phenyl) urea (IB- 16) preparation
Except 5- fluorine-2-nitro methylbenzenes are substituted for 4- fluorin-3-nitrotoluenes, intermediate VIII is substituted for intermediate X IV Outside, remaining required raw material, reagent and the same I of preparation methodA- 36, obtain title compound, 31 milligrams of yellow powder, yield 24%. Mp：274-276℃；Purity：96%；
1H-NMR(400MHz,DMSO-d6)δ:14.73 (s, 1H), 9.82 (s, 1H), 8.69 (d, J=4.8Hz, 1H), 8.09 (s, 1H), 7.90 (s, 1H), 7.65 (d, J=8.4Hz, 2H), 7.43 (d, J=8.4Hz, 2H), 7.27 (d, J= 4.8Hz, 1H), 7.07 (d, J=8.0Hz, 1H), 6.79 (d, J=8.0Hz, 1H), 2.80 (s, 4H), 2.65 (s, 4H), 2.31 (s,3H),2.26(s,3H).HRMS(ESI)m/z calcd for C26H27N7OF3[M+H]+510.2229,found 510.2228.
Embodiment 77
N- (3- methyl -4- (morpholine -4- bases) phenyl)-N '-(4- (3- Trifluoromethyl-1 H- pyrazolos [3,4-b] pyridine - 4- yls) phenyl) urea (IB- 17) preparation
Except 5- fluorine-2-nitro methylbenzenes are substituted for the fluoro- 5- nitrotoleunes of 2-, N methyl piperazine is substituted for morpholine, intermediate Body VIII is substituted for outside intermediate X IV, remaining required raw material, reagent and the same I of preparation methodA- 36, title compound is obtained, breast 105 milligrams of white powder, yield 84%.Mp：85-87℃；Purity：99%；
1H-NMR(400MHz,DMSO-d6)δ:14.69 (s, 1H), 8.87 (s, 1H), 8.69 (d, J=4.4Hz, 1H), 8.60 (s, 1H), 7.61 (d, J=8.4Hz, 2H), 7.41 (d, J=8.4Hz, 2H), 7.30 (s, 1H), 7.27 (d, J= 4.4Hz, 1H), 7.04 (s, 1H), 6.99 (d, J=8.4Hz, 1H), 3.73 (t, 4H), 2.79 (t, 4H), 2.26 (s, 3H) .HRMS(ESI)m/z calcd for C25H24N6O2F3[M+H]+497.1913,found 497.1914.
Embodiment 78
N- (2- (morpholine -4- bases) phenyl)-N '-(4- (3- Trifluoromethyl-1 H- pyrazolos [3,4-b] pyridin-4-yl) benzene Base) urea (IB- 18) preparation
Except 5- fluorine-2-nitro methylbenzenes are substituted for 2- fluoronitrobenzenes, N methyl piperazine is substituted for morpholine, intermediate VIII It is substituted for outside intermediate X IV, remaining required raw material, reagent and the same I of preparation methodA- 36, obtain title compound, white powder 36 milligrams, yield 30%.Mp：224-226℃；Purity：100%；
1H-NMR(400MHz,DMSO-d6)δ:14.74 (s, 1H), 9.77 (s, 1H), 8.69 (d, J=4.4Hz, 1H), 8.21 (s, 1H), 8.08 (d, J=8.0Hz, 1H), 7.65 (d, J=8.4Hz, 2H), 7.44 (d, J=8.4Hz, 2H), 7.27 (d, J=4.4Hz, 1H), 7.21 (d, J=8.0Hz, 1H), 7.10 (t, J=7.6Hz, 1H), 7.00 (t, J=7.6Hz, 1H), 3.87(s,4H),2.83(s,4H).HRMS(ESI)m/z calcd for C24H22N6O2F3[M+H]+483.1756,found 483.1756.
Embodiment 79
N- (5- methyl -2- (morpholine -4- bases) phenyl)-N '-(4- (3- Trifluoromethyl-1 H- pyrazolos [3,4-b] pyridine - 4- yls) phenyl) urea (IB- 19) preparation
Except 5- fluorine-2-nitro methylbenzenes are substituted for the fluoro- 5- nitrotoleunes of 2-, N methyl piperazine is substituted for morpholine, intermediate Body VIII is substituted for outside intermediate X IV, remaining required raw material, reagent and the same I of preparation methodA- 36, title compound is obtained, it is yellow 43 milligrams of color powder, yield 34%.Mp：153-155℃；Purity：91%；
1H-NMR(400MHz,DMSO-d6)δ:14.74 (s, 1H), 9.77 (s, 1H), 8.69 (d, J=4.4Hz, 1H), 8.22 (s, 1H), 7.94 (s, 1H), 7.65 (d, J=8.4Hz, 2H), 7.43 (d, J=8.4Hz, 2H), 7.27 (d, J= 4.4Hz, 1H), 7.09 (d, J=8.0Hz, 1H), 6.81 (d, J=8.0Hz, 1H), 3.86 (s, 4H), 2.79 (s, 4H), 2.26 (s,3H).HRMS(ESI)m/z calcd for C25H24N6O2F3[M+H]+497.1913,found 497.1914.
Embodiment 80
N- (4- (4- methylpiperazine-1-yls) phenyl)-N '-(4- (3- Trifluoromethyl-1 H- pyrazolo [3,4-b] pyridines -4- Base) phenyl) thiocarbamide (IB- 20) preparation
In addition to 5- fluorine-2-nitro methylbenzenes are substituted for 4- fluoronitrobenzenes, remaining required raw material, reagent and preparation method With intermediate X VI, intermediate X IX is obtained：4- (4- methylpiperazine-1-yls) aniline.
Intermediate X IX is taken, 200 milligrams are dissolved in 4 milliliters of dichloromethane, at nitrogen protection and 0 DEG C, are added dropwise to dichloride In dichloromethane (6 milliliters) solution of sulphur (240 microlitres), 124 milligrams of sodium hydroxides are added in, when reaction 3 is small under room temperature.Reaction knot Shu Hou is filtered, washed with dichloromethane, is evaporated under reduced pressure, is obtained residue.Residue is dissolved in 5 milliliters of ethyl alcohol, is added thereto Enter 70 milligrams of 4- (3- Trifluoromethyl-1 H- pyrazoles [3,4-b] pyridin-4-yl) aniline (intermediate X IV), reaction 1 is small under room temperature When.After reaction, it is evaporated under reduced pressure, residue is through column chromatography for separation (methanol:Dichloromethane=1:30, v/v) title compound, is obtained 76 milligrams of object, yield 59%.Mp：153-155℃；Purity：99%；
1H-NMR(400MHz,DMSO-d6)δ:14.76 (s, 1H), 9.76 (d, J=15.2Hz, 2H), 8.71 (d, J= 4.4Hz, 1H), 7.70 (d, J=7.6Hz, 2H), 7.44 (d, J=7.6Hz, 2H), 7.28 (d, J=5.6Hz, 3H), 6.94 (d, J=8.0Hz, 2H), 3.13 (s, 4H), 2.45 (s, 4H), 2.24 (s, 3H) .HRMS (ESI) m/z calcd for C25H24N7OF3S[M+H]+512.1844,found 512.1974.
Embodiment 81
N- ((4- diethylin) phenyl)-N '-(4- (3- Trifluoromethyl-1 H- pyrazolos [3,4-b] pyridin-4-yl) benzene Base) urea (IB- 21) preparation
Except 5- fluorine-2-nitro methylbenzenes are substituted for p-fluoronitrobenzene, N methyl piperazine is substituted for diethylamine, intermediate VIII is substituted for outside intermediate X IV, remaining required raw material, reagent and the same I of preparation methodA- 36, obtain 23 milli of title compound Gram, puce solid, yield 20%.Mp：253-254℃；Purity：99%；
1H-NMR(400MHz,DMSO-d6)δ:14.70 (s, 1H), 8.76 (s, 1H), 8.68 (d, J=4.0Hz, 1H), 8.33 (s, 1H), 7.58 (d, J=8.0Hz, 2H), 7.39 (d, J=8.0Hz, 2H), 7.25 (d, J=8.0Hz, 3H), 6.64 (d, J=8.0Hz, 2H), 3.29 (dd, J=13.2,6.4Hz, 4H), 1.07 (t, J=6.4Hz, 6H) .HRMS (ESI) m/z calcd for C24H24N6OF3[M+H]+469.1964,found 469.1962.
Embodiment 82
N- ((3- dimethylamino) phenyl)-N '-(4- (3- Trifluoromethyl-1 H- pyrazolos [3,4-b] pyridin-4-yl) benzene Base) urea (IB- 22) preparation
In addition to changing intermediate VIII into intermediate X IV, remaining required raw material, reagent and the same I of preparation methodA- 45, Obtain 80 milligrams of title compound, yellow solid, yield 72%.Mp：82-84℃；Purity：98%；
1H-NMR(400MHz,DMSO-d6)δ:14.73 (s, 1H), 8.84 (s, 1H), 8.69 (d, J=4.8Hz, 1H), 8.62 (s, 1H), 7.60 (d, J=8.4Hz, 2H), 7.41 (d, J=8.4Hz, 2H), 7.27 (d, J=4.8Hz, 1H), 7.08 (t, J=8.0Hz, 1H), 6.95 (s, 1H), 6.74 (d, J=8.0Hz, 1H), 6.39 (d, J=8.0Hz, 1H), 2.89 (s, 6H).HRMS(ESI)m/z calcd for C22H20N6OF3[M+H]+441.1650,found 441.1651.
Embodiment 83
N- ((3- diethylin) phenyl)-N '-(4- (3- Trifluoromethyl-1 H- pyrazolos [3,4-b] pyridin-4-yl) benzene Base) urea (IB- 23) preparation
Except changing intermediate VIII into intermediate X IV, formalin is changed into outside acetaldehyde solution, remaining required raw material, Reagent and the same I of preparation methodA- 45, obtain title compound, 54 milligrams of chocolate brown powder, yield 46%.Mp：151-153℃；It is pure Degree：98%；
1H-NMR(400MHz,DMSO-d6)δ:14.72 (s, 1H), 8.81 (s, 1H), 8.68 (d, J=4.4Hz, 1H), 8.56 (s, 1H), 7.59 (d, J=8.4Hz, 2H), 7.41 (d, J=8.4Hz, 2H), 7.26 (d, J=4.4Hz, 1H), 7.04 (t, J=8.0Hz, 1H), 6.91 (t, J=2.0Hz, 1H), 6.63 (dd, J=8.0,1.2Hz, 1H), 6.31 (dd, J=8.0, 2.0Hz, 1H), 3.31 (t, J=7.2,4H), 1.10 (t, J=7.2,6H) .HRMS (ESI) m/z calcd for C24H24N6OF3[M+H]+469.1964,found 469.1962.
Embodiment 84
N- (4- ((dimethylamino) methyl) phenyl)-N '-(4- (3- Trifluoromethyl-1 H- pyrazolo [3,4-b] pyridines -4- Base) phenyl) urea (IB- 24) preparation
Except being substituted for 5- fluorine-2-nitro methylbenzenes to nitro benzyl chloride, N methyl piperazine is substituted for dimethylamine, intermediate VIII is substituted for outside intermediate X IV, remaining required raw material, reagent and the same I of preparation methodA- 36, obtain title compound, yellow 86 milligrams of solid, yield 75%.Mp：200-202℃；Purity：95%；
1H-NMR(400MHz,DMSO-d6)δ:14.52 (s, 1H), 8.93 (s, 1H), 8.78 (s, 1H), 8.69 (d, J= 4.4Hz, 1H), 7.61 (d, J=8.0Hz, 2H), 7.43 (t, J=8.0Hz, 4H), 7.26 (d, J=4.4Hz, 1H), 7.21 (d, J=8.0Hz, 2H), 3.34 (s, 3H), 2.15 (s, 6H) .HRMS (ESI) m/z calcd for C23H22N6OF3[M+H]+ 455.1807,found 455.1809.
Embodiment 85
N- (4- ((diethylin) methyl) phenyl)-N '-(4- (3- Trifluoromethyl-1 H- pyrazolo [3,4-b] pyridines -4- Base) phenyl) urea (IB- 25) preparation
Except being substituted for 5- fluorine-2-nitro methylbenzenes to nitro benzyl chloride, N methyl piperazine is substituted for diethylamine, intermediate VIII is substituted for outside intermediate X IV, remaining required raw material, reagent and the same I of preparation methodA- 36, obtain title compound, yellow 94 milligrams of solid, yield 74%.Mp：90-93℃；Purity：95%；
1H-NMR(400MHz,DMSO-d6)δ:14.52 (s, 1H), 8.93 (s, 1H), 8.77 (s, 1H), 8.68 (d, J= 4.4Hz, 1H), 7.61 (d, J=8.0Hz, 2H), 7.42 (d, J=4.8Hz, 4H), 7.26 (d, J=4.4Hz, 1H), 7.23 (d, J=8.0Hz, 1H), 3.50 (s, 2H), 2.47 (t, J=6.8Hz, 4H), 0.99 (t, J=6.8Hz, 6H) .HRMS (ESI) m/z calcd for C25H26N6OF3[M+H]+483.21210,found 483.2121.
Embodiment 86
N- (3- ((dimethylamino) methyl) phenyl)-N '-(4- (3- Trifluoromethyl-1 H- pyrazolo [3,4-b] pyridines -4- Base) phenyl) urea (IB- 26) preparation
Except 5- fluorine-2-nitro methylbenzenes are substituted for a nitrobenzyl bromine, N methyl piperazine is substituted for dimethylamine, intermediate VIII is substituted for outside intermediate X IV, remaining required raw material, reagent and the same I of preparation methodA- 36, obtain title compound, yellow 26 milligrams of solid, yield 23%.Mp：96-98℃；Purity：99%；
1H-NMR(400MHz,DMSO-d6)δ:14.39 (s, 1H), 8.92 (s, 1H), 8.82 (s, 1H), 8.69 (d, J= 4.4Hz, 1H), 7.62 (d, J=8.4Hz, 2H), 7.49 (s, 1H), 7.42 (d, J=8.4Hz, 2H), 7.34 (d, J=8.0Hz, 1H), 7.27 (d, J=4.4Hz, 1H), 7.23 (d, J=7.6Hz, 1H), 6.91 (d, J=7.6Hz, 1H), 3.40 (s, 2H), 2.17(s,6H).HRMS(ESI)m/z calcd for C23H22N6OF3[M+H]+455.1807,found 455.1806.
Embodiment 87
N- ((4- dimethylamino) phenyl)-N '-(4- (3- Trifluoromethyl-1 H- pyrazolos [3,4-b] pyridin-4-yl) benzene Base) urea (IB- 27) preparation
Except 5- fluorine-2-nitro methylbenzenes are substituted for p-fluoronitrobenzene, N methyl piperazine is substituted for dimethylamine, intermediate VIII is substituted for outside intermediate X IV, remaining required raw material, reagent and the same I of preparation methodA- 36, title compound is obtained, it is blue or green brown 10 milligrams of color solid, yield 9%.Mp：219-221℃；Purity：80%；
1H-NMR(400MHz,DMSO-d6)δ::14.71 (s, 1H), 8.80 (s, 1H), 8.68 (d, J=4.8Hz, 1H), 8.43 (s, 1H), 7.58 (d, J=8.8Hz, 2H), 7.39 (d, J=8.8Hz, 2H), 7.27 (d, J=9.2Hz, 2H), 6.87 (s, 1H), 6.71 (d, J=9.2Hz, 2H), 2.84 (s, 6H) .HRMS (ESI) m/z calcd for C23H22N6OF3[M+H]+ 441.1651,found 441.1649.
Embodiment 88
N- (3- ((diethylin) methyl) phenyl)-N '-(4- (3- Trifluoromethyl-1 H- pyrazolo [3,4-b] pyridines -4- Base) phenyl) urea (IB- 28) preparation
Except 5- fluorine-2-nitro methylbenzenes are substituted for a nitrobenzyl bromine, N methyl piperazine is substituted for diethylamine, intermediate VIII is substituted for outside intermediate X IV, remaining required raw material, reagent and the same I of preparation methodA- 36, obtain title compound, yellow 32 milligrams of solid, yield 26%.Mp：70-72℃；Purity：98%；
1H-NMR(400MHz,DMSO-d6)δ:14.73 (s, 1H), 8.94 (d, 2H), 8.69 (d, J=4.4Hz, 1H), 7.61 (d, J=8.4Hz, 2H), 7.49 (s, 1H), 7.42 (d, J=8.4Hz, 2H), 7.37 (d, J=8.4Hz, 2H), 7.27 (d, J=7.6,1H), 7.24 (d, J=4.4,1H), 6.95 (d, J=7.6Hz, 1H), 3.60 (s, 2H), 2.54 (q, J= 7.2Hz, 3H), 1.02 (t, J=7.2Hz, 6H) .HRMS (ESI) m/z calcd for C25H26N6OF3[M+H]+483.2120, found 483.2120.
Embodiment 89
The experimental method and result that the compounds of this invention inhibits three kinds of receptor tyrosine kinase activities
The method of the compounds of this invention kinase activity test is that mobility shift assay is used under the concentration levels of KmATP (Mobility Shift Assay) method, chooses VEGFR-2, PGDFR- α and tri- kinds of vitro kinases of c-KIT carry out active survey Examination, and by the use of compound Imatinib as standard control.Each compound is first configured to 50 μM of solution, is diluted to 10 concentration Point (concentration between each concentration point differs 4 times) carries out single hole detection.
The compounds of this invention is as shown in table 1 to above-mentioned 3 kinds of tyrosine receptor kinase activity datas, is found that 29 this hairs altogether Bright compound has c-KIT preferable inhibitory activity, IC50<100nM, wherein 17 derivatives have c-KIT extremely strong inhibition to live Property, half effective inhibition concentration 1nM<IC50<10nM；It is found that 33 the compounds of this invention have good inhibition to PDGFR α altogether Activity, half effective inhibition concentration IC50<1000nM, wherein 8 the compounds of this invention have preferable inhibitory activity to PDGFR α, Half effective inhibition concentration 10nM<IC50<100nM；1 the compounds of this invention has PDGFR α extremely strong inhibitory activity, and half has Imitate inhibition concentration 1nM<IC50<10nM；Do not find there is preferable inhibitory activity (IC to VEGFR-250<Derivative 1000nM) Object has VEGFR-2 certain inhibitory activity, half effective inhibition concentration 1000nM more than (41) derivative of half< IC50<10000nM；Activity data refers to table 1 and subordinate list 1：Illustrate that the compound of the present invention is hopeful exploitation as Mutiple Targets receptor Tyrosine kinase inhibitor series antineoplastic medicament.
In table 1, c-KIT represents type III tyrosine kinase receptor, and PDGFRa represents platelet derived growth factor receptor α, VEGFR2 represent VEGF R2, and Linifanib and imatinib mesylate are positive control drug, wherein Linifanib is the antitumor drug candidate that Abbott of the U.S. releases, and imatinib mesylate is the use of FDA approvals in 2002 It is that first cellular signal transduction for clinical treatment malignant tumour inhibits in that cannot cut off and (or) metastatic GISTs Agent.
1 the compounds of this invention of table is to the inhibitory activity data (IC of three kinds of tyrosine kinase50, nM)
Subordinate list 1
Embodiment 90
The GI that the compounds of this invention is tested for the antiproliferative of a variety of homologous BaF3 cell lines50Determination experiment method and result
The compounds of this invention is with all best I of c-KIT and PDGFRA kinase activitiesAExemplified by -41, detection compound is to a variety of The antiproliferative activity of homologous BaF3 cell lines.The experiment is by the testing compound mother liquor (DMSO) of 10mM, according to 73 times of concentration Dilution is prepared into medicine plate, is preserved with suitable condition, while uses the DMSO solvents of equal volume as blank control, Imatinib As positive control.Corresponding exponential phase cell is taken to be prepared into cell plates, is cultivated under suitable condition, after dosing, 37 DEG C, 5%CO2When incubation 72 is small in incubator, 10 μ L CellTiter-Glo cell Proliferation luciferase assay reagents are added in, stand 10 points Clock detects the operative condition of drug and cell by Envision Plate-Reader readings.Activity data such as table 2,
2 the compounds of this invention I of tableA- 41 couples of a variety of homologous BaF3The antiproliferative assay activity data (GI of cell line50, μM)
GI50(μM) IA41 Imatinib
BaF3 4.031 4.686
c-KIT-BaF3 0.0181 0.3819
c-KIT-A829P-BaF3 0.01159 0.1482
c-KIT-L576P-BaF3 0.01056 0.04508
c-KIT-C674S-BaF3 0.01045 0.02493
c-KIT-D816H-BaF3 0.1341 1.245
c-KIT-D816V-BaF3 ＞ 10 ＞ 10
c-KIT-T670I-BaF3 0.03924 ＞ 10
c-KIT-V559D-T670I-BaF3 0.03637 ＞ 10
c-KIT-V654A-BaF3 0.1365 0.8031
c-KIT-N822K-BaF3 0.01109 1.466
c-KIT-V559D-BaF3 0.09645 0.03598
c-KIT-V559D-V654A-BaF3 0.3303 0.803
PDGFRα-BaF3 0.01044 0.01066
PDGFRα-T674I-BaF3 0.1348 ＞ 10
FLT3-BaF3 0.0107 ＞ 10
FLT3-ITD-BaF3 0.01043 2.014
As can be seen from Table 2：Compound IA- 41 pairs of major parts c-KIT, PDGFR α and mutational cell lines show relatively strong Inhibitory action, but to c-KIT-D816V-BaF3 without obvious inhibiting effect.Wherein, with the anti-increasing of marketed drug Imatinib It grows activity to compare, compound IA- 41 couples of c-KIT-T670I-BaF3, c-KIT-V559D-T670I-BaF3, c-KIT-N822K- BaF3, PDGFR α-T674I-BaF3, FLT3-BaF3, FLT3-ITD-BaF3 cellular antiproliferative effect have breakthrough raising；It is right The target spots such as c-KIT-BaF3, c-KIT-A829P-BaF3, c-KIT-D816H-BaF3, c-KIT-V559D-V654A-BaF3 it is thin Born of the same parents' anti-proliferative effect has great raising；To c-KIT-L576P-BaF3, c-KIT-C674S-BaF3, c-KIT-V654A-BaF3 Cellular antiproliferative effect has good raising.
Embodiment 91
The compounds of this invention is for the antiproliferative experiment GI of a variety of real tumor cell lines50Assay method and result
In view of in embodiment 90, compound IAThe kinases such as -41 couples of c-KIT, PDGFRa and its mutation show stronger Anti-proliferative effect, the present embodiment will open up the antiproliferative experimental method stated this compound and be directed to 8 kinds of real tumor cell lines.Cell System includes hamster ovary cell system (CHL, CHO), GIST cell lines (GIST-T1, GIST-882, GIST-48B), BCR-ABL swash Enzyme cell line (MEG-01, K562, KU812), under each suitable condition of culture, except GIST-882 adds in 10 μ LCCK8 Outside cell Proliferation detection reagent is detected, for other cell specific implementation steps with embodiment 90, activity data is shown in Table 3.
3 the compounds of this invention I of tableAThe antiproliferative assay activity data (GI of -41 pairs of a variety of real tumor cell lines50, μM)
Cell line IA41(GI50μM) Imatinib (GI50μM)
CHO 7.036 >10
CHL >10 >10
GIST-48B >10 6.986
K562 >10 0.147
MEG-01 9.092 0.0453
GIST-T1 <0.003 0.003
GIST-882 <0.003 0.0202
KU812 >10 0.11
MOLM14 0.0107 6.452
MV4-11 0.0105 3.589
As can be seen from Table 3, compound IA- 41 couples of GIST-T1 (<0.003μM)、GIST-882(<0.003μM)、 MOLM14 (0.0107 μM), MV4-11 (0.0105 μM) cell line effect are notable, to KU812, MEG-01, K562, GIST- 48B, CHL, Chinese hamster ovary celI strain are without effect or effect unobvious.This result shows that, the compounds of this invention IA- 41 pairs of normal cells Without inhibited proliferation, there is efficient selective to the treatment of gastrointestinal stromal tumor, for further exploitation anti-gastrointestinal tract mesenchymoma target Direction is provided to drug.
Embodiment 92
The compounds of this invention Pharmacokinetic Characteristics experimental determining method and result
In view of the compounds of this invention IA- 41 good kinase inhibiting activities and inhibiting tumour cells activity, then to its into The investigations of Pharmacokinetic Characteristics is gone.Choose 30%HP- β-CD, PEG400 and micro DMSO (11:8:1) it is solvent, configuration IA- 41 ultimate density is 2mg/mL, and is administered intravenously in 6 male SD rats by the dosage of 2mg/kg；Right times into Row sample collection (jugular vein adopts about 0.2mL blood) and data analysis；Rat single dose intravenous gives IAIndividual and average blood after -41 Concentration-time graph (n=3) is shown in plasma drug concentration datas of Fig. 1 according to drug, uses pharmacokinetics software for calculation The non-compartment models of WinNonlin6.2.1 calculate the pharmacokinetic parameter of tested material respectively, are shown in Table 4.Experimental data shows： In intravenous injection, compound IA- 41 show acceptable half-life period and clearance rate.
4 rat single dose intravenous of table gives IAI after -41A- 41 main pharmacokinetic parameters
NA：It is inapplicable；-：Without calculated value
Embodiment 93
Test method that the compounds of this invention acts on hERG potassium channels using system for automatic patch-clamp QPatch detection methods and As a result
Choose IA- 41 are used as representation compound, by CHO-hERG cell culture in suitable condition and after progress is appropriate Continuous processing, to ensure cell density as 2~5 × 106/mL.The compound stock solutions of 2 μ L 20mM is taken to add in 998 μ L extracellular fluids, Then 3 times of serial dilutions are carried out successively in the extracellular fluid containing 0.2%DMSO to obtain needing the ultimate density tested, are selected simultaneously Cisapride is taken to analyze medicine using the electro physiology process of system for automatic patch-clamp QPatch detection methods record as positive control Object is shown in Table 5. to the effects of CHO-hERG cells, experimental data
5 compound I of tableAThe histamine result of -41 pairs of hERG potassium currents
Compound Maximum concentration inhibiting rate (%) IC50(μm)
IA-41 39.78 >40
Cisapride 98.91 0.13
Note：>40 μM refer to the compound depression effect and are less than 50% at 40 μM
The compounds of this invention I is can be seen that from above-mentioned experimental resultAThe inhibitory action of -41 pairs of hERG potassium channels is very weak, Show that cardiac toxic is very low, there is preferable drug safety window, be conducive to exploitation as clinical medicine.
Embodiment 94
Effect experiment method and result of the compounds of this invention in GIST-T1 tumour cell mouse transplantation models
I is chosen in this experimentA- 41 are used as representation compound, and 0.5%MC+0.4%Tween80 is as solvent, solvent group conduct Blank control and Imatinib are as positive control.GIST-T1 cells 1* is inoculated at omoplate before the test mice right side 106/ only, when mice with tumor mean tumour volume reaches 100-200mm3When, mouse is randomly divided into 5 groups.Respectively medicine is carried out by table 6 Effect learns experimental design and table 7 carries out the preparation of compound concentration.Intraperitoneal injection of drugs once a day, and measure gross tumor volume And weight.Experimental data one-way analysis of variance (one way ANOVA) method of inspection comparison therapy group gross tumor volume and knurl Weight has that there was no significant difference compared with the control group, and experimental result is shown in Fig. 2-7.Finally each group mouse GIST-T1 cells are carried out TUNEL dyeing, Ki67 dyeing and HE staining analysis, observation the compounds of this invention IA- 41 pairs of tumor cell proliferations and apoptosis It influences (see Fig. 8).
6 pharmacodynamic experiment of table designs
7 by reagent of table, comparison medicine preparation method
As can be seen from the above results：
1) weight：During the experiment, the weight of each group mouse from starting to experiment to terminate, there is a degree of growth, His no abnormality seen.
2) gross tumor volume：During experiment, blank control group and low dose group (IA- 41 25mg/kg) tumour of mouse goes out Now increase substantially.The gross tumor volume of high dose group mouse shows stronger tumor inhibition effect.
3) gross tumor volume relative percentage：There are inhibitory action to mouse tumor for high dose group drug.Low dose group drug Act on unobvious.Display drug cannot penetrate tumour well, when the concentration only in body fluid reaches a certain level, can just wear Saturating tumour plays the inhibitory action of drug.
4) knurl weight of tumour：The compounds of this invention I is shown by experimental dataAThe inhibition of -41 pairs of gastrointestinal stromal tumors Significance degree is in the same order of magnitude with marketed drug Imatinib.
5) immunohistochemical experiment result：According to coloration, HE coloration results are shown：It cellular morphology and has organized It is whole, there is not necrosis, subsequently to illustrate that drug effect provides foundation.Low dose group tumour can be seen that by the coloration result of Ki 67 Cell Proliferation is very fast, and high dose group and Imatinib groups, since tumour cell is suppressed, the cell in vegetative state It significantly reduces.By TUNEL dye result can be seen that high dose group dye brown cell it is substantially more, in tumour It occupies the majority in the cell of apoptotic state.
Totally show：The compounds of this invention IA- 41 in the case where high dose 100mg/kg is injected intraperitoneally, to GIST-T1 Tumour has apparent antiproliferative and pro-apoptotic drug effect, and nearly equivalent to marketed drug Imatinib, it can be seen that, IA-41 It is expected to develop into targeting Gastrointestinal Stromal tumor medicine.
Substitution (1H- pyrazoles [3,4-b] pyridine) ureas antitumoral compounds of the present invention are the small molecule of a kind of new construction Compound, with Mutiple Targets tyrosine-kinase enzyme inhibition activity, to a variety of homologous BaF3 cell lines and real tumour cell With anti-proliferative capacity, while with good medicine for feature and acardia toxicity, in animal effect experiment, also show Go out preferable antitumor multiplication phenomenon, and its preparation process is succinct, and production cost is low, therefore is expected to develop into a kind of new knot The tyrosine kinase antitumor drug of the Mutiple Targets of structure is especially expected to develop into clinical candidate's medicine of anti-gastrointestinal tract mesenchymoma Object.
All references mentioned in the present invention is incorporated herein by reference, independent just as each document It is incorporated as with reference to such.In addition, it should also be understood that, after reading the above teachings of the present invention, those skilled in the art can To be made various changes or modifications to the present invention, such equivalent forms equally fall within the model that the application the appended claims are limited It encloses.

Claims (10)

1. compound shown in a kind of Formulas I or its pharmaceutically acceptable salt,
Wherein,
X is O or S；
R1For C1~C4Straight or branched alkyl or C1~C4Linear chain or branch chain halogenated alkyl；
R2For substituted or unsubstituted C1~C6Straight or branched alkyl, substituted or unsubstituted C3~C8Cycloalkyl, substitution or not Substituted C6~C10Aryl, substituted or unsubstituted 4-10 unit's heteroaryls；
Wherein, the substitution refers to 1-3 substituent groups selected from the group below：Halogen, hydroxyl, nitro, cyano, C1-C4Alkyl, C1- C4Halogenated alkyl, C1-C4Alkoxy ,-NRaRb, 4-10 unit's heteroaryls, 4-8 membered heterocycloalkyls, C6~C10Aryl；
And the C in above-mentioned substituent group6~C10Aryl can be not necessarily further by 1-3 selected from halogen, hydroxyl, nitro, cyanogen Base, C1-C6Alkyl, C1-C4Halogenated alkyl, C1-C4Substituent group substitution in alkoxy；
And the C in above-mentioned substituent group1-C4Alkyl can not necessarily further by 1-3 selected from halogen, hydroxyl, nitro, cyano ,- Substituent group substitution in NRaRb；
Ra and Rb are each independently H and C1-C4Alkyl；
The 4-10 unit's heteroaryls and 4-8 membered heterocycloalkyls contain the 1-3 hetero atoms in N, O and S independently；
And the halogen is fluorine, chlorine, bromine or iodine.
2. compound shown in Formulas I as described in claim 1 or its pharmaceutically acceptable salt, which is characterized in that the R1 For C1~C4Straight or branched alkyl or C1~C4Linear chain or branch chain perfluoroalkyl, it is preferred that the R1It is taken for methyl or perfluor The methyl in generation.
3. compound shown in Formulas I as described in claim 1 or its pharmaceutically acceptable salt, which is characterized in that the formula Compound shown in I has one or more features selected from the group below：
(a) C described in1~C6Straight or branched alkyl is selected from：Ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, tertiary butyl, N-pentyl, isopentyl, neopentyl, n-hexyl, isobutyl group, new butyl；
(b) C3~C8Cycloalkyl is selected from：Cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, suberyl, cyclooctyl；
(c) C described in6~C10Aryl is selected from：Phenyl, naphthalene, dihydro indenyl, it is preferred that the C6~C10Aryl is selected from：Benzene Base, 2,3- dihydro -1H- indenes -2- bases, naphthalene -1- bases, naphthalene -2- bases；
(d) the 4-10 unit's heteroaryls described in are selected from：Pyrazolyl, pyridyl group, quinolyl, furyl, thienyl, it is preferred that described 4-10 unit's heteroaryls be selected from：1H- pyrazoles -5- bases, pyridine -2- bases, pyridin-3-yl, pyridin-4-yl, quinoline -3- bases, furans - 2- bases, thiophene -2- bases；
(e) the 4-8 membered heterocycloalkyls described in are selected from：Piperidyl, morpholinyl, piperazinyl (4- methyl piperazines base), pyrrolidinyl, four Hydrogen pyranose, it is preferred that the 4-8 membered heterocycloalkyls are selected from：2- piperidin-1-yls, 2- morpholine -4- bases, morpholine -4- bases, 4- Methylpiperazine-1-yl.
4. compound shown in Formulas I as described in claim 1 or its pharmaceutically acceptable salt, which is characterized in that the substitution C1~C6Straight or branched alkyl has Formula II structure,
Wherein, R3For 5-6 unit's heteroaryls, 5-6 membered heterocycloalkyls, C6~C10Aryl；
And the C6~C10Aryl can be not necessarily further by 1-3 selected from halogen, C1-C6Alkyl, C1-C4In alkoxy Substituent group substitutes；
The 5-6 unit's heteroaryls and 5-6 membered heterocycloalkyls contain the 1-3 hetero atoms in N, O and S independently；
Also, n is the integer between 1~4.
5. compound shown in Formulas I as described in claim 1 or its pharmaceutically acceptable salt, which is characterized in that the substitution C1~C6Straight or branched alkyl has formula III structure,
Wherein, R4For C1-C2Alkyl, and n is the integer between 1~3.
6. compound shown in Formulas I as described in claim 1 or its pharmaceutically acceptable salt, which is characterized in that the substitution C6~C10Aryl for substitution phenyl and with formula IV structure,
Wherein, R5For hydrogen or C1~C4Alkyl；R6For 5-6 membered heterocycloalkyls orWherein, the 5-6 circle heterocycles Alkyl can be not necessarily further by 1-3 selected from halogen, C1-C4Substituent group substitution in alkyl；And R4For C1-C2Alkyl, And n is the integer between 0~3.
7. compound shown in Formulas I as described in claim 1 or its pharmaceutically acceptable salt, which is characterized in that the formula Compound I is selected from the group：
N- ethyls-N '-(4- (3- methyl-1 H- pyrazolos [3,4-b] pyridin-4-yl) phenyl) urea, N- propyl-N '-(4- (3- first Base -1H- pyrazolos [3,4-b] pyridin-4-yl) phenyl) urea, N- butyl-N '-(4- (3- methyl-1 H- pyrazolos [3,4-b] pyrroles Pyridine -4- bases) phenyl) urea, N- isobutyl groups-N '-(4- (3- methyl-1 H- pyrazolos [3,4-b] pyridin-4-yl) phenyl) urea, uncle N- Butyl-N '-(4- (3- methyl-1 H- pyrazolos [3,4-b] pyridin-4-yl) phenyl) urea, N- n-pentyls-N '-(4- (3- methyl- 1H- pyrazolos [3,4-b] pyridin-4-yl) phenyl) urea, N- n-hexyls-N '-(4- (3- methyl-1 H- pyrazolos [3,4-b] pyrroles Pyridine -4- bases) phenyl) urea, N- n-hexyls-N '-(4- (3- Trifluoromethyl-1 H- pyrazolos [3,4-b] pyridin-4-yl) phenyl) urea, N- cyclohexyl-N '-(4- (3- methyl-1 H- pyrazolos [3,4-b] pyridin-4-yl) phenyl) urea, N- cyclopropyl-N '-(4- (3- first Base -1H- pyrazolos [3,4-b] pyridin-4-yl) phenyl) urea, N- cyclobutyl-N '-(4- (3- methyl-1 H- pyrazolos [3,4-b] Pyridin-4-yl) phenyl) urea, N- cyclopenta-N '-(4- (3- methyl-1 H- pyrazolos [3,4-b] pyridin-4-yl) phenyl) urea, N- (pyridin-3-yl)-N '-(4- (3- methyl-1 H- pyrazolos [3,4-b] pyridin-4-yl) phenyl) urea, N- (pyridine -2- bases)-N ' - (4- (3- methyl-1 H- pyrazolos [3,4-b] pyridin-4-yl) phenyl) urea, N- (1H- pyrazoles -5- bases)-N '-(4- (3- methyl - 1H- pyrazolos [3,4-b] pyridin-4-yl) phenyl) urea, N- (naphthalene -2- bases)-N '-(4- (3- methyl-1 H- pyrazolos [3,4-b] Pyridin-4-yl) phenyl) urea, N- (2,3- dihydro -1H- indenes -2- bases)-N '-(4- (3- methyl-1 H- pyrazolos [3,4-b] pyridine - 4- yls) phenyl) urea, N- (quinoline -3- bases)-N '-(4- (3- methyl-1 H- pyrazolos [3,4-b] pyridin-4-yl) phenyl) urea, N- (thiophene -2- ylmethyls)-N '-(4- (3- methyl-1 H- pyrazolos [3,4-b] pyridin-4-yl) phenyl) urea, N- (furans -2- bases Methyl)-N '-(4- (3- methyl-1 H- pyrazolos [3,4-b] pyridin-4-yl) phenyl) urea, N- (pyridin-4-yl methyl)-N '- (4- (3- methyl-1 H- pyrazolos [3,4-b] pyridin-4-yl) phenyl) urea, N- (2- piperidin-1-yls ethyl)-N '-(4- (3- tri- Methyl fluoride -1H- pyrazolos [3,4-b] pyridin-4-yl) phenyl) urea, N- (2- morpholine -4- bases ethyl)-N '-(4- (3- fluoroforms Base -1H- pyrazolos [3,4-b] pyridin-4-yl) phenyl) urea, N- (2- morpholine -4- bases ethyl)-N '-(4- (3- methyl-1 H- pyrroles Azoles simultaneously [3,4-b] pyridin-4-yl) phenyl) urea, N- benzyls-N '-(4- (3- methyl-1 H- pyrazolos [3,4-b] pyridin-4-yl) Phenyl) urea, N- (3- methylbenzyls)-N '-(4- (3- methyl-1 H- pyrazolos [3,4-b] pyridin-4-yl) phenyl) urea, N- (4- Fluorobenzene ethyl)-N '-(4- (3- methyl-1 H- pyrazolos [3,4-b] pyridin-4-yl) phenyl) urea, N- (3,4- dimethoxy benzene second Base)-N '-(4- (3- methyl-1 H- pyrazolos [3,4-b] pyridin-4-yl) phenyl) urea, N- (2- chlorobenzyls)-N '-(4- (3- first Base -1H- pyrazolos [3,4-b] pyridin-4-yl) phenyl) urea, N- (4- methylbenzyls)-N '-(4- (3- methyl-1 H- pyrazolos [3,4-b] pyridin-4-yl) phenyl) urea, N- (4- chlorobenzene ethyls)-N '-(4- (3- methyl-1 H- pyrazolo [3,4-b] pyridines -4- Base) phenyl) urea, N- (2- luorobenzyls)-N '-(4- (3- methyl-1 H- pyrazolos [3,4-b] pyridin-4-yl) phenyl) urea, N- (4- Phenyl butyl)-N '-(4- (3- methyl-1 H- pyrazolos [3,4-b] pyridin-4-yl) phenyl) urea, N- (3- phenyl propyls)-N '- (4- (3- methyl-1 H- pyrazolos [3,4-b] pyridin-4-yl) phenyl) urea, N- (2,6- difluorobenzyls)-N '-(4- (3- methyl- 1H- pyrazolos [3,4-b] pyridin-4-yl) phenyl) urea, N- (2- phenylethyls)-N '-(4- (3- methyl-1 H- pyrazolos [3,4- B] pyridin-4-yl) phenyl) urea, N- (2- phenethyls)-N '-(4- (3- Trifluoromethyl-1 H- pyrazolos [3,4-b] pyridin-4-yl) Phenyl) urea, N- (3- phenylpropyls)-N '-(4- (3- Trifluoromethyl-1 H- pyrazolos [3,4-b] pyridin-4-yl) phenyl) urea, N- (4- chlorobenzene ethyls)-N '-(4- (3- Trifluoromethyl-1 H- pyrazolos [3,4-b] pyridin-4-yl) phenyl) urea, N- (2- diformazan ammonia Base ethyl)-N '-(4- (3- Trifluoromethyl-1 H- pyrazolos [3,4-b] pyridin-4-yl) phenyl) urea, N- (2- lignocaine second Base)-N '-(4- (3- Trifluoromethyl-1 H- pyrazolos [3,4-b] pyridin-4-yl) phenyl) urea, N- (3- dimethylamino-propyls)- N '-(4- (3- Trifluoromethyl-1 H- pyrazolos [3,4-b] pyridin-4-yl) phenyl) urea, N- (3- lignocaines propyl)-N '-(4- (3- Trifluoromethyl-1 H- pyrazolos [3,4-b] pyridin-4-yl) phenyl) urea, N- (2- dimethylaminoethyls)-N '-(4- (3- first Base -1H- pyrazolos [3,4-b] pyridin-4-yl) phenyl) urea, N- (4- (4- methylpiperazine-1-yls) phenyl)-N '-(4- (3- tri- Methyl fluoride -1H- pyrazolos [3,4-b] pyridin-4-yl) phenyl) thiocarbamide, N- (4- (4- methylpiperazine-1-yls) phenyl)-N '-(4- (3- Trifluoromethyl-1 H- pyrazolos [3,4-b] pyridin-4-yl) phenyl) urea, N- (2- methyl -4- (4- methylpiperazine-1-yls) benzene Base)-N '-(4- (3- Trifluoromethyl-1 H- pyrazolos [3,4-b] pyridin-4-yl) phenyl) urea, N- (3- methyl -4- (4- methyl piperazines Piperazine -1- bases) phenyl)-N '-(4- (3- Trifluoromethyl-1 H- pyrazolos [3,4-b] pyridin-4-yl) phenyl) urea, N- (3- (4- first Base piperazine -1- bases) phenyl)-N '-(4- (3- Trifluoromethyl-1 H- pyrazolos [3,4-b] pyridin-4-yl) phenyl) urea, N- (2- (4- methylpiperazine-1-yls) phenyl)-N '-(4- (3- Trifluoromethyl-1 H- pyrazolos [3,4-b] pyridin-4-yl) phenyl) urea, N- (5- methyl -2- (4- methylpiperazine-1-yls) phenyl)-N '-(4- (3- Trifluoromethyl-1 H- pyrazolos [3,4-b] pyridin-4-yl) Phenyl) urea, N- (3- methyl -4- (morpholine -4- bases) phenyl)-N '-(4- (3- Trifluoromethyl-1 H- pyrazolos [3,4-b] pyridine - 4- yls) phenyl) urea, N- (2- (morpholine -4- bases) phenyl)-N '-(4- (3- Trifluoromethyl-1 H- pyrazolo [3,4-b] pyridines -4- Base) phenyl) urea, N- (5- methyl -2- (morpholine -4- bases) phenyl)-N '-(4- (3- methyl-1 H- pyrazolo [3,4-b] pyridines -4- Base) phenyl) urea, N- (2- methyl -4- (4- methylpiperazine-1-yls) phenyl)-N '-(4- (3- methyl-1 H- pyrazolos [3,4-b] Pyridin-4-yl) phenyl) urea, N- (3- methyl -4- (4- methylpiperazine-1-yls) phenyl)-N '-(4- (3- methyl-1 H- pyrazolos [3,4-b] pyridin-4-yl) phenyl) urea, N- (3- (4- methylpiperazine-1-yls) phenyl)-N '-(4- (3- methyl-1 H- pyrazolos [3,4-b] pyridin-4-yl) phenyl) urea, N- (2- (4- methylpiperazine-1-yls) phenyl)-N '-(4- (3- methyl-1 H- pyrazolos [3,4-b] pyridin-4-yl) phenyl) urea, N- (5- methyl -2- (4- methylpiperazine-1-yls) phenyl)-N '-(4- (3- methyl-1s H- Pyrazolo [3,4-b] pyridin-4-yl) phenyl) urea, N- (3- methyl -4- (morpholine -4- bases) phenyl)-N '-(4- (3- methyl-1s H- Pyrazolo [3,4-b] pyridin-4-yl) phenyl) urea, N- (2- (morpholine -4- bases) phenyl)-N '-(4- (3- methyl-1 H- pyrazolos [3,4-b] pyridin-4-yl) phenyl) urea, N- (5- methyl -2- (morpholine -4- bases) phenyl)-N '-(4- (3- methyl-1 H- pyrazolos [3,4-b] pyridin-4-yl) phenyl) urea, N- ((4- diethylin) phenyl)-N '-(4- (3- Trifluoromethyl-1 H- pyrazolos [3, 4-b] pyridin-4-yl) phenyl) urea, N- ((3- diethylin) phenyl)-N '-(4- (3- Trifluoromethyl-1 H- pyrazolos [3,4-b] Pyridin-4-yl) phenyl) urea, N- ((3- dimethylamino) phenyl)-N '-(4- (3- Trifluoromethyl-1 H- pyrazolos [3,4-b] pyrroles Pyridine -4- bases) phenyl) urea, N- (4- ((dimethylamino) methyl) phenyl)-N '-(4- (3- Trifluoromethyl-1 H- pyrazolos [3,4-b] Pyridin-4-yl) phenyl) urea, N- (4- ((diethylin) methyl) phenyl)-N '-(4- (3- Trifluoromethyl-1 H- pyrazolos [3,4- B] pyridin-4-yl) phenyl) urea, N- (3- ((dimethylamino) methyl) phenyl)-N '-(4- (3- Trifluoromethyl-1 H- pyrazolos [3, 4-b] pyridin-4-yl) phenyl) urea, N- (3- ((diethylin) methyl) phenyl)-N '-(4- (3- Trifluoromethyl-1 H- pyrazolos [3,4-b] pyridin-4-yl) phenyl) urea, N- ((4- dimethylamino) phenyl)-N '-(4- (3- Trifluoromethyl-1 H- pyrazolos [3, 4-b] pyridin-4-yl) phenyl) urea, N- ((4- diethylin) phenyl)-N '-(4- (3- methyl-1 H- pyrazolos [3,4-b] pyrroles Pyridine -4- bases) phenyl) urea, N- ((3- diethylin) phenyl)-N '-(4- (3- methyl-1 H- pyrazolos [3,4-b] pyridin-4-yl) Phenyl) urea, N- ((3- dimethylamino) phenyl)-N '-(4- (3- methyl-1 H- pyrazolos [3,4-b] pyridin-4-yl) phenyl) urea, N- (4- ((dimethylamino) methyl) phenyl)-N '-(4- (3- methyl-1 H- pyrazolos [3,4-b] pyridin-4-yl) phenyl) urea, N- (4- ((diethylin) methyl) phenyl)-N '-(4- (3- methyl-1 H- pyrazolos [3,4-b] pyridin-4-yl) phenyl) urea, N- (3- ((dimethylamino) methyl) phenyl)-N '-(4- (3- methyl-1 H- pyrazolos [3,4-b] pyridin-4-yl) phenyl) urea, N- ((4- dimethylamino) phenyl)-N '-(4- (3- methyl-1 H- pyrazolos [3,4-b] pyridin-4-yl) phenyl) urea.
8. a kind of pharmaceutical composition, which is characterized in that the pharmaceutical composition includes：
(a) compound or its pharmaceutically acceptable salt shown in the Formulas I described in claim 1 of therapeutically effective amount,
And optional (b) pharmaceutically acceptable carrier.
9. compound or the purposes of its pharmaceutically acceptable salt shown in a kind of Formulas I described in claim 1, which is characterized in that (i) is used to prepare to inhibit tumour cell or treat the pharmaceutical composition of tumour, (ii) receptor tyrosine kinase inhibitors.
A kind of 10. external method for inhibiting receptor tyrosine kinase, which is characterized in that including step：
(a) by compound shown in receptor tyrosine kinase and Formulas I described in claim 1 or its pharmaceutically acceptable salt into Row contact, so as to inhibit the activity of receptor tyrosine kinase.
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