CN102702068B - 3-pyrrolo-cyclohexylidene-2-dihydroindolone derivative, and application of 3-pyrrolo-cyclohexylidene-2-dihydroindolone derivative - Google Patents

3-pyrrolo-cyclohexylidene-2-dihydroindolone derivative, and application of 3-pyrrolo-cyclohexylidene-2-dihydroindolone derivative Download PDF

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CN102702068B
CN102702068B CN201210162848.5A CN201210162848A CN102702068B CN 102702068 B CN102702068 B CN 102702068B CN 201210162848 A CN201210162848 A CN 201210162848A CN 102702068 B CN102702068 B CN 102702068B
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indoles
methyl
tetrahydrochysene
oxo
carboxylic acid
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CN102702068A (en
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唐锋
沈晗
金秋
丁磊
杨洁
殷晓进
卢是玥
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Nanjing Yoko Biomedical R & D Ltd
NANJING YOKO PHARMACEUTICAL CO Ltd
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NANJING YOKO BIO-MEDICAL RESEARCH Co Ltd
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Abstract

The invention relates to a 3-pyrrolo-cyclohexylidene-2-dihydroindolone derivative and an application of the 3-pyrrolo-cyclohexylidene-2-dihydroindolone derivative. Biology experiments show that the compound or pharmaceutically acceptable salts of the compound have a function in adjusting the activity of protein kinase and are capable of inhibiting activity of a plurality of tyrosine kinases and synchronously inhibiting proliferation of a plurality of tumor cells.

Description

3-pyrrole ring caproic subunit-2-dihydroindolone derivatives and uses thereof
The application is to be that " on December 03rd, 2007 ", application number are the divisional application that " 200780006890.5 ", name are called the application for a patent for invention of " 3-pyrrole ring caproic subunit-2-dihydroindolone derivatives and uses thereof " applying date.
Technical field
The present invention relates to 3-pyrrole ring caproic subunit-2-dihydroindolone derivatives and uses thereof.The invention still further relates to the preparation method of this compounds and the intermediate of this compounds.
Background technology
Below offering of materials and do not think prior art of the present invention as a setting only.
At present, many 2-dihydroindolone micromolecular compounds have been attempted to identify as kinases inhibitor, be widely used in the multiple disease relevant to aberrant kinase activity for the treatment of, if tumour, psoriasis, liver cirrhosis, diabetes, blood vessel generation, ophthalmic diseases, rheumatoid arthritis and other inflammatory disease, Immunological diseases, cardiovascular disorder are as arteriosclerosis and multiple ephrosis.Wherein, indirubin compounds (PCT WO2001037819, PCT WO2002092079), 3-methylene pyrrole-2-indoline ketone compounds (US6642251, PCT WO2001060814, PCT WO2003035009, PCT WO2005053686), 3-pyrrolocyclopenta subunit-2-indoline ketone compounds (PCT WO2005016875) and other 2-indoline ketone compounds (PCT WO 2000012084) etc. are all described for treating the kinase inhibitor of cancer.
Mammalian cell has similar molecular mechanism, regulates propagation, differentiation and the death of cell within the whole cell cycle.Wherein, protein phosphorylation is the main mechanism of cross-film or intracellular signal transduction, have the function of regulating cell circulation, and phosphorylation is subject to the control of protein kinase (PKs) and phosphoprotein phosphatase.Protein kinase is current known maximum protein family, and all kinases have a very conservative catalytic core and various regulation and control model.The effect of protein kinase is that the γ phosphate of ATP is transferred to specific amino-acid residue on their substrates.According to the specificity of these amino-acid residues, these kinases are divided into 4 classes, wherein two main classes are albumen serine/threonine kinase (STKs) and protein tyrosine kinase (PTKs).In eukaryote, between the acceptor of cell surface and endonuclear re-reading system, there is separation and the distance of physics, extracellular signal affects the effect of the cascade system of some protein kinase by acceptor, through the phosphorylation of multistep protein, finally change the activity of transcription factor, genetic transcription is activated or retardance.Wherein, protein tyrosine kinase and albumen serine/threonine kinase have vital role in Normocellular signal transduction mechanism, their unconventionality expression will cause the generation of numerous disease, as tumour, arteriosclerosis, psoriasis and inflammatory reaction etc., thereby regulate and control these kinase whose activity, recover physiological equilibrium and can be used as a kind of new treatment means.
Family tyrosine kinase participates in cell signalling widely with transmembrane receptor (receptor tyrosine kinase, RTKs) or kytoplasm form (nonreceptor tyrosine kinase, CTKs).In human genome, protein kinase group comprises 30 kinds of family tyrosine kinases, contains altogether 90 kinds of different protein tyrosine kinases, and wherein 58 kinds is receptor tyrosine kinase.The discussion more detailed to Tyrosylprotein kinase, referring to Manning G, Science, 2002,298:1912, it comprises that any drawing proposes as an entirety in full, incorporated herein by reference.Receptor tyrosine kinase is the transmembrane protein that a class has kytoplasm region, and extracellular region is ligand structure territory, and part is solubility or membrane-bound polypeptide or protein hormone, comprises Regular Insulin and multiple somatomedin.Born of the same parents' inner segment is the catalytic site of protein tyrosine kinase, and has autophosphorylation site, and its inherent catalytic activity is activated when with ligand binding.This receptoroid mainly contains EGFR(EGF-R ELISA), VEGFR(vascular endothelial growth factor receptor), PDGFR(platelet derived growth factor receptor), FGFR(fibroblast growth factor acceptor) etc.Most important downstream signal cascade reaction is to be activated by RTKs, comprising ERK/MAPK signal path, and PI-3 kinases-AKT signal path and JAK/STAT signal path.PTKs maintains mutual signal and communication in all these different transduction pathway, the transcribing of final regulation and control gene.In addition, other cascade reaction also can be used.The regulation mechanism of non-acceptor PTKs differs greatly, they by with the effect of transmembrane receptor generation physical property, and then participate in extracellular signal response (Grosios k, et al, Drugs Fut, 2003,28:679).
Such as, in many intracellular signal proteins (Shc, Grb2, Src, Cbl, Phospholipase C g and 3 '-Phosphoinoside kinase [PI-3kinase] etc.), these tyrosine residuess that are phosphorylated are present in the calmodulin binding domain CaM of Tyrosine O-phosphate as docking site.The mixture that these are activated in cytolemma has impelled initial signal cascade reaction, and this has crucial effect to downstream signal and biological effect.If receptor deficiency catalytic activity, can with the coupling of non-acceptor PTKs phase, the kytoplasm region by non-covalent associating and a receptor subunit forms " binary acceptor ".Most important downstream signal cascade is to be activated by RTKs, comprising ERK/MAPK signal path, and PI-3 kinases-AKT signal path and JAK/STAT signal path.PTKs maintains mutual signal and communication in all these different transduction pathway, the transcribing of final regulation and control gene.In addition, other cascade reaction also can be used, and for example insulin receptor (InsR) utilizes adenylyl cyclase signal transduction system, the serine-threonine Special Proteins kinases that activation cAMP relies on.
The regulation mechanism of nonreceptor tyrosine kinase (CTKs) differs greatly, and they are by for example, with transmembrane receptor (hormone, cytokine and growth factor receptors) physical property effect occurring, and then the response of participation extracellular signal.In the specified phase of cell cycle, in the time that combining with extracellular part or cell adhesion composition, these acceptors are activated.
In normal cell, the rapid internalization of the RTKs of activation is also left cell surface, thereby modification inhibitory enzyme activity occurs.This activation of guaranteeing signal cascade reaction is of short duration, and cell can return to non-stimulation state in time.But, the change of many structures, as single amino acids replaces and the amino acid whose disappearance of large section, or the imbalance of Inhibitory signal and self-acting control mechanism, can cause kinases and catalysis region thereof to continue in active state.The PTKs sustained activation that numerous disease causes to this sudden change and PTKs false demonstration or overexpression are relevant.In the characterization of molecules process of malignant tumour, finding the PTKs that nearly half is known,, there is sudden change or the situation of overexpression in such as EGFR, ErbB2, Ret, Kit, Src, Abl, PDGFR, VEGF1/2/3, FGFR1/2/3 etc.Meanwhile, the prediction of the overexpression of clinical studies show Tyrosylprotein kinase or the prognosis of imbalance to tumour patient and symptom has important references and is worth (Madhusudan S, et al, Clin Biochem, 2004,37:618).From the above mentioned, Tyrosylprotein kinase is very important to the autologous adjusting of physiology, and transgenation/rearrangement can make PTKs extremely or overexpression, thereby causes the generation of disease, therefore can use the agonist of these enzymes or antagonist to treat.
For example, no matter be that potential gene alteration or the existence of abnormal receptor all can have disease phenotype (cancer) separately, and relevant with extracellular signal transmission in cell cycle and born of the same parents, for example paracrine and Autocrine transmission.The overexpression of somatomedin (for example EGF, VEGF, PDGF) acceptor and somatomedin often causes propagation and tumor-blood-vessel growth and the transfer of tumour cell.
Vasculogenesis (angiogenesis) refers to from already present blood vessel grows the vascular system making new advances.Normal vasculogenesis only exists in some short-term, specific physiological process, as reproduction, wound healing etc.Abnormal vasculogenesis is one of pathological manifestations of the malignant diseases such as tumour, rheumatic arthritis, diabetic retinopathy.Folkman has proposed tumor growth and has depended on the hypothesis of vasculogenesis on the basis of a large amount of clinical practices and experiment accumulation: tumour is at the commitment forming owing to lacking new vessel, and diameter is limited in 2 ~ 3nm, and number of cells is no more than 1,000,000; Only at tumor angiogenesis factor (the Tumor-angiogenesis Factor of tumor cell secretion, TAF) intravasation generation under mediation, obtain after sufficient oxygen and nutriment supply, tumour ability ramp (Folkman J, N Engl J Med, 1971,285:1182), thus based on blocking-up TAF angiogenesis inhibitor can be used as new oncotherapy means.
Tumour cell can be secreted multiple angiogenesis factor, between them, connect each other and regulate and control, its vascular endothelial growth factor (VEGF) is in core status, it is the angiogenesis factor that current known activity is the strongest, specificity is the highest, and other angiogenesis factor mostly produces effect (Zhang QX, et al, the J Surg Res of vasculogenesis by strengthening the expression of VEGF, 1997,67:147).VEGF in vivo Various Tissues has expression as in lung, spleen, kidney, liver etc. and most tumour cells.The expression of VEGF is regulated and controled by many factors, and anoxic is the factor of the strongest induction vegf expression found up to now; Prostatropin (bFGF), Urogastron (EGF), platelet derived growth factor (PDGF), keratinocyte growth factor (KGF), placenta growth factor (PLGF), transforming growth factor-beta (TGF β), insulin-like growth factor-i (IGF-1), tumor necrosis factor alpha (TNF α), interleukin (IL)-1 β, IL-6 and NO etc. also can promote the expression of VEGF; And interferon-' alpha ' (IFN-α), IL-10 and IL-12 etc. can suppress the expression of VEGF; In addition, oncogene ras, raf, src and cancer suppressor gene vHL, the sudden change of p53 all can increase the expression (Neufeld G, et al, FASEB J, 1999,13:9) of VEGF.
Vegf receptor (VEGFR) is at present known 3 kinds: VEGFR-1/Flt-1, VEGFR-2(Flk-1/KDR) and VEGFR-3/Flt-4.Wherein VEGFR-1 and VEGFR-2 have expression specifically on vascular endothelial cell, closely related with vasculogenesis.VEGFR belongs to tyrosine kinase receptor family, is the transmembrane protein that a class has kytoplasm region, and its expression is subject to the induction of VEGF.Compared with the low expression level of normal human tissue, in most malignant tumours, all present the high expression level of VEGF and acceptor (VEGFR) thereof, and VEGFR is not only expressed in vascular endothelial cell, also be expressed in tumour cell, thereby think except paracrine, also there is autocrine approach, as vascular endothelial cell specificity mitogen, produce VEGF by malignant cell secretion and act on adjacent matrix vascular endothelial cell vegf receptor, promote vascular endothelial cell division, propagation, induced tumor angiogenesis, increase vascular permeability promotes tumor growth to shift simultaneously, and directly act on tumour cell, Tumor Cell Growth Stimulated.(referring to Li Rong, foreign medical science physiology, pathology science and clinical fascicle, 2002,22:475 and citing document thereof)
Sudden change, the crosstalking of signal protein of PKs are the pathology reasons that causes tumour, equally also can cause the generation of Other diseases.In some immunodeficiency symptoms, can observe the mutagenicity inactivation of non-receptor tyrosine, the inactivation of for example JAK3 causes serious severe combined immunodeficiency (Leonard WJ, Nat Rev Immunol, 2001,1:200; Leonard WJ, Int J Hematol, 2001,73:271).Bruton protein tyrosine kinase (BTK or BPK, ATK) belongs to Src family, it is the ripe necessary a kind of Tyrosylprotein kinase of B cell development, and that Btk transgenation meeting causes is congenital without Immunoglobulinemia (Cheng G, et al, Proc Natl Acad Sci USA, 1994,91:8152; Maas A, et al, J Immunol, 1999,162:6526).PTK also has important physiological action in central nervous system, its not normal generation that also can cause corresponding disease, for example relevant (the Ferguson SS of immunoreactivity of neurone spot and neuregulin-1 (neuregulin-1) and ErbB4 in AD, Trends Neurosci, 2003,26:119; Chaudhury AR, et al, J Neuropathol Exp Neurol, 2003,62:42).RhIGF-1 (IGFs) and adjusting albumen thereof are to be secreted by cardiovascular systems, these factor dysregulations can cause developing of coronary atherosclerosis and restenosis, and the effect of IGFs is mediated by specific membranes acceptor, wherein IGF receptor type I has tyrosine kinase activity, comes across the smooth muscle cell of atherosclerotic lesions, inflammatory cell and arterial endothelial cell (Bayes-genis A, et al, Circ Res, 2000,86:125; Bayes-genis A, et al, Artherio Thromb and Vascu Biol, 2001,21:335; Che WY, et al, Circ Res, 2002,90:1222).Vascular endothelial growth factor and acceptor thereof are expressed in the various kinds of cell of rheumatoid arthritis, and are the key factors (De Bandt M, et al, J Immunol, 2003,1712:4853) in rheumatoid arthritis rationality angiogenic process.Jak2 is endochylema nonreceptor tyrosine kinase, and JAK2 transgenation at least causes three kinds of diseases (Spivak JL, Blood, 2002,100:4272; Thiele J, et al, Acta Haematol, 2004,111:155)---polycythemia vera (PV), idiopathic myelofibrosis (IMF), primary thrombocytosis (ET) and some other myeloproliferative diseases that is not true to type (MPD).The trans-regional sudden change of fibroblast growth factor acceptor can cause the most common heredity nanism---osteochondrodysplasia (Shiang R, et al, Cell, 1994,78:335).
In addition, numerous disease and shortage PTK signal correction, for example non-insulin-dependent diabetes mellitus (NIDDM) and peripheral neuropathy, and can effectively improve symptom (Hunter T, Cell, 2000,100:111) by the transmission of wild phase induction signal.For some other and blood vessel, relevant disease occurs, for example some cardiovascular disorder, stimulates vasculogenesis than suppressing more effective.
Along with molecular biological research is goed deep into, on molecular level, for cell signalling, the function of the growth regulation factor and regulation and control oncogene are the effective ways that suppresses cell proliferation and treat tumour.This approach can weaken the effect of improper signalling channel, stops the growth of tumour, also can impel death of neoplastic cells simultaneously.Find that there is so far half proto-oncogene and on encoding histone, all there is PTK structure, they participate in cell signalling by phosphorylation and dephosphorylation, simultaneously in tumour generating process, the PTK of variation or overexpression can change normal cell into cancer cells, promotes growth and the mitotic division of tumour cell simultaneously.
Meanwhile, the growth of malignant tumour and shift all must be by new vessel around to continue to provide sufficient nutrient.The process that tumour generates blood vessel roughly can be divided into blood vessel early stage and two stages of blood vessel phase, and two stage conversion is called angiogenic switch (angiogenic switch).Tumour cell transfers to and generates blood vessel hyperplasia phenotype and in knurl malignization process, play keying action: when around while thering is no vasculogenesis, tumour cell cannot obtain enough nutrients also cannot discharge metabolite simultaneously, main dependence disperse is in pericellular oxygen and nutritive substance existence, and tumour can only grow to diameter 1-2mm; But once change blood vessel hyperplasia phenotype into, avascular tumour can be utilized nutrition in self-blood and Fast Growth, and these malignant cells can cause the phenotypic alternation of other cell simultaneously, as endotheliocyte etc., and then impel neovascularization.Angiogenesis factor modulating vascular generates switch, the migration, propagation and the form that cause endotheliocyte change, thereby generation tumor vessel, and all known angiogenesis factors are all mainly the parts of PTKs at present, as (Bergers G, et al, Nat Rev Cancer such as VEGF, bFGF, PD-ECGF, 2003,3:401).Therefore use tyrosine kinase inhibitor as angiogenesis inhibitor material, stoping tumor-blood-vessel growth is also the effective way of controlling malignant growth.
Because Tyrosylprotein kinase has important effect in the carinogenicity conversion process of cell, and have directly or indirectly and contact with the generation of tumour and development, the treatment that therefore tyrosine kinase inhibitor is applied to tumour is particularly suitable.
Serine-threonine kinase (STKs) is the kinases family of a large class specificity catalytic protein Serine and threonine residues phosphorylation.The same with non-acceptor PTKs, STKs is dominate in cell, although only have several STK receptor kinases.STKs is modal cytosol kinases, and kinases is brought into play their function in tenuigenin part rather than in cytoplasmic organoid and cytoskeleton, and then affects the inside biological chemistry of cell, often as the descending reaction to PTK event.STK can participate in signalling process simultaneously, and the latter causes the synthetic mitotic division with causing subsequently cell proliferation of DNA.In addition STKs has related to polytype cancer, as mammary cancer (Cance et al, Int.J.Cancer, 1993,55,571) etc.
In a word, PTKs and STKs all obviously and host's pathological condition comprise related to cancer.Other pathological condition relevant with PKs also includes but is not limited to psoriasis, liver cirrhosis, diabetes, blood vessel generation, restenosis, ophthalmic diseases, rheumatoid arthritis and other inflammatory disease, Immunological diseases, cardiovascular disorder as arteriosclerosis and multiple ephrosis.
At present, attempt to identify the 2-dihydroindolone micromolecular compound as PK inhibitor, for example indirubin compounds (PCT WO2001037819, PCT WO2002092079), 3-methylene pyrrole-2-indoline ketone compounds (US6642251, PCT WO2001060814, PCT WO2003035009, PCT WO2005053686) and 3-pyrrolocyclopenta subunit-2-indoline ketone compounds (PCT WO2005016875) and other 2-indoline ketone compounds (PCT WO 2000012084) etc. be all described for treating STK and/or the ptk inhibitor of cancer.
Summary of the invention
The present invention relates to new 2-indoline ketones derivant, they show has regulating effect to the activity of protein kinase, the propagation of tumour cell is had to inhibition ability simultaneously.In addition the present invention relates to the to come into the open Preparation Method And Their Intermediate of compound.
The term " 2-dihydroindolone ", " the 2-oxyindole " and " 2-oxindole " that are used interchangeably at this refer to the molecule with following chemical structure.
" pyrrole ring caproic subunit " refers to the molecule with following chemical structure.
Figure BDA00001671821300042
" 3-pyrrole ring caproic subunit-2-dihydroindolone " refers to the compound with the formula showing in formula (I).
" pyrrole ring caproic ketone " refers to the compound with the formula showing in formula (II).
" pharmacy acceptable salt " represents to retain the biological effectiveness of parent compound and those salt of character.This class salt comprises:
(1) with sour salify, free alkali by parent compound reacts and obtains with mineral acid or organic acid, mineral acid is (but being not limited to) hydrochloric acid for example, Hydrogen bromide, nitric acid, phosphoric acid, metaphosphoric acid, sulfuric acid, sulfurous acid and perchloric acid etc., organic acid is (but being not limited to) acetic acid for example, propionic acid, vinylformic acid, oxalic acid, (D) or (L) oxysuccinic acid, fumaric acid, toxilic acid, hydroxy-benzoic acid, gamma-hydroxybutyric acid, methoxybenzoic acid, phthalic acid, methylsulfonic acid, ethyl sulfonic acid, naphthalene-1-sulfonic acid, naphthalene-2-sulfonic acid, tosic acid, Whitfield's ointment, tartrate, citric acid, lactic acid, amygdalic acid, succsinic acid or propanedioic acid etc.
(2) salt that is present in that acid proton in parent compound is replaced by metal ion or is generated with organic bases ligand compound, metal ion is alkalimetal ion, alkaline-earth metal ions or aluminum ion for example, and organic bases is thanomin, diethanolamine, trolamine, Trometamol, N-METHYL-ALPHA-L-GLUCOSAMINE etc. such as.
" medicinal compositions " refers to one or more compounds described here or their pharmacy acceptable salt and prodrug and other chemical composition, for example mixture of pharmaceutically acceptable carrier and vehicle.The object of medicinal compositions is to promote the administration of compound to organism.
" pharmaceutically acceptable carrier " refers to organism do not caused obvious pungency and do not disturb the biological activity of given compound and the carrier of character or thinner.
" vehicle " refers to and joins in medicinal compositions with the further convenient inert substance that gives compound.The example of vehicle comprises (being not limited to) calcium carbonate, calcium phosphate, various saccharides and polytype starch, derivatived cellulose, gelatin, vegetables oil and polyoxyethylene glycol.
1. chemistry
A. general structure feature
The compound with formula (I) structure the present invention relates to:
Figure BDA00001671821300051
Wherein:
R 1hydrogen, halogen, alkyl, cycloalkyl, aryl, heteroaryl, heterolipid cyclic group, hydroxyl, alkoxyl group ,-C (O) R 7,-NR 8r 9,-(CH 2) nr 10or-C (O) NR 11r 12;
R 2hydrogen, halogen, alkyl, haloalkyl, hydroxyl, alkoxyl group, halogenated alkoxy, nitro, cyano group ,-NR 8r 9,-NR 8c (O) R 9,-C (O) R 7, aryl, heteroaryl ,-C (O) NR 11r 12,-S (O) 2nR 8r 9or-SO 2r 13;
R 3hydrogen, halogen, alkyl, haloalkyl, hydroxyl, alkoxyl group ,-C (O) R 7,-NR 8r 9, aryl, heteroaryl ,-NR 8s (O) 2r 9,-S (O) 2nR 8r 9,-NR 8c (O) R 9,-NR 8c (O) OR 9or-SO 2r 13;
R 4be hydrogen, halogen, alkyl, hydroxyl, alkoxyl group or-NR 8r 9;
R 5be hydrogen, alkyl or-C (O) R 14;
R 6hydroxyl, alkoxyl group, aryloxy ,-N (R 15) (CH 2) rr 16,-NR 8r 9or-N (R 17)-CH (R 18)-CR 19(OH)-CH (R 20) Z;
R 7hydrogen, hydroxyl, alkoxyl group or aryloxy;
R 8and R 9independently selected from hydrogen, alkyl, cycloalkyl, aryl or heteroaryl, or R 8and R 9form altogether a heterocyclic radical;
R 10hydroxyl ,-C (O) R 7,-NR 8r 9or-C (O) NR 8r 9;
R 11and R 12independently selected from hydrogen, alkyl or aryl, or R 11and R 12together with the nitrogen-atoms connecting with them, form heterocyclic radical;
R 13alkyl, aryl, aralkyl, heteroaryl or heteroaralkyl;
R 14be hydroxyl, alkoxyl group, aryloxy or-NR 8r 9;
R 15it is hydrogen or alkyl;
R 16hydroxyl ,-NR 8r 9,-C (O) R 7, aryl, heteroaryl ,-N +(O -) R 8r 9,-N (OH) R 8or-NHC (O) R a, wherein R afor unsubstituted alkyl, haloalkyl or aralkyl;
R 17, R 18, R 19and R 20independently selected from hydrogen or alkyl;
Z be aryl, heteroaryl, heterocyclic radical or-NR 8r 9;
N and r are 1,2,3 or 4 independently.
Unless otherwise indicated, the following term using in specification sheets and claim has implication discussed below:
" alkyl " represents the saturated aliphatic radical of 1-20 carbon atom, comprise straight chain and the branched group (digital scope of mentioning in the application's book, for example " 1-20 ", refer to this group, it is now alkyl, can contain 1 carbon atom, 2 carbon atoms, 3 carbon atoms etc., until comprise 20 carbon atoms).Alkyl containing 1-4 carbon atom is called low alkyl group.In the time that low alkyl group does not have substituting group, be called unsubstituted low alkyl group.More preferably, alkyl is the medium sized alkyl that has 1-10 carbon atom, such as methyl, ethyl, propyl group, 2-propyl group, normal-butyl, isobutyl-, the tertiary butyl, amyl group etc.Preferably, alkyl is the low alkyl group that has 1-4 carbon atom, such as methyl, ethyl, propyl group, 2-propyl group, normal-butyl, isobutyl-or the tertiary butyl etc.Alkyl can be that replace or unsubstituted.In the time being the alkyl replacing, this substituting group preferably one or more, more preferably 1-3, most preferably 1 or 2 substituting group, they are independently preferably from following group: halogen, hydroxyl, lower alkoxy, aryl, aryloxy, heteroaryl, heterolipid cyclic group ,-C (O) R 7,-NR 8r 9with-C (O) NR 11r 12, wherein R 7, R 8, R 9, R 11and R 12define the same.
" cycloalkyl " represents to be all the monocycle of carbon or the ring condensing (" condensing " ring means the shared a pair of carbon atom adjoining of other ring in each ring and the system in system) group, wherein one or more rings do not have the π-electron system connecting completely, and the example (being not limited to) of cycloalkyl is cyclopropane, tetramethylene, pentamethylene, cyclopentenes, hexanaphthene, diamantane, cyclohexadiene, suberane and cycloheptatriene.Cycloalkyl can be replacement with unsubstituted.In the time being substituted; substituting group is preferably one or more following groups that are selected from separately; comprise: alkyl, aryl, heteroaryl, heterolipid cyclic group, hydroxyl, alkoxyl group, aryloxy, sulfydryl, alkane sulfydryl, aromatic thiohydroxy, cyano group, halogen, carbonyl, thiocarbonyl, C-carboxyl, O-carboxyl, O-formamyl, N-formamyl, C-amido, N-amido, nitro, amino and-NR 8r 9, wherein R 8and R 9define the same.
" aryl " represents full carbon monocycle or the fused polycycle group of 1 to 12 carbon atom, has the π-electron system of total conjugated.The limiting examples of aryl has phenyl, naphthyl and anthryl.Aryl can be that replace or unsubstituted.In the time being substituted; substituting group is preferably one or more; more preferably one, two or three; and then more preferably one or two, independently selected from by low alkyl group, three alkylhalide groups, halogen, hydroxyl, lower alkoxy, sulfydryl, (low alkyl group) sulfenyl, cyano group, acyl group, sulfo-acyl group, O-formamyl, N-formamyl, O-thiocarbamoyl, N-thiocarbamoyl, C-amido, N-amido, nitro, N-sulfonamido, S-sulfonamido, R 8s (O)-, R 8s (O) 2-,-C (O) OR 8, R 8c (O) O-and-NR 8r 9the group of composition, R 8and R 9define the same.Preferably, aryl is replaced by one or two substituting group alternatively, and substituting group is independently selected from halogen, low alkyl group, three alkylhalide groups, hydroxyl, sulfydryl, cyano group, N-amido, list or dialkyl amino, carboxyl or N-sulfonamido.
" heteroaryl " represents monocycle or the fused rings group of 5 to 12 annular atomses, contains one, two, three or four ring hetero atoms that are selected from N, O or S, and all the other annular atomses are C, have in addition the π-electron system of total conjugated.Unsubstituted heteroaryl ground limiting examples has pyrroles, furans, thiophene, imidazoles, oxazole, thiazole, pyrazoles, pyrimidine, quinoline, isoquinoline 99.9, purine, tetrazolium, triazine and carbazole.Heteroaryl can be that replace or unsubstituted.In the time being substituted; substituting group is preferably one or more; more be preferably one, two or three; and then more preferred one or two; independently selected from following group, comprising: low alkyl group, three alkylhalide groups, halogen, hydroxyl, lower alkoxy, sulfydryl, (low alkyl group) sulfenyl, cyano group, acyl group, sulfo-acyl group, O-formamyl, N-formamyl, O-thiocarbamoyl, N-thiocarbamoyl, C-amido, N-amido, nitro, N-sulfonamido, S-sulfonamido, R 8s (O)-, R 8s (O) 2-,-C (O) OR 8, R 8c (O) O-and-NR 8r 9, wherein R 8and R 9define the same.Preferred heteroaryl is replaced by one or two substituting group alternatively, and substituting group is independently selected from halogen, low alkyl group, three alkylhalide groups, hydroxyl, sulfydryl, cyano group, N-amido, list or dialkyl amino, carboxyl or N-sulfonamido.
" heterolipid cyclic group " represents monocycle or fused rings group, has 5 to 9 annular atomses in ring, and wherein one or two annular atoms is to be selected from N, O or S (O) mthe heteroatoms of (wherein m is 0 to 2 integer), all the other annular atomses are C.These rings can have one or more pair of key, but these rings do not have the π-electron system of total conjugated.The limiting examples of unsubstituted heterolipid cyclic group has pyrrolidyl, piperidino-(1-position only), Piperazino, morpholino base, thiomorpholine Dai Ji etc.Heterolipid cyclic group can be that replace or unsubstituted.In the time being substituted; that substituting group is preferably is one or more, more preferably one, two or three; and then more preferably one or two; independently selected from following group, comprising: low alkyl group, three alkylhalide groups, halogen, hydroxyl, lower alkoxy, sulfydryl, (low alkyl group) sulfenyl, cyano group, acyl group, sulfo-acyl group, O-formamyl, N-formamyl, O-thiocarbamoyl, N-thiocarbamoyl, C-amido, N-amido, nitro, N-sulfonamido, S-sulfonamido, R 8s (O)-, R 8s (O) 2-,-C (O) OR 8, R 8c (O) O-and-NR 8r 9, wherein R 8and R 9define the same.Preferably, heterolipid cyclic group is replaced by one or two substituting group alternatively, and substituting group is independently selected from halogen, low alkyl group, three alkylhalide groups, hydroxyl, sulfydryl, cyano group, N-amido, list or dialkyl amino, carboxyl or N-sulfonamido.
" heterocyclic radical " represents the saturated cyclic group of 3 to 8 annular atomses, and wherein one or two annular atoms is to be selected from N, O or S (O) mthe heteroatoms of (wherein m is 0 to 2 integer), all the other annular atomses are C, wherein one or two C atom can be replaced by carbonyl alternatively.The ring of heterocyclic radical can be alternatively replaced by one, two or three substituting groups independently, substituting group be selected from low alkyl group (replaced by one or two substituting group alternatively, substituting group is independently selected from carboxyl or ester group), haloalkyl, halogen, nitro, cyano group, hydroxyl, alkoxyl group, amino, monoalkyl amido, dialkyl amino, aralkyl, heteroaralkyl ,-C (O) R(wherein R be alkyl) and-(CH 2) nY, wherein Y is heterolipid cyclic group or R 10, wherein n is 0 to 2 integer, R 10define the same.More specifically, term heterocyclic radical includes but not limited to THP trtrahydropyranyl, 2,2-dimethyl-1,3-dioxolane, piperidino-(1-position only), N-methyl piperidine-3-base, Piperazino, N-methylpyrrolidin-3-base, pyrrolidyl, morpholino base, thiomorpholine are for base, thiomorpholine generation-1-oxide compound, thiomorpholine generation-1,1-dioxide, 4-ethoxycarbonyl Piperazino, 3-oxo Piperazino, 2-imidazolone, 2-Pyrrolidone, tetrahydropyrimidin-2-ones and derivative thereof.Preferably, heterocyclic group is replaced by one or two substituting group alternatively, low alkyl group, the low alkyl group, hydroxyl, list or the dialkyl amino that are replaced by heterolipid cyclic group and heterolipid cyclic group that substituting group replaces independently selected from halogen, low alkyl group, by hydroxyl, carboxyl or ester group, wherein heterolipid cyclic group limiting examples has pyrrolidyl, piperidino-(1-position only), Piperazino etc.
" hydroxyl " expression-OH group.
The unsubstituted alkyl of " alkoxyl group " expression-O-() and-the unsubstituted cycloalkyl of O-().Representative example includes but not limited to methoxyl group, oxyethyl group, propoxy-, butoxy, ring propoxy-, cyclobutoxy group, cyclopentyloxy, cyclohexyloxy etc.
" aryloxy " expression-O-aryl and-O-heteroaryl.Representative example includes but not limited to phenoxy group, pyridyloxy, furans oxygen base, thiophene oxy, 2-pyrimidinyl oxy, pyrazine oxygen base etc. and derivative thereof.
" sulfydryl " expression-SH group.
" acyl group " expression-C (O)-R ' group; wherein R ' is selected from following group: hydrogen, unsubstituted low alkyl group, trihalogenmethyl, unsubstituted cycloalkyl, alternatively by one or more, preferably by 1,2 or 3 be selected from unsubstituted low alkyl group, trihalogenmethyl, unsubstituted lower alkoxy, halogen and-NR 8r 9the aryl that the substituting group of group replaces, wherein R 8and R 9define the same, alternatively by one or more, preferably by 1,2 or 3 be selected from unsubstituted low alkyl group, trihalogenmethyl, unsubstituted lower alkoxy, halogen and-NR 8r 9the heteroaryl (by ring carbon atom bonding) that the substituting group of group replaces, and alternatively by one or more, preferably by 1,2 or 3 be selected from unsubstituted low alkyl group, trihalogenmethyl, unsubstituted lower alkoxy, halogen and-NR 8r 9the heterolipid cyclic group (by ring carbon atom bonding) that the substituting group of group replaces, representational acyl group includes but not limited to ethanoyl, trifluoroacetyl group, benzoyl etc.
" sulfo-acyl group " expression-C (S)-R ' group, wherein R ' defines the same.
" ester group " expression-C (O) O-R ' group, wherein R ' define the same, but R ' can not be hydrogen.
" ethanoyl " expression-C (O) CH 3group.
" halogen " represents fluorine, chlorine, bromine or iodine, is preferably fluorine, chlorine or bromine.
" trihalogenmethyl " expression-CX 3group, wherein X is halogen as defined above.
" cyano group " expression-CN group.
" S-sulfonamido " expression-S (O) 2nR 8r 9group, wherein R 8and R 9define the same.
" N-sulfonamido " expression-NR 8s (O) 2r 9group, wherein R 8and R 9define the same.
" O-formamyl " expression-OC (O) NR 11r 12group, wherein R 11and R 12define the same.
" N-formamyl " represents R 8oC (O) NR 9-group, wherein R 8and R 9define the same.
" O-thiocarbamoyl " expression-OC (S) NR 11r 12group, wherein R 11and R 12define the same.
" N-thiocarbamoyl " represents R 8oC (S) NR 9-group, wherein R 8and R 9define the same.
" amino " expression-NH 2group.
" C-amido " expression-C (O) NR 8r 9group, wherein R 8and R 9define the same.
" N-amido " represents R 8c (O) NR 9-group, wherein R 8and R 9define the same.
" nitro " expression-NO 2group.
" haloalkyl " represents alkyl, preferably low alkyl group as defined above, and it is replaced by one or more identical or different halogen atoms, for example-CH 2cl ,-CF 3,-CCl 3,-CH 2cF 3,-CH 2cCl 3deng.
" halogenated alkoxy " represents alkoxyl group, preferably as defined above-O-alkyl, and wherein alkyl is replaced by one or more identical or different halogen atoms, preferably three halogen methoxyl groups, for example-OCF 3.
" aralkyl " represents alkyl, preferably low alkyl group as defined above, and it is replaced by aryl as defined above, for example-CH 2phenyl ,-(CH 2) 2phenyl ,-(CH 2) 3phenyl, CH 3cH (CH 3) CH 2phenyl and derivative thereof.
" heteroaralkyl " represents alkyl, preferably low alkyl group as defined above, and it is replaced by heteroaryl, for example-CH 2pyridyl ,-(CH 2) 2pyrimidyl ,-(CH 2) 3imidazolyl etc. and derivative thereof.
" monoalkyl amido " represents group-NHR, and wherein R is alkyl or unsubstituted cycloalkyl, such as methylamino, (1-methylethyl) amido, cyclohexylamino etc. as defined above.
" dialkyl amino " represents group-NRR, and wherein each R is alkyl or unsubstituted cycloalkyl, such as dimethyl amido, diethyl amido, N-methylcyclohexyl amido etc. as defined above independently.
" Piperazino " refers to the group with following chemical structure.
Figure BDA00001671821300081
" morpholino base " refers to the group with following chemical structure.
Figure BDA00001671821300082
" piperidino-(1-position only) " refers to the group with following chemical structure.
Figure BDA00001671821300083
" pyrrolidyl " refers to the group with following chemical structure.
Figure BDA00001671821300084
" optional " or " alternatively " mean subsequently described event or environment can but needn't occur, this explanation comprises the occasion that this event or environment occur and do not occur.For example, " heteroaryl is replaced by one or two substituting group alternatively " mean heteroaryl substituting group can but need not to be one, this explanation comprises the situation that situation that heteroaryl is replaced by substituting group and heteroaryl are replaced by two substituting groups.
B. preferred constitutional features
The compound preferably with formula (I) structure the present invention relates to:
Wherein:
R 1hydrogen, halogen, alkyl, cycloalkyl, aryl, heteroaryl, heterolipid cyclic group, hydroxyl, alkoxyl group ,-C (O) R 7,-NR 8r 9,-(CH 2) nr 10or-C (O) NR 11r 12;
R 2hydrogen, halogen, alkyl, trihalogenmethyl, hydroxyl, alkoxyl group, three halogen methoxyl groups, nitro, cyano group ,-NR 8r 9,-NR 8c (O) R 9,-C (O) R 7, aryl, heteroaryl ,-C (O) NR 11r 12,-S (O) 2nR 8r 9or-SO 2r 13;
R 3hydrogen, halogen, alkyl, trihalogenmethyl, hydroxyl, alkoxyl group ,-C (O) R 7,-NR 8r 9, aryl, heteroaryl ,-NR 8s (O) 2r 9,-S (O) 2nR 8r 9,-NR 8c (O) R 9,-NR 8c (O) OR 9or-SO 2r 13;
R 4be hydrogen, halogen, alkyl, hydroxyl, alkoxyl group or-NR 8r 9;
R 5be hydrogen, alkyl or-C (O) R 14;
R 6hydroxyl, alkoxyl group ,-NR 8r 9,-N (R 15) (CH 2) rr 16or-NHCH (R 18)-CR 19(OH)-CH (R 20) Z;
R 7hydrogen, hydroxyl, alkoxyl group or aryloxy;
R 8and R 9independently selected from hydrogen, alkyl, cycloalkyl, aryl or heteroaryl, or R 8and R 9form altogether a heterocyclic radical;
R 10hydroxyl ,-C (O) R 7,-NR 8r 9or-C (O) NR 8r 9;
R 11and R 12independently selected from hydrogen, alkyl or aryl, or R 11and R 12together with the nitrogen-atoms connecting with them, form heterocyclic radical;
R 13alkyl, aryl, aralkyl, heteroaryl or heteroaralkyl;
R 14be hydroxyl, alkoxyl group, aryloxy or-NR 8r 9;
R 15it is hydrogen or alkyl;
R 16be hydroxyl, aryl, heteroaryl or-NR 8r 9;
R 18, R 19and R 20independently selected from hydrogen or alkyl;
Z be aryl, heteroaryl, heterocyclic radical or-NR 8r 9;
N is 1,2,3 or 4;
R is 1,2 or 3.
C. most preferred constitutional features
The most preferred compound with formula (I) structure the present invention relates to:
R 1, R 3and R 4that hydrogen, halogen or alkyl are the preferred features of the present invention;
R 2hydrogen, halogen, alkyl, alkoxyl group, three halogen methoxyl groups, nitro ,-NR 8c (O) R 9,-C (O) R 7,-S (O) 2nR 8r 9or-C (O) NR 11r 12the preferred feature of the present invention, wherein R 7preferably hydroxyl, alkoxyl group or aryloxy, R 11and R 12preferably hydrogen, alkyl or aryl, or R 11and R 12together with the nitrogen-atoms connecting with them, form heterocyclic radical;
R 5that methyl is the preferred feature of the present invention;
R 6hydroxyl ,-NR 8r 9,-N (R 15) (CH 2) rr 16or-NHCH 2cH (OH) CH 2-NR 8r 9be the preferred feature of the present invention, wherein r is 1,2 or 3, R 15preferably hydrogen or alkyl, R 8and R 9preferably hydrogen, alkyl, cycloalkyl, aryl or heteroaryl, or R 8and R 9form altogether a heterocyclic radical, R 16preferably hydroxyl, aryl, heteroaryl or-NR 8r 9, wherein-NR 8r 9be preferably-N (CH 3) 2,-N (CH 2cH 3) 2, morpholino base, Piperazino, piperidino-(1-position only), pyrrolidyl, N-methyl-Piperazino, N-methyl-cyclohexyl base amido, Isosorbide-5-Nitrae '-bis-piperidines-1 '-Ji, 2-(tetramethyleneimine-1-methyl)-pyrrolidin-1-yl, 4-(2-hydroxyethyl)-piperazine-1-base etc.;
2. synthetic and combinatorial libraries
A. combinatorial libraries
One aspect of the present invention is that the 2-oxyindole of formula (III) and the pyrrole ring caproic reactive ketone of formula (II) form the combinatorial libraries with formula (I) structural compounds.
Figure BDA00001671821300101
Wherein R 1, R 2, R 3, R 4, R 5and R 6there is illustrated implication in general structure (A).
" combinatorial libraries " refers in the compound of multidimensional array by each compound of one dimension and reacts with the compound in other each dimension all compounds that form as used herein.In the context of the invention, described array is 2-oxyindole class and all pyrrole ring caproic ketone of two-dimensional representation the present invention two dimension and that one-dimensional representation the present invention is all.Each 2-oxyindole can be with each pyrrole ring caproic reactive ketone to form 3-pyrrole ring caproic subunit-2-indolinone compounds as shown in the formula (I).The all 3-pyrrole ring caproic subunit-2-indolinone compounds that form with the method are in the scope of the invention.The less combinatorial libraries forming through some 2-oxyindoles and all pyrrole ring caproic reactive ketones, all 2-oxyindole and some pyrrole ring caproic reactive ketones or some 2-oxyindoles and some pyrrole ring caproic reactive ketones is also in the scope of the invention.
2-oxyindole in above combinatorial libraries is preferably for example, from 2-oxyindole itself and the 2-oxyindole replacing, the fluoro-2-dihydroindolone of (but being not limited to) 5-, the chloro-2-dihydroindolone of 5-, the bromo-2-dihydroindolone of 5-, 5-hydroxyl-2-dihydroindolone, 5-methyl-2-dihydroindolone, 5-ethyl-2-dihydroindolone, 5-normal-butyl-2-dihydroindolone, 5-methoxyl group-2-dihydroindolone, 5-trifluoromethoxy-2-dihydroindolone, 5-oxyethyl group-2-dihydroindolone, 5-nitro-2-dihydroindolone, 5-amino-2-dihydroindolone, 5-ethanoyl-2-dihydroindolone, 5-acetylaminohydroxyphenylarsonic acid 2-dihydroindolone, 5-is to fluoroanilino alkylsulfonyl-2-dihydroindolone, 5-amino-sulfonyl-2-dihydroindolone, 5-isopropylamino alkylsulfonyl-2-dihydroindolone, 5-dimethylamino-sulfonyl-2-dihydroindolone, 5-trifluoromethyl-2-dihydroindolone, 5-carboxyl-2-dihydroindolone, 5-carboxylate methyl ester-2-dihydroindolone, the fluoro-2-indoline of 6-, the fluoro-2-indoline of 7-, 6-methoxyl group-2-dihydroindolone, 6-methyl-2-dihydroindolone, the chloro-2-dihydroindolone of 6-, the fluoro-2-dihydroindolone of 4-, 4-methyl-2-dihydroindolone, 4-methyl-5-chloro-2-dihydroindolone, 5,7-dimethyl-2-dihydroindolone.
Pyrrole ring caproic ketone in above combinatorial libraries is preferably from (but being not limited to) 2-methyl-7-oxo-4, 5, 6, 7-tetrahydrochysene-1H-Indole-3-Carboxylic Acid, 2-methyl-7-oxo-4, 5, 6, 7-tetrahydrochysene-1H-Indole-3-Carboxylic Acid ethyl ester, N-(2-diethylin ethyl)-2-methyl-7-oxo-4, 5, 6, 7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides, N-(2-dimethylamino ethyl)-2-methyl-7-oxo-4, 5, 6, 7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides, N-(2-hydroxyethyl)-2-methyl-7-oxo-4, 5, 6, 7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides, 2-methyl-3-(4-methyl-piperazine-1-carbonyl)-7-oxo-4, 5, 6, 7-tetrahydrochysene-1H-indoles, 2-methyl-3-(morpholine-4-carbonyl)-7-oxo-4, 5, 6, 7-tetrahydrochysene-1H-indoles, N-[2-(piperidin-1-yl)-ethyl]-2-methyl-7-oxo-4, 5, 6, 7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides, N-[2-(pyrrolidin-1-yl)-ethyl]-2-methyl-7-oxo-4, 5, 6, 7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides, N-[2-(morpholine-4-yl)-ethyl]-2-methyl-7-oxo-4, 5, 6, 7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides, N-[2-(4-methyl-piperazine-1-yl)-ethyl]-2-methyl-7-oxo-4, 5, 6, 7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides, N-(3-dimethylamino-propyl)-2-methyl-7-oxo-4, 5, 6, 7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides, N-[3-(pyrrolidin-1-yl)-propyl group]-2-methyl-7-oxo-4, 5, 6, 7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides, N-[3-(piperidin-1-yl)-propyl group]-2-methyl-7-oxo-4, 5, 6, 7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides, N-[3-(morpholine-4-yl)-propyl group]-2-methyl-7-oxo-4, 5, 6, 7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides, N-[3-(4-methyl-piperazine-1-yl)-propyl group]-2-methyl-7-oxo-4, 5, 6, 7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides, N-(3-diethylin propyl group)-2-methyl-7-oxo-4, 5, 6, 7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides, N-[3-(diethylin)-2-hydroxypropyl]-2-methyl-7-oxo-4, 5, 6, 7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides, N-[3-(dimethylin)-2-hydroxypropyl]-2-methyl-7-oxo-4, 5, 6, 7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides, N-[3-(morpholine-4-yl)-2-hydroxypropyl]-2-methyl-7-oxo-4, 5, 6, 7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides, N-[3-(pyrrolidin-1-yl)-2-hydroxypropyl]-2-methyl-7-oxo-4, 5, 6, 7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides, N-[3-(piperidin-1-yl)-2-hydroxypropyl]-2-methyl-7-oxo-4, 5, 6, 7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides, N-[3-(4-methyl-piperazine-1-yl)-2-hydroxypropyl]-2-methyl-7-oxo-4, 5, 6, 7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides, N-[3-(N-methylcyclohexyl amido)-2-hydroxypropyl]-2-methyl-7-oxo-4, 5, 6, 7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides, N-[2-(dimethylin) ethyl]-N, 2-dimethyl-7-oxo-4, 5, 6, 7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides, 3-(1, 4 '-bis-piperidines-1 '-carbonyls)-2-methyl-5, 6-dihydro-1H-7 (4H)-one, 3-[4-(2-hydroxyethyl) piperazine-1-carbonyl]-2-methyl-5, 6-dihydro-1H-indoles-7 (4H)-one, (S)-2-methyl-3-[2-(tetramethyleneimine-1-methyl)-tetramethyleneimine-1-carbonyl]-5, 6-dihydro-1H-indoles-7 (4H)-one, N-[2-(2-pyridyl)-ethyl]-2-methyl-7-oxo-4, 5, 6, 7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides.
B. general synthetic method
(1) intermediate formula (II)
The pyrrole ring caproic ketone of intermediate formula (II) involved in the present invention is synthetic according to following route: 6-amino-5-oxo hexanoate hydrochlorate (S1) generates with methyl aceto acetate back flow reaction in biphosphate sodium water solution the pyrroles (S2) who replaces, then take polyphosphoric acid (PPA) as reaction solvent, Vanadium Pentoxide in FLAKES (P 2o 5) be dewatering agent, at 70 ℃, reaction generates 2-methyl-7-oxo-4,5,6,7-tetrahydrochysene-1H-Indole-3-Carboxylic Acid's ethyl ester (S3), in the 1mol/L LiOH aqueous solution, be hydrolyzed subsequently and obtain 2-methyl-7-oxo-4,5,6,7-tetrahydrochysene-1H-Indole-3-Carboxylic Acid (S4), finally with N, N-METHYLFORMAMIDE (DMF) is solvent, under condensing agent existence condition, with H-R 6under room temperature, react the pyrrole ring caproic ketone that makes formula (II) for 24 hours.
Figure BDA00001671821300111
The intermediate with formula (II) structure the present invention relates to:
Wherein:
R 5be hydrogen, alkyl or-C (O) R 14;
R 6hydroxyl, alkoxyl group ,-N (R 15) (CH 2) rr 16,-NR 8r 9or-NHCH (R 18)-CR 19(OH)-CH (R 20) Z;
R 8and R 9independently selected from hydrogen, alkyl, cycloalkyl, aryl or heteroaryl, or R 8and R 9form altogether a heterocyclic radical;
R 14be hydroxyl, alkoxyl group, aryloxy or-NR 8r 9;
R 15it is hydrogen or alkyl;
R 16hydroxyl ,-NR 8r 9or heteroaryl;
R 18, R 19and R 20independently selected from hydrogen or alkyl;
Z be aryl, heteroaryl, heterocycle or-NR 8r 9;
R is 2 or 3.
Above-mentioned intermediate is preferably:
R 5it is methyl;
R 6be-N (R 15) (CH 2) rr 16,-NR 8r 9or-NHCH 2cH (OH) CH 2-NR 8r 9, or R 6oxyethyl group (formula (S3)), or R 6hydroxyl (formula (S4));
R 8and R 9independently selected from hydrogen, alkyl, cycloalkyl, aryl or heteroaryl, or R 8and R 9form altogether a heterocyclic radical;
R 15it is hydrogen or alkyl;
R 16hydroxyl ,-NR 8r 9or heteroaryl;
R is 2 or 3.
Condensing agent includes but is not limited to N, N'-dicyclohexylcarbodiimide (DCC), N, N'-DIC (DIC), 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (EDCI), 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT), 2,4-bis-chloro-6-methoxyl group-1.3.5-triazine (DCMT), 1,1'-carbonyl dimidazoles (CDI) and I-hydroxybenzotriazole (HOBt), be preferably EDCI and HOBt.
Described reaction is at room temperature carried out, and preferred temperature of reaction is 20 ℃ to 25 ℃.
(2) formula (I) compound
The invention provides the method (A) for the synthesis of 3-pyrrole ring caproic subunit-2-dihydroindolone of formula (I), the method is included under catalyzer existence, make the 2-oxyindole of formula (III) and the pyrrole ring caproic reactive ketone of formula (II) in solvent, wherein each substituting group is described in general structure (A), preferably:
R 1, R 3and R 4hydrogen, halogen or alkyl;
R 2hydrogen, halogen, alkyl, alkoxyl group, three halogen methoxyl groups, nitro ,-NR 8c (O) R 9,-C (O) R 7,-S (O) 2nR 8r 9or-C (O) NR 11r 12;
R 5it is methyl;
R 6hydroxyl, alkoxyl group ,-NR 8r 9,-N (R 15) (CH 2) rr 16or-NHCH 2cH (OH) CH 2-NR 8r 9;
R 7hydroxyl, alkoxyl group or aryloxy;
R 8and R 9independently selected from hydrogen, alkyl, cycloalkyl, aryl or heteroaryl, or R 8and R 9form altogether a heterocyclic radical;
R 11and R 12independently selected from hydrogen, alkyl or aryl, or R 11and R 12together with the nitrogen-atoms connecting with them, form heterocyclic radical;
R 15it is hydrogen or alkyl;
R 16be hydroxyl, aryl, heteroaryl or-NR 8r 9;
R is 1,2 or 3.
This reaction can be carried out under catalyzer exists, and wherein catalyzer is Lewis acid, includes but is not limited to AlCl 3, BF 3, SnCl 4, SnCl 2, ZnCl 2, TiCl 4, in the preferred embodiment of the invention, described Lewis acid is preferably as TiCl 4.
The solvent that described reaction is carried out is aprotic solvent." aprotic solvent " is the solvent of non-metastatic proton in molecule, and this kind solvent can be divided into again non-proton protophilia solvent and inert solvent." non-proton protophilia solvent " is characterised in that in molecule without proton, more no acidic with water, also without amphoteric character, but have weak accept proton tendency different with degree become hydrogen bond ability, example includes but is not limited to amides, ketone, nitrile, methyl-sulphoxide, pyridine." inert solvent " do not have soda acid character or acid-basicity extremely a little less than, self is without proton transfer, in the time that solute bronsted lowry acids and bases bronsted lowry reacts in solvent, solvent molecule does not participate in reaction, example includes but is not limited to pentane, hexane, hexanaphthene, benzene, toluene.
In the preferred embodiment of the invention, described solvent is aprotic solvent, is preferably pyridine.
Described reaction is carried out at the temperature higher than room temperature.This temperature is generally 50 ℃ to 150 ℃, is preferably 85 ℃ to 120 ℃, most preferably is 100 ℃ to 110 ℃.
The reaction times of described reaction is 1 hour to 20 hours, and the preferred time is 5 hours to 13 hours, and the most preferred time is 8 hours to 10 hours.
Another aspect of the present invention has been to provide another method (B) for the synthesis of 3-pyrrole ring caproic subunit-2-dihydroindolone of formula (I).The method is the reaction conditions of (A) first according to the method described above, the 2-oxyindole of through type (III) and 2-methyl-7-oxo-4,5,6,7-tetrahydrochysene-1H-Indole-3-Carboxylic Acid (S4) reaction, obtains structure suc as formula the compound shown in (IV), then with N, dinethylformamide (DMF) is solvent, under the existence of condensing agent, with H-R 6room temperature reaction 24 hours, wherein R 1, R 2, R 3, R 4, R 6definition is as shown in method (A).
Figure BDA00001671821300131
The condensing agent of described reaction includes but is not limited to N, N'-dicyclohexylcarbodiimide (DCC), N, N'-DIC (DIC), 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (EDCI), 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT), 2,4-bis-chloro-6-methoxyl group-1.3.5-triazine (DCMT), 1,1'-carbonyl dimidazoles (CDI) and I-hydroxybenzotriazole (HOBt), be preferably EDCI and HOBt.
In addition, compound S 1 involved in the present invention can be prepared with reference to the existing bibliographical information in this area, as Lartillot, and Serge.et al, Bulletin de la Societe Chimique de France, 1964,4:783; MacGee, J.et al.Biochem Med, 1977,17:31; Evans DA, et al, J.C.S.Chem.Comm, the pertinent literature that quote 1978,17:753 and they.Formula HNR 8r 9, HN (R 15) (CH 2) rr 16and H 2nCH 2cH (OH) CH 2-NR 8r 9be commercially available amine or can be prepared with reference to the existing bibliographical information in this area and similar approach thereof, as patent GB 276012; US 1790096; CA975364; PCT WO2002066463 etc. and the pertinent literature of quoting thereof.In synthetic method provided by the invention (A), the 2-oxyindole of related intermediate formula (III) is commercially available or can be prepared with reference to the existing bibliographical information in this area and similar approach thereof, as " Rodd ' s Chemistry of Carbon Compounds " second edition, S.Coffey, IV rolls up A portion, l973, pp.448-450; Gassman PG, et al, J Org Chem, l977,42:l340; Wright WB et al, J Am Chem Soc, l956,78:22l; Kisteneva, MS.Zhurnal Obshchei Khimii, 1956,26:2251; Beckett AH, et al, Tetrahedron, l968,24:6093; Walker GN, J Am Chem Soc, l955,77:3844; Protiva M, et al, Collect Czech Chem Commun, l979,44:2l08; McEvoy FJ, et al, J Org Chem, l973,38:3350; Simet L, J Org Chem, l963,28:3580; Wieland T, et al, Chem Ber, l963,96:253; The pertinent literature that quote U.S. Pat 3882236,4006l6l and 4l60032, Chinese patent CN200410067904.2 and they.
Meanwhile, by for those skilled in the art understand, be also available for generating other route of synthesis of the compounds of this invention, embodiment provided in this article only supplies for example and not limitation.
3. biological assessment
Purposes in the medicine of the compounds of this invention or salt protein kinase related disorder in for the preparation for the treatment of organism.Relevant disease or the relevant disease of serine-threonine kinase of disease, nonreceptor tyrosine kinase that the preferred autoreceptor Tyrosylprotein kinase of wherein said protein kinase related disorder is relevant; Described protein kinase related disorder or preferably from the relevant disease of vascular endothelial growth factor receptor, relevant relevant disease or the relevant disease of tire liver kinases of disease, IGF-1 of disease, platelet derived growth factor receptor that EGF-R ELISA is relevant; Described protein kinase related disorder or preferably from squamous cell carcinoma, stellate cell cancer, Kaposi's sarcoma, spongioblast cancer, lung cancer, bladder cancer, head and neck cancer, melanoma, ovarian cancer, prostate cancer, mammary cancer, neurospongioma, colorectal carcinoma, liver cancer, kidney, genitourinary cancer, carcinoma of the pancreas or gastrointestinal cancer; Described protein kinase related disorder or preferably from diabetes, excess proliferative disease, blood vessel generation, inflammatory diseases, immunological disease or cardiovascular disorder; Described organism is Mammals or people; And a kind of medicinal compositions that is used for the treatment of protein kinase related disorder in organism, it comprises the compounds of this invention or salt and pharmaceutically acceptable carrier or vehicle.
3.1 enzymic activity tests
Linked immunosorbent assay (ELISA) can be used for checking and measuring the existence of tyrosine kinase activity.The phosphorylation reaction of the peptide substrate of the tyrosine-kinase enzyme catalysis ATP such as VEGFR-2, PDGFR-β, c-Kit and vitamin H mark mark, inhibitory enzyme activity will suppress this reaction.According to ELISA method measuring principle, be attached to on the coated enzyme plate of Streptavidin containing biotin labeled phosphorylated substrate peptide, produce with it specific reaction by anti-phosphorylated substrate peptide monoclonal antibody, be combined with the sheep anti-mouse antibody of horseradish peroxidase-labeled again, add the colour developing of TMB liquid, measure determinand inhibition activity to Tyrosylprotein kinases such as VEGFR-2, PDGFR-β, c-Kit under different concns by measuring A450-A630 difference.Thereby, adopt this method can measure the active function of the compounds of this invention to above-mentioned Tyrosylprotein kinase, utilize method well known in the art simultaneously, can use similar measuring method to other protein kinase.
3.2 inhibition tumor cell proliferation activity tests
Suppress cell proliferating determining method and take conventional mtt assay: the desaturase in viable cell plastosome can reduce yellow bromination 3-(4,5-dimethylthiazole-2)-2,5-phenylbenzene tetrazole (MTT) is hepatic water-fast Jia Za (Formazan) Jia Za number can be determined at 570nm by microplate reader absorption value (OD value) can learn, thereby Jia Za growing amount is directly proportional to viable count under normal conditions, therefore can infer the number that viable cell according to OD value, understand the ability of medicine inhibition or killer cell.This measuring method can, for measuring the inhibition ability of different the compounds of this invention to one or more cancer cell multiplications, utilize method well known in the art, can use similar measuring method to any cancer cells.
Embodiment
Provide following preparation example and embodiment, make those skilled in the art can more clearly understand and implement the present invention.They should not be interpreted as limiting the scope of the invention, and are only its illustration and representative.
Synthetic example
Embodiment 1:2-methyl-7-oxo-4,5,6,7-tetrahydrochysene-1H-Indole-3-Carboxylic Acid (S4)
Figure BDA00001671821300141
Step 1
6-amino-5-oxo hexanoate hydrochlorate (S1) 22.44g(0.12mol) (Lartillot, Serge.et al, Bulletin de la Societe Chimique de France, 1964,4:783) be dissolved in about 6.1L phosphate sodium dihydrogen buffer solution (300g SODIUM PHOSPHATE, MONOBASIC solid is dissolved in 6L water, and regulates pH to 6.5 left and right with the saturated NaOH aqueous solution), add 16.12g(0.12mol) methyl aceto acetate, temperature rising reflux reacts half an hour, reaction solution Na later to be cooled 2cO 3regulate pH to 8 left and right, and with 100ml chloroform extraction once, water is adjusted pH to 1 left and right with 6mol/L hydrochloric acid, separates out a large amount of brown solids, filters vacuum-drying and obtains solid 4-(4-ethoxy carbonyl-5-methyl isophthalic acid H-pyrroles-3-yl) butyric acid (S2) 20.29g(71% yield).
1HNMR(500 MHz,DMSO-d 6)δ11.89(s,1H,-COOH),10.90(s,1H,-NH-1),6.38(s,1H,pyrrole-2),4.14(q，2H，- CH 2 CH 3)，2.56(t，2H，- CH 2 CH 2CH 2COOH)，2.36(s，3H，-CH 3-5)，2.18(t，2H，-CH 2CH 2 CH 2 -COOH),1.71(m,2H,-CH 2 CH 2 CH 2COOH),1.25(t,3H,-CH 2 CH 3 ).
Step 2
In 142g polyphosphoric acid, add 7.1g Vanadium Pentoxide in FLAKES, stir 30 minutes at 70 ℃, then add 6.3g(0.026mol) 4-(4-ethoxy carbonyl-5-methyl isophthalic acid H-pyrroles-3-yl) butyric acid (S2), at this temperature, continue stirring reaction after 48 hours, pour in frozen water, use saturated Na 2cO 3the aqueous solution is adjusted pH to 8 left and right, and ethyl acetate is extracted.Water and saturated NaCl solution washing organic layer, after anhydrous sodium sulfate drying, concentrate and remove most of ethyl acetate to state of saturation, low temperature crystallization at-5 ℃, filter, vacuum-drying obtains white solid 2-methyl-7-oxo-4,5,6,7-tetrahydrochysene-1H-Indole-3-Carboxylic Acid's ethyl ester (S3) 3.5g(61%).
1HNMR(500 MHz,CDCl 3)δ10.23(s,1H,-NH-1),4.30(q,2H,- CH 2 CH 3),3.00(t,2H,-CH 2-4),2.59(s,3H,-CH 3-2),2.50(t,2H,-CH 2-6),2.12(m,2H,-CH 2-5),1.36(t,3H,-CH 2 CH 3 );
ESI-MS:222.1[M+H] +;220.1[M-H] -.
Step 3
In the 25ml LiOH aqueous solution (1mol/L), add 1.0g(4.5mmol) 2-methyl-7-oxo-4,5,6,7-tetrahydrochysene-1H-Indole-3-Carboxylic Acid's ethyl ester (S3) reacted after 48 hours at 70 ℃, pour in frozen water, with 6mol/L salt acid for adjusting pH to 1～2, separate out a large amount of solids, filter, washing, obtains 0.64g(74% after vacuum-drying) be the title compound of gray solid.
1HNMR(500 MHz,DMSO-d 6)δ12.03(bs,2H,-NH-1,-COOH),2.87(t,2H,-CH 2-4),2.42(s,3H,-CH 3-2),2.34(t,2H,-CH 2-6),1.98(m,2H,-CH 2-5);
ESI-MS:194.1[M+H] +.
Embodiment 2:N-(2-diethylin ethyl)-2-methyl-7-oxo-4,5,6,7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides (II-1)
0.2g(1.0mmol) 2-methyl-7-oxo-4, 5, 6, 7-tetrahydrochysene-1H-Indole-3-Carboxylic Acid (S4), 0.16g HOBt(1.2mmol), 0.24g(1.2mmol) EDCI and 0.2g(2.0mmol) triethylamine is dissolved in 10ml DMF, under room temperature, stir after 20min, add 0.24g(2.1mmol) N, N-diethyl-1, 2-quadrol, under room temperature, stir after 24 hours, reaction solution is poured in frozen water, with dichloromethane extraction, water and saturated NaCl solution washing organic layer, after anhydrous sodium sulfate drying, the concentrated solid obtaining obtains 0.23g(79% through purification by silica gel column chromatography (eluent is methylene dichloride: methyl alcohol 30:1)) be the title compound of white solid.
1HNMR(500 MHz,CDCl 3)δ9.67(s,1H,-NH-1),6.41(s,1H,-CONH-),3.46(bs,2H,-CONH CH 2 CH 2-),2.93(t,2H,-CH 2-4),2.64~2.59(m,6H,-NHCH 2 CH 2 N( CH 2 CH 3) 2),2.58(s,3H,-CH 3-2),2.49(t,2H,-CH 2-6),2.16(m,2H,-CH 2-5),1.04(s,6H,-(CH 2 CH 3 ) 2);
ESI-MS:292.2[M+H] +,314.2[M+Na] +;290.3[M-H] -.
Embodiment 3:N-(2-hydroxyethyl)-2-methyl-7-oxo-4,5,6,7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides (II-2)
Figure BDA00001671821300152
Use the method for embodiment 2,0.2g(1.0mmol) 2-methyl-7-oxo-4,5,6,7-tetrahydrochysene-1H-Indole-3-Carboxylic Acid (S4) and 0.13g(2.1mmol) 2-monoethanolamine reaction, the reaction solution directly concentrated solid obtaining obtains 0.20g(85% through purification by silica gel column chromatography (eluent is methylene dichloride: methyl alcohol 10:1)) be the title compound of white solid.
1HNMR(300 MHz,DMSO-d 6)δ11.84(s,1H,-NH-1),7.17(t,1H,-CONH-),4.69(t,1H,-OH),3.48(q,2H,-CONH CH 2 CH 2-),3.28(q,2H,- CH 2 OH),2.79(t,2H,-CH 2-4),2.34~2.31(m,5H,-CH 3-2,-CH 2-6),1.97(m,2H,-CH 2-5);
ESI-MS:237.1[M+H] +,259.1[M+Na] +.
Embodiment 4:N-(2-dimethylamino ethyl)-2-methyl-7-oxo-4,5,6,7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides (II-3)
Figure BDA00001671821300161
Use the method for embodiment 2,0.2g(1.0mmol) 2-methyl-7-oxo-4,5,6,7-tetrahydrochysene-1H-Indole-3-Carboxylic Acid (S4) and 0.19g(2.1mmol) N, N-dimethyl-1，2-diaminoethane reacts to obtain 0.21g(80%) be the title compound of white solid.
1HNMR(300 MHz,CDCl 3)δ10.80(s,1H,-NH-1),6.17(s,1H,-CONH-),3.51(q,2H,-CONH CH 2 CH 2-),2.80(t,2H,-CH 2-4),2.55(t,2H,-CH 2-6),2.51(s,3H,-CH 3-2),2.46(t,2H,- CH 2 N(CH 3) 2),2.29(s,6H,-CH 2N( CH 3 ) 2),2.09(m,2H,-CH 2-5);
ESI-MS:264.1[M+H] +,286.2[M+Na] +.
Embodiment 5:N-(3-dimethylamino-propyl)-2-methyl-7-oxo-4,5,6,7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides (II-4)
Use the method for embodiment 2,0.2g(1.0mmol) 2-methyl-7-oxo-4,5,6,7-tetrahydrochysene-1H-Indole-3-Carboxylic Acid (S4) and 0.21g(2.1mmol) N, N-dimethyl-1,3-propylene diamine reacts to obtain 0.23g(83%) be the title compound of white solid.
1HNMR(300MHz,CDCl 3)δ10.76(s,1H,-NH-1),7.11(s,1H,-CONH-),3.50(t,2H,-CONH CH 2 CH 2CH 2-),2.89(t,2H,-CH 2-4),2.56(s,3H,-CH 3-2),2.50~2.41(m,4H,-CH 2-6,- CH 2 N(CH 3) 2),2.21(s,6H,-CH 2N( CH 3 ) 2),2.13(m,2H,-CH 2-5),1.72(m,2H,-CONHCH 2 CH 2 CH 2-);
ESI-MS:278.2[M+H] +,300.1[M+Na] +.
Embodiment 6:N-[2-(morpholine-4-yl)-ethyl]-2-methyl-7-oxo-4,5,6,7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides (II-5)
Figure BDA00001671821300163
Use the method for embodiment 2,0.2g(1.0mmol) 2-methyl-7-oxo-4,5,6,7-tetrahydrochysene-1H-Indole-3-Carboxylic Acid (S4) and 0.27g(2.1mmol) 2-(morpholine-4-yl)-ethylamine reacts to obtain 0.25g(82%) be the title compound of white solid.
1HNMR(300 MHz,CDCl 3)δ6.32(bs,1H,-CONH-),3.75(t,4H,-CH 2N(CH 2 CH 2 ) 2O),3.52(q,2H,-CONHC H 2 ),2.93(t,2H,-CH 2-4),2.59(t,5H,-CH 3-2,-CH 2-6),2.53(m,6H,- CH 2 N( CH2CH 2) 2O),2.16(m,2H,-CH 2-5);
ESI-MS:306.2[M+H] +.
Embodiment 7:N-[2-(piperidin-1-yl)-ethyl]-2-methyl-7-oxo-4,5,6,7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides (II-6)
Figure BDA00001671821300164
Use the method for embodiment 2,0.2g(1.0mmol) 2-methyl-7-oxo-4,5,6,7-tetrahydrochysene-1H-Indole-3-Carboxylic Acid (S4) and 0.27g(2.1mmol) 2-(piperidin-1-yl)-ethylamine react to obtain 0.26g(86%) be the title compound of white solid.
1HNMR(300 MHz,CDCl 3)δ10.21(bs,1H,-NH-1),6.47(bs,1H,-CONH-),3.48(q,2H,-CONH CH 2 CH 2-),2.93(t,2H,-CH 2-4),2.58(s,3H,-CH 3-2),2.51(m,4H,-CH 2-6,-NHCH 2 CH 2 N(CH 2CH 2) 2CH 2),2.43(s,4H,-NHCH 2CH 2N( CH 2 CH 2) 2CH 2),2.15(m,2H,-CH 2-5),1.59(m,4H,-N(CH 2 CH 2 ) 2CH 2),1.46(m,2H,-N(CH 2CH 2) 2 CH 2 );
ESI-MS:304.2[M+H] +.
Embodiment 8:N-[2-(pyrrolidin-1-yl)-ethyl]-2-methyl-7-oxo-4,5,6,7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides (II-7)
Figure BDA00001671821300171
Use the method for embodiment 2,0.2g(1.0mmol) 2-methyl-7-oxo-4,5,6,7-tetrahydrochysene-1H-Indole-3-Carboxylic Acid (S4) and 0.24g(2.1mmol) 2-(pyrrolidin-1-yl)-ethylamine react to obtain 0.21g(73%) be the title compound of white solid.
1HNMR(300MHz,CDCl 3)δ10.81(bs,1H,-NH-1),6.33(bs,1H,-CONH-),3.55(q,2H,-CONHC H 2 ),2.82(m,4H,-CH 2-4,- CH 2 N(CH 2CH 2) 2),2.68(s,4H,-CH 2N( CH 2 CH 2)),2.50(s,3H,-CH 3-2),2.46(t,2H,-CH 2-6),2.09(m,2H,-CH 2-5),1.82(m,4H,-CH 2N(CH 2 CH 2 ) 2,);
ESI-MS:290.1[M+H] +;312.1[M+Na] +.
Embodiment 9:N-[3-(morpholine-4-yl)-propyl group]-2-methyl-7-oxo-4,5,6,7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides (II-8)
Figure BDA00001671821300172
Use the method for embodiment 2,0.2g(1.0mmol) 2-methyl-7-oxo-4,5,6,7-tetrahydrochysene-1H-Indole-3-Carboxylic Acid (S4) and 0.30g(2.1mmol) 3-(morpholine-4-yl)-propyl group amine reacts to obtain 0.27g(85%) be the title compound of white solid.
1HNMR(300MHz,CDCl 3)δ10.29(bs,1H,-NH-1),6.19(bs,1H,-CONH-),3.62(t,4H,-CH 2N(CH 2 CH 2 ) 2O),3.46(q,2H,-CONHC H 2 ),2.93(t,2H,-CH 2-4),2.57(s,3H,-CH 3-2),2.48(m,8H,-CH 2-6,-CH 2 CH 2 N( CH 2 CH 2) 2O),2.15(m,2H,-CH 2-5),1.78(m,2H,- CH 2 CH 2N(CH 2CH 2) 2O);
ESI-MS:320.2[M+H] +;342.2[M+Na] +.
Embodiment 10:N-(3-diethylin propyl group)-2-methyl-7-oxo-4,5,6,7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides (II-9)
Figure BDA00001671821300173
Use the method for embodiment 2,0.2g(1.0mmol) 2-methyl-7-oxo-4,5,6,7-tetrahydrochysene-1H-Indole-3-Carboxylic Acid (S4) and 0.27g(2.1mmol) N, N-diethyl-1,3-propylene diamine reacts to obtain 0.26g(85%) be the title compound of white solid.
1HNMR(300 MHz,CDCl 3)δ9.98(bs,1H,-NH-1),6.95(bs,1H,-CONH-),3.52(q,2H,-CONH CH 2 CH 2-),2.90(t,2H,-CH 2-4),2.55(m,11H,-CH 2 CH 2 N( CH 2 CH 3) 2-CH 2-6,-CH 3-2),2.12(m,2H,-CH 2-5),1.74(m,2H，-NHCH 2 CH 2 CH 2-),1.01(t,6H,-(CH 2 CH 3 ) 2);
ESI-MS:306.2[M+H] +.
Embodiment 11:N-[3-(pyrrolidin-1-yl)-propyl group]-2-methyl-7-oxo-4,5,6,7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides (II-10)
Figure BDA00001671821300181
Use the method for embodiment 2,0.2g(1.0mmol) 2-methyl-7-oxo-4,5,6,7-tetrahydrochysene-1H-Indole-3-Carboxylic Acid (S4) and 0.27g(2.1mmol) 3-(pyrrolidin-1-yl)-propyl group amine react to obtain 0.25g(82%) be the title compound of white solid.
1HNMR(300 MHz,CDCl 3)δ10.06(bs,1H,-NH-1),6.92(bs,1H,-CONH-),3.51(q,2H,-CONH CH 2 ),2.90(t,2H,-CH 2-4),2.61(t,2H,-CH 2-6),2.56(s,3H,-CH 3-2),2.50(m,6H,- CH 2 N( CH 2 CH 2) 2),2.13(m,2H,-CH 2-5),1.76(m,6H,- CH 2 CH 2N(CH 2 CH 2 ) 2);
ESI-MS:304.2[M+H] +;326.2[M+Na] +.
Embodiment 12:N-[3-(4-methyl-piperazine-1-yl)-propyl group]-2-methyl-7-oxo-4,5,6,7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides (II-11)
Figure BDA00001671821300182
Use the method for embodiment 2,0.2g(1.0mmol) 2-methyl-7-oxo-4,5,6,7-tetrahydrochysene-1H-Indole-3-Carboxylic Acid (S4) and 0.33g(2.1mmol) 3-(4-methyl-piperazine-1-yl)-propyl group amine reacts to obtain 0.26g(78%) be the title compound of white solid.
1HNMR(300 MHz,CDCl 3)δ10.43(bs,1H,-NH-1),6.44(bs,1H,-CONH-),3.49(q,2H,-CONH CH 2 CH 2-),2.91(t,2H,-CH 2-4),2.67(m,10H,- CH 2 N( CH 2 CH 2 ) 2NCH 3),2.56(s,3H,-CH 3-2),2.44(t,2H,-CH 2-6),2.37(s,3H，-NCH 3),2.10(m,2H,-CH 2-5),1.85(m,2H,-CH 2 CH 2 CH 2-);
ESI-MS:333.2[M+H] +.
Embodiment 13:N-[3-(diethylin)-2-hydroxypropyl]-2-methyl-7-oxo-4,5,6,7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides (II-12)
Figure BDA00001671821300183
0.2g(1.0mmol) 2-methyl-7-oxo-4, 5, 6, 7-tetrahydrochysene-1H-Indole-3-Carboxylic Acid (S4), 0.16g HOBt(1.2mmol), 0.24g(1.2mmol) EDCI and 0.2g(2.0mmol) triethylamine is dissolved in 10ml DMF, under room temperature, stir after 20min, add 0.31g(2.1mmol) 1-amino-3-diethylin-propyl-2-alcohol, under room temperature, stir after 24 hours, reaction solution is poured in frozen water, with dichloromethane extraction, water and saturated NaCl solution washing organic layer, after anhydrous sodium sulfate drying, the concentrated solid obtaining obtains 0.26g(81% through purification by silica gel column chromatography (eluent is methylene dichloride: methyl alcohol 3:1)) be the title compound of white solid.
1HNMR(300 MHz,CDCl 3)δ10.09(s,1H,-NH-1),6.74(t,1H,-CONH-),4.40(m,1H,-CONHC H(H)-)，3.83(m，1H，-CONHCH( H)-)，3.58(m，1H，- CH(OH)-)，3.26~3.15(m，6H，- CH 2 N( CH 2 CH 3) 2),3.00(t,2H,-CH 2-4),2.56(s,3H,-CH 3-2),2.46(t,2H,-CH 2-6),2.15(m,2H,-CH 2-5),1.44(t,6H,-CH 2N(CH 2 CH 3 ) 2);
ESI-MS:322.2[M+H] +.
Embodiment 14:N-[3-(dimethylin)-2-hydroxypropyl]-2-methyl-7-oxo-4,5,6,7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides (II-13)
Figure BDA00001671821300191
Use the method for embodiment 13,0.2g(1.0mmol) 2-methyl-7-oxo-4,5,6,7-tetrahydrochysene-1H-Indole-3-Carboxylic Acid (S4) and 0.25g(2.1mmol) 1-amino-3-dimethylin-propyl-2-alcohol react to obtain 0.24g(82%) be the title compound of white solid.
1HNMR(300 MHz,CDCl 3)δ10.43(s,1H,-NH-1),6.23(t,1H,-CONH-),3.86(m,1H,-CONHCH( H)-),3.69(m,1H,-CONHCH( H)-),3.32(m,1H,- CH(OH)-),2.93(t,2H,-CH 2-4),2.58(s,3H,-CH 3-2),2.49(t,2H,-CH 2-6),2.40~2.30(m,8H,- CH 2 N( CH 3 ) 2),2.14(m,2H,-CH 2-5);
ESI-MS:294.1[M+H] +.
Embodiment 15:N-[3-(morpholine-4-yl)-2-hydroxypropyl]-2-methyl-7-oxo-4,5,6,7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides (II-14)
Figure BDA00001671821300192
Use the method for embodiment 13,0.2g(1.0mmol) 2-methyl-7-oxo-4,5,6,7-tetrahydrochysene-1H-Indole-3-Carboxylic Acid (S4) and 0.34g(2.1mmol) 1-amino-3-(morpholine-4-yl)-propyl-2-alcohol reacts to obtain 0.27g(81%) be the title compound of white solid.
1HNMR(300 MHz,CDCl 3)δ10.00(s,1H,-NH-1),6.08(s,1H,-CONH-),3.94(s,1H,-CONHC H(H)-),3.75~3.71(m,6H,-OH,-CONHCH( H)-,-CH 2N(CH 2 CH 2 ) 2O),3.33(m,1H,- CH(OH)-),2.90(t,2H,-CH 2-4),2.67(m,2H,- CH 2 N(CH 2CH 2) 2O),2.58(s,3H,-CH 3-2),2.51~2.40(m,6H,-CH 2-6,-CH 2N( CH 2 CH 2) 2O),2.15(m,2H,-CH 2-5);
ESI-MS:336.0[M+H] +,358.0[M+Na] +.
Embodiment 16:N-[3-(pyrrolidin-1-yl)-2-hydroxypropyl]-2-methyl-7-oxo-4,5,6,7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides (II-15)
Figure BDA00001671821300193
Use the method for embodiment 13,0.2g(1.0mmol) 2-methyl-7-oxo-4,5,6,7-tetrahydrochysene-1H-Indole-3-Carboxylic Acid (S4) and 0.30g(2.1mmol) 1-amino-3-(pyrrolidin-1-yl)-propyl-2-alcohol react to obtain 0.26g(82%) be the title compound of white solid.
1HNMR(300 MHz,CDCl 3)δ9.61(s,1H,-NH-1),6.20(s,1H,-CONH-),3.92(m,1H,-CONHC H(H)-),3.76(m,1H,-CONHCH( H)-),3.39(m,1H,- CH(OH)-),2.96(t,2H,-CH 2-4),2.75(m,3H,alkyl),2.60~2.46(m,8H,-CH 2-6,-CH 3-2,alkyl),2.20(m,2H,-CH 2-5),1.84(s,4H,-CH 2N(CH 2 CH 2 CH 2 CH 2));
ESI-MS:320.2[M+H] +,342.1[M+Na] +;318.2[M-H] -.
Embodiment 17:N-[3-(piperidin-1-yl)-2-hydroxypropyl]-2-methyl-7-oxo-4,5,6,7-tetrahydrochysene-1H indoles-3-carboxylic acid amides (II-16)
Use the method for embodiment 13,0.2g(1.0mmol) 2-methyl-7-oxo-4,5,6,7-tetrahydrochysene-1H-Indole-3-Carboxylic Acid (S4) and 0.34g(2.1mmol) 1-amino-3-(piperidin-1-yl)-propyl-2-alcohol react to obtain 0.26g(78%) be the title compound of white solid.
1HNMR(300 MHz,CDCl 3)δ10.33(s,1H,-NH-1),6.11(t,1H,-CONH-),3.88(m,1H,-CONHC H(H)-),3.68(m,1H,-CONHCH( H)-),3.29(m,1H,- CH(OH)-),2.92(t,2H,-CH 2-4),2.63~2.57(m,5H,- CH 2 N(CH 2) 5,-CH 3-2),2.49(t,2H,-CH 2-6),2.36(m,4H,-CH 2N( CH 2 CH 2CH 2CH 2 CH 2 )),2.17(m,2H,-CH 2-5),1.58(m,4H,-N(CH 2 CH 2 CH 2 CH 2 CH 2)),1.46(m,2H,-N(CH 2CH 2 CH 2 CH 2CH 2));
ESI-MS:334.2[M+H] +,356.3[M+Na] +;332.3[M-H] -.
Embodiment 18:N-[3-(4-methyl-piperazine-1-yl)-2-hydroxypropyl]-2-methyl-7-oxo-4,5,6,7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides (II-17)
Figure BDA00001671821300202
Use the method for embodiment 13,0.2g(1.0mmol) 2-methyl-7-oxo-4,5,6,7-tetrahydrochysene-1H-Indole-3-Carboxylic Acid (S4) and 0.36g(2.1mmol) 1-amino-3-(4-methyl-piperazine-1-yl)-propyl-2-alcohol reacts to obtain 0.25g(72%) be the title compound of white solid.
1HNMR(300 MHz,CDCl 3)δ9.53(s,1H,-NH-1),6.09(s,1H,-CONH-),3.93(m,1H,-CONHC H(H)-),3.69(m,1H,-CONHCH( H)-),3.33(m,1H,- CH(OH)-),2.92(t,2H,-CH 2-4),2.78(bs,2H,- CH 2 N(CH 2CH 2) 2NCH 3),2.56~2.40(m,13H,-CH 3-2,-CH 2N( CH 2 CH 2 ) 2NCH 3,-CH 2-6),2.33(s,3H,-N(CH 2CH 2) 2N CH 3 ),2.15(m,2H,-CH 2-5);
ESI-MS:349.2[M+H] +.
Embodiment 19:N-[3-(N-methylcyclohexyl amido)-2-hydroxypropyl]-2-methyl-7-oxo-4,5,6,7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides (II-18)
Figure BDA00001671821300203
Step 1
By 7.2g(0.03mol) N-(3-chlorine-2-hydroxyl propyl group-1)-phthalic imidine (Weizmann, M.et al.Bull.soc.chim.1930,47:356-61) and 6.8g(0.06mol) N-methylcyclohexylamine is added in 25ml ethanol, back flow reaction 6 hours, boil off solvent, in residual oily matter, add the hydrochloric acid of 60ml 20%, then back flow reaction 3 hours.After cooling, remove by filter insolubles, filtrate is concentrated into 15ml, with NaOH solid alkalize to pH be 13～14, with dichloromethane extraction, organic layer, after anhydrous sodium sulfate drying, concentrates and obtains colourless liquid 1-amino-3-(N-methylcyclohexyl amido)-propyl-2-alcohol 1.75g(31%).
ESI-MS：187.1[M+H] +.
Step 2
Use the method for embodiment 13,0.2g(1.0mmol) 2-methyl-7-oxo-4,5,6,7-tetrahydrochysene-1H-Indole-3-Carboxylic Acid (S4) and 0.39g(2.1mmol) 1-amino-3-(N-methylcyclohexyl amido)-propyl-2-alcohol reacts to obtain 0.30g(83%) be the title compound of white solid.
1hNMR (300 MHz, CDCl 3) δ 9.91 (s, 1H ,-NH-1), 6.43 (s, 1H ,-CONH-), 4.16 (m, 1H ,-CONHC h(H)-), 3.77 (m, 1H ,-CONHCH ( h)-), 3.47 (m, 1H ,- cH(OH)-), 2.97 ~ 2.87 (m, 4H ,-CH 2-4 ,-CH (OH)- cH 2 n-), 2.62 (s, 3H ,-CH 3), 2.58 (s, 3H ,-CH 3), 2.48 (t, 2H ,-CH 2-6), 2.18 ~ 2.01 (m, 4H ,-CH 2-5, cyclohexyl), 1.90 (d, 2H, cyclohexyl), 1.71 (d, 1H, cyclohexyl), 1.41 ~ 1.22 (m, 5H, cyclohexyl), 1.10 (m, 1H, cyclohexyl);
ESI-MS:362.3[M+H] +.
Embodiment 20:2-methyl-7-[1,2-dihydro-2-oxo--3H-indoles-(Z)-3-subunit]-4,5,6,7-tetrahydrochysene-1H-Indole-3-Carboxylic Acid (IV-1)
Figure BDA00001671821300211
0.37g(2.8mmol) 2-oxyindole and 0.5g(2.6mmol) 2-methyl-7-oxo-4,5,6,7-tetrahydrochysene-1H-Indole-3-Carboxylic Acid (S4) is dissolved in 15ml anhydrous pyridine, adds TiCl 40.4ml, at 100 ℃～110 ℃, stirring reaction is after 10 hours, pour in frozen water, separate out a large amount of solids, with 6mol/L salt acid for adjusting pH to 1～2, filter, washing, vacuum-drying obtains 0.58g(72%) for the title compound crude product of tawny solid, after DMF and water recrystallization, obtain the title compound 0.43g(54% of yellow solid).
1HNMR(300 MHz,DMSO-d 6)δ14.64(s,1H,-NH-1),12.03(s,1H,-COOH),10.91(s,1H,-NH-1’),7.63(d,1H,J=7.56Hz,H-4’),7.14(t,1H,H-6’),6.99(t,1H,H-5’),6.91(d,1H,J=6.69Hz,H-7’),3.12(t,2H,-CH 2-4),2.92(t,2H,-CH 2-6),2.53(s,3H,-CH 3-2),1.94(m,2H,-CH 2-5);
ESI-MS:307.2[M-H] -.
Embodiment 21:2-methyl-7-[1, the fluoro-2-oxo-3H-of 2-dihydro-5-indoles-(Z)-3-subunit]-4,5,6,7-tetrahydrochysene-1H-Indole-3-Carboxylic Acid (IV-2)
Use the method for embodiment 20, temperature of reaction is adjusted to 50 ℃ ~ 60 ℃, react 20 hours, 0.42g(2.8mmol) the fluoro-2-oxyindole of 5-and 0.5g(2.6mmol) 2-methyl-7-oxo-4,5,6,7-tetrahydrochysene-1H-Indole-3-Carboxylic Acid (S4) reacts to obtain 0.30g(35%) be the title compound of yellow solid.
1HNMR(300 MHz,DMSO-d 6)δ14.68(s,1H,-NH-1),12.08(s,1H,-COOH),10.93(s,1H,-NH-1’),7.45(dd,1H,J=11.91Hz,H-4’),6.97(t,1H,H-6’),6.87(t,1H,H-7’),3.08(t,2H,-CH 2-4),2.92(t,2H,-CH 2-6),2.54(s,3H,-CH 3-2),1.94(m,2H,-CH 2-5);
ESI-MS:325.2[M-H] -.
Embodiment 22:2-methyl-7-[1,2-dihydro-5-chloro-2-oxo-3H-indoles-(Z)-3-subunit]-4,5,6,7-tetrahydrochysene-1H-Indole-3-Carboxylic Acid (IV-3)
Figure BDA00001671821300221
Use the method for embodiment 20, temperature of reaction is adjusted to 145 ℃ ~ 150 ℃, 1 hour reaction times, 0.47g(2.8mmol) 5-chlorine-2-hydroxyl indoles and 0.5g(2.6mmol) 2-methyl-7-oxo-4,5,6,7-tetrahydrochysene-1H-Indole-3-Carboxylic Acid (S4) reacts to obtain 0.28g(31%) be the title compound of yellow solid.
1HNMR(500 MHz,DMSO-d 6)δ14.60(s,1H,-NH-1),12.04(s,1H,-COOH),11.04(s,1H,-NH-1’),7.60(s,1H,H-4’),7.42(d,1H,J=8.5Hz,H-6’),6.91(d,1H,J=8.2Hz,H-7’),3.08(t,2H,-CH 2-4),2.93(t,2H,-CH 2-6),2.54(s,3H,-CH 3-2),1.96(m,2H,-CH 2-5);
ESI-MS:341.1[M-H] -.
Embodiment 23:2-methyl-7-[1,2-dihydro-5-methyl-2-oxo-3H-indoles-(Z)-3-subunit]-4,5,6,7-tetrahydrochysene-1H-Indole-3-Carboxylic Acid (IV-4)
Use the method for embodiment 20, temperature of reaction is adjusted to 80 ℃ ~ 90 ℃, 13 hours reaction times, 0.41g(2.8mmol) 5-methyl-2-oxyindole and 0.5g(2.6mmol) 2-methyl-7-oxo-4,5,6,7-tetrahydrochysene-1H-Indole-3-Carboxylic Acid (S4) reacts to obtain 0.39g(46%) be the title compound of yellow solid.
1HNMR(500 MHz,DMSO-d 6)δ14.66(s,1H,-NH-1),12.03(s,1H,-COOH),10.82(s,1H,-NH-1’),7.46(s,1H,H-4’),6.96(d,1H,J=7.70Hz,H-6’),6.80(d,1H,J=7.75Hz,H-7’),3.10(t,2H,-CH 2-4),2.93(t,2H,-CH 2-6),2.53(s,3H,-CH 3-2),2.32(s,3H,-CH 3-5’),1.95(m,2H,-CH 2-5);
ESI-MS:323.2[M+H] +;321.1[M-H] -.
Embodiment 24:2-methyl-7-[1, the fluoro-2-oxo-3H-of 2-dihydro-5-indoles-(Z)-3-subunit]-4,5,6,7-tetrahydrochysene-1H-Indole-3-Carboxylic Acid's ethyl ester (I-1)
Figure BDA00001671821300223
Use the method for embodiment 20, temperature of reaction is adjusted to 115 ℃ ~ 120 ℃, 6 hours reaction times, 0.39g(2.6mmol) the fluoro-2-oxyindole of 5-and 0.5g(2.3mmol) 2-methyl-7-oxo-4, 5, 6, after 7-tetrahydrochysene-1H-Indole-3-Carboxylic Acid's ethyl ester (S3) reaction finishes, reaction solution is poured into after frozen water, directly with dichloromethane extraction, water and saturated NaCl solution washing organic layer, after anhydrous sodium sulfate drying, the concentrated solid obtaining obtains 0.22g(27% through purification by silica gel column chromatography (eluent is methylene dichloride: ethyl acetate 4:1)) be the title compound of yellow solid.
1HNMR(500 MHz,CDCl 3)δ14.36(s,1H,-NH-1),7.74(s,1H,-NH-1’),7.36(d,1H,J=10.53Hz,H-4’),6.86~6.79(m,2H,H-6’,H-5’),4.31(q,2H,- CH 2 CH 3),3.10(t 2H,-CH 2-4),3.05(t 2H,-CH 2-6),2.62(s,3H,-CH 3-2),2.05(m,2H,-CH 2-5),1.38(t,3H,-CH 2 CH 3 ).
ESI-MS:355.3[M+H] +,377.2[M+Na] +;353.2[M-H] -.
Embodiment 25:N-(2-diethylin ethyl)-2-methyl-7-[1, the fluoro-2-oxo-3H-of 2-dihydro-5-indoles-(Z)-3-subunit]-4,5,6,7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides (I-2)
Figure BDA00001671821300231
0.12g(0.79mmol) the fluoro-2-oxyindole of 5-and 0.20g(0.69mmol) N-(2-diethylin ethyl)-2-methyl-7-oxo-4,5,6,7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides (II-1) is dissolved in 10ml anhydrous pyridine, adds TiCl 40.2ml, at 100 ℃～110 ℃, stirring reaction is after 10 hours, reaction solution is poured in frozen water, with dichloromethane extraction, water and saturated NaCl solution washing organic layer, after anhydrous sodium sulfate drying, the concentrated solid obtaining obtains 0.09g(31% through purification by silica gel column chromatography (eluent is methylene dichloride: methyl alcohol 30:1)) be the title compound of yellow solid.
1HNMR(300 MHz,CDCl 3)δ14.32(s,1H,-NH-1),7.70(s,1H,-NH-1’),7.36(dd,1H,J=10.62Hz,H-4’),6.91~6.78(m,2H,H-6’,H-7’),6.44(bs,1H,-CONH-),3.51(bs,2H,-CONH CH 2 CH 2-),3.11(t,2H,-CH 2-4),2.97(t,2H,-CH 2-6),2.62(bs,9H,-CH 3-2,-NHCH 2 CH 2 N( CH 2 CH 3) 2),2.08(m,2H,-CH 2-5),1.07(bs,6H,-(CH 2 CH 3 ) 2);
ESI-MS:425.1[M+H] +.
Embodiment 26:N-(2-diethylin ethyl)-2-methyl-7-[1,2-dihydro-5-chloro-2-oxo-3H-indoles-(Z)-3-subunit]-4,5,6,7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides (I-3)
Figure BDA00001671821300232
Use the method for embodiment 25,0.13g(0.78mmol) 5-chlorine-2-hydroxyl indoles and 0.20g(0.69mmol) N-(2-diethylin ethyl)-2-methyl-7-oxo-4,5,6,7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides (II-1) reacts to obtain 0.08g(26%) be the title compound of yellow solid.
1HNMR(500 MHz,CDCl 3)δ14.25(s,1H,-NH-1),8.55(s,1H,-NH-1’),7.55(s,1H,H-4’),7.10(dd,1H,J=8.2Hz,H-6’),6.81(d,1H,J=8.2Hz,H-7’),6.48(s,1H,-CONH-),3.51(s,2H,-CONH CH 2 CH 2-),3.06(t,2H,-CH 2-4),2.89(t,2H,-CH 2-6),2.68(s,2H,-CONHCH 2 CH 2 -),2.60(m,7H,-CH 3-2,-NHCH 2CH 2N( CH 2 CH 3) 2),2.03(m,2H,-CH 2-5),1.05(t,6H,-(CH 2 CH 3 ) 2);
ESI-MS:441.1[M+H] +,463.3[M+Na] +;439.2[M-H] -.
Embodiment 27:N-(2-diethylin ethyl)-2-methyl-7-[1,2-dihydro-5-methyl-2-oxo-3H-indoles-(Z)-3-subunit]-4,5,6,7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides (I-4)
Use the method for embodiment 25,0.12g(0.82mmol) 5-methyl-2-oxyindole and 0.20g(0.69mmol) N-(2-diethylin ethyl)-2-methyl-7-oxo-4,5,6,7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides (II-1) reacts to obtain 0.09g(31%) be the title compound of yellow solid.
1HNMR(300 MHz,CDCl 3)δ14.30(s,1H,-NH-1),8.11(s,1H,-NH-1’),7.42(s,1H,H-4’),6.97(d,1H,J=7.92Hz,H-6’),6.80(d,1H,J=7.83Hz,H-7’),6.47(bs,1H,-CONH-),3.51(m,2H,-CONH CH 2 CH 2-),3.14(t,2H,-CH 2-4),2.94(t,2H,-CH 2-6),2.68~2.57(m,9H,-CH 3-2,-NHCH 2 CH 2 N( CH 2 CH 3) 2),2.38(s,3H,-CH 3-5’),2.03(m,2H,-CH 2-5),1.05(t,6H,-(CH 2 CH 3 ) 2);
ESI-MS:421.1[M+H] +.
Embodiment 28:N-(2-diethylin ethyl)-2-methyl-7-[1,2-dihydro-2-oxo--3H-indoles-(Z)-3-subunit]-4,5,6,7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides (I-5)
Use the method for embodiment 25,0.11g(0.83mmol) 2-oxyindole and 0.20g(0.69mmol) N-(2-diethylin ethyl)-2-methyl-7-oxo-4,5,6,7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides (II-1) reacts to obtain 0.09g(32%) be the title compound of yellow solid.
1HNMR(300 MHz,CDCl 3)δ14.27(s,1H,-NH-1),8.06(s,1H,-NH-1’),7.62(s,1H,J=7.71Hz,H-4’),7.15(t,1H,H-6’),7.04(t,1H,H-5’),6.91(d,1H,J=7.56Hz,H-7’),6.46(bs,1H,-CONH-),3.51(m,2H,-CONH CH 2 CH 2-),3.15(t,2H,-CH 2-4),2.93(t,2H,-CH 2-6),2.67~2.59(m,9H,-CH 3-2,-NHCH 2 CH 2 N( CH 2 CH 3) 2),2.05(m,2H,-CH 2-5),1.05(t,6H,-(CH 2 CH 3 ) 2);
ESI-MS:407.3[M+H] +.
Embodiment 29:N-(2-dimethylamino ethyl)-2-methyl-7-[1, the fluoro-2-oxo-3H-of 2-dihydro-5-indoles-(Z)-3-subunit]-4,5,6,7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides (I-6)
Figure BDA00001671821300243
Use the method for embodiment 25,0.13g(0.86mmol) the fluoro-2-oxyindole of 5-and 0.18g(0.68mmol) N-(2-dimethylamino ethyl)-2-methyl-7-oxo-4,5,6,7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides (II-3) reacts to obtain 0.09g(33%) be the title compound of yellow solid.
1HNMR(300 MHz,CDCl 3)δ14.21(s,1H,-NH-1),8.70(s,1H,-NH-1’),7.32(d,1H,J=12.07Hz,H-4’),6.87~6.76(m,2H,H-6’,H-7’),6.59(bs,1H,-CONH-),3.57(m,2H,-CONH CH 2 CH 2-),2.99(t,2H,-CH 2-4),2.76(t,2H,-CH 2-6),2.65(s,2H,-NHCH 2 CH 2 N(CH 3) 2),2.57(s,3H,-CH 3-2),2.38(s,6H,-N( CH 3 ) 2),1.94(m,2H,-CH 2-5);
ESI-MS:397.3[M+H] +.
Embodiment 30:N-(3-dimethylamino-propyl)-2-methyl-7-[1,2-dihydro-5-chloro-2-oxo-3H-indoles-(Z)-3-subunit]-4,5,6,7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides (I-7)
Figure BDA00001671821300251
Use the method for embodiment 25,0.13g(0.78mmol) 5-chlorine-2-hydroxyl indoles and 0.20g(0.72mmol) N-(3-dimethylamino-propyl)-2-methyl-7-oxo-4,5,6,7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides (II-4) reacts to obtain 0.10g(33%) be the title compound of yellow solid.
1HNMR(300 MHz,CDCl 3)δ14.25(s,1H,-NH-1),7.83(s,1H,-NH-1’),7.59(s,1H,H-4’),7.12(m,2H,H-6’,-CONH-),6.83(d,1H,J=8.28Hz,H-7’),3.54(s,2H,-CONH CH 2 CH 2CH 2-),3.11(s,2H,-CH 2-4),2.94(s,2H,-CH 2-6),2.60(s,3H,-CH 3-2),2.51(s,2H,-CONHCH 2CH 2 CH 2 -),2.28(s,6H,-N( CH 3 ) 2),2.07(m,2H,-CH 2-5),1.79(bs,2H,-CONHCH 2 CH 2 CH 2-);
ESI-MS:427.2[M+H] +.
Embodiment 31:N-(2-hydroxyethyl)-2-methyl-7-[1,2-dihydro-2-oxo--3H-indoles-(Z)-3-subunit]-4,5,6,7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides (I-8)
Use the method for embodiment 25,0.11g(0.83mmol) 2-oxyindole and 0.17g(0.72mmol) N-(2-hydroxyethyl)-2-methyl-7-oxo-4,5,6,7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides (II-2) reacts to obtain 0.07g(28%) be the title compound of yellow solid.
1HNMR(300 MHz,CDCl 3)δ14.49(s,1H,-NH-1),10.83(s,1H,-NH-1’),7.64(d,1H,J=7.83 Hz,H-4’),7.26(t,1H,-CONH-),7.13(t,1H,H-6’),7.01~6.91(m,2H,H-5’,H-7’),4.65(bs,1H,-OH),3.51(s,2H,-CONH CH 2 CH 2-),3.31(m,2H,-CONHCH 2 CH 2 -),3.13(t,2H,-CH 2-4),2.84(t,2H,-CH 2-6),2.46(s,3H,-CH 3-2),1.99(m,2H,-CH 2-5);
ESI-MS:352.3[M+H] +,374.1[M+Na] +;350.2[M-H] -.
Embodiment 32:N-(2-hydroxyethyl)-2-methyl-7-[1, the fluoro-2-oxo-3H-of 2-dihydro-5-indoles-(Z)-3-subunit]-4,5,6,7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides (I-9)
Use the method for embodiment 25,0.13g(0.86mmol) the fluoro-2-oxyindole of 5-and 0.17g(0.72mmol) N-(2-hydroxyethyl)-2-methyl-7-oxo-4,5,6,7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides (II-2) reacts to obtain 0.08g(30%) be the title compound of yellow solid.
1HNMR(300 MHz,CDCl 3)δ14.54(s,1H,-NH-1),10.84(s,1H,-NH-1’),7.44(dd,1H,J=10.9Hz,H-4’),7.26(t,1H,-CONH-),6.98~6.85(m,2H,H-6’,H-7’),4.63(t,1H,-OH),3.52(q,2H,-CONH CH 2 CH 2-),3.32(m,2H,-CONHCH 2 CH 2 -),3.08(t,2H,-CH 2-4),2.85(t,2H,-CH 2-6),2.47(s,3H,-CH 3-2),1.98(m,2H,-CH 2-5);
ESI-MS:368.1[M-H] -.
Embodiment 33:2-methyl-3-(morpholine-4-carbonyl)-7-[1, the fluoro-2-oxo-3H-of 2-dihydro-5-indoles-(Z)-3-subunit]-4,5,6,7-tetrahydrochysene-1H-indoles (I-10)
Use the method for embodiment 2,0.15g(0.46mmol) 2-methyl-7-[1, the fluoro-2-oxo-3H-of 2-dihydro-5-indoles-(Z)-3-subunit]-4,5,6,7-tetrahydrochysene-1H-Indole-3-Carboxylic Acid (IV-2) and 0.13g(1.5mmol) morpholine react to obtain 0.12g(66%) be the title compound of yellow solid.
1HNMR(300 MHz,CDCl 3)δ14.23(s,1H,-NH-1),7.95(s,1H,-NH-1’),7.35(dd,1H,J=10.58Hz,H-4’),6.88~6.77(m,2H,H-6’,H-7’),3.69(s,4H,-N( CH 2 CH 2) 2O),3.63(s,4H,-N(CH 2 CH 2 ) 2O),3.09(t,2H,-CH 2-4),2.70(t,2H,-CH 2-6),2.42(s,3H,-CH 3-2),2.06(m,2H,-CH 2-5);
ESI-MS:396.2[M+H] +,418.2[M+Na] +,434.0[M+K] +;394.2[M-H] -.
Embodiment 34:2-methyl-3-(morpholine-4-carbonyl)-7-[1,2-dihydro-5-chloro-2-oxo-3H-indoles-(Z)-3-subunit]-4,5,6,7-tetrahydrochysene-1H-indoles (I-11)
Figure BDA00001671821300262
Use the method for embodiment 2,0.15g(0.44mmol) 2-methyl-7-[1,2-dihydro-5-chloro-2-oxo-3H-indoles-(Z)-3-subunit]-4,5,6,7-tetrahydrochysene-1H-Indole-3-Carboxylic Acid (IV-3) and 0.12g(1.4mmol) morpholine react to obtain 0.13g(72%) be the title compound of yellow solid.
1HNMR(500 MHz,CDCl 3)δ14.19(s,1H,-NH-1),7.90(s,1H,-NH-1’),7.59(s,1H,H-4’),7.12(dd,1H,J=8.19 Hz,H-6’),6.82(d,1H,J=8.23Hz,H-7’),3.70(s,4H,-N( CH 2 CH 2) 2O),3.63(s,4H,-N(CH 2 CH 2 ) 2O),3.12(s,2H,-CH 2-4),2.71(s,2H,-CH 2-6),2.43(s,3H,-CH 3-2),2.06(m,2H,-CH 2-5);
ESI-MS:412.2[M+H] +,434.1[M+Na] +;410.2[M-H] -.
Embodiment 35:2-methyl-3-(morpholine-4-carbonyl)-7-[1,2-dihydro-2-oxo--3H-indoles-(Z)-3-subunit]-4,5,6,7-tetrahydrochysene-1H-indoles (I-12)
Figure BDA00001671821300263
Use the method for embodiment 2,0.14g(0.45mmol) 2-methyl-7-[1,2-dihydro-2-oxo--3H-indoles-(Z)-3-subunit]-4,5,6,7-tetrahydrochysene-1H-Indole-3-Carboxylic Acid (IV-1) and 0.13g(1.5mmol) morpholine react to obtain 0.12g(71%) be the title compound of yellow solid.
1HNMR(300 MHz,CDCl 3)δ14.20(s,1H,-NH-1),8.07(s,1H,-NH-1’),7.63(d,1H,J=7.86Hz,H-4’),7.16(t,1H,H-6’),7.05(t,1H,H-5’),6.90(dd,1H,J=7.63Hz,H-7’),3.70(s,4H,-N( CH 2 CH 2) 2O),3.64(s,4H,-N(CH 2 CH 2 ) 2O),3.15(t,2H,-CH 2-4),2.70(s,2H,-CH 2-6),2.42(s,3H,-CH 3-2),2.05(m,2H,-CH 2-5);
ESI-MS:378.1[M+H] +;376.2[M-H] -.
Embodiment 36:2-methyl-3-(4-methyl-piperazine-1-carbonyl)-7-[1,2-dihydro-2-oxo--3H-indoles-(Z)-3-subunit]-4,5,6,7-tetrahydrochysene-1H-indoles (I-13)
Figure BDA00001671821300271
Use the method for embodiment 2,0.15g(0.49mmol) 2-methyl-7-[1,2-dihydro-2-oxo--3H-indoles-(Z)-3-subunit]-4,5,6,7-tetrahydrochysene-1H-Indole-3-Carboxylic Acid (IV-1) and 0.15g(1.5mmol) N methyl piperazine react to obtain 0.14g(73%) be the title compound of yellow solid.
1HNMR(300 MHz,CDCl 3)δ14.17(s,1H,-NH-1),7.90(s,1H,-NH-1’),7.64(d,1H,J=7.83Hz,H-4’),7.15(t,1H,H-6’),7.05(t,1H,H-5’),6.91(d,1H,J=7.60Hz,H-7’),3.65(s,4H,-N( CH 2 CH 2) 2NCH 3),3.16(t,2H,-CH 2-4),2.70(s,2H,-CH 2-6),2.41(s,7H,-CH 3-2,-N(CH 2 CH 2 ) 2NCH 3),2.33(s,3H,-N(CH 2CH 2) 2N CH 3 ),2.06(m,2H,-CH 2-5);
ESI-MS:391.2[M+H] +;389.2[M-H] -.
Embodiment 37:2-methyl-3-(4-methyl-piperazine-1-carbonyl)-7-[1, the fluoro-2-oxo-3H-of 2-dihydro-5-indoles-(Z)-3-subunit]-4,5,6,7-tetrahydrochysene-1H-indoles (I-14)
Figure BDA00001671821300272
Use the method for embodiment 2,0.15g(0.46mmol) 2-methyl-7-[1, the fluoro-2-oxo-3H-of 2-dihydro-5-indoles-(Z)-3-subunit]-4,5,6,7-tetrahydrochysene-1H-Indole-3-Carboxylic Acid (IV-2) and 0.15g(1.5mmol) N methyl piperazine react to obtain 0.14g(75%) be the title compound of yellow solid.
1HNMR(300 MHz,CDCl 3)δ14.21(s,1H,-NH-1),7.70(s,1H,-NH-1’),7.36(dd,1H,J=10.61Hz,H-4’),6.89~6.78(m,2H,H-6’,H-7’),3.66(bs,4H,-N( CH 2 CH 2) 2NCH 3),3.11(t,2H,-CH 2-4),2.71(s,2H,-CH 2-6),2.42(s,7H,-CH 3-2,-N(CH 2 CH 2 ) 2NCH 3),2.35(s,3H,-N(CH 2CH 2) 2N CH 3 ),2.06(m,2H,-CH 2-5);
ESI-MS:409.3[M+H] +;407.3[M-H] -.
Embodiment 38:N, N-dimethyl-2-methyl-7-[1,2-dihydro-2-oxo--3H-indoles-(Z)-3-subunit]-4,5,6,7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides (I-15)
Figure BDA00001671821300273
Use the method for embodiment 2,0.10g(0.32mmol) 2-methyl-7-[1,2-dihydro-2-oxo--3H-indoles-(Z)-3-subunit]-4,5,6,7-tetrahydrochysene-1H-Indole-3-Carboxylic Acid (IV-1) and 0.12g(1.5mmol) dimethylamine hydrochloride, and add 0.23g(1.5mmol) DBU reaction, obtain 50mg(47%) be the title compound of yellow solid.
1HNMR(500 MHz,CDCl 3)δ14.14(s,1H,-NH-1),7.85(bs,1H,-NH-1’),7.63(s,1H,J=7.90Hz,H-4’),7.15(t,1H,H-6’),7.04(t,1H,H-5’),6.90(d,1H,J=7.64Hz,H-7’),3.16(s,2H,-CH 2-4),3.06(s,3H,-N CH 3 (CH 3)),2.71(s,2H,-CH 2-6),2.40(s,3H,-CH 3-2),2.04(m,2H,-CH 2-5),1.57(s,3H,-NCH 3( CH 3 ));
ESI-MS:336.1[M+H] +;334.2[M-H] -.
Embodiment 39:N-[2-(morpholine-4-yl)-ethyl]-2-methyl-7-[1,2-dihydro-5-methyl-2-oxo-3H-indoles-(Z)-3-subunit]-4,5,6,7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides (I-16)
Use the method for embodiment 25,0.12g(0.82mmol) 5-methyl-2-oxyindole and 0.21g(0.69mmol) N-[2-(morpholine-4-yl)-ethyl]-2-methyl-7-oxo-4,5,6,7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides (II-5) reacts to obtain 0.10g(33%) be the title compound of yellow solid.
1HNMR(300 MHz,CDCl 3)δ14.34(s,1H,-NH-1),7.70(s,1H,-NH-1’),7.45(s,1H,H-4’),6.99(d,1H,J=7.71Hz,H-6’),6.82(d,1H,J=7.83Hz,H-7’),6.35(bs,1H,-CONH-),3.75(s,4H,-CH 2N(CH 2 CH 2 ) 2O),3.56(s,2H,-CONHCH 2),3.16(s,2H,-CH 2-4),2.99(s,2H,-CH 2-6),2.63~2.55(m,9H,-CH 3-2,- CH 2 N( CH 2 CH 2)2O),2.40(s,3H,-CH 3-6’),2.07(m,2H,-CH 2-5);
ESI-MS:435.2[M+H] +;457.2[M+Na] +;473.2[M+K] +.
Embodiment 40:N-[3-(morpholine-4-yl)-propyl group]-2-methyl-7-[1,2-dihydro-5-methyl-2-oxo-3H-indoles-(Z)-3-subunit]-4,5,6,7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides (I-17)
Figure BDA00001671821300282
Use the method for embodiment 25,0.15g(1.02mmol) 5-methyl-2-oxyindole and 0.27g(0.85mmol) N-[3-(morpholine-4-yl)-propyl group]-2-methyl-7-oxo-4,5,6,7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides (II-8) reacts to obtain 0.13g(34%) be the title compound of yellow solid.
1HNMR(300 MHz,CDCl 3)δ14.32(s,1H,-NH-1),7.70(s,1H,-NH-1’),7.45(s,1H,H-4’),6.99(d,1H,J=7.26Hz,H-6’),6.82(d,1H,J=7.80Hz,H-7’),6.18(bs,1H,-CONH-),3.71(bs,4H,-CH 2N(CH 2 CH 2 ) 2O),3.57(m,2H,-CONH CH 2 ),3.19(t,2H,-CH 2-4),2.97(t,2H,-CH 2-6),2.61(s,3H,-CH 3-2),2.49(bs,6H,-CH 2 CH 2 N( CH 2 CH 2) 2O),2.40(s,3H,-CH 3-6’),2.13(m,2H,-CH 2-5),1.82(s,2H,- CH 2 CH 2N(CH 2CH 2) 2O);
ESI-MS:449.2[M+H] +;471.2[M+Na] +.
Embodiment 41:N-[2-(morpholine-4-yl)-ethyl]-2-methyl-7-[1,2-dihydro-2-oxo--3H-indoles-(Z)-3-subunit]-4,5,6,7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides (I-18)
Use the method for embodiment 25,0.11g(0.83mmol) 2-oxyindole and 0.20g(0.65mmol) N-[2-(morpholine-4-yl)-ethyl]-2-methyl-7-oxo-4,5,6,7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides (II-5) reacts to obtain 0.10g(37%) be the title compound of yellow solid.
1HNMR(300 MHz,CDCl 3)δ14.33(s,1H,-NH-1),7.87(s,1H,-NH-1’),7.64(d,1H,J=7.89Hz,H-4’),7.17(t,1H,H-6’),7.09(t,1H,H-5’),6.94(d,1H,J=7.09Hz,H-7’),6.34(bs,1H,-CONH-),3.77(bs，4H，-CH 2N(CH 2 CH 2 ) 2O)，3.58(bs，2H，-CONH CH 2 )，3.19(t，2H，-CH 2-4)，2.97(s，2H，-CH 2-6),2.63~2.56(m,9H,-CH 3-2,- CH 2 N( CH 2 CH 2) 2O),2.09(m,2H,-CH 2-5);
ESI-MS:421.2[M+H] +;443.2[M+Na] +.
Embodiment 42:N-[2-(morpholine-4-yl)-ethyl]-2-methyl-7-[1,2-dihydro-5-chloro-2-oxo-3H-indoles-(Z)-3-subunit]-4,5,6,7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides (I-19)
Figure BDA00001671821300292
Use the method for embodiment 25,0.15g(0.90mmol) 5-chlorine-2-hydroxyl indoles and 0.23g(0.75mmol) N-[2-(morpholine-4-yl)-ethyl]-2-methyl-7-oxo-4,5,6,7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides (II-5) reacts to obtain 0.11g(32%) be the title compound of yellow solid.
1HNMR(300 MHz,CDCl 3)δ14.29(s,1H,-NH-1),7.80(bs,1H,-NH-1’),7.62(s,1H,H-4’),7.15(dd,1H,J=8.15Hz,H-6’),6.83(d,1H,J=8.19Hz,H-7’),6.35(bs,1H,-CONH-),3.74(s,4H,-CH 2N(CH 2 CH 2 ) 2O),3.56(s,2H,-CONH CH 2 ),3.13(t,2H,-CH 2-4),2.98(t,2H,-CH 2-6),2.63~2.55(m,9H,-CH 3-2,- CH 2 N( CH 2 CH 2) 2O),2.12(m,2H,-CH 2-5);
ESI-MS:455.1[M+H] +.
Embodiment 43:N-[2-(morpholine-4-yl)-ethyl]-2-methyl-7-[1, the fluoro-2-oxo-3H-of 2-dihydro-5-indoles-(Z)-3-subunit]-4,5,6,7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides (I-20)
Figure BDA00001671821300293
Use the method for embodiment 25,0.15g(1.0mmol) the fluoro-2-oxyindole of 5-and 0.23g(0.75mmol) N-[2-(morpholine-4-yl)-ethyl]-2-methyl-7-oxo-4,5,6,7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides (II-5) reacts to obtain 0.12g(36%) be the title compound of yellow solid.
1HNMR(300 MHz,CDCl 3)δ14.40(s,1H,-NH-1),7.73(bs,1H,-NH-1’),7.42(dd,1H,J=10.6Hz,H-4’),6.95(m,2H,H-6’,H-7’),6.37(bs,1H,-CONH-),3.78(m,4H,-CH 2N(CH 2 CH 2 ) 2O),3.58(s,2H,-CONH CH 2 ),3.19(t,2H,-CH 2-4),3.04(t,2H,-CH 2-6),2.67~2.51(m,9H,-CH 3-2,- CH 2 N( CH 2 CH 2) 2O),2.16(m,2H,-CH 2-5);
ESI-MS:439.2[M+H] +;461.2[M+Na] +.
Embodiment 44:N-[3-(morpholine-4-yl)-propyl group]-2-methyl-7-[1, the fluoro-2-oxo-3H-of 2-dihydro-5-indoles-(Z)-3-subunit]-4,5,6,7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides (I-21)
Figure BDA00001671821300301
Use the method for embodiment 25,0.15g(1.0mmol) the fluoro-2-oxyindole of 5-and 0.26g(0.81mmol) N-[3-(morpholine-4-yl)-propyl group]-2-methyl-7-oxo-4,5,6,7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides (II-8) reacts to obtain 0.11g(30%) be the title compound of yellow solid.
1HNMR(300 MHz,CDCl 3)δ7.65(s,1H,-NH-1’),7.29(d,1H,J=9.2Hz,H-4’),6.82~6.72(m,2H,H-6’,H-7’),6.15(bs,1H,-CONH-),3.62(s,4H,-CH 2N(CH 2 CH 2 ) 2O),3.46(m,2H,-CONH CH 2 ),3.05(t,2H,-CH 2-4),2.87(t,2H,-CH 2-6),2.53(s,3H,-CH 3-2),2.49(bs,6H,-CH 2 CH 2 N( CH 2 CH 2) 2O),2.01(m,2H,-CH 2-5),1.76(s,2H,- CH 2 CH 2N(CH 2CH 2) 2O);
ESI-MS:453.2[M+H] +;475.2[M+Na] +;491.2[M+K] +.
Embodiment 45:N-[3-(morpholine-4-yl)-propyl group]-2-methyl-7-[1, the bromo-2-oxo-3H-of 2-dihydro-5-indoles-(Z)-3-subunit]-4,5,6,7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides (I-22)
Figure BDA00001671821300302
Use the method for embodiment 25,0.21g(1.0mmol) the bromo-2-oxyindole of 5-and 0.26g(0.81mmol) N-[3-(morpholine-4-yl)-propyl group]-2-methyl-7-oxo-4,5,6,7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides (II-8) reacts to obtain 0.10g(24%) be the title compound of yellow solid.
1HNMR(300 MHz,CDCl 3)δ14.27(s,1H,-NH-1),7.76~7.72(d,2H,-NH-1’,H-4’),7.27(m,1H,H-6’),6.80(d,1H,J=8.21Hz,H-7’),6.24(bs,1H,-CONH-),3.70(bs,4H,-CH 2N(CH 2 CH 2 ) 2O),3.56(m,2H,-CONHC H 2 ),3.13(t,2H,-CH 2-4),2.95(t,2H,-CH 2-6),2.60(s,3H,-CH 3-2),2.50(bs,6H,-CH 2 CH 2 N( CH 2 CH 2) 2O),2.10(m,2H,-CH 2-5),1.83(s,2H,-CH 2 CH 2 CH 2-);
ESI-MS:514.2[M+H] +.
Embodiment 46:N-[2-(morpholine-4-yl)-ethyl]-2-methyl-7-[1, the fluoro-2-oxo-3H-of 2-dihydro-7-indoles-(Z)-3-subunit]-4,5,6,7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides (I-23)
Figure BDA00001671821300303
Use the method for embodiment 25,0.15g(1.0mmol) the fluoro-2-oxyindole of 7-and 0.23g(0.75mmol) N-[2-(morpholine-4-yl)-ethyl]-2-methyl-7-oxo-4,5,6,7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides (II-5) reacts to obtain 0.11g(33%) be the title compound of yellow solid.
1HNMR(300 MHz,DMSO-d 6)δ14.47(s,1H,-NH-1),11.37(s,1H,-NH-1’),7.47(d,1H,J=7.2Hz,H-4’),7.32(t,1H,-CONH-),7.01(m,2H,H-5’,H-6’),3.58(t,4H,-CH 2N(CH 2 CH 2 ) 2O),3.31(q,2H,-CONH CH 2 ),3.11(t,2H,-CH 2-4),2.85(t,2H,-CH 2-6),2.51(m,5H,-CH 3-2,-CONHCH 2 CH 2 -),2.42(m,4H,-CH 2N( CH 2 CH 2) 2O),1.96(m,2H,-CH 2-5);
ESI-MS:439.2[M+H] +;461.2[M+Na] +.
Embodiment 47:N-[2-(pyrrolidin-1-yl)-ethyl]-2-methyl-7-[1,2-dihydro-2-oxo--3H-indoles-(Z)-3-subunit]-4,5,6,7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides (I-24)
Figure BDA00001671821300311
Use the method for embodiment 25,0.15g(1.12mmol) 2-oxyindole and 0.26g(0.90mmol) N-[2-(pyrrolidin-1-yl)-ethyl]-2-methyl-7-oxo-4,5,6,7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides (II-7) reacts to obtain 0.15g(41%) be the title compound of yellow solid.
1HNMR(300 MHz,CDCl 3)δ14.16(s,1H,-NH-1),8.90(s,1H,-NH-1’),7.60(d,1H,J=7.75Hz,H-4’),7.16(t,1H,H-6’),7.07(t,1H,H-5’),6.90(dd,1H,J=7.58Hz,H-7’),6.61(bs,1H,-CONH-),3.61(d，2H，J=4.29Hz，-CONHC H 2 )，3.03(t，2H，-CH 2-4)，2.82(s，2H，-CH 2-6)，2.70(s，6H，- CH 2 N( CH 2 CH 2) 2),2.57(s,3H,-CH 3-2),1.95~1.85(m,6H,-CH 2N(CH 2 CH 2 ) 2,-CH 2-5);
ESI-MS:405.2[M+H] +;427.2[M+Na] +.
Embodiment 48:N-[2-(piperidin-1-yl)-ethyl]-2-methyl-7-[1,2-dihydro-2-oxo--3H-indoles-(Z)-3-subunit]-4,5,6,7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides (I-25)
Figure BDA00001671821300312
Use the method for embodiment 25,0.15g(1.12mmol) 2-oxyindole and 0.27g(0.90mmol) N-[2-(piperidin-1-yl)-ethyl]-2-methyl-7-oxo-4,5,6,7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides (II-6) reacts to obtain 0.14g(37%) be the title compound of yellow solid.
1HNMR(300 MHz,DMSO-d 6)δ14.51(s,1H,-NH-1),10.89(s,1H,-NH-1’),7.64(d,1H,J=7.85Hz,H-4’),7.21(t,1H,-CONH-),7.12(t,1H,H-6’),6.97(t,1H,H-5’),6.92(d,1H,J=7.53Hz,H-7’),3.32(m，2H，-CONH CH 2 )，3.10(t，2H，-CH 2-4)，2.84(t，2H，-CH 2-6)，2.46(s，3H，-CH 3-2)，2.40(m，6H,- CH 2 N( CH 2 CH 2) 2CH 2),1.94(m,2H,-CH 2-5);1.51(m,4H,-CH 2N(CH 2 CH 2 ) 2CH 2);1.39(m,2H,-CH 2N(CH 2CH 2) 2 CH 2 );
ESI-MS:419.2[M+H] +.
Embodiment 49:N-[2-(piperidin-1-yl)-ethyl]-2-methyl-7-[1, the fluoro-2-oxo-3H-of 2-dihydro-5-indoles-(Z)-3-subunit]-4,5,6,7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides (I-26)
Figure BDA00001671821300321
Use the method for embodiment 25,0.15g(1.0mmol) the fluoro-2-oxyindole of 5-and 0.24g(0.80mmol) N-[2-(piperidin-1-yl)-ethyl]-2-methyl-7-oxo-4,5,6,7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides (II-6) reacts to obtain 0.14g(40%) be the title compound of yellow solid.
1HNMR(300 MHz,CDCl 3)δ8.32(s,1H,-NH-1’),7.27(d,1H,J=10.7Hz,H-4’),6.81~6.70(m,2H,H-6’,H-7’),6.47(bs,1H,-CONH-),3.48(q,2H,-CONH CH 2 CH 2-),2.98(t,2H,-CH 2-4),2.81(t,2H,-CH 2-6),2.53~2.41(m,9H,-CH 3-2,-NHCH 2 CH 2 N( CH 2 CH 2) 2CH 2),1.94(m,2H,-CH 2-5),1.53(s,6H,-N(CH 2 CH 2 ) 2 CH 2 );
ESI-MS:437.2[M+H] +;459.2[M+Na] +.
Embodiment 50:N-[2-(pyrrolidin-1-yl)-ethyl]-2-methyl-7-[1, the fluoro-2-oxo-3H-of 2-dihydro-5-indoles-(Z)-3-subunit]-4,5,6,7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides (I-27)
Figure BDA00001671821300322
Use the method for embodiment 25,0.15g(1.0mmol) the fluoro-2-oxyindole of 5-and 0.23g(0.80mmol) N-[2-(pyrrolidin-1-yl)-ethyl]-2-methyl-7-oxo-4,5,6,7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides (II-7) reacts to obtain 0.12g(35%) be the title compound of yellow solid.
1HNMR(300 MHz,DMSO-d 6)δ14.53(s,1H,-NH-1),10.90(s,1H,-NH-1’),7.42(m,2H,-CONH-,H-4’),6.92~6.82(m,2H,H-6’,H-7’),3.37(q,2H,-CONH CH 2 ),3.06(t,2H,-CH 2-4),2.81(t,2H,-CH 2-6),2.70(s,6H,- CH 2 N( CH 2 CH 2) 2),2.43(s,3H,-CH 3-2),1.91(m,2H,-CH 2-5),1.72(s,4H,-CH 2N(CH 2 CH 2 ) 2);
ESI-MS:423.1[M+H] +;445.1[M+Na] +.
Embodiment 51:N-[3-(pyrrolidin-1-yl)-propyl group]-2-methyl-7-[1, the fluoro-2-oxo-3H-of 2-dihydro-5-indoles-(Z)-3-subunit]-4,5,6,7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides (I-28)
Figure BDA00001671821300323
Use the method for embodiment 25,0.15g(1.0mmol) the fluoro-2-oxyindole of 5-and 0.23g(0.75mmol) N-[3-(pyrrolidin-1-yl)-propyl group]-2-methyl-7-oxo-4,5,6,7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides (II-10) reacts to obtain 0.10g(31%) be the title compound of yellow solid.
1HNMR(300 MHz,DMSO-d 6)δ14.55(s,1H,-NH-1),10.91(s,1H,-NH-1’),7.51(t,1H,-CONH-),7.46(dd,1H,J=10.87Hz,H-4’),6.95(t,1H,H-6’),6.89(dd,1H,J=8.5Hz,H-7’),3.28(q,2H,-CONH CH 2 ),3.09(t， 2H,-CH 2-4),2.84(t，2H,-CH 2-6),2.50~2.45(m,9H,-CH 3-2,- CH 2 N( CH 2 CH 2) 2),1.96(m,2H,-CH 2-5),1.69(m,6H,- CH 2 CH 2N(CH 2 CH 2 ) 2);
ESI-MS:437.2[M+H] +;459.2[M+Na] +.
Embodiment 52:N-[3-(4-methyl-piperazine-1-yl)-propyl group]-2-methyl-7-[1, the fluoro-2-oxo-3H-of 2-dihydro-5-indoles-(Z)-3-subunit]-4,5,6,7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides (I-29)
Figure BDA00001671821300331
Use the method for embodiment 25,0.15g(1.0mmol) the fluoro-2-oxyindole of 5-and 0.27g(0.81mmol) N-[3-(4-methyl-piperazine-1-yl)-propyl group]-2-methyl-7-oxo-4,5,6,7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides (II-11) reacts to obtain 0.12g(32%) be the title compound of yellow solid.
1HNMR(300 MHz,DMSO-d 6)δ14.54(s,1H,-NH-1),10.91(s,1H,-NH-1’),7.46(m,2H,-CONH-,H-4’),6.95(t,1H,H-6’),6.87(dd,1H,J=8.4Hz,H-7’),3.22(q,2H,-CONH CH 2 CH 2-),3.07(t,2H,-CH 2-4),2.82(t,2H,-CH 2-6),2.44(s,3H,CH 3-2),2.34(m,10H,- CH 2 N( CH 2 CH 2 ) 2NCH 3),2.14(s,3H,-NCH 3),1.93(m,2H,-CH 2-5),1.64(m,2H,-NHCH 2 CH 2 CH 2-);
ESI-MS:466.3[M+H] +.
Embodiment 53:N-[3-(pyrrolidin-1-yl)-propyl group]-2-methyl-7-[1, the bromo-2-oxo-3H-of 2-dihydro-5-indoles-(Z)-3-subunit]-4,5,6,7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides (I-30)
Figure BDA00001671821300332
Use the method for embodiment 25,0.21g(1.0mmol) the bromo-2-oxyindole of 5-and 0.23g(0.75mmol) N-[3-(pyrrolidin-1-yl)-propyl group]-2-methyl-7-oxo-4,5,6,7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides (II-10) reacts to obtain 0.10g(27%) be the title compound of yellow solid.
1HNMR(300 MHz,DMSO-d 6)δ14.49(s,1H,-NH-1),11.02(s,1H,-NH-1’),7.72(s,1H,H-4’),7.50(t,1H,-CONH-),7.29(dd,1H,J=8.2Hz,H-6’),6.87(d,1H,J=8.2Hz,H-7’),3.26(q,2H,-CONHC H 2 )，3.08(t，2H，-CH 2-4)，2.83(t，2H，-CH 2-6)，2.49(m，9H，-CH 3-2，- CH 2 N( CH 2 CH 2) 2)，1.95(m,2H,-CH 2-5),1.67(m,6H,- CH 2 CH 2N(CH 2 CH 2 ) 2);
ESI-MS:498.2[M+H] +.
Embodiment 54:N-[2-(piperidin-1-yl)-ethyl]-2-methyl-7-[1,2-dihydro-6-chloro-2-oxo-3H-indoles-(Z)-3-subunit]-4,5,6,7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides (I-31)
Figure BDA00001671821300333
Use the method for embodiment 25,0.17g(1.0mmol) 6-chlorine-2-hydroxyl indoles and 0.24g(0.80mmol) N-[2-(piperidin-1-yl)-ethyl]-2-methyl-7-oxo-4,5,6,7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides (II-6) reacts to obtain 0.13g(36%) be the title compound of yellow solid.
1HNMR(300 MHz,DMSO-d 6)δ14.38(s,1H,-NH-1),11.03(s,1H,-NH-1’),7.63(d,1H,J=8.6Hz,H-4’),7.25(t,1H,-CONH-),7.02(dd,1H,J=8.4Hz,H-5’),6.90(d,1H,J=2.1Hz,H-7’),3.32(q,2H,-CONH CH 2 CH 2-),3.08(t,2H,-CH 2-4),2.84(t,2H,-CH 2-6),2.46(s,3H,-CH 3-2),2.40(m,6H,-NHCH 2 CH 2 N( CH 2 CH 2) 2CH 2),1.93(m,2H,-CH 2-5),1.51(m,4H,-N(CH 2 CH 2 ) 2 CH 2),1.38(m,2H,-N(CH 2CH 2) 2 CH 2 );
ESI-MS:453.2[M+H] +.
Embodiment 55:N-[3-(pyrrolidin-1-yl)-propyl group]-2-methyl-7-[1, the fluoro-2-oxo-3H-of 2-dihydro-4-indoles-(Z)-3-subunit]-4,5,6,7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides (I-32)
Figure BDA00001671821300341
Use the method for embodiment 25,0.15g(1.0mmol) the fluoro-2-oxyindole of 4-and 0.24g(0.80mmol) N-[3-(pyrrolidin-1-yl)-propyl group]-2-methyl-7-oxo-4,5,6,7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides (II-10) reacts to obtain 0.12g(34%) be the title compound of yellow solid.
1HNMR(300 MHz,DMSO-d 6)δ14.31(s,1H,-NH-1),11.04(s,1H,-NH-1’),7.63(m,1H,H-5’),7.51(t,1H,CONH-),6.79(t,1H,H-6’),6.72(dd,1H,J=9.0Hz,H-7’),3.27(q,2H,-CONHC H 2 ),3.07(t,2H,-CH 2-4),2.81(t,2H,-CH 2-6),2.53(m,6H,- CH 2 N( CH 2 CH 2) 2),2.49(s,3H,-CH 3-2),1.95(m,2H,-CH 2-5),1.70(m,6H,-NHCH 2 CH 2 CH 2-，-CH 2N(CH 2 CH 2 ) 2);
ESI-MS:437.2[M+H] +;459.2[M+Na] +.
Embodiment 56:N-[3-(pyrrolidin-1-yl)-propyl group]-2-methyl-7-[1, the fluoro-2-oxo-3H-of 2-dihydro-7-indoles-(Z)-3-subunit]-4,5,6,7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides (I-33)
Figure BDA00001671821300342
Use the method for embodiment 25,0.15g(1.0mmol) the fluoro-2-oxyindole of 7-and 0.24g(0.80mmol) N-[3-(pyrrolidin-1-yl)-propyl group]-2-methyl-7-oxo-4,5,6,7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides (II-10) reacts to obtain 0.11g(32%) be the title compound of yellow solid.
1HNMR(300 MHz,DMSO-d 6)δ14.52(s,1H,-NH-1),11.49(s,1H,-NH-1’),7.44(m,2H,H-4’,H-6’),6.90(m,2H,H-5’,-CONH-),3.25(q,2H,-CONH CH 2 ),3.09(t,2H,-CH 2-4),2.81(t,2H,-CH 2-6),2.48(m,9H,-CH 3-2,- CH 2 N( CH 2 CH 2) 2),1.93(m,2H,-CH 2-5),1.67(m,6H,- CH 2 CH 2N(CH 2 CH 2 ) 2);
ESI-MS:437.3[M+H] +.
Embodiment 57:N-(2-diethylin ethyl)-2-methyl-7-[1,2-dihydro-5,7-dimethyl-2-oxo-3H-indoles-(Z)-3-subunit]-4,5,6,7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides (I-34)
Figure BDA00001671821300343
Use the method for embodiment 25,0.14g(0.87mmol) 5,7-dimethyl-2-oxyindole and 0.22g(0.75mmol) N-(2-diethylin ethyl)-2-methyl-7-oxo-4,5,6,7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides (II-1) reacts to obtain 0.11g(34%) be the title compound of yellow solid.
1HNMR(300 MHz,DMSO-d 6)δ14.58(s,1H,-NH-1),10.75(s,1H,-NH-1’),7.29(s,1H,H-4’),7.18(t,1H,-CONH-),6.77(s,1H,H-6’),3.28(q,2H,-CONHC H 2 ),3.06(t,2H,-CH 2-4),2.82(t,2H,-CH 2-6),2.50~2.41(m,9H,-CH 3-2,- CH 2 N( CH 2 CH 3) 2),2.28(s,3H,-CH 3-5’),2.20(s,3H,-CH 3-7’),1.93(m,2H,-CH 2-5),0.96(t,6H,-CH 2N(CH 2 CH 3 ) 2);
ESI-MS:435.2[M+H] +.
Embodiment 58:N-(2-diethylin ethyl)-2-methyl-7-[N-sec.-propyl-2-oxindole-5-sulphonamide-(Z)-3-subunit]-4,5,6,7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides (I-35)
Figure BDA00001671821300351
Use the method for embodiment 25,0.26g(1.0mmol) N-sec.-propyl-2-oxindole-5-sulphonamide and 0.26g(0.90mmol) N-(2-diethylin ethyl)-2-methyl-7-oxo-4,5,6,7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides (II-1) reacts to obtain 0.08g(17%) be the title compound of yellow solid.
1HNMR(300 MHz,DMSO-d 6)δ14.42(s,1H,-NH-1),11.30(s,1H,-NH-1’),8.03(s,1H,-SO 2NH-),7.60(dd,1H,J=8.2Hz,H-6’),7.46(d,1H,J=7.0Hz,H-4’),7.29(t,1H,-CONH-),7.06(d,1H,J=8.2Hz，H-7’)，3.28(m，2H，-CONH CH 2 )，3.16(m，3H，-CH-，-CH 2-4)，2.87(t，2H，-CH 2-6)，2.51(m，9H，-CH 3-2,- CH 2 N( CH 2 CH 3) 2),1.99(m,2H,-CH 2-5),0.97(m,12H,-CH( CH 3 ) 2,-CH 2N(CH 2 CH 3 ) 2);
ESI-MS:528.3[M+H] +.
Embodiment 59:N-(2-diethylin ethyl)-2-methyl-7-[1, the bromo-2-oxo-3H-of 2-dihydro-5-indoles-(Z)-3-subunit]-4,5,6,7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides (I-36)
Figure BDA00001671821300352
Use the method for embodiment 25,0.21g(1.0mmol) the bromo-2-oxyindole of 5-and 0.22g(0.75mmol) N-(2-diethylin ethyl)-2-methyl-7-oxo-4,5,6,7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides (II-1) reacts to obtain 0.10g(27%) be the title compound of yellow solid.
1HNMR(300 MHz,CDCl 3)δ14.23(s,1H,-NH-1),8.23(s,1H,-NH-1’),7.71(s,1H,H-4’),7.24(d,1H,J=1.75Hz,H-6’),6.79(d,1H,J=8.2Hz,H-7’),6.47(bs,1H,-CONH-),3.50(q,2H,-CONH CH 2 CH 2-)，3.09(t，2H，-CH 2-4)，2.92(t，2H，-CH 2-6)，2.68~2.55(m，9H，-CH 3-2，-NHCH 2 CH 2 N( CH 2 CH 3) 2),2.08(m,2H,-CH 2-5),1.03(t,6H,-(CH 2 CH 3 ) 2);
ESI-MS:486.1[M+H] +.
Embodiment 60:N-(2-diethylin ethyl)-2-methyl-7-[1,2-dihydro-5-nitro-2-oxo-3H-indoles-(Z)-3-subunit]-4,5,6,7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides (I-37)
Figure BDA00001671821300361
Use the method for embodiment 25,0.18g(1.0mmol) 5-nitro-2-oxyindole and 0.22g(0.75mmol) N-(2-diethylin ethyl)-2-methyl-7-oxo-4,5,6,7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides (II-1) reacts to obtain 0.12g(35%) be the title compound of yellow solid.
1HNMR(300 MHz,DMSO-d 6)δ14.29(s,1H,-NH-1),11.51(bs,1H,-NH-1’),8.38(s,1H,H-4’),8.06(dd,1H,J=8.6Hz,H-6’),7.31(t,1H,-CONH-,),7.04(d,1H,J=8.6Hz,H-7’),3.27(q,2H,-CONHC H 2 )，3.18(t，2H，-CH 2-4)，2.86(t，2H，-CH 2-6)，2.56~2.49(m，6H，- CH 2 N( CH 2 CH 3) 2)，2.47(s,3H,-CH 3-2),1.98(m,2H,-CH 2-5),0.98(t,6H,-CH 2N(CH 2 CH 3 ) 2);
ESI-MS:452.2[M+H] +.
Embodiment 61:N-(3-dimethylamino-propyl)-2-methyl-7-[1, the fluoro-2-oxo-3H-of 2-dihydro-5-indoles-(Z)-3-subunit]-4,5,6,7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides (I-38)
Figure BDA00001671821300362
Use the method for embodiment 25,0.15g(1.0mmol) the fluoro-2-oxyindole of 5-and 0.22g(0.80mmol) N-(3-dimethylamino-propyl)-2-methyl-7-oxo-4,5,6,7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides (II-4) reacts to obtain 0.11g(34%) be the title compound of yellow solid.
1HNMR(300 MHz,CDCl 3)δ14.30(s,1H,-NH-1),7.79(s,1H,-NH-1’),7.36(dd,1H,J=10.49Hz,H-4’),7.09(bs,1H,-CONH-),6.85(m,2H,H-6’,H-7’),3.55(q,2H,-CONHC H 2 ),3.11(t,2H,-CH 2-4),2.96(t,2H,-CH 2-6),2.60(s,3H,-CH 3-2),2.56(s,2H,-CH 2 CH 2 N(CH 3) 2),2.32(s,6H,-N (CH 3 ) 2 )),2.08(m,2H,-CH 2-5),1.82(s,2H,- CH 2 CH 2N(CH 3) 2);
ESI-MS:411.2[M+H] +;433.2[M+Na] +.
Embodiment 62:N-(2-diethylin ethyl)-2-methyl-7-[1,2-dihydro-5-carboxylate methyl ester-2-oxo-3H-indoles-(Z)-3-subunit]-4,5,6,7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides (I-39)
Figure BDA00001671821300363
Use the method for embodiment 25,0.19g(1.0mmol) 5-carboxylate methyl ester-2-oxyindole and 0.26g(0.90mmol) N-(2-diethylin ethyl)-2-methyl-7-oxo-4,5,6,7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides (II-1) reacts to obtain 0.13g(31%) be the title compound of yellow solid.
1HNMR(300 MHz,CDCl 3)δ14.18(s,1H,-NH-1),8.32(s,1H,H-4’),8.15(s,1H,-NH-1’),7.90(d,1H,J=8.2Hz,H-6’),6.95(d,1H,J=8.2Hz,H-7’),6.46(bs,1H,-CONH-),3.93(s,3H,-OCH 3),3.51(q,2H,-CONH CH 2 CH 2-),3.25(t,2H,-CH 2-4),2.96(t,2H,-CH 2-6),2.67~2.55(m,9H,-CH 3-2,-NHCH 2 CH 2 N( CH 2 CH 3) 2),2.08(m,2H,-CH 2-5),1.06(t,6H,-(CH 2 CH 3 ) 2);
ESI-MS:465.2[M+H] +;487.2[M+Na] +.
Embodiment 63:N-(2-diethylin ethyl)-2-methyl-7-[1, the fluoro-2-oxo-3H-of 2-dihydro-7-indoles-(Z)-3-subunit]-4,5,6,7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides (I-40)
Figure BDA00001671821300371
Use the method for embodiment 25,0.15g(1.0mmol) the fluoro-2-oxyindole of 7-and 0.22g(0.75mmol) N-(2-diethylin ethyl)-2-methyl-7-oxo-4,5,6,7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides (II-1) reacts to obtain 0.11g(34%) be the title compound of yellow solid.
1HNMR(300 MHz,CDCl 3)δ14.22(s,1H,-NH-1),9.41(s,1H,-NH-1’),7.31(dd,1H,J=7.36Hz,H-4’),6.86(m,2H,H-5’,H-6’),6.39(s,1H,-CONH-),3.43(q,2H,-CONH CH 2 CH 2-),3.05(t,2H,-CH 2-4),2.87(t,2H,-CH 2-6),2.67~2.55(m,9H,-CH 3-2,-NHCH 2 CH 2 N( CH 2 CH 3) 2),2.00(m,2H,-CH 2-5),0.97(t,6H,-(CH 2 CH 3 ) 2);
ESI-MS:425.2[M+H] +.
Embodiment 64:N-(2-diethylin ethyl)-2-methyl-7-[N-(4-fluorophenyl)-5-sulphonamide-2-oxindole-(Z)-3-subunit]-4,5,6,7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides (I-41)
Use the method for embodiment 25,0.31g(1.0mmol) N-is to fluorophenyl-2-oxindole-5-sulphonamide and 0.26g(0.90mmol) N-(2-diethylin ethyl)-2-methyl-7-oxo-4,5,6,7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides (II-1) reacts to obtain 0.10g(19%) be the title compound of yellow solid.
1HNMR(300 MHz,DMSO-d 6)δ14.34(s,1H,-NH-1),11.31(s,1H,-NH-1’),9.97(s,1H,-SO 2NH-),7.78(s,1H,H-4’),7.51(dd,1H,J=8.2Hz,H-6’),7.30(t,1H,-CONH-),7.09(m,4H,4-F-Ph),7.00(d,1H,J=8.2Hz,H-7’),3.27(q,2H,-CONHC H 2 ),2.89(m,4H,-CH 2-4,-CH 2-6),2.53(m,6H,-NHCH 2 CH 2 N( CH 2 CH 3) 2),2.47(s,3H,-CH 3-2),1.94(m,2H,-CH 2-5),1.00(t,6H,-CH 2N(CH 2 CH 3 ) 2);
ESI-MS:580.3[M+H] +;
Embodiment 65:N-(2-diethylin ethyl)-2-methyl-7-[5-(piperidines-1-alkylsulfonyl)-1,2-dihydro-2-oxo--3H-indoles-(Z)-3-subunit]-4,5,6,7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides (I-42)
Use the method for embodiment 25; 0.28g(1.0mmol) 5-(piperidines-1-alkylsulfonyl)-2-oxindole and 0.26g(0.90mmol) N-(2-diethylin ethyl)-2-methyl-7-oxo-4; 5; 6,7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides (II-1) reacts to obtain 0.11g(22%) be the title compound of yellow solid.
1HNMR(300 MHz,DMSO-d 6)δ14.41(s,1H,-NH-1),11.37(s,1H,-NH-1’),7.84(s,1H,H-4’),7.52(dd,1H,J=8.2Hz,H-6’),7.29(t,1H,-CONH-),7.12(d,1H,J=8.2Hz,H-7’),3.29(t,2H,-CONHC H 2 ),3.14(t,2H,-CH 2-4),2.87(m,6H,-CH 2-6,-SO 2N( CH 2 CH 2) 2CH 2),2.51(m,9H,-CH 3-2,- CH 2 N( CH 2 CH 3) 2),1.98(m,2H,-CH 2-5),1.54(m,4H,-SO 2N(CH 2 CH 2 ) 2CH 2),1.35(m,2H,-SO 2N(CH 2CH 2) 2 CH 2 ),0.96(t,6H,-CH 2N(CH 2 CH 3 ) 2);
ESI-MS:554.3[M+H] +.
Embodiment 66:N-(3-diethylin propyl group)-2-methyl-7-[1, the fluoro-2-oxo-3H-of 2-dihydro-5-indoles-(Z)-3-subunit]-4,5,6,7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides (I-43)
Figure BDA00001671821300381
Use the method for embodiment 25,0.15g(1.0mmol) the fluoro-2-oxyindole of 5-and 0.23g(0.75mmol) N-(3-diethylin propyl group)-2-methyl-7-oxo-4,5,6,7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides (II-9) reacts to obtain 0.12g(36%) be the title compound of yellow solid.
1HNMR(300 MHz,DMSO-d 6)δ14.54(s,1H,-NH-1),10.91(s,1H,-NH-1’),7.52(t,1H,-CONH-),7.45(d,1H,J=10.7Hz,H-4’),6.92(m,2H,H-6’,H-7’),3.26(q,2H,-CONH CH 2 CH 2-),3.05(t,2H,-CH 2-4),2.82(t,2H,-CH 2-6),2.49~2.44(m,9H,CH 3-2,-CH 2 CH 2 N( CH 2 CH 3) 2),1.95(m,2H,-CH 2-5),1.61(m,2H,-NHCH 2 CH 2 CH 2-),1.01(t,6H,-(CH 2 CH 3 ) 2);
ESI-MS:439.2[M+H] +;461.2[M+Na] +.
Embodiment 67:N-(2-diethylin ethyl)-2-methyl-7-[1,2-dihydro-5-carboxylic acid-2-oxo-3H-indoles-(Z)-3-subunit]-4,5,6,7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides (I-44)
Figure BDA00001671821300382
123mg(0.26mmol) N-(2-diethylin ethyl)-2-methyl-7-[1,2-dihydro-5-carboxylate methyl ester-2-oxo-3H-indoles-(Z)-3-subunit]-4,5,6,7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides (I-39) is dissolved in the mixed solvent (3:1) of 12ml first alcohol and water, add again the LiOH aqueous solution 5ml of 4mol/L, at 5 ℃, stirring reaction is after 15 hours, with the HCl aqueous solution adjusting PH to 6.0 of 2mol/L, separate out solid, filter, after vacuum-drying 70mg(60%) title compound of yellow solid.
1HNMR(300 MHz,DMSO-d 6)δ14.35(s,1H,-NH-1),11.18(s,1H,-NH-1’),8.18(s,1H,H-4’),7.77(d,1H,J=7.9Hz,H-6’),7.33(t,1H,-CONH-,),7.04(d,1H,J=8.1Hz,H-7’),3.32(q,2H,-CONHC H 2 ),3.16(t,2H,-CH 2-4),2.85(t,2H,-CH 2-6),2.62(m,6H,- CH 2 N( CH 2 CH 3) 2),2.46(s,3H,-CH 3-2),1.98(m,2H,-CH 2-5),1.00(t,6H,-CH 2N(CH 2 CH 3 ) 2);
ESI-MS:451.2[M+H] +;473.2[M+Na] +.
Embodiment 68:N-(2-diethylin ethyl)-2-methyl-7-[1,2-dihydro-5-(N-kharophen)-2-oxo-3H-indoles-(Z)-3-subunit]-4,5,6,7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides (I-45)
0.10g(0.22mmol) N-(2-diethylin ethyl)-2-methyl-7-[1; 2-dihydro-5-nitro-2-oxo-3H-indoles-(Z)-3-subunit]-4; 5; 6; 7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides (I-37) is thrown to 20ml water; add again 0.1g iron powder and 1ml hydrochloric acid soln (6mol/L); the lower 30 ℃ of stirrings of nitrogen protection are after 40 hours; remove by filter iron powder; filtrate is alkalized to PH10 left and right with unsaturated carbonate aqueous solutions of potassium; use 100ml dichloromethane extraction, organic phase is spent the night with anhydrous sodium sulfate drying.Subsequent filtration, in filtrate, directly add Acetyl Chloride 98Min. 30mg(0.38mmol) and 1 pyridine, after stirring at room temperature 6 hours, add a small amount of frozen water termination reaction, regulate water PH to 10 left and right with wet chemical again, collect organic phase, after anhydrous sodium sulfate drying, the solid that the concentrated solids-enriched obtaining obtains obtains 47mg(46% through purification by silica gel column chromatography (eluent is methylene dichloride: methyl alcohol 25:1)) be the title compound of orange solids
1HNMR(300 MHz,DMSO-d 6)δ14.50(s,1H,-NH-1),10.77(s,1H,-NH-1’),9.75(s,1H,CH 3CO NH-),7.84(s,1H,H-4’),7.35(d,1H,J=8.2Hz,H-6’),7.18(bs,1H,-CONH-),6.77(d,1H,J=8.2Hz,H-7’),3.29(m,2H,-CONH CH 2 ),3.00(t,2H,-CH 2-4),2.79(t,2H,-CH 2-6),2.44(m,9H,-CH 3-2,- CH 2 N( CH 2 CH 3) 2),1.96~1.85(m,5H,-CH 2-5,CH 3CO-),0.98(t,6H,-CH 2N(CH 2 CH 3 ) 2);
ESI-MS:464.2[M+H] +.
Embodiment 69:N-(2-diethylin ethyl)-2-methyl-7-[1,2-dihydro-6-chloro-2-oxo-3H-indoles-(Z)-3-subunit]-4,5,6,7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides (I-46)
Use the method for embodiment 25,0.17g(1.0mmol) 6-chlorine-2-hydroxyl indoles and 0.23g(0.80mmol) N-(2-diethylin ethyl)-2-methyl-7-oxo-4,5,6,7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides (II-1) reacts to obtain 0.12g(34%) be the title compound of yellow solid.
1HNMR(300 MHz,CDCl 3)δ14.16(s,1H,-NH-1),8.02(s,1H,-NH-1’),7.51(d,1H,J=8.4Hz,H-4’),7.02(dd,1H,J=8.4Hz,H-5’),6.90(d,1H,J=2Hz,H-7’),6.45(bs,1H,-CONH-),3.49(q,2H,-CONH CH 2 CH 2-)，3.07(t，2H，-CH 2-4)，2.90(t，2H，-CH 2-6)，2.67~2.55(m，9H -CH 3-2，-NHCH 2 CH 2 N( CH 2 CH 3) 2),2.07(m,2H,-CH 2-5),1.03(t,6H,-(CH 2 CH 3 ) 2);
ESI-MS:441.2[M+H] +;463.1[M+Na] +.
Embodiment 70:N-(3-diethylin propyl group)-2-methyl-7-[1,2-dihydro-6-chloro-2-oxo-3H-indoles-(Z)-3-subunit]-4,5,6,7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides (I-47)
Figure BDA00001671821300393
Use the method for embodiment 25,0.17g(1.0mmol) 6-chlorine-2-hydroxyl indoles and 0.23g(0.75mmol) N-(3-diethylin propyl group)-2-methyl-7-oxo-4,5,6,7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides (II-9) reacts to obtain 0.11g(32%) be the title compound of yellow solid.
1HNMR(300 MHz,DMSO-d 6)δ14.37(s,1H,-NH-1),11.03(s,1H,-NH-1’),7.63(d,1H,J=8.5Hz,H-4’),7.52(t,1H,-CONH-),7.02(dd,1H,J=8.4Hz,H-5’),6.91(d,1H,J=2Hz,H-7’),3.25(q,2H,-CONH CH 2 CH 2-),3.08(t,2H,-CH 2-4),2.84(t,2H,-CH 2-6),2.52(m,6H,-CH 2 CH 2 N( CH 2 CH 3) 2),2.45(s,3H,-CH 3-2),1.93(m,2H,-CH 2-5),1.65(bs,2H,-NHCH 2 CH 2 CH 2-),0.97(s,6H,-N(CH 2 CH 3 ) 2);
ESI-MS:455.2[M+H] +;477.2[M+Na] +.
Embodiment 71:N-(3-diethylin propyl group)-2-methyl-7-[1, the bromo-2-oxo-3H-of 2-dihydro-5-indoles-(Z)-3-subunit]-4,5,6,7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides (I-48)
Use the method for embodiment 25,0.21g(1.0mmol) the bromo-2-oxyindole of 5-and 0.23g(0.75mmol) N-(3-diethylin propyl group)-2-methyl-7-oxo-4,5,6,7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides (II-9) reacts to obtain 0.13g(35%) be the title compound of yellow solid.
1HNMR(300 MHz,DMSO-d 6)δ14.47(s,1H,-NH-1),11.03(s,1H,-NH-1’),7.72(d,1H,J=1.5Hz,H-4’),7.52(t,1H,-CONH-),7.29(dd,1H,J=8.2Hz,H-6’),6.87(d,1H,J=8.2Hz,H-7’),3.24(q,2H,-CONH CH 2 CH 2-),3.08(t,2H,-CH 2-4),2.82(t,2H,-CH 2-6),2.46~2.40(m,9H,-CH 3-2,-CH 2 CH 2 N( CH 2 CH 3) 2),1.96(m,2H,-CH 2-5),1.61(m,2H,-NHCH 2 CH 2 CH 2-),0.94(t,6H,-N(CH 2 CH 3 ) 2);
ESI-MS:500.2[M+H] +.
Embodiment 72:N-(2-diethylin ethyl)-2-methyl-7-[1, the fluoro-2-oxo-3H-of 2-dihydro-4-indoles-(Z)-3-subunit]-4,5,6,7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides (I-49)
Figure BDA00001671821300402
Use the method for embodiment 25,0.15g(1.0mmol) the fluoro-2-oxyindole of 4-and 0.23g(0.79mmol) N-(2-diethylin ethyl)-2-methyl-7-oxo-4,5,6,7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides (II-1) reacts to obtain 0.13g(39%) be the title compound of yellow solid.
1HNMR(300 MHz,CDCl 3)δ14.20(s,1H,-NH-1),9.56(s,1H,-NH-1’),7.49(q,1H,H-6’),6.83(dd,1H,J=8.69Hz,H-7’),6.68(t,1H,H-5’),6.50(bs,1H,-CONH-),3.51(m,2H,-CONH CH 2 CH 2-),3.05(t,2H,-CH 2-4),2.89(t,2H,-CH 2-6),2.67~2.55(m,9H,-CH 3-2,-NHCH 2 CH 2 N( CH 2 CH 3) 2),2.04(m,2H,-CH 2-5),1.06(t,6H,-(CH 2 CH 3 ) 2);
ESI-MS:425.2[M+H] +.
Embodiment 73:N-(2-diethylin ethyl)-2-methyl-7-[5-(tetramethyleneimine-1-carbonyl)-1,2-dihydro-2-oxo--3H-indoles-(Z)-3-subunit]-4,5,6,7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides (I-50)
Figure BDA00001671821300411
Use the method for embodiment 2,50mg(0.11mmol) N-(2-diethylin ethyl)-2-methyl-7-[1,2-dihydro-5-carboxylic acid-2-oxo-3H-indoles-(Z)-3-subunit]-4,5,6,7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides (I-44) and 71mg(1.0mmol) tetramethyleneimine react to obtain 38mg(69%) be the title compound of yellow solid.
1HNMR(300 MHz,DMSO-d 6)δ14.45(s,1H,-NH-1),11.05(s,1H,-NH-1’),7.76(s,1H,H-4’),7.34(dd,1H,J=8.0Hz,H-6’),7.25(t,1H,-CONH-,),6.94(d,1H,J=8.0Hz,H-7’),3.48(t,4H,-N( CH 2 CH 2) 2)，3.28(q，2H，-CONHC H 2 )，3.10(t，2H，-CH 2-4)，2.85(t，2H，-CH 2-6)，2.51(m，6H，- CH 2 N( CH 2 CH 3) 2),2.47(s,3H,-CH 3-2),1.86(m,2H,-CH 2-5),1.85(bs,4H,-N(CH 2 CH 2 ) 2),0.97(t,6H,-CH 2N(CH 2 CH 3 ) 2);
ESI-MS:504.3[M+H] +;526.3[M+Na] +.
Embodiment 74:N-(2-diethylin ethyl)-2-methyl-7-[N-(4-fluorophenyl)-5-carboxylic acid amides-1,2-dihydro-2-oxo--3H-indoles-(Z)-3-subunit]-4,5,6,7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides (I-51)
Figure BDA00001671821300412
Use the method for embodiment 2,50mg(0.11mmol) N-(2-diethylin ethyl)-2-methyl-7-[1,2-dihydro-5-carboxylic acid-2-oxo-3H-indoles-(Z)-3-subunit]-4,5,6,7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides (I-44) and 0.10g(0.90mmol) para-fluoroaniline react to obtain 43mg(72%) be the title compound of yellow solid.
1HNMR(300 MHz,DMSO-d 6)δ14.45(s,1H,-NH-1),11.23(s,1H,-NH-1’),10.21(s,1H,-CO NH-ph),8.18(s,1H,H-4’),7.78(m,3H,ph,H-6’),7.29(bs,1H,-CONH-),7.21(t,2H,ph),7.03(d,1H,J=8.1Hz,H-7’),3.24(q,2H,-CONHC H 2 ),2.87(s,2H,-CH 2-4),2.57~2.49(m,11H,-CH 2-6,- CH 2 N( CH 2 CH 3) 2,-CH 3-2),1.98(m,2H,-CH 2-5),1.00(s,6H,-CH 2N(CH 2 CH 3 ) 2);
ESI-MS:544.3[M+H] +.
Embodiment 75:N-(3-diethylin propyl group)-2-methyl-7-[1, the fluoro-2-oxo-3H-of 2-dihydro-7-indoles-(Z)-3-subunit]-4,5,6,7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides (I-52)
Figure BDA00001671821300413
Use the method for embodiment 25,0.15g(1.0mmol) the fluoro-2-oxyindole of 7-and 0.23g(0.75mmol) N-(3-diethylin propyl group)-2-methyl-7-oxo-4,5,6,7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides (II-9) reacts to obtain 0.11g(33%) be the title compound of yellow solid.
1HNMR(300 MHz,CDCl 3)δ14.24(s,1H,-NH-1),8.47(s,1H,-NH-1’),7.41(d,1H,J=7.65Hz,H-4’),6.95(m,3H,H-5’,H-6’,-CONH-),3.56(q,2H,-CONH CH 2 CH 2-),3.17(t,2H,-CH 2-4),2.96(t,2H,-CH 2-6),2.61(s,3H,-CH 3-2),2.54(m,6H,-CH 2 CH 2 N( CH 2 CH 3) 2),2.07(m,2H,-CH 2-5),1.76(m,2H，-NHCH 2 CH 2 CH 2-),1.01(t,6H,-(CH 2 CH 3 ) 2);
ESI-MS:439.2[M+H] +;461.2[M+Na] +.
Embodiment 76:N-(2-diethylin ethyl)-2-methyl-7-[1,2-dihydro-5-methoxyl group-2-oxo-3H-indoles-(Z)-3-subunit]-4,5,6,7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides (I-53)
Figure BDA00001671821300421
Use the method for embodiment 25,0.16g(1.0mmol) 5-methoxyl group-2-oxyindole and 0.22g(0.75mmol) N-(2-diethylin ethyl)-2-methyl-7-oxo-4,5,6,7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides (II-1) reacts to obtain 0.12g(37%) be the title compound of yellow solid.
1HNMR(300 MHz,CDCl 3)δ14.33(s,1H,-NH-1),7.73(s,1H,-NH-1’),7.23(d,1H,J=2.1Hz,H-4’),7.90(d,1H,J=8.4Hz,H-6’),6.95(d,1H,J=8.4Hz,H-7’),6.42(bs,1H,-CONH-),3.83(s,3H,-OCH 3),3.50(q,2H,-CONH CH 2 CH 2-),3.14(t,2H,-CH 2-4),2.95(t,2H,-CH 2-6),2.66~2.53(m,9H,-CH 3-2,-NHCH 2 CH 2 N( CH 2 CH 3) 2),2.08(m,2H,-CH 2-5),1.05(t,6H,-(CH 2 CH 3 ) 2);
ESI-MS:437.2[M+H] +.
Embodiment 77:N-(2-diethylin ethyl)-2-methyl-7-[1,2-dihydro-5-trifluoromethoxy-2-oxo-3H-indoles-(Z)-3-subunit]-4,5,6,7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides (I-54)
Figure BDA00001671821300422
Use the method for embodiment 25,0.15g(0.69mmol) 5-trifluoromethoxy-2-oxyindole and 0.17g(0.60mmol) N-(2-diethylin ethyl)-2-methyl-7-oxo-4,5,6,7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides (II-1) reacts to obtain 0.10g(34%) be the title compound of yellow solid.
1HNMR(300 MHz,CDCl 3)δ14.22(s,1H,-NH-1),8.62(s,1H,-NH-1’),7.45(s,1H,H-4’),7.04(dd,1H,J=8.4Hz,H-6’),6.87(d,1H,J=8.4Hz,H-7’),6.53(s,1H,-CONH-),3.53(q,2H,-CONH CH 2 CH 2-),3.06(t,2H,-CH 2-4),2.86(t,2H,-CH 2-6),2.69~2.57(m,9H,-CH 3-2,-NHCH 2 CH 2 N( CH 2 CH 3) 2),2.03(m,2H,-CH 2-5),1.06(t,6H,-N(CH 2 CH 3 ) 2);
ESI-MS:491.2[M+H] +.
Embodiment 78:N-(2-diethylin ethyl)-2-methyl-7-[N-methyl-5-sulphonamide-2-oxindole-(Z)-3-subunit]-4,5,6,7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides (I-55)
Figure BDA00001671821300423
Use the method for embodiment 25,0.23g(1.0mmol) N-methyl-2-oxindole-5-sulphonamide and 0.26g(0.90mmol) N-(2-diethylin ethyl)-2-methyl-7-oxo-4,5,6,7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides (II-1) reacts to obtain 0.06g(13%) be the title compound of yellow solid.
1HNMR(300 MHz,DMSO-d 6)δ14.42(s,1H,-NH-1),11.32(s,1H,-NH-1’),7.99(s,1H,-SO 2NH-),7.57(dd,1H,J=8.1Hz,H-6’),7.31(m,2H,-CONH-,H-4’),7.05(d,1H,J=8.1Hz,H-7’),3.30(m,2H,-CONHC H 2 ),3.15(t,2H,-CH 2-4),2.87(t,2H,-CH 2-6),2.51(m,9H,-CH 3-2,- CH 2 N( CH 2 CH 3) 2),2.39(d,3H,J=5.1Hz,CH 3NH-),1.97(m,2H,-CH 2-5),0.97(t,6H,-CH 2N(CH 2 CH 3 ) 2);
ESI-MS:500.2[M+H] +.
Embodiment 79:N-[2-(2-pyridyl)-ethyl]-2-methyl-7-[1, the fluoro-2-oxo-3H-of 2-dihydro-5-indoles-(Z)-3-subunit]-4,5,6,7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides (I-56)
Use the method for embodiment 2,0.15g(0.46mmol) 2-methyl-7-[1, the fluoro-2-oxo-3H-of 2-dihydro-5-indoles-(Z)-3-subunit]-4,5,6, after the reaction of 7-tetrahydrochysene-1H-Indole-3-Carboxylic Acid (IV-2) and 85mg(0.70mmol) 2-(pyridine-2-yl) ethamine, reaction solution is poured into water and alkalizes to PH10 left and right, dichloromethane extraction, dry, the concentrated solid obtaining obtains 0.07g(35% through column chromatography for separation (methylene dichloride: methyl alcohol=8:1)) be the title compound of yellow solid.
1HNMR(300 MHz,DMSO-d 6)δ14.54(s,1H,-NH-1),10.91(s,1H,-NH-1’),8.52(d,1H,Py-6),7.74(t,1H,Py-4),7.56(t,1H,-CONH-),7.45(dd,1H,J=10.80Hz,H-4’),7.31(d,1H,J=7.78Hz,Py-3),7.23(t,1H,Py-5),6.95(t,1H,H-6’),6.87(dd,1H,J=8.4Hz,H-7’),3.60(q,2H,-CONHC H 2 )，3.06(t，2H，-CH 2-4)，2.99(t，2H，- CH 2 -Py)，2.72(t，2H，-CH 2-6)，2.40(s，3H，-CH 3-2)，1.90(m,2H,-CH 2-5);
ESI-MS:431.1[M+H] +;453.1[M+Na] +.
Embodiment 80:N-[2-(dimethylin) ethyl]-N, 2-dimethyl-7-[1, the fluoro-2-oxo-3H-of 2-dihydro-5-indoles-(Z)-3-subunit]-4,5,6,7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides (I-57)
Figure BDA00001671821300432
Use the method for embodiment 2,0.15g(0.46mmol) 2-methyl-7-[1, the fluoro-2-oxo-3H-of 2-dihydro-5-indoles-(Z)-3-subunit]-4,5,6,7-tetrahydrochysene-1H-Indole-3-Carboxylic Acid (IV-2) and 71mg(0.70mmol) N, N, N '-trimethylammonium-1，2-diaminoethane reacts to obtain 0.10g(53%) be the title compound of yellow solid.
1HNMR(300 MHz,DMSO-d 6)δ14.46(s,1H,-NH-1),10.89(s,1H,-NH-1’),7.44(dd,1H,J=10.9Hz,H-4’),6.95(t,1H,H-6’),6.86(dd,1H,J=8.4Hz,H-7’),3.50(bs,2H,-CON(CH 3) CH 2 -),3.08(s,2H,-CH 2-4),2.92(s,3H,-CON( CH 3 )-),2.56(s,2H,-CH 2-6),2.42(bs,2H,- CH 2 N(CH 3) 2),2.29(s,3H,-CH 3-2),2.18(bs,2H,-CH 2-5),1.96(m,6H,-N (CH 3 ) 2 );
ESI-MS:411.2[M+H] +;433.2[M+Na] +.
Embodiment 81:N-[2-(dimethylin) ethyl]-N, 2-dimethyl-7-[1,2-dihydro-6-chloro-2-oxo-3H-indoles-(Z)-3-subunit]-4,5,6,7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides (I-58)
Figure BDA00001671821300441
Use the method for embodiment 20,0.10g(0.6mmol) 6-chlorine-2-hydroxyl indoles and 0.11g(0.55mmol) 2-methyl-7-oxo-4,5,6,7-tetrahydrochysene-1H-Indole-3-Carboxylic Acid (S4) reacts to obtain the 0.16g 2-methyl-7-[1 that is brown solid, 2-dihydro-6-chloro-2-oxo-3H-indoles-(Z)-3-subunit]-4,5,6,7-tetrahydrochysene-1H-Indole-3-Carboxylic Acid crude product, directly uses the method for embodiment 2 without purifying, and 60mg(0.59mmol) N, N, N '-trimethylammonium-1，2-diaminoethane reacts to obtain 0.05g(19%) be the title compound of yellow solid.
1HNMR(300 MHz,DMSO-d 6)δ14.30(s,1H,-NH-1),11.14(s,1H,-NH-1’),7.63(d,1H,J=8.5Hz,H-4’),7.01(d,1H,J=8.3Hz,H-5’),6.90(s,1H,H-7’),3.50(m,2H,-CON(CH 3) CH 2 -),3.08(s,2H,-CH 2-4),2.92(s,3H,-CON( CH 3 )-),2.59(s,2H,-CH 2-6),2.42(bs,2H,- CH 2 N(CH 3) 2),2.29(s,3H,-CH 3-2),2.18(bs,2H,-CH 2-5),1.93(m,6H,-N (CH 3 ) 2 );
ESI-MS:427.2[M+H] +.
Embodiment 82:N-benzyl-N, 2-dimethyl-7-[1, the fluoro-2-oxo-3H-of 2-dihydro-5-indoles-(Z)-3-subunit]-4,5,6,7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides (I-59)
Figure BDA00001671821300442
Use the method for embodiment 2,0.15g(0.46mmol) 2-methyl-7-[1, the fluoro-2-oxo-3H-of 2-dihydro-5-indoles-(Z)-3-subunit]-4,5,6,7-tetrahydrochysene-1H-Indole-3-Carboxylic Acid (IV-2) and 85mg(0.70mmol) N-methylbenzylamine react to obtain 0.13g(66%) be the title compound of yellow solid.
1HNMR(300 MHz,DMSO-d 6)δ14.51(s,1H,-NH-1),10.91(s,1H,-NH-1’),7.40(m,6H),6.95(t,1H),6.87(t,1H),4.62(s,2H,ph- CH 2 -),3.09(s,2H,-CH 2-4),2.84(s,3H,-NCH 3),2.64(s,2H,-CH 2-6),2.33(s,3H,-CH 3-2),1.97(m,2H,-CH 2-5);
ESI-MS:430.2[M+H] +;452.1[M+Na] +.
Embodiment 83:2-methyl-3-[(S)-2-(tetramethyleneimine-1-methyl)-tetramethyleneimine-1-carbonyl]-7-[1, the fluoro-2-oxo-3H-of 2-dihydro-5-indoles-(Z)-3-subunit]-4,5,6,7-tetrahydrochysene-1H-indoles (I-60)
Figure BDA00001671821300451
Use the method for embodiment 2,0.15g(0.46mmol) 2-methyl-7-[1, the fluoro-2-oxo-3H-of 2-dihydro-5-indoles-(Z)-3-subunit]-4,5,6,7-tetrahydrochysene-1H-Indole-3-Carboxylic Acid (IV-2) and 0.11g(0.71mmol) (S)-1,2 '-dipyrromethene alkane reacts to obtain 0.12g(56%) be the title compound of yellow solid.
1HNMR(300 MHz,DMSO-d 6)δ14.47(s,1H,-NH-1),10.90(s,1H,-NH-1’),7.44(dd,1H,J=10.7Hz,H-4’),6.98~6.84(m,2H,H-6’,H-7’),4.29(bs,1H),3.08(m,2H,-CH 2-4),2.63~2.49(m,10H),2.31(s,3H,-CH 3-2),1.99~1.84(m,6H),1.62(bs,4H)
ESI-MS:463.2[M+H] +.
Embodiment 84:2-methyl-3-[4-(2-hydroxyethyl)-piperazine-1-carbonyl]-7-[1, the fluoro-2-oxo-3H-of 2-dihydro-5-indoles-(Z)-3-subunit]-4,5,6,7-tetrahydrochysene-1H-indoles (I-61)
Figure BDA00001671821300452
Use the method for embodiment 2,0.15g(0.46mmol) 2-methyl-7-[1, the fluoro-2-oxo-3H-of 2-dihydro-5-indoles-(Z)-3-subunit]-4,5,6,7-tetrahydrochysene-1H-Indole-3-Carboxylic Acid (IV-2) and 0.09g(0.70mmol) 4-(2-hydroxyethyl)-piperazine reacts to obtain 0.10g(50%) be the title compound of yellow solid.
1HNMR(300 MHz,DMSO-d 6)δ14.50(s,1H,-NH-1),10.90(s,1H,-NH-1’),7.44(dd,1H,J=10.9Hz,H-4’),6.95(t,1H,H-6’),6.88(dd,1H,J=8.1Hz,H-7’),4.42(t,1H,-OH),3.47(m,6H,-CON( CH 2 CH 2) 2N-CH 2-,- CH 2 -OH),3.08(t,2H,-CH 2-4),2.59(t,2H,-CH 2-6),2.40(6H,- CH 2 -N( CH 2 CH 2) 2N-),2.31(s,3H,CH 3-2),1.94(bs,2H,-CH 2-5);
ESI-MS:439.2[M+H] +;461.1[M+Na] +.
Embodiment 85:2-methyl-3-(Isosorbide-5-Nitrae '-bis-piperidines-1 '-carbonyl)-7-[1, the fluoro-2-oxo-3H-of 2-dihydro-5-indoles-(Z)-3-subunit]-4,5,6,7-tetrahydrochysene-1H-indoles (I-62)
Figure BDA00001671821300453
Use the method for embodiment 2,0.15g(0.46mmol) 2-methyl-7-[1, the fluoro-2-oxo-3H-of 2-dihydro-5-indoles-(Z)-3-subunit]-4,5,6,7-tetrahydrochysene-1H-Indole-3-Carboxylic Acid (IV-2) and 0.12g(0.71mmol) Isosorbide-5-Nitrae '-bis-piperidines reacts to obtain 0.14g(64%) be the title compound of yellow solid.
1HNMR(300 MHz,DMSO-d 6)δ14.49(s,1H,-NH-1),10.90(s,1H,-NH-1’),7.45(dd,1H,J=10.9Hz,H-4’),6.95(t,1H,H-6’),6.88(dd,1H,J=7.0Hz,H-7’),3.09(s,2H,-CH 2-4),2.59(s,2H,-CH 2-6),2.50(m,4H,piperidine),2.42(m,5H,piperidine),2.30(s,3H,-CH 3-2),1.94(s,2H,-CH 2-5),1.72(m,2H,piperidine),1.46(m,4H,piperidine),1.37(m,4H,piperidine);
ESI-MS:477.2[M+H] +;499.3[M+Na] +.
Embodiment 86:N-[3-(diethylin)-2-hydroxypropyl]-2-methyl-7-[1,2-dihydro-2-oxo--3H-indoles-(Z)-3-subunit]-4,5,6,7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides (I-63)
Figure BDA00001671821300461
0.11g(0.83mmol) 2-oxyindole and 0.24g(0.75mmol) N-[3-(diethylin)-2-hydroxypropyl]-2-methyl-7-oxo-4,5,6,7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides (II-12) is dissolved in 10ml anhydrous pyridine, adds TiCl 40.3ml, at 100 ℃～110 ℃, stirring reaction is after 10 hours, reaction solution is poured in frozen water, with dichloromethane extraction, water and saturated NaCl solution washing organic layer, after anhydrous sodium sulfate drying, the concentrated solid obtaining obtains 0.09g(28% through purification by silica gel column chromatography (eluent is methylene dichloride: methyl alcohol 10:1)) be the title compound of yellow solid.
1HNMR(500 MHz,CDCl 3)δ14.26(s,1H,-NH-1),8.20(bs,1H,-NH-1’),7.61(d,1H,J=7.90Hz,H-4’),7.15(t,1H,H-6’),7.04(t,1H,H-5’),6.90(d,1H,J=7.61Hz,H-7’),6.23(s,1H,-CONH-),3.86(m,1H,-CONHC H(H)-),3.73(m,1H,-CONHCH( H)-),3.33(m,1H,- CH(OH)-),3.11(t,2H,-CH 2-4),2.87(t,2H,-CH 2-6),2.69(m,2H,- CH 2 N(CH 2CH 3) 2),2.59~2.40(m,7H,-CH 3-2,-CH 2N( CH 2 CH 3) 2),2.01(m,2H,-CH 2-5),1.05(t,6H,-CH 2N(CH 2 CH 3 ) 2);
ESI-MS:437.2[M+H] +.
Embodiment 87:N-[3-(diethylin)-2-hydroxypropyl]-2-methyl-7-[1, the fluoro-2-oxo-3H-of 2-dihydro-5-indoles-(Z)-3-subunit]-4,5,6,7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides (I-64)
Figure BDA00001671821300462
Use the method for embodiment 86,0.12g(0.79mmol) the fluoro-2-oxyindole of 5-and 0.23g(0.72mmol) N-[3-(diethylin)-2-hydroxypropyl]-2-methyl-7-oxo-4,5,6,7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides (II-12) reacts to obtain 0.11g(34%) be the title compound of yellow solid.
1HNMR(300 MHz,CDCl 3)δ14.32(s,1H,-NH-1),8.27(bs,1H,-NH-1’),7.35(dd,1H,J=10.67Hz,H-4’),6.92~6.80(m,2H,H-6’,H-7’),6.28(t,1H,-CONH-),3.90(m,1H,-CONHC H(H)-),3.74(m,1H,-CONHCH( H)-),3.38(m,1H,- CH(OH)-),3.09(t,2H,-CH 2-4),2.92(t,2H,-CH 2-6),2.72(m,2H,- CH 2 N(CH 2CH 3) 2),2.62(s,3H,-CH 3-2),2.61~2.40(m,4H,-CH 2N( CH 2 CH 3) 2),2.07(m,2H,-CH 2-5),1.08(t,6H,-CH 2N(CH 2 CH 3 ) 2);
ESI-MS:455.3[M+H] +.
Embodiment 88:N-[3-(diethylin)-2-hydroxypropyl]-2-methyl-7-[1,2-dihydro-5-chloro-2-oxo-3H-indoles-(Z)-3-subunit]-4,5,6,7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides (I-65)
Figure BDA00001671821300471
Use the method for embodiment 86,0.13g(0.78mmol) 5-chlorine-2-hydroxyl indoles and 0.23g(0.72mmol) N-[3-(diethylin)-2-hydroxypropyl]-2-methyl-7-oxo-4,5,6,7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides (II-12) reacts to obtain 0.10g(30%) be the title compound of yellow solid.
1HNMR(300 MHz,CDCl 3)δ14.25(s,1H,-NH-1),8.18(bs,1H,-NH-1’),7.57(s,1H,H-4’),7.12(dd,1H,J=8.23Hz,H-6’),6.83(d,1H,J=8.23Hz,H-7’),6.25(s,1H,-CONH-),3.87(m,1H,-CONHC H(H)-)，3.70(m，1H，-CONHCH( H)-)，3.34(m，1H，- CH(OH)-)，3.07(t，2H，-CH 2-4)，2.89(t，2H,-CH 2-6),2.71(m,2H,- CH 2 N(CH 2CH 3) 2),2.66~2.40(m,7H,-CH 3-2,-CH 2N( CH 2 CH 3) 2),2.06(m,2H,-CH 2-5),1.07(t,6H,-CH 2N(CH 2 CH 3 ) 2);
ESI-MS:471.3[M+H] +,493.2[M+Na] +.
Embodiment 89:N-[3-(dimethylin)-2-hydroxypropyl]-2-methyl-7-[1, the fluoro-2-oxo-3H-of 2-dihydro-5-indoles-(Z)-3-subunit]-4,5,6,7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides (I-66)
Use the method for embodiment 86,0.12g(0.79mmol) the fluoro-2-oxyindole of 5-and 0.21g(0.72mmol) N-[3-(dimethylin)-2-hydroxypropyl]-2-methyl-7-oxo-4,5,6,7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides (II-13) reacts to obtain 0.08g(26%) be the title compound of yellow solid.
1HNMR(300 MHz,CDCl 3)δ14.33(s,1H,-NH-1),7.77(bs,1H,-NH-1’),7.35(dd,1H,J=10.39Hz,H-4’),6.91~6.78(m,2H,H-6’,H-7’),6.19(bs,1H,-CONH-),3.90(m,1H,-CONHC H(H)-),3.69(m,1H,-CONHCH( H)-),3.37(m,1H,- CH(OH)-),3.09(t,2H,-CH 2-4),2.92(t,2H,-CH 2-6),2.61(s,3H,-CH 3-2),2.44~2.34(m,8H,- CH 2 N( CH 3 ) 2),2.06(m,2H,-CH 2-5);
ESI-MS:427.3[M+H] +.
Embodiment 90:N-[3-(morpholine-4-yl)-2-hydroxypropyl]-2-methyl-7-[1,2-dihydro-2-oxo--3H-indoles-(Z)-3-subunit]-4,5,6,7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides (I-67)
Figure BDA00001671821300473
Use the method for embodiment 86,0.11g(0.83mmol) 2-oxyindole and 0.25g(0.75mmol) N-[3-(morpholine-4-yl)-2-hydroxypropyl]-2-methyl-7-oxo-4,5,6,7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides (II-14) reacts to obtain 0.12g(35%) be the title compound of yellow solid.
1HNMR(300 MHz,CDCl 3)δ14.29(s,1H,-NH-1),7.99(s,1H,-NH-1’),7.62(d,1H,J=7.86Hz,H-4’),7.17(t,1H,H-6’),7.06(t,1H,H-5’),6.90(d,1H,J=7.47Hz,H-7’),6.12(s,1H,-CONH-),3.95(s,1H,-CONHC H(H)-),3.69(s,6H,-OH,-CONHCH( H)-,-CH 2N(CH 2 CH 2 ) 2O),3.37(m,1H,- CH(OH)-),3.13(t,2H,-CH 2-4),2.90(t,2H,-CH 2-6),2.69(m,2H,- CH 2 N(CH 2CH 2) 2O),2.60(s,3H,-CH 3-2),2.46(m,4H,-CH 2N( CH 2 CH 2) 2O),2.04(m,2H,-CH 2-5);
ESI-MS:451.3[M+H] +.
Embodiment 91:N-[3-(morpholine-4-yl)-2-hydroxypropyl]-2-methyl-7-[1, the fluoro-2-oxo-3H-of 2-dihydro-5-indoles-(Z)-3-subunit]-4,5,6,7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides (I-68)
Figure BDA00001671821300481
Use the method for embodiment 86,0.12g(0.79mmol) the fluoro-2-oxyindole of 5-and 0.24g(0.72mmol) N-[3-(morpholine-4-yl)-2-hydroxypropyl]-2-methyl-7-oxo-4,5,6,7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides (II-14) reacts to obtain 0.11g(33%) be the title compound of yellow solid.
1HNMR(300 MHz,CDCl 3)δ14.34(s,1H,-NH-1),7.65(s,1H,-NH-1’),7.32(d,1H,J=11.4Hz,H-4’),6.87~6.79(m,2H,H-6’,H-7’),6.06(s,1H,-CONH-),3.92(s,1H,-CONHC H(H)-),3.72(bs,6H,-OH,-CONHCH( H)-,-CH 2N(CH 2 CH 2 ) 2O),3.34(m,1H,- CH(OH)-),3.10(t,2H,-CH 2-4),2.96(s,2H,-CH 2-6),2.65~2.60(m,5H,- CH 2 N(CH 2CH 2) 2O,-CH 3-2),2.45(m,4H,-CH 2N( CH 2 CH 2) 2O),2.07(m,2H,-CH 2-5);
ESI-MS:469.2[M+H] +,491.2[M+Na] +;467.3[M-H] -.
Embodiment 92:N-[3-(morpholine-4-yl)-2-hydroxypropyl]-2-methyl-7-[1,2-dihydro-5-chloro-2-oxo-3H-indoles-(Z)-3-subunit]-4,5,6,7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides (I-69)
Figure BDA00001671821300482
Use the method for embodiment 86,0.12g(0.72mmol) 5-chlorine-2-hydroxyl indoles and 0.22g(0.66mmol) N-[3-(morpholine-4-yl)-2-hydroxypropyl]-2-methyl-7-oxo-4,5,6,7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides (II-14) reacts to obtain 0.11g(34%) be the title compound of yellow solid.
1HNMR(500 MHz,CDCl 3)δ14.30(s,1H,-NH-1),7.70(s,1H,-NH-1’),7.59(s,1H,H-4’),7.12(d,1H,J=7.95Hz,H-6’),6.83(d,1H,J=8.35Hz,H-7’),6.09(s,1H,-CONH-),3.93(s,1H,-CONHC H(H)-),3.72(bs,6H,-OH,-CONHCH( H)-,-CH 2N(CH 2 CH 2 ) 2O),3.34(m,1H,- CH(OH)-),3.12(t,2H,-CH 2-4),2.95(s,2H,-CH 2-6),2.67(s,2H,- CH 2 N(CH 2CH 2) 2O),2.61(s,3H,-CH 3-2),2.46(m,4H,-CH 2N( CH 2 CH 2) 2O),2.09(m,2H,-CH 2-5);
ESI-MS:485.2[M+H] +;483.1[M-H] -.
Embodiment 93:N-[3-(pyrrolidin-1-yl)-2-hydroxypropyl]-2-methyl-7-[1,2-dihydro-2-oxo--3H-indoles-(Z)-3-subunit]-4,5,6,7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides (I-70)
Figure BDA00001671821300491
Use the method for embodiment 86,0.11g(0.83mmol) 2-oxyindole and 0.24g(0.75mmol) N-[3-(pyrrolidin-1-yl)-2-hydroxypropyl]-2-methyl-7-oxo-4,5,6,7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides (II-15) reacts to obtain 0.10g(31%) be the title compound of yellow solid.
1HNMR(500 MHz,CDCl 3)δ14.32(s,1H,-NH-1),7.80(bs,1H,-NH-1’),7.63(d,1H,J=7.95Hz,H-4’),7.15(t,1H,H-6’),7.05(t,1H,H-5’),6.91(d,1H,J=7.73Hz,H-7’),6.44(bs,1H,-CONH-),4.02(s，1H，-CONHC H(H)-)，3.75(m，1H，-CONHCH( H)-)，3.51(m，1H，- CH(OH)-)，3.15(s， 2H，-CH 2-4),2.94(m,4H,-CH 2-6,- CH 2 N(CH 2) 4),2.85(m,4H,-CH 2N( CH 2 CH 2CH 2 CH 2 )),2.61(s,3H,-CH 3-2),2.06(m,2H,-CH 2-5),1.94(s,4H,-CH 2N(CH 2 CH 2 CH 2 CH 2));
ESI-MS:435.3[M+H] +,457.2[M+Na] +.
Embodiment 94:N-[3-(pyrrolidin-1-yl)-2-hydroxypropyl]-2-methyl-7-[1, the fluoro-2-oxo-3H-of 2-dihydro-5-indoles-(Z)-3-subunit]-4,5,6,7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides (I-71)
Use the method for embodiment 86,0.12g(0.79mmol) the fluoro-2-oxyindole of 5-and 0.23g(0.72mmol) N-[3-(pyrrolidin-1-yl)-2-hydroxypropyl]-2-methyl-7-oxo-4,5,6,7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides (II-15) reacts to obtain 0.09g(28%) be the title compound of yellow solid.
1HNMR(300 MHz,CDCl 3)δ14.33(s,1H,-NH-1),7.89(bs,1H,-NH-1’),7.36(d,1H,J=10.92Hz,H-4’),6.86~6.80(m,2H,H-6’,H-7’),6.22(s,1H,-CONH-),3.91(s,1H,-CONHC H(H)-),3.73(m,1H,-CONHCH( H)-),3.37(m,1H,- CH(OH)-),3.08(s,2H,-CH 2-4),2.93(s,2H,-CH 2-6),2.74(m,2H,- CH 2 N(CH 2) 4),2.67~2.45(m,7H,-CH 3-2,-CH 2N( CH 2 CH 2CH 2 CH 2 )),2.06(m,2H,-CH 2-5),1.81(bs,4H,-CH 2N(CH 2 CH 2 CH 2 CH 2));
ESI-MS:453.3[M+H] +,475.2[M+Na] +.
Embodiment 95:N-[3-(pyrrolidin-1-yl)-2-hydroxypropyl]-2-methyl-7-[1,2-dihydro-5-chloro-2-oxo-3H-indoles-(Z)-3-subunit]-4,5,6,7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides (I-72)
Figure BDA00001671821300493
Use the method for embodiment 86,0.14g(0.84mmol) 5-chlorine-2-hydroxyl indoles and 0.23g(0.72mmol) N-[3-(pyrrolidin-1-yl)-2-hydroxypropyl]-2-methyl-7-oxo-4,5,6,7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides (II-15) reacts to obtain 0.11g(33%) be the title compound of yellow solid.
1HNMR(300 MHz,DMSO-d 6)δ14.52(s,1H,-NH-1),11.02(s,1H,-NH-1’),7.61(s,1H,H-4’),7.52(t,1H,-CONH-),7.18(dd,1H,J=8.24Hz,H-6’),6.93(d,1H,J=8.25Hz,H-7’),5.71(bs,1H,-CH( OH)-),3.99(bs,1H,- CH(OH)-),3.31(m,7H,- CH 2 CH(OH) CH 2 -,-CH 3-2),3.10(m,6H,-CH 2N( CH 2 CH 2CH 2 CH 2 ),-CH 2-4),2.86(t,2H,-CH 2-6),1.96(m,6H,-CH 2-5,-CH 2N(CH 2 CH 2 CH 2 CH 2));
ESI-MS:469.2[M+H] +.
Embodiment 96:N-[3-(piperidin-1-yl)-2-hydroxypropyl]-2-methyl-7-[1,2-dihydro-2-oxo--3H-indoles-(Z)-3-subunit]-4,5,6,7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides (I-73)
Figure BDA00001671821300501
Use the method for embodiment 86,0.11g(0.83mmol) 2-oxyindole and 0.24g(0.72mmol) N-[3-(piperidin-1-yl)-2-hydroxypropyl]-2-methyl-7-oxo-4,5,6,7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides (II-16) reacts to obtain 0.09g(28%) be the title compound of yellow solid.
1HNMR(300 MHz,CDCl 3)δ14.31(s,1H,-NH-1),7.75(bs,1H,-NH-1’),7.64(d,1H,J=7.99Hz,H-4’),7.16(t,1H,H-6’),7.07(t,1H,H-5’),6.91(d,1H,J=7.67Hz,H-7’),6.19(bs,1H,-CONH-),3.95(m,1H,-CONHC H(H)-),3.69(m,1H,-CONHCH( H)-),3.38(m,1H,- CH(OH)-),3.13(t,2H,-CH 2-4),2.94(s,2H,-CH 2-6),2.67(bs,2H,- CH 2 N(CH 2)5),2.60(s,3H,-CH 3-2),2.45(bs,4H,-CH 2N( CH 2 CH 2CH 2CH 2 CH 2 )),2.06(m,2H,-CH 2-5),1.64~1.43(m,6H,-CH 2N(CH 2 CH 2 -CH 2 -CH 2 CH 2));
ESI-MS:449.4[M+H] +,471.3[M+Na] +.
Embodiment 97:N-[3-(piperidin-1-yl)-2-hydroxypropyl]-2-methyl-7-[1, the fluoro-2-oxo-3H-of 2-dihydro-5-indoles-(Z)-3-subunit]-4,5,6,7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides (I-74)
Figure BDA00001671821300502
Use the method for embodiment 86,0.12g(0.79mmol) the fluoro-2-oxyindole of 5-and 0.23g(0.69mmol) N-[3-(piperidin-1-yl)-2-hydroxypropyl]-2-methyl-7-oxo-4,5,6,7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides (II-16) reacts to obtain 0.10g(31%) be the title compound of yellow solid.
1HNMR(300 MHz,CDCl 3)δ14.30(s,1H,-NH-1),8.09(bs,1H,-NH-1’),7.35(d,1H,J=10.5Hz,H-4’),6.93~6.80(m,2H,H-6’,H-7’),6.21(s,1H,-CONH-),3.93(s,1H,-CONHC H(H)-),3.71(d,1H,-CONHCH( H)-),3.30(m,1H,- CH(OH)-),3.01(s,2H,-CH 2-4),2.88(s,2H,-CH 2-6),2.59(bs,5H,-CH 3-2,- CH 2 N(CH 2) 5),2.38(m,4H,-CH 2N( CH 2 CH 2CH 2CH 2 CH 2 )),2.03(m,2H,-CH 2-5),1.60(bs,6H,-CH 2N(CH 2 CH 2 CH 2 CH 2 CH 2));
ESI-MS:465.3[M-H] -.
Embodiment 98:N-[3-(piperidin-1-yl)-2-hydroxypropyl]-2-methyl-7-[1,2-dihydro-5-chloro-2-oxo-3H-indoles-(Z)-3-subunit]-4,5,6,7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides (I-75)
Figure BDA00001671821300511
Use the method for embodiment 86,0.14g(0.84mmol) 5-chlorine-2-hydroxyl indoles and 0.23g(0.69mmol) N-[3-(piperidin-1-yl)-2-hydroxypropyl]-2-methyl-7-oxo-4,5,6,7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides (II-16) reacts to obtain 0.12g(36%) be the title compound of yellow solid.
1HNMR(300 MHz,CDCl 3)δ14.25(s,1H,-NH-1),8.11(bs,1H,-NH-1’),7.57(s,1H,H-4’),7.13(d,1H,J=8.67Hz,H-6’),6.83(d,1H,J=8.46Hz,H-7’),6.20(s,1H,-CONH-),3.92(m,1H,-CONHC H(H)-)，3.72(m，1H，-CONHCH( H)-)，3.32(m，1H，- CH(OH)-)，3.08(s，2H，-CH 2-4)，2.89(s,2H,-CH 2-6),2.59(s,5H,-CH 3-2,- CH 2 N(CH 2) 5),2.40(m,4H,-CH 2N( CH 2 CH 2CH 2CH 2 CH 2 )),2.05(m,2H,-CH 2-5),1.60~1.43(m,6H,-CH 2N(CH 2 CH 2 -CH 2 -CH 2 CH 2));
ESI-MS:483.3[M+H] +.
Embodiment 99:N-[3-(4-methyl-piperazine-1-yl)-2-hydroxypropyl]-2-methyl-7-[1,2-dihydro-2-oxo--3H-indoles-(Z)-3-subunit]-4,5,6,7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides (I-76)
Use the method for embodiment 86,0.11g(0.83mmol) 2-oxyindole and 0.25g(0.72mmol) N-[3-(4-methyl-piperazine-1-yl)-2-hydroxypropyl]-2-methyl-7-oxo-4,5,6,7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides (II-17) reacts to obtain 0.11g(33%) be the title compound of yellow solid.
1HNMR(300 MHz,CDCl 3)δ14.29(s,1H,-NH-1),7.96(s,1H,-NH-1’),7.63(d,1H,J=8.14Hz,H-4’),7.15(t,1H,H-6’),7.06(t,1H,H-5’),6.91(dd,1H,J=7.69Hz,H-7’),6.13(t,1H,-CONH-),3.94(m，1H，-CONHC H(H)-)，3.70(m，1H，-CONHCH( H)-)，3.36(m，1H，- CH(OH)-)，3.14(t，2H，-CH 2-4),2.90(t,2H,-CH 2-6),2.72(bs,2H,- CH 2 N(CH 2CH 2) 2NCH 3),2.60(s,3H,-CH 3-2),2.46~2.37(m,8H,-N( CH 2 CH 2 ) 2NCH 3),2.30(s,3H,-N(CH 2CH 2) 2N CH 3 ),2.06(m,2H,-CH 2-5);
ESI-MS:464.1[M+H] +,486.0[M+Na] +.
Embodiment 100:N-[3-(4-methyl-piperazine-1-yl)-2-hydroxypropyl]-2-methyl-7-[1, the fluoro-2-oxo-3H-of 2-dihydro-5-indoles-(Z)-3-subunit]-4,5,6,7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides (I-77)
Figure BDA00001671821300513
Use the method for embodiment 86,0.13g(0.86mmol) the fluoro-2-oxyindole of 5-and 0.25g(0.72mmol) N-[3-(4-methyl-piperazine-1-yl)-2-hydroxypropyl]-2-methyl-7-oxo-4,5,6,7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides (II-17) reacts to obtain 0.10g(29%) be the title compound of yellow solid.
1HNMR(300 MHz,CDCl 3)δ14.32(s,1H,-NH-1),8.07(bs,1H,-NH-1’),7.35(dd,1H,J=10.6Hz,H-4’),6.89~6.78(m,2H,H-6’,H-7’),6.16(t,1H,-CONH-),3.94(s,1H,-CONHC H(H)-),3.73(m,1H,-CONHCH( H)-),3.33(m,1H,- CH(OH)-),3.09(t,2H,-CH 2-4),2.90(t,2H,-CH 2-6),2.74(s,2H,- CH 2 N(CH 2CH 2) 2NCH 3),2.60(s,3H,-CH 3-2),2.47~2.37(m,8H,-N( CH 2 CH 2 ) 2NCH 3),2.30(s,3H,-N(CH 2CH 2) 2N CH 3 ),2.07(m,2H,-CH 2-5);
ESI-MS:482.0[M+H] +.
Embodiment 101:N-[3-(4-methyl-piperazine-1-yl)-2-hydroxypropyl]-2-methyl-7-[1,2-dihydro-5-chloro-2-oxo-3H-indoles-(Z)-3-subunit]-4,5,6,7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides (I-78)
Figure BDA00001671821300521
Use the method for embodiment 86,0.14g(0.84mmol) 5-chlorine-2-hydroxyl indoles and 0.25g(0.72mmol) N-[3-(4-methyl-piperazine-1-yl)-2-hydroxypropyl]-2-methyl-7-oxo-4,5,6,7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides (II-17) reacts to obtain 0.11g(31%) be the title compound of yellow solid.
1HNMR(300 MHz,CDCl 3)δ14.28(s,1H,-NH-1),7.97(s,1H,-NH-1’),7.59(s,1H,H-4’),7.13(dd,1H,J=8.22 Hz,H-6’),6.83(d,1H,J=8.23Hz,H-7’),6.15(s,1H,-CONH-),3.94(m,1H,-CONHC H(H)-)，3.73(m，1H，-CONHCH( H)-)，3.35(m，1H，- CH(OH)-)，3.11(t，2H-CH 2-4)，2.92(t，2H,-CH 2-6),2.77(bs,2H,- CH 2 N(CH 2CH 2) 2NCH 3),2.60(s,3H,-CH 3-2),2.52~2.40(m,8H,-N( CH 2 CH 2 ) 2NCH 3),2.33(s,3H,-N(CH 2CH 2) 2N CH 3 ),2.08(m,2H,-CH 2-5);
ESI-MS:498.0[M+H] +,520.0[M+Na] +.
Embodiment 102:N-[3-(N-methylcyclohexyl amido)-2-hydroxypropyl]-2-methyl-7-[1,2-dihydro-5-methyl-2-oxo-3H-indoles-(Z)-3-subunit]-4,5,6,7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides (I-79)
Figure BDA00001671821300522
Use the method for embodiment 86,0.13g(0.88mmol) 5-methyl-2-oxyindole and 0.27g(0.75mmol) N-[3-(N-methylcyclohexyl amido)-2-hydroxypropyl]-2-methyl-7-oxo-4,5,6,7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides (II-18) reacts to obtain 0.14g(38%) be the title compound of yellow solid.
1hNMR (300 MHz, CDCl 3) δ 14.29 (s, 1H ,-NH-1), 8.06 (s, 1H ,-NH-1 '), 7.42 (s, 1H, H-4 '), 6.97 (d, 1H, J=7.88Hz, H-6 '), 6.80 (d, 1H, J=7.82Hz, H-7 '), 6.23 (t, 1H ,-CONH-), 3.88 (m, 1H ,-CONHC h(H)-), 3.74 (m, 1H ,-CONHCH ( h)-), 3.33 (m, 1H ,- cH(OH)-), 3.12 (t, 2H ,-CH 2-4), 2.89 (t, 2H ,-CH 2-6), 2.59 (s, 3H ,-CH 3-2), 2.52 (m, 2H ,-CONHCH 2cH (OH)- cH 2 n-), 2.38 (s, 3H ,-N cH 3 -), 2.33 (s, 3H ,-CH 3-5 '), 2.05 (m, 2H ,-CH 2-5), 1.88 ~ 1.62 (m, 6H, cyclohexyl), 1.32 ~ 1.04 (m, 5H, cyclohexyl);
ESI-MS：491.1[M+H] +.
Embodiment 103:N-[3-(diethylin)-2-hydroxypropyl]-2-methyl-7-[1, the bromo-2-oxo-3H-of 2-dihydro-5-indoles-(Z)-3-subunit]-4,5,6,7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides (I-80)
Figure BDA00001671821300531
Use the method for embodiment 86,0.18g(0.85mmol) the bromo-2-oxyindole of 5-and 0.25g(0.78mmol) N-[3-(diethylin)-2-hydroxypropyl]-2-methyl-7-oxo-4,5,6,7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides (II-12) reacts to obtain 0.12g(30%) be the title compound of yellow solid.
1HNMR(300 MHz,CDCl 3)δ14.22(s,1H,-NH-1),8.33(bs,1H,-NH-1’),7.70(s,1H,H-4’),7.24(1H,H-6’),6.78(d,1H,J=8.2Hz,H-7’),6.28(t,1H,-CONH-),3.86(m,1H,-CONHC H(H)-),3.70(m,1H,-CONHCH( H)-),3.34(m,1H,- CH(OH)-),3.07(t,2H,-CH 2-4),2.88(t,2H,-CH 2-6),2.71(m,2H,- CH 2 N(CH 2CH 3) 2),2.58~2.37(m,7H,-CH 3-2,-CH 2N( CH 2 CH 3)2),2.01(m,2H,-CH 2-5),1.07(t,6H,-CH 2N(CH 2 CH 3 ) 2);
ESI-MS:516.2[M+H] +.
Embodiment 104:N-[3-(morpholine-4-yl)-2-hydroxypropyl]-2-methyl-7-[1,2-dihydro-6-chloro-2-oxo-3H-indoles-(Z)-3-subunit]-4,5,6,7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides (I-81)
Figure BDA00001671821300532
Use the method for embodiment 86,0.15g(0.90mmol) 6-chlorine-2-hydroxyl indoles and 0.25g(0.75mmol) N-[3-(morpholine-4-yl)-2-hydroxypropyl]-2-methyl-7-oxo-4,5,6,7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides (II-14) reacts to obtain 0.12g(33%) be the title compound of yellow solid.
1HNMR(300 MHz,CDCl 3)δ14.20(s,1H,-NH-1),7.69(s,1H,-NH-1’),7.53(d,1H,J=8.7Hz,H-4’),7.02(d,1H,J=8.4Hz,H-5’),6.90(s,1H,H-7’),6.08(bs,1H,-CONH-),3.92(s,1H,-CONHC H(H)-),3.72(s,6H,-OH,-CONHCH( H)-,-CH 2N(CH 2 CH 2 ) 2O),3.40(m,1H,- CH(OH)-),3.11(t,2H,-CH 2-4),2.95(t,2H,-CH 2-6),2.67(m,2H,- CH 2 N(CH 2CH 2) 2O),2.61(s,3H,-CH 3-2),2.44(m,4H,-CH 2N( CH 2 CH 2) 2O),2.08(m,2H,-CH 2-5);
ESI-MS:485.2[M+H] +;507.2[M+Na] +.
Embodiment 105:N-[3-(N-methylcyclohexyl amido)-2-hydroxypropyl]-2-methyl-7-[1, the fluoro-2-oxo-3H-of 2-dihydro-5-indoles-(Z)-3-subunit]-4,5,6,7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides (I-82)
Use the method for embodiment 86,0.15g(1.0mmol) the fluoro-2-oxyindole of 5-and 0.30g(0.83mmol) N-[3-(N-methylcyclohexyl amido)-2-hydroxypropyl]-2-methyl-7-oxo-4,5,6,7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides (II-18) reacts to obtain 0.12g(29%) be the title compound of yellow solid.
1HNMR(300 MHz,CDCl 3)δ14.26(s,1H,-NH-1),8.90(bs,1H,-NH-1’),7.24(dd,1H,J=10.7Hz,H-4’),6.85(m,2H,H-6’,H-7’),6.22(t,1H,-CONH-),3.79(m,1H,-CONHC H(H)-),3.65(m,1H,-CONHCH( H)-),3.22(m,1H,- CH(OH)-),2.95(t,2H,-CH 2-4),2.76(t,2H,-CH 2-6),2.49(s,3H,-CH 3-2),2.42(m,2H,-CH(OH)- CH 2 N-),2.22(s,3H,-N CH 3 -),1.94(m,2H,-CH 2-5),1.77~1.53(m,6H,cyclohexyl),1.23～1.00(m,5H,cyclohexyl);
ESI-MS:495.3[M+H] +;517.3[M+Na] +.
Embodiment 106:N-[3-(morpholine-4-yl)-2-hydroxypropyl]-2-methyl-7-[1, the bromo-2-oxo-3H-of 2-dihydro-5-indoles-(Z)-3-subunit]-4,5,6,7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides (I-83)
Figure BDA00001671821300541
Use the method for embodiment 86,0.18g(0.85mmol) the bromo-2-oxyindole of 5-and 0.25g(0.75mmol) N-[3-(morpholine-4-yl)-2-hydroxypropyl]-2-methyl-7-oxo-4,5,6,7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides (II-14) reacts to obtain 0.10g(25%) be the title compound of yellow solid.
1HNMR(300 MHz,CDCl 3)δ14.30(s,1H,-NH-1),7.72(s,2H,-NH-1’,H-4’),7.26(1H,H-6’)6.80(d,1H,J=8.22Hz,H-7’),6.24(bs,1H,-CONH-),3.94(s,1H,-CONHC H(H)-),3.69(s,6H,-OH,-CONHCH( H)-,-CH 2N(CH 2 CH 2 ) 2O),3.37(m,1H,- CH(OH)-),3.13(t,2H,-CH 2-4),2.94(t,2H,-CH 2-6),2.69(m,2H,- CH 2 N(CH 2CH 2) 2O),2.61(s,3H,-CH 3-2),2.46(m,4H,-CH 2N( CH 2 CH 2) 2O),2.06(m,2H,-CH 2-5);
ESI-MS:530.2[M+H] +.
Biology embodiment
Adopt following test to screen those compounds of the required activity with optimum extent.
1. the active ELISA experiment of external protein kinase (PK)
Following experiment in vitro can be used for determining activity and the exposure level of various compounds of the present invention to one or more PK.The method of knowing in operation, all tests like design class in the same way for any kinases.
Enzyme-linked immunosorbent assay (ELISA) can be used for checking and measuring the existence of tyrosine kinase activity.ELISA can carry out in accordance with known methods, such as Voller etc., 1980, " enzyme-linked immunosorbent assay " (Enzyme-Linkd Immunosorbent Assay), see " clinical immunology handbook " (Manual of Clinical Immunology) that Rose and Friedman write, the 2nd edition, pp 359-371, AAM publishes, Washington D.C..
The phosphorylation reaction of the tyrosine-kinase enzyme catalysis ATP such as VEGFR-2, PDGFR-β, c-Kit and biotin labeled peptide substrate, inhibitory enzyme activity will suppress this reaction.According to ELISA method measuring principle, be attached to on the coated enzyme plate of Streptavidin containing biotin labeled phosphorylated substrate peptide, produce with it specific reaction by anti-phosphorylated substrate peptide monoclonal antibody, be combined with the sheep anti-mouse antibody of horseradish peroxidase-labeled again, add the colour developing of TMB liquid, measure determinand inhibition activity to Tyrosylprotein kinases such as VEGFR-2, PDGFR-β, c-Kit under different concns by measuring A450-A630 difference.Thereby, adopt this method can measure the active function of the compounds of this invention to above-mentioned Tyrosylprotein kinase, utilize method well known in the art simultaneously, can use similar measuring method to other protein kinase.
1.1 materials and methods
VEGFR-2, PDGFR-β and c-Kit detection kit (containing kinases, 1.25M DTT, peptide substrate, ATP, P-Tyr-100 and 4 × HTScan kinase buffer liquid etc.), Cell Signaling Technology company; Horseradish peroxidase-labeled sheep anti-mouse antibody, Protein Tech company; TMB, Pierce company; Streptavidin coated elisa plate, Greiner Bio-one company; Infinite M200 detector, Tecan company.
1.2 experimental technique
1.2.1 immediately enzyme is moved on ice from-80 ° of C, of short duration centrifugal to managing at the end at 4 ° of C after melting, and put back to rapidly on ice;
1.2.2 add 10ul DTT(1.25M) to (200mM HEPES, pH7.5,20mM MgCl in 4 × HTScan kinase buffer liquid of 2.5ml 2, 20mMMnCl 2, 12uM Na 3vO 4).Get 0.6ml and add above-mentioned enzyme pipe, get 12.5ul, and add the compound of 12.5ul different concns, set up blank hole, without enzyme control wells, negative control hole and positive control hole simultaneously, at room temperature hatch 5 minutes;
1.2.3 add 10ul mM ATP in 1.25ml 6uM peptide substrate, use dH 2o is diluted to 2.5ml, gets 25ul to above-mentioned system, hatches 30 minutes under room temperature;
1.2.4 add 50ul/ hole stop buffer (50mM EDTA, pH 8) termination reaction, 25ul is got in every hole, and adds 75ul dH 2in the coated enzyme plate of O to Streptavidin, under room temperature, hatch 60 minutes.With 200ul/ hole PBS/T(1 × PBS, 0.05%Tween-20) wash three times;
1.2.5 add the P-Tyr-100(Phospho-Tyrsine mAb of 100ul containing the PBS/T 1:500 dilution of 1%BSA), under room temperature, hatch 60 minutes.With 200ul/ hole PBS/T(1 × PBS, 0.05%Tween-20) wash three times;
1.2.6 add the sheep anti-mouse antibody of 100ul containing the horseradish peroxidase-labeled of the PBS/T 1:500 dilution of 1%BSA, under room temperature, hatch 30 minutes.With 200ul/ hole PBS/T(1 × PBS, 0.05%Tween-20) wash five times;
1.2.7 add 100ul/ hole TMB, colour developing 1-10 minute, adds the 2M H of 50 μ l 2sO 4termination reaction, with Infinite M200 mensuration A 450-A 630value.
1.2.8 try to achieve inhibiting rate by following formula:
Figure BDA00001671821300551
Simultaneously, according to the sample enzyme of the each concentration inhibiting rate of living, adopt the same Logit[I of logarithm with compound concentration] linear regression, obtain the enzyme testing compound concentration IC of inhibiting rate while being 50% that live 50.
1.3 experimental result
1.3.1 kinase activity inhibiting rate
Be 10 in concentration -7mol/L, part of compounds of the present invention to the kinase whose maximum inhibition of difference in table 1:
Table 1
Figure BDA00001671821300552
1.3.2VEGFR-2 kinase activity half-inhibition concentration (IC 50nmol/L)
Half-inhibition concentration (the IC of part of compounds of the present invention to VEGFR-2 kinase activity 50) respectively in table 2:
Table 2
Compound I-2 I-3 I-4 I-5 I-9 I-14 I-19 I-21 I-26 I-34 I-36 I-40 I-44
IC 50 nmol/L 76 5.3 5.6 9 30 79 31 27 9.1 11 6.3 82 6.8
Compound I-45 I-46 I-49 I-51 I-53 I-55 I-56 I-57 I-60 I-68 I-71 I-74 I-77
IC 50 nmol/L 8.0 11 12 54 13 19 17 13 14 43 34 13 25
2. inhibition tumor cell proliferation assay method (mtt assay)
Measure bromination tetrazole indigo plant (MTT) method that adopts routinely.Succinodehydrogenase in viable cell plastosome can make exogenous bromination tetrazole indigo plant be reduced to the bluish voilet crystallisate (Formazan) of insoluble and be deposited in cell, and dead cell is without this function.Purple crystal thing in dimethyl sulfoxide (DMSO) (DMSO) energy dissolved cell, measures its absorbance value with enzyme-linked immunosorbent assay instrument at 570nm wavelength place, can indirectly reflect viable cell quantity.Thereby, adopt mtt assay can measure the inhibition ability of cell proliferation of the compounds of this invention, utilize method well known in the art simultaneously, can use similar measuring method to any cancer cells.
2.1 reagent and instrument
RPMI 1640 substratum (RPMI 1640+12% calf serum+HEPES 3.5g/l+NaHCO 32.2g/l+ penicillin 0.13g/l+ Streptomycin sulphate 0.15g/l);
RPMI 1640 substratum (RPMI 1640+12% foetal calf serum+HEPES 3.5g/l+NaHCO 32.2g/l+ penicillin 0.13g/l+ Streptomycin sulphate 0.15g/l);
DMEM in high glucose substratum (DMEM+10% calf serum+HEPES 3.5g/l+NaHCO 32.2g/l+ penicillin 0.13g/l+ Streptomycin sulphate 0.15g/l);
DMEM in high glucose substratum (DMEM+12% foetal calf serum+HEPES 3.5g/l+NaHCO 32.2g/l+ penicillin 0.13g/l+ Streptomycin sulphate 0.15g/l);
MC COYS 5-A substratum (DMEM+12% foetal calf serum+HEPES 3.5g/l+NaHCO 32.2g/l+ penicillin 0.13g/l+ Streptomycin sulphate 0.15g/l);
Trypsinase;
Amresco company of MTT(U.S. product);
Microplate reader (TECAN infinite M200)
2.2 JEG-3
2.2.1 people's gastric adenocarcinoma cells strain (BGC)
2.2.2 Non-small cell lung carcinoma (A549)
2.2.3 human leukemia cell line (K562)
2.2.4 human pancreas cancer cell strain (PANC-1)
2.2.5 human small cell lung carcinoma (NCI-H446)
As 2.1,2.2,2.3,2.4 and 2.5 RPMI 1640 substratum containing 12% calf serum for listed JEG-3, in 37 ℃, 5%CO 2incubator in cultivate;
2.2.6 human pancreas cancer cell strain (BXPC-3)
2.2.7 human bladder cancer cell's strain (T24)
As RPMI 1640 substratum of 12% foetal calf serum for 2.2.6 and the listed JEG-3 of 2.2.7, in 37 ℃, 5%CO 2incubator in cultivate;
2.2.8 human hepatoma cell strain (HEPG2)
2.2.9 human breast cancer cell strain (MCF-7)
As the DMEM in high glucose substratum of 12% calf serum for 2.2.8 and the listed JEG-3 of 2.2.9, in 37 ℃, 5%CO 2incubator in cultivate;
2.2.10 human colon adenocarcinoma cell's strain (CACO-2)
The DMEM in high glucose substratum of 12% foetal calf serum for JEG-3 as listed in 2.2.10, in 37 ℃, 5%CO 2incubator in cultivate;
2.2.11 human colon cancer cell strain (HT29)
2.2.12 human colon cancer cell strain (HCT116)
2.2.13 human oophoroma cell line (SK-OV-3)
As the MC COYS 5-A substratum of 12% foetal calf serum for 2.2.11,2.2.12 and the listed JEG-3 of 2.2.13, in 37 ℃, 5%CO 2incubator in cultivate.
2.3 experimental technique
2.3.1 inoculation: get in exponential phase of growth, one bottle, cell in good condition, add appropriate tryptic digestive juice, digestion comes off attached cell, with containing RPMI1640(or DMEM or the 5A of 12% calf serum) nutrient solution is made into cell suspension, counting, and cell density adjustment is diluted to 1.67 × 10 4/ ml obtained cell suspension is inoculated on 96 orifice plates, 180ul/ hole (containing tumour cell 3000/ hole).
2.3.2 cultivate: culture plate is proceeded to constant temperature CO 2in incubator, at 37 ℃, 5%CO 2and under saturated humidity condition, cultivate 24 hours.
2.3.3 primary dcreening operation: testing compound is first mixed with 0.1M concentration with DMSO, remakes 3 extent of dilution, and for primary dcreening operation, concentration is followed successively by 10 -5mol/L, 10 -6mol/L and 10 -7mol/L.Add testing compound, 20ul/ hole, cultivates 72 hours.Establish 3 parallel holes for every group, and repeat 3 times, measure the 96 every hole of orifice plate light absorption values, record result and calculate inhibitory rate of cell growth, get mean value three times.
2.3.4 dyeing:
2.3.4.1 MTT is added in 96 orifice plates (attached cell), 20ul/ hole, is placed in incubator and hatches 4 hours, inhales and abandons supernatant liquor in hole, adds DMSO 100ul/ hole, on horizontalization plate shaking table, shakes 5 minutes.
2.3.4.2 MTT is added to (suspension cell) in 96 orifice plates, 20ul/ hole, is placed in incubator and hatches 4 hours, then add 20%SDS50ul/ hole, is placed in incubator and spends the night.
2.3.5 measure: it is 570nm that microplate reader is set wavelength, and reference wavelength is 630nm, measure the 96 every hole of orifice plate light absorption values, record result and calculate inhibitory rate of cell growth, to judge the anti-tumor activity of tested medicine.
2.3.6 sieve again: be 10 in primary dcreening operation concentration -5when mol/L, the compound of 3 cell inhibitory rate>=50%, for multiple sieve, remakes 10 extent of dilution by 0.1mol/L, and concentration is followed successively by 10 -5mol/L, 0.5 × 10 -5mol/L, 10 -6mol/L, 0.8 × 10 -6mol/L, 0.6 × 10 -6mol/L, 0.4 × 10 -6mol/L, 0.2 × 10 -6mol/L, 10 -7mol/L, 0.8 × 10 -7mol/L and 0.4 × 10 -7mol/L.Add test-compound, 20ul/ hole, cultivates 48 hours.Establish 3 parallel holes for same every group, and repeat 3 times, and according to prescreening method, measure the 96 every hole of orifice plate light absorption values, record result and calculate inhibitory rate of cell growth.
2.3.7 inhibitory rate of cell growth and IC 50calculating:
Figure BDA00001671821300571
Simultaneously, according to the growth inhibition ratio of each concentration, adopt the same Logit[I of logarithm with compound concentration] linear regression, obtain the testing compound concentration IC when suppressing growth rate and being 50% 50, get mean value three times.
2.4 experimental result
2.4.1 inhibitory rate of cell growth
Be 10 in concentration -5mol/L, part of compounds of the present invention to the growth inhibition ratio of different tumour cells respectively in table 3 and table 4:
Table 3
Figure BDA00001671821300572
Figure BDA00001671821300581
Table 4
2.4.2 Growth of Cells half-inhibition concentration (IC 50umol/L)
Half-inhibition concentration (the IC of part of compounds of the present invention to different growth of tumour cell 50) respectively in table 5 and table 6:
Table 5
Figure BDA00001671821300591
Table 6
Figure BDA00001671821300592
Experiment conclusion: the compound with formula (I) structure of preparing in the embodiment of the present invention has good restraining effect to multiple kinase activity, its half-inhibition concentration (IC to VEGFR-2 kinase activity 50) generally 10 -7below mol/L.The compound that the present invention has formula (I) structure can be applicable to prepare the medicine for the treatment of protein kinase related disorder in organism.Meanwhile, the compound with formula (I) structure of preparing in the embodiment of the present invention is inhibited to the propagation of kinds of tumor cells, and wherein the effect of majority of compounds inhibition tumor cell propagation is remarkable, its IC 5010 -5below mol/L.The compound that the present invention has formula (I) structure can be applicable to the preparation of antitumor drug.

Claims (11)

1. compound or its pharmacy acceptable salt, be selected from
2-methyl-7-[1,2-dihydro-2-oxo--3 h-indoles-(Z)-3-subunit]-4,5,6,7-tetrahydrochysene-1 h-Indole-3-Carboxylic Acid;
2-methyl-7-[1, the fluoro-2-of 2-dihydro-5-oxo-3 h-indoles-(Z)-3-subunit]-4,5,6,7-tetrahydrochysene-1 h-Indole-3-Carboxylic Acid;
2-methyl-7-[1,2-dihydro-5-chloro-2-oxo-3 h-indoles-(Z)-3-subunit]-4,5,6,7-tetrahydrochysene-1 h-Indole-3-Carboxylic Acid;
2-methyl-7-[1,2-dihydro-5-methyl-2-oxo-3 h-indoles-(Z)-3-subunit]-4,5,6,7-tetrahydrochysene-1 h-Indole-3-Carboxylic Acid;
2-methyl-7-[1, the fluoro-2-of 2-dihydro-5-oxo-3 h-indoles-(Z)-3-subunit]-4,5,6,7-tetrahydrochysene-1 h-Indole-3-Carboxylic Acid ethyl ester;
N-(2-diethylin ethyl)-2-methyl-7-[1, the fluoro-2-of 2-dihydro-5-oxo-3 h-indoles-(Z)-3-subunit]-4,5,6,7-tetrahydrochysene-1 h-indoles-3-carboxylic acid amides;
N-(2-diethylin ethyl)-2-methyl-7-[1,2-dihydro-5-chloro-2-oxo-3 h-indoles-(Z)-3-subunit]-4,5,6,7-tetrahydrochysene-1 h-indoles-3-carboxylic acid amides;
N-(2-diethylin ethyl)-2-methyl-7-[1,2-dihydro-5-methyl-2-oxo-3 h-indoles-(Z)-3-subunit]-4,5,6,7-tetrahydrochysene-1 h-indoles-3-carboxylic acid amides;
N-(2-diethylin ethyl)-2-methyl-7-[1,2-dihydro-2-oxo--3 h-indoles-(Z)-3-subunit]-4,5,6,7-tetrahydrochysene-1 h-indoles-3-carboxylic acid amides;
N-(2-dimethylamino ethyl)-2-methyl-7-[1, the fluoro-2-of 2-dihydro-5-oxo-3 h-indoles-(Z)-3-subunit]-4,5,6,7-tetrahydrochysene-1 h-indoles-3-carboxylic acid amides;
N-(3-dimethylamino-propyl)-2-methyl-7-[1,2-dihydro-5-chloro-2-oxo-3 h-indoles-(Z)-3-subunit]-4,5,6,7-tetrahydrochysene-1 h-indoles-3-carboxylic acid amides;
N-(2-hydroxyethyl)-2-methyl-7-[1,2-dihydro-2-oxo--3 h-indoles-(Z)-3-subunit]-4,5,6,7-tetrahydrochysene-1 h-indoles-3-carboxylic acid amides;
N-(2-hydroxyethyl)-2-methyl-7-[1, the fluoro-2-of 2-dihydro-5-oxo-3 h-indoles-(Z)-3-subunit]-4,5,6,7-tetrahydrochysene-1 h-indoles-3-carboxylic acid amides;
2-methyl-3-(morpholine-4-carbonyl)-7-[1, the fluoro-2-of 2-dihydro-5-oxo-3 h-indoles-(Z)-3-subunit]-4,5,6,7-tetrahydrochysene-1 h-indoles;
2-methyl-3-(morpholine-4-carbonyl)-7-[1,2-dihydro-5-chloro-2-oxo-3 h-indoles-(Z)-3-subunit]-4,5,6,7-tetrahydrochysene-1 h-indoles;
2-methyl-3-(morpholine-4-carbonyl)-7-[1,2-dihydro-2-oxo--3 h-indoles-(Z)-3-subunit]-4,5,6,7-tetrahydrochysene-1 h-indoles;
2-methyl-3-(4-methyl-piperazine-1-carbonyl)-7-[1,2-dihydro-2-oxo--3 h-indoles-(Z)-3-subunit]-4,5,6,7-tetrahydrochysene-1 h-indoles;
2-methyl-3-(4-methyl-piperazine-1-carbonyl)-7-[1, the fluoro-2-of 2-dihydro-5-oxo-3 h-indoles-(Z)-3-subunit]-4,5,6,7-tetrahydrochysene-1 h-indoles;
N, N-dimethyl-2-methyl-7-[1,2-dihydro-2-oxo--3 h-indoles-(Z)-3-subunit]-4,5,6,7-tetrahydrochysene-1 h-indoles-3-carboxylic acid amides;
N-[2-(morpholine-4-yl)-ethyl]-2-methyl-7-[1,2-dihydro-5-methyl-2-oxo-3 h-indoles-(Z)-3-subunit]-4,5,6,7-tetrahydrochysene-1 h-indoles-3-carboxylic acid amides;
N-[3-(morpholine-4-yl)-propyl group]-2-methyl-7-[1,2-dihydro-5-methyl-2-oxo-3 h-indoles-(Z)-3-subunit]-4,5,6,7-tetrahydrochysene-1 h-indoles-3-carboxylic acid amides;
N-[2-(morpholine-4-yl)-ethyl]-2-methyl-7-[1,2-dihydro-2-oxo--3 h-indoles-(Z)-3-subunit]-4,5,6,7-tetrahydrochysene-1 h-indoles-3-carboxylic acid amides;
N-[2-(morpholine-4-yl)-ethyl]-2-methyl-7-[1,2-dihydro-5-chloro-2-oxo-3 h-indoles-(Z)-3-subunit]-4,5,6,7-tetrahydrochysene-1 h-indoles-3-carboxylic acid amides;
N-[2-(morpholine-4-yl)-ethyl]-2-methyl-7-[1, the fluoro-2-of 2-dihydro-5-oxo-3 h-indoles-(Z)-3-subunit]-4,5,6,7-tetrahydrochysene-1 h-indoles-3-carboxylic acid amides;
N-[3-(morpholine-4-yl)-propyl group]-2-methyl-7-[1, the fluoro-2-of 2-dihydro-5-oxo-3 h-indoles-(Z)-3-subunit]-4,5,6,7-tetrahydrochysene-1 h-indoles-3-carboxylic acid amides;
N-[3-(morpholine-4-yl)-propyl group]-2-methyl-7-[1, the bromo-2-of 2-dihydro-5-oxo-3 h-indoles-(Z)-3-subunit]-4,5,6,7-tetrahydrochysene-1 h-indoles-3-carboxylic acid amides;
N-[2-(morpholine-4-yl)-ethyl]-2-methyl-7-[1, the fluoro-2-of 2-dihydro-7-oxo-3 h-indoles-(Z)-3-subunit]-4,5,6,7-tetrahydrochysene-1 h-indoles-3-carboxylic acid amides;
N-[2-(pyrrolidin-1-yl)-ethyl]-2-methyl-7-[1,2-dihydro-2-oxo--3 h-indoles-(Z)-3-subunit]-4,5,6,7-tetrahydrochysene-1 h-indoles-3-carboxylic acid amides;
N-[2-(piperidin-1-yl)-ethyl]-2-methyl-7-[1,2-dihydro-2-oxo--3 h-indoles-(Z)-3-subunit]-4,5,6,7-tetrahydrochysene-1 h-indoles-3-carboxylic acid amides;
N-[2-(piperidin-1-yl)-ethyl]-2-methyl-7-[1, the fluoro-2-of 2-dihydro-5-oxo-3 h-indoles-(Z)-3-subunit]-4,5,6,7-tetrahydrochysene-1 h-indoles-3-carboxylic acid amides;
N-[2-(pyrrolidin-1-yl)-ethyl]-2-methyl-7-[1, the fluoro-2-of 2-dihydro-5-oxo-3 h-indoles-(Z)-3-subunit]-4,5,6,7-tetrahydrochysene-1 h-indoles-3-carboxylic acid amides;
N-[3-(pyrrolidin-1-yl)-propyl group]-2-methyl-7-[1, the fluoro-2-of 2-dihydro-5-oxo-3 h-indoles-(Z)-3-subunit]-4,5,6,7-tetrahydrochysene-1 h-indoles-3-carboxylic acid amides;
N-[3-(4-methyl-piperazine-1-yl)-propyl group]-2-methyl-7-[1, the fluoro-2-of 2-dihydro-5-oxo-3 h-indoles-(Z)-3-subunit]-4,5,6,7-tetrahydrochysene-1 h-indoles-3-carboxylic acid amides;
N-[3-(pyrrolidin-1-yl)-propyl group]-2-methyl-7-[1, the bromo-2-of 2-dihydro-5-oxo-3 h-indoles-(Z)-3-subunit]-4,5,6,7-tetrahydrochysene-1 h-indoles-3-carboxylic acid amides;
N-[2-(piperidin-1-yl)-ethyl]-2-methyl-7-[1,2-dihydro-6-chloro-2-oxo-3 h-indoles-(Z)-3-subunit]-4,5,6,7-tetrahydrochysene-1 h-indoles-3-carboxylic acid amides;
N-[3-(pyrrolidin-1-yl)-propyl group]-2-methyl-7-[1, the fluoro-2-of 2-dihydro-4-oxo-3 h-indoles-(Z)-3-subunit]-4,5,6,7-tetrahydrochysene-1 h-indoles-3-carboxylic acid amides;
N-[3-(pyrrolidin-1-yl)-propyl group]-2-methyl-7-[1, the fluoro-2-of 2-dihydro-7-oxo-3 h-indoles-(Z)-3-subunit]-4,5,6,7-tetrahydrochysene-1 h-indoles-3-carboxylic acid amides;
N-(2-diethylin ethyl)-2-methyl-7-[1,2-dihydro-5,7-dimethyl-2-oxo-3 h-indoles-(Z)-3-subunit]-4,5,6,7-tetrahydrochysene-1 h-indoles-3-carboxylic acid amides;
N-(2-diethylin ethyl)-2-methyl-7-[N-sec.-propyl-2-oxindole-5-sulphonamide-(Z)-3-subunit]-4,5,6,7-tetrahydrochysene-1 h-indoles-3-carboxylic acid amides;
N-(2-diethylin ethyl)-2-methyl-7-[1, the bromo-2-of 2-dihydro-5-oxo-3 h-indoles-(Z)-3-subunit]-4,5,6,7-tetrahydrochysene-1 h-indoles-3-carboxylic acid amides;
N-(2-diethylin ethyl)-2-methyl-7-[1,2-dihydro-5-nitro-2-oxo-3 h-indoles-(Z)-3-subunit]-4,5,6,7-tetrahydrochysene-1 h-indoles-3-carboxylic acid amides;
N-(3-dimethylamino-propyl)-2-methyl-7-[1, the fluoro-2-of 2-dihydro-5-oxo-3 h-indoles-(Z)-3-subunit]-4,5,6,7-tetrahydrochysene-1 h-indoles-3-carboxylic acid amides;
N-(2-diethylin ethyl)-2-methyl-7-[1,2-dihydro-5-carboxylate methyl ester-2-oxo-3 h-indoles-(Z)-3-subunit]-4,5,6,7-tetrahydrochysene-1 h-indoles-3-carboxylic acid amides;
N-(2-diethylin ethyl)-2-methyl-7-[1, the fluoro-2-of 2-dihydro-7-oxo-3 h-indoles-(Z)-3-subunit]-4,5,6,7-tetrahydrochysene-1 h-indoles-3-carboxylic acid amides;
N-(2-diethylin ethyl)-2-methyl-7-[N-(4-fluorophenyl)-5-sulphonamide-2-oxindole-(Z)-3-subunit]-4,5,6,7-tetrahydrochysene-1 h-indoles-3-carboxylic acid amides;
N-(2-diethylin ethyl)-2-methyl-7-[5-(piperidines-1-alkylsulfonyl)-1,2-dihydro-2-oxo--3 h-indoles-(Z)-3-subunit]-4,5,6,7-tetrahydrochysene-1 h-indoles-3-carboxylic acid amides;
N-(3-diethylin propyl group)-2-methyl-7-[1, the fluoro-2-of 2-dihydro-5-oxo-3 h-indoles-(Z)-3-subunit]-4,5,6,7-tetrahydrochysene-1 h-indoles-3-carboxylic acid amides;
N-(2-diethylin ethyl)-2-methyl-7-[1,2-dihydro-5-carboxylic acid-2-oxo-3 h-indoles-(Z)-3-subunit]-4,5,6,7-tetrahydrochysene-1 h-indoles-3-carboxylic acid amides;
N-(2-diethylin ethyl)-2-methyl-7-[1,2-dihydro-5-(N-kharophen)-2-oxo-3 h-indoles-(Z)-3-subunit]-4,5,6,7-tetrahydrochysene-1 h-indoles-3-carboxylic acid amides;
N-(2-diethylin ethyl)-2-methyl-7-[1,2-dihydro-6-chloro-2-oxo-3 h-indoles-(Z)-3-subunit]-4,5,6,7-tetrahydrochysene-1 h-indoles-3-carboxylic acid amides;
N-(3-diethylin propyl group)-2-methyl-7-[1,2-dihydro-6-chloro-2-oxo-3 h-indoles-(Z)-3-subunit]-4,5,6,7-tetrahydrochysene-1 h-indoles-3-carboxylic acid amides;
N-(3-diethylin propyl group)-2-methyl-7-[1, the bromo-2-of 2-dihydro-5-oxo-3 h-indoles-(Z)-3-subunit]-4,5,6,7-tetrahydrochysene-1 h-indoles-3-carboxylic acid amides;
N-(2-diethylin ethyl)-2-methyl-7-[1, the fluoro-2-of 2-dihydro-4-oxo-3 h-indoles-(Z)-3-subunit]-4,5,6,7-tetrahydrochysene-1 h-indoles-3-carboxylic acid amides;
N-(2-diethylin ethyl)-2-methyl-7-[5-(tetramethyleneimine-1-carbonyl)-1,2-dihydro-2-oxo--3 h-indoles-(Z)-3-subunit]-4,5,6,7-tetrahydrochysene-1 h-indoles-3-carboxylic acid amides;
N-(2-diethylin ethyl)-2-methyl-7-[N-(4-fluorophenyl)-5-carboxylic acid amides-1,2-dihydro-2-oxo--3 h-indoles-(Z)-3-subunit]-4,5,6,7-tetrahydrochysene-1 h-indoles-3-carboxylic acid amides;
N-(3-diethylin propyl group)-2-methyl-7-[1, the fluoro-2-of 2-dihydro-7-oxo-3 h-indoles-(Z)-3-subunit]-4,5,6,7-tetrahydrochysene-1 h-indoles-3-carboxylic acid amides;
N-(2-diethylin ethyl)-2-methyl-7-[1,2-dihydro-5-methoxyl group-2-oxo-3 h-indoles-(Z)-3-subunit]-4,5,6,7-tetrahydrochysene-1 h-indoles-3-carboxylic acid amides;
N-(2-diethylin ethyl)-2-methyl-7-[1,2-dihydro-5-trifluoromethoxy-2-oxo-3 h-indoles-(Z)-3-subunit]-4,5,6,7-tetrahydrochysene-1 h-indoles-3-carboxylic acid amides;
N-(2-diethylin ethyl)-2-methyl-7-[N-methyl-5-sulphonamide-2-oxindole-(Z)-3-subunit]-4,5,6,7-tetrahydrochysene-1 h-indoles-3-carboxylic acid amides;
N-[2-(2-pyridyl)-ethyl]-2-methyl-7-[1, the fluoro-2-oxo-3H-of 2-dihydro-5-indoles-(Z)-3-subunit]-4,5,6,7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides;
N-[2-(dimethylin) ethyl]-N, 2-dimethyl-7-[1, the fluoro-2-of 2-dihydro-5-oxo-3 h-indoles-(Z)-3-subunit]-4,5,6,7-tetrahydrochysene-1 h-indoles-3-carboxylic acid amides;
N-[2-(dimethylin) ethyl]-N, 2-dimethyl-7-[1,2-dihydro-6-chloro-2-oxo-3 h-indoles-(Z)-3-subunit]-4,5,6,7-tetrahydrochysene-1 h-indoles-3-carboxylic acid amides;
N-benzyl-N, 2-dimethyl-7-[1, the fluoro-2-of 2-dihydro-5-oxo-3 h-indoles-(Z)-3-subunit]-4,5,6,7-tetrahydrochysene-1 h-indoles-3-carboxylic acid amides;
2-methyl-3-[(S)-2-(tetramethyleneimine-1-methyl)-tetramethyleneimine-1-carbonyl]-7-[1, the fluoro-2-of 2-dihydro-5-oxo-3 h-indoles-(Z)-3-subunit]-4,5,6,7-tetrahydrochysene-1 h-indoles;
2-methyl-3-[4-(2-hydroxyethyl)-piperazine-1-carbonyl]-7-[1, the fluoro-2-of 2-dihydro-5-oxo-3 h-indoles-(Z)-3-subunit]-4,5,6,7-tetrahydrochysene-1 h-indoles;
2-methyl-3-(Isosorbide-5-Nitrae '-bis-piperidines-1 '-carbonyl)-7-[1, the fluoro-2-of 2-dihydro-5-oxo-3 h-indoles-(Z)-3-subunit]-4,5,6,7-tetrahydrochysene-1 h-indoles;
N-[3-(diethylin)-2-hydroxypropyl]-2-methyl-7-[1,2-dihydro-2-oxo--3 h-indoles-(Z)-3-subunit]-4,5,6,7-tetrahydrochysene-1 h-indoles-3-carboxylic acid amides;
N-[3-(diethylin)-2-hydroxypropyl]-2-methyl-7-[1, the fluoro-2-of 2-dihydro-5-oxo-3 h-indoles-(Z)-3-subunit]-4,5,6,7-tetrahydrochysene-1 h-indoles-3-carboxylic acid amides;
N-[3-(diethylin)-2-hydroxypropyl]-2-methyl-7-[1,2-dihydro-5-chloro-2-oxo-3 h-indoles-(Z)-3-subunit]-4,5,6,7-tetrahydrochysene-1 h-indoles-3-carboxylic acid amides;
N-[3-(dimethylin)-2-hydroxypropyl]-2-methyl-7-[1, the fluoro-2-of 2-dihydro-5-oxo-3 h-indoles-(Z)-3-subunit]-4,5,6,7-tetrahydrochysene-1 h-indoles-3-carboxylic acid amides;
N-[3-(morpholine-4-yl)-2-hydroxypropyl]-2-methyl-7-[1,2-dihydro-2-oxo--3 h-indoles-(Z)-3-subunit]-4,5,6,7-tetrahydrochysene-1 h-indoles-3-carboxylic acid amides;
N-[3-(morpholine-4-yl)-2-hydroxypropyl]-2-methyl-7-[1, the fluoro-2-of 2-dihydro-5-oxo-3 h-indoles-(Z)-3-subunit]-4,5,6,7-tetrahydrochysene-1 h-indoles-3-carboxylic acid amides;
N-[3-(morpholine-4-yl)-2-hydroxypropyl]-2-methyl-7-[1,2-dihydro-5-chloro-2-oxo-3 h-indoles-(Z)-3-subunit]-4,5,6,7-tetrahydrochysene-1 h-indoles-3-carboxylic acid amides;
N-[3-(pyrrolidin-1-yl)-2-hydroxypropyl]-2-methyl-7-[1,2-dihydro-2-oxo--3 h-indoles-(Z)-3-subunit]-4,5,6,7-tetrahydrochysene-1 h-indoles-3-carboxylic acid amides;
N-[3-(pyrrolidin-1-yl)-2-hydroxypropyl]-2-methyl-7-[1, the fluoro-2-of 2-dihydro-5-oxo-3 h-indoles-(Z)-3-subunit]-4,5,6,7-tetrahydrochysene-1 h-indoles-3-carboxylic acid amides;
N-[3-(pyrrolidin-1-yl)-2-hydroxypropyl]-2-methyl-7-[1,2-dihydro-5-chloro-2-oxo-3 h-indoles-(Z)-3-subunit]-4,5,6,7-tetrahydrochysene-1 h-indoles-3-carboxylic acid amides;
N-[3-(piperidin-1-yl)-2-hydroxypropyl]-2-methyl-7-[1,2-dihydro-2-oxo--3 h-indoles-(Z)-3-subunit]-4,5,6,7-tetrahydrochysene-1 h-indoles-3-carboxylic acid amides;
N-[3-(piperidin-1-yl)-2-hydroxypropyl]-2-methyl-7-[1, the fluoro-2-of 2-dihydro-5-oxo-3 h-indoles-(Z)-3-subunit]-4,5,6,7-tetrahydrochysene-1 h-indoles-3-carboxylic acid amides;
N-[3-(piperidin-1-yl)-2-hydroxypropyl]-2-methyl-7-[1,2-dihydro-5-chloro-2-oxo-3 h-indoles-(Z)-3-subunit]-4,5,6,7-tetrahydrochysene-1 h-indoles-3-carboxylic acid amides;
N-[3-(4-methyl-piperazine-1-yl)-2-hydroxypropyl]-2-methyl-7-[1,2-dihydro-2-oxo--3 h-indoles-(Z)-3-subunit]-4,5,6,7-tetrahydrochysene-1 h-indoles-3-carboxylic acid amides;
N-[3-(4-methyl-piperazine-1-yl)-2-hydroxypropyl]-2-methyl-7-[1, the fluoro-2-of 2-dihydro-5-oxo-3 h-indoles-(Z)-3-subunit]-4,5,6,7-tetrahydrochysene-1 h-indoles-3-carboxylic acid amides;
N-[3-(4-methyl-piperazine-1-yl)-2-hydroxypropyl]-2-methyl-7-[1,2-dihydro-5-chloro-2-oxo-3 h-indoles-(Z)-3-subunit]-4,5,6,7-tetrahydrochysene-1 h-indoles-3-carboxylic acid amides;
N-[3-(N-methylcyclohexyl amido)-2-hydroxypropyl]-2-methyl-7-[1,2-dihydro-5-methyl-2-oxo-3 h-indoles-(Z)-3-subunit]-4,5,6,7-tetrahydrochysene-1 h-indoles-3-carboxylic acid amides;
N-[3-(diethylin)-2-hydroxypropyl]-2-methyl-7-[1, the bromo-2-of 2-dihydro-5-oxo-3 h-indoles-(Z)-3-subunit]-4,5,6,7-tetrahydrochysene-1 h-indoles-3-carboxylic acid amides;
N-[3-(morpholine-4-yl)-2-hydroxypropyl]-2-methyl-7-[1,2-dihydro-6-chloro-2-oxo-3 h-indoles-(Z)-3-subunit]-4,5,6,7-tetrahydrochysene-1 h-indoles-3-carboxylic acid amides;
N-[3-(N-methylcyclohexyl amido)-2-hydroxypropyl]-2-methyl-7-[1, the fluoro-2-of 2-dihydro-5-oxo-3 h-indoles-(Z)-3-subunit]-4,5,6,7-tetrahydrochysene-1 h-indoles-3-carboxylic acid amides;
N-[3-(morpholine-4-yl)-2-hydroxypropyl]-2-methyl-7-[1, the bromo-2-of 2-dihydro-5-oxo-3 h-indoles-(Z)-3-subunit]-4,5,6,7-tetrahydrochysene-1 h-indoles-3-carboxylic acid amides.
2. compound or its pharmacy acceptable salt, be selected from
N-(2-diethylin ethyl)-2-methyl-7-[1, the fluoro-2-oxo-3H-of 2-dihydro-5-indoles-(Z)-3-subunit]-4,5,6,7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides;
N-(2-dimethylamino ethyl)-2-methyl-7-[1, the fluoro-2-oxo-3H-of 2-dihydro-5-indoles-(Z)-3-subunit]-4,5,6,7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides;
N-[2-(morpholine-4-yl)-ethyl]-2-methyl-7-[1, the fluoro-2-oxo-3H-of 2-dihydro-5-indoles-(Z)-3-subunit]-4,5,6,7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides;
N-[3-(morpholine-4-yl)-propyl group]-2-methyl-7-[1, the fluoro-2-oxo-3H-of 2-dihydro-5-indoles-(Z)-3-subunit]-4,5,6,7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides;
N-[2-(piperidin-1-yl)-ethyl]-2-methyl-7-[1, the fluoro-2-oxo-3H-of 2-dihydro-5-indoles-(Z)-3-subunit]-4,5,6,7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides;
N-[2-(pyrrolidin-1-yl)-ethyl]-2-methyl-7-[1, the fluoro-2-oxo-3H-of 2-dihydro-5-indoles-(Z)-3-subunit]-4,5,6,7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides;
N-[3-(pyrrolidin-1-yl)-propyl group]-2-methyl-7-[1, the fluoro-2-oxo-3H-of 2-dihydro-5-indoles-(Z)-3-subunit]-4,5,6,7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides;
N-(3-dimethylamino-propyl)-2-methyl-7-[1, the fluoro-2-oxo-3H-of 2-dihydro-5-indoles-(Z)-3-subunit]-4,5,6,7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides;
N-[3-(diethylin)-2-hydroxypropyl]-2-methyl-7-[1, the fluoro-2-oxo-3H-of 2-dihydro-5-indoles-(Z)-3-subunit]-4,5,6,7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides;
N-[3-(dimethylin)-2-hydroxypropyl]-2-methyl-7-[1, the fluoro-2-oxo-3H-of 2-dihydro-5-indoles-(Z)-3-subunit]-4,5,6,7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides;
N-[3-(morpholine-4-yl)-2-hydroxypropyl]-2-methyl-7-[1, the fluoro-2-oxo-3H-of 2-dihydro-5-indoles-(Z)-3-subunit]-4,5,6,7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides;
N-[3-(pyrrolidin-1-yl)-2-hydroxypropyl]-2-methyl-7-[1, the fluoro-2-oxo-3H-of 2-dihydro-5-indoles-(Z)-3-subunit]-4,5,6,7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides;
N-[3-(piperidin-1-yl)-2-hydroxypropyl]-2-methyl-7-[1, the fluoro-2-oxo-3H-of 2-dihydro-5-indoles-(Z)-3-subunit]-4,5,6,7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides;
N-[3-(4-methyl-piperazine-1-yl)-2-hydroxypropyl]-2-methyl-7-[1, the fluoro-2-oxo-3H-of 2-dihydro-5-indoles-(Z)-3-subunit]-4,5,6,7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides.
3. compound or its pharmacy acceptable salt, be selected from
N-(2-diethylin ethyl)-2-methyl-7-[1, the fluoro-2-oxo-3H-of 2-dihydro-5-indoles-(Z)-3-subunit]-4,5,6,7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides;
N-(3-dimethylamino-propyl)-2-methyl-7-[1, the fluoro-2-oxo-3H-of 2-dihydro-5-indoles-(Z)-3-subunit]-4,5,6,7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides;
N-[3-(morpholine-4-yl)-2-hydroxypropyl]-2-methyl-7-[1, the fluoro-2-oxo-3H-of 2-dihydro-5-indoles-(Z)-3-subunit]-4,5,6,7-tetrahydrochysene-1H-indoles-3-carboxylic acid amides.
4. compound or its pharmacy acceptable salt, described compound is the intermediate of compound described in claim 1,2 or 3, is selected from:
N-(2-diethylin ethyl)-2-methyl-7-oxo-4,5,6,7-tetrahydrochysene-1 h-indoles-3-carboxylic acid amides;
N-(2-hydroxyethyl)-2-methyl-7-oxo-4,5,6,7-tetrahydrochysene-1 h-indoles-3-carboxylic acid amides;
N-(2-dimethylamino ethyl)-2-methyl-7-oxo-4,5,6,7-tetrahydrochysene-1 h-indoles-3-carboxylic acid amides;
N-(3-dimethylamino-propyl)-2-methyl-7-oxo-4,5,6,7-tetrahydrochysene-1 h-indoles-3-carboxylic acid amides;
N-[2-(morpholine-4-yl)-ethyl]-2-methyl-7-oxo-4,5,6,7-tetrahydrochysene-1 h-indoles-3-carboxylic acid amides;
N-[2-(piperidin-1-yl)-ethyl]-2-methyl-7-oxo-4,5,6,7-tetrahydrochysene-1 h-indoles-3-carboxylic acid amides;
N-[2-(pyrrolidin-1-yl)-ethyl]-2-methyl-7-oxo-4,5,6,7-tetrahydrochysene-1 h-indoles-3-carboxylic acid amides;
N-[3-(morpholine-4-yl)-propyl group]-2-methyl-7-oxo-4,5,6,7-tetrahydrochysene-1 h-indoles-3-carboxylic acid amides;
N-(3-diethylin propyl group)-2-methyl-7-oxo-4,5,6,7-tetrahydrochysene-1 h-indoles-3-carboxylic acid amides;
N-[3-(pyrrolidin-1-yl)-propyl group]-2-methyl-7-oxo-4,5,6,7-tetrahydrochysene-1 h-indoles-3-carboxylic acid amides;
N-[3-(4-methyl-piperazine-1-yl)-propyl group]-2-methyl-7-oxo-4,5,6,7-tetrahydrochysene-1 h-indoles-3-carboxylic acid amides;
N-[3-(diethylin)-2-hydroxypropyl]-2-methyl-7-oxo-4,5,6,7-tetrahydrochysene-1 h-indoles-3-carboxylic acid amides;
N-[3-(dimethylin)-2-hydroxypropyl]-2-methyl-7-oxo-4,5,6,7-tetrahydrochysene-1 h-indoles-3-carboxylic acid amides;
N-[3-(morpholine-4-yl)-2-hydroxypropyl]-2-methyl-7-oxo-4,5,6,7-tetrahydrochysene-1 h-indoles-3-carboxylic acid amides;
N-[3-(pyrrolidin-1-yl)-2-hydroxypropyl]-2-methyl-7-oxo-4,5,6,7-tetrahydrochysene-1 h-indoles-3-carboxylic acid amides;
N-[3-(piperidin-1-yl)-2-hydroxypropyl]-2-methyl-7-oxo-4,5,6,7-tetrahydrochysene-1 h-indoles-3-carboxylic acid amides;
N-[3-(4-methyl-piperazine-1-yl)-2-hydroxypropyl]-2-methyl-7-oxo-4,5,6,7-tetrahydrochysene-1 h-indoles-3-carboxylic acid amides;
N-[3-(N-methylcyclohexyl amido)-2-hydroxypropyl]-2-methyl-7-oxo-4,5,6,7-tetrahydrochysene-1 h-indoles-3-carboxylic acid amides.
5. pharmaceutical composition, comprises the compound described in any one or its pharmacy acceptable salt and pharmaceutically acceptable carrier or vehicle in claim 1,2 or 3.
6. the purposes in the medicine of the compound described in any one or its pharmacy acceptable salt protein kinase related disorder in for the preparation for the treatment of organism in claim 1,2 or 3.
7. purposes according to claim 6, wherein said protein kinase related disorder is selected from relevant disease or the relevant disease of serine-threonine kinase of disease, nonreceptor tyrosine kinase that receptor tyrosine kinase is relevant.
8. purposes according to claim 6, wherein said protein kinase related disorder is selected from relevant relevant relevant disease or the relevant disease of tire liver kinases of disease, IGF-1 of disease, platelet derived growth factor receptor of disease, EGF-R ELISA that vascular endothelial growth factor receptor is relevant.
9. purposes according to claim 6, wherein said protein kinase related disorder is selected from squamous cell carcinoma, stellate cell cancer, Kaposi's sarcoma, spongioblast cancer, lung cancer, bladder cancer, head and neck cancer, melanoma, ovarian cancer, prostate cancer, mammary cancer, neurospongioma, colorectal carcinoma, liver cancer, kidney, genitourinary cancer, carcinoma of the pancreas or gastrointestinal cancer.
10. purposes according to claim 6, wherein said protein kinase related disorder is selected from diabetes, excess proliferative disease, blood vessel generation, inflammatory diseases, immunological disease or cardiovascular disorder.
11. purposes according to claim 6, wherein said organism is Mammals.
CN201210162848.5A 2007-12-03 2007-12-03 3-pyrrolo-cyclohexylidene-2-dihydroindolone derivative, and application of 3-pyrrolo-cyclohexylidene-2-dihydroindolone derivative Expired - Fee Related CN102702068B (en)

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