CN102212062B - Derivative of amino ester, salt thereof and using method - Google Patents

Derivative of amino ester, salt thereof and using method Download PDF

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CN102212062B
CN102212062B CN201110075705.6A CN201110075705A CN102212062B CN 102212062 B CN102212062 B CN 102212062B CN 201110075705 A CN201110075705 A CN 201110075705A CN 102212062 B CN102212062 B CN 102212062B
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base
group
oxygen
bicyclic
aliphatics
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CN102212062A (en
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习宁
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Guangdong HEC Pharmaceutical
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Abstract

The invention relates to the medical field and discloses amino ester compounds, salt thereof and a medicinal preparation thereof, which are used to regulate activity and intercellular or intracellular signal response of protein tyrosine kinase. The invention also relates to a pharmaceutically acceptable and the compounds disclosed by the invention contained medicinal composition and a method for treating highly proliferative diseases of mammals, particularly human beings, by using the composition.

Description

Derivative of amino ester and salt thereof and using method
Invention field
The invention relates to new heterocyclic amino group ester derivative and salt thereof, be used for the treatment of the disease of higher proliferation, as the cancer relevant with Mammals.The present invention especially about the compound of arrestin tyrosine kinase activity, thus between T suppression cell or intracellular signal response.The present invention be equally about use compound of the present invention or pharmaceutically comprise the compounds of this invention composition to treat Mammals, the especially method of mankind's hyperproliferative disease.
Background of invention
Protein kinase represents the protein that a large class plays an important role in cellular function retentive control and various cytopathic regulation and control.Protein tyrosine kinase can range growth factor receptors (as: VEGFR, EGFR, PDGFR, FGFR and erbB2) or non-acceptor (as: c-src and bcr-abl) kinases.The Tyrosylprotein kinase of acceptor type can be divided into again 20 kinds of different subfamilies; But not the Tyrosylprotein kinase of acceptor type has a variety of subfamily.Receptor tyrosine kinase is a large fermentoid, and somatomedin can be made to cross over cytolemma and keep extracellular calmodulin binding domain CaM, cross-film district and intracellular portion are as having kinase whose function, and phosphorylation in a concrete protein-tyrosine residue, thus affects cell proliferation.Variant or inappropriate protein kinase activity can cause the deterioration of the state of an illness.
The list of described kinases part comprises abl, AATK, ALK, Akt, axl, bmx, bcr-abl, Blk, Brk, Btk, csk, c-kit, c-Met, c-src, c-fins, CDK1, CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK8, CDK9, CDK10, cRaf1, CSF1R, CSK, DDR1, DDR2, EPHA, EPHB, EGFR, ErbB2, ErbB3, ErbB4, Erk, Fak, fes, FER, FGFR1, FGFR2, FGFR3, FGFR4, FGFR5, Fgr, flt-1, Fps, Frk, Fyn, GSG2, GSK, Hck, ILK, INSRR, IRAK4, ITK, IGF-1R, INS-R, Jak, KSR1, KDR, LMTK2, LMTK3, LTK, Lck, Lyn, MATK, MERTK, MLTK, MST1R, MUSK, NPR1, NTRK, MEK, PLK4, PTK, p38, PDGFR, PIK, PKC, PYK2, RET, ROR1, ROR2, RYK, ros, Ron, SGK493, SRC, SRMS, STYK1, SYK, TEC, TEK, TEX14, TNK1, TNK2, TNNI3K, TXK, TYK2, TYR03, tie, tie2, TRK, Yes and Zap70.Suppress the therapeutic goal that described kinases has become important.Some disease known relates to vasculogenesis out of control, such as eye neovascularization, retinopathy (comprising diabetic retinopathy), the macular degeneration relevant with the age, psoriasis, hemangioblastoma, vascular tumor, arteriosclerosis, inflammatory diseases, such as rheumatoid or rheumatic inflammatory disease, particularly sacroiliitis (rheumatoid arthritis), or other chronic inflammatory diseases, such as chronic asthma, artery or transplant artery atherosis, endometriosis and proliferative disease, such as usually said noumenal tumour and liquid tumors (such as leukemia).
Vasculogenesis is the important component part of general physiological process, and as the formation of embryo and the healing of wound, but the vasculogenesis of variant can cause pathology in disorder, can cause tumor growth what is more.VEGF-A (VEGF-A) promotes that tumor neovasculature forms the key factor of (blood vessel generation).VEGF has high-affinity receptor as fms tyrosine kinase receptor by two, Flt-1, and inserts the acceptor in field containing kinases, and the signal response of KDR comes inducing cell proliferation and transfer.These signal responses all depend primarily on the dimerisation of acceptor and the activation of inherent receptor tyrosine kinase (RTK).In conjunction with the dimerisation of VEGF as dimerization disulphide costimulatory receptor and the activation in RTK field.Kinase activity autophosphorylation acts on the tyrosine residues of cytosol receptor, can be used as the binding site that molecule cascade signal is propagated.
It is very attracting target in Therapeutic cancer that VEGF signal breaks, because vasculogenesis is the prerequisite that all solid tumor growth and ripe endothelial tissue keep geo-stationary.A lot of experimental technique is used for checking and suppresses VEGF signal, comprise and use neutralizing antibody receptor antagonist, small molecular antagonists, antisense construct and dominant negatives strategy (" Molecular basis for Sunitinib efficacy and future clinicaldevelopment. " Nature Review Drug Discovery, 2007,6,734; " Angiogenesis:anorganizing principle for drug discovery? " Nature Review Drug Discovery, 2007,6,273.).
PHGF (HGF), i.e. dispersion factor is a multi-functional somatomedin, can be strengthened transform and tumor development by mitotic division and cell movement.In order to produce cytological effect, HGF must in conjunction with his acceptor, c-Met, receptor tyrosine kinase.C-Met, to the significant percentage process LAN of dissimilar human tumor, also often amplifies the conversion between primary tumor and metabolism.C-Met also involves atherosclerosis and pulmonary fibrosis (" Molecular cancer therapy:can our expectation be MET. " Euro.J.Cancer, 2008,44,641-651).Cancer cell invasion growth thoroughly enhances the interaction of tumour-interstitial, comprises HGF/c-Met (HGF acceptor) approach.The combination of HGF and c-Met causes receptor phosphorylation effect and Ras/ to urge the activation of cell fission activated protein kinase (MAPK) signal response approach, thus strengthens disadvantageous cancer cells behavior.In addition, the hormesis of HGF/c-Met approach can cause the inducing action of vegf expression, and can play direct effect (" From Tpr-Met to Met to the activity of vasculogenesis, tumorigenesis and tubes. " Oncogene.2007,26,1276; " Targeting the c-Met Signaling Pathway in Cancer. " Clin.Cancer Res.2006,12,3657; " Drug development of MET inhibitors:targeting oncogene addiction and expedience. " Nature Review Drug Discovery, 2008,7,504.).
The antitumor approach being target with VEGF/VEGFR and HGF/c-Met signal response can prevent tumour cell from overcoming the independent inhibiting ability of VEGFR or HGFR, and the cancer treatment method that representative improves.The invention describes some small molecules, these small molecules can the activity of effective arrestin Tyrosylprotein kinase, as vegf receptor KDR or HGF acceptor c-Met, and other.
Abstract of invention
The present invention relates to the method for new heteroaromatic compounds and treatment cell proliferation disorders.Compound for protein tyrosine kinase activity of the present invention has restraining effect.More satisfactory, compound of the present invention has multiple inhibitor function, can suppress to respond as VEGF or HGF receptor signal.Correspondingly, present invention also offers a kind of inhibitor of new protein tyrosine kinase receptor signal response, as vegf receptor signal response, or the response of HGF receptor signal, comprise vegf receptor KDR, or HGF acceptor c-Met.
Especially, compound involved in the present invention, and pharmaceutically acceptable composition, can be effective as the inhibitor of c-Met or KDR.
On the one hand, the present invention relates to one such as formula the compound shown in (I):
Or its racemic mixture, diastereomer, enantiomer, geometrical isomer, tautomer, oxynitride, hydrate, solvate, meta-bolites, or pharmacy acceptable salt, wherein, R 1, R 2, R 3, R 4, Y 1, Y 2, shown in W and Q is defined as follows.
Some of them embodiment is, R 1, R 2, R 3and R 4be selected from H independently of one another ,-C (=O) R 11,-C (=O) OR 11,-C (=O) NR 11r 11a, R 11r 11an-O 2s-, R 11o 2s-, R 11ar 11n-alkyl, R 11o-alkyl, aliphatics, halogenated aliphatic, aromatic yl aliphat, heterocyclic radical aliphatics, cycloalkyl aliphatics, aryl, heteroaryl, heterocyclic radical or carbocylic radical; Or R 1, R 2, and together with the nitrogen-atoms be connected with them, the heterocycle of that can form arbitrarily replacement or non-substituted 3-8 unit; Or R 3, R 4, and together with the carbon atom be connected with them, the carbocyclic ring of that can form arbitrarily replacement or non-substituted 3-8 unit or heterocycle;
Y 1and Y 2be selected from divalent group independently of one another: aliphatics-C (=O)-, aliphatics-C (=O) O-, aliphatics-C (=O) NR 11-,-R 11n-O 2s-aliphatics ,-O 2s-,-R 11n-aliphatics ,-S (=O)-aliphatics, or-R 11n-C (=O)-aliphatics; Or sub-condensed-bicyclic base alkyl, Asia condenses assorted bicyclic group alkyl, sub-spiral shell bicyclic group alkyl, sub-spiral shell is mixed bicyclic group alkyl, sub-aralkyl, sub-heteroaralkyl, alkylidene group, halogeno alkylen, sub-heterocyclic radical, sub-carbocylic radical, sub-cycloheteroalkylalkyl, sub-carbocylic radical alkyl, sub-condensed-bicyclic base, Asia condenses assorted bicyclic group, sub-spiral shell bicyclic group, sub-spiral shell is mixed bicyclic group, arylidene or inferior heteroaryl;
W is selected from O, N-R 11or (CR 12r 12a) m; Wherein m is 0,1,2 or 3;
Q is selected from following structural formula:
Wherein U is CR 12or N;
R 5and R 6be selected from H independently of one another, F, Cl, Br, I ,-CN, hydroxyl, R 11ar 11n-,-C (=O)-R 11,-C (=O)-OR 11,-C (=O) NR 11r 11a,-OC (=O) NR 11r 11a,-OC (=O) OR 11,-NR 11c (=O) NR 11r 11a,-NR 11c (=O) OR 11a,-NR 11c (=O)-R 11a, R 11r 11an-O 2s-, R 11o 2s-, R 11o 2sR 11an-, R 11ar 11n-alkyl, R 11(S=O)-alkyl, R 11r 11an-(C=O)-alkyl, R 11ar 11n-alkoxyl group, R 11(S=O)-alkoxyl group, R 11r 11an-(C=O)-alkoxyl group, aliphatics, alkoxyl group, hydroxy alkoxy base, aminoalkoxy, the aminoalkoxy that hydroxyl replaces, halogenated alkoxy, the amino halogenated alkoxy replaced, alkylamino halogenated alkoxy, the halogenated alkoxy that hydroxyl replaces, alkylaminoalkoxy, alkyloxy-alkoxy, alkoxy aryl, heterocyclylalkoxy, carbocyclylalkoxy, heterocyclic radical (hydroxy alkoxy base), carbocylic radical (hydroxy alkoxy base), aryl (hydroxy alkoxy base), aryloxy alkoxyl group, aryloxy, heterocyclyloxy base alkoxyl group, carbocylic radical oxygen base alkoxyl group, heterocyclyloxy base, cycloalkyl oxy, (heterocyclic radical) hydroxy alkoxy base, azido-alkoxyl group, condensed-bicyclic base, condense assorted bicyclic group, condensed-bicyclic base aliphatics, condense assorted bicyclic group aliphatics, condensed-bicyclic base oxygen base, condense assorted bicyclic group oxygen base, condensed-bicyclic base oxygen base alkoxyl group, condense assorted bicyclic group oxygen base alkoxyl group, condensed-bicyclic base aminoalkoxy, condense assorted bicyclic group aminoalkoxy, spiral shell bicyclic group, spiral shell is mixed bicyclic group, spiral shell bicyclic group aliphatics, spiral shell is mixed bicyclic group aliphatics, spiral shell bicyclic group oxygen base, spiral shell is mixed bicyclic group oxygen base, spiral shell bicyclic group oxygen base alkoxyl group, spiral shell is mixed bicyclic group oxygen base alkoxyl group, spiral shell bicyclic group aminoalkoxy, spiral shell is mixed bicyclic group aminoalkoxy, aryl, heteroaryl, aromatic yl aliphat or heteroaryl aliphatics,
R 7independently selected from H, F, Cl, Br, I ,-CN, hydroxyl, R 11ar 11n-, aliphatics, alkoxyl group, haloalkyl, heterocyclic radical, cycloheteroalkylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkyl alkoxy, or heterocyclylalkoxy;
R 8, R 9and R 10be selected from H independently of one another ,-C (=O) R 11,-C (=O) OR 11,-C (=O) NR 11r 11a, R 11r 11an-O 2s-, R 11o 2s-, R 11ar 11n-alkyl, R 11(S=O)-alkyl, R 11r 11an-(C=O)-alkyl, aliphatics, hydroxyalkyl, the aminoalkyl group that hydroxyl replaces, haloalkyl, the amino haloalkyl replaced, alkylamino haloalkyl, the haloalkyl that hydroxyl replaces, alkoxyalkyl, aralkyl, cycloheteroalkylalkyl, carbocylic radical alkyl, heterocyclic radical-hydroxyalkyl, carbocylic radical-hydroxyalkyl, aryl-hydroxyalkyl, aryloxy alkyl, heterocyclyloxyalkyl, carbocylic radical oxygen base alkyl, heterocyclic radical, cycloalkyl, (heterocyclic radical) hydroxyalkyl, azido-alkyl, condensed-bicyclic base, condense assorted bicyclic group, condensed-bicyclic base aliphatics, condense assorted bicyclic group aliphatics, condensed-bicyclic base oxygen base alkyl, condense assorted bicyclic group oxygen base alkyl, condensed-bicyclic base aminoalkyl group, condense assorted bicyclic group aminoalkyl group, spiral shell bicyclic group, spiral shell is mixed bicyclic group, spiral shell bicyclic group aliphatics, spiral shell is mixed bicyclic group aliphatics, spiral shell bicyclic group oxygen base alkyl, spiral shell is mixed bicyclic group oxygen base alkyl, spiral shell bicyclic group aminoalkyl group, spiral shell is mixed bicyclic group aminoalkyl group, aryl, heteroaryl, aromatic yl aliphat or heteroaryl aliphatics,
R 11and R 11abe selected from H independently of one another, aliphatics, halogenated aliphatic, hydroxyl group aliphatic, amino aliphatics, alkoxyl group aliphatics, alkylamino aliphatics, alkylthio aliphatics, aromatic yl aliphat, heterocyclic radical aliphatics, cycloalkyl aliphatics, aryl, heteroaryl, heterocyclic radical, or carbocylic radical; Or
Work as R 11and R 11abe connected with same nitrogen-atoms, so R 11, R 11a, and together with the nitrogen-atoms be connected with them, substituted or non-substituted 3-8 ring can be formed arbitrarily, comprise volution or dicyclo; With
R 12and R 12abe selected from H independently of one another, F, Cl, Br, I ,-CN, hydroxyl ,-NR 11ar 11,-OC (=O) R 11,-C (=O) R 11,-C (=O) OR 11,-C (=O) NR 11r 11a,-OC (=O) NR 11r 11a,-OC (=O) OR 11,-NR 11c (=O) NR 11r 11a,-NR 11c (=O) OR 11a,-NR 11c (=O)-R 11a, R 11r 11an-O 2s-, R 11o 2s-, R 11o 2s-N (R 11a)-, alkoxyl group, cycloalkyl oxy, heterocyclylalkoxy, aliphatics, halogenated aliphatic, hydroxyl group aliphatic, amino aliphatics, alkoxyl group aliphatics, alkylamino aliphatics, alkylthio aliphatics, aromatic yl aliphat, heterocyclic radical aliphatics, cycloalkyl aliphatics, aryl, heteroaryl, heterocyclic radical, or carbocylic radical; Or
Work as R 12and R 12abe connected with same carbon atom, so R 12, R 12a, and together with the carbon atom be connected with them, carbocyclic ring or the heterocycle of substituted or non-substituted 3-8 unit can be formed arbitrarily;
Wherein each substituting group, as :-C (=O) R 11,-C (=O) OR 11,-C (=O) NR 11r 11a, R 11r 11an-O 2s-, R 11o 2s-, R 11ar 11n-,-OC (=O) NR 11r 11a,-OC (=O) OR 11,-NR 11c (=O) NR 11r 11a,-NR 11c (=O) OR 11a,-NR 11c (=O)-R 11a, R 11o 2s-N (R 11a)-, R 11s (=O)-alkyl, R 11r 11an-C (=O)-alkyl, R 11ar 11n-alkoxyl group, R 11s (=O)-alkoxyl group, R 11r 11an-C (=O)-alkoxyl group, R 11ar 11n-alkyl, R 11o-alkyl, aliphatics-C (=O) R 11, aliphatics-C (=O) OR 11, aliphatics-C (=O) NR 11r 11a, R 11r 11an-O 2s-aliphatics, R 11o 2s-, R 11ar 11n-aliphatics, R 11o-aliphatics, R 11(S=O)-aliphatics, R 11r 11an-(C=O)-aliphatics, aliphatics, halogenated aliphatic, aromatic yl aliphat, heterocyclic radical aliphatics, cycloalkyl aliphatics, aryl, heteroaryl, heterocyclic radical, carbocylic radical, haloalkyl, condensed-bicyclic base, condense assorted bicyclic group, condensed-bicyclic base aliphatics, condense assorted bicyclic group aliphatics, spiral shell bicyclic group, spiral shell is mixed bicyclic group, sieve bicyclic group aliphatics, spiral shell is mixed bicyclic group aliphatics, alkoxyl group, hydroxy alkoxy base, aminoalkoxy, the aminoalkoxy that hydroxyl replaces, halogenated alkoxy, the amino halogenated alkoxy replaced, alkylamino halogenated alkoxy, the halogenated alkoxy that hydroxyl replaces, alkylaminoalkoxy, alkyloxy-alkoxy, alkoxy aryl, heterocyclylalkoxy, carbocyclylalkoxy, heterocyclic radical (hydroxy alkoxy base), carbocylic radical (hydroxy alkoxy base), aryl (hydroxyl-alkoxy), aryloxy alkoxyl group, aryloxy, heterocyclyloxy base alkoxyl group, carbocylic radical oxygen base alkoxyl group, heterocyclyloxy base, cycloalkyl oxy, (heterocyclic radical) hydroxy alkoxy base, azido-alkoxyl group, condensed-bicyclic base oxygen base, condense assorted bicyclic group oxygen base, condensed-bicyclic base oxygen base alkoxyl group, condense assorted bicyclic group oxygen base alkoxyl group, condensed-bicyclic base aminoalkoxy, condense assorted bicyclic group aminoalkoxy, spiral shell bicyclic group oxygen base, spiral shell is mixed bicyclic group oxygen base, spiral shell bicyclic group oxygen base alkoxyl group, spiral shell is mixed bicyclic group oxygen base alkoxyl group, spiral shell bicyclic group aminoalkoxy, spiral shell is mixed bicyclic group aminoalkoxy, heteroaryl aliphatics, cycloheteroalkylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkyl alkoxy, heterocyclylalkoxy, hydroxyalkyl, the aminoalkyl group that hydroxyl replaces, haloalkyl, the amino haloalkyl replaced, alkylamino haloalkyl, the haloalkyl that hydroxyl replaces, alkoxyalkyl, arylalkyl, carbocylic radical alkyl, heterocyclic radical (hydroxyalkyl), carbocylic radical (hydroxyalkyl), aryl (hydroxyalkyl), aryloxy alkyl, heterocyclyloxyalkyl, carbocylic radical oxygen base alkyl, (heterocyclic radical) hydroxyalkyl, azido-alkyl, condensed-bicyclic base oxygen base alkyl, condense assorted bicyclic group oxygen base alkyl, condensed-bicyclic base aminoalkyl group, condense assorted bicyclic group aminoalkyl group, spiral shell bicyclic group oxygen base alkyl, spiral shell is mixed bicyclic group oxygen base alkyl, spiral shell bicyclic group aminoalkyl group, spiral shell is mixed bicyclic group aminoalkyl group, hydroxyl group aliphatic, amino aliphatics, alkoxyl group aliphatics, alkylamino aliphatics, sub-condensed-bicyclic base alkyl, Asia condenses assorted bicyclic group alkyl, sub-spiral shell bicyclic group alkyl, sub-spiral shell is mixed bicyclic group alkyl, sub-aralkyl, sub-heteroaralkyl, alkylidene group, halogeno alkylen, sub-heterocyclic radical, sub-carbocylic radical, sub-cycloheteroalkylalkyl, sub-carbocylic radical alkyl, sub-condensed-bicyclic base, Asia condenses assorted bicyclic group, sub-spiral shell bicyclic group, sub-spiral shell is mixed bicyclic group, arylidene, inferior heteroaryl or alkylthio aliphatics can be independently substituted or non-substituted substituting groups.
Some of them embodiment is, pharmacy acceptable salt is hydrochloride, hydrobromate, vitriol, nitrate, phosphoric acid salt, acetate, maleate, succinate, mandelate, fumarate, malonate, malate, 2 hydroxy propanoic acid salt, pyruvate salt, oxalate, oxyacetate, salicylate, glucuronate, galacturonic hydrochlorate, citrate, tartrate, aspartate, glutaminate, benzoate, cinnamate, tosilate, benzene sulfonate, mesylate, esilate, fluoroform sulphonate or their combination.
Some of them embodiment is, R in formula (I) 1, R 2, R 3and R 4the common a-amino acid group defined is naturally occurring or the a-amino acid that obtained by commercial sources or its optically active isomer.
Other embodiment is, naturally occurring or be Isoleucine by the a-amino acid that commercial sources obtains, leucine, Methionin, methionine(Met), phenylalanine, Threonine, tryptophane, α-amino-isovaleric acid, L-Ala, l-asparagine, aspartic acid, L-glutamic acid, glutamine, proline(Pro), Serine, to tyrosine, arginine, Histidine, halfcystine, glycine, sarkosine, N, N-N-methylsarcosine, homoserine, norvaline, nor-leucine, ornithine, homocysteine, hyperphenylalaninemia, phenylglycocoll, adjacent tyrosine, m-Tyrosine or oxyproline.
Other embodiment is, naturally occurring or be Isoleucine by the a-amino acid that commercial sources obtains, leucine, Methionin, methionine(Met), phenylalanine, Threonine, tryptophane, α-amino-isovaleric acid, L-Ala, l-asparagine, aspartic acid, L-glutamic acid, glutamine, proline(Pro), Serine, tyrosine, arginine or Histidine, wherein each amino acid above-mentioned has S configuration at alpha position.
Other embodiment is, naturally occurring or be the halfcystine at alpha position with R configuration by the a-amino acid that commercial sources obtains.
Other embodiment is, naturally occurring or be glycine by the a-amino acid that commercial sources obtains, and sarkosine, or DMG, wherein each amino acid above-mentioned is the molecule not having chirality.
Some of them embodiment is, Y 1and Y 2be selected from divalent group independently of one another: C 1-6aliphatics-C (=O)-, C 1-6aliphatics-C (=O) O-, C 1-6aliphatics-C (=O) NR 11-,-R 11n-O 2sC 1-6aliphatics ,-O 2s-C 1-6aliphatics ,-R 11nC 1-6aliphatics ,-S (=O) C 1-6aliphatics, or-R 11n-C (=O)-C 1-6aliphatics; Condense C 6-10bicyclic group C 1-6alkylidene group, condenses C 5-9assorted bicyclic group C 1-6alkylidene group, spiral shell C 7-11bicyclic group C 1-6alkylidene group, spiral shell C 6-10assorted bicyclic group C 1-6alkylidene group, C 1-6halogeno alkylen, C 2-8sub-heterocyclic radical, C 3-8sub-carbocylic radical, C 2-8heterocyclic radical C 1-6alkylidene group, C 3-8carbocylic radical C 1-6alkylidene group, condenses C 6-10sub-bicyclic group, condenses C 5-9sub-assorted bicyclic group, spiral shell C 7-11sub-bicyclic group or spiral shell C 6-10sub-assorted bicyclic group;
W is O, N-R 11or (CR 12r 12a) m; Wherein m is 0,1 or 2;
Q is selected from following structural formula:
Wherein U is CH or N;
R 5and R 6be selected from H or methoxyl group independently of one another;
R 7h or F;
R 10phenyl or fluorophenyl;
R 11and R 11abe selected from H independently of one another, C 1-3alkyl, C 1-3haloalkyl, C 1-3hydroxyalkyl, C 1-3aminoalkyl group, C 1-3alkoxy C 1-3alkyl, C 1-3alkylamino C 1-3alkyl, C 6-10aryl C 1-3alkyl, C 5-9heterocyclic radical C 1-3alkyl, C 3-6cycloalkyl C 1-3alkyl, C 6-10aryl, C 5-9heteroaryl, C 2-5heterocyclic radical or C 3-6carbocylic radical; Or
Work as R 11and R 11abe connected with same nitrogen-atoms, so R 11, R 11a, and together with the nitrogen-atoms be connected with them, substituted or non-substituted 3-8 ring can be formed arbitrarily, comprise volution or condensed-bicyclic; With
R 12and R 12abe selected from H independently of one another, F, Cl, Br, I, hydroxyl ,-NR 11ar 11,-OC (=O) R 11,-C (=O) R 11,-C (=O) OR 11,-C (=O) NR 11r 11a,-OC (=O) NR 11r 11a,-OC (=O) OR 11,-NR 11c (=O) NR 11r 11a,-NR 11c (=O) OR 11a,-NR 11c (=O)-R 11a, R 11r 11an-O 2s-, R 11o 2s-, R 11r 11ao 2sN-,-CN, C 1-6alkoxyl group, C 3-6cycloalkyloxy, C 2-5heterocyclic radical C 1-6alkoxyl group, C 1-6aliphatics, C 1-6halogenated aliphatic, hydroxyl C 1-6aliphatics, amino C 1-6aliphatics, C 1-6alkoxy C 1-6aliphatics, C 1-6alkylamino C 1-6aliphatics, C 1-6alkylthio C 1-6aliphatics, C 6-10aryl C 1-6aliphatics, C 1-9heteroaryl C 1-6aliphatics, C 2-5heterocyclic radical C 1-6aliphatics, C 3-6cycloalkyl C 1-6aliphatics, C 6-10aryl, C 1-9heteroaryl, C 2-5heterocyclic radical or C 3-6carbocylic radical; Or
Work as R 12and R 12abe connected with same carbon atom, so R 12, R 12a, and together with the carbon atom be connected with them, carbocyclic ring or the heterocycle of substituted or non-substituted 3-8 unit can be formed arbitrarily.
Some of them embodiment is, Q is selected from following structural formula:
Wherein R 5and R 6be selected from H or OMe independently of one another; Z is H or F.
Some of them embodiment is, the Y in formula (I) 1, Y 2, the minor structure that W and Q is common defined is selected from following structural formula:
Wherein AA is R 1, R 2, R 3and R 4the common glycyl base section defined; X is H or OH; 0,1,2 or 3 with p.
In other embodiment, the present invention relates to following one of them compound and pharmacy acceptable salt, solvate, but be never limited to these compounds:
One aspect of the present invention relates to pharmaceutical composition, comprises compound of the present invention, or their steric isomer, geometrical isomer, tautomer, oxynitride, hydrate, solvate, meta-bolites, pharmacy acceptable salt or their prodrug, or optional pharmaceutically acceptable carrier, vehicle, thinner, assistant agent, vehicle, or their combination.Some of them embodiment is, these compounds are protein tyrosine kinase inhibitors, and other embodiment is, these compounds are vegf receptor signal responses, or the inhibitor of HGF receptor signal response.
Some of them embodiment is, pharmaceutical composition of the present invention comprises additional treatment agent further, and these additional treatment agent are preferably chemotherapeutic agent, antiproliferative, be used for the treatment of atherosclerotic medicine, be used for the treatment of the medicine of pulmonary fibrosis, or their combination.
Some of them embodiment is, additional treatment agent of the present invention is Zorubicin (Adriamycin), Wyeth-Ayerst Laboratories (Rapamycin), Temsirolimus, everolimus (Everolimus), Ixabepilone, gemcitabine (Gemcitabin), endoxan (Cyclophosphamide), dexamethasone (Dexamethasone), Etoposide (Etoposide), Fluracil (Fluorouracil), imatinib mesylate (Imatinib mesylate), Dasatinib (Dasatinib), nilotinib (Nilotinib), erlotinib (Erlotinib), lapatinibditosylate (Lapatinib), Iressa (Iressa), Xarelto (Sorafenib), Sutent (Sunitinib), Interferon, rabbit (Interferon), carboplatin (Carboplatin), Hycamtin (Topotecan), taxol, vinealeucoblastine(VLB), vincristine(VCR), Temozolomide (Temozolomide), tositumomab (Tositumomab), Trabedectin, Avastin (Bevacizumab), Trastuzumab (Trastuzumab), Cetuximab (Cetuximab), Victibix (Panitumumab), or their combination.
The present invention relates to protection on the other hand, processes, treats or alleviate the method for patient's proliferative disorders, and described method comprises the pharmaceutically acceptable effective dose of use compound of the present invention and carries out administration to patient.
The present invention relates to protection on the other hand, processes, treats or alleviate the method for patient's proliferative disorders, and the pharmaceutically acceptable effective dose that described method comprises the pharmaceutical composition of use containing compound of the present invention carries out administration to patient.
The present invention relates to a kind of compound of the present invention of use on the other hand and produces for protection, process or treatment patient proliferative disorders, and alleviates the purposes of the medicine of its severity.
The present invention relates to a kind of pharmaceutical composition comprising compound of the present invention of use on the other hand and produces for protection, process or treatment patient proliferative disorders, and alleviates the purposes of the medicine of its severity.
Some of them embodiment is, proliferative disorders of the present invention is metastatic carcinoma.Other embodiment is, proliferative disorders of the present invention is colorectal carcinoma, adenocarcinoma of stomach, bladder cancer, breast cancer, kidney, liver cancer, lung cancer, thyroid carcinoma, brain tumor, neck cancer, prostate cancer, carcinoma of the pancreas, the cancer of CNS (central nervous system), glioblastoma, or myeloproliferative disease.Other embodiment is, proliferative disorders of the present invention is atherosclerosis or pulmonary fibrosis.
The present invention relates to a kind of method suppressing in biological sample or adjust protein kinase activity on the other hand, and described method comprises use compound of the present invention and contacts with described biological sample.
The present invention relates on the other hand a kind of the suppression in biological sample or the method for adjustment protein kinase activity, and described method comprises and uses the pharmaceutical composition comprising compound of the present invention to contact with described biological sample.
Some of them embodiment is, protein kinase of the present invention is receptor tyrosine kinase, and other embodiment is, described receptor tyrosine kinase is KDR or c-Met.
The present invention relates to a kind of method of arrestin Tyrosylprotein kinase on the other hand, and the method comprises kinases and contacts with compound of the present invention or composition.Present invention is specifically related to a kind of suppression vegf receptor signal response, or the method for HGF receptor signal response, the method comprises acceptor and contacts with compound of the present invention or composition.Suppress receptor protein kinase active, particularly VEGF or HGF receptor signal response, can carry out in unicellular or multi-cell organism.If be present in multi-cell organism, method described in the invention comprises use compound of the present invention or composition carries out administration to organism.Some of them embodiment is, described organism is Mammals, and other embodiment is, described organism is the mankind.Other embodiment is, described method further comprises the contact of kinases and additional treatment agent.
The present invention relates on the other hand a kind of method of inhibition of cell proliferation activity, and the method comprises cell and compound of the present invention or composition can the dose of exposure of effective inhibition of cell proliferation.Other embodiment is, described method further comprises the contact of cell and additional treatment agent.
The present invention relates to the treatment to Patient cells's proliferative disease on the other hand, and the method comprises the dosage that needs of patients effectively treats required compound of the present invention or its composition administration.Other embodiment is, described method further comprises the administration of additional treatment agent.
The present invention relates to a kind of method suppressing patient tumors to grow on the other hand, and the method comprises the dosage that needs of patients effectively treats required compound of the present invention or its composition administration.Other embodiment is, described method further comprises the administration of additional treatment agent.
The present invention relates on the other hand the preparation of compound that formula (I) comprises, the method for abstraction and purification.
Content noted earlier only outlines some aspect of the present invention, but is not limited to these aspects.The content of these aspects and other aspect will do more specifically complete description below.
Accompanying drawing explanation
Fig. 1 is the U87MG Tumor growth inhibition of embodiment 53.
Fig. 2 is the MKN45 Tumor growth inhibition of embodiment 72.
Fig. 3 is the operational flowchart that embodiment Gc-Met restraining effect measures.
Circumstantial letter of the present invention
Definition and general terms
The present invention will list the document corresponding to the content specialized determined in detail, and embodiment is all attended by the diagram of structural formula and chemical formula.The present invention has expectedly contains all choices, variant and coordinator, and these may be included in existing invention field as claim defines.Those skilled in the art is by many for identification similar or be equal to method described herein and material, and these can be applied in practice of the present invention and go.The present invention is limited to absolutely not the description of method and material.Have a lot of document distinguish with similar material and the present patent application or conflict, comprising but be never limited to the definition of term, the usage of term, the technology of description, or as the scope that the present patent application controls.
Unless other aspects of the following definition of application show by the present invention.According to object of the present invention, chemical element according to the periodic table of elements, CAS version and pharmaceutical chemicals handbook, 75, thed, 1994 define.In addition, organic chemistry General Principle is shown in " Organic Chemistry; " Thomas Sorrell, University Science Books, Sausalito:1999, and " March ' s Advanced Organic Chemistry; " by Michael B.Smith and Jerry March, John Wiley & Sons, New York:2007, therefore all contents have all merged reference.
As described in the invention, compound of the present invention can optionally replace by one or more substituting group, as general formula compound above, or special example inside picture embodiment, subclass, and the compounds that the present invention comprises.Should be appreciated that " optional replacement " this term can exchange use with " substituted or non-substituted " this term.Generally speaking, term " optionally " no matter before whether being positioned at term " replacement ", represent give the one or more hydrogen atoms in structure replace by concrete substituting group.Unless other aspects show, an optional substituted radical can have a substituting group to replace in each commutable position of group.Not only one or more substituting groups that position can be selected from concrete group in given structural formula replaced, and so substituting group can replace in each position identical or differently.Wherein said substituting group can be, but be not limited to, hydroxyl, amino, halogen, cyano group, aryl, heteroaryl, alkoxyl group, alkyl, thiazolinyl, alkynyl, heterocyclic radical, sulfydryl, nitro, aryloxy etc.
The term " aliphatic " that the present invention uses or " aliphatic group ", represent straight chain (i.e. non-branched) or side chain, substituted or non-substituted completely saturated or contain the hydrocarbon chain of one or more degree of unsaturation.Unless otherwise detailed instructions, aliphatic group contains 1-20 carbon atom, and some of them embodiment is, aliphatic group contains 1-10 carbon atom, other embodiment is, aliphatic group contains 1-8 carbon atom, and other embodiment is, aliphatic group contains 1-6 carbon atom, other embodiment is, aliphatic group contains 1-4 carbon atom, and other embodiment is, aliphatic group contains 1-3 carbon atom.Suitable aliphatic group comprises, but is not limited to, straight or branched, substituted or non-substituted alkyl, alkylidene group, alkenyl or alkynyl group, as methyl, and ethyl, propyl group, vinyl etc.
The term " alkyl " that the present invention uses comprises the univalence hydrocarbyl of 1-20 carbon atom saturated straight chain or side chain, wherein alkyl can independently optionally replace by one or more substituting group described in the invention.Some of them embodiment is, aliphatic group contains 1-10 carbon atom, other embodiment is, aliphatic group contains 1-8 carbon atom, and other embodiment is, aliphatic group contains 1-6 carbon atom, other embodiment is, aliphatic group contains 1-4 carbon atom, and other embodiment is, aliphatic group contains 1-3 carbon atom.Alkyl group further example comprises, but is not limited to, methyl (Me ,-CH 3), ethyl (Et ,-CH 2cH 3), n-propyl (n-Pr ,-CH 2cH 2cH 3), sec.-propyl (i-Pr ,-CH (CH 3) 2), normal-butyl (n-Bu ,-CH 2cH 2cH 2cH 3), isobutyl-(i-Bu ,-CH 2cH (CH 3) 2), sec-butyl (s-Bu ,-CH (CH 3) CH 2cH 3), the tertiary butyl (t-Bu ,-C (CH 3) 3), n-pentyl (-CH 2cH 2cH 2cH 2cH 3), 2-amyl group (-CH (CH 3) CH 2cH 2cH 3), 3-amyl group (-CH (CH 2cH 3) 2), 2-methyl-2-butyl (-C (CH 3) 2cH 2cH 3), 3-methyl-2-butyl (-CH (CH 3) CH (CH 3) 2), 3-methyl isophthalic acid-butyl (-CH 2cH 2cH (CH 3) 2), 2-methyl-1-butene base (-CH 2cH (CH 3) CH 2cH 3), n-hexyl (-CH 2cH 2cH 2cH 2cH 2cH 3), 2-hexyl (-CH (CH 3) CH 2cH 2cH 2cH 3), 3-hexyl (-CH (CH 2cH 3) (CH 2cH 2cH 3)), 2-methyl-2-amyl group (-C (CH 3) 2cH 2cH 2cH 3), 3-methyl-2-amyl group (-CH (CH 3) CH (CH 3) CH 2cH 3), 4-methyl-2-amyl group (-CH (CH 3) CH 2cH (CH 3) 2), 3-methyl-3-amyl group (-C (CH 3) (CH 2cH 3) 2), 2-methyl-3-amyl group (-CH (CH 2cH 3) CH (CH 3) 2), 2,3-dimethyl-2-butyl (-C (CH 3) 2cH (CH 3) 2), 3,3-dimethyl-2-butyl (-CH (CH 3) C (CH 3) 3), n-heptyl, n-octyl, etc.Term " alkyl " and its prefix " alkane " use herein, all comprise the saturated carbon chains of straight chain and side chain.Term " alkylene " uses herein, and represent the saturated bivalent hydrocarbon radical obtained from straight or branched saturated carbon hydride cancellation two hydrogen atoms, such example comprises, but is not limited to, methylene radical, ethylidine, secondary sec.-propyl etc.
The present invention use term " halogenated aliphatic " represent aliphatic group replace by one or more identical or different halogen atom, wherein aliphatic group has implication as described in the present invention, halogen atom and fluorine, chlorine, bromine or iodine, such example comprises, but be not limited to trifluoromethyl, trifluoroethyl etc.
The term " hydroxyl group aliphatic " that the present invention uses represents that aliphatic group is optionally substituted with one or more hydroxyl group and replaces, wherein aliphatic group has implication as described in the present invention, and such example comprises, but is not limited to hydroxyethyl, 2-hydroxypropyl, methylol etc.
The present invention use term " amino aliphatics " represent aliphatic group replace by one or more amino group, wherein aliphatic group has implication as described in the present invention, and such example comprises, but is not limited to amino methyl, 2-amino-ethyl, the amino sec.-propyl of 2-etc.
Term used in the present invention " divalent group " represents the group removing two hydrogen atoms and obtain from target molecule.Some of them embodiment is, removes two hydrogen atoms from the same atom of target molecule; Other embodiment is, to get on to fall two hydrogen atoms from the not homoatomic of target molecule.
Term " alkylidene group " represents the saturated bivalent hydrocarbon radical group removing two hydrogen atoms and obtain from the saturated hydrocarbyl of straight or branched.And described alkylidene group can be substituted or non-substituted, and wherein substituting group can be, but is not limited to, hydroxyl, amino, halogen, cyano group, aryl, heteroaryl, alkoxyl group, alkyl, thiazolinyl, alkynyl, heterocyclic radical, sulfydryl, nitro, or aryloxy.Such example comprises, but is not limited to, methylene radical, ethylidene, isopropylidene, ethane-1,1-bis-base, 2-methoxy propane-1,1-bis-base, 2-hydroxy propane-1,1-bis-base, 2-methyl-2-hydroxy propane-1,1-bis-base etc.
Term " alkenyl " represents the monovalent hydrocarbon of 2-12 carbon atom straight chain or side chain, and wherein at least one position is undersaturated condition, and namely a C-C is sp 2double bond, the group of its alkenyl groups can independently optionally replace by one or more substituting group described in the invention, comprise the location that group has negation " just " or " E " " Z ", wherein concrete example comprises, but be not limited to, vinyl (-CH=CH 2), allyl group (-CH 2cH=CH 2), etc.
Term " alkynyl " represents the monovalent hydrocarbon of 2-12 carbon atom straight chain or side chain, wherein at least one position is undersaturated condition, namely a C-C is sp triple bond, wherein alkynyl group can independently optionally replace by one or more substituting group described in the invention, concrete example comprises, but be not limited to, ethynyl (-C three CH), propargyl (-CH 2c tri-CH), etc.
Term " annular aliphatic ", " carbocyclic ring ", " carbocylic radical " or " cycloalkyl " refer to monovalence or multivalence, non-aromatic, the unsaturated ring of saturated or part, comprise the monocycle of 3-12 carbon atom or two rings of 7-12 carbon atom.The bicyclic carbocyclic ring with 7-12 atom can be two rings [4,5], [5,5], [5,6] or [6,6] system, and the bicyclic carbocyclic ring simultaneously with 9 or 10 atoms can be two rings [5,6] or [6,6] system.Suitable cyclic aliphatic group comprises, but is not limited to, cycloalkyl, cycloalkenyl group and cycloalkynyl radical.The example of cyclic aliphatic group comprises further, but is never limited to, cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopentyl-1-thiazolinyl, 1-cyclopentyl-2-thiazolinyl, 1-cyclopentyl-3-thiazolinyl, cyclohexyl, 1-cyclohexyl-1-thiazolinyl, 1-cyclohexyl-2-thiazolinyl, 1-cyclohexyl-3-thiazolinyl, cyclohexadienyl, suberyl, ring octyl group, ring nonyl, ring decyl, ring undecyl, cyclo-dodecyl, etc.And described " annular aliphatic ", carbocyclic ring ", " carbocylic radical " or " cycloalkyl " can be substituted or non-substituted, wherein substituting group can be, but is not limited to; hydroxyl, amino, halogen; cyano group, aryl, heteroaryl; alkoxyl group, alkyl, thiazolinyl; alkynyl, heterocyclic radical, sulfydryl; nitro, aryloxy etc.
Term " sub-carbocylic radical " represents and removes containing the monocycle of 3-12 carbon atom or the dicyclo of 7-12 carbon atom the hydrocarbon ring of saturated divalence that two hydrogen atoms obtain, wherein carbocylic radical has implication as described in the present invention, such example comprises, but be not limited to, cyclopropylidene, sub-cyclobutyl, cyclopentylidene, 1-ring penta-1-alkenylene, 1-ring penta-2-alkenylene etc.
Term " carbocylic radical alkyl " represent alkyl group can replace by one or more carbocylic radical, wherein carbocylic radical and alkyl group have implication as described in the present invention.Such example comprises, but is not limited to, Cvclopropvlmethvl, cyclopentyl-methyl, hydroxycyclopropyl methyl, mcthoxycyclopropyl methyl, cyclopentyl ethyl etc.
Term " sub-carbocylic radical alkyl " represents the hydrocarbon ring of saturated divalence that carbocylic radical alkyl removes two hydrogen atoms and obtains, wherein carbocylic radical alkyl has implication as described in the present invention, such example comprises, but be not limited to 1-methoxyl group cyclopropane-1-methylene radical, 1-hydroxy-cyclopentane-1-methylene radical, 1-methoxyl group pentamethylene-1-methylene radical, 1-hydroxyl cyclopropane-1-methylene radical etc.
Term " cycloalkyl oxy " or " carbocylic radical oxygen base " comprise the optional cycloalkyl replaced, as defined herein, be connected on Sauerstoffatom, and be connected with all the other molecules by Sauerstoffatom, such example comprises, but is not limited to cyclopropyl oxygen base, cyclopentyloxy, cyclohexyl oxygen base, the cyclopropyl oxygen base etc. that hydroxyl replaces.
Term " cycloalkyl amino " represent amino group replace by one or two group of naphthene base, wherein cycloalkyl has implication as described in the present invention, such example comprises, but be not limited to cyclopropylamino, clopentylamino, Cyclohexylamino, the cyclopropylamino that hydroxyl replaces, dicyclohexyl is amino, and Bicyclopropyl is amino.
Term " carbocylic radical oxygen base alkoxyl group " represent alkoxyl group replace by one or more carbocylic radical oxygen base group, wherein alkoxyl group and carbocylic radical oxygen base group have implication as described in the present invention, such example comprises, but be not limited to cyclopropyl Oxymethoxy, cyclopropyl oxygen base oxethyl, cyclopentyloxy oxyethyl group, cyclohexyl oxygen base oxethyl, cyclohexenyl-3-oxygen base oxethyl etc.
Term " cycloalkyl oxy aliphatics " represent aliphatic group replace by one or more cycloalkyl oxy group, wherein aliphatic group and cycloalkyl oxy group have implication as described in the present invention, such example comprises, but be not limited to cyclopropyl oxygen ylmethyl, cyclopropyl oxygen base ethyl, cyclopentyloxymethyl, cyclopentyloxy ethyl, cyclohexyl oxygen base ethyl, halogenated cyclopropyl oxygen base ethyl etc.
Term " cycloalkyl amino aliphatics " represent aliphatic group replace by one or more cycloalkylamino group, wherein aliphatic group and cycloalkylamino group have implication as described in the present invention, such example comprises, but be not limited to Cyclopropylaminomethyl, cyclopropylaminoethyl, clopentylamino methyl, clopentylamino ethyl, Cyclohexylamino ethyl, halogenated cyclopropyl amino-ethyl etc.
Term " cycloalkyl aliphatics " represent aliphatic group can replace by one or more group of naphthene base, wherein cycloalkyl and aliphatic group have implication as described in the present invention, such example comprises, but be not limited to Cvclopropvlmethvl, cyclopropylethyl, Cyclopropylpropyl, cyclopentyl-methyl, cyclohexyl-ethyl etc.
Term " cycloalkyl alkoxy " or " carbocyclylalkoxy " represent alkoxy base replace by one or more group of naphthene base, wherein group of naphthene base and alkoxy base have implication as described in the present invention, such example comprises, but be not limited to cyclo propyl methoxy, cyclopropylethoxy, cyclopentyl oxyethyl group, cyclohexylethoxy radical, cyclohexyl methoxy, cyclopropyl propoxy-etc.
Term " cyclopropyl alkoxyl group " represent alkoxy base replace by one or more cyclopropyl group, wherein alkoxy base has implication as described in the present invention, such example comprises, but be not limited to cyclo propyl methoxy, cyclopropylethoxy, cyclopropyl propoxy-, cyclopropyl butoxy etc.
Term " the cyclopropyl alkoxyl group that hydroxyl replaces " representative ring propyl group alkoxy base is optionally substituted with one or more hydroxyl group and replaces, wherein hydroxyl can replace in any commutable position of cyclopropyl alkoxyl group, it can be cyclopropyl moieties, also can be alkoxy portion, wherein cyclopropyl alkoxyl group has implication as described in the present invention, such example comprises, but be not limited to 1-(1-hydroxycyclopropyl) methoxyl group, 2-(1-hydroxycyclopropyl) oxyethyl group, 3-(1-hydroxycyclopropyl) propoxy-, 4-(1-hydroxycyclopropyl) butoxy, 3-cyclopropyl-2-hydroxy propyloxy group, 3-cyclopropyl-3-hydroxy propyloxy group, 4-cyclopropyl-3-hydroxybutoxy etc.And described cyclopropyl can be substituted or non-substituted, and wherein substituting group can be, but is not limited to, hydroxyl, amino, halogen, cyano group, aryl, heteroaryl, alkoxyl group, alkyl, thiazolinyl, alkynyl, heterocyclic radical, sulfydryl, nitro, aryloxy etc.
Term " heterocycle ", " heterocyclic radical ", " assorted alicyclic " or " heterocycle " commutative use herein, all refer to monocycle, dicyclo, or three-ring system, wherein on ring one or more atom can independently optionally replace by heteroatoms, ring can be completely saturated or comprise one or more degree of unsaturation, but is never the fragrant same clan, only has a tie point to be connected to other molecules and gets on.One or more ring hydrogen atom independent optionally replace by one or more substituting group described in the invention.Some of them embodiment is, " heterocycle ", " heterocyclic radical ", " assorted alicyclic " or " heterocycle " group be 3-7 ring monocycle (1-6 carbon atom be selected from N, O, P, 1-3 the heteroatoms of S, this S or P optionally replace by one or more Sauerstoffatom obtain picture SO, SO 2, PO, PO 2group, when described ring is triatomic ring, wherein only have a heteroatoms), or the dicyclo of 7-10 unit (4-9 carbon atom and be selected from N, 1-3 the heteroatoms of O, P, S, at this S or P optionally replace by one or more Sauerstoffatom and obtain as SO, SO 2, PO, PO 2group).
Heterocyclic radical can be carbon back or heteroatoms base." heterocyclic radical " equally also comprises heterocyclic group and the saturated or unsaturated ring of part or heterocyclic fused formed group.The example of heterocycle comprises, but be not limited to, pyrrolidyl, tetrahydrofuran base, dihydrofuran base, tetrahydro-thienyl, THP trtrahydropyranyl, dihydro pyranyl, tetrahydro thiapyran base, piperidyl, morpholinyl, thio-morpholinyl, thioxane base, piperazinyl, homopiperazine base, azelidinyl, oxetanylmethoxy, thietanyl, homopiperidinyl, epoxypropyl, azacycloheptyl, oxepane base, thia suberyl, oxygen azatropylidene base, diazepine base, sulphur azatropylidene base, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxacyclohexyl, 1, 3-dioxy amyl group, pyrazolinyl, dithiane base, dithiode alkyl, dihydro-thiophene base, pyrazolidyl imidazolinyl, imidazolidyl, 1, 2, 3, 4-tetrahydro isoquinolyl, 3-azabicyclo [3.1.0] hexyl, 3-azabicyclo [4.1.0] heptyl, azabicyclo [2.2.2] hexyl, 3H-indyl quinolizinyl and N-pyridyl urea.The example of heterocyclic group also comprises, 1,1-dioxidothiomorpholinyl, and wherein on ring two carbon atoms replace by Sauerstoffatom as pyrimidine dione base.And described heterocyclic radical can be substituted or non-substituted, and wherein substituting group can be, but is not limited to, hydroxyl, amino, halogen, cyano group, aryl, heteroaryl, alkoxyl group, alkyl, thiazolinyl, alkynyl, heterocyclic radical, sulfydryl, nitro, aryloxy etc.
Term " sub-heterocyclic radical " represents monocycle, dicyclo or three-ring system, wherein on ring one or more atom independently selected from heteroatoms, and can be completely saturated or comprise one or more degree of unsaturation, but do not belong to the fragrant same clan, have two tie points to be connected with molecule rest part, wherein heterocyclyl groups has implication as described in the present invention.Such example comprises, but is not limited to, piperidines-Isosorbide-5-Nitrae-two base, piperazine-Isosorbide-5-Nitrae-two base, tetrahydrofuran (THF)-2,4-bis-base, tetrahydrofuran (THF)-3,4-bis-base, azetidine-1,3-bis-base, tetramethyleneimine-1,3-bis-base etc.
Term " cycloheteroalkylalkyl " comprises the alkyl that heterocyclic radical replaces; Term " heterocyclylalkoxy " comprises the alkoxyl group that heterocyclic radical replaces, and wherein Sauerstoffatom is connected with the rest part of molecule; Term " heterocyclic radical alkylamino " comprises the alkylamino that heterocyclic radical replaces, and wherein nitrogen-atoms is connected with the rest part of molecule; Wherein heterocyclic radical, alkyl, alkoxyl group and alkylamino radicals have implication as described in the present invention.Such example comprises, but is not limited to pyrroles-2-methyl, morpholine-4-methyl, pyrroles-2-methoxyl group, piperidines-2-oxyethyl group, piperazine-2-ethylamino, morpholine-4-propoxy-, morpholine-4-ethylamino etc.
Term " sub-cycloheteroalkylalkyl " represents the group that cycloheteroalkylalkyl removes two hydrogen atoms and obtains, and wherein cycloheteroalkylalkyl has implication as described in the present invention.Such example comprises, but is not limited to morpholine-4-methylmethylene, piperidines-N-methylmethylene, piperazine-4-ethyl-1-base, piperidines-4-methyl isophthalic acid-Ji, piperidines-4-ethyl-1-base, tetramethyleneimine-2-methyl isophthalic acid-Ji etc.
Term " heterocyclic radical aliphatics " represents the aliphatic group that heterocyclic radical replaces, wherein heterocyclic radical and aliphatic group have implication as described in the present invention, such example comprises, but be not limited to pyrroles-2-methyl, piperidines-2-ethyl, piperazine-2-ethyl, piperidines-2-methyl, morpholine-4-methyl, morpholine-4-ethyl etc.
Term " heterocyclyloxy base " comprises the optional heterocyclic radical replaced, as defined herein, be connected on Sauerstoffatom, wherein Sauerstoffatom is connected with molecule rest part, and such example comprises, but be not limited to pyrroles-2-oxygen base, pyrroles-3-oxygen base, piperidines-2-oxygen base, piperidines-3-oxygen base, piperazine-2-oxygen base, piperidines-4-oxygen base etc.
Term " heterocyclylamino group " represent amino group replace by one or two heterocyclyl groups, wherein nitrogen-atoms is connected with molecule rest part, and heterocyclic radical has implication as described in the present invention, such example comprises, but is not limited to pyrroles-2-amino, pyrroles-3-is amino, piperidines-2-is amino, and piperidines-3-is amino, and piperidines-4-is amino, piperazine-2-is amino, and two pyrroles-2-are amino.
Term " heterocyclyloxy base alkoxyl group " represent alkoxyl group replace by one or more heterocyclyloxy base group, wherein alkoxyl group and heterocyclyloxy base group have implication as described in the present invention, such example comprises, but be not limited to pyrroles-2-Oxymethoxy, pyrroles-3-oxygen base oxethyl, piperidines-2-oxygen base oxethyl, piperidines-3-oxygen base oxethyl, piperazine-2-Oxymethoxy, piperidines-4-oxygen base oxethyl etc.
Term " heterocyclyloxy base aliphatics " represent aliphatic group replace by one or more heterocyclyloxy base group, wherein aliphatic group and heterocyclyloxy base group have implication as described in the present invention, such example comprises, but be not limited to pyrroles-2-oxygen ylmethyl, piperazine-3-oxygen base ethyl, piperazine-2-oxygen base ethyl, morpholine-2-oxygen ylmethyl, piperidines-2-oxygen base ethyl etc.
Term " heterocyclylamino group aliphatics " represent aliphatic group replace by one or more heterocyclylamino group group, wherein aliphatic group and heterocyclylamino group group have implication as described in the present invention, such example comprises, but be not limited to pyrroles-2-amino methyl, piperazine-3-amino-ethyl, piperazine-2-amino-ethyl, piperidines-2-amino-ethyl, morpholine-2-amino methyl etc.
Term " heterocyclic radical (hydroxy alkoxy base) " represent hydroxy alkoxy base replace by one or more heterocyclyl groups, wherein heterocyclyl groups and hydroxy alkoxy base group have implication as described in the present invention, such example comprises, but be not limited to pyrroles-2-base hydroxyl methoxyl group, morpholine-4-base hydroxyl methoxyl group etc.
Term " heteroatoms " represents one or more O, S, N, P and Si, comprises N, the form of any oxidation state of S and P; The form of primary, secondary, tertiary amine and quaternary ammonium salt; Or the form that the hydrogen in heterocycle on nitrogen-atoms is substituted, such as, N (N as in 3,4-dihydro-2 h-pyrrole base), NH (NH as in pyrrolidyl) or NR (NR as in the pyrrolidyl that N-replaces).
Term " halogen " refers to F, Cl, Br or I.
Term used in the present invention " undersaturated " represents that part is containing one or more degree of unsaturation.The term " alkoxyl group " used in the present invention, relates to alkyl, defines as the present invention, is connected in main carbochain by Sauerstoffatom (" alkoxyl group ").
Term " hydroxy alkoxy base " represents that alkoxy base is optionally substituted with one or more hydroxyl group and replaces, and wherein alkoxyl group has implication as described in the present invention, and such example comprises, but be not limited to hydroxyl methoxyl group, 2-hydroxyl-oxethyl, 2-hydroxy propyloxy group, 2-hydroxyl isopropoxy etc.
Term " aminoalkoxy " represent alkoxy base replace by one or more amino group, wherein alkoxyl group has implication as described in the present invention, and such example comprises, but be not limited to aminomethoxy, 2-amino ethoxy, the amino propoxy-of 2-, the amino isopropoxy of 2-etc.
Term " azido-alkoxyl group " represent alkoxyl group replace by one or more azido-group, wherein alkoxyl group has implication as described in the present invention, and such example comprises, but is not limited to 2-azido-oxyethyl group, 3-azido-propoxy-, 2-azido-propoxy-etc.
Term " alkyloxy-alkoxy " represent alkoxy base replace by one or more alkoxy base, wherein alkoxy base has implication as described in the present invention, such example comprises, but be not limited to methoxymethoxy, methoxy ethoxy, oxyethyl group methoxyl group, ethoxy ethoxy, oxyethyl group propoxy-etc.
Term used in the present invention " alkoxyl group aliphatics " represent aliphatic group replace by one or more alkoxy base, wherein aliphatic group and alkoxy base have implication as described in the present invention, such example comprises, but be not limited to methoxymethyl, ethoxyl methyl, ethoxyethyl group, ethoxy-c thiazolinyl etc.
Term used in the present invention " alkylamino aliphatics " represent aliphatic group replace by one or more alkylamino radicals, wherein aliphatic group and alkylamino radicals have implication as described in the present invention, such example comprises, but be not limited to dimethylaminoethyl, methylaminoethyl, Diethylaminomethyl, diethyllaminoethyl etc.
Term used in the present invention " alkylthio aliphatics " represent aliphatic group replace by one or more alkylthio radicals, wherein aliphatic group and alkylthio radicals have implication as described in the present invention, such example comprises, but be not limited to methylmercaptoethyl, methylthio, ethylthio-ethyl, methylthio group propenyl etc.
Term " haloalkyl ", " haloalkenyl group " or " halogenated alkoxy " represents alkyl, thiazolinyl or alkoxyl group can by one or more halogen atom situation about replacing.Wherein alkyl, thiazolinyl and alkoxy base have implication as described in the present invention, and such example comprises, but is not limited to trifluoromethyl, trifluoromethoxy, and 2-is fluoride-based.
Term " halogeno alkylen " represents that haloalkyl moiety has two tie points and is connected with molecule rest part.Wherein alkylene group has implication as described in the present invention, and such example comprises, but is not limited to diflouromethylene etc.
Term " amino replace halogenated alkoxy " represent halogenated alkoxy replace by one or more amino group, wherein halogenated alkoxy has implication as described in the present invention, and such example comprises, but is not limited to 3-amino-2-chlorine propoxy-etc.
Term " halogenated alkoxy that hydroxyl replaces " represents that halogenated alkoxy is optionally substituted with one or more hydroxyl group and replaces, wherein halogenated alkoxy has implication as described in the present invention, such example comprises, but is not limited to 3-hydroxyl-2-fluorine propoxy-, methylol trifluoromethoxy etc.
Term " aryl " can be used alone or as most of " aralkyl " " aralkoxy " or " aryloxy alkyl ", represent the monocycle altogether containing 6-14 ring, dicyclo, with the carbocyclic ring system of three rings, wherein, at least one member ring systems is aromatic, and wherein each member ring systems comprises 3-7 ring, and only has an attachment point to be connected with the rest part of molecule.Term " aryl " can exchange with term " aromatic nucleus " and use, as aromatic nucleus can comprise phenyl, and naphthyl and anthracene.And described aryl can be substituted or non-substituted, and wherein substituting group can be, but is not limited to, hydroxyl, amino, halogen, cyano group, aryl, heteroaryl, alkoxyl group, alkyl, thiazolinyl, alkynyl, heterocyclic radical, sulfydryl, nitro, aryloxy etc.
Term " arylidene " represents that aryl systems has two tie points and is connected with molecule rest part.Wherein aromatic yl group has implication as described in the present invention, and such example comprises, but is not limited to, phenylene, sub-to fluorophenyl etc.
Term " aromatic yl aliphat " represent aliphatic group replace by one or more aromatic yl group, wherein aliphatic group and aromatic yl group have implication as described in the present invention, and such example comprises, but be not limited to styroyl, phenmethyl, to methylphenylethyl, styryl etc.
Term " sub-aralkyl " represents that aralkyl system has two tie points to be connected with molecule rest part, and wherein aralkyl has implication as described in the present invention.Such example comprises, but is not limited to benzene methylene, benzene ethylene etc.
Term " aryloxy " comprises the optional aryl replaced, as defined herein, be connected on Sauerstoffatom, and be connected with molecule rest part by Sauerstoffatom, wherein aromatic yl group has implication as described in the present invention, and such example comprises, but is not limited to phenoxy group, to tolyloxy, to second phenoxy group etc.
Term " virtue amino " represent amino group replace by one or two aromatic yl group, wherein aryl has implication as described in the present invention, and such example comprises, but is not limited to phenyl amino, diphenyl amino, and xylyl is amino.
Term " aryloxy alkoxyl group " represent alkoxyl group replace by one or more aryloxy group, wherein alkoxyl group and aryloxy group have implication as described in the present invention, and such example comprises, but are not limited to phenoxy group methoxyl group, phenoxy group, Phenoxypropoxy etc.
Term " aryloxy aliphatics " represent aliphatic group replace by one or more aryloxy group, wherein aryloxy and aliphatic group have implication as described in the present invention, such example comprises, but be not limited to phenoxymethyl, Phenoxyethyl, tolyloxyethyl, phenoxy propyl etc.
Term " fragrant amino aliphatics " represent represent aliphatic group replace by one or more fragrant amino group, wherein virtue amino and aliphatic group have implication as described in the present invention, such example comprises, but be not limited to phenylaminomethyl, phenylaminoethyl, toluino ethyl, phenylamino propyl group, phenylamino allyl group etc.
Term " aryl (hydroxy alkoxy base) " represent hydroxy alkoxy base replace by one or more aromatic yl group, wherein aromatic yl group and hydroxy alkoxy base have implication as described in the present invention, such example comprises, but be not limited to phenyl methylol, phenyl hydroxyethyl, p-methylphenyl hydroxyethyl etc.
Term " heteroaryl " can be used alone or as most of " heteroarylalkyl " or " heteroarylalkoxy ", represent the monocycle altogether containing 5-14 ring, dicyclo, and three-ring system, wherein at least one member ring systems is aromatic, and at least one member ring systems comprises one or more heteroatoms, wherein each member ring systems comprises 3-7 ring, and only has an attachment point to be connected with molecule rest part.Term " heteroaryl " can exchange with term " fragrant heterocycle " or " heteroaromatics " and use.And described heteroaryl can be substituted or non-substituted, and wherein substituting group can be, but is not limited to, hydroxyl, amino, halogen, cyano group, aryl, heteroaryl, alkoxyl group, alkyl, thiazolinyl, alkynyl, heterocyclic radical, sulfydryl, nitro, aryloxy etc.
Other embodiment is, virtue heterocycle comprises following monocycle, but be not limited to these monocycles: 2-furyl, 3-furyl, TMSIM N imidazole base, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, N-pyrryl, 2-pyrryl, 3-pyrryl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-pyrimidyl, pyridazinyl (as 3-pyridazinyl), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazyl (as 5-tetrazyl), triazolyl (as 2-triazolyl and 5-triazolyl), 2-thienyl, 3-thienyl, pyrazolyl (as 2-pyrazolyl), isothiazolyl, 1, 2, 3-oxadiazolyl, 1, 2, 5-oxadiazolyl, 1, 2, 4-oxadiazolyl, 1, 2, 3-triazolyl, 1, 2, 3-thio biphosphole base, 1, 3, 4-thio biphosphole base, 1, 2, 5-thio biphosphole base, pyrazinyl, 1, 3, 5-triazinyl, also following dicyclo is comprised, but be never limited to these dicyclos: benzimidazolyl-, benzofuryl, benzothienyl, indyl (as 2-indyl), purine radicals, quinolyl (as 2-quinolyl, 3-quinolyl, 4-quinolyl), isoquinolyl (as 1-isoquinolyl, 3-isoquinolyl or 4-isoquinolyl) etc.
Term " inferior heteroaryl " represents that heteroaromatic system has two tie points and is connected with molecule rest part.Wherein heteroaryl groups has implication as described in the present invention, and such example comprises, but is not limited to, pyridylidene, sub-pyrryl, sub-thiazolyl, sub-imidazolyl etc.
Term " heteroaryl oxygen base " comprises the optional heteroaryl replaced, as defined herein, be connected on Sauerstoffatom, and be connected with molecule rest part by Sauerstoffatom, wherein heteroaryl groups has implication as described in the present invention, and such example comprises, but be not limited to pyridine-2-oxygen base, thiazole-2-oxygen base, imidazoles-2-oxygen base, pyrimidine-2-oxygen base etc.
Term " heteroaryl oxygen base aliphatics " represent aliphatic group replace by one or more heteroaryl oxygen base group, wherein aliphatic group and heteroaryl oxygen base group have implication as described in the present invention, such example comprises, but be not limited to pyridine-2-oxygen base ethyl, thiazole-2-oxygen ylmethyl, imidazoles-2-oxygen base ethyl, pyrimidine-2-oxygen base propyl group etc.
Term " heteroarylalkyl " represent alkyl group replace by one or more heteroaryl groups, wherein alkyl group and heteroaryl groups have implication as described in the present invention, such example comprises, but be not limited to pyridine-2-ethyl, thiazole-2-methyl, imidazoles-2-ethyl, pyrimidine-2-propyl group etc.
Term " heteroarylalkylene " represents that heteroarylalkyl system has two tie points and is connected with molecule rest part, wherein heteroarylalkyl has implication as described in the present invention, such example comprises, but be not limited to pyridine-2-ethylene, thiazole-2-methylene, imidazoles-2-ethylene, pyrimidine-2-methylene etc.
No matter term " alkylsulfonyl ", be used alone or be used in conjunction with other term picture " alkyl sulphonyl ", represent the group-SO of divalence respectively 2-.Term " alkyl sulphonyl " refers to the sulphonyl groups that alkyl replaces, and forms alkyl sulphonyl (-SO 2cH 3).
Term " sulphonamide ", " amino-sulfonyl " or " sulfamyl " represents the amino sulphonyl groups replaced, and forms sulfamyl (-SO 2nH 2).
No matter term " carboxyl ", be used alone or be used in conjunction with other terms, as " carboxyalkyl ", and expression-CO 2h; No matter term " carbonyl ", be used alone or be used in conjunction with other terms, as " aminocarboxyl " or " acyloxy ", represent-(C=O)-.
Term " alkylthio " comprises C 1-10the alkyl of straight or branched is connected on the sulphur atom of divalence, and wherein alkyl group has implication as described in the present invention.Some of them embodiment is, alkylthio is more rudimentary C 1-3alkylthio, such example comprises, but is not limited to methylthio group (CH 3s-), ethylmercapto group etc.
Term " halogenated alkylthio " comprises C 1-10haloalkyl be connected on bivalent sulfur atom, wherein haloalkyl has implication as described in the present invention.Some of them embodiment is, halogenated alkylthio is more rudimentary C 1-3halogenated alkylthio, such example comprises, but is not limited to trifluoromethylthio.
Term " aralkyl " comprises the alkyl group that aryl replaces, and wherein aryl and alkyl group have implication as described in the present invention.Some of them embodiment is, aromatic alkyl group refers to " more rudimentary aralkyl " group, and namely aromatic yl group is connected to C 1-6alkyl group on.Other embodiment is that aromatic alkyl group refers to containing C 1-3" the benzene alkylene " of alkyl.Wherein specific examples comprises benzyl, diphenyl methyl, styroyl etc.And the aryl on aralkyl can further by halogen, alkyl, alkoxyl group, and haloalkyl and halogenated alkoxy replaced.
Term " alkylamino " comprises " N-alkylamino " and " N, N-dialkyl amido ", wherein amino group separately replace by one or two alkyl group, wherein alkyl group has implication as described in the present invention.Some of them embodiment is, alkylamino is one or two C 1-6alkyl is connected to the more rudimentary alkylamino group on nitrogen-atoms.Other embodiment is, alkylamino is C 1-3more rudimentary alkylamino group.Suitable alkylamino group can be alkyl monosubstituted amino or dialkyl amido, and such example comprises, but is not limited to, N-methylamino-, N-ethylamino, N, N-dimethylamino, N, N-diethylin etc.
Term " alkylamino halogenated alkoxy " represent halogenated alkoxy replace by one or more alkylamino radicals, wherein halogenated alkoxy and alkylamino radicals have implication as described in the present invention, such example comprises, but be not limited to methylamino-difluoromethoxy, ethylamino trifluoromethoxy etc.
Term " virtue amino " represent amino group replace by one or two aromatic yl group, wherein aromatic yl group has implication as described in the present invention.Such example comprises, but is not limited to N-phenylamino.Some of them embodiment is, the aromatic ring on fragrant amino can be substituted further.
Term " heteroaryl amino " represent amino group replace by one or two heteroaryl, wherein heteroaryl groups has implication as described in the present invention.Such example comprises, but is not limited to N-thienyl amino.Some of them embodiment is, the hetero-aromatic ring on heteroaryl amino can be substituted further.
Term " aminoalkyl group " comprise the C that replaces by one or more amino 1-10straight or branched alkyl group, wherein alkyl group has implication as described in the present invention.Some of them embodiment is, aminoalkyl group the C that replaces by one or more amino group 1-6" more rudimentary aminoalkyl group ", such example comprises, but is not limited to, aminomethyl, aminoethyl, aminopropyl, ammonia butyl and ammonia hexyl.
Term " alkyl amino alkyl " comprises the alkyl group replaced by alkylamino, and wherein alkylamino and alkyl group have implication as described in the present invention.Some of them embodiment is, alkylaminoalkyl group is C 1-6more rudimentary alkyl amino alkyl.Other embodiment is, alkylaminoalkyl group is C 1-3more rudimentary alkyl amino alkyl.Suitable alkyl amino alkyl group can be that monoalkyl or dialkyl group replace, and such example comprises, but is not limited to, N-Methylaminomethyl, N, N-dimethyl aminoethyl, N, N-diethylamino methyl etc.
Term " alkylaminoalkoxy " comprises the alkoxy base replaced by alkylamino, and wherein alkylamino and alkoxy base have implication as described in the present invention.Suitable alkylaminoalkoxy can by monoalkyl or dialkyl group replace, such example comprises, but is not limited to, N-methyl amino ethoxy, N, N-dimethylamino ethoxy, N, N-diethyl amino base oxethyl etc.
Term " alkylaminoalkoxy alkoxyl group " represent the alkoxy base that replaces by alkylaminoalkoxy, wherein alkylaminoalkoxy and alkoxy base have implication as described in the present invention.Suitable alkylaminoalkoxy alkoxyl group can by monoalkyl or dialkyl group replace, such example comprises, but be not limited to, N-methylamino methoxy ethoxy, N-methyl amino ethoxy oxyethyl group, N, N-dimethylamino ethoxy oxyethyl group, N, N-diethylamino methoxymethoxy etc.
Term " carboxyalkyl " comprise can the C that replaces by one or more carboxyl 1-10straight or branched alkyl, wherein carboxyl and alkyl group have implication as described in the present invention.Such example comprises, but is not limited to, carboxymethyl, carboxylic propyl group etc.
Term " aryloxy " comprises the optional aryl replaced, and define as the present invention, be connected by Sauerstoffatom with molecule rest part, such example comprises, but is not limited to phenoxy group, to tolyloxy etc.
Term " heteroaryl oxygen base " comprises the optional heteroaryl replaced, and as defined herein, is connected with molecule rest part by Sauerstoffatom.Such example comprises, but is not limited to pyridyl-2-oxygen base, pyridyl-4-oxygen base, thiazolyl-2-oxygen base etc.
The heteroarylalkyl group that term " heteroarylalkoxy " comprises containing Sauerstoffatom is connected with molecule rest part by Sauerstoffatom, and wherein heteroaryl and alkoxy base have implication as described in the present invention.Such example comprises, but is not limited to pyridyl-2-methoxyl group, pyridyl-4-oxyethyl group, thiazolyl-2-oxyethyl group, imidazoles-3-propoxy-etc.
Term " cycloalkylalkyl " represent alkyl group can replace by one or more group of naphthene base, wherein cycloalkyl and alkyl group have implication as described in the present invention.Such example comprises, but is not limited to cyclohexyl methyl, cyclopropylethyl etc.Described cycloalkyl can further by halogen, alkyl, and alkoxyl group and hydroxyl replaced.
Term " condensed-bicyclic ", " condensed ring ", " condensed-bicyclic base ", " condensed ring radical " represents saturated bridged-ring system, relates to the bicyclic system of non-aromatic.Such system can comprise independently or the undersaturated condition of conjugation, but its core texture does not comprise aromatic nucleus or fragrant heterocycle (but aromatic series can as the substituting group on it).Each ring in condensed-bicyclic is carbocyclic ring or is that assorted alicyclic, such example comprises, but is not limited to, six hydrogen-furo [3,2-b] furans, 2,3,3a, 4,7,7a-six hydrogen-1H-indenes, 7-azabicyclo [2.2.1] heptane, condensed-bicyclic [3.3.0] octane, condensed-bicyclic [3.1.0] hexane, 1,2,3,4,4a, 5,8,8a-octahydro naphthalene, these are included within the system of condensed-bicyclic.And described condensed-bicyclic base can be substituted or non-substituted, and wherein substituting group can be, but is not limited to, hydroxyl, amino, halogen, cyano group, aryl, heteroaryl, alkoxyl group, alkyl, thiazolinyl, alkynyl, heterocyclic radical, sulfydryl, nitro, aryloxy etc.
Term " condenses assorted bicyclic group " and represents saturated or undersaturated fused ring system, relates to the bicyclic system of non-aromatic.Such system can comprise independently or the undersaturated condition of conjugation, but its core texture does not comprise aromatic nucleus or fragrant heterocycle (but aromatic series can as the substituting group on it).And at least one member ring systems comprises one or more heteroatoms, wherein each member ring systems comprises 3-7 ring, namely comprises 1-6 carbon atom and be selected from N, 1-3 the heteroatoms of O, P, S, at this S or P optionally replace by one or more Sauerstoffatom and obtain as SO, SO 2, PO, PO 2group, such example comprises, but is not limited to six hydrogen-furo [3,2-b] furans, 7-azabicyclo [2.2.1] heptane etc.And described in condense assorted bicyclic group can be substituted or non-substituted, wherein substituting group can be, but is not limited to, hydroxyl, amino, halogen, cyano group, aryl, heteroaryl, alkoxyl group, alkyl, thiazolinyl, alkynyl, heterocyclic radical, sulfydryl, nitro, aryloxy etc.
Term " condensed-bicyclic base aliphatics " represent aliphatic group replace by one or more condensed-bicyclic base group, wherein aliphatic group and condensed-bicyclic base group have implication as described in the present invention, and such example comprises, but be not limited to 1,2,3,4,4a, 5,8,8a-octahydro naphtylethyl group, 1,2,3,4,4a, 5,8,8a-octahydro naphthyl methyl, 1,2,3,4,4a, 5,8,8a-octahydro naphthylpropyl, condensed-bicyclic [3.3.0] octyl methyl, condensed-bicyclic [3.1.0] hexyl ethyl etc.
Term " condensed-bicyclic base alkyl " represent alkyl group replace by one or more condensed-bicyclic base group, wherein alkyl group and condensed-bicyclic base group have implication as described in the present invention, and such example comprises, but is not limited to 1,2,3,4,4a, 5,8,8a-octahydro naphtylethyl group, 1,2,3,4,4a, 5,8,8a-octahydro naphthyl methyl, 1,2,3,4,4a, 5,8,8a-octahydro naphthylpropyl, condensed-bicyclic [3.3.0] octyl methyl, condensed-bicyclic [3.1.0] hexyl ethyl etc.
Term " condense assorted bicyclic group aliphatics " and represent aliphatic group by one or more condense assorted bicyclic group group replace, wherein aliphatic group and condense assorted bicyclic group group there is implication as described in the present invention, such example comprises, but be not limited to six hydrogen-furo [3,2-b] furans-2-base ethyl, six hydrogen-furo [3,2-b] furans-2-ylmethyl, 7-azabicyclo [2.2.1] heptane-2-ylmethyl, 7-azabicyclo [2.2.1] heptane-2-base ethyl, 7-azabicyclo [2.2.1] heptane-4-ylmethyl etc.
Term " condense assorted bicyclic group alkyl " and represent alkyl group by one or more condense assorted bicyclic group group replace, wherein alkyl group and condense assorted bicyclic group group there is implication as described in the present invention, such example comprises, but be not limited to six hydrogen-furo [3,2-b] furans-2-base ethyl, six hydrogen-furo [3,2-b] furans-2-ylmethyl, 7-azabicyclo [2.2.1] heptane-2-ylmethyl, 7-azabicyclo [2.2.1] heptane-2-base ethyl, 7-azabicyclo [2.2.1] heptane-4-ylmethyl etc.
Term " condensed-bicyclic base oxygen base " comprises the optional condensed-bicyclic base replaced, and defines, be connected on Sauerstoffatom as the present invention, and be connected with molecule rest part by Sauerstoffatom, such example comprises, but is not limited to 1,2,3,4,4a, 5,8,8a-octahydro naphthyl oxygen base, condensed-bicyclic [3.3.0] octane-2-oxygen base, condensed-bicyclic [3.1.0] hexane-2-oxygen base etc.
Term " condense assorted bicyclic group oxygen base " and comprise optional replace condense assorted bicyclic group, define as the present invention, be connected on Sauerstoffatom, and be connected with molecule rest part by Sauerstoffatom, such example comprises, but is not limited to six hydrogen-furo [3,2-b] furans-2-base oxygen bases, 7-azabicyclo [2.2.1] heptane-2-base oxygen base, 7-azabicyclo [2.2.1] heptane-4-base oxygen base etc.
Term " condensed-bicyclic base amino " represent amino group replace by one or two condensed-bicyclic base, wherein condensed-bicyclic base has implication as described in the present invention, and such example comprises, but is not limited to 1,2,3,4,4a, 5,8,8a-octahydro naphthyl-amino, two (1,2,3,4,4a, 5,8,8a-octahydro naphthyl) amino, condensed-bicyclic [3.3.0] octyl is amino, and condensed-bicyclic [3.1.0] hexyl is amino.
Term " condense assorted bicyclic group amino " represent amino group by one or two condense assorted bicyclic group replace, wherein condense assorted bicyclic group and there is implication as described in the present invention, such example comprises, but be not limited to six hydrogen-furo [3,2-b] furans-2-base amino, 7-azabicyclo [2.2.1] heptane-2-base is amino, and 7-azabicyclo [2.2.1] heptane-4-base is amino.
Term " condensed-bicyclic base oxygen base alkoxyl group " represent alkoxyl group replace by one or more condensed-bicyclic base oxygen base group, wherein alkoxyl group and condensed-bicyclic base oxygen base have implication as described in the present invention, and such example comprises, but be not limited to 1,2,3,4,4a, 5,8,8a-octahydro naphthyl Oxymethoxy, 1,2,3,4,4a, 5,8,8a-octahydro naphthyl oxygen base oxethyl, condensed-bicyclic [3.3.0] octane-2-oxygen base oxethyl, condensed-bicyclic [3.1.0] hexane-2-oxygen base propoxy-etc.
Term " condense assorted bicyclic group oxygen base alkoxyl group " and represent alkoxyl group by one or more condense assorted bicyclic group oxygen base group replace, wherein alkoxyl group and condense assorted bicyclic group oxygen base there is implication as described in the present invention, such example comprises, but be not limited to six hydrogen-furo [3, 2-b] furans-2-base oxygen base propoxy-, 7-azabicyclo [2.2.1] heptane-2-base oxygen base oxethyl, 7-azabicyclo [2.2.1] heptane-4-base oxygen base propoxy-, six hydrogen-furo [3, 2-b] furans-2-base oxygen base oxethyl, 7-azabicyclo [2.2.1] heptane-2-base oxygen base propoxy-, 7-azabicyclo [2.2.1] heptane-4-base oxygen base oxethyl etc.
Term " condensed-bicyclic base aminoalkoxy " represent alkoxyl group by one or more condensed-bicyclic base amino replace, wherein alkoxyl group and condensed-bicyclic base amino have implication as described in the present invention, such example comprises, but be not limited to 1, 2, 3, 4, 4a, 5, 8, 8a-octahydro naphthyl-amino oxyethyl group, 1, 2, 3, 4, 4a, 5, 8, 8a-octahydro naphthyl-amino propoxy-, two (1, 2, 3, 4, 4a, 5, 8, 8a-octahydro naphthyl) amino propoxy-, condensed-bicyclic [3.3.0] octane-2-amino ethoxy, the amino propoxy-of condensed-bicyclic [3.1.0] hexane-2-etc.
Term " condense assorted bicyclic group aminoalkoxy " and represent alkoxyl group by one or more condense assorted bicyclic group amino replace, wherein alkoxyl group and condense assorted bicyclic group amino there is implication as described in the present invention, such example comprises, but be not limited to 7-azabicyclo [2.2.1] heptane-2-base amino ethoxy, the amino propoxy-of 7-azabicyclo [2.2.1] heptane-4-base, six hydrogen-furo [3, 2-b] furans-2-base amino ethoxy, six hydrogen-furo [3, 2-b] the amino propoxy-of furans-2-base, six hydrogen-furo [3, 2-b] furans-2-base aminomethoxy etc.
Term " sub-condensed-bicyclic base " represents that fused bicyclic carbocycle has two tie points and is connected with molecule rest part, and wherein condensed-bicyclic base has implication as described in the present invention.Such example comprises, but is not limited to dicyclo [3.1.0] hexane-3,6-bis-base etc.
Term " Asia condenses assorted bicyclic group " represents that condensing assorted bicyclic system has two tie points and be connected with molecule rest part.Such example comprises, but is not limited to 3-azabicyclo [3.1.0] hexane-3,6-bis-base etc.
Term " sub-condensed-bicyclic base alkyl " represents that condensed-bicyclic base alkyl has two tie points and is connected with molecule rest part, and wherein condensed-bicyclic base alkyl has implication as described in the present invention.
Term " Asia condenses assorted bicyclic group alkyl " represents that condensing assorted bicyclic group alkyl has two tie points and be connected with molecule rest part, wherein condenses assorted bicyclic group alkyl and has implication as described in the present invention.
Term " volution base ", " volution ", " spiral shell bicyclic group ", " spiral shell dicyclo " represents that a ring originates from ring-type carbon special on another ring.Such as, as described below, a saturated bridged-ring system (ring B and B ') is called as " condensed-bicyclic ", otherwise ring A and ring B shares a carbon atom in two saturated member ring systems, be then called as " volution ".Each ring inside volution is carbocyclic ring or is assorted alicyclic.Such example comprises, but is not limited to 4-azaspiro [2.4] heptane-5-base, 4-oxaspiro [2.4] heptane-5-base, 5-azaspiro [2.4] heptane-5-base, spiral shell [2.4] heptane base, spiral shell [4.4] nonyl, 7-hydroxyl-5-azaspiro [2.4] heptane-5-base etc.And described spiral shell bicyclic group can be substituted or non-substituted, and wherein substituting group can be, but is not limited to, hydroxyl, amino, halogen, cyano group, aryl, heteroaryl, alkoxyl group, alkyl, thiazolinyl, alkynyl, heterocyclic radical, sulfydryl, nitro, aryloxy etc.
Term " spiral shell mix bicyclic group " represents that a ring originates from ring-type carbon special on another ring.Such as, as described above, a saturated bridged-ring system (ring B and B ') is called as " condensed-bicyclic ", otherwise ring A and ring B shares a carbon atom in two saturated member ring systems, be then called as " volution ".And at least one member ring systems comprises one or more heteroatoms, wherein each member ring systems comprises 3-7 ring, namely comprises 1-6 carbon atom and be selected from N, 1-3 the heteroatoms of O, P, S, at this S or P optionally replace by one or more Sauerstoffatom and obtain as SO, SO 2, PO, PO 2group, such example comprises, but is not limited to 4-azaspiro [2.4] heptane-5-base, 4-oxaspiro [2.4] heptane-5-base, 5-azaspiro [2.4] heptane-5-base, 7-hydroxyl-5-azaspiro [2.4] heptane-5-base etc.And described spiral shell is mixed, bicyclic group can be substituted or non-substituted, and wherein substituting group can be, but is not limited to, hydroxyl, amino, halogen, cyano group, aryl, heteroaryl, alkoxyl group, alkyl, thiazolinyl, alkynyl, heterocyclic radical, sulfydryl, nitro, aryloxy etc.
Term " spiral shell bicyclic group aliphatics " represent aliphatic group replace by one or more spiral shell bicyclic group group, wherein aliphatic group and spiral shell bicyclic group group have implication as described in the present invention, such example comprises, but be not limited to spiral shell [2.4] heptane ylmethyl, spiral shell [2.4] heptane base ethyl, spiral shell [2.4] heptane base propyl group, spiral shell [4.4] nonyl methyl, spiral shell [4.4] nonyl ethyl, 4-azaspiro [2.4] heptane-5-ylmethyl, 4-azaspiro [2.4] heptane-5-base ethyl, 4-oxaspiro [2.4] heptane-5-base ethyl, 5-azaspiro [2.4] heptane-5-base propyl group, 7-hydroxyl-5-azaspiro [2.4] heptane-5-base propyl group etc.
Term " spiral shell bicyclic group alkyl " represent alkyl group replace by one or more spiral shell bicyclic group group, wherein alkyl group and spiral shell bicyclic group group have implication as described in the present invention, such example comprises, but be not limited to spiral shell [2.4] heptane ylmethyl, spiral shell [2.4] heptane base ethyl, spiral shell [2.4] heptane base propyl group, spiral shell [4.4] nonyl methyl, spiral shell [4.4] nonyl ethyl, 4-azaspiro [2.4] heptane-5-ylmethyl, 4-azaspiro [2.4] heptane-5-base ethyl, 4-oxaspiro [2.4] heptane-5-base ethyl, 5-azaspiro [2.4] heptane-5-base propyl group, 7-hydroxyl-5-azaspiro [2.4] heptane-5-base propyl group etc.
Term " spiral shell mix bicyclic group aliphatics " represent aliphatic group by one or more spiral shell mix bicyclic group group replace, wherein aliphatic group and spiral shell bicyclic group group of mixing has implication as described in the present invention, such example comprises, but be not limited to 4-azaspiro [2.4] heptane-5-ylmethyl, 4-azaspiro [2.4] heptane-5-base ethyl, 4-oxaspiro [2.4] heptane-5-base ethyl, 5-azaspiro [2.4] heptane-5-base propyl group, 7-hydroxyl-5-azaspiro [2.4] heptane-5-base propyl group etc.
Term " spiral shell mix bicyclic group alkyl " represent alkyl group by one or more spiral shell mix bicyclic group group replace, wherein alkyl group and spiral shell bicyclic group group of mixing has implication as described in the present invention, such example comprises, but be not limited to 4-azaspiro [2.4] heptane-5-ylmethyl, 4-azaspiro [2.4] heptane-5-base ethyl, 4-oxaspiro [2.4] heptane-5-base ethyl, 5-azaspiro [2.4] heptane-5-base propyl group, 7-hydroxyl-5-azaspiro [2.4] heptane-5-base propyl group etc.
Term " spiral shell bicyclic group oxygen base " comprises the optional spiral shell bicyclic group replaced, define as the present invention, be connected on Sauerstoffatom, and be connected with molecule rest part by Sauerstoffatom, such example comprises, but be not limited to spiral shell [2.4] heptane-2-oxygen base, spiral shell [2.4] heptane-3-oxygen base, spiral shell [2.4] heptane-4-oxygen base, spiral shell [4.4] nonane-2-oxygen base, spiral shell [4.4] nonane-4-oxygen base, 4-azaspiro [2.4] heptane-5-oxygen base etc.
Term " spiral shell mix bicyclic group oxygen base " comprises the optional spiral shell replaced and to mix bicyclic group, define as the present invention, be connected on Sauerstoffatom, and be connected with molecule rest part by Sauerstoffatom, such example comprises, but be not limited to 4-azaspiro [2.4] heptane-5-base oxygen base, 4-oxaspiro [2.4] heptane-5-base oxygen base, 5-azaspiro [2.4] heptane-5-base oxygen base etc.
Term " spiral shell bicyclic group amino " represent amino group replace by one or two spiral shell bicyclic group group, wherein spiral shell bicyclic group has implication as described in the present invention, such example comprises, but it is amino to be not limited to spiral shell [2.4] heptane-2-, spiral shell [2.4] heptane-3-is amino, and spiral shell [2.4] heptane-4-is amino, and spiral shell [4.4] nonane-2-is amino, spiral shell [4.4] nonane-4-is amino, and 4-azaspiro [2.4] heptane-5-is amino.
Term " spiral shell mix bicyclic group amino " represent amino group by one or two spiral shell mix bicyclic group group replace, wherein spiral shell bicyclic group of mixing has implication as described in the present invention, such example comprises, but it is amino to be not limited to 4-azaspiro [2.4] heptane-5-base, 4-azaspiro [2.4] heptane-2-base is amino, 4-oxaspiro [2.4] heptane-5-base is amino, and 5-azaspiro [2.4] heptane-5-base is amino.
Term " spiral shell bicyclic group oxygen base alkoxyl group " represent alkoxyl group replace by one or more spiral shell bicyclic group oxygen base group, wherein spiral shell bicyclic group oxygen base and alkoxy base have implication as described in the present invention, such example comprises, but be not limited to spiral shell [2.4] heptane-2-oxygen base oxethyl, spiral shell [2.4] heptane-3-oxygen base propoxy-, spiral shell [2.4] heptane-4-oxygen base propoxy-, spiral shell [4.4] nonane-2-oxygen base oxethyl, spiral shell [4.4] nonane-4-oxygen base propoxy-, 4-azaspiro [2.4] heptane-5-oxygen base propoxy-etc.
Term " spiral shell mix bicyclic group oxygen base alkoxyl group " represent alkoxyl group by one or more spiral shell mix bicyclic group oxygen base group replace, wherein mix bicyclic group oxygen base and alkoxy base of spiral shell has implication as described in the present invention, such example comprises, but be not limited to 4-azaspiro [2.4] heptane-5-base oxygen base oxethyl, 4-oxaspiro [2.4] heptane-5-base oxygen base oxethyl, 5-azaspiro [2.4] heptane-5-base oxygen base oxethyl, 4-azaspiro [2.4] heptane-5-base oxygen base propoxy-, 4-oxaspiro [2.4] heptane-5-base oxygen base propoxy-, 5-azaspiro [2.4] heptane-5-base oxygen base propoxy-etc.
Term " spiral shell bicyclic group aminoalkoxy " represent alkoxyl group by one or more spiral shell bicyclic group amino replace, wherein alkoxyl group and spiral shell bicyclic group amino have implication as described in the present invention, such example comprises, but be not limited to spiral shell [2.4] heptane-2-amino ethoxy, the amino propoxy-of spiral shell [2.4] heptane-3-, spiral shell [2.4] heptane-4-amino ethoxy, spiral shell [4.4] nonane-2-amino ethoxy, the amino propoxy-of spiral shell [4.4] nonane-4-, the amino propoxy-of 4-azaspiro [2.4] heptane-5-etc.
Term " spiral shell mix bicyclic group aminoalkoxy " represent alkoxyl group by one or more spiral shell mix bicyclic group amino replace, wherein alkoxyl group and spiral shell bicyclic group amino of mixing has implication as described in the present invention, such example comprises, but be not limited to 4-azaspiro [2.4] heptane-5-base amino ethoxy, the amino propoxy-of 4-azaspiro [2.4] heptane-2-base, 4-oxaspiro [2.4] heptane-5-base amino ethoxy, the amino propoxy-of 5-azaspiro [2.4] heptane-5-base etc.
Term " sub-spiral shell bicyclic group " represents that spiral shell bicyclic system has two tie points and is connected with molecule rest part, and wherein spiral shell bicyclic group has implication as described in the present invention.Such example comprises, but is not limited to 5-spiral shell [2.4] heptane-5,7-bis-base, spiral shell [4.4] nonane-2,7-bis-base etc.
Term " sub-spiral shell mix bicyclic group " represents that spiral shell bicyclic system of mixing has two tie points and is connected with molecule rest part, and wherein spiral shell bicyclic group of mixing has implication as described in the present invention.Such example comprises, but is not limited to 5-azaspiro [2.4] heptane-5,7-bis-base, 2-azaspiro [4.4] nonane-2,7-bis-base etc.
Term " sub-spiral shell bicyclic group alkyl " represents that spiral shell bicyclic group alkyl system has two tie points and is connected with molecule rest part, and wherein spiral shell bicyclic group alkyl has implication as described in the present invention.
Term " sub-spiral shell mix bicyclic group alkyl " represents that spiral shell bicyclic group alkyl system of mixing has two tie points and is connected with molecule rest part, and wherein spiral shell bicyclic group alkyl of mixing has implication as described in the present invention.
As described in the invention, substituting group is drawn a key and is connected to the member ring systems (as shown below) that the ring at center is formed and represents substituting group any commutable position on ring and can replace.Such as, figure a represents any position that may be substituted on B ring, as shown in figure b.
As described in the invention, inside member ring systems, dotted line key represents a double bond or singly-bound.Such as, the structure scheming c represents any one structure elected inside figure d.
Unless other aspects show, structural formula described in the invention comprises all isomeric forms (as enantiomerism, diastereo-isomerism, with rotamerism (or conformational isomerism)): R, S configuration such as containing asymmetric center, (Z), (E) isomer of double bond, and (Z), (E) conformer.Therefore, the single three-dimensional chemical isomer of compound of the present invention or its enantiomer, diastereomer, or the mixture of geometrical isomer (or conformer) all belongs to scope of the present invention.
Term used in the present invention " prodrug ", represents a compound and is converted into formula (I), (IV), the compound shown in (V) in vivo.Such conversion by prodrug be hydrolyzed in blood or blood or tissue in through enzymatic conversion be the impact of precursor structure.Prodrug compounds of the present invention can be ester, and in existing invention, ester can have phenyl ester class, aliphatics (C as prodrug 1-24) ester class, acyloxymethyl ester class, carbonic ether, amino formate and amino acid esters.Such as, a compound in the present invention comprises hydroxyl, namely its acidylate can be obtained the compound of prodrug form.Other prodrug form comprises phosphoric acid ester, if these phosphate compounds are that di on parent obtains.Can with reference to Publication about Document about the complete discussion of prodrug: T.Higuchi and V.Stella, Pro-drugs as Novel Delivery Systems, Vol.14 of the A.C.S.Symposium Series, Edward B.Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, J.Rautio et al, Prodrugs:Design and Clinical Applications, Nature Review Drug Discovery, 2008, 7, 255-270, and S.J.Hecker et al, Prodrugs of Phosphates and Phosphonates, Journal of Medicinal Chemistry, 2008, 51, 2328-2345.
Unless other aspects show, all tautomeric forms of compound of the present invention are included within scope of the present invention.In addition, unless other aspects show, the structural formula of compound described in the invention comprises the enriched isotope of one or more different atom.
" meta-bolites " refers to concrete compound or its salt in vivo by product that metabolism obtains.The meta-bolites of a compound can be identified by the known technology in affiliated field, and its activity can be characterized by such method of test that adopts as described in the present invention.Such product can be by passing through oxidation to drug compound, and reduction, hydrolysis, amidated, desamido-effect, esterification, fat abstraction, enzymatic lysis etc. method obtains.Correspondingly, the present invention includes the meta-bolites of compound, comprise and compound of the present invention and Mammals fully contacted the meta-bolites that for some time produces.
The definition of neutral body chemistry of the present invention and the usual reference of the use of convention are with Publication about Document: S.P.Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; And Eliel, E.and Wilen, S., " Stereochemistry of Organic Compounds ", John Wiley & Sons, Inc., New York, 1994. compounds of the present invention can comprise asymmetric center or chiral centre, therefore there is different steric isomers.The stereoisomeric forms in any ratio that compound of the present invention is all, include, but not limited to, diastereomer, enantiomer, atropisomer, and their mixture, as racemic mixture, constitutes a part of the present invention.A lot of organic compound all exists with optical active forms, i.e. the plane of their capable Plane of rotation polarized light.When describing optically active compound, prefix D, L or R, S are used for representing the absolute configuration at molecular chiral center.Prefix d, l or (+), (-) are used for the symbol naming compound plane polarized light to rotate, and (-) or l refer to that compound is left-handed, and prefix (+) or d refer to that compound is dextrorotation.The chemical structure of these steric isomers is identical, but their three-dimensional arrangement is different.Specific steric isomer can be enantiomorph, and the mixture of isomer is commonly referred to enantiomeric mixture.The mixture of enantiomers of 50:50 is called as racemic mixture or racemic modification, and this may cause not having stereoselectivity or stereospecificity in chemical reaction process.Term " racemic mixture " and " racemic modification " refer to the mixture of equimolar two enantiomers, lack optical activity.
Term " tautomer " or " tautomeric form " refer to that the isomers of the structure of different-energy can be transformed mutually by low energy barrier.Such as proton tautomer (i.e. prototropic tautomer) comprises the change by proton shifting, as the isomerization of keto-enol and imine-enamine.Valence (valency) tautomer comprises the change reassembling into bonding electron.
Term " tautomer " or " tautomeric form " represent that the isomers of different-energy can be transformed mutually by lower energy barrier.Such example comprises, but is not limited to, and proton tautomer (i.e. prototropy isomer) comprises the change by proton shifting, the isomerization of such as keto-enol and imine-enamine.Valence tautomer comprises the restructuring change of some bonding electronss.
" pharmacy acceptable salt " used in the present invention refers to organic salt and the inorganic salt of compound of the present invention.Pharmacy acceptable salt in affiliated field known by us, as document: S.M.Berge et al., describe pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences, 66:1-19, described in 1977..The salt that pharmaceutically acceptable nontoxic acid is formed comprises, but is not limited to, and reacting with amino group the inorganic acid salt formed has hydrochloride, hydrobromate, phosphoric acid salt, vitriol, perchlorate, and organic acid salt is as acetate, oxalate, maleate, tartrate, Citrate trianion, succinate, malonate, or obtain these salt by additive method such as ion exchange method described on books document.Other pharmacy acceptable salts comprise adipate, oxysuccinic acid, 2 hydroxy propanoic acid, alginate, ascorbate salt, aspartate, benzene sulfonate, benzoate, bisulfate, borate, butyrates, camphorate, camsilate, cyclopentyl propionate, digluconate, dodecyl sulfate, esilate, formate, fumarate, gluceptate, glycerophosphate, gluconate, Hemisulphate, enanthate, hexanoate, hydriodate, 2-hydroxy-ethanesulfonate salt, lactobionate, lactic acid salt, lauroleate, lauryl sulfate, malate, malonate, mesylate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pamoate, pectate, persulphate, 3-phenylpropionic acid salt, picrate, pivalate, propionic salt, stearate, thiocyanate-, tosilate, undecylate, valerate, etc..The salt obtained by suitable alkali comprises basic metal, alkaline-earth metal, ammonium and N +(C 1-4alkyl) 4salt.The quaternary ammonium salt that the compound that the present invention also intends the group contemplating any comprised N is formed.Water-soluble or oil soluble or dispersion product can be obtained by quaternization.Basic metal or alkaline earth salt comprise sodium, lithium, potassium, calcium, magnesium, etc.Pharmacy acceptable salt comprises suitable, nontoxic ammonium further, the amine positively charged ion that quaternary ammonium salt and gegenions are formed, as halogenide, and oxyhydroxide, carboxylate, hydrosulfate, phosphoric acid compound, nitric acid compound, C 1-8azochlorosulfonate acid compound and aromatic sulphonic acid compound.
" solvate " of the present invention refers to the associated complex that one or more solvent molecule and compound of the present invention are formed.The solvent forming solvate comprises, but is not limited to, water, Virahol, ethanol, methyl alcohol, methyl-sulphoxide, ethyl acetate, acetic acid, monoethanolamine.Term " hydrate " refers to that solvent molecule is the associated complex that water is formed.
Time term " blocking group " or " Pg " refer to a substituting group and other reacted with functional groups, be commonly used to block or protect special functional.Such as; " amino blocking group " refer to a substituting group be connected with amino group block or protect in compound amino functional; suitable amido protecting group comprises ethanoyl; trifluoroacetyl group; tertbutyloxycarbonyl (BOC), carbobenzoxy-(Cbz) (CBZ) and the sub-methoxycarbonyl (Fmoc) of 9-fluorenes.Similarly, " hydroxy-protective group " refers to that the substituting group of hydroxyl is used for blocking or protecting the functional of hydroxyl, and suitable blocking group comprises ethanoyl and silyl." carboxy protective group " refers to that the substituting group of carboxyl is used for blocking or protecting the functional of carboxyl, and general carboxyl-protecting group comprises-CH 2cH 2sO 2ph; cyano ethyl; 2-(TMS) ethyl; 2-(TMS) ethoxyl methyl; 2-(p-toluenesulfonyl) ethyl, 2-(p-nitrophenyl alkylsulfonyl) ethyl, 2-(diphenylphosphino) ethyl; nitro-ethyl, etc.Can reference for the general description of blocking group: T W.Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991; And P.J.Kocienski, Protecting Groups, Thieme, Stuttgart, 2005.
The description of the compounds of this invention
The heterogeneous ring compound that the present invention relates to and pharmaceutical preparation thereof, to tyrosine kinase receptor, especially the disease of KDR, c-Met acceptor or IGF regulation or the treatment of illness have potential purposes.On the one hand, the present invention relates to one such as formula the compound shown in (I):
Or its racemic mixture, diastereomer, enantiomer, geometrical isomer, tautomer, oxynitride, hydrate, solvate, meta-bolites, or pharmacy acceptable salt, wherein, R 1, R 2, R 3, R 4, Y 1, Y 2, shown in W and Q is defined as follows.
Some of them embodiment is, R 1, R 2, R 3and R 4be selected from H independently of one another ,-C (=O) R 11,-C (=O) OR 11,-C (=O) NR 11r 11a, R 11r 11an-O 2s-, R 11o 2s-, R 11ar 11n-alkyl, R 11o-alkyl, aliphatics, halogenated aliphatic, aromatic yl aliphat, heterocyclic radical aliphatics, cycloalkyl aliphatics, aryl, heteroaryl, heterocyclic radical or carbocylic radical; Or R 1, R 2, and together with the nitrogen-atoms be connected with them, the heterocycle of that can form arbitrarily replacement or non-substituted 3-8 unit; Or R 3, R 4, and together with the carbon atom be connected with them, the carbocyclic ring of that can form arbitrarily replacement or non-substituted 3-8 unit or heterocycle;
Y 1and Y 2be selected from divalent group independently of one another: aliphatics-C (=O)-, aliphatics-C (=O) O-, aliphatics-C (=O) NR 11-,-R 11n-O 2s-aliphatics ,-O 2s-,-R 11n-aliphatics ,-S (=O)-aliphatics, or-R 11n-C (=O)-aliphatics; Or sub-condensed-bicyclic base alkyl, Asia condenses assorted bicyclic group alkyl, sub-spiral shell bicyclic group alkyl, sub-spiral shell is mixed bicyclic group alkyl, sub-aralkyl, sub-heteroaralkyl, alkylidene group, halogeno alkylen, sub-heterocyclic radical, sub-carbocylic radical, sub-cycloheteroalkylalkyl, sub-carbocylic radical alkyl, sub-condensed-bicyclic base, Asia condenses assorted bicyclic group, sub-spiral shell bicyclic group, sub-spiral shell is mixed bicyclic group, arylidene or inferior heteroaryl;
W is selected from O, N-R 11or (CR 12r 12a) m; Wherein m is 0,1,2 or 3;
Q is selected from following structural formula:
Wherein U is CR 12or N;
R 5and R 6be selected from H independently of one another, F, Cl, Br, I ,-CN, hydroxyl, R 11ar 11n-,-C (=O)-R 11,-C (=O)-OR 11,-C (=O) NR 11r 11a,-OC (=O) NR 11r 11a,-OC (=O) OR 11,-NR 11c (=O) NR 11r 11a,-NR 11c (=O) OR 11a,-NR 11c (=O)-R 11a, R 11r 11an-O 2s-, R 11o 2s-, R 11o 2sR 11an-, R 11ar 11n-alkyl, R 11(S=O)-alkyl, R 11r 11an-(C=O)-alkyl, R 11ar 11n-alkoxyl group, R 11(S=O)-alkoxyl group, R 11r 11an-(C=O)-alkoxyl group, aliphatics, alkoxyl group, hydroxy alkoxy base, aminoalkoxy, the aminoalkoxy that hydroxyl replaces, halogenated alkoxy, the amino halogenated alkoxy replaced, alkylamino halogenated alkoxy, the halogenated alkoxy that hydroxyl replaces, alkylaminoalkoxy, alkyloxy-alkoxy, alkoxy aryl, heterocyclylalkoxy, carbocyclylalkoxy, heterocyclic radical (hydroxy alkoxy base), carbocylic radical (hydroxy alkoxy base), aryl (hydroxy alkoxy base), aryloxy alkoxyl group, aryloxy, heterocyclyloxy base alkoxyl group, carbocylic radical oxygen base alkoxyl group, heterocyclyloxy base, cycloalkyl oxy, (heterocyclic radical) hydroxy alkoxy base, azido-alkoxyl group, condensed-bicyclic base, condense assorted bicyclic group, condensed-bicyclic base aliphatics, condense assorted bicyclic group aliphatics, condensed-bicyclic base oxygen base, condense assorted bicyclic group oxygen base, condensed-bicyclic base oxygen base alkoxyl group, condense assorted bicyclic group oxygen base alkoxyl group, condensed-bicyclic base aminoalkoxy, condense assorted bicyclic group aminoalkoxy, spiral shell bicyclic group, spiral shell is mixed bicyclic group, spiral shell bicyclic group aliphatics, spiral shell is mixed bicyclic group aliphatics, spiral shell bicyclic group oxygen base, spiral shell is mixed bicyclic group oxygen base, spiral shell bicyclic group oxygen base alkoxyl group, spiral shell is mixed bicyclic group oxygen base alkoxyl group, spiral shell bicyclic group aminoalkoxy, spiral shell is mixed bicyclic group aminoalkoxy, aryl, heteroaryl, aromatic yl aliphat or heteroaryl aliphatics,
R 7independently selected from H, F, Cl, Br, I ,-CN, hydroxyl, R 11ar 11n-, aliphatics, alkoxyl group, haloalkyl, heterocyclic radical, cycloheteroalkylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkyl alkoxy, or heterocyclylalkoxy;
R 8, R 9and R 10be selected from H independently of one another ,-C (=O) R 11,-C (=O) OR 11,-C (=O) NR 11r 11a, R 11r 11an-O 2s-, R 11o 2s-, R 11ar 11n-alkyl, R 11(S=O)-alkyl, R 11r 11an-(C=O)-alkyl, aliphatics, hydroxyalkyl, the aminoalkyl group that hydroxyl replaces, haloalkyl, the amino haloalkyl replaced, alkylamino haloalkyl, the haloalkyl that hydroxyl replaces, alkoxyalkyl, aralkyl, cycloheteroalkylalkyl, carbocylic radical alkyl, heterocyclic radical-hydroxyalkyl, carbocylic radical-hydroxyalkyl, aryl-hydroxyalkyl, aryloxy alkyl, heterocyclyloxyalkyl, carbocylic radical oxygen base alkyl, heterocyclic radical, cycloalkyl, (heterocyclic radical) hydroxyalkyl, azido-alkyl, condensed-bicyclic base, condense assorted bicyclic group, condensed-bicyclic base aliphatics, condense assorted bicyclic group aliphatics, condensed-bicyclic base oxygen base alkyl, condense assorted bicyclic group oxygen base alkyl, condensed-bicyclic base aminoalkyl group, condense assorted bicyclic group aminoalkyl group, spiral shell bicyclic group, spiral shell is mixed bicyclic group, spiral shell bicyclic group aliphatics, spiral shell is mixed bicyclic group aliphatics, spiral shell bicyclic group oxygen base alkyl, spiral shell is mixed bicyclic group oxygen base alkyl, spiral shell bicyclic group aminoalkyl group, spiral shell is mixed bicyclic group aminoalkyl group, aryl, heteroaryl, aromatic yl aliphat or heteroaryl aliphatics,
R 11and R 11abe selected from H independently of one another, aliphatics, halogenated aliphatic, hydroxyl group aliphatic, amino aliphatics, alkoxyl group aliphatics, alkylamino aliphatics, alkylthio aliphatics, aromatic yl aliphat, heterocyclic radical aliphatics, cycloalkyl aliphatics, aryl, heteroaryl, heterocyclic radical, or carbocylic radical; Or work as R 11and R 11abe connected with same nitrogen-atoms, so R 11, R 11a, and together with the nitrogen-atoms be connected with them, substituted or non-substituted 3-8 ring can be formed arbitrarily, comprise volution or dicyclo; With
R 12and R 12abe selected from H independently of one another, F, Cl, Br, I ,-CN, hydroxyl ,-NR 11ar 11,-OC (=O) R 11,-C (=O) R 11,-C (=O) OR 11,-C (=O) NR 11r 11a,-OC (=O) NR 11r 11a,-OC (=O) OR 11,-NR 11c (=O) NR 11r 11a,-NR 11c (=O) OR 11a,-NR 11c (=O)-R 11a, R 11r 11an-O 2s-, R 11o 2s-, R 11o 2s-N (R 11a)-, alkoxyl group, cycloalkyl oxy, heterocyclylalkoxy, aliphatics, halogenated aliphatic, hydroxyl group aliphatic, amino aliphatics, alkoxyl group aliphatics, alkylamino aliphatics, alkylthio aliphatics, aromatic yl aliphat, heterocyclic radical aliphatics, cycloalkyl aliphatics, aryl, heteroaryl, heterocyclic radical, or carbocylic radical; Or work as R 12and R 12abe connected with same carbon atom, so R 12, R 12a, and together with the carbon atom be connected with them, carbocyclic ring or the heterocycle of substituted or non-substituted 3-8 unit can be formed arbitrarily;
Wherein each substituting group, as :-C (=O) R 11,-C (=O) OR 11,-C (=O) NR 11r 11a, R 11r 11an-O 2s-, R 11o 2s-, R 11ar 11n-,-OC (=O) NR 11r 11a,-OC (=O) OR 11,-NR 11c (=O) NR 11r 11a,-NR 11c (=O) OR 11a,-NR 11c (=O)-R 11a, R 11o 2s-N (R 11a)-, R 11s (=O)-alkyl, R 11r 11an-C (=O)-alkyl, R 11ar 11n-alkoxyl group, R 11s (=O)-alkoxyl group, R 11r 11an-C (=O)-alkoxyl group, R 11ar 11n-alkyl, R 11o-alkyl, aliphatics-C (=O) R 11, aliphatics-C (=O) OR 11, aliphatics-C (=O) NR 11r 11a, R 11r 11an-O 2s-aliphatics, R 11o 2s-, R 11ar 11n-aliphatics, R 11o-aliphatics, R 11(S=O)-aliphatics, R 11r 11an-(C=O)-aliphatics, aliphatics, halogenated aliphatic, aromatic yl aliphat, heterocyclic radical aliphatics, cycloalkyl aliphatics, aryl, heteroaryl, heterocyclic radical, carbocylic radical, haloalkyl, condensed-bicyclic base, condense assorted bicyclic group, condensed-bicyclic base aliphatics, condense assorted bicyclic group aliphatics, spiral shell bicyclic group, spiral shell is mixed bicyclic group, sieve bicyclic group aliphatics, spiral shell is mixed bicyclic group aliphatics, alkoxyl group, hydroxy alkoxy base, aminoalkoxy, the aminoalkoxy that hydroxyl replaces, halogenated alkoxy, the amino halogenated alkoxy replaced, alkylamino halogenated alkoxy, the halogenated alkoxy that hydroxyl replaces, alkylaminoalkoxy, alkyloxy-alkoxy, alkoxy aryl, heterocyclylalkoxy, carbocyclylalkoxy, heterocyclic radical (hydroxy alkoxy base), carbocylic radical (hydroxy alkoxy base), aryl (hydroxyl-alkoxy), aryloxy alkoxyl group, aryloxy, heterocyclyloxy base alkoxyl group, carbocylic radical oxygen base alkoxyl group, heterocyclyloxy base, cycloalkyl oxy, (heterocyclic radical) hydroxy alkoxy base, azido-alkoxyl group, condensed-bicyclic base oxygen base, condense assorted bicyclic group oxygen base, condensed-bicyclic base oxygen base alkoxyl group, condense assorted bicyclic group oxygen base alkoxyl group, condensed-bicyclic base aminoalkoxy, condense assorted bicyclic group aminoalkoxy, spiral shell bicyclic group oxygen base, spiral shell is mixed bicyclic group oxygen base, spiral shell bicyclic group oxygen base alkoxyl group, spiral shell is mixed bicyclic group oxygen base alkoxyl group, spiral shell bicyclic group aminoalkoxy, spiral shell is mixed bicyclic group aminoalkoxy, heteroaryl aliphatics, cycloheteroalkylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkyl alkoxy, heterocyclylalkoxy, hydroxyalkyl, the aminoalkyl group that hydroxyl replaces, haloalkyl, the amino haloalkyl replaced, alkylamino haloalkyl, the haloalkyl that hydroxyl replaces, alkoxyalkyl, arylalkyl, carbocylic radical alkyl, heterocyclic radical (hydroxyalkyl), carbocylic radical (hydroxyalkyl), aryl (hydroxyalkyl), aryloxy alkyl, heterocyclyloxyalkyl, carbocylic radical oxygen base alkyl, (heterocyclic radical) hydroxyalkyl, azido-alkyl, condensed-bicyclic base oxygen base alkyl, condense assorted bicyclic group oxygen base alkyl, condensed-bicyclic base aminoalkyl group, condense assorted bicyclic group aminoalkyl group, spiral shell bicyclic group oxygen base alkyl, spiral shell is mixed bicyclic group oxygen base alkyl, spiral shell bicyclic group aminoalkyl group, spiral shell is mixed bicyclic group aminoalkyl group, hydroxyl group aliphatic, amino aliphatics, alkoxyl group aliphatics, alkylamino aliphatics, sub-condensed-bicyclic base alkyl, Asia condenses assorted bicyclic group alkyl, sub-spiral shell bicyclic group alkyl, sub-spiral shell is mixed bicyclic group alkyl, sub-aralkyl, sub-heteroaralkyl, alkylidene group, halogeno alkylen, sub-heterocyclic radical, sub-carbocylic radical, sub-cycloheteroalkylalkyl, sub-carbocylic radical alkyl, sub-condensed-bicyclic base, Asia condenses assorted bicyclic group, sub-spiral shell bicyclic group, sub-spiral shell is mixed bicyclic group, arylidene, inferior heteroaryl or alkylthio aliphatics can be independently substituted or non-substituted substituting groups.
Other embodiment is, R 1, R 2, R 3and R 4be selected from H independently of one another ,-C (=O) R 11,-C (=O) OR 11,-C (=O) NR 11r 11a, R 11r 11an-O 2s-, R 11o 2s-, R 11ar 11n-C 1-6alkyl, R 11o-C 1-6alkyl, the C replaced arbitrarily 1-6aliphatics, C 1-6halogenated aliphatic, C 6-10aryl C 1-6aliphatics, C 2-6heterocyclic radical C 1-6aliphatics, C 3-6cycloalkyl C 1-6aliphatics, C 6-10aryl, C 1-9heteroaryl, C 2-6heterocyclic radical, and C 3-6carbocylic radical; Or R 1and R 2, and replacement can be formed arbitrarily together with the nitrogen-atoms be connected with them or the heterocycle of non-substituted 3-8 unit; Or R 3and R 4, and substituted or non-substituted 3-8 unit's carbocyclic ring or heterocycle together with the carbon atom be connected with them, can be formed arbitrarily;
Y 1and Y 2be selected from divalent group independently of one another: C 1-6aliphatics-C (=O)-, C 1-6aliphatics-C (=O) O-, C 1-6aliphatics-C (=O) NR 11-,-R 11n-O 2s-C 1-6aliphatics ,-O 2s-C 1-6aliphatics ,-R 11nC 1-6aliphatics ,-S (=O) C 1-6aliphatics, or-R 11n-C (=O)-C 1-6aliphatics; Condense C 6-10bicyclic group C 1-6alkylidene group, condenses C 5-9assorted bicyclic group C 1-6alkylidene group, spiral shell C 7-11bicyclic group C 1-6alkylidene group, spiral shell C 6-10assorted bicyclic group C 1-6alkylidene group, C 1-6halogeno alkylen, C 2-8heterocyclic radical C 1-6alkylidene group, C 3-8carbocylic radical C 1-6alkylidene group, C 2-8sub-heterocyclic radical, C 3-8sub-carbocylic radical, condenses C 6-10sub-bicyclic group, condenses C 5-9sub-assorted bicyclic group, spiral shell C 7-11sub-bicyclic group or spiral shell C 6-10sub-assorted bicyclic group;
W is selected from O, N-R 11, (CR 12r 12a) m; M is 0,1 or 2;
Q is selected from following structural formula:
Wherein U is CR 12or N;
R 5and R 6be selected from H independently of one another, halogen, cyano group (CN), R 11ar 11n-C 1-6alkoxyl group, R 11(S=O)-C 1-6alkoxyl group, R 11r 11an-(C=O)-C 1-6alkoxyl group, the C replaced arbitrarily 1-6aliphatics, the C replaced arbitrarily 1-6alkoxyl group, hydroxyl C 2-6alkoxyl group, the amino C that hydroxyl replaces 2-6alkoxyl group, C 1-6halogenated alkoxy, the amino C replaced 2-6halogenated alkoxy, C 1-6alkylamino C 2-6halogenated alkoxy, the C that hydroxyl replaces 2-6halogenated alkoxy, C 1-6alkoxy C 1-6alkoxyl group, C 6-10aryl C 1-6alkoxyl group, C 2-5heterocyclic radical C 1-6alkoxyl group, C 3-6carbocylic radical C 1-6alkoxyl group, C 2-5heterocyclic radical (hydroxyl C 2-6alkoxyl group), C 3-6carbocylic radical (hydroxyl C 2-6alkoxyl group), C 6-10aryl (hydroxyl C 2-6alkoxyl group), C 6-10aryloxy C 1-6alkoxyl group, C 6-10aryloxy, C 2-5heterocyclyloxy base C 1-6alkoxyl group, C 3-6carbocylic radical oxygen base C 1-6alkoxyl group, C 2-5heterocyclyloxy base, C 3-6cycloalkyl oxy, (C 2-5heterocyclic radical) hydroxyl C 1-6alkoxyl group, azido-C 2-6alkoxyl group, condenses C 6-10bicyclic group, condenses C 5-9assorted bicyclic group, condenses C 6-10bicyclic group C 1-6aliphatics, condenses C 5-9assorted bicyclic group C 1-6aliphatics, condenses C 6-10bicyclic group oxygen base, condenses C 5-9assorted bicyclic group oxygen base, condenses C 6-10bicyclic group oxygen base C 1-6alkoxyl group, condenses C 5-9assorted bicyclic group oxygen base C 1-6alkoxyl group, condenses C 6-10the amino C of bicyclic group 1-6alkoxyl group, condenses C 5-9the amino C of assorted bicyclic group 1-6alkoxyl group, spiral shell C 7-11bicyclic group, spiral shell C 6-10assorted bicyclic group, spiral shell C 7-11bicyclic group C 1-6aliphatics, spiral shell C 6-10assorted bicyclic group C 1-6aliphatics, spiral shell C 7-11bicyclic group oxygen base, spiral shell C 6-10assorted bicyclic group oxygen base, spiral shell C 7-11bicyclic group oxygen base C 1-6alkoxyl group, spiral shell C 6-10assorted bicyclic group oxygen base C 1-6alkoxyl group, spiral shell C 7-11the amino C of bicyclic group 1-6alkoxyl group, spiral shell C 6-10the amino C of assorted bicyclic group 1-6alkoxyl group, C 6-10aryl, C 1-9heteroaryl, C 6-10aryl C 1-6aliphatics or C 1-9heteroaryl C 1-6aliphatics;
R 7h, halogen (F, Cl, Br or I) ,-CN, hydroxyl, R 11ar 11n-, C 1-6aliphatics, C 1-6alkoxyl group, C 1-6haloalkyl, C 2-5heterocyclic radical, C 2-5heterocyclic radical C 1-6alkyl, C 3-6cycloalkyl, C 3-6cycloalkyl C 1-6alkyl, C 3-6cycloalkyl C 1-6alkoxyl group, or C 2-5heterocyclic radical C 1-6alkoxyl group;
R 8, R 9and R 10be selected from H independently of one another ,-C (=O) R 11,-C (=O) OR 11,-C (=O) NR 11r 11a, R 11ar 11n-C 1-6alkyl, R 11o-C 1-6alkyl, R 11(S=O)-C 1-6alkyl, R 11r 11an-(C=O)-C 1-6alkyl, the C replaced arbitrarily 1-6aliphatics, C 6-10aryl C 1-6alkyl, C 1-9heteroaryl C 1-6alkyl, C 2-5heterocyclic radical C 1-6alkyl, C 3-6carbocylic radical C 1-6alkyl, C 6-10aryloxy C 1-6alkyl, C 1-9heteroaryloxy C 1-6alkyl, C 2-5heterocyclyloxy base C 1-6alkyl, C 3-6carbocylic radical oxygen base C 1-6alkyl, C 2-5heterocyclic radical, C 3-6cycloalkyl, azido-C 1-6alkyl, condenses C 6-10bicyclic group, condenses C 5-9assorted bicyclic group, condenses C 6-10bicyclic group C 1-6aliphatics, condenses C 5-9assorted bicyclic group C 1-6aliphatics, condenses C 6-10bicyclic group oxygen base C 1-6alkyl, condenses C 5-9assorted bicyclic group oxygen base C 1-6alkyl, condenses C 6-10the amino C of bicyclic group 1-6alkyl, condenses C 5-9the amino C of assorted bicyclic group 1-6alkyl, spiral shell C 7-11bicyclic group, spiral shell C 6-10assorted bicyclic group, spiral shell C 7-11bicyclic group C 1-6aliphatics, spiral shell C 6-10assorted bicyclic group C 1-6aliphatics, spiral shell C 7-11bicyclic group oxygen base C 1-6alkyl, spiral shell C 6-10assorted bicyclic group oxygen base C 1-6alkyl, spiral shell C 7-11the amino C of bicyclic group 1-6alkyl, spiral shell C 6-10the amino C of assorted bicyclic group 1-6alkyl, C 6-10aryl, or C 1-9heteroaryl;
R 11and R 11abe selected from H independently of one another, C 1-6aliphatics, C 1-6halogenated aliphatic, C 1-6hydroxyl group aliphatic, C 1-6amino aliphatics, C 1-6alkoxy C 1-6aliphatics, C 1-6alkylamino C 1-6aliphatics, C 1-6alkylthio C 1-6aliphatics, C 6-10aryl C 1-6aliphatics, C 5-9heterocyclic radical C 1-6aliphatics, C 3-6cycloalkyl C 1-6aliphatics, C 6-10aryl, C 1-9heteroaryl, C 2-5heterocyclic radical, or C 3-6carbocylic radical; Or work as R 11and R 11abe connected with same nitrogen-atoms, so R 11and R 11a, and together with the nitrogen-atoms be connected with them, substituted or non-substituted 3-8 unit heterocycle can be formed arbitrarily, condense C 5-9assorted dicyclo or spiral shell C 6-10assorted dicyclo.
R 12and R 12abe selected from H independently of one another, F, Cl, Br, I ,-CN, hydroxyl ,-NR 11ar 11,-OC (=O) R 11,-C (=O) R 11,-C (=O) OR 11,-C (=O) NR 11r 11a,-OC (=O)-NR 11r 11a,-OC (=O) OR 11,-NR 11c (=O) NR 11r 11a,-NR 11c (=O) OR 11a,-NR 11c (=O)-R 11a, R 11o 2s-, R 11r 11anO 2s-, R 11o 2s-N (R 11a)-, C 1-6alkoxyl group, C 3-6cycloalkyloxy, C 2-5heterocyclic radical C 1-6alkoxyl group, C 1-6aliphatics, C 1-6halogenated aliphatic, hydroxyl C 1-6aliphatics, amino C 1-6aliphatics, C 1-6alkoxy C 1-6aliphatics, C 1-6alkylamino C 1-6aliphatics, C 1-6alkylthio C 1-6aliphatics, C 6-10aryl C 1-6aliphatics, C 2-5heterocyclic radical C 1-6aliphatics, C 3-6cycloalkyl C 1-6aliphatics, C 6-10aryl, C 1-9heteroaryl, C 2-5heterocyclic radical, or C 3-6carbocylic radical; Or work as R 12and R 12abe connected with same carbon atom, so R 12and R 12a, and together with the carbon atom be connected with them, substituted or non-substituted 3-8 unit's carbocyclic ring or heterocycle can be formed arbitrarily;
Other embodiment is, R in formula (I) 1, R 2, R 3and R 4the common amino acid defined be selected from natural existence or by business by way of the a-amino acid obtained or their optically active isomer.Some of them embodiment is, natural existence or by business by way of obtain a-amino acid be Isoleucine, leucine, Methionin, methionine(Met), phenylalanine, Threonine, tryptophane, α-amino-isovaleric acid, L-Ala, l-asparagine, aspartic acid, L-glutamic acid, proline(Pro), glutamine, Serine, tyrosine, arginine, Histidine, halfcystine, glycine, sarkosine, N, N-N-methylsarcosine, homoserine, norvaline, nor-leucine, ornithine, homocysteine, hyperphenylalaninemia, phenylglycocoll, adjacent tyrosine, m-Tyrosine, oxyproline.Other embodiment is, the a-amino acid with chiral centre is naturally occurring.Other embodiment is, Isoleucine, leucine, Methionin, methionine(Met), phenylalanine, Threonine, tryptophane, α-amino-isovaleric acid, L-Ala, l-asparagine, aspartic acid, L-glutamic acid, glutamine, proline(Pro), Serine, tyrosine, arginine, Histidine are S configuration in α position; Halfcystine is R configuration in α position; Glycine, sarkosine, DMG are the molecule not having chirality.
Y 1and Y 2be selected from divalent group independently of one another: C 1-6aliphatics-C (=O)-, C 1-6aliphatics-C (=O) O-, C 1-6aliphatics-C (=O) NR 11-,-R 11n-O 2s-C 1-6aliphatics ,-O 2s-C 1-6aliphatics ,-R 11n-C 1-6aliphatics ,-S (=O) C 1-6aliphatics, or-R 11n-C (=O)-C 1-6aliphatics; C 1-6halogeno alkylen, C 2-8sub-heterocyclic radical, C 3-8sub-carbocylic radical, C 2-8heterocyclic radical C 1-6alkylidene group, C 3-8carbocylic radical C 1-6alkylidene group, condenses C 6-10sub-bicyclic group, condenses C 5-9sub-assorted bicyclic group, condenses C 6-10bicyclic group C 1-6alkylidene group, condenses C 5-9assorted bicyclic group C 1-6alkylidene group, spiral shell C 7-11sub-bicyclic group, spiral shell C 6-10sub-assorted bicyclic group, spiral shell C 7-11bicyclic group C 1-6alkylidene group, or spiral shell C 6-10assorted bicyclic group C 1-6alkylidene group;
W is selected from O, N-R 11, or (CR 12r 12a) m; M is 0,1 or 2;
Q is selected from following structural formula:
Wherein U is CH or N;
R 5and R 6be selected from H or methoxyl group independently of one another;
R 7h or F;
R 10phenyl or fluorophenyl;
Some of them embodiment is, Q is selected from following structural formula:
Wherein R 5and R 6be selected from H or OMe independently of one another; Z is H or F.
Some of them embodiment is, the Y in formula (I) 1, Y 2, the minor structure that W and Q is common defined is selected from following structural formula:
Wherein AA is R 1, R 2, R 3and R 4the common glycyl base section defined; X is H or OH; 0,1,2 or 3 with p.
In other embodiment, the present invention relates to one of them structure following, or its racemic mixture, diastereomer, enantiomer, geometrical isomer, tautomer, oxynitride, hydrate, solvate, meta-bolites, or its pharmacy acceptable salt, but be never limited to these compounds:
The present invention also comprises the application of compound of the present invention and pharmacy acceptable salt thereof, and the disease of mediation occurs for the production of pharmaceutical prod treatment acute and chronic blood vessel, comprises that those are described in the invention.Compound of the present invention is producing the application in cancer therapy drug.Compound of the present invention is used for alleviating for the production of a kind of pharmaceuticals equally, stops, and controls or treats the illness mediated by KDR, c-Met or IGF1R.The present invention comprises pharmaceutical composition, and this pharmaceutical composition comprises compound representated by formula (I) and at least one pharmaceutically acceptable carrier, the effective treatment consumption needed for the combination of assistant agent or thinner.
The present invention comprises the disease that treatment patient vessel occurs to mediate equally, or the method to this illness sensitivity, and the treatment significant quantity that the method comprises the representative compound of use formula (I) is treated patient.
Unless other aspects show, the steric isomer that compound of the present invention is all, geometrical isomer, tautomer, oxynitride, hydrate, solvate, meta-bolites, salt and pharmaceutically acceptable prodrug all belong to scope of the present invention.
Specifically, salt is pharmacy acceptable salt.It must be applicable to chemistry or toxicologically that term " pharmaceutically acceptable " comprises material or composition, relevant with other components of composition preparation and the Mammals that is used for the treatment of.
The salt of compound of the present invention also comprise for the preparation of or purifying formula (I) shown in the salt of enantiomer of compound separation shown in the intermediate of compound or formula (I), but not necessarily pharmacy acceptable salt.
If compound of the present invention is alkaline, then conceivable salt can be prepared by any suitable method that document provides, and such as, uses mineral acid, example hydrochloric acid, Hydrogen bromide, sulfuric acid, nitric acid and phosphoric acid etc.Or use organic acid, as acetic acid, toxilic acid, succsinic acid, amygdalic acid, fumaric acid, propanedioic acid, pyruvic acid, oxalic acid, hydroxyethanoic acid and Whitfield's ointment; Pyrans saccharic acid, as glucuronic acid and galacturonic acid; Alpha-hydroxy acid, as citric acid and tartrate; Amino acid, as aspartic acid and L-glutamic acid; Aromatic acid, as phenylformic acid and styracin; Sulfonic acid, as tosic acid, ethyl sulfonic acid, etc.
If compound of the present invention is acid, then conceivable salt can be prepared by suitable method, e.g., uses mineral alkali or organic bases, as ammonia (uncle's ammonia, parahelium, tertiary ammonia), and alkali metal hydroxide or alkaline earth metal hydroxides, etc.Suitable salt comprises, but is not limited to, from the organic salt that amino acid obtains, as glycine and arginine, and ammonia, as uncle ammonia, parahelium and tertiary ammonia, and ring-type ammonia, as piperidines, morpholine and piperazine etc., and from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminium and lithium obtain inorganic salt.
The composition of compound of the present invention, preparation and administration
According to another aspect, the feature of pharmaceutical composition of the present invention comprises the compound of formula (I), the compound listed by the present invention, or the compound of embodiment 1-79, and pharmaceutically acceptable carrier, assistant agent, or vehicle.In composition of the present invention, the amount of compound detectably can suppress the protein kinase in biological sample or patient body effectively.
There is free form in compound of the present invention, or suitable, as pharmaceutically acceptable derivates.According to the present invention, pharmaceutically acceptable derivates comprises, but be not limited to, pharmaceutically acceptable prodrug, salt, ester, the salt of ester class, or can directly or indirectly according to other any adducts or derivatives of needing administration of patient, the compound described by other aspects of the present invention, its meta-bolites or his residue.
As described in the invention, the pharmaceutically acceptable composition of the present invention comprises pharmaceutically acceptable carrier, assistant agent further, or vehicle, these are applied as the present invention, comprise any solvent, thinner, or other liquid excipients, dispersion agent or suspension agent, tensio-active agent, isotonic agent, thickening material, emulsifying agent, sanitas, solid binder or lubricant, etc., be suitable for distinctive target formulation.As with described by Publication about Document: In Remington:The Science and Practice of Pharmacy, 21st edition, 2005, ed.D.B.Troy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds.J.Swarbrick and J.C.Boylan, 1988-1999, Marcel Dekker, New York, the content of comprehensive document herein, show that different carriers can be applicable to preparation and their known preparation methods of pharmaceutically acceptable composition.Except carrier medium and the inconsistent scope of compound of the present invention of any routine, such as produced any bad biological effect or the interaction produced in harmful mode with any other component of pharmaceutically acceptable composition, their purposes is also the scope that the present invention considers.
The material that can be used as pharmaceutically acceptable carrier comprises, but be not limited to, ion-exchanger, aluminium, aluminum stearate, Yelkin TTS, serum protein, as human serum protein, buffer substance is as phosphoric acid salt, glycine, Sorbic Acid, potassium sorbate, the partial glyceride mixtures of saturated vegetable fatty acid, water, salt or ionogen, as protamine sulfate, Sodium phosphate dibasic, potassium hydrogen phosphate, sodium-chlor, zinc salt, colloidal silicon, Magnesium Trisilicate, polyvinylpyrrolidone, polyacrylate, wax, polyethylene-polyoxypropylene-blocking-up polymer, lanolin, sugar, as lactose, dextrose plus saccharose, starch is as W-Gum and potato starch, Mierocrystalline cellulose and its derivative as Xylo-Mucine, ethyl cellulose and rhodia, natural gum powder, Fructus Hordei Germinatus, gelatin, talcum powder, auxiliary material is as cocoa butter and suppository wax, oily as peanut oil, oleum gossypii seminis, Thistle oil, sesame oil, sweet oil, Semen Maydis oil and soya-bean oil, glycol compound, as propylene glycol and polyoxyethylene glycol, ester class is as ethyl oleate and Ethyl Lauroyl acid esters, agar, buffer reagent is as magnesium hydroxide and aluminium hydroxide, Lalgine, pyrogen-free water, isotonic salt, Lin Ge (family name) solution, ethanol, phosphate buffer solution, and other nontoxic proper lubrication agent are as Sulfuric acid,monododecyl ester, sodium salt and Magnesium Stearate, tinting material, releasing agent, coating agents, sweeting agent, seasonings and spices, sanitas and antioxidant.
Composition of the present invention can be oral administration, drug administration by injection, Aerosol inhalation, topical, per rectum administration, nose administration, containing taking administration, and vagina administration or by the administration of implantable medicine box.Term as used herein " through injection " comprises subcutaneous, vein, intramuscular, IA, in synovial membrane (chamber), intrasternal, in film, intraocular, in liver, intralesional, and the injection of encephalic or infusion techniques.Preferred composition is oral administration, to Intraperitoneal medication or intravenous injection.The injection system of composition sterile of the present invention can be water or oleaginous suspension.These suspension can adopt suitable dispersion agent, wetting agent and suspension agent to manufacture by formula according to known technology.Aseptic injection can be aseptic parenteral solution or suspension, is the nontoxic acceptable thinner of injection or solvent, as 1,3 butylene glycol solution.These acceptable vehicle and solvent can be water, Ringer's solution and isotonic sodium chlorrde solution.Further, aseptic nonvolatile oil by convention can as solvent or suspension medium.
With this end in view, the nonvolatile oil of any gentleness can be list or the DG of synthesis.Lipid acid, as oleic acid and its glyceride derivative can be used for the preparation of injectable, as natural pharmaceutically acceptable grease, as sweet oil or Viscotrol C, particularly their polyoxyethylene deriv.These oil solutions or suspension can comprise long-chain alcohol diluents or dispersion agent, and as carboxymethyl cellulose or similar dispersing agents, the pharmaceutical preparation being generally used for pharmaceutically acceptable formulation comprises emulsion and suspension.Other conventional tensio-active agents, as Tweens, the reinforcer of spans and other emulsifying agents or bioavailability, is generally used for pharmaceutically acceptable solid, liquid, or other formulations, and can be applied to the preparation of targeted drug formulation.
The pharmaceutically acceptable composition of the present invention can be carry out oral administration with any acceptable oral dosage form, comprising, but be not limited to, capsule, tablet, water suspension or solution.Orally use about tablet, carrier generally comprises lactose and W-Gum.Lubricant, as Magnesium Stearate, is all typically added.For capsule oral administration, suitable thinner comprises lactose and dry W-Gum.When oral administration is water suspension, its effective constituent is made up of emulsifying agent and suspension agent.If expect these formulations, some sweeting agent, seasonings or tinting material also can be added.
In addition, the pharmaceutically acceptable composition of the present invention can with the form rectal administration of suppository.These can form by reagent and suitable non-perfusing adjuvant being mixed with, and this adjuvant is at room temperature solid but is then liquid at the temperature of rectum, thus melts in the rectum and discharge medicine.Such material comprises cocoa butter, beeswax, and polyethylene glycols.The pharmaceutically acceptable composition of the present invention can be topical, and particularly during local application, the therapeutic goal relating to region or organ easily reaches, as the disease of eye, skin or lower intestinal tract.Suitable using topical preparations can prepare and be applied to these fields or organ.
Rectal suppository (see above content) or suitable enema can be applied to the local application of lower intestine.Local skin spot also can medication like this.For local application, pharmaceutically acceptable composition can be prepared into suitable ointment by formulation method, and this ointment packets is suspended in or is dissolved in one or more carrier containing activeconstituents.The carrier compound of topical of the present invention comprises, but is not limited to mineral oil, whiteruss, white vaseline, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water.In addition, pharmaceutically acceptable composition can be prepared into suitable lotion or emulsion, and this lotion or emulsion comprise activeconstituents and is suspended in or is dissolved in one or more pharmaceutically acceptable carrier.Suitable carrier comprises, but is not limited to, mineral oil, Arlacel-60 (Arlacel-60), polysorbate60 (Polysorbate 60), cetyl esters wax, palmityl alcohol, 2-Standamul G, phenylcarbinol and water.
Preparation can be prepared into for eye, pharmaceutically acceptable composition; as isotonic micronized suspension, the Sterile Saline of pH regulator or other aqueous solution, preferably; the Sterile Saline of isotonic solution and pH regulator or other aqueous solution, can add disinfection preservative as benzalkonium chloride.In addition, for eye, pharmaceutically acceptable composition can be prepared into ointment as vaseline oil by pharmaceutical formulation.The pharmaceutically acceptable composition of the present invention can carry out administration by the gaseous solvents of nose or inhalation.Such composition can prepare according to the known technology of pharmaceutical formulation, maybe can be prepared into salts solution, use phenylcarbinol or other suitable sanitass, absorption enhancer, fluorocarbon or other conventional solubilizing agent or dispersion agent to improve bioavailability.
The liquid dosage form of oral administration comprises, but is not limited to, pharmaceutically acceptable emulsion, microemulsion, solution, suspension, syrup and elixir.In addition to the active compound, liquid dosage form can comprise known general inert diluent, such as, and water or other solvents, solubilizing agent and emulsifying agent, as ethanol, Virahol, ethyl-carbonate, ethyl acetate, phenylcarbinol, peruscabin, propylene glycol, 1,3 butylene glycol, dimethyl formamide, grease (particularly cottonseed, Semen arachidis hypogaeae, corn, microorganism, olive, castor-oil plant and sesame oil), glycerine, Tetrahydrofurfuryl Alcohol, polyoxyethylene glycol, sorbitan alcohol fatty acid ester, and their mixture.Except the thinner of inertia, oral compositions also can comprise assistant agent as wetting agent, emulsifying agent or suspension agent, sweeting agent, seasonings and perfume compound.
Injection, as aseptic parenteral solution or oleaginous suspension can adopt suitable dispersion agent, wetting agent and suspension agent to prepare by pharmaceutical formulation according to known technology.Aseptic injection can be nontoxic aseptic parenteral solution, suspension or the emulsion made through acceptable thinner or solvent parenterally, such as, and 1,3 butylene glycol solution.Acceptable vehicle and solvent can be water, Lin Ge (family name) solution, U.S.P. and isotonic sodium chlorrde solution.In addition, aseptic nonvolatile oil is by convention as solvent or suspension medium.With this end in view the nonvolatile oil of any gentleness can comprise list or the DG of synthesis.In addition, lipid acid such as oleic acid can be applied to injection.
Injection can be aseptic, as defended metre filter by bacterium, or mixes disinfectant with the form of aseptic solid composite, and disinfectant can be dissolved in or be scattered in sterilized water or other sterile injectable medium before use.In order to extend the effect of compound of the present invention, usually need the absorption being slowed down compound by subcutaneous injection or intramuscularly.Can realize like this utilizing liquid suspension to solve the problem of crystal or amorphous material poorly water-soluble.The specific absorption of compound depends on and depends on grain size and crystal shape successively by its dissolution rate.In addition, can be dissolved in oil vehicles by compound or disperse to have come the delay of compound injection administration to absorb.
Injection storage form is by biodegradable polymkeric substance, and the microcapsule matrix as many lactic acid-polyglycolide formation compound completes.The controlled release ratio of compound depends on the ratio of compound formation polymkeric substance and the character of particular polymer.Other biodegradable polymers comprise poly-(positive ester class) and poly-(acid anhydrides).Injection storage form also can embed the liposome compatible with bodily tissue by compound or microemulsion prepares.
Some of them embodiment is, the composition of rectum or vagina administration is suppository, suppository can prepare by the auxiliary material of compound of the present invention and suitable non-perfusing or carrier being mixed, as cocoa butter, polyoxyethylene glycol, or suppository wax, they are solid in room temperature but are then liquid under body temperature, therefore in vagina or cavity of tunica vaginalis, just melt release of active compounds.
The solid dosage of oral administration comprises capsule, tablet, pill, pulvis and granula.In these formulations, active compound mixes with the pharmaceutically acceptable inert excipient of at least one or carrier, as Trisodium Citrate or calcium phosphate or filling agent or a) weighting agent as starch, lactose, sucrose, glucose, N.F,USP MANNITOL and silicic acid, b) tackiness agent is as carboxymethyl cellulose, alginate, gelatin, Povidone, sucrose and gum arabic, c) wetting Agent for Printing Inks is as glycerine, d) disintegrating agent is as agar, calcium carbonate, potato starch or tapioca (flour), Lalgine, some silicate and sodium carbonate, e) retarding agent solution is as paraffin, f) absorption enhancer is as quaternary ammonium compounds, g) wetting agent is as hexadecanol and glyceryl monostearate, h) absorption agent is as white bole and bentonite, i) lubricant is as talcum powder, calcium stearate, Magnesium Stearate, solid polyethylene glycol, Sulfuric acid,monododecyl ester, sodium salt, and their mixture.As for capsule, tablet and pill, these formulations can comprise buffer reagent.
The solids composition of similar type can be that weighting agent riddles soft or hard capsule, and the auxiliary material used has lactose and high molecular polyoxyethylene glycol etc.The agent of solid dosage photo, lozenge, capsule, pill and granula can by dressing, add shell such as known coating method on enteric coating and other drug preparation and prepare.They optionally can comprise opalizer, or preferably, in certain part of enteron aisle, at random, with the sole active agent in the method release composition postponed.As implant compositions can comprise multimeric species and wax.
Active compound can form microcapsule formulations together with one or more vehicle described in the invention.The agent of solid dosage photo, lozenge, capsule, pill and granula by dressing or can add shell, as enteric coating, controlled release coat and other known drug formulation process.In these solid dosages, active compound can mix with at least one inert diluent, as sucrose, and lactose or starch.Such formulation also can comprise substance besides inert diluents as general application, if tableting lubricant and other compression aids are as Magnesium Stearate and Microcrystalline Cellulose.As for capsule, tablet and pill, these formulations can comprise buffer reagent.They optionally can comprise tranquilizer, or preferably, in certain part of enteron aisle, with the sole active agent in the method release composition postponed arbitrarily.Applicable implant compositions can comprise, but is not limited to, polymer and wax.
Compound of the present invention by local or formulation through percutaneous drug delivery comprise ointment, paste, emulsion, lotion, gelifying agent, pulvis, solution, sprays, inhalation, paster.Activeconstituents mixes mutually with pharmaceutically acceptable carrier and any required sanitas or required buffer reagent under sterile conditions.The pharmaceutical preparation of ophthalmology, ear drop and eye drops are all the scopes that the present invention considers.In addition, the present invention also considers the application of transdermal patch, and it is delivered in body at control compound more advantage, and such formulation can by dissolving or preparing in decentralized compound to suitable medium.Absorption enhancer can increase compound through the flow of skin, and through-rate controls film or compound is scattered in polymer matrix or gelatin to control its speed.
Compound of the present invention is preferably prepared into dosage unit form to alleviate the homogeneity of dosage and dosage by pharmaceutical formulation.Term " dosage " unit type " refer to that patient obtains the physical dispersion unit of the required medicine of suitably treatment herein.But, should be appreciated that compound of the present invention or composition every day total usage will judge determine according to reliable medical science scope by doctor in charge.Concrete effective dose level will depend on that many factors comprise the seriousness of illness and the illness be treated for any one special patient or organism, the activity of particular compound, concrete composition used, age of patient, body weight, healthy state, sex and food habits, administration time, the discharge rate of route of administration and particular compound used, the time length for the treatment of, medicinal application in drug combination or with specific compound coupling, and the known factor of some other pharmaceutical field.
The change that can produce the consumption of the compound of the present invention of single dosage form composition in conjunction with carrier substance is depended on and is cured mainly and special mode of administration.Some of them embodiment is, composition can be prepared into the inhibitor of dosage in 0.01-200mg/kg body weight/day by formulation method, and the amount being accepted composition by patient carries out administration.
Compound of the present invention can carry out administration with only pharmaceutical agents or in conjunction with the agent of one or more other additional treatment (pharmacy), wherein drug combination causes acceptable untoward reaction, and this has special meaning for the treatment of high proliferative disease as cancer.In this case, compound of the present invention can in conjunction with known cytotoxic agent, single transduction inhibitor or other antitumor and anticancer agents, and their mixture and combination.As used in the present invention, the disease that the normal drug treatment of additional treatment agent is special is exactly known " suitably disease therapy "." additional treatment agent " used in the present invention comprises chemotherapeutic agent or other antiproliferative medicines can in conjunction with compounds for treating proliferative disease of the present invention or cancer.
Chemotherapeutic agent or other anti-proliferative drugs comprise histon deacetylase (HDAC) (HDAC) inhibitor, include, but are not limited to, SAHA, MS-275, MGO103, and those compounds described by following patent: WO 2006/010264, WO 03/024448, WO 2004/069823, US 2006/0058298, US2005/0288282, WO 00/71703, WO 01/38322, WO 01/70675, WO 03/006652, WO2004/035525, WO2005/030705, WO 2005/092899, comprise with demethylating agent, but be not limited to, 5-mixes nitrogen-2 '-Deoxyribose cytidine (5-aza-dC), azacitidine (Vidaza), Decitabine (Decitabine) and with the compound described by Publication about Document: US 6, 268137, US 5, 578, 716, US5, 919, 772, US6, 054, 439, US 6, 184, 211, US 6, 020, 318, US 6, 066, 625, US 6, 506, 735, US 6, 221, 849, US 6, 953, 783, US 11/393, 380.
Other embodiment is, chemotherapeutic agent or other anti-proliferative drugs can in conjunction with compounds for treating proliferative disease of the present invention and cancers.Known chemotherapeutic agent comprises, but be not limited to, other therapies or carcinostatic agent can be combined carcinostatic agent of the present invention and be comprised surgery, (a little example is as gamma-radiation for radiotherapy, neutron beam radiotherapy, electron beam evaporation therapy, proton therapy, brachytherapy and system isotope therapy), endocrinotherapy, taxanes (taxol, Docetaxel etc.), the derivative of platinum, biological response modifier (Interferon, rabbit, interleukin, tumour necrosis factor (TNF), the effect of TRAIL receptor target and vehicle), overheated and psychrotherapy, dilute the reagent (as antiemetic) of any untoward reaction, with the chemotherapeutic agent of other accreditations, include, but are not limited to, alkylating drug (mustargen, Chlorambucil, endoxan, melphalan, ifosfamide), metabolic antagonist (methotrexate, pemetrexed (Pemetrexed) etc.), purine antagonist and Pyrimidine antagonists (6-MP (6-Mercaptopurine), 5 FU 5 fluorouracil, Cytarabile, gemcitabine (Gemcitabine)), spindle poison (vinealeucoblastine(VLB), vincristine(VCR), vinorelbine, taxol), podophyllotoxin (Etoposide, irinotecan (Irinotecan), Hycamtin (Topotecan)), microbiotic (Dx (Doxorubicin), bleomycin (Bleomycin), mitomycin (Mitomycin)), nitrosourea (carmustine (Carmustine), lomustine (Lomustine)), mineral ion (cis-platinum, carboplatin), (KSP passes through mitotic kinesin inhibitors to cell division cycle inhibitor, CENP-E and CDK inhibitor), ferment (asparaginase), hormone (tamoxifen (Tamoxifen), Leuprolide (Leuprolide), flutamide (Flutamide), megestrol (Megestrol)), imatinib mesylate (Gleevec), Zorubicin (Adriamycin), dexamethasone (Dexamethasone), and endoxan.Anti-angiogenesis (Avastin (Avastin) and other), kinase inhibitor (imatinib (Imatinib), Sutent (Sutent), Xarelto (Nexavar), Cetuximab (Erbitux), Trastuzumab (Herceptin), Tarceva (Tarceva), Iressa (Iressa) and other).Drug inhibition or activate cancer approach as mTOR, HIF (hypoxia inducible factor) approach and other.Cancer therapy more widely forum is shown in http:// www.nci.nih.gov/, the oncologic inventory of FAD accreditation is shown in http:// www.fda.gov/cder/cancer/druglist-rame.htm, and Merck Manual, the 18 edition .2006, all contents are all combine reference.
Other embodiment is, compound of the present invention can in conjunction with cytotoxic anticancer agent.Such carcinostatic agent can find the 13 edition the Merck index (2001) is inner.These carcinostatic agents comprise, but be never limited to, Asparaginase (Asparaginase), bleomycin (Bleomycin), carboplatin, carmustine (Carmustine), Chlorambucil (Chlorambucil), cis-platinum, L-ASP (Colaspase), endoxan, cytosine arabinoside (Cytarabine), Dacarbazine (Dacarbazine), dactinomycin (Dactinomycin), daunorubicin (Daunorubicin), Zorubicin (Dx), epirubicin (Epirubicin), Etoposide (Etoposide), 5-fluor-uracil, hexamethyl trimeric cyanamide, hydroxyurea, ifosfamide, irinotecan, folinic acid, lomustine, mustargen, Ismipur, mesna (Mesna), methotrexate (Methotrexate), ametycin (Mitomycin C), mitoxantrone (Mitoxantrone), prednisolone (Prednisolone), prednisone (Prednisone), Procarbazine (Procarbazine), raloxifene (Raloxifen), streptozocin (Streptozocin), tamoxifen (Tamoxifen), Tioguanine (Thioguanine), Hycamtin, vinealeucoblastine(VLB), vincristine(VCR), vindesine.
Comprise with other suitable cytotoxic drugs of compound drug combination of the present invention, but be not limited to, these are applied to the compound of neoplastic disease treatment admittedly, as with described in Publication about Document: Goodman and Gilman ' s The Pharmacological Basis of Therapeutics (Ninth Edition, 1996, McGraw-Hill.), these carcinostatic agents comprise, but be never limited to, aminoglutethimide (Aminoglutethimide), ASP, azathioprine, 5-azacytidine, CldAdo (Cladribine), busulfan (Busulfan), stilboestrol, 2 ', 2 '-difluoro dCDP choline, Docetaxel, red hydroxyl nonyl VITAMIN B4 (Erythrohydroxynonyladenine), Ethinylestradiol, 5 FU 5 fluorouracil deoxynucleoside, floxuridine monophosphate, fludarabine phosphate (Fludarabine phosphate), Fluoxymesterone (Fluoxymesterone), flutamide (Flutamide), Hydroxyprogesterone caproate bp 98, idarubicin (Idarubicin), Interferon, rabbit, medroxyprogesterone acetate, Magace, melphalan (Melphalan), mitotane (Mitotane), taxol, pentostatin (Pentostatin), N-phosphate base-L-Aspartic acid (PALA), Plicamycin (Plicamycin), Me-CCNU (Semustine), teniposide (Teniposide), Uniteston, phosphinothioylidynetrisaziridine (Thiotepa), trimethylammonium trimeric cyanamide, urine nucleosides and vinorelbine.
What other were suitable comprises newfound cytotoxic substance with the cytotoxin class carcinostatic agent of compound combined utilization of the present invention, comprising, but be not limited to, oxaliplatin (Oxaliplatin), gemcitabine (Gemcitabine), capecitabine (Capecitabine), Macrolide antitumour drug and derivative that is natural or synthesis thereof, Temozolomide (Temozolomide) (Quinn et al., J.Clin.Oncology, 2003, 21 (4), 646-651), tositumomab (Bexxar), Trabedectin (Vidal et al., Proceedings of the American Society for Clinical Oncology, 2004, 23, abstract 3181), with kinesin spindle body protein inhibitor Eg5 (Wood et al., Curr.Opin.Pharmacol.2001, 1, 370-377).
Other embodiment is, compound of the present invention can in conjunction with other signal transduction inhibitors.What is interesting is signal transduction inhibitor using EGFR family as target, as EGFR, HER-2 and HER-4 (Raymond et al., Drugs, 2000,60 (Suppl.l), 15-23; Harari et al., Oncogene, 2000,19 (53), 6102-6114) and their respective parts.Such reagent comprises, but is never limited to, antibody therapy as Trastuzumab (trastuzumab), Cetuximab (Erbitux), and handkerchief trastuzumab (Pertuzumab).Such therapy also comprises, but be never limited to, small molecule kinase inhibitors as Iressa (Gefitinib), Tarceva (Erlotinib), Tykerb (Lapatinib), CANERTINIB (CI1033), AEE788 (Traxler et al., Cancer Research, 2004,64,4931-4941).
Other embodiment is, compound of the present invention is in conjunction with the receptor kinase (VEGFR, FGFR, PDGFR, flt-3, c-kit, c-fins, etc.) of other signal transduction inhibitor targetings in division kinase domain family, and their respective parts.Such reagent comprises, but is not limited to, and antibody is as rhuMAb-VEGF (Avastin).Such reagent comprises, but be never limited to, micromolecular inhibitor is as Gleevec/Imanitib, Sprycel (Dasatinib), Tasigna/Nilotinib, Nexavar (Vandetanib), Vatalanib (PTK787/zK222584) (Wood et al., Cancer Res.2000, 60 (8), 2178-2189), Telatinib/BAY-57-9352, BMS-690514, BMS-540215, Axitinib/AG-013736, Motesanib/AMG706, Sutent/Sunitinib/SU-11248, ZD-6474 (Hennequin et al., 92ndAACR Meeting, New Orleans, Mar.24-28, 2001, abstract 3152), KRN-951 (Taguchi et al., 95th AACR Meeting, Orlando, FIa, 2004, abstract 2575), CP-547, 632 (Beebe etal., Cancer Res.2003, 63, 7301-7309), CP-673, 451 (Roberts et al., Proceedings of the American Association of Cancer Research, 2004, 45, abstract 3989), CHIR-258 (Lee et al., Proceedings of the American Association of Cancer Research, 2004, 45, abstract 2130), MLN-518 (Shen et al., Blood, 2003, 102, 11, abstract 476).
Other embodiment is, compound of the present invention can bonding histone deacetylase inhibitors.Such reagent comprises, but be never limited to, suberoylanilide hydroxamic acid (SAHA), LAQ-824 (Ottmann et al., Proceedings of the American Society for Clinical Oncology, 2004, 23, abstract3024), LBH-589 (Beck et al., Proceedings of the American Society for Clinical Oncology, 2004, 23, abstract 3025), MS-275 (Ryan et al., Proceedings of the American Association of Cancer Research, 2004, 45, abstract 2452), FR-901228 (Piekarz et al., Proceedings of the American Society for Clinical Oncology, 2004, 23, abstract 3028) and MGCDOI 03 (US 6, 897, 220).
Other embodiment is, compound of the present invention can in conjunction with other carcinostatic agents as proteasome inhibitor and m-TOR inhibitor.These comprise, but be never limited to, Velcade (Bortezomib) (Mackay et al., Proceedings of the American Societ for Clinical Oncology, 2004,23, Abstract3109), and CCI-779 (Wu et al., Proceedings of the American Association of Cancer Research, 2004,45, abstract 3849).Compound of the present invention in conjunction with other carcinostatic agents as topoisomerase enzyme inhibitor, can also include, but not limited to camptothecine.
Those additional treatment agent can separate administration with the composition comprising compound of the present invention, as a part for many dosage regimens.Or those therapeutical agents can be parts for one-pack type, form single composition together with compound of the present invention.If administration is as a part for many dosage regimens, two promoting agents can transmit mutually simultaneously continuously or within for some time, thus obtain destination agent activity.
The change that can produce the compound of one-pack type and the consumption (those compositions comprising an additional treatment agent are as described in the invention) of additional treatment agent in conjunction with carrier substance is depended on and is cured mainly and special mode of administration.Normally, the amount of composition additional treatment of the present invention agent comprises the amount of therapeutical agent as the normal administration of unique promoting agent using being no more than composition.On the other hand, the scope of the amount of existing disclosed composition additional treatment agent is approximately the 50%-100% of existing composition normal amount, and the reagent comprised is as sole active therapeutical agent.Comprise in the composition of additional treatment agent at those, additional treatment agent will play synergy with compound of the present invention.
The purposes of compound of the present invention and composition
The feature of pharmaceutical composition of the present invention comprises the compound shown in formula (I) or the compound listed by the present invention, and pharmaceutically acceptable carrier, assistant agent or vehicle.In composition of the present invention compound amount can effectively detectably arrestin kinases as the activity of VEGFR/KDR, IGF/IGF1R or HGF/c-Met.Compound of the present invention using be applied to as antitumor drug treatment or reduce the deleterious effect of VEGF, IGF and HGF.
Compound of the present invention will be applied to, but never be limited to, and use the significant quantity of compound of the present invention or composition prevent patient's administration or treat patient's proliferative disease.Such disease comprises cancer, especially metastatic carcinoma, atherosclerosis, and pulmonary fibrosis.
The treatment being applied to knurl is comprised cancer and metastatic carcinoma by compound of the present invention, includes, but are not limited to further, and cancer is as bladder cancer, mammary cancer, colorectal carcinoma, kidney, liver cancer, lung cancer (comprising small cell lung cancer), esophagus cancer, carcinoma of gallbladder, ovarian cancer, carcinoma of the pancreas, cancer of the stomach, cervical cancer, thyroid carcinoma, prostate cancer, and skin carcinoma (comprising squamous cell carcinoma); Lymphsystem hematopoetic tumor (comprises leukemia, the Cystic leukemia of acute lymphoblastic, acute lymphoblastic leukemia, B cell lymphoma, t cell lymphoma, He Jiejin (family name) lymphoma, non-hodgkin's (family name) lymphoma, hairy cell leukemia and Burkitt lymphoma); Marrow system hematopoetic tumor (comprise acute and chronic myelocytic leukemia, myelodysplastic syndrome, and promyelocitic leukemia); The tumour (comprising fibrosarcoma and rhabdosarcoma, and other sarcomas, as soft tissue and cartilage) of mesenchymal cell origin; Maincenter peripheral nervous system knurl (comprise astrocytoma, neuroblastoma, neurospongioma, and schwannoma); With other tumours (comprising melanoma, spermocytoma, teratocarcinoma, osteosarcoma, xenoderoma pigmentosum, keratoctanthoma, thyroid follicle knurl and Ka Bo Ji (family name) sarcoma).
Compound of the present invention also can be used for treatment eye disease such as corneal graft rejection, and the new vessel of eye is formed, and retinal neovascularazation comprises damage or metainfective new vessel is formed; Diabetic retinopathy; Retrolental fibroplasia, and neovascular glaucoma; Retinal ischemia; Vitreous hemorrhage; Ulcer disease is as stomach ulcer; Pathological but non-malignant situation, as vascular tumor, comprises baby's hemangioendothelioma, the hemangiofibroma of nasopharynx and ANB; Female repro ductive system is disorderly as endometriosis.These compounds are equally also used for the treatment of oedema and the too high situation of vascular permeability.
Compound of the present invention may be used for processing the situation relevant to diabetes as diabetic retinopathy and microangiopathy.Compound of the present invention is equally for the situation of cancer patients's volume of blood flow minimizing.Compound of the present invention reduces patient tumors transfer also has beneficial effect.
Compound of the present invention, except useful to human treatment, also can be applicable to veterinary treatment pet, the animal of introduced variety and the animal on farm, comprises Mammals, rodent etc.The example of other animal comprises horse, dog and cat.At this, compound of the present invention comprises its pharmaceutically acceptable derivates.
Plural form is being applied to compound, and when salt etc., it also means single compound, salt etc.
Comprise the methods for the treatment of of compound of the present invention or composition administration, comprise the administration to patient's additional treatment agent (combination therapy) further, wherein additional treatment agent is selected from: chemotherapy, antiproliferative or anti-inflammatory agent, wherein additional treatment agent is applicable to treated disease, and additional treatment agent can with compound of the present invention or composition Combined Preparation, compound of the present invention or composition are as single formulation, or the compound separated or composition are as a part for multi-form.Additional treatment agent can from compound of the present invention administration simultaneously or different time administration.The situation of the latter, administration can be staggered and be carried out as 6 hours, 12 hours, 1 day, 2 days, 3 days, 1 week, 2 weeks, 3 weeks, within 1 month or 2 months, carries out.
The present invention comprises the cytostatic method of VEGFR, IGF1R or c-Met of expression equally, and this method comprises compound of the present invention or composition and cells contacting, thus cell growth inhibiting.The cell of the suppressed growth of energy comprises: breast cancer cell, colorectal cancer cell, lung carcinoma cell, papillary carcinoma cell, prostate cancer cell, lymphoma cell, colon cancer cell, pancreatic cancer cell, ovarian cancer cell, cervical cancer cell, central nervous system cancer cells, human osteosarcoma cell, kidney cancer cell, hepatocellular carcinoma cells, transitional cell bladder carcinoma cell line, stomach cancer cell, head or carcinoma of neck cell, melanoma cell and leukemia cell.
The invention provides and suppress VEGFR in biological sample, the method for IGF1R or c-Met kinase activity, this method comprises and compound of the present invention or composition being contacted with biological sample.Term used in the present invention " biological sample " refers to the sample of vitro, include, but not limited to, cell cultures or cell extraction; From the examination of living tissue material that Mammals or its extract obtain; Blood, saliva, urine, ight soil, seminal fluid, tears, or other living tissue liquid substance and extracts thereof.Suppress kinase activity, particularly VEGFR, IGF1R or c-Met kinase activity in biological sample, can be used for the known multiple use of one of ordinary skill in the art.Such purposes comprises, but is never limited to, hematometachysis, organ transplantation, biological sample storage and biological assay.
" significant quantity " or " effective dose " of compound of the present invention or pharmaceutically acceptable composition refer to process or alleviate one or more the present invention mention the significant quantity of the severity of illness.According to method of the present invention, compound and composition can be any dosage and any route of administration come effectively for the treatment of or the severity that palliates a disease.Situation according to patient changes by required measuring accurately, and this depends on race, the age, the general condition of patient, the severity of infection, special factor, administering mode, etc.Compound or composition can with one or more other treatment agent Combined Preparation, as discussed in the present invention.
Compound of the present invention or its pharmaceutical composition can be applied to the dressing of implantable medical device, as prosthese, and artificial valve, artificial blood vessel, stem and catheter.Such as, vascular stem, has been used to overcome restenosis (shrinking again of vessel wall after injury).But patient uses stem or other implantable devices to have the risk of clot formation or platelet activation.These disadvantageous effects can stop by using the pharmaceutically acceptable composition precoating device comprising compound of the present invention or alleviate.
The general preparation method of suitable dressing and the dressing of implantable device at document US 6,099,562; US5,886,026; With US 5,304, described by having in 121, dressing is that biocompatible polymeric material, as hydrogel polymer, gathers methyl two silicon ether, polycaprolactone, polyoxyethylene glycol, poly(lactic acid), ethane-acetic acid ethyenyl ester typically, and composition thereof.Dressing can optionally further cover by suitable dressing, as fluoro Simethicone, polysaccharidase, polyoxyethylene glycol, phospholipid, or their combination, carry out the feature of performance group compound Co ntrolled release.Another aspect of the present invention comprises the implantable device using compound of the present invention coating.Compound of the present invention also can be coated on the medical instruments in implantable, as pearl, or provide " medicine storage institute " with polymkeric substance or other molecular mixing, therefore compare with pharmaceutical aqueous solution administering mode, allow drug release to have longer time limit.
General synthetic method
Usually, compound of the present invention can be prepared by method described in the invention, and unless there are further instruction, wherein substituent definition is such as formula shown in (I).Reaction scheme below and embodiment are used for illustrating content of the present invention further.
Those skilled in the art will realize that: chemical reaction described in the invention can be used for preparing many other compounds of the present invention suitably, and is all contemplated within the scope of the present invention for the preparation of other method of compound of the present invention.Such as; synthesis according to the compound of those non-illustrations of the present invention can successfully be completed by modifying method by those skilled in the art; as suitable protection interference group, by the reagent that utilizes other known except described in the invention, or reaction conditions is made the amendment of some routines.In addition, reaction disclosed in this invention or known reaction conditions are also applicable to the preparation of other compounds of the present invention admittedly.
The embodiments described below, to be decided to be degree Celsius unless other aspects show all temperature.Reagent is bought in goods providers as Aldrich Chemical Company, Arco Chemical Company and Alfa Chemical Company, all not through being further purified, unless other aspects show during use.General reagent from Xi Long chemical plant, Shantou, Guangdong brilliance chemical reagent factory, Guangzhou Chemical Reagent Factory, Tianjin Hao Yuyu Chemical Company, Qingdao Teng Long chemical reagent company limited, and Haiyang Chemical Plant, Qingdao buy obtain.
Anhydrous tetrahydro furan, dioxane, toluene, ether is through sodium Metal 99.5 backflow drying and obtains.Anhydrous methylene chloride and chloroform are through hydrolith backflow drying and obtain.Ethyl acetate, sherwood oil, normal hexane, N,N-dimethylacetamide and DMF are through the prior Dryly use of anhydrous sodium sulphate.
Below reacting is generally under nitrogen or argon gas positive pressure or on anhydrous solvent, overlap a drying tube (unless showing in other), the soft rubber ball that reaction flask is suitable all beyond the Great Wall, and substrate is squeezed into by syringe.Glassware is all dried.
Chromatographic column uses silicagel column.Silica gel (300-400 order) is purchased from Haiyang Chemical Plant, Qingdao.NMR (Nuclear Magnetic Resonance) spectrum is with CDCl 3, d 6-DMSO, CD 3oD or d 6-acetone is solvent (reporting in units of ppm), with TMS (0ppm) or chloroform (7.25ppm) as reference standard.In time there is multiplet, abbreviation below will be used: s (singlet, unimodal), d (doublet, bimodal), t (triplet, triplet), m (multiplet, multiplet), br (broadened, broad peak), dd (doublet of doublets, quartet), dt (doublet of triplets, two triplet).Coupling constant, represents with hertz (Hz).
Algorithm (MS) data are measured by the spectrograph of the serial LC-MS of Agilent 6320 being equipped with G1312A binary pump and a G1316ATCC (column temperature remains on 30 DEG C), G1329A automatic sampler and G1315B DAD detector applies are in analysis, and ESI source is applied to LC-MS spectrograph.
Algorithm (MS) data are measured by the spectrograph of the serial LC-MS of Agilent 6120 being equipped with G1311A quaternary pump and G1316ATCC (column temperature remains on 30 DEG C), G1329A automatic sampler and G1315D DAD detector applies are in analysis, and ESI source is applied to LC-MS spectrograph.
Above two kinds of spectrographs are provided with Agilent Zorbax SB-C18 post, and specification is 2.1 × 30mm, 5 μm.Volume injected is determined by sample concentration; Flow velocity is 0.6mL/min; The peak value of HPLC records reading by the UV-Vis wavelength at 210nm and 254nm place.Moving phase is the formic acid acetonitrile solution (phase A) of 0.1% and the formic acid ultrapure water solution (phase B) of 0.1%.Condition of gradient elution is as shown in table 1:
Table 1
Compound purifying is evaluated by Agilent 1100 series of high efficiency liquid chromatography (HPLC), wherein UV detects at 210nm and 254nm place, Zorbax SB-C18 post, specification is 2.1 × 30mm, 4 μm, 10 minutes, flow velocity was 0.6mL/min, (0.1% aqueous formic acid) of (the 0.1% formic acid acetonitrile solution) of 5-95%, column temperature remains on 40 DEG C.
The use of brief word below runs through the present invention:
Kinase inhibitor 8 can be prepared by synthetic method 1.The aromatics 1 replaced passes through suitable nitrating agent as HNO 3at a proper temperature as 0 DEG C nitratedly obtains compound 2.Then NO 2group is going back original reagent as iron powder, zinc powder, or is reduced under the condition of Pd/C shortening.Amino benzenes compounds 3 and formic ether compounds (as ethyl formate) in the basic conditions condensation obtain the quinolines 4 that replaces.Oh group on compound 4 by chlorizating agent as POCl 3or SOCl 2under the condition of heating, be converted into chlorine atom obtain chloroquinoline compounds 5.Compound 5 is coupled with suitable fragrance derivatives (with OH group) two aromatic oxide compounds 6 (for references, see Kubo, K., et al, J.Med Chem., 2005,48,1359 obtaining replacing; Harmange, J.-C., et al, J.Med Chem., 2008,51,1649.).Slough protecting group PG and obtain compound 7, and then (as OMs, Cl, Br or I, E is R to the suitable leavings group of L=with E-L 1-R 4, Y 1, Y 2the part common defined with W) condensation obtains targeted kinase inhibitor 8.
Synthetic method 2
The pyrazolone derivatives 11 replaced can be prepared by synthetic method 2.First 5-methyl-2-aryl-1,2-pyrazoline-3-ketone is in the basic conditions (as Ca (OH) 2under the condition heated in dioxane or 2-MeTHF) obtain compound 9 with Alkyl chloroformates acidylate.In compound 9, nitrogen-atoms exposed on pyrazolone ring can pass through chiral epoxy ethane at Lewis acid as Mg (ClO 4) 2, Ca (SO 3cF 3) 2deng alkylation under existent condition, obtain the intermediate of ethanol class, under the existence of condensing agent as EDCI/DMAP, carry out condensation with the amino acid (as the a-amino acid that Boc-or Cbz-protects) through protecting and obtain intermediate 10.Compound 10 hydrogenation under Pd/C catalysis obtains compound 11, compound 11 is carried out acid treatment (ref.:Liu, L.et al, J.Med Chem.2008,51,3688) afterwards.
Synthetic method 3
The kinase inhibitor 16 replaced can be prepared by synthetic method 3.Compound 12 is obtained compound 13 with the condensation of nitryl aromatic derivative under the condition of heating.Slough protecting group PG and obtain compound 14.Be coupled with E group again and reduce nitryl group and obtain compound 15.Amino benzenes compounds 15 and acid condensation under condensing agent is as EDCI or HATU existent condition are obtained targeted kinase inhibitor 16, and wherein R represents pyrazolone or 1-(aryl-amino-carbonyl) cyclopropenyl radical group.
Synthetic method 4
Or kinase inhibitor of the present invention can be prepared by synthetic method 4.As, compound 20 can be obtained by Pd Study on Catalytic Amination of Alcohols by 2-chloropyridines derivative 19.Amino benzenes compounds 20 and sour condensation, then go protecting group PG to obtain compound 22 (ref.:Liu, L.et al, J.Med Chem.2008,51,3688.).The proper group comprising free hydroxyl (OH) part is connected with quinoline moiety and obtains compound 23.When special, PG can be the methyl group of compound 7, obtains targeted kinase inhibitor 21.
Synthetic method 5
Or kinase inhibitor 26 of the present invention can be prepared by synthetic method 5.First amino derivative 24 and sour 11 condensations obtain a-amino acid analog derivative 25.Then, at the standard conditions, blocking group PG (as Boc or Cbz) is gone to obtain kinase inhibitor 26.Be preferably the form of pharmacy acceptable salt.
Synthetic method 6
n=1,2,3,4 or 5.
Or kinase inhibitor 32 can be prepared by the method described in synthetic method 6.Free hydroxyl group 7 and compound 27 in the basic conditions condensation obtain compound 28.Then blocking group (as acetate groups, the amino acid of phenylformic acid ester group or protection) is gone to obtain alcohol compound 29 at the standard conditions.Under the existence of condensing agent as EDCI/DAMP, compound 29 and a-amino acid 30 condensation of protection are obtained compound 31.Then go protecting group (as Boc or Cbz) to obtain kinase inhibitor 32 at the standard conditions, be preferably the form of pharmacy acceptable salt.
Embodiment
Embodiment 1
(S)-((R)-1-(4-(the fluoro-4-of 3-(7-methoxy quinoline-4-base oxygen base) phenylcarbamoyl)-5-methyl-3-oxygen-2-phenyl-2,3-pyrazoline-1-base) propane-2-base) 2-aminopropan acid esters fumarate
Step 1) (S)-((R)-1-(4-(the fluoro-4-of 3-(7-methoxy quinoline-4-base oxygen base) phenylcarbamoyl)-5-methyl-3-oxygen-2-phenyl-2,3-pyrazoline-1-base) propane-2-base) 2-(benzyloxycarbonyl-amino) propionic ester
By (R)-N-(the fluoro-4-of 3-(7-methoxy quinoline-4-base oxygen base) phenyl-1-(2-hydroxypropyl)-5-methyl-3-oxygen-2-phenyl-2,3-dihydro-1 h-pyrazole-4-carboxylic acid amides (2.0g, 3.68mmol), (S)-N-carbobenzoxy-(Cbz) third ammonia (1.647g, 7.36mmol, (1.647g, 7.36mmol, the Shanghai biochemical company limited of vast letter) and DMAP (0.90g, 7.36mmol, Aladdin) be dissolved in 30mL methylene dichloride, then at 0 DEG C, add EDC solid (2.116g in batches, 11.04mmol, Aladdin).After reaction solution stirs 2 hours at 0 DEG C, the temperature of solution rises to room temperature and continues at room temperature to stir 20 hours.Add 180mL dchloromethane reaction solution, and with 0.5N HCl solution washing three times, each 10mL, then uses saturated NaHCO 3solution washing five times, each 10mL, aqueous phase EtOAc (50mL × 3) extraction, uses Na after being merged by organic phase solution 2sO 4drying, filters, concentrates in a vacuum.Residuum silica gel column chromatography (ethyl acetate) carries out purifying, and to obtain target compound be faint yellow compound (2.1g, 73.1%).
MS(ESI，pos.ion)m/z：748(M+1)；
1H NMR(400MHz，CDCl 3)：δ1.21(d，J＝5.4Hz，3H)，1.39(d，J＝6.6Hz，3H)，3.0(s，3H)，3.75(d，J＝3.2Hz，1H)，3.78(s，3H)，4.05(m，1H)，4.23(t，1H)，4.95(s，1H)，5.09(dd，J＝12.4Hz，J＝37.2Hz，2H)，5.22(d，J＝7.2Hz，1H)，6.40(dd，J＝0.8Hz，J＝6.0Hz，1H)，7.16(t，1H)，7.22(dd，J＝2.8Hz，J＝12Hz，1H)，7.27(t，2H)，7.35(m，5H)，7.41(m，1H)，7.47(m，1H)，7.55(m，2H)，7.90(dd，J＝2.0Hz，J＝14.4Hz，1H)，8.28(d，J＝9.2Hz，1H)，8.66(d，J＝5.2Hz，1H)，10.81(s，1H)。
Step 2) (S)-((R)-1-(4-(the fluoro-4-of 3-(7-methoxy quinoline-4-base oxygen base) phenylcarbamoyl)-5-methyl-3-oxygen-2-phenyl-2,3-pyrazoline-1-base) propane-2-base) 2-aminopropan acid esters
By (S)-((R)-1-(4-(the fluoro-4-of 3-(7-methoxy quinoline-4-base oxygen base) phenylcarbamoyl)-5-methyl-3-oxygen-2-phenyl-2; 3-pyrazoline-1-base) propane-2-base) 2-(benzyloxycarbonyl-amino) propionic ester (74.7mg; 0.1mmol) be dissolved in 15mL ethyl acetate and 10mL methyl alcohol; then in nitrogen protection, catalytic amount Pd/C (10% is added; ~ 55%w/w water-content, 20mg). then suspension is degassed is in a vacuum filled with hydrogen.Reaction mixture is under hydrogen shield, and stirring at room temperature was filtered after 20 minutes, and solids with methanol (5mL × 3) washs.Gained filtrate is immediately for next step reaction.
MS(ESI，pos.ion)m/z：614.1(M+1)。
Step 3) (S)-((R)-1-(4-(the fluoro-4-of 3-(7-methoxy quinoline-4-base oxygen base) phenylcarbamoyl)-5-methyl-3-oxygen-2-phenyl-2,3-pyrazoline-1-base) propane-2-base) 2-aminopropan acid esters fumarate
By (S)-((R)-1-(4-(the fluoro-4-of 3-(7-methoxy quinoline-4-base oxygen base) phenylcarbamoyl)-5-methyl-3-oxygen-2-phenyl-2; 3-pyrazoline-1-base) propane-2-base) 2-aminopropan acid esters (61.3mg; 0.1mmol) be dissolved in EtOAc (15mL)/MeOH (10mL) mixed solvent; add fumaric acid (23.2mg; 0.2mmol, western Gansu Province, Shantou chemical reagent factory).Stirring at room temperature is after 40 minutes, and reaction solution concentrates in a vacuum.Residuum MeOH/EtOAc (12mL, v/v=1: 5) carry out recrystallization.Filter, with EtOAc (5mL × 3) washing, also drying obtains target compound is in a vacuum white solid (68.2mg, 81%).
MS(ESI，pos.ion)m/z：614.1(M+1)；LC-MS Rt：3.418min；
1H NMR(400MHz，d 6-DMSO)：δ1.06(d，J＝6.4Hz，3H)，1.23(d，J＝2.0Hz，3H)，2.79(s，3H)，3.59(dd，J＝7.2Hz，J＝14.4Hz，1H)，3.94(s，3H)，3.98(dd，J＝3.2Hz，J＝16Hz，1H)，4.27(dd，J＝9.2Hz，J＝16Hz，1H)，4.83(m，1H)，6.47(d，J＝5.2Hz，1H)，6.60(s，4H)，7.31(dd，J＝2.4Hz，J＝9.2Hz，1H)，7.36(dd，J＝2.0Hz，J＝8.8Hz，1H)，7.43(m，4H)，7.53(m，1H)，7.62(t，2H)，7.98(dd，J＝2.4Hz，J＝12.8Hz，1H)，8.23(d，J＝9.2Hz，1H)，8.62(d，J＝5.2Hz，1H)，10.87(s，1H)。
Embodiment 2
(S)-((R)-1-(4-(the fluoro-4-of 3-(7-methoxy quinoline-4-base oxygen base) phenylcarbamoyl)-5-methyl-3-oxygen-2-phenyl-2,3-pyrazoline-1-base) propane-2-base) 2-aminopropan acid esters benzoate
Target compound is according to step 3 in embodiment 1) the operation described; with (S)-((R)-1-(4-(the fluoro-4-of 3-(7-methoxy quinoline-4-base oxygen base) phenylcarbamoyl)-5-methyl-3-oxygen-2-phenyl-2; 3-pyrazoline-1-base) propane-2-base) 2-aminopropan acid esters (61.3mg; 0.1mmol) and phenylformic acid (24.4mg; 0.2mmol, Tianjin chemical reagents corporation) synthesize.Obtaining target compound is faint yellow solid (64mg, 80%).
MS(ESI，pos.ion)m/z：614.1(M+1)；LC-MS Rt：3.422min；
1H NMR(400MHz，d 6-DMSO)：δ1.28(d，J＝4.0Hz，3H)，1.32(d，J＝6.8Hz，3H)，2.87(s，3H)，3.61(m，1H)，3.79(dd，J＝3.6Hz，J＝19.2Hz，1H)，3.99(s，3H)，4.09(m，1H)，4.97(m，2H)，5.28(s，2H)，6.46(d，J＝5.6Hz，1H)，7.17(t，1H)，7.28(m，3H)，7.38(d，J＝7.6Hz，1H)，7.46(m，3H)，7.57(m，3H)，7.91(dd，J＝2.0Hz，J＝14.4Hz，1H)，8.10(d，J＝7.6Hz，3H)，8.28(d，J＝9.2Hz，1H)，8.67(d，J＝5.2Hz，1H)，10.78(s，1H)。
Embodiment 3
(S)-((R)-1-(4-(the fluoro-4-of 3-(7-methoxy quinoline-4-base oxygen base) phenylcarbamoyl)-5-methyl-3-oxygen-2-phenyl-2,3-pyrazoline-1-base) propane-2-base) 2-aminopropan acid esters mesylate
Target compound is according to step 3 in embodiment 1) the operation described; with (S)-((R)-1-(4-(the fluoro-4-of 3-(7-methoxy quinoline-4-base oxygen base) phenylcarbamoyl)-5-methyl-3-oxygen-2-phenyl-2; 3-pyrazoline-1-base) propane-2-base) 2-aminopropan acid esters (61.3mg; 0.1mmol) and methylsulfonic acid (19.3mg; 0.2mmol, Shanghai Run Jie chemical reagent company limited) synthesize.Obtaining target compound is faint yellow solid (61.2mg, 76%).
MS(ESI，pos.ion)m/z：614.1(M+1)；LC-MS Rt：3.47min。
Embodiment 4
(S)-((R)-1-(4-(the fluoro-4-of 3-(7-methoxy quinoline-4-base oxygen base) phenylcarbamoyl)-5-methyl-3-oxygen-2-phenyl-2,3-pyrazoline-1-base) propane-2-base) 2-aminopropan acid esters tosilate
By (S)-((R)-1-(4-(the fluoro-4-of 3-(7-methoxy quinoline-4-base oxygen base) phenylcarbamoyl)-5-methyl-3-oxygen-2-phenyl-2; 3-pyrazoline-1-base) propane-2-base) 2-aminopropan acid esters (61.3mg; 0.1mmol) be dissolved in the mixing solutions of EtOAc (15mL)/MeOH (10mL); add tosic acid (38mg; 0.2mmol, Solution on Chemical Reagents in Shanghai company).Stir after 40 minutes, reaction mixture concentrates in a vacuum, the oily matter obtained first uses mixed solvent MeOH/EtOAc (12mL, v/v=1: 5) crystallization, filter, with ethyl acetate (5mL × 3) washing, obtaining target compound is yellow oil (59.6mg, 60%).
MS(ESI，pos.ion)m/z：614.1(M+1)；LC-MS Rt：3.59min。
Embodiment 5
(S)-((R)-1-(4-(the fluoro-4-of 3-(7-methoxy quinoline-4-base oxygen base) phenylcarbamoyl)-5-methyl-3-oxygen-2-phenyl-2,3-pyrazoline-1-base) propane-2-base) 2-alanine ester oxalate
Target compound is according to step 3 in embodiment 1) the operation described; with (S)-((R)-1-(4-(the fluoro-4-of 3-(7-methoxy quinoline-4-base oxygen base) phenylcarbamoyl)-5-methyl-3-oxygen-2-phenyl-2; 3-pyrazoline-1-base) propane-2-base) 2-aminopropan acid esters (61.3mg; 0.1mmol); and oxalic acid (25.2mg; 0.2mmol, Tianjin chemical reagents corporation) synthesize.Obtaining target compound is white solid (66.3mg, 94.0%).
MS(ESI，pos.ion)m/z：614.1(M+1)；LC-MS Rt：3.53min；
1H NMR(400MHz，d 6-DMSO)：δ1.07(d，J＝8.4Hz，3H)，1.34(d，J＝7.2Hz，3H)，2.79(s，3H)，3.89(dd，J＝6.8Hz，J＝14Hz，1H)，3.94(s，3H)，4.03(dd，J＝7.2Hz，J＝14Hz，1H)，4.30(dd，J＝9.2Hz，J＝16Hz，1H)，4.87(m，1H)，6.47(d，J＝4.8Hz，1H)，7.32(dd，J＝2.8Hz，J＝9.2Hz，1H)，7.36(dd，J＝1.6Hz，J＝8.8Hz，1H)，7.44(m，4H)，7.54(t，1H)，7.62(t，2H)，7.98(dd，J＝2.4Hz，J＝13.2Hz，1H)，8.23(d，J＝9.2Hz，1H)，8.63(d，J＝5.2Hz，1H)，10.87(s，1H)。
Embodiment 6
(S)-((R)-1-(4-(the fluoro-4-of 3-(7-methoxy quinoline-4-base oxygen base) phenylcarbamoyl)-5-methyl-3-oxygen-2-phenyl-2,3-pyrazoline-1-base) propane-2-base) 2-aminopropan acid esters L-TARTARIC ACID salt
Target compound is according to step 3 in embodiment 1) the operation described; with (S)-((R)-1-(4-(the fluoro-4-of 3-(7-methoxy quinoline-4-base oxygen base) phenylcarbamoyl)-5-methyl-3-oxygen-2-phenyl-2; 3-pyrazoline-1-base) propane-2-base) 2-aminopropan acid esters (61.3mg; 0.1mmol) and L-TARTARIC ACID (30.0mg, 0.2mmol) synthesize.The target compound obtained is white solid (70.5mg, 89.2%).
MS(ESI，pos.ion)m/z：614.1(M+1)；LC-MS Rt：3.60min；
1H NMR(400MHz，d 6-DMSO)：δ1.08(d，J＝6.4Hz，3H)，1.29(d，J＝6.8Hz，3H)，1.99(s，1H)，2.79(s，3H)，3.77(dd，J＝7.2Hz，J＝12.8Hz，1H)，3.94(s，3H)，4.0(dd，J＝2.8Hz，J＝15.2Hz，1H)，4.18(s，5H)，4.29(dd，J＝9.6Hz，J＝16.8Hz，1H)，4.86(m，1H)，6.47(d，J＝5.2Hz，1H)，7.31(dd，J＝2.4Hz，J＝8.8Hz，1H)，7.36(dd，J＝2.0Hz，J＝8.8Hz，1H)，7.44(m，4H)，7.54(t，1H)，7.62(t，2H)，7.99(dd，J＝2.4Hz，J＝13.2Hz，1H)，8.23(d，J＝9.2Hz，1H)，8.63(d，J＝5.2Hz，1H)，10.88(s，1H).
Embodiment 7
(S)-((R)-1-(4-(the fluoro-4-of 3-(7-methoxy quinoline-4-base oxygen base) phenylcarbamoyl)-5-methyl-3-oxygen-2-phenyl-2,3-pyrazoline-1-base) propane-2-base) 2-alanine ester hydrochloride
Target compound is according to step 3 in embodiment 1) the operation described; with (S)-((R)-1-(4-(the fluoro-4-of 3-(7-methoxy quinoline-4-base oxygen base) phenylcarbamoyl)-5-methyl-3-oxygen-2-phenyl-2; 3-pyrazoline-1-base) propane-2-base) 2-aminopropan acid esters (61.3mg, 0.1mmol) and the saturated solution of hydrogenchloride in ethyl acetate (3mL) synthesize.The target compound obtained is faint yellow solid (57.1mg, 83%).
MS(ESI，pos.ion)m/z：614.1(M+1)；LC-MS Rt：3.61min；
1H NMR(400MHz，d 6-DMSO)：δ1.07(d，J＝6.4Hz，3H)，1.34(d，J＝7.2Hz，3H)，2.78(s，3H)，3.88(dd，J＝6.8Hz，J＝12.4Hz，1H)，4.0(s，3H)，4.04(d，J＝3.6Hz，1H)，4.29(dd，J＝8.8Hz，J＝16Hz，1H)，4.85(m，1H)，6.87(d，J＝4.8Hz，1H)，7.42(m，2H)，7.54(m，2H)，7.61(m，3H)，8.04(dd，J＝2.4Hz，J＝12.8Hz，1H)，8.44(m，3H)，8.9(d，J＝6.0Hz，1H)，10.93(s，1H)。
Embodiment 8
(S)-((R)-1-(4-(the fluoro-4-of 3-(7-methoxy quinoline-4-base oxygen base) phenylcarbamoyl)-5-methyl-3-oxygen-2-phenyl-2,3-pyrazoline-1-base) propane-2-base) 2-aminopropan acid esters Citrate trianion
Target compound is according to step 3 in embodiment 1) the operation described; with (S)-((R)-1-(4-(the fluoro-4-of 3-(7-methoxy quinoline-4-base oxygen base) phenylcarbamoyl)-5-methyl-3-oxygen-2-phenyl-2; 3-pyrazoline-1-base) propane-2-base) 2-aminopropan acid esters (61.3mg; 0.1mmol) and citric acid (38.4mg; 0.2mmol, Tianjin chemical reagents corporation) synthesize.The target compound obtained is white solid (78.7mg, 79%).
MS(ESI，pos.ion)m/z：614.1(M+1)；LC-MS Rt：3.61min。
Embodiment 9
(S)-((R)-1-(4-(the fluoro-4-of 3-(7-methoxy quinoline-4-base oxygen base) phenylcarbamoyl)-5-methyl-3-oxygen-2-phenyl-2,3-pyrazoline-1-base) propane-2-base) 2-aminopropan acid esters vitriol
Target compound is according to step 3 in embodiment 1) the operation described; with (S)-((R)-1-(4-(the fluoro-4-of 3-(7-methoxy quinoline-4-base oxygen base) phenylcarbamoyl)-5-methyl-3-oxygen-2-phenyl-2; 3-pyrazoline-1-base) propane-2-base) 2-aminopropan acid esters (61.3mg; 0.1mmol) and sulfuric acid (19.6mg, 0.2mmol) synthesize.The target compound obtained is white solid (63.4mg, 89.2%).
MS(ESI，pos.ion)m/z：614.1(M+1)；LC-MS Rt：3.59min。
Embodiment 10
(S)-((R)-1-(4-(the fluoro-4-of 3-(7-methoxy quinoline-4-base oxygen base) phenylcarbamoyl)-5-methyl-3-oxygen-2-phenyl-2,3-pyrazoline-1-base) propane-2-base) 2-aminopropan acid esters succinate
Target compound is according to step 3 in embodiment 1) the operation described; with (S)-((R)-1-(4-(the fluoro-4-of 3-(7-methoxy quinoline-4-base oxygen base) phenylcarbamoyl)-5-methyl-3-oxygen-2-phenyl-2; 3-pyrazoline-1-base) propane-2-base) 2-aminopropan acid esters (61.3mg; 0.1mmol) and succinic acid (23.6mg; 0.2mmol, western Gansu Province, Shantou chemical reagent factory) synthesize.The target compound obtained is white solid (68.5mg, 93.7%).
MS(ESI，pos.ion)m/z：614.1(M+1)；LC-MS Rt：3.418min；
1H NMR(400MHz，d 6-DMSO)：δ1.06(d，J＝6.4Hz，3H)，1.23(d，J＝2.0Hz，3H)，2.79(s，3H)，3.59(dd，J＝7.2Hz，J＝14.4Hz，1H)，3.94(s，3H)，3.98(dd，J＝3.2Hz，J＝16Hz，1H)，4.27(dd，J＝9.2Hz，J＝16Hz，1H)，4.83(m，1H)，6.47(d，J＝5.2Hz，1H)，6.60(s，4H)，7.31(dd，J＝2.4Hz，J＝9.2Hz，1H)，7.36(dd，J＝2.0Hz，J＝8.8Hz，1H)，7.43(m，4H)，7.53(m，1H)，7.62(t，2H)，7.98(dd，J＝2.4Hz，J＝12.8Hz，1H)，8.23(d，J＝9.2Hz，1H)，8.62(d，J＝5.2Hz，1H)，10.87(s，1H)。
Embodiment 11
(S)-((R)-1-(4-(the fluoro-4-of 3-(7-methoxy quinoline-4-base oxygen base) phenylcarbamoyl)-5-methyl-3-oxygen-2-phenyl-2,3-pyrazoline-1-base) propane-2-base) 2-aminopropan acid esters maleate
By (S)-((R)-1-(4-(the fluoro-4-of 3-(7-methoxy quinoline-4-base oxygen base) phenylcarbamoyl)-5-methyl-3-oxygen-2-phenyl-2; 3-pyrazoline-1-base) propane-2-base) 2-aminopropan acid esters (61.3mg; 0.1mmol) be dissolved in the mixed solvent of EtOAc (15mL)/MeOH (10mL); add toxilic acid (23.2mg; 0.2mmol, western Gansu Province, Shantou chemical reagent factory).Stirring at room temperature is after 40 minutes, reaction mixture concentrates in a vacuum, the oily matter obtained first uses mixed solvent MeOH/EtOAc (12mL, v/v=1: 5) crystallization, filter, with ethyl acetate (5mL × 3) washing, obtain the target compound (62.6mg, 85.6%) that target compound is yellow oily.
MS(ESI，pos.ion)m/z：614.1(M+1)；LC-MS Rt：3.428min。
Embodiment 12
(S)-((R)-1-(4-(the fluoro-4-of 3-(7-methoxy quinoline-4-base oxygen base) phenylcarbamoyl)-5-methyl-3-oxygen-2-phenyl-2,3-pyrazoline-1-base) propane-2-base) 2-aminopropan acid esters phosphoric acid salt
By (S)-((R)-1-(4-(the fluoro-4-of 3-(7-methoxy quinoline-4-base oxygen base) phenylcarbamoyl)-5-methyl-3-oxygen-2-phenyl-2; 3-pyrazoline-1-base) propane-2-base) 2-aminopropan acid esters (61.3mg; 0.1mmol) be dissolved in the mixed solvent of EtOAc (15mL)/MeOH (10mL); add phosphoric acid (19.6mg, 0.2mmol).Stirring at room temperature is after 40 minutes, reaction mixture concentrates in a vacuum, the oily matter mixed solvent MeOH/EtOAc (12mL obtained, v/v=1: 5) crystallization, filter, with ethyl acetate (5mL × 3) washing, obtain the target compound (67.2mg, 91.9%) that target compound is yellow oily.
MS(ESI，pos.ion)m/z：614.1(M+1)；LC-MS Rt：3.47min。
Embodiment 13
(S)-((R)-1-(4-(5-(7-methoxy quinoline-4-base oxygen base) pyridine-2-base formamyl)-5-methyl-3-oxygen-2-phenyl-2,3-pyrazoline-1-base) propane-2-base) 2-aminopropan acid esters fumarate
Step 1) (S)-((R)-1-(4-(5-(7-methoxy quinoline-4-base oxygen base) pyridine-2-base formamyl)-5-methyl-3-oxygen-2-phenyl-2,3-pyrazoline-1-base) propane-2-base) 2-(benzyloxycarbonyl amino) propionic ester
By (R)-1-(2-hydroxypropyl)-N-(5-(7-methoxy quinoline-4-base oxygen base) pyridine-2-base)-5-methyl-3-oxygen-2-phenyl-2,3-dihydro-1 h-pyrazole-4-carboxylic acid amides (1.93g, 3.68mmol), (S)-N-carbobenzoxy-(Cbz) L-Ala (1.647g, 7.36mmol, the Shanghai biochemical company limited of vast letter) and DMAP (0.90g, 7.36mmol, Aladdin) be dissolved in 30mL methylene dichloride, add EDC solid (2.116g at 0 DEG C in batches, 11.04mmol, Aladdin).Reaction solution stirs after 2 hours at 0 DEG C, and solution is warming up to room temperature naturally, continues stirring 20 hours.After reaction terminates, in reaction solution, add 180mL methylene dichloride, and with the saturated NaHCO of 30mL 0.5N HCl and 50mL 3solution gradation is washed, and aqueous phase EtOAc (50mL × 3) extracts.Organic phase solution uses Na after merging 2sO 4drying, filters, concentrates in a vacuum.Residuum silica gel column chromatography (ethyl acetate) carries out purifying, and obtaining target compound is faint yellow compound (2.0g, 74.1%).
MS(ESI，pos.ion)m/z：731.3(M+1)；
1H NMR(400MHz，CDCl 3)：δ1.09(d，J＝6.4Hz，3H)，1.33(d，J＝8.0Hz，3H)，2.82(s，3H)，3.79(dd，J＝4.0Hz，J＝15.6Hz，1H)，3.98(s，3H)，4.01(dd，J＝3.2Hz，J＝8.8Hz，1H)，4.13(dd，J＝6.8Hz，J＝14.0Hz，1H)，4.24(m，1H)，4.96(dd，J＝3.6Hz，J＝6.0Hz，1H)，5.06(s，2H)，5.18(d，J＝7.2Hz，1H)，6.35(d，J＝5.2Hz，1H)，7.23(dd，J＝2.4Hz，J＝9.2Hz，1H)，7.31-7.50(m，8H)，7.55(t，2H)，8.22(t，2H)，8.39(d，J＝9.2Hz，1H)，8.55(d，J＝5.2Hz，1H)，11.20(s，1H)。
Step 2) (S)-((R)-1-(4-(5-(7-methoxy quinoline-4-base oxygen base) pyridine-2-base formamyl)-5-methyl-3-oxygen-2-phenyl-2,3-pyrazoline-1-base) propane-2-base) 2-aminopropan acid esters
By (S)-((R)-1-(4-(5-(7-methoxy quinoline-4-base oxygen base) pyridine-2-base formamyl)-5-methyl-3-oxygen-2-phenyl-2; 3-pyrazoline-1-base) propane-2-base) 2-(benzyloxycarbonyl amino) propionic ester (73mg; 0.1mmol) be dissolved in the mixed solvent of 15mL ethyl acetate and 10mL methyl alcohol; then the Pd/C (10% of catalytic amount is added under nitrogen protection; ~ 55%w/w water-content; 18mg), then suspension is degassed is in a vacuum filled with hydrogen.Reaction mixture is under hydrogen shield, and stirring at room temperature was filtered after 20 minutes, and solids with methanol (5mLx3) washs.Gained filtrate is immediately in next step reaction.
MS(ESI，pos.ion)m/z：597.1(M+1)。
Step 3) (S)-((R)-1-(4-(5-(7-methoxy quinoline-4-base oxygen base) pyridine-2-base formamyl)-5-methyl-3-oxygen-2-phenyl-2,3-pyrazoline-1-base) propane-2-base) 2-aminopropan acid esters fumarate
By (S)-((R)-1-(4-(5-(7-methoxy quinoline-4-base oxygen base) pyridine-2-base formamyl)-5-methyl-3-oxygen-2-phenyl-2; 3-pyrazoline-1-base) propane-2-base) 2-aminopropan acid esters (59.6mg; 0.1mmol) be dissolved in EtOAc (15mL)/MeOH (10mL) mixed solvent; add fumaric acid (23.2mg; 0.2mmol, western Gansu Province, Shantou chemical reagent factory).Stirring at room temperature is after 40 minutes, reaction mixture concentrates in a vacuum, the oily matter mixed solvent MeOH (2mL) obtained/EtOAc (10mL) (v/v=1: 5) crystallization, filter, wash by ethyl acetate (5mL × 3), dried overnight in a vacuum, obtains target compound.This target compound is white solid (65mg, 91.2%).
MS(ESI，pos.ion)m/z：597.1(M+1)；LC-MS Rt：3.013min；
1H NMR(400MHz，d 6-DMSO)：δ1.05(d，J＝6.4Hz，3H)，1.18(d，J＝6.8Hz，3H)，2.81(s，3H)，3.49(dd，J＝6.8Hz，J＝14Hz，1H)，3.94(s，3H)，3.98(dd，J＝2.8Hz，J＝14.4Hz，1H)，4.27(dd，J＝9.2Hz，J＝16Hz，1H)，4.82(m，1H)，6.53(d，J＝5.2Hz，1H)，6.58(s，2H)，7.31(dd，J＝2.4Hz，J＝9.2Hz，1H)，7.43(m，3H)，7.54(m，1H)，7.82(t，2H)，7.82(dd，J＝2.8Hz，J＝9.2Hz，1H)，8.22(d，J＝9.2Hz，1H)，8.34(t，1H)，8.37(s，1H)，8.63(d，J＝5.2Hz，1H)，11.19(s，1H)。
Embodiment 14
(S)-((R)-1-(4-(5-(7-methoxy quinoline-4-base oxygen base) pyridine-2-base formamyl)-5-methyl-3-oxygen-2-phenyl-2,3-pyrazoline-1-base) propane-2-base) 2-aminopropan acid esters benzoate
Target compound is according to step 3 in embodiment 13) the operation described process; with (S)-((R)-1-(4-(5-(7-methoxy quinoline-4-base oxygen base) pyridine-2-base formamyl)-5-methyl-3-oxygen-2-phenyl-2; 3-pyrazoline-1-base) propane-2-base) 2-aminopropan acid esters (59.6mg; 0.1mmol) and phenylformic acid (24.4mg; 0.2mmol, western Gansu Province, Shantou chemical reagent factory) synthesize.The target compound obtained is faint yellow solid (61.2mg, 85%).MS(ESI，pos.ion)m/z：597.1(M+1)；LC-MS Rt：3.077min。
Embodiment 15
(S)-((R)-1-(4-(5-(7-methoxy quinoline-4-base oxygen base) pyridine-2-base formamyl)-5-methyl-3-oxygen-2-phenyl-2,3-pyrazoline-1-base) propane-2-base) 2-aminopropan acid esters mesylate
Target compound is according to step 3 in embodiment 13) the operation described; with (S)-((R)-1-(4-(5-(7-methoxy quinoline-4-base oxygen base) pyridine-2-base formamyl)-5-methyl-3-oxygen-2-phenyl-2; 3-pyrazoline-1-base) propane-2-base) 2-aminopropan acid esters (59.6mg; 0.1mmol) and methylsulfonic acid (19.3mg; 0.2mmol, the synthesis of Shanghai Run Jie chemical reagent company limited.The target compound obtained is yellow oil (66.5mg, 84%).
MS(ESI，pos.ion)m/z：597.1(M+1)；LC-MS Rt：3.130min。
Embodiment 16
(S)-((R)-1-(4-(5-(7-methoxy quinoline-4-base oxygen base) pyridine-2-base formamyl)-5-methyl-3-oxygen-2-phenyl-2,3-pyrazoline-1-base) propane-2-base) 2-aminopropan acid esters tosilate
Target compound is according to step 3 in embodiment 13) the operation described; with (S)-((R)-1-(4-(5-(7-methoxy quinoline-4-base oxygen base) pyridine-2-base formamyl)-5-methyl-3-oxygen-2-phenyl-2; 3-pyrazoline-1-base) propane-2-base) 2-aminopropan acid esters (59.6mg; 0.1mmol) and tosic acid (38mg; 0.2mmol, Solution on Chemical Reagents in Shanghai company) synthesize.The target compound obtained is faint yellow solid (71mg, 92.5%).
MS(ESI，pos.ion)m/z：597.1(M+1)；LC-MS Rt：3.181min。
Embodiment 17
(S)-((R)-1-(4-(5-(7-methoxy quinoline-4-base oxygen base) pyridine-2-base formamyl)-5-methyl-3-oxygen-2-phenyl-2,3-pyrazoline-1-base) propane-2-base) 2-alanine ester oxalate
Target compound is according to step 3 in embodiment 13) the operation described; with (S)-((R)-1-(4-(5-(7-methoxy quinoline-4-base oxygen base) pyridine-2-base formamyl)-5-methyl-3-oxygen-2-phenyl-2; 3-pyrazoline-1-base) propane-2-base) 2-aminopropan acid esters (59.6mg; 0.1mmol) and two oxalic acid hydrate (25.2mg; 0.2mmol, Tianjin chemical reagents corporation) synthesize.The target compound obtained is white solid (65mg, 95%).
MS(ESI，pos.ion)m/z：597.1(M+1)；LC-MS Rt：3.121min；
1H NMR(400MHz，d 6-DMSO)：δ1.08(d，J＝6.4Hz，3H)，1.33(d，J＝7.2Hz，3H)，2.81(s，3H)，3.92(dd，J＝7.2Hz，J＝14.8Hz，1H)，3.94(s，3H)，4.02(dd，J＝3.2Hz，J＝16Hz，1H)，4.28(dd，J＝2.4Hz，J＝8.8Hz，1H)，4.85(m，1H)，6.51(d，J＝5.2Hz，1H)，7.31(dd，J＝6.0Hz，J＝8.8Hz，1H)，7.43(d，J＝2.8Hz，2H)，7.45(m，1H)，7.55(t，1H)，7.63(t，2H)，7.83(dd，J＝3.2Hz，J＝9.2Hz，1H)，8.22(d，J＝9.2Hz，1H)，8.35(t，2H)，8.63(d，J＝5.2Hz，1H)，11.19(s，1H).
Embodiment 18
(S)-((R)-1-(4-(5-(7-methoxy quinoline-4-base oxygen base) pyridine-2-base formamyl)-5-methyl-3-oxygen-2-phenyl-2,3-pyrazoline-1-base) propane-2-base) 2-aminopropan acid esters L-TARTARIC ACID salt
Target compound is according to step 3 in embodiment 13) the operation described; with (S)-((R)-1-(4-(5-(7-methoxy quinoline-4-base oxygen base) pyridine-2-base formamyl)-5-methyl-3-oxygen-2-phenyl-2; 3-pyrazoline-1-base) propane-2-base) 2-aminopropan acid esters (59.6mg; 0.1mmol) and L-TARTARIC ACID (30.0mg, 0.2mmol) synthesize.The target compound obtained is white solid (71.2mg, 95.4%).
MS(ESI，pos.ion)m/z：597.1(M+1)；LC-MS Rt：3.045min；
1H NMR(400MHz，d 6-DMSO)：δ1.07(d，J＝6.4Hz，3H)，1.28(d，J＝7.2Hz，3H)，2.81(s，3H)，3.77(m，1H)，3.94(s，3H)，4.0(dd，J＝2.8Hz，J＝15.6Hz，1H)，4.16(s，4H)，4.29(dd，J＝8.8Hz，J＝16Hz，1H)，4.85(m，1H)，6.52(d，J＝5.2Hz，1H)，7.31(dd，J＝2.4Hz，J＝9.2Hz，1H)，7.44(m，3H)，7.54(t，1H)，7.63(t，2H)，7.83(dd，J＝3.2Hz，J＝9.2Hz，1H)，8.22(d，J＝8.8Hz，1H)，8.34(d，J＝3.6Hz，2H)，8.63(d，J＝5.2Hz，1H)，11.19(s，1H).
Embodiment 19
(S)-((R)-1-(4-(5-(7-methoxy quinoline-4-base oxygen base) pyridine-2-base formamyl)-5-methyl-3-oxygen-2-phenyl-2,3-pyrazoline-1-base) propane-2-base) 2-alanine ester hydrochloride
Target compound is according to step 3 in embodiment 13) the operation described; with (S)-((R)-1-(4-(5-(7-methoxy quinoline-4-base oxygen base) pyridine-2-base formamyl)-5-methyl-3-oxygen-2-phenyl-2; 3-pyrazoline-1-base) propane-2-base) 2-aminopropan acid esters (59.6mg, 0.1mmol) and the saturated solution of hydrogenchloride in ethyl acetate (3mL) synthesize.The target compound obtained is faint yellow solid (55.6mg, 87.4%).
MS(ESI，pos.ion)m/z：597.1(M+1)；LC-MS Rt：3.076min；
1H NMR(400MHz，d 6-DMSO)：δ1.08(d，J＝6.4Hz，3H)，1.36(d，J＝7.2Hz，3H)，2.81(s，3H)，3.88(dd，J＝7.6Hz，J＝14.4Hz，1H)，4.03(s，3H)，4.07(d，J＝12Hz，1H)，4.31(dd，J＝9.2Hz，J＝16.4Hz，1H)，4.85(m，1H)，7.04(dd，J＝6.4Hz，J＝8.8Hz，1H)，7.44(t，2H)，7.56(m，1H)，7.63(m，3H)，7.74(d，J＝2.4Hz，1H)，7.98(dd，J＝2.8Hz，J＝9.2Hz，1H)，8.44(d，J＝8.8Hz，1H)，8.47(d，J＝2.8Hz，1H)，8.51(dd，J＝2.8Hz，J＝9.6Hz，1H)，8.98(dd，J＝3.2Hz，J＝6.8Hz，1H)，11.37(s，1H)。
Embodiment 20
(S)-((R)-1-(4-(5-(7-methoxy quinoline-4-base oxygen base) pyridine-2-base formamyl)-5-methyl-3-oxygen-2-phenyl-2,3-pyrazoline-1-base) propane-2-base) 2-aminopropan acid esters Citrate trianion
Target compound is according to step 3 in embodiment 13) the operation described; with (S)-((R)-1-(4-(5-(7-methoxy quinoline-4-base oxygen base) pyridine-2-base formamyl)-5-methyl-3-oxygen-2-phenyl-2; 3-pyrazoline-1-base) propane-2-base) 2-aminopropan acid esters (59.6mg; 0.1mmol) and citric acid (38.4mg; 0.2mmol, Tianjin chemical reagents corporation) synthesize.The target compound obtained is white solid (75.4mg, 95.7%).MS(ESI，pos.ion)m/z：597.1(M+1)；LC-MS Rt：3.018min；
1H NMR(400MHz，d 6-DMSO)：δ1.08(d，J＝6.4Hz，3H)，1.33(d，J＝7.2Hz，3H)，1.99(s，1H)，2.60(dd，J＝15.2Hz，J＝36.8Hz，8H)，2.81(s，3H)，3.88(dd，J＝7.2Hz，J＝14.4Hz，1H)，3.94(s，3H)，4.02(m，1H)，4.31(dd，J＝9.2Hz，J＝16Hz，1H)，4.86(m，1H)，6.51(d，J＝5.2Hz，1H)，7.31(dd，J＝2.8Hz，J＝9.2Hz，1H)，7.43(t，3H)，7.55(t，1H)，7.63(t，2H)，7.83(d，J＝2.8Hz，J＝8.8Hz，1H)，8.22(d，J＝9.2Hz，1H)，8.34(d，J＝3.2Hz，1H)，8.37(s，1H)，8.63(d，J＝5.2Hz，1H)，11.19(s，1H)。
Embodiment 21
(S)-((R)-1-(4-(5-(7-methoxy quinoline-4-base oxygen base) pyridine-2-base formamyl)-5-methyl-3-oxygen-2-phenyl-2,3-pyrazoline-1-base) propane-2-base) 2-aminopropan acid esters vitriol
Target compound is according to step 3 in embodiment 13) the operation described; with (S)-((R)-1-(4-(5-(7-methoxy quinoline-4-base oxygen base) pyridine-2-base formamyl)-5-methyl-3-oxygen-2-phenyl-2; 3-pyrazoline-1-base) propane-2-base) 2-aminopropan acid esters (59.6mg; 0.1mmol) and sulfuric acid (19.6mg, 0.2mmol) synthesize.The target compound obtained is white solid (56.5mg, 78.5%).
MS(ESI，pos.ion)m/z：597.1(M+1)；LC-MS Rt：3.057min；
1H NMR(400MHz，d 6-DMSO)：δ1.07(d，J＝6.4Hz，3H)，1.26(d，J＝7.2Hz，3H)，2.80(s，3H)，3.71(dd，J＝6.4Hz，J＝14.0Hz，1H)，3.94(s，3H)，3.99(d，J＝16Hz，1H)，4.29(dd，J＝9.2Hz，J＝16Hz，1H)，4.84(m，1H)，6.52(d，J＝5.2Hz，1H)，7.31(dd，J＝2.4Hz，J＝9.2Hz，1H)，7.44(d，J＝7.6Hz，3H)，7.54(t，1H)，7.62(t，2H)，7.82(dd，J＝2.8Hz，J＝9.2Hz，1H)，8.22(d，J＝8.8Hz，1H)，8.34(t，2H)，8.37(s，1H)，8.63(d，J＝5.2Hz，1H)，11.19(s，1H)。
Embodiment 22
(S)-((R)-1-(4-(5-(7-methoxy quinoline-4-base oxygen base) pyridine-2-base formamyl)-5-methyl-3-oxygen-2-phenyl-2,3-pyrazoline-1-base) propane-2-base) 2-aminopropan acid esters succinate
Target compound is according to step 3 in embodiment 13) the operation described; with (S)-((R)-1-(4-(5-(7-methoxy quinoline-4-base oxygen base) pyridine-2-base formamyl)-5-methyl-3-oxygen-2-phenyl-2; 3-pyrazoline-1-base) propane-2-base) 2-aminopropan acid esters (59.6mg; 0.1mmol) and succinic acid (23.6mg; 0.2mmol, Shantou Xi Long chemical reagents corporation) synthesize.The target compound obtained is white solid (55mg, 78%).MS(ESI，pos.ion)m/z：597.1(M+1)；LC-MS Rt：3.021min。
Embodiment 23
(S)-((R)-1-(4-(5-(7-methoxy quinoline-4-base oxygen base) pyridine-2-base formamyl)-5-methyl-3-oxygen-2-phenyl-2,3-pyrazoline-1-base) propane-2-base) 2-aminopropan acid esters maleate
Target compound is according to step 3 in embodiment 13) the operation described; with (S)-((R)-1-(4-(5-(7-methoxy quinoline-4-base oxygen base) pyridine-2-base formamyl)-5-methyl-3-oxygen-2-phenyl-2; 3-pyrazoline-1-base) propane-2-base) 2-aminopropan acid esters (59.6mg; 0.1mmol) and toxilic acid (23.2mg; 0.2mmol, Shantou Xi Long chemical reagents corporation) synthesize.The target compound obtained is white solid (67.8mg, 95.2%).
MS(ESI，pos.ion)m/z：597.1(M+1)；LC-MS Rt：3.011min；
1H NMR(400MHz，d 6-DMSO)：δ1.09(d，J＝6.4Hz，3H)，1.34(d，J＝7.2Hz，3H)，2.81(s，3H)，3.91(d，J＝6.8Hz，1H)，3.92(s，3H)，4.02(dd，J＝2.8Hz，J＝16Hz，1H)，4.30(dd，J＝9.2Hz，J＝16.4Hz，1H)，4.86(m，1H)，6.15(s，3H)，7.33(dd，J＝2.4Hz，J＝9.2Hz，1H)，7.44(t，3H)，7.55(t，1H)，7.63(t，2H)，7.84(dd，J＝2.8Hz，J＝8.8Hz，1H)，8.24(d，J＝9.2Hz，1H)，8.36(t，2H)，8.66(d，J＝5.6Hz，1H)，11.20(s，1H)。
Embodiment 24
(S)-((R)-1-(4-(5-(7-methoxy quinoline-4-base oxygen base) pyridine-2-base formamyl)-5-methyl-3-oxygen-2-phenyl-2,3-pyrazoline-1-base) propane-2-base) 2-aminopropan acid esters phosphoric acid salt
Target compound is according to step 3 in embodiment 13) the operation described; with (S)-((R)-1-(4-(5-(7-methoxy quinoline-4-base oxygen base) pyridine-2-base formamyl)-5-methyl-3-oxygen-2-phenyl-2; 3-pyrazoline-1-base) propane-2-base) 2-aminopropan acid esters (59.6mg; 0.1mmol) and phosphoric acid (19.6mg, 0.2mmol) synthesize.The target compound obtained is yellow oil (60.2mg, 84.5%).
MS(ESI，pos.ion)m/z：597.1(M+1)；LC-MS Rt：3.013min。
Embodiment 25
(S)-((R)-1-(4-(5-(7-methoxy quinoline-4-base oxygen base) pyridine-2-base formamyl)-5-methyl-3-oxygen-2-phenyl-2,3-pyrazoline-1-base) propane-2-base) 2-aminopropan acid esters acetate
Target compound is according to step 3 in embodiment 13) the operation described; with (S)-((R)-1-(4-(5-(7-methoxy quinoline-4-base oxygen base) pyridine-2-base formamyl)-5-methyl-3-oxygen-2-phenyl-2; 3-pyrazoline-1-base) propane-2-base) 2-aminopropan acid esters (59.6mg; 0.1mmol) and acetic acid (12.2mg, 0.2mmol) synthesize.The target compound obtained is faint yellow solid (58.5mg, 89.2%).
MS(ESI，pos.ion)m/z：597.1(M+1)；LC-MS Rt：3.078min；
1H NMR(400MHz，d 6-DMSO)：δ1.06(d，J＝6.4Hz，3H)，1.22(s，3H)，1.29(d，J＝7.2Hz，3H)，2.79(s，3H)，3.82(dd，J＝6.8Hz，J＝14.0Hz，1H)，3.93(s，3H)，3.99(dd，J＝3.2Hz，J＝16.0Hz，1H)，4.28(dd，J＝9.2Hz，J＝16.0Hz，1H)，4.83(m，1H)，6.51(dd，J＝5.2Hz，J＝7.6Hz，1H)，7.29(dd，J＝2.4Hz，J＝9.2Hz，1H)，7.42(m，3H)，7.53(m，1H)，7.64(m，3H)，7.81(dd，J＝3.2Hz，J＝9.2Hz，1H)，8.21(dd，J＝2.8Hz，J＝9.2Hz，1H)，8.35(dd，J＝3.2Hz，J＝9.2Hz，1H)，8.61(dd，J＝2.0Hz，J＝5.6Hz，1H)，11.18(s，1H)。
Embodiment 26
(S)-((R)-1-(4-(5-(7-methoxy quinoline-4-base oxygen base) pyridine-2-base formamyl)-5-methyl-3-oxygen-2-phenyl-2,3-pyrazoline-1-base) propane-2-base) 2-aminopropan acid esters esilate
Target compound is according to step 3 in embodiment 13) the operation described; with (S)-((R)-1-(4-(5-(7-methoxy quinoline-4-base oxygen base) pyridine-2-base formamyl)-5-methyl-3-oxygen-2-phenyl-2; 3-pyrazoline-1-base) propane-2-base) 2-aminopropan acid esters (59.6mg; 0.1mmol) and ethyl sulfonic acid (22.1mg; 0.2mmol, Shanghai Run Jie chemical reagent company limited) synthesize.The target compound obtained is yellow oil (57.6mg, 80.8%).
MS(ESI，pos.ion)m/z：597.1(M+1)；LC-MS Rt：3.123min。
Embodiment 27
(S)-((S)-1-(4-(the fluoro-4-of 3-(7-methoxy quinoline-4-base oxygen base) phenylcarbamoyl)-5-methyl-3-oxygen-2-phenyl-2,3-pyrazoline-1-base) propane-2-base) 2-aminopropan acid esters fumarate
Step 1) (S)-((S)-1-(4-(the fluoro-4-of 3-(7-methoxy quinoline-4-base oxygen base) phenylcarbamoyl)-5-methyl-3-oxygen-2-phenyl-2,3-pyrazoline-1-base) propane-2-base) 2-(benzyloxycarbonyl amino) propionic ester
By (S)-N-(the fluoro-4-of 3-(7-methoxy quinoline-4-base oxygen base) phenyl-1-(2-hydroxypropyl)-5-methyl-3-oxygen-2-phenyl-2,3-dihydro-1 h-pyrazole-4-carboxylic acid amides (2.0g, 3.68mmol), (S)-N-carbobenzoxy-(Cbz) third ammonia (1.647g, 7.36mmol, (1.647g, 7.36mmol, the Shanghai biochemical company limited of vast letter) and DMAP (0.90g, 7.36mmol, Aladdin) be dissolved in 30mL methylene dichloride, then at 0 DEG C, add EDC solid (2.116g in batches, 11.04mmol, Aladdin).Reaction solution stirs 2 hours at 0 DEG C, is naturally warming up to room temperature, continues stirring 20 hours.After reaction terminates, add 180mL dchloromethane solution, and with 0.5N HCl (10mL × 3) and saturated NaHCO 3solution (15mL × 3) washs, and aqueous phase EtOAc (50mL × 3) extracts.Na is used after being merged by organic phase solution 2sO 4drying, filters, and filter vacuum concentrates, and residuum silica gel column chromatography (ethyl acetate) carries out purifying and obtains faint yellow compound (2.1g, 73%).
MS(ESI，pos.ion)m/z：748(M+1)；
1H NMR(400MHz，CDCl 3)：δ1.21(d，J＝5.4Hz，3H)，1.39(d，J＝6.6Hz，3H)，3.0(s，3H)，3.75(d，J＝3.2Hz，1H)，3.78(s，3H)，4.05(m，1H)，4.23(t，1H)，4.95(s，1H)，5.09(dd，J＝12.4Hz，J＝37.2Hz，2H)，5.22(d，J＝7.2Hz，1H)，6.40(dd，J＝0.8Hz，J＝6.0Hz，1H)，7.16(t，1H)，7.22(dd，J＝2.8Hz，J＝12Hz，1H)，7.27(t，2H)，7.35(m，5H)，7.41(m，1H)，7.47(m，1H)，7.55(m，2H)，7.90(dd，J＝2.0Hz，J＝14.4Hz，1H)，8.28(d，J＝9.2Hz，1H)，8.66(d，J＝5.2Hz，1H)，10.81(s，1H)。
Step 2) (S)-((S)-1-(4-(the fluoro-4-of 3-(7-methoxy quinoline-4-base oxygen base) phenylcarbamoyl)-5-methyl-3-oxygen-2-phenyl-2,3-pyrazoline-1-base) propane-2-base) 2-aminopropan acid esters
By (S)-((S)-1-(4-(the fluoro-4-of 3-(7-methoxy quinoline-4-base oxygen base) phenylcarbamoyl)-5-methyl-3-oxygen-2-phenyl-2; 3-pyrazoline-1-base) propane-2-base) 2-(benzyloxycarbonyl amino) propionic ester (74.7mg; 0.1mmol) be dissolved in 15mL ethyl acetate and 10mL methanol mixed solvent; add catalytic amount Pd/C (10% under nitrogen protection; ~ 55%w/w water-content; 20mg), then suspension is degassed is in a vacuum filled with hydrogen.Reaction mixture stirring at room temperature 20 minutes under hydrogen shield, filter, solids with methanol (5mLx3) washs.Gained filtrate is immediately in next step reaction.
MS(ESI，pos.ion)m/z：614.1(M+1)。
Step 3) (S)-((S)-1-(4-(the fluoro-4-of 3-(7-methoxy quinoline-4-base oxygen base) phenylcarbamoyl)-5-methyl-3-oxygen-2-phenyl-2,3-pyrazoline-1-base) propane-2-base) 2-aminopropan acid esters fumarate
With (S)-((S)-1-(4-(the fluoro-4-of 3-(7-methoxy quinoline-4-base oxygen base) phenylcarbamoyl)-5-methyl-3-oxygen-2-phenyl-2, 3-pyrazoline-1-base) propane-2-base) 2-aminopropan acid esters (61.3mg, 0.1mmol) be dissolved in the mixed solvent of EtOAc (15mL) and MeOH (10mL), add fumaric acid (23.2mg, 0.2mmol, Shantou Xi Long chemical reagents corporation), stirred at ambient temperature 40 minutes, concentrated, residuum MeOH/EtOAc (12mL, v/v=1: 5) crystallization, filter, wash with EtOAc (5mL × 3), dry under solid vacuum, obtain target compound.The target compound obtained is faint yellow solid (68.5mg, 94.0%).
MS(ESI，pos.ion)m/z：614.1(M+1)；LC-MS Rt：3.418min；
1H NMR(400MHz，d 6-DMSO)：δ1.04(d，J＝5.6Hz，3H)，1.09(d，J＝6.8Hz，3H)，2.77(s，3H)，3.93(s，5H)，4.27(m，1H)，4.81(s，1H)，6.47(d，J＝5.6Hz，1H)，6.55(s，2H)，7.32(dd，J＝9.2Hz，J＝28.8Hz，2H)，7.40(m，4H)，7.51(t，1H)，7.59(t，1H)，7.95(d，J＝13.6Hz，2H)，8.21(d，J＝8.8Hz，1H)，8.59(d，J＝5.2Hz，1H)，10.84(s，1H)。
Embodiment 28
(S)-((S)-1-(4-(the fluoro-4-of 3-(7-methoxy quinoline-4-base oxygen base) phenylcarbamoyl)-5-methyl-3-oxygen-2-phenyl-2,3-pyrazoline-1-base) propane-2-base) 2-aminopropan acid esters benzoate
Target compound is according to step 3 in enforcement 27) the operation described; with (S)-((S)-1-(4-(the fluoro-4-of 3-(7-methoxy quinoline-4-base oxygen base) phenylcarbamoyl)-5-methyl-3-oxygen-2-phenyl-2; 3-pyrazoline-1-base) propane-2-base) 2-aminopropan acid esters (61.3mg; 0.1mmol) and phenylformic acid (48.8mg; 0.4mmol, Shantou Xi Long chemical reagents corporation) synthesize.The target compound obtained is faint yellow solid (64.1mg, 97.2%).MS(ESI，pos.ion)m/z：614.1(M+1)；LC-MS Rt：3.422min；
1H NMR(400MHz，d 6-DMSO)：δ1.28(d，J＝4.0Hz，3H)，1.32(d，J＝6.8Hz，3H)，2.87(s，3H)，3.61(m，1H)，3.79(dd，J＝3.6Hz，J＝19.2Hz，1H)，3.99(s，3H)，4.09(m，1H)，4.97(m，2H)，5.28(s，2H)，6.46(d，J＝5.6Hz，1H)，7.17(t，1H)，7.28(m，3H)，7.38(d，J＝7.6Hz，1H)，7.46(m，3H)，7.57(m，3H)，7.91(dd，J＝2.0Hz，J＝14.4Hz，1H)，8.10(d，J＝7.6Hz，3H)，8.28(d，J＝9.2Hz，1H)，8.67(d，J＝5.2Hz，1H)，10.78(s，1H)。
Embodiment 29
(S)-((S)-1-(4-(the fluoro-4-of 3-(7-methoxy quinoline-4-base oxygen base) phenylcarbamoyl)-5-methyl-3-oxygen-2-phenyl-2,3-pyrazoline-1-base) propane-2-base) 2-aminopropan acid esters mesylate
Target compound is according to step 3 in enforcement 27) the operation described; with (S)-((S)-1-(4-(the fluoro-4-of 3-(7-methoxy quinoline-4-base oxygen base) phenylcarbamoyl)-5-methyl-3-oxygen-2-phenyl-2; 3-pyrazoline-1-base) propane-2-base) 2-aminopropan acid esters (61.3mg; 0.1mmol) and methylsulfonic acid (19.3mg; 0.2mmol, Shanghai Run Jie chemical reagent company limited) synthesize.The target compound obtained is faint yellow solid (58.2mg, 82.1%).
MS(ESI，pos.ion)m/z：614.1(M+1)；LC-MS Rt：3.47min。
Embodiment 30
(S)-((S)-1-(4-(the fluoro-4-of 3-(7-methoxy quinoline-4-base oxygen base) phenylcarbamoyl)-5-methyl-3-oxygen-2-phenyl-2,3-pyrazoline-1-base) propane-2-base) 2-aminopropan acid esters tosilate
Target compound is according to step 3 in enforcement 27) the operation described; with (S)-((S)-1-(4-(the fluoro-4-of 3-(7-methoxy quinoline-4-base oxygen base) phenylcarbamoyl)-5-methyl-3-oxygen-2-phenyl-2; 3-pyrazoline-1-base) propane-2-base) 2-aminopropan acid esters (61.3mg; 0.1mmol) and to methylsulfonic acid (38mg; 0.2mmol, Solution on Chemical Reagents in Shanghai company) synthesize.The target compound obtained is faint yellow solid (70.8mg, 90.2%).MS(ESI，pos.ion)m/z：614.1(M+1)；LC-MS Rt：3.59min；
1H NMR(400MHz，CDCl 3)：δ1.04(d，J＝6Hz，3H)，1.37(d，J＝6.8Hz，3H)，2.34(s，3H)，2.78(s，3H)，3.76-3.86(m，2H)，3.92-3.96(m，1H)，4.02(s，3H)，4.09-4.15(m，1H)，4.89-4.98(m，1H)，6.66(d，J＝5.2Hz，1H)，7.13-7.23(m，4H)，7.34-7.57(m，6H)，7.75(d，J＝7.6Hz，4H)，7.92(dd，J＝19.6Hz，J＝2Hz，1H)，8.35(d，J＝9.2Hz，1H)，8.73(d，J＝5.6Hz，1H)，10.84(s，1H)。
Embodiment 31
(S)-((S)-1-(4-(the fluoro-4-of 3-(7-methoxy quinoline-4-base oxygen base) phenylcarbamoyl)-5-methyl-3-oxygen-2-phenyl-2,3-pyrazoline-1-base) propane-2-base) 2-aminopropan acid esters vitriol
Target compound is according to step 3 in enforcement 27) the operation described; with with (S)-((S)-1-(4-(the fluoro-4-of 3-(7-methoxy quinoline-4-base oxygen base) phenylcarbamoyl)-5-methyl-3-oxygen-2-phenyl-2; 3-pyrazoline-1-base) propane-2-base) 2-aminopropan acid esters (61.3mg; 0.1mmol) and sulfuric acid (1mL; 0.1mol/L, Shantou Xi Long chemical reagents corporation) synthesize.The target compound obtained is yellow solid (61.5mg, 86.5%).
MS(ESI，pos.ion)m/z：614.1(M+1)；LC-MS Rt：3.53min。
Embodiment 32
(S)-((S)-1-(4-(the fluoro-4-of 3-(7-methoxy quinoline-4-base oxygen base) phenylcarbamoyl)-5-methyl-3-oxygen-2-phenyl-2,3-pyrazoline-1-base) propane-2-base) 2-aminopropan acid esters maleate
Target compound is according to step 3 in enforcement 27) the operation described; with (S)-((S)-1-(4-(the fluoro-4-of 3-(7-methoxy quinoline-4-base oxygen base) phenylcarbamoyl)-5-methyl-3-oxygen-2-phenyl-2; 3-pyrazoline-1-base) propane-2-base) 2-aminopropan acid esters (61.3mg; 0.1mmol) and toxilic acid (23.3mg; 0.2mmol, Shanghai Run Jie chemical reagent company limited) synthesize.The target compound obtained is yellow solid (68.7mg, 94.2%).
MS(ESI，pos.ion)m/z：614.1(M+1)；LC-MS Rt：3.60min；
1H NMR(400MHz，CDCl 3)：δ1.13(d，J＝7.6Hz，3H)，1.39(d，J＝6.8Hz，3H)，2.87(s，3H)，3.74-3.85(m，3H)，3.92-3.96(m，1H)，4.04(s，3H)，4.09-4.15(m，1H)，4.96-5.05(m，1H)，6.31(s，2H)，6.66(d，J＝5.2Hz，1H)，7.18-7.22(m，1H)，7.31-7.41(m，4H)，7.50-7.52(m，1H)，7.56-7.66(m，3H)，7.96(dd，J＝20.4Hz，J＝2Hz，1H)，8.36(d，J＝9.6Hz，1H)，8.72(d，J＝8.4Hz，1H)，10.86(s，1H)。
Embodiment 33
(S)-1-(4-(the fluoro-4-of 3-(7-methoxy quinoline-4-base oxygen base) phenylcarbamoyl)-5-methyl-3-oxygen-2-phenyl-2,3-pyrazoline-1-base) propane-2-base-2-Padil ester hydrochloride
Step 1) (S)-1-(4-(4-(7-methoxy quinoline-4-base oxygen base)-3-Fluorophenylamino formyl radical)-2,3-dihydro-5-methyl-3-oxygen-2-benzene pyrazol-1-yl) propane-2-base-(tertbutyloxycarbonylamino) acetic ester
By (S)-N-(the fluoro-4-of 3-(7-methoxy quinoline-4-base oxygen base) phenyl)-1-(2-hydroxypropyl)-5-methyl-3-oxygen-2-phenyl-2,3-dihydro-1 h-pyrazole-4-carboxylic acid amides (1.0g, 1.84mmol), N-t-butoxycarbonyl glycine (0.644g, 3.68mmol, and DMAP (0.45g ABCR), 3.68mmol, Aladdin) be dissolved in 12mL methylene dichloride, then at 0 DEG C, add EDC solid (1.0582g in batches, 5.52mmol, Aladdin).Reaction solution stirs after 2 hours at 0 DEG C, is naturally warming up to room temperature, continues stirring 20 hours.After reaction terminates, add 100mL dchloromethane solution, and with 0.5N HCl (10mL × 2), saturated NaHCO 3solution (10mL × 2) and water (20mL) washing.Aqueous phase EtOAc (15mL × 3) extracts.Organic phase solution uses Na after merging 2sO 4drying, filters, concentrates in a vacuum.Residuum silica gel column chromatography (ethyl acetate: normal hexane=2: 1) purifying obtains target compound.The target compound obtained is yellow solid (1.46g, 70.1%).
MS(ESI，pos.ion)m/z：700.2(M+1)；LC-MS Rt：4.536min；
1H NMR(400MHz，CDCl 3)：δ1.14(d，J＝6.4Hz，3H)，1.45(s，9H)，2.85(s，3H)，3.68-3.72(m，1H)，3.78-3.82(m，1H)，3.81-3.88(m，1H)，3.97(s，3H)，4.00-4.07(m，1H)，4.91-5.03(m，2H)，6.41(d，J＝5.2Hz，1H)，7.15-7.24(m，2H)，7.26-7.29(m，1H)，7.37-7.41(m，3H)，7.42-7.51(m，1H)，7.56-7.60(m，2H)，7.89(dd，J＝13.2Hz，J＝2.4Hz，1H)，8.27(d，J＝5.2Hz，1H)，8.58(d，J＝5.6Hz，1H)，10.81(s，1H)。
Step 2) (S)-1-(4-(the fluoro-4-of 3-(7-methoxy quinoline-4-base oxygen base) phenylcarbamoyl)-5-methyl-3-oxygen-2-phenyl-2,3-pyrazoline-1-base) propane-2-base-2-Padil ester hydrochloride
By (S)-1-(4-(4-(7-methoxy quinoline-4-base oxygen base)-3-Fluorophenylamino formyl radical)-2; 3-dihydro-5-methyl-3-oxygen-2-benzene pyrazol-1-yl) propane-2-base-(tertbutyloxycarbonylamino) acetic ester (200mg; 0.286mmol) be dissolved in ethyl acetate (10mL), add the saturated solution of 10mL hydrogenchloride in ethyl acetate.At room temperature stir after 30 hours, reacting liquid filtering, solid with ethyl acetate (10mL × 2) washs.Thick product MeOH/EtOAc (12mL, the v/v=1: 5) mixing solutions carries out recrystallization of gained.Filter, with ethyl acetate (5mL × 3) washing, vacuum-drying obtains target compound.The target compound obtained is faint yellow solid ((135.7mg, 75%).
MS(ESI，pos.ion)m/z：600.2(M+1)；LC-MS Rt：3.532min；
1H NMR(400MHz，d 6-DMSO)：δ1.09(d，J＝6.4Hz，3H)，2.78(s，3H)，3.50-3.56(m，1H)，3.77-3.83(m，1H)，3.99-4.04(m，4H)，4.26-4.33(m，1H)，4.87-4.92(m，1H)，6.92(d，J＝4.8Hz，1H)，7.53-7.66(m，3H)，7.42-7.45(m，6H)，8.06(dd，J＝13.2Hz，J＝2.4Hz，1H)，8.47(d，J＝9.2Hz，1H)，8.94(d，J＝5.2Hz，1H)，10.95(s，1H)。
Embodiment 34
(S)-1-(4-(the fluoro-4-of 3-(7-methoxy quinoline-4-base oxygen base) phenylcarbamoyl)-5-methyl-3-oxygen-2-phenyl-2,3-pyrazoline-1-base) propane-2-base-2-aminoacetate maleate
By (S)-1-(4-(4-(7-methoxy quinoline-4-base oxygen base)-3-Fluorophenylamino formyl radical)-2; 3-dihydro-5-methyl-3-oxygen-2-benzene pyrazol-1-yl) propane-2-base-(tertbutyloxycarbonylamino) acetic ester (110.3mg; 0.18mmol) be dissolved in 6mL methyl alcohol; then maleic acid sodium (64mg, 0.4mmol) is added.Stir after 30 minutes, reaction mixture is filtered, and filtrate concentrates under vacuo.The residuum methyl alcohol (2mL) obtained and ethyl acetate (10mL) the solvent mixture carry out recrystallization.Filter, with ethyl acetate (5mL × 3) washing, vacuum-drying obtains target compound.The target compound obtained is yellow solid (124.6mg, 87%).
MS(ESI，pos.ion)m/z：600.1(M+1)；LC-MS Rt：3.47min；
1H NMR(400MHz，d 6-DMSO)：δ1.07(d，J＝6Hz，3H)，2.76(s，3H)，3.32-3.76(m，3H)，3.92(s，3H)，3.97-4.02(m，1H)，4.22-4.31(m，1H)，4.86-492(m，1H)，6.01(s，2H)，6.46(d，J＝5.2Hz，1H)，6.95(d，J＝5.2Hz，1H)，7.28-7.35(m，2H)，7.39-7.44(m，3H)，7.49-7.54(m，1H)，7.58-7.62(m，2H)，7.96(dd，J＝13.2Hz，J＝2.4Hz，1H)，8.21(d，J＝9.2Hz，1H)，8.61(d，J＝5.2Hz，1H)，10.86(s，1H)。
Embodiment 35
(S)-1-(4-(the fluoro-4-of 3-(7-methoxy quinoline-4-base oxygen base) phenylcarbamoyl)-5-methyl-3-oxygen-2-phenyl-2,3-pyrazoline-1-base) propane-2-base-2-(dimethylamino) acetic ester maleate
Step 1) (S)-1-(4-(the fluoro-4-of 3-(7-methoxy quinoline-4-base oxygen base) phenylcarbamoyl)-5-methyl-3-oxygen-2-phenyl-2,3-pyrazoline-1-base) propane-2-base-2-(dimethylamino) acetic ester
At 0 DEG C, to (S)-N-(the fluoro-4-of 3-(7-methoxy quinoline-4-base oxygen base)-phenyl-1-(2-hydroxypropyl)-5-methyl-3-oxygen-2-phenyl-2, 3-dihydro-1 h-pyrazole-4-carboxylic acid amides (0.54g, 1mmol), N, N-N-methylsarcosine (0.206g, 2mmol, and DMAP (0.244g Alfa), 2mmol, Aladdin) in dichloromethane solution (15mL), gradation adds EDC solid (0.575g, 3mmol, Aladdin), reaction solution continues stirring 2 hours at 0 DEG C, then room temperature reaction 20 hours are naturally warmed up to.Reaction solution 100mL dichloromethane solution dilution, washes twice with the hydrochloric acid soln of 0.5N, each 10mL, wash twice with saturated sodium hydrogen carbonate solution again, each 20mL, finally wash eight times with water, each 20mL, aqueous phase is extracted with ethyl acetate twice, each 15mL.Merge organic phase, with anhydrous sodium sulfate drying, concentrated, residue is through silica gel column chromatography (eluent ethyl acetate) purifying, and obtaining target compound is yellow solid (0.387g, 61.6%).
MS(ESI，pos.ion)m/z：628.1(M+1)；
1H NMR(400MHz，CDCl 3)：δ1.09(d，J＝6.4Hz，3H)，2.67(s，6H)，2.84(s，3H)，2.98-3.12(m，2H)，3.73-3.78(m，1H)，3.94(s，3H)，3.99-4.03(m，1H)，4.94-5.05(m，1H)，6.40(d，J＝5.2Hz，1H)，7.13-7.22(m，3H)，7.36-7.40(m，3H)，7.45-7.57(m，3H)，7.89(dd，J＝12.4Hz，J＝2.0Hz，1H)，8.25(d，J＝9.2Hz，1H)，8.57(d，J＝5.2Hz，1H)，10.82(s，1H)。
Step 2) (S)-1-(4-(the fluoro-4-of 3-(7-methoxy quinoline-4-base oxygen base) phenylcarbamoyl)-5-methyl-3-oxygen-2-phenyl-2,3-pyrazoline-1-base) propane-2-base-2-(dimethylamino) acetic ester maleate
By (S)-1-(4-(the fluoro-4-of 3-(7-methoxy quinoline-4-base oxygen base) phenylcarbamoyl)-5-methyl-3-oxygen-2-phenyl-2; 3-pyrazoline-1-base) propane-2-base-2-(dimethylamino) acetic ester (110.3mg; 0.176mmol) be dissolved in methyl alcohol (6mL); add toxilic acid (20.4mg; 0.176mmol; Shanghai San ' aisi Reagent Co., Ltd).Stirring at room temperature is after 30 minutes, and reaction solution evaporated under reduced pressure, with MeOH/EtOAc, (12mL, v/v=1: 5) mixing solutions crystallization, filter residue, solid with ethyl acetate washing (5mL × 3) obtained, dry, obtains target compound.The target compound obtained is yellow solid (112.3mg, 86%).
MS(ESI，pos.ion)m/z：628.1(M+1)；LC-MS Rt：3.50min；
1H NMR(400MHz，CDCl 3)：δ1.10(d，J＝6.4Hz，3H)，2.52(s，6H)，2.79(s，3H)，3.19-3.23(m，2H)，3.69-3.78(m，1H)，3.95(s，3H)，3.98-4.04(m，1H)，4.89-5.02(m，1H)，6.08(s，2H)，6.49(d，J＝5.2Hz，1H)，7.31-7.38(m，2H)，7.43-7.46(m，4H)，7.50-7.57(m，1H)，7.61-7.65(m，2H)，7.98(dd，J＝13.2Hz，J＝2.4Hz，1H)，8.24(d，J＝9.2Hz，1H)，8.64(d，J＝5.2Hz，1H)，10.87(s，1H)。
Embodiment 36
(S)-1-(4-(the fluoro-4-of 3-(7-methoxy quinoline-4-base oxygen base) phenylcarbamoyl)-5-methyl-3-oxygen-2-phenyl-2,3-pyrazoline-1-base) propane-2-base-2-(dimethylamino) acetic ester benzoate
Target compound is according to step 2 in enforcement 35) the operation described; with (S)-1-(4-(the fluoro-4-of 3-(7-methoxy quinoline-4-base oxygen base) phenylcarbamoyl)-5-methyl-3-oxygen-2-phenyl-2; 3-pyrazoline-1-base) propane-2-base-2-(dimethylamino) acetic ester (63mg; 0.2mmol) and phenylformic acid (24.4mg; 0.2mmol
Tianjin chemical reagent factory) synthesize.The target compound obtained is white solid (67.4mg, 90%).
MS(ESI，pos.ion)m/z：628.1(M+1)；LC-MS Rt：3.49min；
1H NMR(400MHz，CDCl 3)：δ1.10(d，J＝6.4Hz，3H)，2.41(s，6H)，2.84(s，3H)，3.08-3.13(m，2H)，3.34(d，J＝16.8Hz，1H)，3.65-3.79(m，1H)，3.98(s，3H)，4.0-4.04(m，1H)，5.01-5.06(m，1H)，6.49(d，J＝5.6Hz，1H)，7.17-7.20(m，1H)，7.25-7.32(m，2H)，7.38-7.50(m，5H)，7.51-7.58(m，3H)，7.62(d，J＝2.4Hz，1H)，7.94(dd，J＝9.2Hz，J＝2.4Hz，1H)，8.11(d，J＝8Hz，2H)，8.42(d，J＝6.8Hz，1H)，8.71(d，J＝5.6Hz，1H)，10.80(s，1H)。
Embodiment 37
(S)-1-(4-(the fluoro-4-of 3-(7-methoxy quinoline-4-base oxygen base) phenylcarbamoyl)-5-methyl-3-oxygen-2-phenyl-2,3-pyrazoline-1-base) propane-2-base-2-(dimethylamino) acetic ester tosilate
Target compound is according to step 2 in embodiment 35) the operation described; with (S)-1-(4-(the fluoro-4-of 3-(7-methoxy quinoline-4-base oxygen base) phenylcarbamoyl)-5-methyl-3-oxygen-2-phenyl-2; 3-pyrazoline-1-base) propane-2-base-2-(dimethylamino) acetic ester (62.9mg; 0.1mmol) and tosic acid (34.6mg; 0.2mmol, Shanghai chemical reagent factory) synthesize.The target compound obtained is yellow solid (56.1mg, 70%).
MS(ESI，pos.ion)m/z：628.1(M+1)；LC-MS Rt：3.42min；
1H NMR(400MHz，CDCl 3)：δ1.16(d，J＝6.4Hz，3H)，2.38(s，3H)，2.51(s，6H)，2.88(s，3H)，3.23(d，J＝16.8Hz，1H)，3.34-3.51(m，1H)，3.84(dd，J＝15.2Hz，J＝3.6Hz，1H)，4.05(s，3H)，4.06-4.12(m，1H)，5.06-5.09(m，1H)，6.66(d，J＝6Hz，1H)，7.20-7.28(m，3H)，7.33-7.42(m，5H)，7.46-7.62(m，3H)，7.86-7.88(m，3H)，8.0(dd，J＝12.4Hz，J＝2Hz，1H)，8.38(d，J＝9.2Hz，1H)，8.74(d，J＝6Hz，1H)，10.95(s，1H)。
Embodiment 38
(S)-1-(4-(the fluoro-4-of 3-(7-methoxy quinoline-4-base oxygen base) phenylcarbamoyl)-5-methyl-3-oxygen-2-phenyl-2,3-pyrazoline-1-base) propane-2-base-2-(dimethylamino) acetic ester mesylate
Target compound is according to step 2 in embodiment 35) the operation described; with (S)-1-(4-(the fluoro-4-of 3-(7-methoxy quinoline-4-base oxygen base) phenylcarbamoyl)-5-methyl-3-oxygen-2-phenyl-2; 3-pyrazoline-1-base) propane-2-base-2-(dimethylamino) acetic ester (63.1mg; 0.1mmol) and methylsulfonic acid (15.5mg; 0.16mmol; Shanghai RichJoint Chemical Reagents CO., Ltd). synthesis.The target compound obtained is yellow solid (60.3mg, 83%).
MS(ESI，pos.ion)m/z：628.0(M+1)；LC-MS Rt：3.28min；
1H NMR(400MHz，CDCl 3)：δ1.13(d，J＝7.6Hz，3H)，2.79(s，6H)，2.83(s，3H)，2.88(s，3H)，3.78(d，J＝17.2Hz，1H)，3.87(dd，J＝15.6Hz，J＝3.6Hz，1H)，3.98-4.02(m，1H)，4.05(s，3H)，4.07-4.19(m，2H)，5.06-5.09(m，1H)，6.78(d，J＝6Hz，1H)，7.17-7.22(m，1H)，7.28-7.30(m，1H)，7.36-7.41(m，3H)，7.42-7.58(m，3H)，7.86(d，J＝2.4Hz，1H)，7.94(dd，J＝12.4Hz，J＝2Hz，1H)，8.37(d，J＝9.2Hz，1H)，8.78(d，J＝6.4Hz，1H)，10.89(s，1H)。
Embodiment 39
(R)-1-(4-(the fluoro-4-of 3-(7-methoxy quinoline-4-base oxygen base) phenylcarbamoyl)-5-methyl-3-oxygen-2-phenyl-2,3-pyrazoline-1-base) propane-2-base-2-(methylamino) acetic ester maleate
Step 1) (R)-1-(4-(the fluoro-4-of 3-(7-methoxy quinoline-4-base oxygen base) phenylcarbamoyl)-5-methyl-3-oxygen-2-phenyl-2, 3-pyrazoline-1-base) propane-2-base-2-((carbobenzoxy-(Cbz)) (methyl) amino) acetic ester is at 0 DEG C, to (R)-N-(the fluoro-4-of 3-(7-methoxy quinoline-4-base oxygen base)-phenyl-1-(2-hydroxypropyl)-5-methyl-3-oxygen-2-phenyl-2, 3-dihydro-1 h-pyrazole-4-carboxylic acid amides (2.0g, 3.68mmol), N-Cbz-sarkosine (1.643g, 7.36mmol) with DMAP (0.9g, 7.36mmol, Aladdin) in dichloromethane solution (15mL), add EDC solid (1.06g in batches, 5.52mmol, Aladdin).At 0 DEG C, continue stirring 2 hours, reaction solution is warming up to room temperature naturally, and stirring is spent the night.Reaction terminates the dichloromethane solution dilution of rear 100mL, 0.5N hydrochloric acid (10mL × 2) is first used to wash, saturated sodium bicarbonate solution (20mL × 2) is used to wash again, saturated nacl aqueous solution (20mL) is finally used to wash, aqueous phase ethyl acetate (50mL × 3) extracts, merge organic phase, with anhydrous sodium sulfate drying, concentrating under reduced pressure after filtering.Residue purification by silica gel column chromatography, obtaining target compound is faint yellow solid (2.31g, 84%).
MS(ESI，pos.ion)m/z：748.2(M+1)；LC-MS Rt：4.56min；
1H NMR(400MHz，CDCl 3)：δ1.10(d，J＝6.0Hz，3H)，2.80(d，J＝11.2Hz，3H)，2.92(s，3H)，3.69-3.82(m，2H)，3.96(s，3H)，4.0-4.12(m，2H)，4.95-5.08(m，3H)，6.52-6.56(m，1H)，7.13-7.17(m，1H)，7.26-7.46(m，10H)，7.53-7.55(m，3H)，7.89-7.95(m，1H)，8.21-8.31(m，1H)，8.58-8.63(m，1H)，10.87(s，1H)。
Step 2) (R)-1-(4-(the fluoro-4-of 3-(7-methoxy quinoline-4-base oxygen base) phenylcarbamoyl)-5-methyl-3-oxygen-2-phenyl-2,3-pyrazoline-1-base) propane-2-base-2-(methylamino) acetic ester
By (R)-1-(4-(the fluoro-4-of 3-(7-methoxy quinoline-4-base oxygen base) phenylcarbamoyl)-5-methyl-3-oxygen-2-phenyl-2; 3-pyrazoline-1-base) propane-2-base-2-((carbobenzoxy-(Cbz)) (methyl) is amino) acetic ester (1.404g; 1.876mmol) be dissolved in the mixed solution of ethyl acetate (100mL) and methyl alcohol (100mL); catalytic amount Pd/C (10% is added under nitrogen protection in this solution; ~ 55%w/w water content; 100mg); by degassed for the decompression of this suspension, then pass into hydrogen.Reaction mixture stirring at room temperature one hour under hydrogen shield, filter, residue methyl alcohol (50mLx3) is washed.Filtrate drops into next step reaction immediately.
MS(ESI，pos.ion)m/z：614.1(M+1)；LC-MS Rt：3.47min。
Step 3) (R)-1-(4-(the fluoro-4-of 3-(7-methoxy quinoline-4-base oxygen base) phenylcarbamoyl)-5-methyl-3-oxygen-2-phenyl-2,3-pyrazoline-1-base) propane-2-base-2-(methylamino) acetic ester maleate
By (R)-1-(4-(the fluoro-4-of 3-(7-methoxy quinoline-4-base oxygen base) phenylcarbamoyl)-5-methyl-3-oxygen-2-phenyl-2; 3-pyrazoline-1-base) propane-2-base-2-(methylamino) acetic ester (82.3mg; 0.134mmol) be dissolved in the mixing solutions of ethyl acetate (10mL) and methyl alcohol (10mL); add toxilic acid (31.1mg; 0.268mmol; Shanghai San ' aisi Reagent Co., Ltd).Stirring at room temperature is after 40 minutes, and reaction solution concentrating under reduced pressure, with MeOH/EtOAc, (12mL, v/v=1: mixed solvent crystallization 5), filter residue, and solid with ethyl acetate (5mL × 3) washs, and vacuum-drying, obtains target compound.The target compound obtained is yellow solid (60.2mg, 61.5%).
MS(ESI，pos.ion)m/z：614.1(M+1)；LC-MS Rt：3.518min；
1H NMR(400MHz，d 6-DMSO)：δ1.16(d，J＝5.6Hz，3H)，2.55(s，3H)，2.76(s，3H)，3.34-3.39(m，1H)，3.76-3.80(m，1H)，3.95(s，3H)，3.99-4.04(m，2H)，4.91-5.0(m，1H)，6.20(s，2；H)，6.58(d，J＝5.6Hz，1H)，7.35-7.39(m，2H)，7.41-7.46(m，4H)，7.53-7.59(m，1H)，7.59-7.63(m，2H)，7.98(dd，J＝13.2Hz，J＝2.8Hz，1H)，8.28(d，J＝9.2Hz，1H)，8.70(d，J＝5.6Hz，1H)，10.88(s，1H)。
Embodiment 40
(R)-1-(4-(the fluoro-4-of 3-(7-methoxy quinoline-4-base oxygen base) phenylcarbamoyl)-5-methyl-3-oxygen-2-phenyl-2,3-pyrazoline-1-base) propane-2-base-2-(methylamino) acetic ester fumarate
Target compound is according to step 3 in embodiment 39) the operation described; with (R)-1-(4-(the fluoro-4-of 3-(7-methoxy quinoline-4-base oxygen base) phenylcarbamoyl)-5-methyl-3-oxygen-2-phenyl-2; 3-pyrazoline-1-base) propane-2-base-2-(methylamino) acetic ester (82.3mg; 0.134mmol) and fumaric acid (31.1mg; 0.268mmol, western Gansu Province, Shantou chemical company) synthesize.The target compound obtained is yellow solid (76.3mg, 78%).
MS(ESI，pos.ion)m/z：614.1(M+1)；LC-MS Rt：3.509min；
1H NMR(400MHz，d 6-DMSO)：δ1.05(d，J＝6.0Hz，3H)，2.25(s，3H)，2.78(s，3H)，3.15-3.42(m，2H)，3.94-3.97(m，4H)，4.22-4.28(m，1H)，4.88-4.91(m，1H)，6.48(d，J＝5.2Hz，1H)，6.56(s，2H)，7.29-7.37(m，2H)，7.41-7.46(m，4H)，7.50-7.54(m，1H)，7.60-7.64(m，2H)，7.97(dd，J＝12.8Hz，2.4Hz，1H)，8.23(d，J＝7.2Hz，1H)，8.62(d，J＝5.2Hz，1H)，10.87(s，1H)。
Embodiment 41
(R)-1-(4-(the fluoro-4-of 3-(7-methoxy quinoline-4-base oxygen base) phenylcarbamoyl)-5-methyl-3-oxygen-2-phenyl-2,3-pyrazoline-1-base) propane-2-base-2-(methylamino) acetic ester hydrochloride
Target compound is according to step 3 in embodiment 39) the operation described; with (R)-1-(4-(the fluoro-4-of 3-(7-methoxy quinoline-4-base oxygen base) phenylcarbamoyl)-5-methyl-3-oxygen-2-phenyl-2; 3-pyrazoline-1-base) the ethyl acetate saturated solution (3mL) of propane-2-base-2-(methylamino) acetic ester (82.3mg, 0.134mmol) and hydrogenchloride synthesizes.The target compound obtained is yellow solid (64.5mg, 74%).
MS(ESI，pos.ion)m/z：614.1(M+1)；LC-MS Rt：3.754min；
1H NMR(400MHz，d 6-DMSO)：δ1.09(d，J＝6.0Hz，3H)，2.53(s，3H)，2.79(s，3H)，3.87-3.97(m，1H)，4.0-4.07(m，4H)，4.26-4.32(m，1H)，4.90-4.94(m，1H)，6.95(d，J＝6.4Hz，1H)，7.42-7.45(m，3H)，7.55-7.65(m，5H)，7.73-7.77(m，1H)，8.07(dd，J＝15.6Hz，2.4Hz，1H)，8.49(d，J＝9.2Hz，1H)，8.97(d，J＝6.4Hz，1H)，10.95(s，1H)。
Embodiment 42
(R)-1-(4-(the fluoro-4-of 3-(7-methoxy quinoline-4-base oxygen base) phenylcarbamoyl)-5-methyl-3-oxygen-2-phenyl-2,3-pyrazoline-1-base) propane-2-base-2-(methylamino) acetic ester vitriol
Target compound is according to step 3 in embodiment 39) the operation described; with (R)-1-(4-(the fluoro-4-of 3-(7-methoxy quinoline-4-base oxygen base) phenylcarbamoyl)-5-methyl-3-oxygen-2-phenyl-2; 3-pyrazoline-1-base) H of propane-2-base-2-(methylamino) acetic ester (82.3mg, 0.134mmol) and 2N 2sO 4solution (5mL) synthesizes.The target compound obtained is yellow solid (77.3mg, 81%).
MS(ESI，pos.ion)m/z：614.1(M+1)；LC-MS Rt：3.452min；
1H NMR(400MHz，d 6-DMSO)：δ1.10(d，J＝6.4Hz，3H)，2.57(s，3H)，2.78(s，3H)，3.75-3.82(m，1H)，3.97-4.07(m，5H)，4.26-4.32(m，1H)，4.90-4.95(m，1H)，6.82(d，J＝6.0Hz，1H)，7.40-7.45(m，3H)，7.50-7.57(m，4H)，7.61-7.65(m，2H)，8.04(dd，J＝12.8Hz，1.6Hz，1H)，8.41(d，J＝8.8Hz，1H)，8.87(d，J＝6.0Hz，1H)，10.94(s，1H)。
Embodiment 43
(R)-1-(4-(the fluoro-4-of 3-(7-methoxy quinoline-4-base oxygen base) phenylcarbamoyl)-5-methyl-3-oxygen-2-phenyl-2,3-pyrazoline-1-base) propane-2-base-2-(methylamino) acetic ester phosphoric acid salt
Target compound is according to step 3 in embodiment 39) the operation described; with (R)-1-(4-(the fluoro-4-of 3-(7-methoxy quinoline-4-base oxygen base) phenylcarbamoyl)-5-methyl-3-oxygen-2-phenyl-2; 3-pyrazoline-1-base) H of propane-2-base-2-(methylamino) acetic ester (82.3mg, 0.134mmol) and 2N 3pO 4solution (4mL) synthesizes.The target compound obtained is yellow oil (82.3mg, 86%).
MS(ESI，pos.ion)m/z：614.1(M+1)；LC-MS Rt：3.424min。
Embodiment 44
(R)-1-(4-(the fluoro-4-of 3-(7-methoxy quinoline-4-base oxygen base) phenylcarbamoyl)-5-methyl-3-oxygen-2-phenyl-2,3-pyrazoline-1-base) propane-2-base-2-(methylamino) acetic ester mesylate
Target compound is according to step 3 in embodiment 39) the operation described; with (R)-1-(4-(the fluoro-4-of 3-(7-methoxy quinoline-4-base oxygen base) phenylcarbamoyl)-5-methyl-3-oxygen-2-phenyl-2; 3-pyrazoline-1-base) propane-2-base-2-(methylamino) acetic ester (82.3mg; 0.134mmol) and methylsulfonic acid (25.7mg; 0.268mmol; Shanghai RichJoint Chemical Reagents CO., Ltd) synthesize.The target compound obtained is yellow solid (63.8mg, 67%).
MS(ESI，pos.ion)m/z：614.1(M+1)；LC-MS Rt：3.453min；
1H NMR(400MHz，d 6-DMSO)：δ1.10(d，J＝6.0Hz，3H)，2.35(s，3H)，2.57(s，3H)，2.79(s，3H)，3.78-3.84(m，1H)，3.96-4.07(m，5H)，4.26-4.33(m，1H)，4.91-4.95(m，1H)，7.02(d，J＝6.4Hz，1H)，7.44-7.46(m，3H)，7.53-7.65(m，6H)，8.07(dd，J＝12.8Hz，2.4Hz，1H)，8.52(d，J＝9.2Hz，1H)，9.02(d，J＝6.4Hz，1H)，10.97(s，1H)。
Embodiment 45
(R)-1-(4-(the fluoro-4-of 3-(7-methoxy quinoline-4-base oxygen base) phenylcarbamoyl)-5-methyl-3-oxygen-2-phenyl-2,3-pyrazoline-1-base) propane-2-base-2-(methylamino) acetic ester esilate
Target compound is according to step 3 in embodiment 39) the operation described; with (R)-1-(4-(the fluoro-4-of 3-(7-methoxy quinoline-4-base oxygen base) phenylcarbamoyl)-5-methyl-3-oxygen-2-phenyl-2; 3-pyrazoline-1-base) propane-2-base-2-(methylamino) acetic ester (82.3mg; 0.134mmol) and acetic acid (29.5mg; 0.268mmol, Alfa Aesar) synthesize.The target compound obtained is yellow solid (72.8mg, 75%).
MS(ESI，pos.ion)m/z：614.1(M+1)；LC-MS Rt：3.456min；
1H NMR(400MHz，d 6-DMSO)：δ1.03(d，J＝6.8Hz，3H)，1.05-1.09(m，3H)，2.63-2.67(m，2H)，2.78(s，3H)，3.62-3.66(m，1H)，3.82-3.86(m，1H)，3.94(s，3H)，4.0-4.08(m，1H)，4.24-4.30(m，1H)，4.88-4.96(m，1H)，6.47(d，J＝5.6Hz，1H)，7.30-7.36(m，2H)，7.42-7.46(m，4H)，7.52-7.56(m，1H)，7.60-7.64(m，2H)，7.97(dd，J＝13.2Hz，J＝2.4Hz，1H)，8.22(d，J＝9.2Hz，1H)，8.62(d，J＝5.2Hz，1H)，10.92(s，1H)。
Embodiment 46
(R)-1-(4-(the fluoro-4-of 3-(7-methoxy quinoline-4-base oxygen base) phenylcarbamoyl)-5-methyl-3-oxygen-2-phenyl-2,3-pyrazoline-1-base) propane-2-base-2-(methylamino) acetic ester benzoate
Target compound is according to step 3 in embodiment 39) the operation described; with (R)-1-(4-(the fluoro-4-of 3-(7-methoxy quinoline-4-base oxygen base) phenylcarbamoyl)-5-methyl-3-oxygen-2-phenyl-2; 3-pyrazoline-1-base) propane-2-base-2-(methylamino) acetic ester (82.3mg; 0.134mmol) and phenylformic acid (32.7mg; 0.268mmol, Tianjin chemical reagent factory) synthesize.The target compound obtained is yellow solid (71.3mg, 72%).
MS(ESI，pos.ion)m/z：614.1(M+1)；LC-MS Rt：3.523min。
Embodiment 47
(R)-1-(4-(the fluoro-4-of 3-(7-methoxy quinoline-4-base oxygen base) phenylcarbamoyl)-5-methyl-3-oxygen-2-phenyl-2,3-pyrazoline-1-base) propane-2-base-2-(methylamino) acetic ester tosilate
Target compound is according to step 3 in embodiment 39) the operation described; with (R)-1-(4-(the fluoro-4-of 3-(7-methoxy quinoline-4-base oxygen base) phenylcarbamoyl)-5-methyl-3-oxygen-2-phenyl-2; 3-pyrazoline-1-base) propane-2-base-2-(methylamino) acetic ester (82.3mg; 0.134mmol) and tosic acid (50.2mg; 0.268mmol, Solution on Chemical Reagents in Shanghai factory) synthesize.The target compound obtained is yellow solid (88.5mg, 84%).
MS(ESI，pos.ion)m/z：614.1(M+1)；LC-MS Rt：3.376min；
1H NMR(400MHz，d 6-DMSO)：δ1.09(d，J＝6.4Hz，3H)，2.28(s，3H)，2.78(s，3H)，3.78-3.83(m，1H)，3.97-4.06(m，5H)，4.25-4.32(m，1H)，4.90-4.96(m，1H)，7.0(d，J＝5.2Hz，1H)，7.10-7.12(m，3H)，7.43-7.49(m，6H)，7.53-7.64(m，5H)，8.07(dd，J＝13.2Hz，J＝2.4Hz，1H)，8.51(d，J＝5.2Hz，1H)，9.0(d，J＝6.4Hz，1H)，10.96(s，1H)。
Embodiment 48
(R)-1-(4-(the fluoro-4-of 3-(7-methoxy quinoline-4-base oxygen base) phenylcarbamoyl)-5-methyl-3-oxygen-2-phenyl-2,3-pyrazoline-1-base) propane-2-base-2-(methylamino) acetic ester acetate
Target compound is according to step 3 in embodiment 39) the operation described; with (R)-1-(4-(the fluoro-4-of 3-(7-methoxy quinoline-4-base oxygen base) phenylcarbamoyl)-5-methyl-3-oxygen-2-phenyl-2; 3-pyrazoline-1-base) propane-2-base-2-(methylamino) acetic ester (82.3mg; 0.134mmol) and acetic acid (31.6mg; 0.268mmol, western Gansu Province, Shantou chemical company) synthesize.The target compound obtained is white solid (77.5mg, 79%).MS(ESI，pos.ion)m/z：614.1(M+1)；LC-MS Rt：3.532min。
Embodiment 49
(R)-1-(4-(the fluoro-4-of 3-(7-methoxy quinoline-4-base oxygen base) phenylcarbamoyl)-5-methyl-3-oxygen-2-phenyl-2,3-pyrazoline-1-base) propane-2-base-2-(methylamino) acetic ester L-TARTARIC ACID salt
Target compound is according to step 3 in embodiment 39) the operation described; with (R)-1-(4-(the fluoro-4-of 3-(7-methoxy quinoline-4-base oxygen base) phenylcarbamoyl)-5-methyl-3-oxygen-2-phenyl-2; 3-pyrazoline-1-base) propane-2-base-2-(methylamino) acetic ester (82.3mg; 0.134mmol) and L-TARTARIC ACID (40.2mg, 0.268mmol) synthesize.The target compound obtained is white solid (90.1mg, 88%).
MS(ESI，pos.ion)m/z：614.1(M+1)；LC-MS Rt：3.489min；
1H NMR(400MHz，d 6-DMSO)：δ1.07(d，J＝6.4Hz，3H)，2.36(s，3H)，2.77(s，3H)，3.62-3.66(m，1H)，3.82-3.86(m，1H)，3.94(s，2H)，4.05(s，3H)，4.0-4.04(m，3H)，4.20-4.29(m，1H)，4.89-4.92(m，1H)，6.47(d，J＝5.2Hz，1H)，7.30-7.36(m，2H)，7.42-7.46(m，4H)，7.51-7.55(m，1H)，7.60-7.64(m，2H)，7.97(dd，J＝13.2Hz，J＝2.4Hz，1H)，8.23(d，J＝9.2Hz，1H)，8.62(d，J＝5.2Hz，1H)，10.87(s，1H)。
Embodiment 50
(R)-1-(4-(the fluoro-4-of 3-(7-methoxy quinoline-4-base oxygen base) phenylcarbamoyl)-5-methyl-3-oxygen-2-phenyl-2,3-pyrazoline-1-base) propane-2-base-2-(methylamino) acetic ester oxalate
Target compound is according to step 3 in embodiment 39) the operation described; with (R)-1-(4-(the fluoro-4-of 3-(7-methoxy quinoline-4-base oxygen base) phenylcarbamoyl)-5-methyl-3-oxygen-2-phenyl-2; 3-pyrazoline-1-base) propane-2-base-2-(methylamino) acetic ester (82.3mg; 0.134mmol) and oxalic acid (33.8mg; 0.268mmol, western Gansu Province, Shantou chemical company) synthesize.The target compound obtained is yellow solid (79.2mg, 80%).
MS(ESI，pos.ion)m/z：614.1(M+1)；LC-MS Rt：3.417min。
Embodiment 51
(R)-1-(4-(the fluoro-4-of 3-(7-methoxy quinoline-4-base oxygen base) phenylcarbamoyl)-5-methyl-3-oxygen-2-phenyl-2,3-pyrazoline-1-base) propane-2-base-2-(methylamino) acetic ester Citrate trianion
Target compound is according to step 3 in embodiment 39) the operation described; with (R)-1-(4-(the fluoro-4-of 3-(7-methoxy quinoline-4-base oxygen base) phenylcarbamoyl)-5-methyl-3-oxygen-2-phenyl-2; 3-pyrazoline-1-base) propane-2-base-2-(methylamino) acetic ester (82.3mg; 0.134mmol) and citric acid (51.5mg; 0.268mmol, Tianjin chemical reagent factory) synthesize.The target compound obtained is yellow solid (90.6mg, 84%).
MS(ESI，pos.ion)m/z：614.1(M+1)；LC-MS Rt：3.426min。
Embodiment 52
(R)-1-(4-(the fluoro-4-of 3-(7-methoxy quinoline-4-base oxygen base) phenylcarbamoyl)-5-methyl-3-oxygen-2-phenyl-2,3-pyrazoline-1-base) propane-2-base-2-(methylamino) acetate succinate salt
Target compound is according to step 3 in embodiment 39) the operation described; with (R)-1-(4-(the fluoro-4-of 3-(7-methoxy quinoline-4-base oxygen base) phenylcarbamoyl)-5-methyl-3-oxygen-2-phenyl-2; 3-pyrazoline-1-base) propane-2-base-2-(methylamino) acetic ester (82.3mg; 0.134mmol) and succsinic acid (31.6mg; 0.268mmol, Guangdong chemical reagent engineering and Technology R & D Center) synthesize.The target compound obtained is yellow solid (70.5mg, 72%).
MS(ESI，pos.ion)m/z：614.1(M+1)；LC-MS Rt：3.506min；
1H NMR(400MHz，d 6-DMSO)：δ1.06(d，J＝6.4Hz，3H)，2.41(s，4H)，2.78(s，3H)，3.36-3.40(m，1H)，3.90-3.97(m，4H)，4.0-4.06(m，1H)，4.22-4.28(m，1H)，4.85-4.90(m，1H)，6.48(d，J＝5.2Hz，1H)，7.30-7.36(m，2H)，7.40-7.44(m，4H)，7.49-7.53(m，1H)，7.58-7.63(m，2H)，7.97(dd，J＝13.2Hz，J＝2.4Hz，1H)，8.23(d，J＝9.2Hz，1H)，8.62(d，J＝14.8Hz，1H)，10.87(s，1H)。
Embodiment 53
(R)-1-(4-(the fluoro-4-of 3-(7-methoxy quinoline-4-base oxygen base) phenylcarbamoyl)-5-methyl-3-oxygen-2-phenyl-2,3-pyrazoline-1-base) propane-2-base-2-Padil ester hydrochloride
Step 1) (R)-1-(4-(the fluoro-4-of 3-(7-methoxy quinoline-4-base oxygen base) phenylcarbamoyl)-5-methyl-3-oxygen-2-phenyl-2,3-pyrazoline-1-base) propane-2-base-2-(tertbutyloxycarbonylamino) acetic ester
At 0 DEG C, to (R)-N-(the fluoro-4-of 3-(7-methoxy quinoline-4-base oxygen base)-phenyl-1-(2-hydroxypropyl)-5-methyl-3-oxygen-2-phenyl-2, 3-dihydro-1 h-pyrazole-4-carboxylic acid amides (1.0g, 1.84mmol), N-t-butoxycarbonyl glycine (0.644g, 3.68mmol, and DMAP (0.45g ABCR), 3.68mmol, Aladdin) in dichloromethane solution (12mL), add EDC solid (1.0582g in batches, 5.52mmol, Aladdin), reaction mixture continues stirring two hours at 0 DEG C, naturally room temperature is warming up to, stirring is spent the night.After reaction terminates, the methylene dichloride of 100mL is added in reaction solution, the solution of gained uses 0.5N hydrochloric acid (10mL × 2), saturated sodium bicarbonate solution (10mL × 2) and water (20mL) to wash successively, concentrating under reduced pressure after organic phase with sodium sulfate drying.(ethyl acetate: normal hexane=2: 1) purifying, obtain target compound is yellow solid (1.158g, 90%) to residue obtained silica gel column chromatography.
MS(ESI，pos.ion)m/z：700.2(M+1)；LC-MS Rt：4.502min；
1H NMR(400MHz，CDCl 3)：δ1.15(d，J＝6.4Hz，3H)，1.44(s，9H)，2.86(s，3H)，3.67-3.73(m，1H)，3.79-3.83(m，1H)，3.86-3.92(m，1H)，3.98(s，3H)，4.02-4.07(m，1H)，4.96-5.05(m，2H)，6.43(d，＝5.6Hz，1H)，7.16-7.25(m，2H)，7.26-7.30(m，1H)，7.37-7.40(m，3H)，7.42-7.52(m，1H)，7.57-7.61(m，2H)，7.93(dd，J＝12.4Hz，J＝2.4Hz，1H)，8.28(d，J＝7.2Hz，1H)，8.60(d，J＝5.6Hz，1H)，10.82(s，1H)。
Step 2) (R)-1-(4-(the fluoro-4-of 3-(7-methoxy quinoline-4-base oxygen base) phenylcarbamoyl)-5-methyl-3-oxygen-2-phenyl-2,3-pyrazoline-1-base) propane-2-base-2-Padil ester hydrochloride
By (R)-1-(4-(the fluoro-4-of 3-(7-methoxy quinoline-4-base oxygen base) phenylcarbamoyl)-5-methyl-3-oxygen-2-phenyl-2, 3-pyrazoline-1-base) propane-2-base-2-(tertbutyloxycarbonylamino) acetic ester (200mg, 0.286mmol) be dissolved in ethyl acetate (10mL), add the ethyl acetate saturated solution (10mL) of hydrogenchloride, stirring at room temperature is after 30 hours, reacting liquid filtering, solid with ethyl acetate is washed (10mLx3), use methanol/ethyl acetate=1 again: the mixed solvent recrystallization of 5 (12mL), filter, solid with ethyl acetate (5mL × 3) washs, vacuum-drying, obtain target compound.The target compound obtained is yellow solid (135.7mg, 75%).
MS(ESI，pos.ion)m/z：600.2(M+1)；LC-MS Rt：3.532min；
1H NMR(400MHz，d 6-DMSO)：δ1.09(d，J＝6.4Hz，3H)，2.78(s，3H)，3.50-3.56(m，1H)，3.77-3.83(m，1H)，3.99-4.04(m，4H)，4.26-4.33(m，1H)，4.87-4.92(m，1H)，6.92(d，J＝4.8Hz，1H)，7.53-7.66(m，3H)，7.42-7.45(m，6H)，8.06(dd，J＝13.2Hz，J＝2.4Hz，1H)，8.47(d，J＝9.2Hz，1H)，8.94(d，J＝5.2Hz，1H)，10.95(s，1H)。
Embodiment 54
(R)-1-(4-(the fluoro-4-of 3-(7-methoxy quinoline-4-base oxygen base) phenylcarbamoyl)-5-methyl-3-oxygen-2-phenyl-2,3-pyrazoline-1-base) propane-2-base-2-(dimethylamino) acetic ester hydrochloride
Step 1) (R)-1-(4-(the fluoro-4-of 3-(7-methoxy quinoline-4-base oxygen base) phenylcarbamoyl)-5-methyl-3-oxygen-2-phenyl-2,3-pyrazoline-1-base) propane-2-base-2-(dimethylamino) acetic ester
At 0 DEG C, to (R)-N-(the fluoro-4-of 3-(7-methoxy quinoline-4-base oxygen base)-phenyl-1-(2-the hydroxypropyl)-5-methyl-3-oxygen-2-phenyl-2 with nitrogen protection, 3-dihydro-1 h-pyrazole-4-carboxylic acid amides (1.08g, 2.0mmol), N, N-N-methylsarcosine (0.516g, 5mmol Alfa Aesar), HATU (1.902g.5mmol) and DMAP (62.5mg, 0.5mmol, Aladdin) TEA (1.012g is added in DMF solution, 10mmol), reaction solution continues reaction 2 hours at 0 DEG C, then naturally room temperature is warming up to, continue reaction to spend the night.The CH2Cl2 solution dilution of reaction solution 100mL, then each 10mL is washed twice with the hydrochloric acid soln of 0.5N, wash twice with saturated sodium bicarbonate solution again, each 20mL, finally uses 20mL water washing once, organic phase anhydrous sodium sulfate drying, concentrated, residue is with purification by silica gel column chromatography (EtOAc/MeOH=2/1 wash-out), and obtaining target compound is yellow solid (1.1367g, 84%).
MS(ESI，pos.ion)m/z：628.1(M+1)；LC-MS Rt：3.232min；
1H NMR(400MHz，CDCl 3)：δ1.12(d，J＝6.4Hz，3H)，2.11(s，3H)，2.32(s，6H)，2.98-3.25(m，2H)，3.78-3.83(m，1H)，3.99(s，3H)，4.01-4.08(m，1H)，5.03-5.07(m，1H)，6.43-6.45(m，1H)，7.17-7.21(m，1H)，7.30-7.31(m，2H)，7.39-7.45(m，4H)，7.57-7.62(m，2H)，7.90-7.95(m，1H)，8.28(d，J＝9.2Hz，1H)，8.61(d，J＝5.2Hz，1H)，10.87(s，1H)。
Step 2) (R)-1-(4-(the fluoro-4-of 3-(7-methoxy quinoline-4-base oxygen base) phenylcarbamoyl)-5-methyl-3-oxygen-2-phenyl-2,3-pyrazoline-1-base) propane-2-base-2-(dimethylamino) acetic ester hydrochloride
To (R)-1-(4-(the fluoro-4-of 3-(7-methoxy quinoline-4-base oxygen base) phenylcarbamoyl)-5-methyl-3-oxygen-2-phenyl-2, 3-pyrazoline-1-base) propane-2-base-2-(dimethylamino) acetic ester (100mg, the ethyl acetate solution (5ml) of saturated hydrogenchloride is added in the mixing solutions of methyl alcohol (10mL) 0.16mmol)/ethyl acetate (15mL), stirring at room temperature 40 minutes, concentrating under reduced pressure, residue is recrystallization in the mixing solutions of methyl alcohol (2ml) and ethyl acetate (8ml), filter, filter residue 5ml ethyl acetate washs 3 times, vacuum-drying.Obtaining target compound is yellow solid (90.1mg, 81%).
MS(ESI，pos.ion)m/z：628.1(M+1)；LC-MS Rt：3.295min；
1H NMR(400MHz，CD 3OD)：δ1.12(d，J＝6.8Hz，3H)，1.97(s，3H)，2.87(s，6H)，3.24-3.26(m，2H)，3.52-3.58(m，1H)，3.98(s，3H)，4.17-4.22(m，1H)，5.03-5.07(m，1H)，6.43-6.45(m，1H)，7.17-7.21(m，1H)，7.30-7.39(m，2H)，7.41-7.46(m，4H)，7.57-7.63(m，2H)，8.00-8.03(m，1H)，8.51(d，J＝9.2Hz，1H)，8.80(d，J＝5.2Hz，1H)，10.88(s，1H)。
Embodiment 55
(R)-1-(4-(the fluoro-4-of 3-(7-methoxy quinoline-4-base oxygen base) phenylcarbamoyl)-5-methyl-3-oxygen-2-phenyl-2,3-pyrazoline-1-base) propane-2-base-2-(dimethylamino) acetic ester vitriol
Target compound is according to step 2 in embodiment 54) the operation described; with (R)-1-(4-(the fluoro-4-of 3-(7-methoxy quinoline-4-base oxygen base) phenylcarbamoyl)-5-methyl-3-oxygen-2-phenyl-2; 3-pyrazoline-1-base) sulfuric acid (0.8ml) of propane-2-base-2-(dimethylamino) acetic ester (100mg, 0.16mmol) and 2N synthesizes.The target compound obtained is yellow solid (81.5mg, 70%).
MS(ESI，pos.ion)m/z：628.1(M+1)；LC-MS Rt：3.291min；
1H NMR(400MHz，CD 3OD)：δ1.09(d，J＝6Hz，3H)，1.97(s，3H)，2.81(s，6H)，3，24-3.26(m，2H)，3.65-3.73(m，1H)，3.99(s，3H)，4.11-4.15(m，1H)，5.01-5.05(m，1H)，6.77-6.79(m，1H)，7.28-7.34(m，1H)，7.41-7.44(m，2H)，7.49-7.53(m，4H)，7.56-7.60(m，2H)，7.92-7.95(m，1H)，8.38(d，J＝9.6Hz，1H)，8.72(d，J＝4.8Hz，1H)，10.88(s，1H)。
Embodiment 56
(R)-1-(4-(the fluoro-4-of 3-(7-methoxy quinoline-4-base oxygen base) phenylcarbamoyl)-5-methyl-3-oxygen-2-phenyl-2,3-pyrazoline-1-base) propane-2-base-2-(dimethylamino) acetic ester fumarate
Target compound is according to step 2 in embodiment 54) the operation described; with (R)-1-(4-(the fluoro-4-of 3-(7-methoxy quinoline-4-base oxygen base) phenylcarbamoyl)-5-methyl-3-oxygen-2-phenyl-2; 3-pyrazoline-1-base) propane-2-base-2-(dimethylamino) acetic ester (100mg; 0.16mmol) and fumaric acid (55.44mg; 0.48mmol, western Gansu Province, Shantou chemical reagent factory) synthesize.The target compound obtained is yellow solid (91.5mg, 77%).
MS(ESI，pos.ion)m/z：628.1(M+1)；LC-MS Rt：3.251min；
1H NMR(400MHz，CD 3OD)：δ1.11(d，J＝6Hz，3H)，1.97(s，3H)，2.81(s，6H)，3.25-3.29(m，2H)，3.63-3.68(m，1H)，4.04(s，3H)，4.16-4.21(m，1H)，5.01-5.07(m，1H)，6.74-6.94(m，1H)，7.43-7.59(m.，9H)，7.99-8.02(m，1H)，8.52(d，J＝8Hz，1H)，8.79(d，J＝4.8Hz，1H)，10.88(s，1H)。
Embodiment 57
(R)-1-(4-(the fluoro-4-of 3-(7-methoxy quinoline-4-base oxygen base) phenylcarbamoyl)-5-methyl-3-oxygen-2-phenyl-2,3-pyrazoline-1-base) propane-2-base-2-(dimethylamino) acetic ester acetate
Target compound is according to step 2 in embodiment 54) the operation described; with (R)-1-(4-(the fluoro-4-of 3-(7-methoxy quinoline-4-base oxygen base) phenylcarbamoyl)-5-methyl-3-oxygen-2-phenyl-2; 3-pyrazoline-1-base) propane-2-base-2-(dimethylamino) acetic ester (100mg; 0.16mmol) and acetic acid (28.70mg; 0.48mmol, western Gansu Province, Shantou chemical reagent factory) synthesize.The target compound obtained is yellow solid (83.4mg, 77%).
MS(ESI，pos.ion)m/z：628.1(M+1)；LC-MS Rt：3.339min；
1H NMR(400MHz，CD 3OD)：δ1.07(d，J＝6.4Hz，3H)，1.92(s，3H)，2.84(s，6H)，3.22-3.30(m，2H)，3.53-3.59(m，1H)，3.93(s，3H)，4.20-4.26(m，1H)，5.03-5.05(m，1H)，6.74-6.94(m，1H)，7.29-7.32(m，1H)，7.42-7.46(m，2H)，7.51-7.55(m，4H)，7.58-7.62(m，2H)，7.89-7.92(m，1H)，8.26(d，J＝9.2Hz，1H)，8.50(d，J＝5.2Hz，1H)，10.88(s，1H)。
Embodiment 58
(R)-1-(4-(the fluoro-4-of 3-(7-methoxy quinoline-4-base oxygen base) phenylcarbamoyl)-5-methyl-3-oxygen-2-phenyl-2,3-pyrazoline-1-base) propane-2-base-2-(dimethylamino) acetic ester oxalate
Target compound is according to step 2 in embodiment 54) the operation described; with (R)-1-(4-(the fluoro-4-of 3-(7-methoxy quinoline-4-base oxygen base) phenylcarbamoyl)-5-methyl-3-oxygen-2-phenyl-2; 3-pyrazoline-1-base) propane-2-base-2-(dimethylamino) acetic ester (100mg; 0.16mmol) and oxalic acid (60.3mg; 0.48mmol, western Gansu Province, Shantou chemical reagent factory) synthesize.The target compound obtained is yellow solid (98.5mg, 84%).
MS(ESI，pos.ion)m/z：628.1(M+1)；LC-MS Rt：2.009min；
1H NMR(400MHz，CD 3OD)：δ1.06(d，J＝5.6Hz，3H)，1.15(s，3H)，1.94(s，6H)，2.89-2.91(m，2H)，3.70-3.76(m，1H)，3.98(s，3H)，4.15-4.19(m，1H)，5.04-5.09(m，1H)，6.91-6.94(m，1H)，7.35-7.38(m，1H)，7.41-7.45(m，2H)，7.52-7.55(m，4H)，7.58-7.62(m，2H)，7.98-8.02(m，1H)，8.50(d，J＝9.2Hz，1H)，8.78(d，J＝5.2Hz，1H)，10.87(s，1H)。
Embodiment 59
(R)-1-(4-(5-(7-methoxy quinoline-4-base oxygen base) pyridine-2-base formamyl)-5-methyl-3-oxygen-2-phenyl-2,3-pyrazoline-1-base) propane-2-base-2-(methylamino-) acetic ester maleate
Step 1) (R)-1-(4-(5-(7-methoxy quinoline-4-base oxygen base) pyridine-2-base formamyl)-2,3-dihydro-5-methyl-3-oxygen-2-phenylpyrazole-1-base) propane-2-base-2-(N-Benzyloxycarbonyl-N-methyl is amino) acetic ester
At 0 DEG C, to (R)-1-(2-hydroxypropyl)-N-(5-(7-methoxy quinoline-4-base oxygen base) pyridine-2-base)-5-methyl-3-oxygen-2-phenyl-2,3-dihydro-1 h-pyrazole-4-carboxylic acid amides (2.0g, 3.81mmol), N-Cbz-sarkosine (1.7g, 7.62mmol), DMAP (0.93g, 7.62mmol, Aladdin) in dichloromethane solution (15mL), add EDC solid (2.19g, 11.43mmol, Aladdin) in batches.Reaction solution continues stirring 2 hours at 0 DEG C, is then heated to 40 DEG C and stirs to spend the night.Reaction solution dichloromethane solution (100mL) dilutes, then wash twice with the hydrochloric acid soln of 0.5N, each 10mL, then wash twice with saturated sodium bicarbonate solution, each 20mL, finally use 20mL water washing once, organic phase anhydrous sodium sulfate drying, concentrated, residue is with purification by silica gel column chromatography (EtOAc/MeOH=4/1 wash-out), obtaining target compound is yellow solid (2.15g, 77.3%).
MS(ESI，pos.ion)m/z：731.28(M+1)；LC-MS Rt：4.199min；
1H NMR(400MHz，CDCl 3)：δ1.13(d，J＝6.4Hz，3H)，1.29(s，3H)，2.86(d，J＝6.4Hz，2H)，2.94(s，3H)，3.97(s，3H)，3.99(s，2H)，4.16-4.21(m，1H)，5.12(s，2H)，6.39-6.42(m，1H)，7.22-7.25(m，1H)，7.29-7.58(m，13H)，8.22-8.25(m，1H)，8.33-8.37(m，1H)，8.57-8.61(m，1H)，11.20(s，1H)。
Step 2) (R)-1-(4-(5-(7-methoxy quinoline-4-base oxygen base) pyridine-2-base formamyl)-5-methyl-3-oxygen-2-phenyl-2,3-pyrazoline-1-base) propane-2-base-2-(methylamino-) acetic ester
Under nitrogen protection; to (R)-1-(4-(5-(7-methoxy quinoline-4-base oxygen base) pyridine-2-base formamyl)-2; 3-dihydro-5-methyl-3-oxygen-2-phenylpyrazole-1-base) propane-2-base-2-(N-Benzyloxycarbonyl-N-methyl is amino) acetic ester (1.0g; in methanol solution (100mL) 1.4mmol); add Pd/C (10%; ~ 55%w/w water content; 20mg), stirring at room temperature 20 minutes under hydrogen shield.By reacting liquid filtering, by methanol wash 3 times, each 35mL.The solution obtained is at once in next step.
MS(ESI，pos.ion)m/z：597.24(M+1)；LC-MS Rt：3.201min。
Step 3) (R)-1-(4-(5-(7-methoxy quinoline-4-base oxygen base) pyridine-2-base formamyl)-5-methyl-3-oxygen-2-phenyl-2,3-pyrazoline-1-base) propane-2-base-2-(methylamino-) acetic ester maleate
To (R)-1-(4-(5-(7-methoxy quinoline-4-base oxygen base) pyridine-2-base formamyl)-5-methyl-3-oxygen-2-phenyl-2; 3-pyrazoline-1-base) propane-2-base-2-(methylamino-) acetic ester (80mg; in methanol solution (10mL) 0.134mmol); add toxilic acid (46.74mg; 0.40mmol; Shanghai san ' aisi reagent CO.; LTD); stirring at room temperature 40 minutes, concentrates in a vacuum.With recrystallization in methyl alcohol (2mL)/ethyl acetate (8mL) mixing solutions, filter, solid with ethyl acetate washs three times, each 5mL, vacuum-drying, and the target compound obtained is yellow solid (68.8mg, 72%).
MS(ESI，pos.ion)m/z：597.24(M+1)；LC-MS Rt：3.221min；
1H NMR(400MHz，CD 3OD)：δ1.14(d，J＝6.4Hz，3H)，1.25(s，3H)，2.17-2.20(m，1H)，2.78-2.83(m，3H)，2.89-2.95(m，2H)，3.85-3.93(m，2H)，4.06-4.10(m，3H)，5.10-5.12(m，1H)，6.29-6.35(m，2H)，6.98-7.00(m，1H)，7.35-7.56(m，8H)，7.71-7.72(m，1H)，8.21-8.30(m，2H)，8.77-8.78(m，1H)，11.15(s，1H)。
Embodiment 60
(R)-1-(4-(5-(7-methoxy quinoline-4-base oxygen base) pyridine-2-base formamyl)-5-methyl-3-oxygen-2-phenyl-2,3-pyrazoline-1-base) propane-2-base-2-(methylamino-) acetic ester hydrochloride
Target compound is according to step 3 in embodiment 59) the operation described; with (R)-1-(4-(5-(7-methoxy quinoline-4-base oxygen base) pyridine-2-base formamyl)-5-methyl-3-oxygen-2-phenyl-2; 3-pyrazoline-1-base) the ethyl acetate solution synthesis of propane-2-base-2-(methylamino-) acetic ester (100mg, 0.168mmol) and saturated hydrogenchloride.The target compound obtained is yellow solid (80.7mg, 76%).
MS(ESI，pos.ion)m/z：597.24(M+1)；LC-MS Rt：3.262min；
1H NMR(400MHz，CD 3OD)：δ1.33(d，J＝4.8Hz，3H)，1.45(s，3H)，2.17-2.25(m，1H)，2.96-3.02(m，3H)，3.03-3.12(m，2H)，3.62-3.68(m，2H)，4.19-4.29(m，3H)，5.20-5.26(m，1H)，6.92-7.30(m，1H)，7.60-7.81(m，8H)，8.04-8.12(m，1H)，8.35-8.73(m，2H)，9.00-9.04(m，1H)，11.15(s，1H)。
Embodiment 61
(R)-1-(4-(5-(7-methoxy quinoline-4-base oxygen base) pyridine-2-base formamyl)-5-methyl-3-oxygen-2-phenyl-2,3-pyrazoline-1-base) propane-2-base-2-(methylamino-) acetic ester oxalate
Target compound is according to step 3 in embodiment 59) the operation described; with (R)-1-(4-(5-(7-methoxy quinoline-4-base oxygen base) pyridine-2-base formamyl)-5-methyl-3-oxygen-2-phenyl-2; 3-pyrazoline-1-base) propane-2-base-2-(methylamino-) acetic ester (100mg; 0.168mmol) with oxalic acid (63.5mg; 0.50mmol, western Gansu Province, Shantou chemical reagent factory) synthesize.The target compound obtained is yellow solid (84.1mg, 73%).
MS(ESI，pos.ion)m/z：597.24(M+1)；LC-MS Rt：3.227min；
1H NMR(400MHz，CD 3OD)：δ1.23(d，J＝6Hz，3H)，1.41(s，3H)，2.06-2.15(m，1H)，2.79-2.83(m，3H)，2.90-3.00(m，2H)，3.88-3.98(m，2H)，4.07-4.15(m，3H)，5.10-5.22(m，1H)，6.98-7.07(m，1H)，7.54-7.71(m，8H)，7.90-7.91(m，1H)，8.41-8.61(m，2H)，8.80-8.90(m，1H)，11.15(s，1H)。
Embodiment 62
(R)-1-(4-(5-(7-methoxy quinoline-4-base oxygen base) pyridine-2-base formamyl)-5-methyl-3-oxygen-2-phenyl-2,3-pyrazoline-1-base) propane-2-base-2-(methylamino-) acetic ester fumarate
Target compound is according to step 3 in embodiment 59) the operation described; with (R)-1-(4-(5-(7-methoxy quinoline-4-base oxygen base) pyridine-2-base formamyl)-5-methyl-3-oxygen-2-phenyl-2; 3-pyrazoline-1-base) propane-2-base-2-(methylamino-) acetic ester (100mg; 0.168mmol) with fumaric acid (58.4mg; 0.50mmol, western Gansu Province, Shantou chemical reagent factory) synthesize.The target compound obtained is yellow solid (94.1mg, 79%).
MS(ESI，pos.ion)m/z：597.24(M+1)；LC-MS Rt：3.211min；
1H NMR(400MHz，CD 3OD)：δ1.16(d，J＝5.2Hz，3H)，1.28(s，3H)，2.02-2.06(m，1H)，2.70-2.76(m，3H)，2.86-2.93(m，2H)，3.84-3.89(m，2H)，4.05-4.08(m，3H)，4.64-4.65(m，1H)，6.94-6.98(m，1H)，7.48-7.67(m，8H)，7.84-7.87(m，1H)，8.35-8.54(m，2H)，8.77-8.78(m，1H)，11.15(s，1H)。
Embodiment 63
(R)-1-(4-(5-(7-methoxy quinoline-4-base oxygen base) pyridine-2-base formamyl)-5-methyl-3-oxygen-2-phenyl-2,3-pyrazoline-1-base) propane-2-base-2-(methylamino-) acetic ester acetate
Target compound is according to step 3 in embodiment 59) the operation described; with (R)-1-(4-(5-(7-methoxy quinoline-4-base oxygen base) pyridine-2-base formamyl)-5-methyl-3-oxygen-2-phenyl-2; 3-pyrazoline-1-base) propane-2-base-2-(methylamino-) acetic ester (100mg; 0.168mmol) with acetic acid (30.21mg; 0.50mmol, western Gansu Province, Shantou chemical reagent factory) synthesize.The target compound obtained is yellow solid (89.4mg, 81%).
MS(ESI，pos.ion)m/z：597.24(M+1)；LC-MS Rt：3.103min；
1H NMR(400MHz，CD 3OD)：δ1.11(d，J＝4Hz，3H)，1.23(s，3H)，2.31-2.35(m，1H)，2.67-2.78(m，3H)，2.84-2.87(m，2H)，3.92-3.99(m，2H)，4.05-4.30(m，3H)，5.02-5.04(m，1H)，7.01-7.02(m，1H)，7.43-7.61(m，8H)，7.96-7.99(m，1H)，8.33-8.53(m，2H)，8.80-8.81(m，1H)，11.15(s，1H)。
Embodiment 64
(R)-1-(4-(5-(7-methoxy quinoline-4-base oxygen base) pyridine-2-base formamyl)-5-methyl-3-oxygen-2-phenyl-2,3-pyrazoline-1-base) propane-2-base-2-(methylamino-) acetic ester tosilate
Target compound is according to step 3 in embodiment 59) the operation described; with (R)-1-(4-(5-(7-methoxy quinoline-4-base oxygen base) pyridine-2-base formamyl)-5-methyl-3-oxygen-2-phenyl-2; 3-pyrazoline-1-base) propane-2-base-2-(methylamino-) acetic ester (100mg; 0.168mmol) with methylsulfonic acid (19.3mg; 0.2mmol, Shanghai Run Jie chemical reagent company limited) synthesize.The target compound obtained is yellow solid (105.9mg, 81%).
MS(ESI，pos.ion)m/z：597.24(M+1)；LC-MS Rt：3.070min；
1H NMR(400MHz，CD 3OD)：δ0.89(d，J＝4.4Hz，3H)，1.23(s，3H)，2.20-2.36(m，4H)，2.52-2.68(m，3H)，2.78-2.92(m，2H)，3.47-3.89(m，2H)，3.98-4.13(m，3H)，5.10-5.30(m，1H)，6.98-7.05(m，1H)，7.20-7.65(m，12H)，8.11-8.19(m，1H)，8.51-8.65(m，2H)，8.90-8.99(m，1H)，11.15(s，1H)。
Embodiment 65
(R)-1-(4-(5-(7-methoxy quinoline-4-base oxygen base) pyridine-2-base formamyl)-5-methyl-3-oxygen-2-phenyl-2,3-pyrazoline-1-base) propane-2-base-2-(methylamino-) acetic ester Citrate trianion
Target compound is according to step 3 in embodiment 59) the operation described; with (R)-1-(4-(5-(7-methoxy quinoline-4-base oxygen base) pyridine-2-base formamyl)-5-methyl-3-oxygen-2-phenyl-2; 3-pyrazoline-1-base) propane-2-base-2-(methylamino-) acetic ester (100mg; 0.168mmol) with citric acid (51.5mg; 0.268mmol, Tianjin Chemical Plant) synthesize.The target compound obtained is yellow solid (112.4mg, 85%).
MS(ESI，pos.ion)m/z：597.24(M+1)；LC-MS Rt：3.146min。
Embodiment 66
(S)-((S)-1-(4-(the fluoro-4-of 3-(7-methoxy quinoline-4-base oxygen base) phenylcarbamoyl)-5-methyl-3-oxygen-2-phenyl-2,3-pyrazoline-1-base) propane-2-base) 2-amino-3 Methylbutanoic acid ester hydrochloride
Target compound prepares according to the method for embodiment 59.
MS(ESI，pos.ion)m/z：642.2(M+1)，LC-MS Rt：3.419min；
1H NMR(400MHz，D 2O)：δ0.74-0.75(d，J＝6.8Hz，3H)，0.91-0.98(m，4H)，1.10-1.12(d，J＝6Hz，3H)，2.75(s，3H)，3.99(s，3H)，4.04-4.05(d，J＝3.6Hz，2H)，4.83-4.85(m，1H)，6.91-6.92(d，J＝6.8Hz，1H)，7.32-7.38(m，5H)，7.46-7.49(m，1H)，7.58-7.69(m，4H)，8.43-8.45(d，J＝9.2Hz，1H)，8.62-8.64(d，J＝6.8Hz，1H)。
Embodiment 67
(S)-((S)-1-(4-(the fluoro-4-of 3-(7-methoxy quinoline-4-base oxygen base) phenylcarbamoyl)-5-methyl-3-oxygen-2-phenyl-2,3-pyrazoline-1-base) propane-2-base) 2-alanine ester hydrochloride
Target compound prepares according to the method for embodiment 59.
MS(ESI，pos.ion)m/z：614.1(M+1)，LC-MS Rt：3.357min；
1H NMR(400MHz，D 2O)：δ1.25-1.26(d，J＝6Hz，3H)，1.48-1.50(d，J＝4.4Hz，3H)，2.91(s，3H)，4.16(s，3H)，4.20-4.28(m，1H)，4.49-4.55(m，1H)，5.11-5.13(m，1H)，7.08-7.10(d，J＝6.8Hz，1H)，7.48-7.66(m，5H)，7.75-7.86(m，5H)，8.61-8.63(d，J＝9.2Hz，1H)，8.79-8.80(d，J＝6.8Hz，1H)。
Embodiment 68
(S)-((R)-1-(4-(5-(7-methoxy quinoline-4-base oxygen base) pyridine-2-base formamyl)-5-methyl-3-oxygen-2-phenyl-2,3-pyrazoline-1-base) propane-2-base) 2-amino-3 Methylbutanoic acid ester hydrochloride
Target compound prepares according to the method for embodiment 59.
MS(ESI，pos.ion)m/z：625.2(M+1)，LC-MS Rt：3.275min；
1H NMR(400MHz，CD 3OD)：δ1.02-1.11(m，7H)，1.19-1.20(d，J＝6.4Hz，3H)，1.31(s，1H)，2.26-2.32(m，1H)，2.65(s，1H)，2.89(s，3H)，3.84-3.89(m，1H)，4.11(s，3H)，4.36-4.42(m，1H)，5.08-5.11(m，1H)，6.99-7.01(d，J＝6.4Hz，1H)，7.47-7.517(m，3H)，7.58-7.69(m，4H)，7.88-7.89(m，1H)，8.49-8.52(m，1H)，8.57-8.59(m，J＝9.6Hz，1H)，8.83-8.84(d，J＝6.4Hz，1H)。
Embodiment 69
(S)-((R)-1-(4-(5-(7-methoxy quinoline-4-base oxygen base) pyridine-2-base formamyl)-5-methyl-3-oxygen-2-phenyl-2,3-pyrazoline-1-base) propane-2-base) 2-alanine ester hydrochloride
Target compound prepares according to the method for embodiment 59.
MS(ESI，pos.ion)m/z：597.1(M+1)，LC-MS Rt：3.136min；
1H NMR(400MHz，CD 3OD)：δ1.17-1.18(d，J＝6.4Hz，3H)，1.54-1.54(d，J＝3.2Hz，3H)，1.29-1.34(m，2H)，2.88(s，3H)，3.96-4.01(m，1H)，4.33-4.40(m，1H)，5.05-5.10(m，1H)，6.99-7.10(d，J＝6.8Hz，1H)，7.46-7.49(m，3H)，7.57-7.68(m，4H)，7.84-7.89(m，1H)，8.38(s，1H)，8.57-8.59(d，J＝9.6Hz，1H)，8.82-8.84(d，J＝6.8Hz，1H)。
Embodiment 70
1-(2-(4-(4-(1,5-dimethyl-3-oxygen-2-phenyl-2,3-dihydro-1 h-pyrazole-4-carboxamide groups)-2-fluorophenoxy) quinoline-7-base oxygen base) ethyl) cyclopropane base 2-Padil ester hydrochloride
Step 1) 3-hydroxy-propionic acid benzyl ester
3-hydroxy-propionic acid (7.2g, 80.1mmol, TCI, TOKYO KASEI) is dissolved in 250mL methyl alcohol, then at 0 DEG C, in solution, adds KOH (4.49g, 80.1mmol), constantly stir until KOH dissolves completely.Evaporate to dryness methyl alcohol, the anhydrous THF of residue 300mL dissolves.In solution, BnBr (13.85g, 80.1mmol, Aldrich) is added with syringe at 0 DEG C.Reaction solution was 80 DEG C of backflows two days.Then to go out reaction with 30mL shrend, be extracted with ethyl acetate five times, each 30mL, merge organic phase, use anhydrous Na 2sO 4drying, concentrated, residue purification by silica gel column chromatography, developping agent sherwood oil: ethyl acetate=6: 1, obtaining target compound is yellow oil (2.02g, 27.1%).
Step 2) 3-(tetrahydrochysene-2H-pyrans-2-base oxygen base) benzyl propionate
By 3-hydroxy-propionic acid benzyl ester (2.041g, 11.34mmol) and DHP (1.428g, 17.01mmol, Aldrich) be dissolved in 30mL methylene dichloride, then in reactant, PPTS (0.283g, 1.13mmol, Aldrich) is slowly added.40 DEG C of reactions after 3 days, concentrating under reduced pressure reaction solution.Residue purification by silica gel column chromatography, developping agent sherwood oil: ethyl acetate=20: 1, obtaining target compound is yellow oil (2.645g, 88.3%).Step 3) 1-(2-(tetrahydrochysene-2H-pyrans-2-base oxygen base) ethyl) ring propyl alcohol
3-(tetrahydrochysene-2H-pyrans-2-base oxygen base) benzyl propionate (1.1g, 4.17mmol) is dissolved in 14.2mL THF, under room temperature, in nitrogen, in reaction solution, adds Ti (Oi-Pr) with syringe 4(0.252mL, 0.834mmol, 0.955g/L, Ardrich).Then reduce the temperature to 18 DEG C, in two hours, in reaction solution, add EtMgBr (3.54mL, 10.4mmol, 3M diethyl ether solution, Aldrich) with syringe pump.After 3-(tetrahydrochysene-2H-pyrans-2-base oxygen base) benzyl propionate has reacted (monitoring with TLC), with saturated NH4Cl solution (50mL) cancellation reaction.Filter, mother liquor is extracted with ethyl acetate three times, each 30mL, merges organic phase, uses anhydrous Na 2sO 4drying, concentrated, residue purification by silica gel column chromatography, developping agent sherwood oil: ethyl acetate=10: 1, obtaining target compound is yellow oil (507mg, 65%).
1H NMR(400MHz，CDCl 3)：δ0.46(m，2H)，0.75-0.88(d，2H)，1.55-1.83(m，6H)，1.87-1.90(m，2H)，3.55(q，1H)，3.69(q，1H)，3.88(t，1H)，4.06(t，1H)，4.66(s，1H)。
Step 4) 1-(2-hydroxyethyl) ring propyl alcohol
By 1-(2-(tetrahydrochysene-2H-pyrans-2-base oxygen base) ethyl) ring propyl alcohol (507mg, 2.71mmol) be dissolved in 40mL methyl alcohol, then in reactant, PPTS (68.1mg, 0.271mmol, Aldrich) is slowly added.Stir at 40 DEG C and spend the night, to go out reaction with 10mL shrend, with dichloromethane extraction three times, each 20mL.Merge organic phase, use anhydrous Na 2sO 4drying, concentrated, residue purification by silica gel column chromatography, developping agent sherwood oil: ethyl acetate=10: 1, obtaining target compound is yellow oil (150mg, 54.3%).
1H NMR(400MHz，CDCl 3)：δ0.55(t，2H)，0.85(t，2H)，1.85(t，2H)，4.02(t，2H)。
Step 5) 2-(1-hydroxycyclopropyl) ethyl methane sulfonate ester
By 1-(2-hydroxyethyl) ring propyl alcohol (310mg, 3.04mmol) with triethylamine (614.1mg, 6.08mmol) be dissolved in 10mL methylene dichloride, stir 30 minutes at-10 DEG C, in reactant, methylsulfonyl chloride (348mg, 3.04mmol) is slowly added with syringe.-10 DEG C of reactions 1 hour, with 2mL frozen water cancellation reaction, with dichloromethane extraction four times, each 20mL.Merge organic phase, use anhydrous Na 2sO 4drying, concentrated, obtaining target compound is yellow oil (immediately for next step synthesis).
Step 6) N-(the fluoro-4-of 3-(7-(2-(1-hydroxycyclopropyl) oxyethyl group) quinolyl-4 oxygen base) phenyl)-1,5-dimethyl-3-oxygen-2-phenyl-2,3-dihydro-1 h-pyrazole-4-carboxylic acid amides
By N-(the fluoro-4-of 3-(7-hydroxyquinoline-4-base oxygen base) phenyl)-1,5-dimethyl-3-oxygen-2-phenyl-2,3-dihydro-1 h-pyrazole-4-carboxylic acid amides (735.7mg, 1.52mmol) be dissolved in 8mL N with 2-(1-hydroxycyclopropyl) ethyl methane sulfonate ester (3.04mmol), in N-N,N-DIMETHYLACETAMIDE, then in reactant, cesium carbonate (4.955g, 15.2mmol) is added.Stir one day at 40 DEG C, to go out reaction with 5mL shrend, with dichloromethane extraction three times, each 20mL.Merge organic phase, use anhydrous Na 2sO 4drying, concentrated, residue purification by silica gel column chromatography, developping agent methylene dichloride: methyl alcohol=45: 1, obtaining target compound is white solid (270mg, 15.6%).MS(ESI，pos.ion)m/z：569.1(M+1)；(ESI，nat.ion)m/z：567.1(M-1)；
LC-MS Rt：3.948min.
1H NMR(400MHz，CDCl 3)：δ0.57(d，J＝8Hz，2H)，0.86(d，J＝8Hz，2H)，2.14(t，2H)，2.80(s，3H)，3.37(s，3H)，4.43(t，2H)，6.41(d，J＝4Hz，1H)，7.14-7.23(m，2H)，7.26-7.35(m，1H)，7.37-7.38(m，2H)，7.45-7.50(m，2H)，7.50-7.58(m，2H)，7.90-7.93(dd，J＝2.4Hz，1H)，8.27(d，J＝8Hz，1H)，8.58(d，J＝8Hz，1H)，10.89(s，1H)。
Step 7) 1-(2-(4-(4-(1,5-dimethyl-3-oxygen-2-phenyl-2,3-dihydro-1 h-pyrazole-4-carboxamide groups)-2-fluorophenoxy) quinoline-7-base oxygen base) ethyl) cyclopropyl 2-(t-butoxycarbonyl amino) acetic ester
By N-(the fluoro-4-of 3-(7-(2-(1-hydroxycyclopropyl) oxyethyl group) quinolyl-4 oxygen base) phenyl)-1,5-dimethyl-3-oxygen-2-phenyl-2,3-dihydro-1 h-pyrazole-4-carboxylic acid amides (218mg, 0.384mmol), N-carbobenzoxyglycine (133.4mg, 0.768mmol, Alfa), be dissolved in 10mL methylene dichloride with DMAP (7.03mg, 0.058mmol, Aladdin), at 0 DEG C, DCC (323.4mg, 1.54mmol, Aldrich) is added in reactant.At room temperature stir and spend the night, filter, solid 20mL washed with dichloromethane twice.Merge organic phase, with the saturated NaNCO of 20mL 3solution and the water washing of 20mL saturated common salt.Anhydrous Na 2sO 4drying, concentrated, residue purification by silica gel column chromatography, developping agent methylene dichloride: methyl alcohol=45: 1, developping agent sherwood oil: ethyl acetate=1: 6, obtaining target compound is yellow solid (190mg, 70%).
Step 8) 1-(2-(4-(4-(1,5-dimethyl-3-oxygen-2-phenyl-2,3-dihydro-1 h-pyrazole-4-carboxamide groups)-2-fluorophenoxy) quinoline-7-base oxygen base) ethyl) cyclopropane base 2-Padil ester hydrochloride
By 1-(2-(4-(4-(1,5-dimethyl-3-oxygen-2-phenyl-2,3-dihydro-1 h-pyrazole-4-carboxamide groups)-2-fluorophenoxy) quinoline-7-base oxygen base) ethyl) cyclopropyl 2-(t-butoxycarbonyl amino) acetic ester (190mg, 0.262mmol) be dissolved in 8mL ethyl acetate, the ethyl acetate solution (0.93mol/L, 5mL) of HCl is dripped in reactant.At room temperature stir 30 minutes, filter, solid 20mL ethyl acetate washs three times, and obtaining target compound is white solid (54mg, 32%).
MS(ESI，pos.ion)m/z：625(M+1)；(ESI，nat.ion)m/z：624(M-1)；LC-MS Rt：3.871min。
1H NMR(400MHz，MeOD)：δ0.81-0.85(t，J＝13Hz，2H)，0.89-0.92(t，J＝12Hz，2H)，2.34(t，J＝6Hz，2H)，2.65(s，3H)，3.30(s，3H)，3.71(s，2H)，4.36(t，J＝6Hz，2H)，6.88-6.89(d，J＝6Hz，1H)，7.28-7.34(m，4H)，7.41(s，1H)，7.46-7.53(m，4H)，7.92-7.95(d，J＝12Hz，1H)，8.45-8.47(d，J＝9Hz，1H)，8.71-8.73(d，J＝7Hz，1H)。
Embodiment 71
1-(3-(4-(4-(2,3-dimethyl-5-oxygen-1-phenyl-2,5-dihydro-1 h-pyrazole-4-carboxamide groups)-2-fluorophenoxy) quinoline-7-base oxygen base) propyl group) cyclopropyl 2-Padil ester hydrochloride
Step 1) 1-(3-hydroxypropyl) ring propyl alcohol
15 DEG C time, dihydrofuran-2 (3H)-one (2.0g, 23mmol) and Ti (Oi-Pr) 4 (1.32g, 4.6mmol, Aldrich) are dissolved in 80mL THF.At 20 DEG C, in nitrogen, in three hours, in reaction solution, add EtMgBr (60mmol, 20mL, 3M diethyl ether solution, Aldrich) with syringe pump.Stir after three hours, with the saturated NH of 60mL 4the cancellation of Cl solution is reacted, and is extracted with ethyl acetate three times, each 50mL.Merge organic phase, use anhydrous Na 2sO 4drying, concentrated, residue purification by silica gel column chromatography, developping agent ethyl acetate: normal hexane=1: 1, obtaining target compound is yellow liquid (2.5g, 93%).
Step 2) 3-(1-hydroxycyclopropyl) propyl Methanesulfonate
By 1-(3-hydroxypropyl) ring propyl alcohol (140mg, 1.2mmol) be dissolved in 8mL methylene dichloride with triethylamine (0.3mL, 2.1mmol), stir 10 minutes at 0 DEG C, in reactant, methylsulfonyl chloride (180mg, 1.6mmol) is slowly added with syringe.0 DEG C of reaction 1 hour, with 2mL frozen water cancellation reaction, with dichloromethane extraction three times, each 10mL.Merge organic phase, use anhydrous Na 2sO 4drying, concentrated, obtaining target compound is yellow oil (immediately for next step synthesis).
Step 3) N-(the fluoro-4-of 3-(7-(3-(1-hydroxycyclopropyl) propoxy-) quinolyl-4 oxygen base) phenyl)-1,5-dimethyl-3-oxygen-2-phenyl-2,3-dihydro-1 h-pyrazole-4-carboxylic acid amides
By 3-(1-hydroxycyclopropyl) propyl Methanesulfonate (240mg, 1.2mmol) with N-(the fluoro-4-of 3-(7-hydroxyquinoline-4-base oxygen base) phenyl)-1,5-dimethyl-3-oxygen-2-phenyl-2,3-dihydro-1 h-pyrazole-4-carboxylic acid amides (300mg, 0.62mmol) be dissolved in 5mL N, in N-N,N-DIMETHYLACETAMIDE, then in reactant, add cesium carbonate (470mg, 2.4mmol).In stirring at room temperature after 12 hours, 40 DEG C of reactions 6 hours, to go out reaction with 20mL shrend, be extracted with ethyl acetate three times, each 40mL.Merge organic phase, use anhydrous Na 2sO 4drying, concentrated, residue purification by silica gel column chromatography, developping agent is ethyl acetate: normal hexane=5: 1, and obtaining target compound is white solid (68mg, 19%).
MS(ESI，pos.ion)m/z：583.1[M+1]；LC-MS Rt：4.129min.
1H NMR(400MHz，CDCl 3)：δ0.51(m，2H)，0.79(m，2H)，1.81(t，J＝8Hz，2H)，2.15(m，2H)，2.81(s，3H)，3.38(s，3H)，4.24(t，J＝8Hz，2H)，6.41(d，J＝4Hz，1H)，7.15-7.59(m，9)，7.91(m，1H)，8.27(d，J＝8Hz，1H)，8.58(d，J＝4Hz，1H)，10.87(s，1H)。
Step 4) 1-(3-(4-(4-(2,3-dimethyl-5-oxygen-1-phenyl-2,5-dihydro-1 h-pyrazole-4-carboxamide groups)-2-fluorophenoxy) quinoline-7-base oxygen base) propyl group) cyclopropyl 2-(tertbutyloxycarbonylamino) acetic ester
By N-(the fluoro-4-of 3-(7-(3-(1-hydroxycyclopropyl) propoxy-) quinolyl-4 oxygen base) phenyl)-1,5-dimethyl-3-oxygen-2-phenyl-2,3-dihydro-1 h-pyrazole-4-carboxylic acid amides (218mg, 0.374mmol), the tertiary oxygen carbonyl glycine of N-(133.4mg, 0.768mmol, and DMAP (7.03mg Alfa), 0.058mmol, Aladdin) be dissolved in 10mL methylene dichloride, at 0 DEG C, in reaction solution, add DCC (323.4mg, 1.54mmol, Aldrich).At room temperature stir and spend the night, filter, solid 10mL washed with dichloromethane twice.Merge organic phase, with the saturated NaHCO of 15mL 3solution and the water washing of 15mL saturated common salt.Anhydrous Na 2sO 4drying, concentrated, residue purification by silica gel column chromatography, developping agent sherwood oil: ethyl acetate=1: 6, obtaining target compound is yellow solid (160mg, 60%).
MS(ESI，pos.ion)m/z：740.2(M+1)；(ESI，nat.ion)m/z：738.3(M-1)；LC-MS Rt：4.902min。
Step 5) 1-(3-(4-(4-(2,3-dimethyl-5-oxygen-1-phenyl-2,5-dihydro-1 h-pyrazole-4-carboxamide groups)-2-fluorophenoxy) quinoline-7-base oxygen base) propyl group) cyclopropyl 2-Padil ester hydrochloride
By 1-(3-(4-(4-(2,3-dimethyl-5-oxygen-1-phenyl-2,5-dihydro-1 h-pyrazole-4-carboxamide groups)-2-fluorophenoxy) quinoline-7-base oxygen base) propyl group) cyclopropyl 2-(tertbutyloxycarbonylamino) acetic ester (160mg, 0.216mmol) be dissolved in 8mL ethyl acetate, the ethyl acetate solution (0.93mol/L, 5mL) of HCl is dripped in reactant.At room temperature stir 30 minutes, filter, solid 10mL ethyl acetate washes twice, and obtaining target compound is white solid (55mg, 40%).
MS(ESI，pos.ion)m/z：640.1(M+1)；(ESI，nat.ion)m/z：638.1(M-1)；LC-MS Rt：3.674min；
1H NMR(400MHz，CD 3OD：δ0.81-0.84(t，J＝8Hz，2H)，1.00-1.03(t，J＝8Hz，2H)，2.10-2.11(d，J＝2Hz，4H)，2.78(s，3H)，3.43(s，3H)，3.82(s，2H)，4.34-4.35(d，J＝2Hz，2H)，7.00-7.02(dd，J＝1Hz，J＝6Hz，1H)，7.44-7.48(m，4H)，7.52(d，J＝2Hz，1H)，7.58-7.66(m，4H)，8.03-8.07(dd，J＝2Hz，J＝12Hz，1H)，8.57-8.59(d，J＝10Hz，1H)，8.83-8.85(d，J＝6Hz，1H)。
Embodiment 72
1-((4-(4-(2,3-dimethyl-5-oxygen-1-phenyl-2,5-dihydro-1 h-pyrazole-4-carboxamide groups)-2-fluorophenoxy) quinoline-7-base oxygen base) methyl) cyclopropyl 2-Padil ester hydrochloride
Step 1) 2-(tetrahydrochysene-2H-pyrans-2-base oxygen base) ethyl acetate
2-hydroxyl ethyl acetate (2g, 20mmol, Aldrich) and DHP (3.2g, 40mmol, Alfa) are dissolved in 40mL methylene dichloride, then in reactant, slowly add PPTS (500mg, 2mmol, Aldrich).After at room temperature reacting 4 hours skies, reaction solution saturated common salt washing twice, each 20mL.Anhydrous Na 2sO 4drying, concentrated, residue purification by silica gel column chromatography, developping agent methylene dichloride: methyl alcohol=45: 1, developping agent sherwood oil: ethyl acetate=20: 1, obtaining target compound is colourless liquid (3.01g, 81%).
1H NMR(400MHz，CDCl 3)：δ1.22-1.38(m，4H)，1.55-1.63(m，3H)，1.69-1.88(m，3H)，3.50-3.53(m，1H)，3.82-3.88(m，1H)，4.18-4.23(m，4H)，4.73-4.74(t，J＝4Hz，1H)。
Step 2) 1-((tetrahydrochysene-2H-pyrans-2-base oxygen base) methyl) ring propyl alcohol
By 2-(tetrahydrochysene-2H-pyrans-2-base oxygen base) ethyl acetate (1g, 5.3mmol) and Ti (Oi-Pr) 4(1.06mL, 3.5mmol, Aldrich) is dissolved in 18mL THF.At 20 DEG C, in nitrogen, in two hours, in reaction solution, add EtMgBr (4.5mL, 13.25mmol, Aldrich) with syringe pump.Stir after two hours, with the saturated NH of 15mL 4the cancellation of Cl solution is reacted, and is extracted with ethyl acetate five times, each 20mL.Merge organic phase, use anhydrous Na 2sO 4drying, concentrated, residue purification by silica gel column chromatography, developping agent sherwood oil: ethyl acetate=5: 1, obtaining title compound is colourless liquid (500mg, 55%).
1H NMR(400MHz，CDCl 3)：δ0.55-0.85(m，4H)，1.55-1.65(m，4H)，1.74-1.87(m，2H)，3.50-3.55(m，2H)，3.79-3.82(m，1H)，3.93-3.98(m，2H)，4.64-4.66(m，1H)。
Step 3) 1-((tetrahydrochysene-2H-pyrans-2-base oxygen base) methyl) cyclopropaneacetic acid ester
By 1-((tetrahydrochysene-2H-pyrans-2-base oxygen base) methyl) ring propyl alcohol (172mg, 1mmol) with acetic acid (120mg, 2mmol, Xi Long chemical plant, Shantou) be dissolved in 2mL methylene dichloride, then in reactant, DMAP (12mg is added, 0.1mmol, Aladdin).At room temperature react after 30 minutes, at 0 DEG C, in reactant, add DCC (840mg, 4mmol, Aldrich).After 1-((tetrahydrochysene-2H-pyrans-2-base oxygen base) methyl) ring propyl alcohol has reacted (monitoring with TLC), filter, concentrated mother liquor, residue purification by silica gel column chromatography, developping agent sherwood oil: ethyl acetate=20: 1, obtaining target compound is yellow oil (130mg, 60.7%).
1H NMR(400MHz，CDCl 3)：δ0.46(m，2H)，0.75-0.93(m，4H)，1.49-1.82(m，6H)，2.01(s，2H)，3.46-3.49(t，J＝5Hz，1H)，3.73-3.76(d，J＝12Hz，1H)，3.82(m，2H)，3.85-3.88(d，J＝12Hz，1H)，4.63-4.65(t，J＝3Hz，1H)。
Step 4) 1-(methylol) cyclopropaneacetic acid ester
By 1-((tetrahydrochysene-2H-pyrans-2-base oxygen base) methyl) cyclopropaneacetic acid ester (149mg, 0.696mmol) be dissolved in 10mL methyl alcohol, then in reactant, PPTS (18mg, 0.07mmol, Aldrich) is slowly added.At room temperature stir 5 hours, to go out reaction with 10mL shrend, with dichloromethane extraction three times, each 20mL.Merge organic phase, use anhydrous Na 2sO 4drying, concentrated, residue purification by silica gel column chromatography, developping agent sherwood oil: ethyl acetate=10: 1, obtaining target compound is yellow oil (46mg, 35.5%).
1H NMR(400MHz，CDCl 3)：δ0.61-0.66(m，2H)，0.84-0.89(m，2H)，4.18(s，1H)。
Step 5) 3-(1-hydroxycyclopropyl) propyl Methanesulfonate
By 1-(methylol) cyclopropaneacetic acid ester (86mg, 0.843mmol) with triethylamine (136mg, 1.35mmol) be dissolved in 10mL methylene dichloride, stir 30 minutes at-10 DEG C, in reactant, methylsulfonyl chloride (106mg, 0.927mmol) is slowly added with syringe.-10 DEG C of reactions 1 hour, with 1mL frozen water cancellation reaction, with dichloromethane extraction three times, each 20mL.Merge organic phase, use anhydrous Na 2sO 4drying, concentrated, obtaining target compound is yellow oil (immediately for next step synthesis).
Step 6) 1-((4-(4-(1,5-dimethyl-3-oxygen-2-phenyl-2,3-dihydro-1 h-pyrazole-4-carboxamide groups)-2-fluorophenoxy) quinoline-7-base oxygen base) methyl) cyclopropaneacetic acid ester
By N-(the fluoro-4-of 3-(7-hydroxyquinoline-4-base oxygen base) phenyl)-1,5-dimethyl-3-oxygen-2-phenyl-2,3-dihydro-1 h-pyrazole-4-carboxylic acid amides (342mg, 0.708mmol) be dissolved in 5mL N with 3-(1-hydroxycyclopropyl) propyl Methanesulfonate (1.77mmol), in N-N,N-DIMETHYLACETAMIDE, then in reactant, cesium carbonate (2.8g, 8.85mmol) is added.Stir after 1 day at 40 DEG C, concentration of reaction solution, residue purification by silica gel column chromatography, developping agent methylene dichloride: methyl alcohol=50: 1, obtaining target compound is white solid (110mg, 26%).
MS(ESI，pos.ion)m/z：569.1(M+1)；(ESI，nat.ion)m/z：567.1(M-1)；LC-MS Rt：4.152min。
Step 7) N-(the fluoro-4-of 3-(7-((1-hydroxycyclopropyl) methoxyl group) quinolyl-4 oxygen base) phenyl)-1,5-dimethyl-3-oxygen-2-phenyl-2,3-dihydro-1 h-pyrazole-4-carboxylic acid amides
By 1-((4-(4-(1,5-dimethyl-3-oxygen-2-phenyl-2,3-dihydro-1 h-pyrazole-4-carboxamide groups)-2-fluorophenoxy) quinoline-7-base oxygen base) methyl) cyclopropaneacetic acid ester (110mg, 0.18mmo1) be dissolved in 8mL methyl alcohol, then in reactant, KOH (100mg, 1.78mmol) is added.At room temperature stir after 0.5 hour, filter, solid 10mL ethyl acetate washes twice, and obtaining title compound is white solid (100mg, 29%).
MS(ESI，pos.ion)m/z：555.1(M+1)；(ESI，nat.ion)m/z：553.1(M-1)；LC-MS Rt：3.765min；
1H NMR(400MHz，CDCl 3)：δ0.78-0.81(t，J＝5Hz，2H)，1.01-1.04(t，J＝5Hz，2H)，2.82(s，3H)，3.39(s，3H)，4.19(s，2H)，6.42-6.44(d，J＝5Hz，1H)，7.16-7.20(t，J＝8Hz，1H)，7.27-7.33(m，2H)，7.37-7.39(d，J＝9Hz，3H)，7.49-7.52(t J＝8Hz，，1H)，7.56-7.60(m，2H)，7.91-7.95(dd，J＝2Hz，J＝12Hz，1H)，8.29-8.31(d，J＝9Hz，1H)，8.59-8.60(d，J＝5Hz，1H)，10.92(s，1H)。
Step 8) 1-((4-(4-(2,3-dimethyl-5-oxygen-1-phenyl-2,5-dihydro-1 h-pyrazole-4-carboxamide groups)-2-fluorophenoxy) quinoline-7-base oxygen base) methyl) cyclopropyl 2-(tertbutyloxycarbonylamino) acetic ester
By N-(the fluoro-4-of 3-(7-((1-hydroxycyclopropyl) methoxyl group) quinolyl-4 oxygen base) phenyl)-1,5-dimethyl-3-oxygen-2-phenyl-2,3-dihydro-1 h-pyrazole-4-carboxylic acid amides (100mg, 0.18mm ol), N-carbobenzoxyglycine (63mg, 0.36mmol, and DMAP (3mg Alfa), 0.018mmol, Aladdin) be dissolved in 10mL methylene dichloride, at 0 DEG C, in reactant, add DCC (189mg, 0.9mmol, Aldrich).At room temperature stir and spend the night, filter, solid 10mL washed with dichloromethane twice.Merge organic phase, anhydrous Na 2sO 4drying, concentrated, residue purification by silica gel column chromatography, developping agent ethyl acetate: sherwood oil=1: 6, obtaining title compound is yellow solid (100mg, 78%).
MS(ESI，pos.ion)m/z：712.3(M+1)；(ESI，nat.ion)m/z：710.3(M-1)；LC-MS Rt：4.762min。
Step 9) 1-((4-(4-(2,3-dimethyl-5-oxygen-1-phenyl-2,5-dihydro-1 h-pyrazole-4-carboxamide groups)-2-fluorophenoxy) quinoline-7-base oxygen base) methyl) cyclopropyl 2-Padil ester hydrochloride
By 1-((4-(4-(2,3-dimethyl-5-oxygen-1-phenyl-2,5-dihydro-1 h-pyrazole-4-carboxamide groups)-2-fluorophenoxy) quinoline-7-base oxygen base) methyl) cyclopropyl 2-(tertbutyloxycarbonylamino) acetic ester (80mg, 0.112mmol) be dissolved in 8mL ethyl acetate, the ethyl acetate solution (0.93mol/L, 2mL) of HCl is dripped in reactant.At room temperature stir 30 minutes, filter, solid 10mL ethyl acetate washes twice, and obtaining target compound is white solid (11mg, 16%).
MS(ESI，pos.ion)m/z：612.2(M+1)；(ESI，nat.ion)m/z：610.2(M-1)；LC-MS Rt：3.639min；
1H NMR(400MHz，MeOD)：δ1.19-1.23(m，4H)，2.77(s，3H)，3.43(s，3H)，3.43(s，3H)，3.88(s，2H)，4.63(s，2H)，7.01-7.02(d，J＝6Hz，1H)，7.42-7.48(m，4H)，7.51-7.52(d，J＝2Hz，1H)，7.58-7.65(m，4H)，8.03-8.07(dd，J＝2Hz，J＝13Hz，1H)，8.57-8.60(d，J＝9Hz，1H)，8.85-8.86(d，J＝6Hz，1H)，10.96(s，1H)。
Embodiment 73
(R)-1-(4-(4-(6,7-dimethoxy-quinoline-4-base oxygen base)-3-Fluorophenylamino formyl radical)-5-methyl-3-oxygen-2-phenyl-2,3-pyrazoline-1-base) propane-2-base 2-Padil ester hydrochloride
Step 1) 5-((3,4-dimethoxyphenylaminocarbonyl) methyne)-2,2-dimethyl-1,3-dioxane-4,6-diketone are by 3,4-dimethoxyaniline (10g, 65mmol) and CH (OC 2h 5) 3(96.2g, 650mmol) adds in the round-bottomed flask of 500mL, stirred at ambient temperature 30 minutes.In reaction solution, add 2,2-dimethyl-1,3-dioxane-4,6-diketone (9.4g, 65mmol), react 3.5 hours at 90 DEG C.By reaction solution at-20 DEG C of left overnight.Filter, solid 50mL 2-methoxyl group-2-methylpropane washs three times.Finally obtaining target compound is buff powder (17.1g, 85.5%).
MS(ESI，pos.ion)m/z：637.2(M×2+23)；(ESI，nat.ion)m/z：635.2[(M-1)×2+23]；
LC-MS Rt：3.546min.
1H NMR(400MHz，d 6-DMSO)：δ1.09(d，J＝6.4Hz，3H)，2.87(s，3H)，3.84(dd，J＝4.4Hz，J＝15.2Hz，1H)，3.96(s，3H)，4.19(dd，J＝6.8Hz，J＝15.6Hz，1H)，4.29(m，1H)，6.49(d，J＝5.2Hz，1H)，7.28-7.35(m，3H)，7.47-7.62(m，6H)，7.93(d，J＝13.6Hz，1H)，8.29(d，J＝9.2Hz，1H)，8.53(d，J＝5.2Hz，1H)，11.06(s，1H)。
Step 2) 6,7-methoxy quinoline-4-alcohol
In the round-bottomed flask of 1000mL, add 1-phenoxy group benzene (100mL), after being heated to 230 DEG C, add 5-((3,4-dimethoxyaniline) methyne)-2 wherein, 2-dimethyl-1,3-dioxane-4,6-diketone (16.1g, 52mmol).React after 5 minutes, be cooled to 120 DEG C, in reaction solution, add normal hexane (100mL), stir after having solid to separate out and spend the night.Filter, solid with ethyl acetate/normal hexane (50mL, v/v=10/1) recrystallization.Obtain brown solid (10.2g, 95%).
Step 3) 4-(the fluoro-4-nitrophenoxy of 2-)-6,7-dimethoxy-quinolines
By 6,7-base phenoxyl quinoline-4-alcohol (50g, 0.244mol) and Cs 2cO 3(159g, 0.488mol) is dissolved in CH 3in the mixed solvent of CN (300mL)/DMF (300mL), stirring at room temperature 30 minutes.Then in reaction solution, 1,2-bis-furans-4-oil of mirbane (42.7g, 0.268mol) is dripped.Reaction solution, after 3.5 hours, concentrates by room temperature reaction.Add in concentrated solution by frozen water (500mL), placement is spent the night.Filter, solid purification by silica gel column chromatography, developping agent ethyl acetate, obtaining target compound is yellow solid powder (43.1mg, 51.2%).
MS(ESI，pos.ion)m/z：345.1(M+1)；LC-MS Rt：3.394min.
1H NMR(400MHz，CDCl 3)：δ4.04(s，3H)，4.07(s，3H)，6.56(d，J＝5.2Hz，1H)，7.35(t，1H)，7.45(d，J＝8.0Hz，1H)，8.14(d，J＝9.2Hz，1H)，8.20(dd，J＝2.4Hz，J＝9.6Hz，1H)，8.59(d，J＝4.8Hz，1H)。
Step 4) 4-(6,7-methoxy quinoline-4-base oxygen base)-3-fluoroaniline
By 4-(the fluoro-4-nitrophenoxy of 2-)-6,7-dimethoxy-quinoline (16.0g, 0.046mol) and NH 4cl (6.0g, 0.11mol) is dissolved in ethanol/water, and (150mL, v/v=4: in mixed solvent 1), then add Fe powder (12.4g, 0.22mol).Room temperature reaction, after two hours, adds diatomite (10g) and continues stirring 30 minutes.Filter, solids with methanol (20mL × 3) and methylene dichloride (20mL × 3) washing.Merge organic phase, use saturated NaHCO 3solution washing, then aqueous phase uses methylene dichloride (20mL × 3) to extract again.Merge organic phase, wash with saturated aqueous common salt (20mL × 3).Anhydrous Na 2sO 4drying, concentrated, obtaining target compound is yellow solid (9g, 98%).MS(ESI，pos.ion)m/z：315.1(M+1)；(ESI，nat.ion)m/z：313.2(M-1)；LC-MS Rt：2.919min；
1H NMR(400MHz，CDCl 3)：δ4.05(s，3H)，4.07(s，3H)，6.41(d，J＝5.2Hz，1H)，6.51(dd，J＝2.4Hz，J＝8.8Hz，1H)，6.57(dd，J＝2.4Hz，J＝11.6Hz，1H)，7.04(t，1H)，7.42(s，1H)，7.60(s，1H)，8.48(d，J＝5.2Hz，1H)。
Step 5) (R)-N-(4-(6,7-dimethoxy-quinoline-4-base oxygen base)-3-fluorophenyl)-1-(2-hydroxypropyl)-5-methyl-3-oxygen-2-phenyl-2,3-dihydro-1 h-pyrazole-4-carboxylic acid amides
By 4-(6,7-methoxy quinoline-4-base oxygen base)-3-fluoroaniline (5.0g, 0.016mol) with (R)-1-(2-hydroxypropyl)-5-methyl-3-oxygen-2-phenyl-2,3-dihydro-1 h-pyrazole-4-carboxylic acid (6.2g, 0.022mol) be dissolved in methylene dichloride (100mL), at 0 DEG C, triethylamine (5.5g is added in reaction solution, 0.054mol) with HATU (10.3g, 0.027mol), react after two hours, continue to spend the night at room temperature reaction.Reaction solution use water (30mL × 3) washs.Merge organic phase, anhydrous Na 2sO 4drying, concentrated, it is yellow solid (7.8mg, 85.2%) that residue with ethyl acetate/normal hexane recrystallization obtains target compound.
MS(ESI，pos.ion)m/z：573.3(M+1)；(ESI，nat.ion)m/z：571.2(M-1)；LC-MS Rt：3.753min。
1H NMR(400MHz，CDCl 3)：δ1.21(d，J＝5.4Hz，3H)，2.88(s，3H)，3.75(d，J＝3.2Hz，1H)，3.85(m，1H)，4.05(s，3H)，4.07(s，3H)，4.11(t，1H)，6.58(d，J＝5.6Hz，1H)，7.19(t，1H)，7.34(m，2H)，7.44(m，2H)，7.54(m，3H)，7.60(s，1H)，7.95(dd，J＝2.0Hz，J＝12.4Hz，1H)，8.49(d，J＝6.0Hz，1H)，10.91(s，1H)。
Step 6) (R)-1-(4-(4-(6, 7-dimethoxy-quinoline-4-base oxygen base)-3-Fluorophenylamino formyl radical)-5-methyl-3-oxygen-2-phenyl-2, 3-pyrazoline-1-base) propane-2-base-2-(tertbutyloxycarbonylamino) acetic ester is by (R)-N-(4-(6, 7-dimethoxy-quinoline-4-base oxygen base)-3-fluorophenyl)-1-(2-hydroxypropyl)-5-methyl-3-oxygen-2-phenyl-2, 3-dihydro-1 h-pyrazole-4-carboxylic acid amides (2.0g, 3.5mmol), N-Boc-glycine (1.23g, 7.0mmol) with DMAP (0.86g, 7.0mmol) be dissolved in 45mL methylene dichloride, at 0 DEG C, EDC (2.02mg is added in reactant, 10.5mmol).Stir after two hours, continue at room temperature to stir to spend the night.Add methylene dichloride (50mL), with the 0.5N HCl aqueous solution (20mL), saturated NaHCO 3solution (20mL), and saturated aqueous common salt (20mL) washing.Anhydrous Na 2sO 4drying, concentrated, residue purification by silica gel column chromatography, developping agent normal hexane: ethyl acetate=1: 1 to 1: 8, obtaining target compound is white solid (2.43mg, 95.2%).
MS(ESI，pos.ion)m/z：730.3(M+1)；(ESI，nat.ion)m/z：728.3(M-1)；LC-MS Rt：4.534min；
1H NMR(400MHz，CDCl 3)：δ1.14(d，J＝6.4Hz，3H)，1.434(s，9H)，2.86(s，3H)，3.69(dd，J＝5.2Hz，J＝17.6Hz，1H)，3.84(m，2H)，4.02(d，J＝9.6Hz，1H)，4.05(s，3H)，4.07(s，3H)，4.11(t，1H)，5.02(s，1H)，6.43(d，J＝5.2Hz，1H)，7.18(t，1H)，7.30(d，J＝8.4Hz，1H)，7.38(d，J＝7.6Hz，2H)，7.42(s，1H)，7.49(t，1H)，7.58(m，3H)，7.92(d，J＝12.4Hz，1H)，8.49(d，J＝4.8Hz，1H)，10.82(s，1H)。
Step 7) (R)-1-(4-(4-(6; 7-dimethoxy-quinoline-4-base oxygen base)-3-Fluorophenylamino formyl radical)-5-methyl-3-oxygen-2-phenyl-2,3-pyrazoline-1-base) propane-2-base 2-Padil ester hydrochloride
By (R)-1-(4-(4-(6; 7-dimethoxy-quinoline-4-base oxygen base)-3-Fluorophenylamino formyl radical)-5-methyl-3-oxygen-2-phenyl-2; 3-pyrazoline-1-base) propane-2-base-2-(tertbutyloxycarbonylamino) acetic ester (100mg; 0.137mmol) be dissolved in 15mL ethyl acetate, in reactant, drip the ethyl acetate solution of the saturated HCl of 3mL.At room temperature stir and spend the night.Filter, (20mL, v/v=1: 5) after recrystallization, filter, then use ethyl acetate (5mL × 3) to wash, it is white solid (87.9mg, 96.5%) that vacuum-drying obtains target compound to solids with methanol/ethyl acetate.
MS(ESI，pos.ion)m/z：630.3(M+1)；(ESI，nat.ion)m/z：628.2(M-1)；LC-MS Rt：3.323min。
1H NMR(400MHz，CDCl 3)：δ1.09(d，J＝6.4Hz，3H)，2.78(s，3H)，3.55(dd，J＝3.6Hz，J＝9.6Hz，1H)，3.82(m，2H)，3.97(d，J＝2.4Hz，1H)，4.04(s，3H)，4.05(s，3H)，4.35(m，1H)，4.89(s，1H)，6.98(d，J＝6.4Hz，1H)，7.44(dd，J＝1.2Hz，J＝7.2Hz，3H)，7.56(t，2H)，7.62(m，2H)，7.73(s，1H)，7.76(s，1H)，8.07(dd，J＝2.4Hz，J＝12.8Hz，1H)，8.63(d，J＝6.8Hz，1H)，10.95(s，1H)。
Embodiment 74
(S)-((R)-1-(4-(4-(6; 7-dimethoxy-quinoline-4-base oxygen base)-3-Fluorophenylamino formyl radical)-5-methyl-3-oxygen-2-phenyl-2,3-pyrazoline-1-base) propane-2-base) 2-alanine ester hydrochloride
Step 1) (S)-((R)-1-(4-(4-(6, 7-dimethoxy-quinoline-4-base oxygen base)-3-Fluorophenylamino formyl radical)-5-methyl-3-oxygen-2-phenyl-2, 3-pyrazoline-1-base) propane-2-base) 2-(benzyloxycarbonyl amino) propionic ester target compound can by step 6 in embodiment 73) and method synthesis, used reagent has (R)-N-(4-(6, 7-dimethoxy-quinoline-4-base oxygen base)-3-fluorophenyl)-1-(2-hydroxypropyl)-5-methyl-3-oxygen-2-phenyl-2, 3-dihydro-1 h-pyrazole-4-carboxylic acid amides (4.1g, 7.2mmol), (S)-N-Cbz-L-Ala (3.2g, 14.4mmol), obtaining target compound is white powder (4.2g, 75.1%).
1H NMR(400MHz，d 6-DMSO)：δ1.14(d，J＝6.4Hz，3H)，1.39(d，J＝6.6Hz，3H)，2.86(s，3H)，3.84(dd，J＝5.2Hz，J＝17.6Hz，1H)，4.03(s，3H)，4.05(s，3H)，4.07(d，J＝9.6Hz，1H)，4.11(t，1H)，4.97(s，1H)，5.06(s，2H)，5.22(d，J＝7.2Hz，1H)，6.40(dd，J＝0.8Hz，J＝6.0Hz，1H)，7.16(t，1H)，7.22(dd，J＝2.8Hz，J＝12Hz，1H)，7.27(t，2H)，7.35(m，5H)，7.41(m，1H)，7.47(m，1H)，7.55(m，2H)，7.90(dd，J＝2.0Hz，J＝14.4Hz，1H)，8.28(d，J＝9.2Hz，1H)，8.66(d，J＝5.2Hz，1H)，10.81(s，1H)。
Step 2) (S)-((R)-1-(4-(4-(6; 7-dimethoxy-quinoline-4-base oxygen base)-3-Fluorophenylamino formyl radical)-5-methyl-3-oxygen-2-phenyl-2,3-pyrazoline-1-base) propane-2-base) 2-aminopropan acid esters
By (S)-((R)-1-(4-(4-(6; 7-dimethoxy-quinoline-4-base oxygen base)-3-Fluorophenylamino formyl radical)-5-methyl-3-oxygen-2-phenyl-2; 3-pyrazoline-1-base) propane-2-base) 2-(benzyloxycarbonyl amino) propionic ester (200mg; 0.257mmol) be dissolved in ethyl acetate (15mL) and methyl alcohol (10mL); then in reactant, add the Pd/C (10% of catalytic amount; ~ 55%w/w water content, 20mg).Be filled with hydrogen again by after the air removing in reaction system, at room temperature stir 20 minutes.Filter, solids with methanol washing (5mL × 3), mother liquor will be used for next step reaction immediately.
Step 3) (S)-((R)-1-(4-(4-(6; 7-dimethoxy-quinoline-4-base oxygen base)-3-Fluorophenylamino formyl radical)-5-methyl-3-oxygen-2-phenyl-2,3-pyrazoline-1-base) propane-2-base) 2-alanine ester hydrochloride
The synthesis of target compound can the synthetic method of reference example 7; used reagent has (S)-((R)-1-(4-(4-(6; 7-dimethoxy-quinoline-4-base oxygen base)-3-Fluorophenylamino formyl radical)-5-methyl-3-oxygen-2-phenyl-2; 3-pyrazoline-1-base) propane-2-base) 2-aminopropan acid esters (165.3mg; 0.257mmol) and the ethyl acetate solution (5mL) of saturated HCl; obtaining target compound is white powder (160.2mg, 87.5%).
1H NMR(400MHz，d 6-DMSO)：δ1.11(d，J＝5.2Hz，3H)，1.35(d，J＝6.4Hz，3H)，2.84(s，3H)，3.82(dd，J＝6.4Hz，J＝14.4Hz，1H)，4.01(s，3H)，4.03(s，3H)，4.07(d，J＝8.8Hz，1H)，4.10(t，1H)，5.01(s，1H)，5.22(d，J＝3.6Hz，1H)，6.40(dd，J＝0.8Hz，J＝6.0Hz，1H)，7.16(t，1H)，7.22(dd，J＝2.8Hz，J＝12Hz，1H)，7.27(t，2H)，7.41(m，1H)，7.47(m，1H)，7.55(m，2H)，7.90(dd，J＝2.0Hz，J＝14.4Hz，1H)，8.28(d，J＝9.2Hz，1H)，8.66(d，J＝5.2Hz，1H)，10.85(s，1H)。
Embodiment 75
(R)-1-(4-(5-(7-methoxy quinoline-4-base oxygen base) pyridine-2-base formamyl)-5-methyl-3-oxygen-2-phenyl-2,3-pyrazoline-1-base) propane-2-base 2-Padil ester hydrochloride
Step 1) (R)-1-(4-(5-(7-methoxy quinoline-4-base oxygen base) pyridine-2-base formamyl)-5-methyl-3-oxygen-2-phenyl-2,3-pyrazoline-1-base) propane-2-base 2-(tertbutyloxycarbonylamino) acetic ester
The synthesis of target compound can step 6 in reference example 73) synthetic method, used reagent has (R)-1-(2-hydroxypropyl)-N-(6-(7-methoxy quinoline-4-base oxygen base) pyridin-3-yl)-5-methyl-3-oxygen-2-phenyl-2,3-dihydro-1 h-pyrazole-4-carboxylic acid amides (4.2g, 7.9mmol), N-Boc-glycine (2.77g, 15.8mmol, Shanghai Han Hong Chemical Company), the target compound obtained is yellow solid (4.32g, 80.2%).
1H NMR(400MHz，CDCl 3)：δ1.14(d，J＝6.4Hz，3H)，1.43(s，9H)，3.85(s，3H)，3.67(dd，J＝4.8Hz，J＝18.4Hz，1H)，3.81(dd，J＝4.0Hz，J＝15.6Hz，1H)，3.89(dd，J＝6.8Hz，J＝18.8Hz，1H)，3.98(s，3H)，4.04(dd，J＝8.8Hz，J＝24.4Hz，1H)，5.01(m，1H)，6.43(d，J＝5.2Hz，1H)，7.23(dd，J＝2.4Hz，J＝8.8Hz，1H)，7.37(dd，J＝1.2Hz，J＝7.2Hz，2H)，7.42-7.48(t，2H)，7.49-7.58(t，3H)，8.24(dd，J＝2.4Hz，J＝5.2Hz，2H)，8.37(d，J＝8.8Hz，1H)，8.60(d，J＝5.2Hz，1H)，11.19(s，1H)。
Step 2) (R)-1-(4-(5-(7-methoxy quinoline-4-base oxygen base) pyridine-2-base formamyl)-5-methyl-3-oxygen-2-phenyl-2,3-pyrazoline-1-base) propane-2-base 2-Padil ester hydrochloride
The synthesis of target compound can the synthetic method of reference example 7; used reagent has (R)-1-(4-(5-(7-methoxy quinoline-4-base oxygen base) pyridine-2-base formamyl)-5-methyl-3-oxygen-2-phenyl-2; 3-pyrazoline-1-base) propane-2-base 2-(tertbutyloxycarbonylamino) acetic ester (100mg; 0.146mmol) and the ethyl acetate solution (3mL) of saturated HCl; be white solid (84.2mg, 93.1%) with obtaining target compound after methanol/ethyl acetate recrystallization.
1H NMR(400MHz，d 6-DMSO)：δ1.09(d，J＝6.0Hz，3H)，2.80(s，3H)，3.79(dd，J＝5.2Hz，J＝17.6Hz，1H)，4.00(s，2H)，4.04(s，3H)，4.30(dd，J＝9.2Hz，J＝16.4Hz，1H)，4.89(s，1H)，7.01(d，J＝6.8Hz，1H)，7.44(d，J＝7.6Hz，2H)，7.55(t，2H)，7.63(t，3H)，7.74(s，1H)，7.97(d，J＝8.4Hz，1H)，8.43-8.52(m，2H)，8.99(d，J＝6.4Hz，1H)，11.28(s，1H)。
Embodiment 76
1-(N-(4-(7-(3-(7-hydroxyl-5-azaspiro [2.4] heptane-5-base) propoxy-)-6-methoxy quinoline-4-base oxygen base)-3-fluorophenyl)-N-(4-fluorophenyl) cyclopropane-1,1-dicarboxamide)-2-Padil ester hydrochloride
Step 1) 1-acetylcyclopropane carboxylic acid, ethyl ester
Methyl aceto acetate (26g, 200mmol) is dissolved in 500mL acetone, adds salt of wormwood (82.8g, 600mmol) and glycol dibromide (45.12g, 240mmol) in turn.After reaction mixture refluxed reacts 24 hours, filter, filtrate decompression distilled, it is colorless oil (18.7g, 60%) that gained residue obtains title compound through purification by silica gel column chromatography (1: 50 (v/v) ethyl acetate/normal hexane).
MS(ESI，pos.ion)m/z：157(M+1)；
1H NMR(400MHz，CDCl 3)：δ1.25-1.29(t，J＝7.2Hz，3H)，1.45(s，4H)，2.45(s，3H)，4.18-4.20(q，2H)。
Step 2) ethyl 1-(2-acetyl bromide) cyclopropanecarboxylcompound
Add 1-ethanoyl-ethyl cyclopropane dicarboxylate (15.6g, 100mmol) and NBS solid (21.36g, 120mmol) in flask at the bottom of 100mL garden, then add tosic acid (1.9g, 10mmol).Stirred at ambient temperature reacts 8 hours, and reaction mixture, through ether (200mL) extraction, then uses 80mL water washing.The organic phase merged is through anhydrous Na 2sO 4drying, filters, and filtrate decompression distilled, gained residue is through silica gel column chromatography (1: 30 (v/v) ethyl acetate/normal hexane) purifying, and obtaining title compound is colorless oil (16.68g, 71%).
MS(ESI，pos.ion)m/z：235，237(M+1)；
1H NMR(400MHz，CDCl 3)：δ1.27(t，J＝7.2Hz，3H)，1.59-1.64(m，4H)，4.19-4.24(q，J 1＝14.4Hz，J 2＝7.2Hz，2H)，4.49(s，2H)。
Step 3) 5-((R)-α-methylbenzyl)-4,7-dioxy-5-azaspiro [2.4] heptane
(R)-α-methylbenzyl amine (2.9g, 24mmol) and Et is added in THF (60mL) solution being dissolved with 1-(2-acetyl bromide) ethyl cyclopropane dicarboxylate (4.7g, 20mmol) 3n (4.04g, 40mmol).After stirred at ambient temperature reacts 3 days, by reaction mixture underpressure distillation, gained residue, through ethyl acetate (50mL × 2) extraction, then washes (30mL).The organic phase merged is through anhydrous Na 2sO 4drying, filters, and filtrate decompression is distilled, and it is yellow solid (3.66g, 80%) that gained residue obtains target compound through silica gel column chromatography (EtOAc) purifying.
MS(ESI，pos.ion)m/z：230(M+1)；
1H NMR(400MHz，CDCl 3)：δ1.58-1.60(m，4H)，1.62-1.63(d，J＝5.6Hz，3H)，3.49-3.53(d，J＝17.6Hz，1H)，3.83-3.88(d，J＝17.6Hz，1H)，5.80-5.82(q，1H)，7.26-7.39(m，5H)。
Step 4) 5-((R)-α-methylbenzyl)-7-hydroxyl-5-azaspiro [2.4] heptane
By LiAlH 4(0.995g, 26.2mmol) be suspended in THF (40mL), at 0 DEG C, add 5-((R)-α-methylbenzyl)-4 wherein, THF (10mL) solution of 7-dioxy-5-azaspiro [2.4] heptane (3.0g, 13.1mmol), reaction mixture reacts 2 hours at 0 DEG C, then be warming up to 50 DEG C, continue stirring reaction 6 hours.Then reaction mixture is cooled to 0 DEG C, adds EtOAc (10mL) and H wherein 2o (10mL).Filtered by suspended substance, and filtrate decompression distilled, it is colorless oil (2.4g, 85%) that gained residue obtains target compound through silica gel column chromatography (1: 3 (v/v) 2-butanols/normal hexane) purifying.
MS(ESI，pos.ion)m/z：218(M+1)。
Step 5) 7-hydroxyl-5-azaspiro [2.4] heptane
5-((R)-α-methylbenzyl)-7-hydroxyl-5-azaspiro [2.4] heptane (2.4g, 11.1mmol) is dissolved in the ethanol of 30mL, adds the Pd/C of catalytic amount wherein.Suspension stirring reaction after 3 hours under a hydrogen atmosphere, by suspension filtered, and filtrate decompression distillation is obtained target compound is light orange oil (1.23g, 98%).The thick product of gained, without the need to purifying, is directly used in next step reaction.
MS(ESI，pos.ion)m/z：114(M+1)。
Step 6) 4-(7-(benzyloxy)-6-methoxy quinoline-4-base oxygen base)-3-Fluorophenylamino t-butyl formate is by NaH (184mg, 7.68mmol) be suspended in THF (20mL), and add 4-(7-(benzyloxy)-6-methoxy quinoline-4-base oxygen base)-3-fluoroaniline (1g, 2.56mmol) wherein.After stirred at ambient temperature reacts 10 minutes, add wherein (Boc) 2o (1.14mg, 5.12mol), continues at room temperature stirring reaction 36 hours.Then add 2mL shrend to go out reaction, pressure reducing and steaming solvent, adds CH in residue 2cl 2(20mL) with water (10mL), organic phase is separated, and uses anhydrous Na 2sO 4drying, filters, and filtrate decompression is distilled, and gained residue is through silica gel column chromatography (v/v ethyl acetate: normal hexane=1: 5) purifying obtains target compound is pale yellow foam (800mg, 64%).
MS(ESI，pos.ion)m/z：491.2(M+1)；LC-MS Rt：3.475min；
1H-NMR(400MHz，CDCl 3)：δ1.541(s，9H)，4.066(s，3H)，5.330(s，2H)，6.370-6.383(d，J＝5.2Hz，1H)，7.076-7.097(d，J＝8.4Hz，1H)，7.148-7.191(t，J＝8.4Hz，1H)，7.270(s，1H)，7.323-7.359(t，J＝7.2Hz，1H)，7.375-7.412(t，J＝7.2Hz，1H)，7.455(s，1H)，7.508-7.527(d，J＝7.6Hz，2H)，7.549-7.582(d，J＝13.2Hz，1H)，7.601(s，1H)，8.448-8.461(d，J＝5.2Hz，1H)。
Step 7) the fluoro-4-of 3-(7-hydroxyl-6-methoxy quinoline-4-base oxygen base) phenylcarbamate adds the Pd/C of catalytic amount in ethanol (50mL) solution of 4-(7-(benzyloxy)-6-methoxy quinoline-4-base oxygen base)-3-Fluorophenylamino t-butyl formate (800mg, 1.632mmol).Suspension stirring reaction 3 hours under room temperature under nitrogen atmosphere, then filters reaction mixture, and filtrate decompression distillation is obtained target compound is light green solid (650mg, 99%).
MS(ESI，pos.ion)m/z：401.2(M+1)；LC-MS Rt：3.097min；
1H-NMR(400MHz，d-DMSO)：δ1.499(s，9H)，3.954(s，3H)，6.328-6.341(d，J＝5.2Hz，1H)，7.285(s，1H)，7.321-7.334(d，J＝5.2Hz，1H)，7.348-7.391(t，J＝8.4Hz，1H)，7.506(s，1H)，7.631-7.665(d，J＝13.6Hz，1H)，8.391-8.404(d，J＝5.2Hz，1H)，9.763(s，1H)，10.175(s，1H)。
Step 8) the fluoro-4-of 3-(7-(3-hydroxy propyloxy group)-6-methoxy quinoline-4-base oxygen base) phenylcarbamate is by fluoro-for 3-4-(7-hydroxyl-6-methoxy quinoline-4-base oxygen base) phenylcarbamate (400mg, 1mmol) be dissolved in DMF (4mL), add K wherein 2cO 3(276mg, 2mmol) and 3-N-PROPYLE BROMIDE-1-alcohol (154mg, 1.1mmol), stirred at ambient temperature reaction is spent the night.Removal of solvent under reduced pressure, then adds water (10mL) and CH in residue 2cl 2(20mL), organic phase is separated, and by the organic phase of merging through anhydrous Na 2sO 4drying, filters, and filtrate decompression is distilled, and it is light yellow solid (300mg, 65%) that gained residue obtains target compound through purification by silica gel column chromatography (ethyl acetate is to 10% methanol in ethyl acetate).
MS(ESI，pos.ion)m/z：459.2(M+1)；LC-MS Rt：3.021min；
1H-NMR(400MHz，CDCl 3)：δ1.531(s，9H)，2.159-2.215(m，2H)，3.925-3.953(t，J＝5.6Hz，J 2＝5.2Hz，2H)，3.999(s，3H)，4.360-4.389(t，J 1＝5.6Hz，J 2＝6.0Hz，2H)，6.363-6.377(d，J＝5.6Hz，1H)，6.961(s，1H)，7.066-7.080(d，J＝5.6Hz，1H)，7.144-7.187(t，J＝4.8Hz，1H)，7.395(s，1H)，7.528(s，1H)，7.555-7.586(d，J＝12.4Hz，1H)，8.438-8.451(d，J＝5.2Hz，1H)。
Step 9) 3-(4-(4-(tert-butoxycarbonyl)-2-fluorophenoxy)-6-methoxy quinoline-7-base oxygen base) propyl Methanesulfonate
By fluoro-for 3-4-(7-(3-hydroxy propyloxy group)-6-methoxy quinoline-4-base oxygen base) phenylcarbamate and Et 3n is dissolved in CH 2cl 2in, be cooled to 0 DEG C, slowly drip the CH of MsCl 2cl 2solution, and at 0 DEG C stirring reaction 1 hour.Reaction mixture through washing, gained organic phase anhydrous Na 2sO 4drying, it is light yellow solid (351mg) that underpressure distillation obtains title compound.Gained compound, without the need to purifying, is directly used in next step reaction.
MS(ESI，pos.ion)m/z：537.2(M+1)；LC-MS Rt：3.285min。
Step 10) the fluoro-4-of 3-(7-N-(4-(7-(3-(7-hydroxyl-5-azaspiro [2.4] heptane-5-base) propoxy-)-6-methoxy quinoline-4-base oxygen base)) phenylcarbamic acid butyl ester
By 3-(4-(4-(tert-butoxycarbonyl)-2-fluorophenoxy)-6-methoxy quinoline-7-base oxygen base) propyl Methanesulfonate (351mg, 0.655mmol) be dissolved in DMA (4mL), add 7-hydroxyl-5-azaspiro [2.4] heptane (110mg, 0.982mmol) and Cs wherein 2cO 3(975mg, 3mmol).Reaction mixture is heated to 40 DEG C of reactions 24 hours, pressure reducing and steaming solvent, then adds CHCl in residue 3(30mL) with water (15mL), organic phase is separated, by the organic phase of merging through anhydrous Na 2sO 4drying, filters, and filtrate decompression is distilled, and it is light yellow solid (180mg, 50%) that the residue obtained obtains title compound through silica gel column chromatography (ethyl acetate solution of ethyl acetate to 20% ethanol) purifying.
MS(ESI，pos.ion)m/z：554.3(M+1)；LC-MS Rt：2.782min；
1H-NMR(400MHz，CDCl 3)：δ0.661-0.748(m，2H)，0.781-0.830(m，1H)，1.040-1.089(m，1H)，1.542(s，9H)，2.267-2.300(m，2H)，2.726-2.751(d，J＝10Hz，1H)，3.023-3.063(m，2H)，3.075-3.131(dd，J 1＝14.8Hz，J 2＝7.6Hz，1H)，3.282-3.298(d，J＝6.4Hz，1H)，3.306-3.323(d，J＝6.8Hz，1H)，3.852-3.863(d，J＝4.4Hz，1H)，4.028(s，3H)，4.282-4.348(m，2H)，6.374-6.388(d，J＝5.6Hz，1H)，6.948(s，1H)，7.096-7.118(d，J＝8.8Hz，1H)，7.152-7.192(t，J＝8.4Hz，1H)，7.534(s，1H)，7.565-7.601(d，J＝14.4Hz，2H)，8.437-8.450(d，J＝5.2Hz，1H)。
Step 11) the fluoro-4-of 3-(7-N-(4-(7-(3-(7-hydroxyl-5-azaspiro [2.4] heptane-5-base) propoxy-)-6-methoxy quinoline-4-base oxygen base)) aniline
By fluoro-for 3-4-(7-N-(4-(7-(3-(7-hydroxyl-5-azaspiro [2.4] heptane-5-base) propoxy-)-6-methoxy quinoline-4-base oxygen base)) phenylcarbamate (100mg, 0.18mmol) be suspended in EtOAc (1mL), add HCl/EtOAc (3mol/L wherein, 1mL), suspension at room temperature stirring reaction 3 hours.Then reaction mixture underpressure distillation being obtained title compound is white solid (110mg, 100% (hydrochloride)).
MS(ESI，pos.ion)m/z：454.2(M+1)；LC-MS Rt：2.341min。
Step 12) N-(4-(7-(3-(7-hydroxyl-5-azaspiro [2.4] heptane-5-base) propoxy-)-6-methoxy quinoline-4-base oxygen base)-3-fluorophenyl)-N-(4-fluorophenyl) cyclopropane-1,1-bis-carboxamide
By fluoro-for 3-4-(7-N-(4-(7-(3-(7-hydroxyl-5-azaspiro [2.4] heptane-5-base) propoxy-)-6-methoxy quinoline-4-base oxygen base)) aniline (52mg; 0.115mmol) with 1-(4-Fluorophenylamino formyl radical) cyclopropane-carboxylic acid (27mg; 0.12mmol) be dissolved in DCM (2mL); at room temperature; add HOAt (3.2mg wherein; 0.023mmol) with HATU (33mg; 0.17mmol), 2 hours are reacted in stirred at ambient temperature.Reaction mixture is washed through water (25mL), and the organic phase obtained is through anhydrous Na 2sO 4drying, filters, and filtrate decompression is distilled, and it is yellow solid (38mg, 50%) that the residue obtained obtains title compound through silica gel column chromatography.
MS(ESI，pos.ion)m/z：659(M+1)；
1H NMR(400MHz，CDCl 3)：δ0.58-0.66(m，2H)，0.74-0.78(m，1H)，0.95-1.00(m，1H)，1.62-1.65(q，J 1＝7.6Hz，J 2＝8.4Hz，J 3＝4.4Hz，J 4＝5.2Hz，2H)，1.79-1.82(q，J 1＝7.2Hz，J 2＝8.4Hz，J 3＝4.4Hz，J 4＝5.6Hz，2H)，2.05-2.16(m，2H)，2.39-2.42(d，J＝8.8Hz，1H)，2.68-2.77(m，2H)，2.80-2.83(dd，J 1＝J 2＝10Hz，J 3＝J 4＝4.8Hz，1H)，2.96-2.98(d，J＝8.8Hz，1H)，3.03-3.05(d，J＝10Hz，1H)，3.74-3.75(d，J＝3.6Hz，1H)，4.04(s，3H)，4.30-4.31(m，2H)，6.38-6.39(d，J＝5.6Hz，1H)，7.05-7.08(d，J＝6.4Hz，2H)，7.19-7.23(t，J 1＝J 2＝8.4Hz，1H)，7.27-7.29(d，J＝9.6Hz，1H)，7.41-7.47(q，J 1＝J 2＝6.8Hz，J 3＝J 4＝4.8Hz，1H)，7.56(s，1H)，7.69(s，1H)，7.75-7.78(dd，J 1＝J 2＝12Hz，J 3＝J 4＝2.4Hz，1H)，8.38(s，1H)，8.44-8.46(d，J＝5.6Hz，1H)。
Step 13) 1-(N-(4-(7-(3-(7-hydroxyl-5-azaspiro [2.4] heptane-5-base) propoxy-)-6-methoxy quinoline-4-base oxygen base)-3-fluorophenyl)-N-(4-fluorophenyl) cyclopropane-1,1-dicarbamoyl base)-2-(tertbutyloxycarbonylamino) acetic ester
N-(4-(7-(3-(7-hydroxyl-5-azaspiro [2.4] heptane-5-base) propoxy-)-6-methoxy quinoline-4-base oxygen base)-3-fluorophenyl)-N-(4-fluorophenyl) cyclopropane-1 is added respectively in DCM (2mL), 1-bis-carboxamide (100mg, 0.152mmol), glycine (the 40mg of Boc protection, 0.228mmo, Shanghai Hai Qu Chemical Co., Ltd.) and DMAP (10mg, 0.076mmol, Shanghai Hai Qu Chemical Co., Ltd.), and then add EDCI (43.6mg, 0.228mmol, Shanghai Hai Qu Chemical Co., Ltd.).Stirred at ambient temperature reacts 2 hours, then in reaction solution, adds CH 2cl 2(15mL), and wash with water (10mL), the organic phase obtained is through anhydrous Na 2sO 4drying, filter, and by filtrate decompression evaporate to dryness, it is white solid (50mg, 40%) that the residue obtained obtains target compound through silica gel column chromatography.
MS(ESI，pos.ion)m/z：816.4(M+1)；LC-MS Rt：3.334min；
1H NMR(400MHz，CDCl 3)：δ0.68(m，2H)，0.87(m，2H)，1.44(s，9H)，1.63(m，2H)，1.80(m，2H)，2.16(m，2H)，2.53(d，J＝3.0Hz，1H)，2.78(m，2H)，2.93(d，J＝2.8Hz，2H)，3.18(s，1H)，3.92(d，J＝5.6Hz，2H)，4.02(s，3H)，4.26(m，2H)，4.93(d，J＝3.6Hz，1H)，6.38(d，J＝5.2Hz，1H)，7.06(m，2H)，7.21(t，J＝8.8Hz，1H)，7.45(m，3H)，7.55(s，1H)，7.74-7.78(dd，J 1＝2.4Hz，J 2＝2.4Hz，1H)，8.33(s，1H)，8.46(d，J＝5.6Hz，1H)，10.04(s，1H)。
Step 14) 1-(N-(4-(7-(3-(7-hydroxyl-5-azaspiro [2.4] heptane-5-base) propoxy-)-6-methoxy quinoline-4-base oxygen base)-3-fluorophenyl)-N-(4-fluorophenyl) cyclopropane-1,1-dicarbamoyl base)-2-Padil ester hydrochloride
By 1-(N-(4-(7-(3-(7-hydroxyl-5-azaspiro [2.4] heptane-5-base) propoxy-)-6-methoxy quinoline-4-base oxygen base)-3-fluorophenyl)-N-(4-fluorophenyl) cyclopropane-1; 1-dicarbamoyl base)-2-(t-butoxycarbonyl amino) acetic ester (50mg; 0.06mmol) be dissolved in EtOAc (0.5mL); add the ethyl acetate solution (0.5mL) of hydrochloric acid wherein; and react 3 hours under room temperature; it is white solid (30mg, 64%) that pressure reducing and steaming solvent obtains target compound.
MS(ESI，pos.ion)m/z：716.3(M+1)；LC-MS Rt：2.720min；
1H NMR(400MHz，CD 3OD)：δ1.03(m，2H)，1.15(m，2H)，1.60(t，J＝1.6Hz，2H)，1.67(s，2H)，1.99(s，1H)，2.47(m，2H)，3.69-3.76(m，4H)，3.86(m，1H)，3.99(s，2H)，4.11(s，3H)，4.50(s，2H)，5.15(d，J＝12Hz，1H)，6.99(d，J＝6.8Hz，1H)，7.08(m，2H)，7.46-7.58(m，5H)，7.88(s，1H)，7.95(d，J＝12.8Hz，1H)，8.73(d，J＝6.8Hz，1H)。
Embodiment 77
1-(N-(4-(7-(3-(7-hydroxyl-5-azaspiro [2.4] heptane-5-base) propoxy-) quinolyl-4 oxygen base)-3-fluorophenyl)-N-(4-fluorophenyl) cyclopropane-1,1-dicarbamoyl base)-2-Padil ester hydrochloride
Step 1) cyclopropane-1,1-diethyl dicarboxylate
Diethyl malonic ester (3.2g, 20mmol) and Anhydrous potassium carbonate powder (6.9g, 50mmol) are joined in DMF (50.0mL), then adds glycol dibromide (4.136g, 22mmol) wherein.React after 2 hours, in reaction mixture, add the TBAI (0.738g, 2.0mmol) of catalytic amount, continue at room temperature stirring reaction 8 hours.Then filtered by reaction mixture, gained solid ether (10mL) washs three times, and filtrate is washed with 200mL, and with extracted with diethyl ether (75mL × 4).The organic phase merged is washed with 70mL salt, through anhydrous sodium sulfate drying, filter, and filtrate decompression is distilled, it is yellow oil (3.3g, 88.7%) that the residue obtained obtains target compound through short alumina column (1: 10 (v/v) ethyl acetate/normal hexane) chromatography.
1H NMR(400MHz，CDCl 3)：δ1.27(m，J＝6.8Hz，6H)，1.42(m，4H)，4.18(m，4H)。
Step 2) 1-(ethoxycarbonyl) cyclopropane-carboxylic acid
Be dissolved in by cyclopropane-1,1-diethyl dicarboxylate (4.77g, 25.6mmol) in ethanol (40mL), add the KOH aqueous solution (8mL) of 0.18g/mL wherein, reaction mixture at room temperature stirs and spends the night.Pressure reducing and steaming alcohol solvent, the residue HCl (6mL, 5mol/L) obtained neutralizes, and then uses ethyl acetate (100mL × 3) to extract.The organic phase anhydrous sodium sulfate drying merged, filters, and to obtain title compound be white solid (3.58g, 88.4%) by filtrate decompression distillation.
1H NMR(400MHz，CDCl 3)：δ1.27(t，J＝6.7Hz，3H)，1.83(m，2H)，1.86(m，2H)，4.25(m，2H)。
Step 3) 1-(4-Fluorophenylamino formyl radical) ethyl cyclopropane dicarboxylate
By 1-(ethoxycarbonyl) cyclopropane-carboxylic acid (12.9g, 81.6mmol), 4-fluoroaniline (9.06g, 81.6mmol, Alfa-Aesar) and HOAt (2.22g, 16.3mmol, Shanghai Medped company limited) be dissolved in DCM (80mL), and at room temperature, add EDCI (18.76g wherein in batches, 97.9mmol, Shanghai Medped company limited).Then reaction is warming up to 45 DEG C, stirring reaction 3 hours, then washes with water reaction solution (150mL × 5), then with salt washing (100mL).The organic phase merged, through anhydrous sodium sulfate drying, is filtered, and filtrate decompression is distilled, and the residue obtained is through normal hexane crystallization treatment, and obtaining title compound is faint yellow solid (12.83g, 63%).
MS(ESI，pos.ion)m/z：252.0(M+1)；
1H NMR(400MHz，CDCl 3)：δ1.28-1.31(q，3H)，1.61-1.62(d，2H)，1.66-1.69(q，2H)，1.80-1.83(m，2H)，7.00-7.05(m，2H)，7.54-7.57(m，2H)，10.91(s，1H)。
Step 4) 1-(4-Fluorophenylamino formyl radical) cyclopropane-carboxylic acid
By 1-((4-fluorophenyl) formamyl) cyclopropane-carboxylic acid, ethyl ester (8.9g; 35.4mmol) be dissolved in EtOH/THF (50/50mL; Guangdong brilliance Chemical Company); and drip KOH (3.98g with syringe pump wherein; 70.8mmol, Guangdong brilliance Chemical Company) solution.Reaction mixture reacts and spends the night under room temperature under nitrogen atmosphere, afterwards by reaction mixture underpressure distillation, the residue 5N HCl acidifying obtained, and adjust ph to 2.0, then use ethyl acetate (150mL × 4) to extract, the organic phase of merging is through anhydrous sodium sulfate drying, filter, and filtrate decompression is distilled, obtaining residue, to obtain target compound through ethyl acetate/normal hexane (1: 40v/v) recrystallization be white solid (7.66g, 97%).
MS(ESI，neg.ion)m/z：221.9(M-1)；
1H NMR(400MHz，d 6-DMSO)：δ1.41(s，4H)，7.13-7.18(m，2H)，7.61-7.66(m，2H)，10.59(s，1H)，11.09(bs，1H)。
Step 5) N-(4-(7-(benzyloxy) quinolyl-4 oxygen base)-3-fluorophenyl)-N-(4-fluorophenyl) cyclopropane-1,1-bis-carboxamide
By 4-(7-(benzyloxy) quinolyl-4 oxygen base)-3-fluoroaniline) (3.6g; 10mmol) with 1-(4-Fluorophenylamino formyl radical) cyclopropane-carboxylic acid (2.678g; 12mmol) be dissolved in DCM (50mL); and at room temperature; add TEA (1g wherein; 10mmol) with HATU (6.84g, 18mmol), be then warming up to 40 DEG C of stirring reactions and spend the night.Reaction mixture H afterwards 2o (25mL) washes, the organic phase merged, through anhydrous sodium sulfate drying, is filtered, and by filtrate reduced in volume, it is yellow solid (5.5g, 97%) that residue obtains title compound through silica gel column chromatography (1: 1 ethyl acetate/petroleum ether).
MS(ESI，pos.ion)m/z：566.2(M+1)；LC-MS Rt：3.485min；
1H NMR(400MHz，CDCl 3)：δ1.62(q，J 1＝5.2Hz，J 2＝3.2Hz，2H)，1.76(q，J 1＝4.4Hz，J 2＝3.2Hz，2H)，5.21(s，2H)，6.38(q，J 1＝0.8Hz，J 2＝4.8Hz，1H)，7.04(m，2H)，7.07-7.74(m，13H)，7.74-7.78(m，1H)，8.28(d，J＝9.2Hz，1H)，8.56(d，J＝5.2Hz，1H)，8.64(s，1H)，10.13(s，1H)。
Step 6) N-(the fluoro-4-of 3-(7-hydroxyquinoline-4-base oxygen base) phenyl)-N-(4-fluorophenyl) cyclopropane-1,1-bis-carboxamide
By N-(4-(7-(benzyloxy) quinolyl-4 oxygen base)-3-fluorophenyl)-N-(4-fluorophenyl) cyclopropane-1,1-bis-carboxamide (5.5g, 9.73mmol) be dissolved in MeOH (500mL), and add the Pd/C (10%) of catalytic amount wherein.Reaction mixture at room temperature under an n 2 atmosphere stirring reaction spends the night, and then by reaction solution diatomite filtration, it is yellow solid (4.6g, 93%) that filtrate decompression distillation obtains target compound.
MS(ESI，pos.ion)m/z：476.2(M+1)；LC-MS Rt：3.234min；
1H NMR(400MHz，d 6-DMSO)：δ1.49(m，4H)，6.84(d，J＝6.8Hz，1H)，7.16(t，J＝8.8Hz，2H)，7.49-7.66(m，6H)，7.99(d，J＝13.2Hz，1H)，8.46(d，J＝9.2Hz，1H)，8.88(d，J＝6.4Hz，1H)，9.99(s，1H)，10.52(s，1H)，11.80(s，1H)。
Step 7) 3-(7-hydroxyl-5-azaspiro [2.4] heptane-5-base) propyl alcohol
7-hydroxyl-5-azaspiro [2.4] heptane (1.23g, 11.0mmol) is dissolved in THF (40mL), and adds 3-bromopropyl alcohol (2.3g, 16.65mmol) and Et wherein 3n (2.24g, 22.2mmol).Reaction mixture reacts 12 hours in stirred at ambient temperature, then underpressure distillation, and residue is through silica gel column chromatography (100: 50: 2 (v/v/v) EtOAc/CH 3oH/Et 3n) purifying obtains target compound is orange (1.14g, 60%).
MS(ESI，pos.ion)m/z：172(M+1)；LC-MS Rt：0.178min；
1H NMR(400MHz，CDCl 3)：δ0.59(m，1H)，0.62(m，1H)，0.70-0.72(m，1H)，0.87-0.92(m，1H)，1.68-1.74(m，2H)，2.39-2.41(d，J＝9.2Hz，1H)，2.70-2.74(m，2H)，2.84-2.87(m，2H)，2.88-2.92(dd，J 1＝10.4Hz，J 2＝4.8Hz，1H)，3.73-3.75(m，1H)，3.77-3.80(t，J＝5.2Hz，2H)。
Step 8) 3-(7-hydroxyl-5-azaspiro [2.4] heptane-5-base) propyl Methanesulfonate
By 3-(7-hydroxyl-5-azaspiro [2.4] heptane-5-base) propyl alcohol (1.14g, 6.67mmol) and Et 3n (1.35g, 13.34mmol) is dissolved in CH 2cl 2(20mL) in, and at 0 DEG C, slowly drip methylsulfonyl chloride (1.15g wherein, 10mmol), after dropwising, reaction mixture continues reaction 3 hours at 0 DEG C, reaction solution 10mL cold water washing afterwards, the organic phase merged, through anhydrous sodium sulfate drying, is filtered, and to obtain target compound be orange by filtrate decompression distillation.The thick product obtained, without the need to purifying, is directly used in next step reaction.
Step 9) N-(4-(7-(3-(7-hydroxyl-5-azaspiro [2.4] heptane-5-base) propoxy-)-quinolyl-4 oxygen base)-3-fluorophenyl)-N-(4-fluorophenyl) cyclopropane-1,1-bis-carboxamide
By N-(the fluoro-4-of 3-(7-Hydroxy-quinolin-4-base oxygen base) phenyl)-N-(4-fluorophenyl) cyclopropane-1,1-bis-carboxamide (266mg, 0.56mmol) be dissolved in DMA (3mL), and add 3-(7-hydroxyl-5-azaspiro [2.4] heptane-5-base) propyl Methanesulfonate (283mg, 1.14mmol) and Cs wherein 2cO 3(556mg, 1.71mmol).Reaction mixture is after stirred at ambient temperature reacts 2 days, and alkali pressure boils off solvent, in residue, add saturated NaHCO 3solution (15mL) and CHCl 3(30mL), stratification, by the organic phase of merging through anhydrous sodium sulfate drying, filter, and filtrate decompression distilled, residue is through silica gel column chromatography (100: 15: 1 (v/v/v) EtOAc/CH 3oH/Et 3n) purifying obtains title compound is white solid (290mg, 82%).
MS(ESI，pos.ion)m/z：629.0(M+1)；LC-MS Rt：2.768min；
1H-NMR(400MHz，CDCl 3)：δ0.553-0.685(m，2H)，0.712-0.795(m，1H)，0.922-0.985(m，1H)，1.613-1.645(q，J 1＝8Hz，J 2＝2.7Hz，2H)，1.787-1.818(q，J 1＝8Hz，J 2＝4.8Hz，2H)，2.2027-2.095(m，2H)，2.366-2.388(d，J＝8.8Hz，1H)，2.657-2.731(m，2H)，2.786-2.823(dd，J 1＝10Hz，J 2＝4.8Hz，1H)，2.883-2.905(d，J＝8.8Hz，1H)，2.948-2.977(dd，J 1＝10Hz，J 2＝1.6Hz，1H)，3.727-3.739(d，J＝8.8Hz，1H)，4.117-4.183(m，2H)，6.365-6.378(d，J＝8.8Hz，1H)，7.038-7.090(m，2H)，7.188-7.282(m，3H)，7.433-7.475(m，2H)，7.508-7.514(d，J＝2.4Hz，1H)，7.740-7.776(dd，J 1＝12Hz，J 2＝2.4Hz，1H)，8.240-8.263(d，J＝9.2Hz，1H)，8.551-8.575(d，J＝9.6Hz，1H)，9.977(m，1H)。
Step 10) 1-(N-(4-(7-(3-(7-hydroxyl-5-azaspiro [2.4] heptane-5-base) propoxy-) quinolyl-4 oxygen base)-3-fluorophenyl)-N-(4-fluorophenyl) cyclopropane-1, 1-dicarbamoyl base)-2-(tertbutyloxycarbonylamino) acetic ester is by N-(4-(7-(3-(7-hydroxyl-5-azaspiro [2.4] heptane-5-base) propoxy-) quinolyl-4 oxygen base)-3-fluorophenyl)-N-(4-fluorophenyl) cyclopropane-1, 1-bis-carboxamide (50mg, 0.079mmol), glycine (the 21mg of Boc protection, 0.119mmol) with DMAP (2mg, 0.016mmol) be dissolved in CH 2cl 2(1mL), in, EDCI (24mg, 0.12mmol) is added wherein.Reaction mixture adds CH react 2 hours under room temperature after wherein 2cl 2(15mL), and wash with water (10mL), the organic phase obtained is through anhydrous sodium sulfate drying, filter, and filtrate decompression is distilled, it is white foam solid (50mg, 80%) that residue obtains title compound through purification by silica gel column chromatography.
MS(ESI，pos.ion)m/z：786.4(M+1)；LC-MS Rt：3.442min；
1H-NMR(400MHz，CDCl 3)：δ0.632-0.646(m，2H)，0.675-0.703(m，2H)，1.437(s，9H)，1.611-1.642(q，J 1＝7.6Hz，J 2＝4.8Hz，2H)，1.771-1.802(q，J 1＝8Hz，J 2＝4Hz，2H)，2.091(m，2H)，2.457-2.479(d，J＝8.8Hz，1H)，2.709-2.747(t，J＝7.6Hz，2H)，2.889-2.912(d，J＝9.2Hz，2H)，3.095-3.136(dd，J 1＝6.4Hz，J 2＝5.2Hz，2H)3.910-3.924(d，J＝5.6Hz，2H)，4.136-4.194(t，J＝6Hz，2H)，4.934-4.943(d，J＝3.6Hz，1H)，6.356-6.371(d，J＝6Hz，1H)，7.209-7.072(t，J＝8.4Hz，2H)，7.196-7.225(dd，J 1＝9.2Hz，J 2＝2.4Hz，2H)，7.258-7.279(d，J＝8.4Hz，1H)，7.383-7.389(d，J＝2.4Hz，1H)，7.445-7.467(dd，J 1＝8.8Hz，J 2＝2Hz，2H)，7.731-7.767(dd，J 1＝12Hz，J 2＝2.4Hz，1H)，8.231-8.254(d，J＝9.2Hz，1H)，8..556-8.569(d，J＝5.2Hz，1H)，10.055(s，1H)。
Step 11) 1-(N-(4-(7-(3-(7-hydroxyl-5-azaspiro [2.4] heptane-5-base) propoxy-) quinolyl-4 oxygen base)-3-fluorophenyl)-N-(4-fluorophenyl) cyclopropane-1,1-dicarbamoyl base)-2-Padil ester hydrochloride
By 1-(N-(4-(7-(3-(7-hydroxyl-5-azaspiro [2.4] heptane-5-base) propoxy-) quinolyl-4 oxygen base)-3-fluorophenyl)-N-(4-fluorophenyl) cyclopropane-1; 1-dicarbamoyl base)-2-(tertbutyloxycarbonylamino) acetic ester (50mg, 0.064mmol) is dissolved in EtOAc (0.5mL).Reaction mixture reacts 3 hours in stirred at ambient temperature, and it is white solid (50mg) that pressure reducing and steaming solvent obtains title compound.
MS(ESI，pos.ion)m/z：686.2(M+1)；LC-MS Rt：2.712min；
1H-NMR(400MHz，CDCl 3)：δ0.995-1.050(m，2H)，1.143-1.195(m，2H)，1.600(s，3H)，1.663(s，2H)，1.991-2.050(m，2H)，2.453-2.470(d，J＝6.8Hz，2H)，2.488-2.505(dd，J 1＝4.4Hz，J 2＝4Hz，1H)，3.598-3.633(t，J＝6.8Hz，2H)，3.971-3.998(m，2H)，4.468(s，2H)，5.1-5.19(dd，1H)，6.994-7.011(d，J＝6.8Hz，1H)，7.046-7.098(m，2H)，7.482-7.514(m，1H)，7.545-7.579(m，2H)，7.610-7.663(m，2H)，7.975-8.012(t，J＝12.4Hz，1H)，8.580-8.608(dd，J 1＝9.2Hz，J 2＝2Hz，1H)，8.848-8.881(t，J＝6.8Hz，1H)。
Embodiment 78
1-((4-(4-(1-(formamyl) cyclopropane carboxylic acid amido)-2-fluorophenoxy)-6-methoxy quinoline-7-base oxygen base) methyl) cyclopropyl 2-aminoacetate
Step 1) 1-((tetrahydrochysene-2H-pyrans-2-base oxygen base) methyl) cyclopropyl-phenyl manthanoate
1-((tetrahydrochysene-2H-pyrans-2-base oxygen base) methyl) ring propyl alcohol (1.6g, 9.3mmol) and phenylformic acid (1.25g, 11.16mmol, Shanghai Hai Qu Chemical Company) are dissolved in 50mL CH 2cl 2in, add DMAP (227mg, 1.86mmol, Shanghai Hai Qu Chemical Company) and EDCI (2.73g, 14.25mmol, Shanghai Hai Qu Chemical Company) under room temperature wherein.Reaction mixture at room temperature stirring reaction spends the night, then concentrating under reduced pressure, and it is colorless oil (1.8g, 70%) that residue obtains title compound through silica gel column chromatography (20: 1 (v/v) petrol ether/ethyl acetate) purifying.
MS(ESI，pos.ion)m/z：299.2(M+Na)；LC-MS Rt：3.659min；
1H NMR(400MHz，CDCl 3)：δ0.94-1.01(m，2H)，1.04-1.12(m，2H)，1.50-1.63(m，4H)，1.71(m，1H)，1.82(m，1H)，3.44(t，J＝4.8Hz，1H)，3.80(t，J＝8.8Hz，1H)，3.92(d，J＝11.6Hz，1H)，4.02(d，J＝12Hz，1H)，4.69(s，1H)，7.43(t，J＝7.2Hz，2H)，7.55(t，J＝7.2Hz，1H)，8.03(d，J＝8Hz，2H)。
Step 2) 1-(methylol) cyclopropyl-phenyl manthanoate
1-((tetrahydrochysene-2H-pyrans-2-base oxygen base) methyl) cyclopropyl-phenyl manthanoate (2g, 7.2mmol) is dissolved in 30mL MeOH, under room temperature, adds PPTS (2.7g, 10.8mmol, Aldrich) wherein.Reaction mixture at room temperature stirs and spends the night, then concentrating under reduced pressure, and it is colorless oil (1.2g, 87%) that residue obtains target compound through silica gel column chromatography (4: 1 (v/v) petrol ether/ethyl acetate) purifying.
MS(ESI，pos.ion)m/z：215.1(M+Na)；LC-MS Rt：2.949min；
1H NMR(400MHz，CDCl 3)：δ1.05(m，2H)，1.12(m，2H)，3.92(s，2H)，7.45(m，2H)，7.60(m，1H)，8.01(t，J＝1.6Hz，2H)。
Step 3) 1-((sulfonyloxy methyl oxygen base) methyl) cyclopropyl-phenyl manthanoate
1-(methylol) cyclopropyl-phenyl manthanoate (500mg, 2.6mmol) and TEA (394mg, 3.9mmol, Xi Long chemical plant, Shantou) are dissolved in the CH of 50mL drying 2cl 2in, slowly drip MsCl (357mg, 3.12mmol, Shanghai Hai Qu Chemical Company) wherein with syringe under room temperature.At room temperature react after 2 hours, in reaction mixture, add frozen water, and use CH 2cl 2(30mL × 2) extract, and the organic phase of merging, through anhydrous sodium sulfate drying, is filtered, and to obtain title compound be light yellow solid (590mg, 84%) by filtrate decompression distillation.
MS(ESI，pos.ion)m/z：293.1(M+Na)；LC-MS Rt：3.295min；
1H NMR(400MHz，CDCl 3)：δ1.14(s，2H)，1.22(s，2H)，3.04(s，3H)，4.6(s，2H)，7.45(t，J＝7.6Hz，2H)，7.58(d，J＝7.2Hz，1H)，8.02(d，J＝7.6Hz，2H)。
Step 4) 1-((4-(4-(1-(formamyl) cyclopropane carboxylic acid amido)-2-fluorophenoxy)-6-methoxy quinoline-7-base oxygen base) methyl) cyclopropyl-phenyl manthanoate
By 1-((sulfonyloxy methyl oxygen base) methyl) cyclopropyl-phenyl manthanoate (801mg, 2.97mmol) with N-(the fluoro-4-of 3-(7-hydroxyl-6-methoxy quinoline-4-base oxygen base) phenyl)-N-(4-fluorophenyl) cyclopropane-1,1-dicarboxamide (1g, 1.98mmol) be dissolved in DMA (5mL), add Cs wherein 2cO 3(1.93g, 5.94mmol, Aladdin).Reaction mixture is warming up to 45 DEG C, reaction is spent the night.Concentrating under reduced pressure is except desolventizing, residual through CHCl 3(30mL) dilute, be separated organic phase, gained organic phase, through anhydrous sodium sulfate drying, is filtered, and filtrate decompression is distilled, and it is light yellow solid (800mg, 60%) that residue obtains title compound through purification by silica gel column chromatography.
MS(ESI，pos.ion)m/z：680.2(M+1)；LC-MS Rt：3.852min。
Step 5) N-(the fluoro-4-of 3-(7-((1-hydroxycyclopropyl) methoxyl group)-6-methoxy quinoline-4-base oxygen base) phenyl)-N-(4-fluorophenyl) cyclopropane-1,1-dicarboxamide
1-((4-(4-(1-(formamyl) cyclopropane carboxylic acid amido)-2-fluorophenoxy)-6-methoxy quinoline-7-base oxygen base) methyl) cyclopropyl-phenyl manthanoate (800mg, 1.178mmol) is dissolved in CH 3in OH (10mL), add 5mL NaOH solution (0.0188g/mL) wherein.Reaction mixture at room temperature reacts and spends the night, the suspension concentrating under reduced pressure obtained, residue through silica gel column chromatography (from ethyl acetate to 100: 1 (v/v) EtOAc/CH 3oH) purifying obtains target compound is white solid (520mg, 77%).
MS(ESI，pos.ion)m/z：576.2(M+1)；LC-MS Rt：3.167min；
1H NMR(400MHz，CDCl 3)：δ0.767(m，2H)，1.008(m，2H)，1.637(m，2H)，1.807(m，2H)，4.040(s，3H)，4.202(s，2H)，6.397-6.409(d，J＝4.8Hz，1H)，7.047-7.088(d，J＝4.8Hz，2H)，7.222-7.243(d，J＝4.8Hz，1H)，7.410(s，1H)，7.447-7.478(t，J＝6Hz，2H)，7.580(s，1H)，7.761-7.791(d，J＝12Hz，1H)，8.427(s，1H)，8.474-8.487(d，J＝5.2Hz，1H)，10.119(s，1H)。
Step 6) 1-((4-(4-(1-(formamyl) cyclopropane carboxylic acid amido)-2-fluorophenoxy)-6-methoxy quinoline-7-base oxygen base) methyl) cyclopropyl 2-(tert-butoxycarbonyl) acetic ester
By N-(the fluoro-4-of 3-(7-((1-hydroxycyclopropyl) methoxyl group)-6-methoxy quinoline-4-base oxygen base) phenyl)-N-(4-fluorophenyl) cyclopropane-1,1-dicarboxamide (150mg, 0.26mmol), N-Boc-glycine (68mg, 0.39mmol) be dissolved in CH with DMAP (16mg, 0.13mmol) 2cl 2(2mL), in, EDCI (100mg, 0.52mmol) is added wherein.Reaction mixture adds CH after at room temperature reacting 2 hours 2cl 2, and wash with water (10mL) (15mL).The organic phase merged, through anhydrous sodium sulfate drying, filter, and by filtrate reduced in volume, it is white foam solid (150mg, 78.5%) that residue obtains target compound through silica gel column chromatography.
MS(ESI，pos.ion)m/z：733.2(M+1)；LC-MS Rt：3.479min；
1H NMR(400MHz，CDCl 3)：δ1.103-1.134(m，4H)，1.454(s，9H)，1.625-1.656(q，J 1＝7.2Hz，J 2＝8Hz，J 3＝4.4Hz，J 4＝5.2Hz，2H)，1.797-1.829(q，J 1＝7.2Hz，J 2＝8.8Hz，J 3＝4.4Hz，J 4＝5.6Hz，2H)，3.899-3.912(d，J＝5.2Hz，2H)，4.043(s，3H)，4.473(s，2H)，6.404-6.418(d，J＝5.6Hz，1H)，7.055-7.098(t，J＝8.8Hz，2H)，7.205-7.248(t，J＝8.8Hz，1H)，7.283-7.306(d，J＝9.2Hz，1H)，7.394(s，1H)，7.467-7.489(dd，J 1＝10.8Hz，J 2＝8Hz，J 3＝4.4Hz，J 4＝6Hz，2H)，7.585(s，1H)，7.757-7.793(dd，J 1＝12Hz，J 2＝2.4Hz，1H)，8.378(s，1H)，8.472-8.485(d，J＝5.2Hz，1H)，10.031(s，1H)。
Step 7) 1-((4-(4-(1-(formamyl) cyclopropane carboxylic acid amido)-2-fluorophenoxy)-6-methoxy quinoline-7-base oxygen base) methyl) cyclopropyl 2-aminoacetate
By 1-((4-(4-(1-(formamyl) cyclopropane carboxylic acid amido)-2-fluorophenoxy)-6-methoxy quinoline-7-base oxygen base) methyl) cyclopropyl 2-(tert-butoxycarbonyl) acetic ester (150mg; 0.20mmol) be dissolved in EtOAc (1mL); add HCl/EOAc (3mmol/L, 1mL) wherein.After reaction mixture at room temperature reacts 3 hours, concentrating under reduced pressure is white solid (170mg) except desolventizing obtains title compound.
MS(ESI，pos.ion)m/z：634.2(M+1)；LC-MS Rt：2.831min；
1H NMR(400MHz，d-DMSO)：δ1.156-1.183(m，4H)，1.474-1.540(m，4H)，3.809(s，2H)，4.072(s，3H)，4.571(s，2H)，6.914-6.930(d，J＝6.4Hz，1H)，7.132-7.176(t，J＝8.8Hz，2H)，7.531-7.575(t，J＝8.8Hz，1H)，7.623-7.673(m，3H)，7.776-7.794(d，J＝7.2Hz，2H)，7.984-8.018(d，J＝13.6Hz，1H)，8.807-8.823(d，J＝6Hz，1H)，10.047(s，1H)，10.573(s，1H)。
Embodiment 79
1-(2-(4-(the fluoro-4-of 2-(1-(phenylcarbamoyl) cyclopropane carboxylic acid amido) phenoxy group) quinoline-7-base oxygen base) ethyl) cyclopropyl 2-Padil ester hydrochloride
Step 1) 3-hydroxy-propionic acid benzyl ester
By 3-hydroxy-propionic acid solution (12g, 40mmol, 30% aqueous solution, TCI, TOKYOKASEI) and KOH (2.24g, 40mmol, Xi Long chemical plant, Shantou) at room temperature react 30 minutes, then reaction mixture concentrating under reduced pressure is obtained white solid.This white solid is suspended in 50mL DMF, under room temperature, adds BnBr (4.75mL, 40mmol, Aldrich) wherein by syringe, react 5 hours at 80 DEG C.Then by reaction mixture concentrating under reduced pressure, it is colorless oil (3.35g, 46%) that residue obtains target compound through silica gel column chromatography (10: 1 (v/v) petrol ether/ethyl acetate) purifying.
MS(ESI，pos.ion)m/z：203.1(M+Na)；LC-MS Rt：2.743min；
1H NMR(400MHz，CDCl 3)：δ2.61(d，J＝4.4Hz，2H)，3.86(s，J＝4.8Hz，2H)，5.14(s，2H)，7.35(s，5H)。
Step 2) 3-(tetrahydrochysene-2H-pyrans-2-base oxygen base) benzyl propionate
3-hydroxy-propionic acid benzyl ester (3.35g, 18.6mmol) and DHP (3.12g, 37.2mmol, Alfa) are dissolved in methylene dichloride (100mL), add PPTS (5.6g, 22.3mmol, Aldrich) wherein in batches.Reaction mixture at room temperature reacts and spends the night, and then adds 50mL H 2o cancellation is reacted.The organic phase be separated is through anhydrous sodium sulfate drying, filter, and filtrate decompression is distilled, it is colorless oil (4.25g, 86%) that residue obtains title compound through silica gel column chromatography (10: 1 (v/v) petrol ether/ethyl acetate) purifying.
MS(ESI，pos.ion)m/z：287.2(M+Na)；LC-MS Rt：3.915min；
1H NMR(400MHz，CDCl 3)：δ1.49-1.76(m，6H)，2.68(t，J＝6.4Hz，2H)，3.49(t，J＝4.4Hz，1H)，3.72(m，1H)，3.82(t，J＝8.8Hz，1H)，4.03(m，1H)，4.63(s，1H)，5.17(s，2H)，7.35(d，J＝10.4Hz，5H)。
Step 3) 1-(2-(tetrahydrochysene-2H-pyrans-2-base oxygen base) ethyl) ring propyl alcohol
3-(tetrahydrochysene-2H-pyrans-2-base oxygen base) benzyl propionate (4.2g, 15.9mmol) is dissolved in 60mL THF, under atmosphere, wherein adds Ti (Oi-Pr) by syringe in room temperature 4(2.4mL, 07.95mmol, d=0.955g/L, Ardrich).Stirring reaction 30 minutes at 18 DEG C, then by syringe pump in 3 hours, in reaction solution, add EtMgBr (13.25mL, 3.975mmol, 3M diethyl ether solution, Aldrich).Thereafter add 50mL shrend to go out reaction, by reaction mixture by diatomite filtration, filtrate is through extraction into ethyl acetate (100mL × 3).The organic phase merged is through anhydrous sodium sulfate drying, filter, by filtrate reduced in volume, it is colorless oil (2.56g, 86.5%) that residue obtains target compound through silica gel column chromatography (10: 1 (v/v) petrol ether/ethyl acetate) purifying.
MS(ESI，pos.ion)m/z：209.2(M+Na)；LC-MS Rt：2.644min；
1H NMR(400MHz，CDCl 3)：δ0.49(m，2H)，0.80(m，2H)，1.55-1.83(m，6H)，1.87-1.90(m，2H)，3.57(m，1H)，3.72(m，1H)，3.90(m，1H)，4.09(m，1H)，4.68(q，1H)。
Step 4) 1-(2-(tetrahydrochysene-2H-pyrans-2-base oxygen base) ethyl) cyclopropyl-phenyl manthanoate
1-(2-(tetrahydrochysene-2H-pyrans-2-base oxygen base) ethyl) ring propyl alcohol (730mg, 4.05mmol) and phenylformic acid (590mg, 4.86mmol) are dissolved in 30mL CH 2cl 2in, add DMAP (98.8mg, 0.81mmol, Shanghai Hai Qu Chemical Company) and EDCI (1.16g, 6.08mmol, Shanghai Hai Qu Chemical Company) under room temperature wherein.Reaction mixture at room temperature stirring reaction spends the night, concentrating under reduced pressure, and it is colorless oil (690mg, 60%) that residue obtains title compound through silica gel column chromatography (20: 1 (v/v) petrol ether/ethyl acetate) purifying.
MS(ESI，pos.ion)m/z：313.2(M+Na)；LC-MS Rt：3.801min；
1H NMR(400MHz，CDCl 3)：δ0.88(m，2H)，1.02(m，2H)，1.48-1.83(m，7H)，2.16-2.30(m，2H)，3.52(m，1H)，3.61(m，1H)，3.90(m，1H)，3.99(m，1H)，4.62(t，J＝3.2Hz，1H)，7.45(m，2H)，7.56(m，1H)，8.01(m，2H)。
Step 5) 1-(2-hydroxyethyl) cyclopropyl-phenyl manthanoate
By 1-(2-(tetrahydrochysene-2H-pyrans-2-base oxygen base) ethyl) cyclopropyl-phenyl manthanoate (690mg, 2.38mmol) be dissolved in 20mL MeOH, PPTS (896mg, 3.57mmol, Aldrich) is added wherein under room temperature.Reaction mixture at room temperature reacts and spends the night, then concentrating under reduced pressure, and it is light yellow oil (320mg, 65%) that residue obtains target compound through silica gel column chromatography (4: 1 (v/v) petrol ether/ethyl acetate) purifying.
MS(ESI，pos.ion)m/z：229.2(M+Na)；LC-MS Rt：2.997min；
1H NMR(400MHz，CDCl 3)：δ0.92(m，2H)，1.08(m，2H)，2.10(t，J＝6.0Hz，2H)，2.78(s，1H)，3.79(s，2H)，7.46(t，J＝8.0Hz，2H)，7.58(t，J＝7.2Hz，1H)，8.02(t，J＝7.2Hz，2H)。
Step 6) 2-(1-(benzoyloxy group) cyclopropyl) ethyl methane sulfonate ester
1-(2-hydroxyethyl) cyclopropyl-phenyl manthanoate (320mg, 1.55mmol) and TEA (235mg, 2.33mmol, Xi Long chemical plant, Shantou) are dissolved in the CH of 20mL drying 2cl 2in, added wherein by syringe under room temperature and slowly drip MsCl (213mg, 1.86mmol, Shanghai Hai Qu Chemical Company).And after stirred at ambient temperature reacts 2 hours, add frozen water to reaction mixture, and use CH 2cl 2(30mL) extract.The organic phase merged, through anhydrous sodium sulfate drying, filter, and filtrate reduced in volume to be obtained target compound is faint yellow solid (400mg, 90%).
MS(ESI，pos.ion)m/z：307.1(M+Na)；LC-MS Rt：3.348min。
Step 7) 1-(2-(4-(the fluoro-4-of 2-(1-(phenylcarbamoyl) cyclopropane carboxylic acid amido) phenoxy group) quinoline-7-base oxygen base) ethyl) cyclopropyl-phenyl manthanoate
By N-(the fluoro-4-of 3-(7-hydroxyquinoline-4-base oxygen base) phenyl)-N-cyclo-propane-1,1-dicarboxamide (91mg, 0.2mmol) with 2-(1-(benzoyloxy) cyclopropyl) ethyl methane sulfonate ester (113.6mg, 0.4mmol) be dissolved in DMF (3mL), add Cs wherein 2cO 3(195mg, 0.6mmol, Aladdin).Reaction mixture reacts and spends the night at 50 DEG C, and then concentrating under reduced pressure is except desolventizing, and residue is through CHCl 3(30mL) extract, the organic phase of merging, through anhydrous sodium sulfate drying, is filtered, and by filtrate reduced in volume.It is light yellow solid (75mg, 58%) that residue obtains target compound through silica gel column chromatography (EtOAc) purifying.
MS(ESI，pos.ion)m/z：646.2(M+1)；LC-MS Rt：3.686min；
1H NMR(400MHz，CDCl 3)：δ0.93(t，J＝7.2Hz，2H)，1.08(t，J＝6.0Hz，2H)，1.62(m，2H)，1.81(m，2H)，2.48(t，J＝6.4Hz，2H)，4.35(t，J＝6.4Hz，2H)，6.36(d，J＝5.2Hz，1H)，7.07(m，1H)，7.19(t，J＝9.2Hz，2H)，7.35-7.55(m，8H)，7.75(m，1H)，8.0(d，J＝7.6Hz，3H)，8.20(d，J＝9.2Hz，1H)，8.56(d，J＝5.2Hz，1H)，10.14(s，1H)。
Step 8) N-(the fluoro-4-of 3-(7-(2-(1-hydroxycyclopropyl) oxyethyl group) quinolyl-4 oxygen base) phenyl)-N-cyclo-propane-1,1-dicarboxamide
1-(2-(4-(the fluoro-4-of 2-(1-(phenylcarbamoyl) cyclopropane-carboxamido) phenoxy group) quinoline-7-base oxygen base) ethyl) cyclopropyl-phenyl manthanoate (75mg, 0.116mmol) is dissolved in CH 3in OH (5mL), add LiOH (8.35mg/mL) solution (1mL) wherein.Reaction mixture reacts and spends the night under room temperature, by gained suspension concentrating under reduced pressure, residue through silica gel column chromatography (from EtOAc to 100: 1 (v/v) EtOAc/CH 3oH) purifying obtains target compound is white solid (40mg, 64%).
MS(ESI，pos.ion)m/z：542.2(M+1)；LC-MS Rt：3.225min；
1H NMR(400MHz，CD 3OD)：δ0.63(t，J＝5.6Hz，2H)，0.78(t，J＝5.6Hz，2H)，1.67(s，4H)，2.15(t，J＝6.8Hz，2H)，4.44(t，J＝6.8Hz，2H)，6.51(d，J＝5.6Hz，1H)，7.16(t，J＝7.2Hz，1H)，7.32-7.47(m，6H)，7.58(d，J＝8.0Hz，2H)，7.85(m，1H)，8.32(d，J＝9.2Hz，1H)，8.56(d，J＝5.2Hz，1H)。
Step 9) 1-(2-(4-(the fluoro-4-of 2-(1-(phenylcarbamoyl) cyclopropane carboxylic acid amido) phenoxy group) quinoline-7-base oxygen base) ethyl) cyclopropyl 2-(tertbutyloxycarbonylamino) acetic ester
By N-(the fluoro-4-of 3-(7-(2-(1-hydroxycyclopropyl) oxyethyl group)-quinolyl-4 oxygen base) phenyl)-N-cyclo-propane-1,1-dicarboxamide (27mg, 0.05mmol), 2-(tertbutyloxycarbonylamino) acetic acid (13mg, 0.075mmo, Shanghai Hai Qu Chemical Company) and DMAP (3mg, 0.025mmol, Shanghai Hai Qu Chemical Company) be dissolved in dry DCM (3mL), add EDCI (15mg wherein, 0.075mmol, Shanghai Hai Qu Chemical Company).Reaction mixture at room temperature stirring reaction spends the night, then through washing, and the organic phase anhydrous sodium sulfate drying of merging, filter, and filtrate decompression is distilled, it is white solid (30mg, 85%) that residue obtains target compound through Flash silica column chromatography purification.
MS(ESI，pos.ion)m/z：699.2(M+1)；LC-MS Rt：3.656min；
1H NMR(400MHz，CDCl 3)：δ0.88(m，2H)，0.98(m，2H)，1.62(m，2H)，1.81(m，2H)，2.48(t，J＝6.4Hz，2H)，4.35(t，J＝6.4Hz，2H)，6.36(d，J＝5.2Hz，1H)，7.07(m，1H)，7.19(t，J＝9.2Hz，2H)，7.35-7.55(m，8H)，7.75(m，1H)，8.0(d，J＝7.6Hz，3H)，8.20(d，J＝9.2Hz，1H)，8.56(d，J＝5.2Hz，1H)，10.14(s，1H)。
Step 10) 1-(2-(4-(the fluoro-4-of 2-(1-(phenylcarbamoyl) cyclopropane carboxylic acid amido) phenoxy group) quinoline-7-base oxygen base) ethyl) cyclopropyl 2-Padil ester hydrochloride
By 1-(2-(4-(the fluoro-4-of 2-(1-(phenylcarbamoyl) cyclopropane-carboxamido) phenoxy group) quinoline-7-base oxygen base) ethyl) cyclopropyl 2-(tertbutyloxycarbonylamino) acetic ester (23mg; 0.03mmol) be dissolved in EtOAc (1mL); add HCl (the EtOAc solution of 2mol/L, 1mL) wherein.Reaction mixture at room temperature stirring reaction 2 hours, then concentrating under reduced pressure obtains title compound is white solid (15mg, 83%).
MS(ESI，pos.ion)m/z：599.2(M+1)；LC-MS Rt：2.956min；
1H NMR(400MHz，CD 3OD)：δ0.99(t，J＝5.6Hz，2H)，1.08(t，J＝5.6Hz，2H)，1.62(m，2H)，1.69(s，4H)，2.50(t，J＝6.4Hz，2H)，3.86(s，2H)，4.53(t，J＝6.4Hz，2H)，7.02(dd，J 1＝0.8Hz，J 2＝6.4Hz，1H)，7.16(m，1H)，7.34-7.38(m，2H)，7.48-7.67(m，6H)，7.96-7.99(dd，J 1＝2.4Hz，J 2＝12.8Hz，1H)，8.61(d，J＝9.2Hz，1H)，8.88(d，J＝6.8Hz，1H)。
The stability of compound in the aqueous solution, whole blood and hepatomicrosome
Embodiment A
HPLC general analysis method
Agilent 1200 HPLC is equipped with G1311A quaternary syringe pump, and G1322A degasifier, G1316ATCC (column temperature remains on 35 DEG C) is G1315DAD detector and G1329A automatic sampler for what analyze.Adopt Agilent Zorbax Eclipse Plus XDB-C18 post, its specification is: 4.6 × 150mm, analyzes for 5 μMs.The sample of infusion 5 μ L, the peak value of HPLC carrys out record by the UV that wavelength is 210nm.
Analysis condition A: moving phase is acetonitrile (A) and 0.03M KH 2pO 4(B) (pH=6.5 is regulated by the KOH solution of 1.0M); Flow velocity is 1.0mL/min; Gradient condition is: from 30%A, 70%B-70%A in 25 minutes, to 30%B, and then moving phase returned 70%A to 30%B in 5 minutes, continues 5 minutes.Analysis condition B: moving phase is acetonitrile (A) and 0.03M KH 2pO 4(pH=4.0, by the AQ H of 10% for solution (B) 3pO 4regulate); Flow velocity is 2.0mL/min; Its gradient condition is as shown in table 2:
Table 2
Embodiment B
LC/MS/MS general analysis method
The serial LC/MS/MS spectrograph of Agilent 6330 is equipped with G1312A binary syringe pump, is G1367A automatic sampler and G1314C UV detector for what analyze; ESI radioactive source is used for LC/MS/MS spectrograph; Use reference liquid carries out suitable positively charged ion models treated to each analyte and best analysis is carried out in MRM conversion.During analyzing, use Capcell MP-C18 post, specification is: 100 × 4.6mm I.D., 5 μMs (Phenomenex, Torrance, California, USA).Moving phase is 5mM ammonium acetate, 0.1% methanol aqueous solution (A): 5mM ammonium acetate, 0.1% methanol acetonitrile solution (B) (70: 30, v/v); Flow velocity is 0.6mL/min; Column temperature remains on room temperature; Inject 20 μ L samples.
Embodiment C
The measuring method of stability in the aqueous solution
The stability of compound is assessed by one or more external water-based system.Experiment condition in vitro study is summed up as shown in table 3.The equal portions part (20 μ L) be divided into is separated from mother liquor at different time points.Sample adopts the method for HPLC described in the invention to carry out determination and analysis.Sample needed the diluted sample of high density to 0.1mg/mL before being injected into HPLC.
Data analysis
The value of AUC (area under curve) is used for deterministic compound amount in the solution.The amount of residue compound when being then by being zero with the time amount of original chemical carry out comparing calculation and obtain.Transformation period is according to calculating with first order reaction kinetics.
Compound of the present invention generally in 24 hours, and at 4 DEG C and 25 DEG C, when pH value is less than 4, is stable (decomposing < 1.0%) in water and 0.9%NaCl solution.
Table 3
Embodiment D
The measuring method of stability in people's whole blood
By compound dissolution being prepared in Fresh human blood low concentration sample (1 μ g/mL) and enriched sample (10 μ g/ml) (female sample), at 37 DEG C, the equal portions part be divided into is hatched 0 minute respectively, 10 minutes, 30 minutes, 1 hour and 3 hours (samples of repetition, each 50 μ L), and in every equal portions, add rapidly methyl alcohol (100 μ L), with 11, centrifugal 10 minutes of 000rpm, is separated supernatant liquid, and is preserved until carry out LC/MS/MS analysis at-80 DEG C by quenching blood sample.
Data analysis
The amount of residue compound when being by being zero with the time amount of original chemical carry out comparing calculation and obtain.Transformation period is that (k is decomposition rate constant, t according to calculating with first order reaction kinetics 1/2=0.693/k).
The t of compound of the present invention 1/2scope be 7-30 hour.
Embodiment E
The measuring method of stability in people's hepatomicrosome
People's hepatomicrosome is placed in polypropylen tubes hatch, and guides it to copy.Typical hatching mixed solution comprises people's hepatomicrosome (0.5mg protein/mL), target compound (5 μMs) and cumulative volume are NADPH (1.0mM) potassium phosphate buffer (PBS of 200 μ L, 100mM, pH value is 7.4), by compound dissolution in DMSO, and using PBS to be diluted, the concentration of the DMSO solution making it final is 0.05%.And hatch in the water-bath communicated with air at 37 DEG C, in mixed solution, add albumen after preincubate 3min and start reaction.In different time point (0,5,10,15,30 and 60min), add same volume ice-cold acetonitrile termination reaction.Sample is preserved until carry out LC/MS/MS analysis at-80 DEG C.
The concentration of compound in people's hepatomicrosome incubation mixture is measured by the method for LC/MS/MS.The linearity range of concentration range is determined by each test-compound.
By using the microsome of sex change to carry out hatching as negative control, hatching at 37 DEG C, reacting and stopping at different time point (0,15 and 60min).
Dextromethorphane Hbr (70 μMs), as positive control, is hatched at 37 DEG C, reacts and stops at different time point (0,5,10,15,30 and 60min).The positive and negative control sample is all comprised, to ensure the integrity of microsome hatching system in each measuring method.
Data analysis
For each reaction, by compound people's hepatomicrosome hatching in concentration (representing with per-cent) by the plotted as percentage of Relative Zero time point, infer CLint CL in body with this int(ref.:Naritomi Y, Terashita S, Kimura S, Suzuki A, Kagayama A, Sugiyama Y.Prediction of human hepatic clearance from vivo animal experiments and in vitro metabolic studies with liver microsomes from animals and humans.Drug Metabolism and Disposition 2001,29:1316-1324.)
Compound of the present invention generally shows as higher hepatic clearance value (CL int> 12mL/min/kg).
Embodiment F
Pharmacokinetic Evaluation after the oral quantitative the compounds of this invention of mouse, rat, dog and monkey
The present invention assesses the pharmacokinetic of the compounds of this invention in mouse, rat, dog or monkey body.The compounds of this invention carries out administration with the aqueous solution form of the aqueous solution or 2%HPMC+1% twen-80.For intravenous administration, animal gives the dosage of 1mg/kg.For oral dosage (p.o.), rat and mouse is 5mg/kg, and dog and monkey are 10mg/kg.Be within 0.25,0.5,1.0,2.0,3.0,4.0,6.0,8.0,12 and 24 hour, get blood (0.3mL) at time point, and under 3,000rpm centrifugal 10 minutes.Collect plasma solutions, and preserve at-20 DEG C until carry out above-mentioned LC/MS/MS analysis.
Alcohol compound (meta-bolites) is the main compound found in animal plasma.During oral administration, parent compound (amino ester compound) common manifestation goes out lower systematicness and exposes.
Biological activity
Following representational measuring method, but be not limited to these methods, will the biological activity evaluating the compounds of this invention be used for.
Embodiment G
c-Met restraining effect measures
Preliminary study shows, the compound that the present invention filters out can suppress the activity of c-Met.CycLex studies products C ycLex Met kinase assays/inhibitor screening Kit, and refer in single position, the kinase activity for Met recombinant chou catalytic domain carries out semiquantitative immunoassay, and for screening compound of the present invention.Orifice plate is coated in advance easily by " the tyrosine-kinase enzyme-substrate-1 " of Met recombinant chou catalytic domain phosphorylation.Detector antibody is PY-39, specificly can detect the tyrosine residues of " tyrosine-kinase enzyme-substrate-1 " upper phosphorylation.
During detection, with kinase buffer liquid dilution Met recombinant chou catalytic domain, in suction port, at Mg 2+, Mn 2+, under the existence of ATP, make " tyrosine-kinase enzyme-substrate-1 " phosphorylation.By being combined with the PY-39 of horseradish peroxidase, detect the amount of " tyrosine-kinase enzyme-substrate-1 " phosphorylation.PY-39 is anti phosphotyrosine monoclonal antibody, catalyzed coloration substrate-tetramethyl benzidine, after adding termination reagent, becomes blue solution (or yellow) from colourless solution.Carry out quantitatively, reflecting the relative quantity of Met kinase activity in sample to color with spectrophotometry.Operating process as shown in Figure 3.
All samples and standard substance replication three times.Compound during kinase inhibition measures is not only the alcohol compound (meta-bolites) from parent amino ester compound, also comprises amino ester compound of the present invention.The IC that alcohols meta-bolites suppresses c-Met 50value is 1 μM or lower, and some compounds are to the IC of c-Met 50value is lower than 100nM.
Embodiment H
the mensuration of kinase inhibition
the kinase whose mensuration of people c-Met
People c-Met is the MOPS of 7.0,0.2mM EDTA in 8mM pH value, 250 μMs of KKKSPGEYVNIEFG, 10mM MgAcetate and [γ- 33p-ATP] hatch under (specific activity is about 500cpm/pmol, and concentration is determined according to demand) existent condition.Adding MgATP mixture makes reaction start.After incubated at room temperature 40 minutes, add 3% phosphoric acid solution termination reaction.Be mottledly be distributed on P30 strainer by the reaction solution of 10 μ L, cleaned 3 times in 5 minutes with 75mM phosphoric acid, and before dry and scintillation counting, put into methanol solution at once preserve.
The kinase whose mensuration of people KDR
People KDR is the MOPS of 7.0,0.2mM EDTA in 8mM pH value, 0.33mg/mL myelin basic protein, 10mM MgAcetate and [γ- 33p-ATP] hatch under (specific activity is about 500cpm/pmol, and concentration is determined according to demand) existent condition.Adding MgATP mixture makes reaction start to carry out.After incubated at room temperature 40 minutes, add 3% phosphoric acid solution termination reaction.Be mottledly be distributed on P30 strainer by 10 μ L reaction solutions, cleaned 3 times in 5 minutes with 75mM phosphoric acid, and before dry and scintillation counting, put into methanol solution at once preserve.
Above and other kinase assay can at Millipore ' s Kinase Profiler Service, Billerica, MA, US complete.
The IC of alcohol compound (meta-bolites) display to c-Met and/or KDR that amino ester compound of the present invention and metabolism thereof produce 50value is general all at 2 μMs or lower, and some alcohol compounds are to the IC of c-Met and/or KDR 50value is lower than 100nM.
Example I
people's Xenograft Tumor Models
People U87MG glioblastoma Xenograft Tumor Models
Preliminary study shows, effect of the compounds of this invention is evaluated by tumorigenic standard Murine models.Human tumor cells is by people's Malignant glioma cells (U87MG cell, ATCC) produce, as Subcutaneous Tumor Growth (BALB/cAnu/nu in the female nude mice body in 6-7 age in week, Shanghai SLAC Animal Lab.) (for group of solvents n=10, for each dosage group n=8).When gross tumor volume reaches 100-200mm 3time, animal is divided into solvent control group (aqueous solution of 2%HPMC+1% twen-80) and compound group randomly.Follow-up employing comprises the compounds of this invention and carries out gastric infusion (10-100mpk/dose to animal, be dissolved in the aqueous solution of pure water or 2%HPMC+1% twen-80), from 0 to 15 days, announce the result of tumour cell challenge simultaneously anywhere, and generally adhere to that every day carries out once in test.
People MKN45 adenocarcinoma of stomach Xenograft Tumor Models
Xenotransplantation equally can by gastric carcinoma cells (MKN45 cell, ATCC) produce, as Subcutaneous Tumor Growth (BALB/cA nu/nu in the female nude mice body in 6-7 age in week, Shanghai SLAC Animal Lab.) (for group of solvents n=10, for each dosage group n=8).When gross tumor volume reaches 60-150mm 3, animal can be divided into solvent control group (aqueous solution of 2%HPMC+1% twen-80) and compound group randomly.Follow-up employing comprises the compounds of this invention and carries out gastric infusion (10-60mpk/dose to animal, be dissolved in the aqueous solution of pure water or 2%HPMC+1% twen-80), from 0 to 15 days, announce the result of tumour cell challenge simultaneously anywhere, and generally adhere to that every day carries out once in test.
tumor growth inhibition (TGI) is analyzed
The crystallization growth of tumour is undertaken evaluating by gross tumor volume size and the relation of time.Major axis (L) and the minor axis (S) of Subcutaneous tumor measure twice weekly by calipers, and the volume (TV) of tumour is by formula (L × W 2)/2) calculate.TGI is calculated by the intermediate value of group of solvents mouse tumor volume and the difference of medicine group mouse tumor volume-median, represents, calculated by following formula with the per-cent of solvent control group gross tumor volume intermediate value:
Primary statistics is analyzed and has been come by repeating variance determination and analysis (RMANOVA).Next multiple comparisons is carried out by Scheffe psot hoc test method.Separate solvent (2%HPMC+1% twen-80, etc.) be negative control.Compound of the present invention generally all has 100mpk or is less than the activity of 100mpk.
By embodiment 53 with the dosage (p.o.) of every day (QD) 10,30 and 100mg/kg, give 21 days continuously.All dosage has significance statistically, the suppression of dose-dependently can go the growth of the subcutaneous U87MG tumour of athymic nude mice.The last day (the 21st day) of administration, compare with the mean tumour volume of group of solvents, 10,30 and 100mg/kg dosage suppress 47%, 76% and 99% (TGI) of mean tumour volume respectively.Particular case as shown in Figure 1.
By embodiment 72 with the dosage (p.o.) of every day (QD) 10,30 and 60mg/kg, give 18 days continuously.All dosage has significance statistically, the suppression of dose-dependently can go the growth of the subcutaneous MKN45 tumour of athymic nude mice.The last day (the 18th day) of administration, compare with the mean tumour volume of group of solvents, 10,30 and 60mg/kg (administration in 0-10 days and administration in 13-18 days) dosage suppress 29%, 62% and 87% (TGI) of mean tumour volume respectively.Particular case as shown in Figure 2.
Record is finally needed to realize two kinds of modes of the present invention.Correspondingly, embodiments of the invention to be illustratively described, but be not limited to content described in the invention, may be also amendment done within the scope of the present invention or equivalents added in the claims.All publications that the present invention quotes or patent are all as reference of the present invention.

Claims (21)

1. one kind such as formula the compound shown in (I):
Or its racemic mixture, or pharmacy acceptable salt, wherein:
R 1, R 2, R 3and R 4be selected from H independently of one another, C 1 ~ 3aliphatics, or R 1, R 2, R 3and R 4the common Norleucyl base group defined is selected from Isoleucine, leucine, Methionin, methionine(Met), phenylalanine, Threonine, tryptophane, α-amino-isovaleric acid, L-Ala, l-asparagine, aspartic acid, glutaminate, glutamine, proline(Pro), Serine, to tyrosine, arginine, Histidine, halfcystine, sarkosine, glycine, N, N-N-methylsarcosine, homoserine, norvaline, nor-leucine, ornithine, homocysteine, hyperphenylalaninemia, phenylglycocoll, adjacent tyrosine, the group that m-Tyrosine or oxyproline are formed,
Y 1and Y 2be selected from divalent group independently of one another: alkylidene group, C 3-8sub-carbocylic radical or spiral shell C 6-10sub-assorted bicyclic group;
W is O, N-R 11or (CR 12r 12a) m; Wherein m is 0,1 or 2;
Q is selected from following structural formula:
Wherein U is CH or N;
R 5and R 6be selected from H or methoxyl group independently of one another;
R 7h or F;
R 10phenyl or fluorophenyl;
R 11and R 11abe selected from H independently of one another, C 1-3alkyl, C 1-3haloalkyl, C 1-3hydroxyalkyl, C 1-3aminoalkyl group; With
R 12and R 12abe selected from H independently of one another, F, Cl, Br, I, hydroxyl; Or work as R 12and R 12abe connected with same carbon atom, so R 12, R 12a, and together with the carbon atom be connected with them, carbocyclic ring or the heterocycle of substituted or non-substituted 3-8 unit can be formed arbitrarily.
2. compound according to claim 1, wherein pharmacy acceptable salt is hydrochloride, hydrobromate, vitriol, nitrate, phosphoric acid salt, acetate, maleate, succinate, mandelate, fumarate, malonate, malate, 2 hydroxy propanoic acid salt, pyruvate salt, oxalate, oxyacetate, salicylate, glucuronate, galacturonic hydrochlorate, citrate, tartrate, aspartate, glutaminate, benzoate, cinnamate, tosilate, benzene sulfonate, mesylate, esilate, fluoroform sulphonate or their combination.
3. compound according to claim 1, wherein R 1, R 2, R 3and R 4the common Norleucyl base group defined is Isoleucine, leucine, Methionin; methionine(Met), phenylalanine, Threonine; tryptophane, α-amino-isovaleric acid, L-Ala; l-asparagine, aspartic acid, L-glutamic acid; glutamine, proline(Pro), Serine; tyrosine, the group that arginine or Histidine are formed, wherein each amino acid above-mentioned has S configuration at alpha position.
4. compound according to claim 1, wherein R 1, R 2, R 3and R 4the common Norleucyl base group defined is the cysteine residues at alpha position with R configuration.
5. compound according to claim 1, wherein R 1, R 2, R 3and R 4the common Norleucyl base group defined is glycine, and sarkosine, or the group that DMG is formed, wherein each amino acid above-mentioned is the molecule not having chirality.
6. compound according to claim 1, wherein Q is selected from following structural formula:
Wherein R 5and R 6be selected from H or OMe independently of one another; Z is H or F.
7. compound according to claim 1, the Y in its Chinese style (I) 1, Y 2, the minor structure that W and Q is common defined is selected from following structural formula:
Wherein AA is R 1, R 2, R 3and R 4the common glycyl base section defined; X is H or OH; 0,1,2 or 3 with p.
8. compound according to claim 1, it has such as formula the arbitrary shown structure of (1) ~ formula (79):
9. pharmaceutical composition comprises a compound according to claim 1, and pharmaceutically acceptable carrier, vehicle, thinner, assistant agent, vehicle or their combination.
10. pharmaceutical composition according to claim 9, it further comprises additional treatment agent, and these additional treatment agent are selected from chemotherapeutic agent, antiproliferative, be used for the treatment of atherosclerotic medicine, be used for the treatment of the medicine of pulmonary fibrosis, or their combination.
11. pharmaceutical compositions according to claim 10, wherein said additional treatment agent is Zorubicin (Adriamycin), Wyeth-Ayerst Laboratories (Rapamycin), Temsirolimus, everolimus (Everolimus), Ixabepilone, gemcitabine (Gemcitabin), endoxan (Cyclophosphamide), dexamethasone (Dexamethasone), Etoposide (Etoposide), Fluracil (Fluorouracil), imatinib mesylate (Imatinib mesylate), Dasatinib (Dasatinib), nilotinib (Nilotinib), erlotinib (Erlotinib), lapatinibditosylate (Lapatinib), Iressa (Iressa), Xarelto (Sorafenib), Sutent (Sunitinib), Interferon, rabbit (Interferon), carboplatin (Carboplatin), Hycamtin (Topotecan), taxol, vinealeucoblastine(VLB), vincristine(VCR), Temozolomide (Temozolomide), tositumomab (Tositumomab), Trabedectin, Avastin (Bevacizumab), Trastuzumab (Trastuzumab), Cetuximab (Cetuximab), Victibix (Panitumumab), or their combination.
12. 1 kinds use the compound described in claim 1 to produce for protection, process or treatment patient proliferative disease, and alleviate the purposes of the medicine of its severity.
13. 1 kinds use the pharmaceutical composition described in claim 9-11 any one to produce for protection, process or treatment patient proliferative disease, and alleviate the purposes of the medicine of its severity.
14. purposes according to claim 12, wherein said proliferative disease is metastatic carcinoma, colorectal carcinoma, adenocarcinoma of stomach, bladder cancer, breast cancer, kidney, liver cancer, lung cancer, thyroid carcinoma, brain tumor, neck cancer, prostate cancer, carcinoma of the pancreas, the cancer of CNS (central nervous system), glioblastoma, myeloproliferative disease, atherosclerosis or pulmonary fibrosis.
15. purposes according to claim 13, wherein said proliferative disease is metastatic carcinoma, colorectal carcinoma, adenocarcinoma of stomach, bladder cancer, breast cancer, kidney, liver cancer, lung cancer, thyroid carcinoma, brain tumor, neck cancer, prostate cancer, carcinoma of the pancreas, the cancer of CNS (central nervous system), glioblastoma, myeloproliferative disease, atherosclerosis or pulmonary fibrosis.
16. 1 kinds for non-diseases diagnosis or therapeutic purpose, suppress in biological sample or the method for adjustment protein kinase activity, described method comprises and uses compound described in claim 1 to contact with described biological sample.
17. 1 kinds for non-diseases diagnosis or therapeutic purpose, suppress in biological sample or the method for adjustment protein kinase activity, described method comprises and uses pharmaceutical composition described in claim 9 to contact with described biological sample.
18. methods according to claim 16, wherein protein kinase is receptor tyrosine kinase.
19. methods according to claim 18, wherein receptor tyrosine kinase is KDR, c-Met or IGF1R.
20. methods according to claim 17, wherein protein kinase is receptor tyrosine kinase.
21. methods according to claim 20, wherein receptor tyrosine kinase is KDR, c-Met or IGF1R.
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Address after: 523808 No.1, Gongye North Road, Songshanhu Park, Dongguan City, Guangdong Province

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