CN101014603B - Compounds and methods for inhibiting mitotic progression by ingibiting aurora kinase - Google Patents

Compounds and methods for inhibiting mitotic progression by ingibiting aurora kinase Download PDF

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CN101014603B
CN101014603B CN200580023579.2A CN200580023579A CN101014603B CN 101014603 B CN101014603 B CN 101014603B CN 200580023579 A CN200580023579 A CN 200580023579A CN 101014603 B CN101014603 B CN 101014603B
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phenyl
hydrogen
chloro
azepine
base
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CN101014603A (en
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克里斯托弗·F·克莱鲍恩
劳埃德·J·佩恩
理查德·J·博伊斯
托德·B·塞尔斯
斯蒂芬·G·斯特罗德
斯图尔特·特拉维尔斯
特瑞西亚·J·沃斯
加布里埃尔·S·外泽黑德
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Millennium Pharmaceuticals Inc
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Millennium Pharmaceuticals Inc
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Abstract

This invention relates to compounds and methods for the treatment of cancer. In particular, the invention provides compounds that inhibit Aurora kinase, pharmaceutical compositions comprising the compounds, and methods of using the compounds for the treatment of cancer.

Description

By suppressing aurora kinase, suppress mitotic Compounds and methods for
Technical field
The present invention relates to treat the Compounds and methods for of cancer.Particularly, the invention provides the method that suppresses compound, the pharmaceutical composition that contains these compounds of aurora kinase and use these composition treatment cancers.
background technology
According to the data of American Cancer Society, within 2004, nearly 1,400,000 Americans are diagnosed as newly-increased cancer patients, and approximately have 560,000 people to die from cancer.Although medical advance has improved cancer patients's survival rate, people still need new, more effective cancer treatment method.
Cancer has the breeding feature out of control of cell.Mitotic division is a stage of cell division cycle, and in this one-phase, a series of complicated event guarantees that karyomit(e) splits into the fidelity of reproduction of two daughter cells.Current several cancer therapies used, comprise that using the therapy of taxane substances and vinca alkaloids is all to suppress mitotic division mechanism.Mitotic process is to be controlled by proteolyzing and phosphorylation to a great extent, and proteolyzing and phosphorylation are regulated by mitotic kinase.Aurora kinase family member is (such as aurora A, aurora B, aurora C) by regulating centrosome to divide, Spindle kinetics, spindle body microcoenosis check point, Chromosomal arrangement and division of cytoplasm and control mitotic process and (see the article of the people such as Dutertre on < < oncogene > >, 21:6175 (2002), see the article of the people such as Berdnik on < < Contemporary Biology > >, 12:640 (2002)).The overexpression of aurora kinase and/or propagation are relevant with the formation of several cancers, comprising colorectal carcinoma and mammary cancer, (see the article of the people such as Warner on < < molecule cancer therapy > >, 2:589 (1998), see the article on SenDeng Ren EMBO publication, 17:3062 (1998), see the article of the people such as Sen on < < cancer research > >, 94:1320 (2002)).In addition, aurora kinase in inhibition tumor cell can cause mitotic stopping and apoptosis, this shows that these kinases are that important goal in cancer therapy (is shown in the article of Ditchfield on < < cytobiology periodical > >, 161:267 (2003); See the article of the people such as Harrington on < < Natural medicine > >, 1 (2004)).Mitotic division plays leading role in all malignant tumours, and aurora kinase inhibitors can be applicable in multiple human tumor.Therefore, people need novel aurora kinase inhibitors.
Summary of the invention
The invention provides the compound that suppresses aurora kinase.These compounds are for suppressing the aurora kinase of in vitro and in vivo, and these compounds especially can be used for treating cell proliferation disorders, comprising treatment cancer.In the present invention, aurora kinase inhibitors has following molecular formula (A):
Or its acceptable salt in pharmacy, wherein A ring, C ring and every kind of variable radicals R a, R e, R f1, R f2, R x, R y, G has and is defined as follows:
R f1hydrogen, or R f1and R f2form key.
R f2hydrogen, or R f2with R f1or R xform key.
R xand R ycan be hydrogen, fluorine independently of one another, or the optional C replacing 1-6fat group; Or R xand R ytogether with they connect carbon atom thereon, thereby form the optional cycloaliphatic ring of 3 yuan-6 yuan replacing; Or R xand R f2form key.
G is hydrogen, the optional fatty group replacing, or at R f1it during for hydrogen, is B ring; Work as R f1and R f2while forming key, G is hydrogen ,-OR 5,-N (R 4) 2,-SR 5, the optional fatty group replacing or B ring.
A ring is that replace or unsubstituted 5 yuan or 6 yuan of aryl, heteroaryl, cycloaliphatic groups or heterocyclic groups.
B ring be replace or unsubstituted aryl, heteroaryl, cycloaliphatic groups or heterocyclic group.
C ring be replace or unsubstituted aryl, heteroaryl, heterocyclic group or cycloaliphatic groups.
R ahydrogen ,-C (O) R 1,-CO 2r 1,-SO 2r 1or C 1-3aliphatic group; This aliphatic group contains 0-2 substituting group, and substituting group is wherein selected from R independently of one another 3or R 7.
R ehydrogen ,-OR 5,-N (R 4) 2,-SR 5,-NR 4c (O) R 5, NR 4c (O) N (R 4) 2,-NR 4cO 2r 6,-N (R 4) SO 2r 6,-N (R 4) SO 2n(R 4) 2, or by R 3or R 7the optional C replacing 1-3fat group.
R 1c 1-6fatty group, or optional aryl, heteroaryl or the heterocyclic group replacing.
Each R 3independently selected from halogen ,-OH ,-O (C 1-3alkyl) ,-CN ,-N (R 4) 2,-C (O) (C 1-3alkyl) ,-CO 2h ,-CO 2(C 1-3alkyl) ,-C (O) NH 2and-C (O) NH (C 1-3alkyl).
Each R 4hydrogen or optional fatty group, aryl, heteroaryl, the heterocyclic group replacing independently; Or be connected to two R on same nitrogen-atoms 4form 5 yuan of-6 yuan of heteroaryls of optional replacement together with this nitrogen-atoms, or the heterocyclic radical of 4 yuan-8 yuan, in heteroaryl wherein and heterocyclic radical except nitrogen-atoms also with 0-2 heterocyclic atom that is selected from nitrogen, oxygen and sulphur.
Each R 5hydrogen or optional fatty group, aryl, heteroaryl or the heterocyclic radical replacing independently.
Each R 6optional fatty group or the aromatic yl group replacing independently.
Each R 7optional aryl, heterocyclic group or the heteroaryl groups replacing independently.
The present invention also provides the pharmaceutical composition that contains compound shown in molecular formula (A), and the present invention also provides the method for using described compound to suppress the active and disease that treatment aurora kinase mediates of aurora kinase.
Compound in the present invention comprises foregoing those materials and this paper compound of described classification, subclass and kind below.Unless otherwise, otherwise term used herein with the defined meaning below, be as the criterion.
As used herein, term " aurora kinase " refers to any one relevant serine/threonine kinase that mitotic division process is related.The cell protein playing a role in fission process is the aurora kinase Substrate of phosphorylation, and these cell proteins include but not limited to that histone H 3, P53, CENP-A, flesh cyclase protein II regulate light chain, protein phosphatase-1, TPX-2, INCENP, survivin, topoisomerase II α, elastin, MBD-3, MgcRacGAP, desmin, Ajuba, XIEg5 (African toad type), Ndc10p (budding yeast type) and D-TACC (fruit bat type).Aurora kinase itself is also the matrix of phosphorylation; Such as Thr228.Unless separately indicate herein, otherwise term " aurora kinase " referred to any aurora kinase albumen from any kind, including, but not limited to aurora A, aurora B, aurora C, preferred aurora kinase is aurora A and aurora B.Preferred aurora kinase is mankind's aurora kinases.
Term " aurora kinase inhibitors " or " inhibitor of aurora kinase " refer to have structure defined herein and can occur interact and suppress the compound of its enzymic activity with aurora kinase.The activity that suppresses aurora kinase refers to the ability that aurora kinase makes matrix peptide or albumen generation phosphorylation that reduces.In different embodiments of the present invention, the activity of aurora kinase has at least been reduced approximately 50%; Or at least reduced approximately 75%; Or at least reduced approximately 90%; Or at least reduced approximately 95%; Or at least reduced approximately 99%.In different embodiments of the present invention, reduce the active required aurora kinase inhibitors concentration of aurora kinase and be less than approximately 1 μ M; Or be less than about 500nM; Or be less than about 100nM; Or be less than about 50nM.
In certain embodiments, this restraining effect is to have optionally, and aurora kinase inhibitors can reduce the activity that aurora kinase makes matrix peptide or protein generation phosphorylation under finite concentration; But this concentration is not enough to cause certain incoherent biological effect in addition; Such as this concentration can not reduce other kinase whose activity.In certain embodiments, aurora kinase also can reduce another kind of kinase whose activity; Preferred situation is that this another kind kinases is relevant to cancer.
The term " about " used herein meaning be general, necessarily among a small circle in, roughly or left and right.When term " about " and digital scope are when being used, this term by range expansion outside digital numerical value used.Generally speaking, term " about " is that described numerical value is become to large or diminishes 10% in this article.
As used herein, term " comprises " that the meaning is " to comprise; But be not limited to ".
Term " aliphatics " in this article refers to the hydrocarbon of straight chain hydrocarbon, branched-chain hydrocarbon or the ring texture with 1-12 carbon atom, these hydrocarbon or completely stable hydrocarbon; Or with one or more unsaturated units, but unsaturated unit is not aromatics group.For example, applicable aliphatic group comprises the mixture of alkyl, thiazolinyl, alkynyl and these groups of straight chain replacement or unsubstituted, side chain or ring texture; Such as being (cycloalkyl) alkyl, (cycloalkenyl group) alkyl or (cycloalkyl) thiazolinyl.In different embodiments of the present invention, aliphatic group has 1-12,1-8,1-6, a 1-4 or 1-3 carbon atom.
Term " alkyl ", " thiazolinyl " and " alkynyl " are when being used separately or use as a kind of key element of a larger part, and these terms refer to C 1-12straight chain aliphatic group or side chain aliphatic group.With regard to object of the present invention, when the carbon atom that aliphatic group is coupled together with other molecules is saturated carbon atom, just use " alkyl " this term.But alkyl group may be included in unsaturated on other carbon atom.Therefore, alkyl group comprises methyl, ethyl, propyl group, allyl group, propargyl, butyl, amyl group and hexyl, but alkyl is not limited to these groups.
With regard to object of the present invention, when the carbon atom of connection aliphatic group and other molecules becomes the integral part of carbon-to-carbon double bond, just use " thiazolinyl " this term.Thiazolinyl comprises vinyl, 1-propenyl, 1-butylene base, 1-pentenyl and 1-hexenyl, but thiazolinyl is not limited to these groups.
With regard to object of the present invention, when the carbon atom of connection aliphatic group and other molecules becomes the integral part of carbon-to-carbon triple bond, just use " alkynyl " this term.Alkynyl comprises ethynyl, 1-proyl, ethyl acetylene base, 1-pentynyl and 1-hexin base; But alkynyl is not limited to these groups.
Term " alicyclic ", " carbocyclic ring ", " carbocylic radical ", " carbocyclic ring " and " carbocyclic ring class " are when being used separately or use as the key element of a larger part, and these terms refer to C 3-14the ring texture fat lopps material of saturated cyclic structural fatty ring material or fractional saturation, cycloaliphatic ring wherein can be optionally substituted.Alicyclic group comprises cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, suberyl, cycloheptenyl, ring octyl group, cyclooctene base and cyclooctadiene base, but alicyclic group is not limited to these groups.In some embodiment, cycloalkyl has 3-6 carbon atom.Term " alicyclic ", " carbocyclic ring ", " carbocylic radical ", " carbocyclic ring " and " carbocyclic ring class " also comprise the cycloaliphatic ring combining with one or more aromatic rings or non-aromatic ring, such as decahydro naphthyl or tetralyl; Binding site or be positioned on cycloaliphatic ring in conjunction with base wherein.
Term " halogen aliphatics ", " alkylhalide group ", " haloalkenyl " and " halogen alkoxyl group " refer to aliphatics, alkyl, thiazolinyl or the alkoxyl group being replaced by one or more halogen atoms.Just as used herein, term " halogen " or " haloid element " refer to fluorine, chlorine, bromine or iodine.
During when independent use or as a kind of key element of a larger part, term " aryl " and " aromatic series " refer to the C of the aromatic ring that comprises 1-3 optional replacement 6-14aromatic group, such as aralkyl, aralkoxy, aryloxy alkyl.In the preferred case, aryl is C 6-10aromatic yl group.Aromatic yl group comprises phenyl, naphthyl and anthryl; But aryl is not limited to these groups.Just as used herein, term " aromatic series " also comprises some group, and in these groups, aromatic ring merges mutually with one or more heteroaryls, alicyclic group or heterocyclic group; Binding site or be positioned on aromatic ring in conjunction with base wherein.These limiting examples that merge ring comprise indyl, pseudoindoyl, benzothienyl, benzofuryl, dibenzofuran group, indazolyl, benzimidazolyl-, benzothiazolyl, quinolyl, isoquinolyl, cinnolines base, 2,3-phthalazinyl, quinazolyl, quinoxalinyl, carbazyl, acridyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydric quinoline group, tetrahydro isoquinolyl, fluorenyl, 2,3-indanyl, phenanthridinyl, tetralyl, indolinyl, benzo dioctyl and benzo dioxolyl.Aryl can be monocyclic aryl, bicyclic aryl, three cyclophane base or polyaromatics; Preferably monocyclic aryl, bicyclic aryl or three cyclophane bases; More preferably monocyclic aryl and bicyclic aryl.Term " aryl " can exchange and use with term " aromatic yl group ", " aromatic ring " and " aromatic nucleus ".
" aralkyl " or " arylalkyl " group comprises with alkyl group and forms covalently bound aromatic yl group; Aryl wherein or alkyl can be optionally substituted independently.In the preferred case, the structure of aromatic alkyl group is C 6-10aryl (C 1-6alkyl), comprise that phenmethyl, styroyl are with menaphthyl, but aralkyl is not limited to these groups.
When a kind of key element of independent use or the larger part of conduct, term " heteroaryl " and " heteroaromatic " refer to that in ring texture, atomicity is the individual aromatic group of 5-14, in the preferred case, the annular atoms number of heteroaryl is 5,6,9,10, and in ring texture with 6,10 or 14 π shared electrons, except one or more carbon atoms, heteroaryl is also with 1-4 heteroatoms simultaneously.Term " heteroatoms " refers to nitrogen-atoms, Sauerstoffatom, sulphur atom, and comprises the nitrogen of oxidised form, the sulphur of oxidised form and quaternised basic nitrogen.Heteroaryl groups comprises thienyl, furyl, pyrryl, imidazolyl, pyrazolyl, triazolyl, tetrazyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl group, pyridyl, pyridazinyl, pyrimidyl, pyrazinyl, indolizine base, purine radicals, naphthyridine base and pteridyl; But heteroaryl groups is not limited to these groups.Just as used herein, term " heteroaryl " and " heteroaromatic " can also comprise some group, in these groups, assorted aromatic nucleus merges mutually with one or more aryl, alicyclic ring class group or heterocyclic group, and wherein tie point or connection base are positioned on assorted aromatic nucleus.Concrete unrestricted example comprises indyl, pseudoindoyl, benzothienyl, benzofuryl, dibenzofuran group, indazolyl, benzimidazolyl-, benzothiazolyl, quinolyl, isoquinolyl, cinnolines base, 2,3-phthalazinyl, quinazolyl, quinoxalinyl, tetrahydro quinazoline base, carbazyl, acridyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydric quinoline group, tetrahydro isoquinolyl and pyrido [2,3-b]-Isosorbide-5-Nitrae-piperazine-3 (4 hydrogen) ketone.Heteroaryl groups can be bicyclic heteroaryl group, bicyclic heteroaryl group, tricyclic heteroaryl group or polyheteroaromatic group, preferably bicyclic heteroaryl group, bicyclic heteroaryl group and tricyclic heteroaryl group; More preferably bicyclic heteroaryl group and bicyclic heteroaryl group.Term " heteroaryl " can exchange and use with " hetero-aromatic ring ", " heteroaryl groups " or " heteroaromatic ", can select, and the ring in heteroaryl can be optionally substituted.Term " heteroaralkyl " refers to the alkyl group that heteroaryl substitution reaction occurred, and alkyl wherein and heteroaryl can be optionally substituted independently.
Just as used herein " heterocycle ", " heterocyclic radical ", " heterocyclic group " and " heterocycle structure " can exchange use, and refer to 3 yuan of stable-7 yuan of single ring architectures, 7 yuan of-10 yuan of bicyclic heterocycle structures that merge or 6 yuan of-10 yuan of bicyclic heterocycle structures of bridging, these ring texturees can be saturated, also can be fractional saturation, except carbon atom, in these ring texturees, also contain one or more heteroatomss defined above, preferred situation is to contain 1-4 heteroatoms defined above.When being used for representing the structural atomic time of heterocycle ring-type, term " nitrogen " comprises the nitrogen that substitution reaction occurred.For example, be selected from the heteroatomic saturated rings or fractional saturation ring of oxygen, sulphur and nitrogen having 0-3, nitrogen can be N (as the situation in 3,4-dihydro-pyrryl), can be also NH (as the situation in pyrrolidyl) or +nR (as the situation in the pyrrolidyl of nitrogen replacement).
Heterocycle can form on any heteroatoms of rock steady structure or carbon atom and be connected with side group at it, and any one annular atoms all can be optionally substituted.Concrete saturated or fractional saturation heterocyclic group comprises tetrahydrofuran base, tetrahydro-thienyl, pyrrolidyl, pyrrolidone-base, piperidyl, pyrrolinyl, tetrahydric quinoline group, tetrahydro isoquinolyl, decahydroquinolyl, oxazolidinyl, piperazinyl, alkyl dioxin, dihydro penta cyclic group, ten azepine bases, oxygen azepine base, sulphur azepine base, morpholinyl and quinuclidinyl, but saturated or part unsaturation heterocyclic group is not limited to these groups.Term " heterocycle ", " heterocyclic radical ", " heterocyclic radical ring-type structure ", " heterocyclic group ", " heterocyclic moiety " and " heterocycle root " can exchange use, also comprise the group that heterocycle ring texture and one or more aryl, heteroaryl or alicyclic ring texture merge mutually in this class group; Such as indyl, 3 hydrogen indyls, chromanyl, phenanthridinyl or tetrahydric quinoline group, binding site or be positioned in conjunction with base in the ring texture of heterocycle wherein.Heterocyclic group can be monocyclic heterocycles base, bicyclic heterocyclic radical, tricyclic heterocyclic base or encircle heterocyclic radical more, preferably monocyclic heterocycles base, bicyclic heterocyclic radical or tricyclic heterocyclic base, more preferably monocyclic heterocycles base and bicyclic heterocyclic radical.Term " Heterocyclylalkyl " refers to the alkyl group that heterocyclic radical substitution reaction occurred, and alkyl wherein and heterocyclic radical all can be optionally substituted.
As used herein, term " part unsaturation " refers in ring texture between toroidal molecule at least containing two keys or triple bond.Term " part unsaturation " is contained with the undersaturated ring texture in many places, but is not intended to comprise aryl defined herein or heteroaryl.
Term " linking group " or " connector " refer to the organic group that two portions of different compounds are coupled together.Connector generally include such as oxygen or the such atom of sulphur, such as-NH-,-CH 2-,-C (O)-, the such unit of-C (O) NH-or such as the such atomchain of alkene chain.The molecular weight of connector is conventionally between 14-200, and preferred situation is between 14-96, and length approximately has 6 atoms.In certain embodiments, connector is C 1-6alkene chain.
Term " thiazolinyl " refers to the alkyl with double covalence key." alkenylene chain " is polymethylene group ,-(CH 2) n-, wherein n is positive integer.In the preferred case, n is between 1-6; Or between 1-4; Or between 1-3; Or between 1-2; Or between 2-3.Alkenylene chain through replacement is that in polymethylene group, the hydrogen atom on one or more methylene radical is substituted the product after thing replaces.Applicable substituent comprises those specified substituents in the following explanation that the aliphatic group through replacing is carried out.One or more positions of alkene chain can also replace by aliphatic group or through the aliphatic group replacing.
In alkene chain, also optionally insert functional group.It is to realize by the methylene radical in functional group's substituted olefine chain that functional group inserts alkene chain.Comprise-C of the example (R of " the inserting functional group " being suitable for *)=C (R^)-,-C ≡ C-,-O-,-S-,-S (O)-,-S (O) 2-,-S (O) 2n(R +)-,-N (R *)-,-N (R +) CO-,-N (R +) C (O) N (R +)-,-N (R +) CO 2,-C (O) N (R +)-,-C (O)-,-C (O)-C (O)-,-CO 2-,-OC (O)-,-OC (O) O-,-OC (O) N (R +)-,-C (NR *)=N-,-C (OR *)=N-,-N (R +)-N (R +)-,-N (R +) S (O) 2-.Each R +hydrogen independently, or optional aliphatic group, aryl, heteroaryl, the heterocyclic radical replacing; Or two R that coexist on a nitrogen-atoms +form aromatic nucleus or the non-aromatic ring of 5 yuan-8 yuan together with this nitrogen-atoms, these aromatic nucleus or non-aromatic ring also are selected from the heteroatoms of nitrogen, oxygen, sulphur except nitrogen-atoms with 0-2.Each R *hydrogen independently, or optional aliphatic group, aromatic yl group, heteroaryl groups or the heterocyclic radical group replacing.Each R^ is hydrogen ,-CO independently 2r *-,-C (O) N (R +) 2, or optional aliphatic group, aromatic yl group, heteroaryl groups or the heterocyclic radical group replacing.
Comprise-the CH of alkene chain example with 3-6 carbon atom that have-O-inserts 2oCH 2-,-CH 2o (CH 2) 2-,-CH 2o (CH 2) 3-,-CH 2o (CH 2) 4-,-(CH 2) 2oCH 2-,-(CH 2) 2o (CH 2) 2-,-(CH 2) 2o (CH 2) 3-,-(CH 2) 3o (CH 2)-,-(CH 2) 3o (CH 2) 2-and-(CH 2) 4o (CH 2)-.Other are inserted with the comprise-CH of alkene chain of functional group 2gCH 2-,-CH 2g (CH 2) 2-,-CH 2g (CH 2) 3-,-CH 2g (CH 2) 4,-(CH 2) GCH 2-,-(CH 2) 2g (CH 2) 2-,-(CH 2) 2g (CH 2) 3-,-(CH 2) 3g (CH 2)-,-(CH 2) 3g (CH 2) 2-and-(CH 2) 4g (CH 2)-, wherein G is one of listed " insertion " above functional group.
As used herein, term " replacement ", refers to that the one or more hydrogen in specified part are substituted, and this metalepsy meeting causes certain stable or at chemically feasible compound.In the temperature range of approximately-80 ℃ to approximately+40 ℃, and do not having moisture or other can occur under the condition of chemical reaction, at least within a week, there is not large change in the chemical structure of this stable, chemically feasible compound, or this compound should keep its integrity within the sufficiently long time, thereby can carry out therapeutic or preventive administration to patient.As used herein, phrase " one or more substituent " refers to the substituent of some amount, wherein the quantity of substituent equals 1 to possible maximum substituent number, the maximum quantity of substituent depends on available binding site quantity, and precondition is that above-mentioned stability and chemical feasibility is met.
Aryl (comprising contained aryl moiety in aralkyl, aralkoxy, aryloxyalkyl group and similar group) or heteroaryl (comprising contained assorted aromatic portion in heteroaralkyl, assorted aralkoxy and similar group) can contain one or more substituents.Be adapted at the comprise-NO of substituent that carries out substitution reaction on the unsaturated carbon atom of aryl or heteroaryl groups 2,-CN ,-R *,-C (R *)=C (R *) (R^) ,-C ≡ C-R^ ,-OR *,-SR 0,-S (O) R 0,-SO 2r 0,-SO 3r *, SO 2n(R +) 2,-N (R +) 2,-NR +c (O) R *,-NR +c (O) N (R +) 2,-NR +cO 2r 0,-O-CO 2r *,-OC (O) N (R +) 2,-O-C (O) R *,-CO 2r *,-C (O)-C (O) R *,-C (O) R *,-C (O) N (R +) 2,-C (O) N (R +) C (=NR +)-N (R +) 2,-N (R +) C (=NR +)-N (R +)-C (O) R *,-C (=NR +)-N (R +) 2,-C (=NR +)-OR *,-N (R +)-N (R +) 2,-N (R +) C (=NR +)-N (R +) 2,-NR +sO 2r 0,-NR +sO 2n(R +) 2, P (O) (R *) 2,-P (O) (OR *) 2,-O-P (O)-OR *,-P (O) (NR +)-N (R +) 2; Or two adjacent substituents and their insertion atom form unsaturated cyclic structure or the part unsaturated cyclic structure of a kind of 5 yuan-6 yuan, ring texture wherein contains 0-3 annular atoms that is selected from nitrogen, oxygen, sulphur.In these substituents, R 0can also be aliphatic group or the aromatic yl group through optional replacement; R +, R *with R^ as defined above.
Aliphatic group or nonaromatic heterocycles can be replaced by one or more substituent.The substituent that substitution reaction specifically can occur on the unsaturated carbon atom of aliphatic group or non-aromatic heterocycle comprises that above-mentioned listed substituent and following replacement that substitution reaction can occur on the unsaturated carbon atom of aryl or heteroaryl groups get :=O ,=S ,=C (R *) 2,=N-NHR *,=N-N (R *) 2,=N-OR *,=N-NHC (O) R *,=N-NHCO 2r 0,=N-NHSO 2r 0,=N-R *r wherein *and R 0as defined above, but concrete applicable substituent is not limited to these groups.
Be adapted at occurring on the nitrogen-atoms of nonaromatic heterocycles the comprise-R of substituent of substitution reaction *,-N (R *) 2,-C (O) R *,-CO 2r *,-C (O)-C (O) R *-C (O) CH 2c (O) R *,-SO 2r *,-SO 2n(R *) 2,-C (=S) N (R *) 2,-C (=NH)-N (R *) 2and-NR *sO 2r *; Each R wherein *as defined above.
Those of skill in the art should understand, some compound in the present invention exists with tautomeric form, and the compound of all these tautomeric forms all within the scope of the present invention.Unless otherwise, otherwise structure as herein described equally also comprises all steric isomers of these structures, comprises R configuration and S configuration with respect to center of asymmetry.Therefore, the mixture of the steric isomer of the compounds of this invention, enantiomer and diastereomer all within the scope of the present invention.For example, in the compound shown in molecular formula (A), the R in this compound f1during for hydrogen, the carbon atom that connects B ring has R configuration and S configuration.R stereoisomerism configuration, S stereoisomerism configuration and their mixture of this compound are all within the scope of the invention.
Unless otherwise, otherwise structure as herein described also comprises just whether, there is the compound that has difference aspect one or more isotopic enrichment atoms.For example, except hydrogen atom is replaced by deuterium or tritium, or carbon atom quilt 13c-or 14outside C-replaces, all the compound consistent with structure of the present invention be all within the scope of the present invention for rest part.
Unless otherwise, otherwise structure as herein described also comprises solvate form thereof and the hydrated form of described compound.Compound shown in molecular formula (A) in pharmacology acceptable salt also within the scope of the invention, the solvate form thereof of these salts and hydrated form are also within the scope of the invention.
Certain embodiments of the invention are relevant with the compound shown in molecular formula (A), wherein R ehydrogen ,-OR 5,-N (R 4) 2,-SR 5,-NR 4c (O) R 5,-NR 4c (O) N (R 4) 2,-NR 4cO 2r 6,-N (R 4) SO 2r 6,-N (R 4) SO 2n(R 4) 2; Or R 3or R 7the C replacing 1-3aliphatic group.In certain embodiments, R ehydrogen, or by a R 3or R 7the C replacing 1-3aliphatic group.In certain embodiments, R ehydrogen.
In certain embodiments, R xand R ybe selected from independently of one another hydrogen, fluorine or by one or two R 3the optional C replacing 1-6aliphatic group.In certain other embodiments, R xand R yand their carbon atoms of connecting form 3 yuan of-6 yuan of alicyclic ring texturees of optional replacement.In certain other embodiments, R xand R f2form key.In certain embodiments, R xand R yeach is hydrogen naturally.In certain embodiments, R x, R yand R eeach is hydrogen naturally.
Certain embodiments of the present invention are relevant with the compound shown in molecular formula (A), wherein R f1hydrogen; R f2hydrogen; Or R f1and R f2form key; G is hydrogen, or the optional aliphatic group replacing, or B ring.
Some other embodiment of the present invention are relevant with the compound shown in molecular formula (A), wherein R f1and R f2form key, G is hydrogen ,-SR 5,-OR 5,-N (R 4) 2, or the optional aliphatic group replacing.In these embodiments, preferred G is hydrogen ,-OR 5,-N (R 4) 2, or the optional aliphatic group replacing.Preferred situation is that G is-H ,-OH ,-NH 2,-O (C 1-3) ,-NH (C 1-3alkyl) ,-N (C 1-3alkyl), C 1-3alkyl, C 1-3alkyl fluoride RF substituted alkyl ,-O-L 1-R 7,-N (C 1-3alkyl)-L 1-R 7,-L 1-R 7; L wherein 1c 1-3thiazolinyl.
Other embodiments of the present invention are relevant to the subgenus material of compound shown in molecular formula (A), and these subgenus materials represent by molecular formula (A-1),
Or its acceptable salt in pharmacology, R wherein e, R xand R ydefined identical with molecular formula (A) above.In molecular formula (A) and molecular formula (A-1), value and the preferred value of A ring, B ring, C ring will be described below.
A ring is that replace or unsubstituted 5 yuan of-6 yuan of aryl, heteroaryl, alicyclic group or heterocycle structures.The example of concrete A ring comprises furan nucleus, dihydrofuran ring, thiphene ring, dihydro-thiophene ring, ring penta ring, hexamethylene ring, pyrrolin ring, pyrrole ring, pyrroline ring, pyrrolidine ring, oxazole ring, thiazole ring, imidazole ring, tetrahydroglyoxaline ring, imidazolidine ring, pyrazole ring, pyrazoline ring, pyrazolidine ring, isoxazole ring, isothiazole ring, oxadiazole rings, triazole ring, Thiadiazole, dihydropyrane ring, amylene oxide ring, phenyl ring, pyridine ring, piperidine ring, diox ring, morpholine ring, dithiane ring, sulphur cuts down morpholine ring, pyridazine ring, pyrimidine ring, pyrazine ring, piperazine ring and triazine ring, these groups can be through replacing, also can be not through replacing.In the preferred case, preferred A ring comprises replacement and unsubstituted ring texture; These ring texturees are selected from furan nucleus, thiphene ring, pyrrole ring, oxazole ring, thiazole ring, imidazole ring, pyrazole ring, isoxazole ring, isothiazole ring, triazole ring, phenyl ring, pyridine ring, pyridazine ring, pyrimidine ring and pyrazine ring, but A ring is not limited to these groups.
A ring can, through replacing, can be also not through replacing.In certain embodiments, on A ring, commutable saturated carbon atom is not to be substituted, or quilt=O ,=S ,=C (R 5) 2,=N-N (R 4) 2,=N-OR 5,=N-NHC (O) R 5,=N-NHCO 2r 6,=N-NHSO 2r 6,=N-R 5,=N-R breplace, wherein R b, R 4, R 5and R 6define below.On A ring, each commutable unsaturation carbon atom can be unsubstituted, or quilt-R binstitute replaces.Each on A ring can substituted nitrogen atom be unsubstituted, or quilt-R 9binstitute replaces, and a nitrogen-atoms on A ring is optionally oxidized.Each R 9b-C (O) R independently 5,-C (O) N (R 4) 2,-CO 2r 6,-SO 2r 6,-SO 2n(R 4) 2, or by R 3or R 7the optional C replacing 1-4aliphatic group.
Each R br independently 2b, or the optional aliphatic group replacing, or optional aryl, heterocyclic group, the heteroaryl group replacing; Or two adjacent R bform 4 yuan of-8 yuan of aromatic rings or the non-aromatic ring of the fusion of optional replacement with the annular atoms inserting, and this ring contains 0-3 heteroatoms that is selected from oxygen, nitrogen, sulphur.
Each R 2bhalogen radical ,-NO independently 2,-CN ,-C (R 5)=C (R 5) 2,-C (R 5)=C (R 5) (R 10) ,-C ≡ C-R 5,-C ≡ C-R 10,-OR 5,-SR 6,-S (O) R 6,-SO 2r 6,-SO 2n(R 4) 2,-N (R 4) 2,-NR 4c (O) R 5,-NR 4c (O) N (R 4) 2,-NR 4cO 2r 6,-O-CO 2r 5,-OC (O) N (R 4) 2,-O-C (O) R 5,-CO 2r 5,-C (O)-C (O) R 5,-C (O) R 5,-C (O) N (R 4) 2,-C (=NR 4)-N (R 4) 2,-C (=NR 4)-OR 5,-N (R 4)-N (R 4) 2,-N (R 4) C (=NR 4)-N (R 4) 2,-N (R 4) SO 2r 6,-N (R 4) SO 2n(R 4) 2,-P (O) (R 5) 2,-P (O) (OR 5) 2.
Each R 3independently selected from halogen radical ,-OH ,-O (C 1-3alkyl) ,-CN ,-N (R 4) 2,-C (O) (C 1-3alkyl) ,-CO 2h ,-CO 2(C 1-3alkyl) ,-C (O) NH 2and-C (O) NH (C 1-3alkyl).
Each R 4hydrogen independently, or optional aliphatic group, aryl, heteroaryl, the heterocyclic group replacing; Or two R on same nitrogen-atoms 4form 5 yuan of-6 yuan of heteroaryl groups of optional replacement or the heterocyclic group of 4 yuan-8 yuan with this nitrogen-atoms, wherein these heteroaryl groups and heterocyclic group also contain 0-2 heteroatoms that is selected from nitrogen, oxygen, sulphur except this nitrogen-atoms.
Each R 5hydrogen independently, or optional aliphatic group, aromatic yl group, heteroaryl groups, the heterocyclic group replacing.
Each R 6optional aliphatic group or the aromatic yl group replacing independently.
Each R 7optional aromatic yl group, heterocyclic group or the heteroaryl groups replacing independently.
Each R 10be independently-CO 2r 5or-C (O) N (R 4) 2.
In certain embodiments, each R bindependently selected from C 1-6aliphatic group, C 1-6fluorinated aliphatic group ,-R 2b,-R 7b,-T 1-R 2b,-T 1-R 7b; Or two adjacent R bform 4 yuan of-8 yuan of aromatic series or the non-aromatic ring of optional replacement with the annular atoms inserting, this aromatic ring or non-aromatic ring have 0-3 heteroatoms that is selected from oxygen, nitrogen, sulphur.R 2bas defined above, T 1and R 7bbe described below.
T 1r 3or R 3bthe optional C replacing 1-6alkene chain, wherein T 1or T 1the optional part that forms 3 yuan of-7 rings of certain part.
Each R 3independently selected from halogen radical ,-OH ,-O (C 1-3alkyl) ,-CN ,-N (R 4) 2,-C (O) (C 1-3alkyl) ,-CO 2h ,-CO 2(C 1-3alkyl) ,-C (O) NH 2and-C (O) NH (C 1-3alkyl).
Each R 3bindependently by R 3or R 7the optional C replacing 1-3aliphatic group; Or two substituent R on same carbon atom 3bwith the common carbocyclic ring of 3 yuan-6 yuan forming of this carbon atom.
Each R 7boptional aromatic yl group, heteroaryl groups or the heterocyclic group replacing independently.
In certain embodiments, A ring is individual by 0-3,0-2 is individual or 0-1 substituent R breplace, wherein substituent R bcan be identical, can be also different.In certain embodiments, each R bindependently selected from C 1-3aliphatic group, R 2b, R 7b,-T 1-R 2b,-T 1-R 7b; T wherein 1the optional C replacing of fluorine 1-3alkene chain.In certain embodiments, two adjacent R bwith common 4 yuan of-8 yuan of aromatic series or the non-aromatic ring that forms the optional fusion replacing of the ring carbon atom inserting, and aromatic series or non-aromatic ring contain 0-3 heteroatoms that is selected from oxygen, nitrogen, sulphur.In certain embodiments, each R bindependently selected from C 1-3aliphatic group, R 2b,-T 1-R 2b; T wherein 1c 1-3alkene chain, this alkene chain is optionally replaced by fluorine.In such embodiments, each R 2bindependently selected from halogen radical ,-NO 2,-C (R 5)=C (R 5) 2,-C ≡ C-R 5,-OR 5and-N (R 4) 2.
In certain embodiments, A ring is by 0-2 substituent R binstitute replaces.In certain embodiments, each R bc independently 1-3aliphatic group or R 2b, each R 2bindependently selected from halogen radical ,-NO 2,-C (R 5)=C (R 5) 2,-C ≡ C-R 5-OR 5and-N (R 4) 2.In certain embodiments, each R bindependently selected from halogen radical, C 1-3aliphatic group, C 1-3fluoride fat family group and-OR 5, R wherein 5hydrogen or C 1-3aliphatic group.In some preferred embodiment, A ring is replaced by 0,1 or 2 substituting group, and preferred situation is replaced by 0 or 1 substituting group, and substituting group is independently selected from chlorine, fluorine, bromine, methyl, trifluoromethyl and methoxyl group.
Table 1 has shown the example of some A ring.For the ease of observing, the substituent R in ring on carbon atom bwith the R on nitrogen-atoms in ring 9bdo not draw.
The example of table 1A ring
In certain embodiments, two adjacent R one of in above-mentioned A ring band atom therebetween forms 4 yuan of-8 yuan of aromatic series of fusion or the non-aromatic ring of optional replacement, A ring just becomes twin nuclei like this.Table 2 has shown some example of these twin nucleis.These twin nucleis can optionally replace on its commutable ring carbon atom or theheterocyclic nitrogen atom.
The example of table 2 twin nuclei ring
In certain embodiments, the present invention relates to the compound shown in molecular formula (B):
Or relate to these compounds acceptable salt in pharmacology, wherein A ring is through 0-3 R bproduct after replacement.B ring, C ring and variable R e, R xand R ydefined identical with molecular formula A.
In some such embodiment, A ring has molecular formula A-i:
Each R wherein b2and R b3hydrogen or R independently b.In certain embodiments, each R b2and R b3independently selected from hydrogen, halogen radical, C 1-3aliphatic group, C 1-3fluoride fat family group and-OR 5, R wherein 5hydrogen or C 1-3aliphatic group.In certain embodiments, each R b2and R b3independently selected from hydrogen, chlorine, fluorine, bromine, methyl, trifluoromethyl and methoxyl group.In other embodiments, R b2and R b3form fusion 4 yuan of-8 yuan of aromatic nucleus or non-aromatic rings of optional replacement with carbon atom therebetween, this aromatic nucleus or non-aromatic ring contain 0-3 heteroatoms that is selected from oxygen, nitrogen, sulphur.
In the compound shown in molecular formula (A), (A-1), (B) above, B ring can be monocycle, dicyclo or tricyclic structure.In certain embodiments, in B ring and molecule, the binding sites of other parts encircles in B aromatic ring structure or hetero-aromatic ring structure.In other embodiments, binding sites is on heterocyclic group or ring grease group.In the preferred case, B ring is monocycle or twin nuclei.
On B ring, each commutable saturated carbon atom is not to be substituted, or quilt=O ,=S ,=C (R 5) 2,=N-N (R 4) 2,=N-OR 5,=N-NHC (O) R 5,=N-NHCO 2r 6,=N-NHSO 2r 6,=N-R 5, R creplace.Each substitutable carbon atom on B ring is not substituted, or quilt-R cinstitute replaces.Each on B ring can not be substituted by substituted nitrogen atom, or quilt-R 9cinstitute replaces, and a nitrogen-atoms on B ring optionally can be oxidized.Each R 9c-C (O) R independently 5,-C (O) N (R 4) 2,-CO 2r 6,-SO 2r 6,-SO 2n(R 4) 2, or through R 5or R 7the optional C replacing 1-4aliphatic group.Can not there is not substitution reaction in B ring; Also can on its one or more rings, replace, wherein substituting group can be identical, can be also different.In certain embodiments, in B ring, can occur by 0-2 independently selected from R cwith 0-3 independently selected from R 2cor C 1-6the replacement that the substituting group of aliphatic group carries out.Variable radicals R 3, R 4, R 5, R 6and R 7with A is defined identical in encircling above, R c, R 2cto define below.
Each R cr independently 2c, or the optional C1-6 aliphatic group replacing, or optional aryl, heteroaryl group, the heterocyclic group replacing.
Each R 2chalogen radical ,-NO independently 2,-CN ,-C (R 5)=C (R 5) 2,-C (R 5)=C (R 5) (R 10) ,-C ≡ C-R 5,-C ≡ C-R 10,-OR 5,-SR 6,-S (O) R 6,-SO 2r 6,-SO 2n(R 4) 2,-N (R 4) 2,-NR 4c (O) R 5,-NR 4c (O) N (R 4) 2,-NR 4cO 2r 6,-O-CO 2r 5,-OC (O) N (R 4) 2,-O-C (O) R 5,-CO 2r 5,-C (O)-C (O) R 5,-C (O) R 5,-C (O) N (R 4) 2,-C (=NR 4)-N (R 4) 2,-C (=NR 4)-OR 5,-N (R 4)-N (R 4) 2,-N (R 4) C (=NR 4)-N (R 4) 2,-N (R 4) SO 2r 6,-N (R 4) SO 2n(R 4) 2,-P (O) (R 5) 2or-P (O) (OR 5) 2.
In certain embodiments, each R cindependently selected from C 1-6aliphatic group ,-R 2c,-R 7c,-T 1-R 2c,-T 1-R 7c, R 2cwith previously defined identical, T 1and R 7cdefine below.
T 1r 3or R 3bthe optional alkene chain replacing, wherein T 1or T 1certain part form parts of 3 yuan of-7 rings.
Each R 3independently selected from halogen radical ,-OH ,-O (C 1-3alkyl) ,-CN ,-N (R 4) 2,-C (O) (C 1-3alkyl) ,-CO 2h ,-CO 2(C 1-3alkyl) ,-C (O) NH 2and-C (O) NH (C 1-3alkyl).
Each R 3br independently 3or R 7the aliphatic group with 1-3 carbon atom replacing; Or two substituent R on same carbon atom 3bwith the common carbocyclic ring that forms 3 yuan-6 yuan of this carbon atom.
Each R 7coptional aromatic yl group, heterocyclic group or the heteroaryl groups replacing independently.
In certain embodiments, each R cindependently selected from C 1-3aliphatic group, R 2c, R 7c,-T 1-R 2c,-T 1-R 7c, T wherein 1the optional C replacing of fluorine 1-3alkene chain.In certain embodiments, each R cindependently selected from C 1-3aliphatic group, R 2c,-T 1-R 2c; T wherein 1the optional C replacing of fluorine 1-3alkene chain.In some such embodiment, each R 2cindependently selected from halogen radical ,-NO 2,-C (R 5)=C (R 5) 2,-C ≡ C-R 5,-OR 5and-N (R 4) 2.
In certain embodiments, B ring is that replace or unsubstituted monocyclic aryl, bicyclic aryl, bicyclic heteroaryl, bicyclic heteroaryl, these aryl or heteroaryl are selected from furyl, thienyl, pyrryl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl group, phenyl, pyridyl, pyridazinyl, pyrimidyl, pyrazinyl, triazinyl, indolizine base, indyl, pseudoindoyl, indazolyl, benzo [b] furyl, benzo [b] thienyl, benzimidazolyl-, benzothiazolyl, benzoxazolyl, purine radicals, quinolyl, isoquinolyl, cinnolines base, 2, 3-phthalazinyl, quinazolyl, quinoxalinyl, 1, 5-phthalazinyl, pteridyl.
In certain embodiments, B ring is 5 yuan of-6 yuan of aryl or heteroaryls of monocycle, can be by 0-2 independently selected from R in these aryl or heteroaryl cwith 0-2 independently selected from R 2cor C 1-6the substituting group of aliphatic group replaces.In some such embodiment, B ring be replace or unsubstituted phenyl ring or pyridine ring.
In certain embodiments, B ring is by 0-2 substituent R cinstitute replaces.In certain embodiments, each R cc independently 1-3aliphatic group or R 2c, each R 2cindependently selected from halogen radical ,-NO 2,-C (R 5)=C (R 5) 2,-C ≡ C-R 5,-OR 5and-N (R 4) 2.In certain embodiments, each R cindependently selected from halogen radical, C 1-3aliphatic group, C 1-3fluoride fat family group and-OR 5, R wherein 5hydrogen or C 1-3aliphatic group.In some preferred embodiment, B ring is replaced by 0,1 or 2 substituting group, and substituting group is independently selected from chlorine, fluorine, bromine, methyl, trifluoromethyl and methoxyl group.
In certain embodiments, the molecular formula of B ring is B-i:
Each R wherein c1and R c5be hydrogen or R independently c.In certain embodiments, each R c1and R c5independently selected from hydrogen, halogen radical, C 1-3aliphatic group, C 1-3fluoride fat family group and-OR 5, R wherein 5hydrogen or C 1-3aliphatic group.In certain embodiments, each R c1and R c5independently selected from hydrogen, chlorine, fluorine, bromine, methyl, trifluoromethyl and methoxyl group.
In the compound shown in molecular formula (A), (A-1), (B) above, C ring is monocycle, dicyclo or the tricyclic structure that replacement occurred or replacement did not occur.In certain embodiments, in C ring and molecule, the binding sites of other parts encircles in C aromatic ring structure or hetero-aromatic ring structure.In other embodiments, binding sites is on heterocyclic group or alicyclic group.In the preferred case, C ring is monocycle or twin nuclei.
On C ring, each commutable saturated carbon atom is not to be substituted, or quilt=O ,=S ,=C (R 5) 2,=N-N (R 4) 2,=N-OR 5,=N-NHC (O) R 5,=N-NHCO 2r 6,=N-NHSO 2r 6,=N-R 5, R dreplace.Each commutable saturated carbon atom or be not substituted on C ring, or by R dinstitute replaces.Can not be substituted by substituted nitrogen atom on C ring, or quilt-R 9dinstitute replaces, and a nitrogen-atoms on C ring is optionally oxidized.Each R 9d-C (O) R independently 5,-C (O) N (R 4) 2,-CO 2r 6,-SO 2r 6,-SO 2n(R 4) 2, or through R 3or R 7the aliphatic group with 1-4 carbon atom replacing.Can not there is not substitution reaction in C ring, also can on its one or more rings, replace, and wherein substituting group can be identical, can be also different.In certain embodiments, C ring by 0-2 independently selected from R dwith 0-3 independently selected from R 2dor C 1-6the substituting group of aliphatic group replaces.Variable radicals R 3, R 4, R 5, R 6and R 7with A ring and B are defined identical in encircling above, R d, R 2dto define below.
Each R dr independently 2d, or the aliphatic group replacing, or the aryl, heteroaryl group, the heterocyclic group that replace.
Each R 2dhalogen radical ,-NO independently 2,-CN ,-C (R 5)=C (R 5) 2,-C (R 5)=C (R 5) (R 10) ,-C ≡ C-R 5,-C ≡ C-R 10,-OR 5,-SR 6,-S (O) R 6,-SO 2r 6,-SO 2n(R 4) 2,-N (R 4) 2,-NR 4c (O) R 5,-NR 4c (O) N (R 4) 2,-NR 4cO 2r 6,-O-CO 2r 5,-OC (O) N (R 4) 2,-O-C (O) R 5,-CO 2r 5,-C (O)-C (O) R 5,-C (O) R 5,-C (O) N (R 4) 2,-C (=NR 4)-N (R 4) 2,-C (=NR 4)-OR 5,-N (R 4)-N (R 4) 2,-N (R 4) C (=NR 4)-N (R 4) 2,-N (R 4) SO 2r 6,-N (R 4) SO 2n(R 4) 2,-P (O) (R 5) 2or-P (O) (OR 5) 2.In addition R, 2dcan be-SO 3r 5,-C (O) N (R 4) C (=NR 4)-N (R 4) 2or-N (R 4) C (=NR 4)-N (R 4)-C (O) R 5.
In certain embodiments, each R dindependently selected from C 1-6aliphatic group ,-R 2d,-R 7d,-T 2-R 2d,-T 2-R 7d,-V-T 3-R 2dand-V-T 3-R 7d, R wherein 2dwith previously defined identical, T 2, T 3, V and R 7ddefine below.
T 2r 3or R 3bthe optional C replacing 1-6alkene chain, wherein, optionally can insert in alkene chain-C (R 5)=C (R 5)-,-C ≡ C-,-O-,-S-,-S (O)-,-S (O) 2-,-SO 2n(R 4)-,-N (R 4)-,-NR 4c (O)-,-NR 4c (O) N (R 4)-,-N (R 4) CO 2-,-C (O) N (R 4)-,-C (O)-,-C (O)-C (O)-,-CO 2-,-OC (O)-,-OC (O) O-,-OC (O) N (R 4)-,-N (R 4)-N (R 4)-,-N (R 4) SO 2-or-SO 2n(R 4)-, be T wherein 2or T 2a part form the parts of 3 yuan of-7 rings.
T 3r 3or R 3bthe optional C replacing 1-6alkene chain, wherein, optionally can insert in alkene chain-C (R 5)=C (R 5)-,-C ≡ C-,-O-,-S-,-S (O)-,-S (O) 2-,-SO 2n(R 4)-,-N (R 4)-,-NR 4c (O)-,-NR 4c (O) N (R 4)-,-N (R 4) CO 2-,-C (O) N (R 4)-,-C (O)-,-C (O)-C (O)-,-CO 2-,-OC (O)-,-OC (O) O-,-OC (O) N (R 4)-,-N (R 4)-N (R 4)-,-N (R 4) SO 2-or-SO 2n(R 4)-, be T wherein 3or T 3a part form the parts of 3 yuan of-7 rings.
V is-C (R 5)=C (R 5)-,-C ≡ C-,-O-,-S-,-S (O)-,-S (O) 2-,-SO 2n(R 4)-,-N (R 4)-,-NR 4c (O)-,-NR 4c (O) N (R 4)-,-N (R 4) CO 2-,-C (O) N (R 4)-,-C (O)-,-C (O)-C (O)-,-CO 2-,-OC (O)-,-OC (O) O-,-OC (O) N (R 4)-,-C (NR 4)=N-,-C (OR 5)=N-,-N (R 4)-N (R 4)-,-N (R 4) SO 2-,-N (R 4) SO 2n(R 4)-,-P (O) (R 5)-,-P (O) (OR 5)-O-,-P (O)-O-or-P (O) (NR 5)-N (R 5)-.
Each R 3br independently 3or R 7the optional C replacing 1-3aliphatic group; Or two substituent R on same carbon atom 3bwith the common carbocyclic ring that forms 3 yuan-6 yuan of this carbon atom.
Each R 7doptional aromatic yl group, heterocyclic group or the heteroaryl groups replacing independently.
In certain embodiments, each R 2dindependently selected from by halogen radical ,-OR 5,-N (R 4) 2,-N (R 4) C (O)-,-CO 2r 5,-C (O) N (R 4) 2and-SO 2n(R 4) 2in the group forming.In certain other embodiments, each R 2dhalogen radical ,-OR independently 5,-N (R 4) 2,-N (R 4) C (O)-,-CO 2r 5,-C (O) N (R 4) 2,-SO 2n(R 4) 2, C (O) N (R 4) C (=NR 4)-N (R 4) 2or-N (R 4) C (=NR 4)-N (R 4)-C (O) R 5.
In certain embodiments, T 2c 1-6alkene chain, in this alkene chain optionally by one or two substituent R 3breplace R 3bindependently selected from halogen radical, C 1-3aliphatic group ,-OH ,-O (C 1-3aliphatic group), two substituent R or on same carbon atom 3bwith the common carbocyclic ring that forms 3 yuan-6 yuan of this carbon atom.In certain embodiments, T 2in optionally can insert-C (R 5)=C (R 5)-,-C ≡ C-,-O-,-C (O)-,-C (O) N (R 4)-,-N (R 4) C (O)-or-N (R 4)-.
In certain embodiments, V is-C (R 5)=C (R 5)-,-C ≡ C-,-O-,-N (R 4)-,-C (O)-,-N (R 4) CO 2-or-C (O) N (R 4)-.In certain embodiments, T 3c 1-4alkene chain, in this alkene chain optionally by one or two substituent R 3breplacement, R 3bindependently selected from halogen radical, C 1-3aliphatic group ,-OH ,-O (C 1-3aliphatic group), two substituent R or on same carbon atom 3bwith the common carbocyclic ring that forms a kind of 3 yuan-6 yuan of this carbon atom.In certain embodiments, T 3c 1-4alkene chain, and insertion-C (R optionally 5)=C (R 5)-,-C ≡ C-,-O-,-C (O)-,-C (O) N (R 4)-,-N (R 4) C (O)-or-N (R 4)-.
In certain embodiments, each R dindependently selected from C 1-3aliphatic group, R 2d, R 7d,-T 2-R 2d,-T 2-R 7d,-V-T 3-R 2dand-V-T 3-R 7d, R wherein 2dbe selected from halogen radical ,-OR 5,-N (R 4) 2,-N (R 4) C (O)-,-CO 2r 5,-C (O) N (R 4) 2and-SO 2n(R 4) 2.In addition R, 2dcan be-SO 3r 5, C (O) N (R 4) C (=NR 4)-N (R 4) 2or-N (R 4) C (=NR 4)-N (R 4)-C (O) R 5.
In certain embodiments, C ring is at least by a R 7dreplace R 7dbe selected from:
with
And, any substitutable carbon atom in these groups or can on substituted nitrogen atom, optional replacement can occur.
In certain embodiments, C ring is at least by one-T 2-R 2dor-T 2-R 7dreplace, wherein:
T 2c 1-6alkene chain, wherein, T 2optionally by one or two substituent R 3breplace R 3bindependently selected from halogen radical, C 1-3aliphatic group ,-OH ,-O (C 1-3aliphatic group), two substituent R or on same carbon atom 3bwith the common carbocyclic ring that forms 3 yuan-6 yuan of this carbon atom, wherein, T 2in optionally can insert-C (R 5)=C (R 5)-,-C ≡ C-,-O-,-C (O)-,-N (R 4) C (O) R 5,-N (R 4) C (O)-or-N (R 4)-.
R 2dindependently selected from halogen radical ,-OR 5,-N (R 4) 2,-N (R 4) C (O)-,-CO 2r 5,-C (O) N (R 4) 2,-SO 2n(R 4) 2,-C (O) N (R 4) C (=NR 4)-N (R 4) 2and-N (R 4) C (=NR 4)-N (R 4)-C (O) R 5.
In some such embodiment, C encircles by one-T 2-R 2dor-T 2-R 7dreplace, and, the replacement that can also optionally have another substituting group to occur in C ring, another substituting group is selected from hydrogen, halogen radical, C 1-3aliphatic group and-OR 5, R wherein 5hydrogen or with the aliphatic group of 1-3 carbon atom.In certain embodiments, T 2c 1-3alkene chain, and can insert-C (O) N (R optionally 4)-or-N (R 4) C (O)-.
In certain embodiments, C ring by least one-V-T 3-R 2dor-V-T 3-R 7dreplace, wherein:
V is-N (R 4)-,-O-,-C (O) N (R 4)-,-C (O)-or-C ≡ C-.
T 3c 1-4, in this alkene chain, can there is one or two substituent R in alkene chain 3boptional replacement, R 3bindependently selected from halogen radical, C 1-3aliphatic group ,-OH ,-O (C 1-3aliphatic group), two substituent R or on same carbon atom 3bwith the common carbocyclic ring that forms 3 yuan-6 yuan of this carbon atom.
R 2dindependently selected from halogen radical ,-OR 5,-N (R 4) 2,-N (R 4) C (O)-,-CO 2r 5,-C (O) N (R 4) 2,-SO 2n(R 4) 2.
In some such embodiment, C encircles by one-V-T 3-R 2dor-V-T 3-R 7dreplace, and, the replacement that can also have another substituting group to occur in C ring; Another substituting group is selected from hydrogen, halogen radical, C 1-3aliphatic group and-OR 5, R wherein 5hydrogen or C 1-3aliphatic group.
In certain embodiments, in C ring, there is a kind of-V-T 3-R 2dthe replacement occurring, wherein V is-C (O) N (R 4)-, T 3the alkene chain with 2-4 carbon atom, each R 2dbe-N (R 4) 2.Each R 4hydrogen or C independently 1-3aliphatic group, or-N (R 4) 2be 5 yuan of-6 yuan of heteroaryls or 4 yuan of-8 yuan of heterocyclic radicals through replacing, these 5 yuan-6 yuan of heteroaryls or 4 yuan of-8 yuan of heterocyclic radicals, except containing nitrogen-atoms, also contain the heteroatoms that 0-2 is selected from nitrogen, oxygen and sulphur.In some such embodiment ,-N (R 4) 2be the optional heterocyclic radical replacing, be selected from piperidyl, piperazinyl, morpholinyl.In other such embodiments ,-N (R 4) 2be the optional heterocyclic radical replacing, be selected from pyrrolidyl and azetidinyl.
In certain other embodiments, C ring quilt-V-T 3-R 7dreplace, wherein V be-C (O) N (R4)-, T 3c 2-4alkene chain, R 7doptional 4 yuan of-8 yuan of heterocyclic radicals or 5 yuan of-6 yuan of heteroaryls that replace.In some such embodiment, R 7dbe selected from pyridyl, pyridazinyl, pyrimidyl, pyrazinyl, pyrryl, oxazolyl, imidazolyl and pyrazolyl.At some in other these class embodiments, R 7dit is the bicyclic heterocyclic radical of 6 yuan-8 yuan.
In certain embodiments, C ring is replaced by one or two substituting group, and substituting group is wherein independently selected from C 1-3aliphatic group, halogen radical ,-OR 5,-CO 2r 5,-C (O) N (R 4) 2and-SO 2n(R 4) 2.Can be used as in these embodiments comprise-C of other possible groups (=NR of C ring substituents 4) N (R 4) 2-,-N (R 4) C (O) R 5,-C (O) N (R 4) C (=NR 4)-N (R 4) 2and-N (R 4) C (=NR 4)-N (R 4)-C (O) R 5.In certain embodiments, in C ring, at least there is a substituent replacement, be wherein selected from-CO of substituting group 2r 5,-C (O) N (R 4) 2,-C (=NR 4)-N (R 4) 2,-C (O) N (R 4) C (=NR 4)-N (R 4) 2,-N (R 4) C (=NR 4)-N (R 4)-C (O) R 5and-NR 4c (O) R 5.In certain embodiments, in C ring, has one-CO at least 2r 5replacement, R wherein 5hydrogen or C 1-6aliphatic group.
In certain embodiments, C ring by least one-C (O)-N (R 4) 2,-C (=NR 4) N (R 4) 2or-NR 4c (O) R 5replace, wherein ,-N (R 4) 2be 4 yuan of-8 yuan of heterocyclic radicals through optional replacement, this heterocyclic group, except containing nitrogen-atoms, also contains 0-2 heteroatoms that is selected from nitrogen, oxygen and sulphur, and R 5optional nitrogenous 4 yuan of-8 yuan of heterocyclic groups that replace.In some such embodiment ,-N (R 4) 2be the optional heterocyclic group replacing, this heterocyclic group is selected from piperidyl, piperazinyl, morpholinyl, pyrrolidyl and azetidinyl.At some in other such embodiments ,-N (R 4) 2bicyclic heterocyclic group or the spiral bicyclic heterocyclic group of bridging.
In certain embodiments, the replacement through at least being undertaken by a kind of substituent of molecular formula D-i representative in C ring, molecular formula D-i is as follows:
Wherein:
On its one or two ring carbon atom, there is optional replacement in D ring;
X is O or NH;
W 1hydrogen ,-C (O) R 5,-C (O) N (R 4) 2,-CO 2r 6,-SO 2n(R 4) 2, or optional aliphatic group, aromatic yl group, heteroaryl groups or the heterocyclic radical group replacing.
In certain embodiments, the D ring in molecular formula D-i can be through the replacement being occurred by one or two substituting group, and these substituting groups are selected from C 1-3aliphatic group ,-CO 2r 5,-CON (R 4) 2and-T 5-R m; T wherein 5c 1-3alkene chain, R mbe-OR 5,-N (R 4) 2,-CO 2r 5or-C (O) N (R 4) 2.In some such embodiment, the replacement of the D ring in molecular formula D-i through being undertaken by one or two substituting group, these substituting groups are selected from C 1-3aliphatic group ,-CO 2h ,-CO 2(C 1-3alkyl) ,-C (O) N (C 1-3alkyl) ,-C (O) NH (C 1-3alkyl) ,-C (O) NH 2,-(C 1-3alkyl)-OH ,-(C 1-3alkylene)-O (C 1-3alkyl) ,-(C 1-3alkylene)-NH 2,-(C 1-3alkylene)-NH (C 1-3alkyl) ,-(C 1-3alkylene)-N (C 1-3alkyl) 2,-(C 1-3alkylene)-CO 2h ,-(C 1-3alkylene)-CO 2(C 1-3alkyl) ,-(C 1-3alkylene)-C (O) NH 2,-(C 1-3alkylene)-C (O) NH (C 1-3alkyl) and ((C 1-3alkylene)-C (O) N (C 1-3alkyl) 2.
In certain other embodiments, the replacement through being undertaken by least one substituting group in C ring, these substituting groups are D-ii to D-v below:
Wherein:
On its one or two carbon atom, there is optional replacement in D ring;
X is O or NH;
W 2r nor-T 6-R n;
T 6c 1-3alkene chain, this alkene chain is by R 3or R 3boptional replacement;
R nbe-N (R 4) 2or-C (O) N (R 4) 2; And
R zhydrogen ,-CO 2r 5,-C (O) N (R 4) 2,-C (O) R 5; Or through R 3or R 7the C optionally replacing 1-3aliphatic group; Or R z, W 2and the carbon atom that they connect forms a kind of 4 yuan of-7 yuan of alicyclic groups or heterocyclic groups together.
In certain embodiments, the D ring in molecular formula D-ii to D-v can be replaced by one or two substituting group, and these substituting groups are selected from C 1-3aliphatic group ,-CO 2r 5,-C (O) N (R 4) 2,-OR 5,-N (R 4) 2and-T 5-R m; T wherein 5c 1-3alkene chain, R mbe-OR 5,-N (R 4) 2,-CO 2r 5or-C (O) N (R 4) 2.
In certain embodiments, at least one substituting group on C ring is selected from following group:
with
Wherein X is O or NH.
In certain other embodiments, on C ring, at least one substituting group is selected from following group:
with
Wherein X is O or NH, each R 4zbe independently hydrogen or-CH 3.
In certain other embodiments, at least one substituting group on C ring is selected from following group:
with
Wherein X is O or NH, each R 4zbe independently hydrogen or-CH 3.
In certain embodiments, C ring by least one-C (O) N (R 4) 2or-C (=NH) N (R 4) 2institute replaces, one of them R 4hydrogen or C 1-3aromatic yl group, another R 4optional heterocyclic group or the heterocyclic radical alkyl group replacing.In some such embodiment, the substituent that C ring is selected from following group by least one replaces:
and
Wherein X is O or NH.
Other such embodiments at some, a kind of substituent that C ring is at least selected from following group replaces:
with
Wherein X is O or NH, each R 4zbe independently hydrogen or-CH 3.
In certain embodiments, C ring is the aromatic yl group of twin nuclei, in this C ring through by 0-2 independently selected from R dand 0-3 is independently selected from R 2dor C 1-6the replacement that the substituting group of aliphatic group carries out.At some in these embodiment, C ring is and 5 yuan or 6 yuan of phenyl ring that carbocyclic ring, hetero-aromatic ring or heterocycle merge mutually, wherein each ring be independently through replacement or not through replacing.In some this class embodiment, C ring is benzodioxan basic ring or the benzo dioxolyl ring being optionally substituted.At some in other such embodiments, C ring is benzoglyoxaline basic ring, benzothiazole basic ring, benzoxazole basic ring or the phthalimidine basic ring being optionally substituted, and wherein C ring is the phenyl ring encircling by twin nuclei C and being connected with molecular formula (A), (A-1) or other parts (B).
In certain other embodiments, C ring is 5 yuan of single ring architecture or 6 yuan of aryl or heteroaryl, and by 0-2 independently selected from R dsubstituting group and 0-2 independently selected from R 2dreplace with the substituting group of C1-6 aliphatic group.In some such embodiment, C ring is the optional hetero-aromatic ring replacing, and is selected from pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl Yi Ji oxazolyl.In certain other embodiments, C ring is the phenyl ring through replacing or does not pass through the phenyl ring replacing.In certain embodiments, C ring is 5 yuan of single ring architecture or 6 yuan of aromatic rings or hetero-aromatic ring, and by 0,1 or 2 defined R above dreplace.
In other embodiments, C ring is 5 yuan of single ring architecture or 6 yuan of heterocycles or alicyclic ring, and doubly 0-2 independently selected from R 4substituting group and 0-2 independently selected from R 2dor its C 1-6the substituting group of aliphatic group replaces.
Certain embodiments of the present invention are relevant to the subgenus material of molecular formula (A) representative material, and these subgenus materials are defined by molecular formula (I):
Or relevant to these subgenus materials acceptable salt in pharmacology; Wherein A ring, B ring, C encircle and every kind of variable radicals R a, R b, R e, R f1and R f2be defined as follows;
A ring is by 0-3 R breplace.
B ring is aryl or the heteroaryl through replacing or process does not replace.
C ring is aryl or the heteroaryl through replacing or process does not replace.In addition, C ring can be heterocycle or alicyclic group.
R ahydrogen ,-C (O) R 1,-CO 2r 1,-SO 2r 1or C1-3 aliphatic group, wherein this aliphatic group contains 0-2 independently selected from R 3or R 7substituting group.
R 1the C through optional replacement 1-6aliphatic group, or through optional aromatic yl group, heteroaryl groups or the heterocyclic group replacing.
Each R br independently 2b, through the optional aliphatic group replacing, through optional aromatic yl group, heteroaryl groups or the heterocyclic group replacing.In certain embodiments, each R bindependently selected from C 1-6aliphatic group, R 2b, R 7b,-T 1-R 2b,-T 1r 7b.In certain embodiments, two adjacent R band the carbon atom inserting therebetween forms fusion aromatic nucleus or the non-aromatic ring of 4 yuan-8 yuan of optional replacement, and contain 0-3 heteroatoms that is selected from oxygen, nitrogen and sulphur.
T 1c 1-6alkene chain, and by R 3or R 3boptional replacement, wherein T 1or T 1a part optionally form the parts of 3 yuan of-7 rings.
Each R 2bindependently selected from halogen radical ,-NO 2,-CN ,-C (R 5)=C (R 5) 2,-C (R 5)=C (R 5) (R 10) ,-C ≡ C-R 5,-C ≡ C-R 10,-OR 5,-SR 6,-S (O) R 6,-SO 2r 6,-SO 2n(R 4) 2,-N (R 4) 2,-NR 4c (O) R 5,-NR 4c (O) N (R 4) 2,-NR 4cO 2r 6,-O-CO 2r 5,-OC (O) N (R 4) 2,-O-C (O) R 5,-CO 2r 5,-C (O)-C (O) R 5,-C (O) R 5,-C (O) N (R 4) 2,-C (=NR 4)-N (R 4) 2,-C (=NR 4)-OR 5,-N (R 4)-N (R 4) 2,-N (R 4) C (=NR 4)-N (R 4) 2,-N (R 4) SO 2r 6,-N (R 4) SO 2n(R 4) 2,-P (O) (R 5) 2or-P (O) (OR 5) 2.
Each R 3bc independently 1-3aliphatic group, and by R 3or R 7optional replacement, or two R on same carbon atom 3b, form the carbocyclic ring of 3 yuan-6 yuan together with the carbon atom connecting with them.
Each R 7boptional aromatic yl group, heterocyclic group or the heteroaryl groups replacing independently.
R ehydrogen or C 1-3aliphatic group, and by R 3or R 7optional replacement.
R f1and R f2each is hydrogen naturally; Or R f1and R f2form key.
Each R 3independently selected from halogen radical ,-OH ,-O (C 1-3alkyl) ,-CN ,-N (R 4) 2,-C (O) (C 1-3alkyl) ,-CO 2h ,-CO 2(C 1-3alkyl) ,-C (O) NH 2and-C (O) NH (C 1-3alkyl).
Each R 4hydrogen or aliphatic group, aromatic yl group, heteroaryl groups, heterocyclic group through optionally replacing independently, or two R on same nitrogen-atoms 4form hetero-aromatic ring or the heterocycle of 4 yuan-8 yuan or 5 yuan-8 yuan of optional replacement together with this nitrogen-atoms, this hetero-aromatic ring or heterocycle, except containing this nitrogen-atoms, also contain 0-2 heteroatoms that is selected from nitrogen, oxygen, sulphur in ring structure.
Each R 5hydrogen or the optional aliphatic group replacing independently, aromatic yl group, heteroaryl groups or heterocyclic group.
Each R 6optional aliphatic group or the aromatic yl group replacing independently.
Each R 7optional aromatic yl group, heterocyclic group or the heteroaryl groups replacing independently.
Each R 10be independently-CO 2r 5or-C (O) N (R 4).
In certain embodiments, the compound shown in molecular formula (I) is at least gathered around by one, two or three characteristics in following (a)-(f) characteristic:
(a) R ahydrogen or C 1-3alkyl;
(b) R f1and R f2form key;
(c) A ring is through 0-2 R breplace, wherein each R bindependently selected from C 1-3aliphatic group, R 2b, R 7b,-T 1-R 2band-T 1-R 7b; T wherein 1c 1-3alkene chain;
(d) B ring is 5 yuan of single ring architecture or 6 yuan of aryl or heteroaryl, and by 0-2 R creplace, wherein each R cindependently selected from C 1-3aliphatic group, R 2c, R 7c,-T 1-R 2cwith-T 1-R 7b, T wherein 1c 1-3alkene chain;
(e) C ring is aryl or the heteroaryl of monocycle or twin nuclei, and by 0-2 independently selected from R dwith 0-2 independently selected from R 2dor C 1-6the substituting group of aliphatic group replaces;
(f) R ehydrogen.
In certain embodiments, the compound of molecular formula (I) representative has above-mentioned (a)-(f) all 6 features.
Certain embodiments of the present invention are relevant with the subgenus material of molecular formula (A) representative material,, these subgenus materials are defined by molecular formula (B) or molecular formula (II):
R wherein e, R x, R y, and the structure that has of A ring, B ring, C ring and preferred structure with above-mentioned defined identical with molecular formula (I) for molecular formula (B).In some such embodiment, B ring is aryl or the heteroaryl of monocycle or twin nuclei, and by 0-2 independently selected from R cwith 0-2 independently selected from R 2cor C 1-6the substituting group of aliphatic group replaces, and C ring is aryl, heteroaryl, heterocyclic radical or the alicyclic radical of monocycle or twin nuclei, and by 0-2 independently selected from R dwith 0-2 independently selected from R 2dor C 1-6aliphatic substituting group replaces.
In certain embodiments, the compound shown in molecular formula (II) is defined by following molecular formula:
Wherein A ring by 0-2 independently selected from R bsubstituting group replace, and B ring by 0-2 independently selected from R csubstituting group replace.In certain embodiments, the compound shown in molecular formula (IIa) has at least one in following (a)-(c) characteristic:
(a) each R bindependently selected from C 1-3aliphatic group, R 2b, R 7b,-T 1-R 2bor-T 1-R 7b, T wherein 1c 1-3alkene chain, and by fluorine, optionally replaced each R 2bindependently selected from halogen radical ,-NO 2,-C (R 5)=C (R 5) 2,-C ≡ C-R 5and-N (R 4) 2;
(b) each R cindependently selected from C 1-3aliphatics, R 2c, R 7c,-T 1-R 2cand-T 1-R 7c, T wherein 1by the optional C replacing of fluorine 1-3alkene chain, and each R 2cindependently selected from halogen radical ,-NO 2,-C (R 5)=C (R 5) 2,-C ≡ C-R 5and-N (R 4) 2;
(c) R ehydrogen.
Certain embodiments of the present invention are relevant with the subgenus material of molecular formula (IIa) representative material, and these subgenus materials are defined by molecular formula (III):
R wherein b, R c, R e, and the structure that has of C ring and preferred structure with defined identical for any molecular formula above.
Certain embodiments of the present invention are relevant with the subgenus material of molecular formula (IIa) representative material, and these subgenus materials are defined by molecular formula (IIIa):
Each R wherein b2and R b3be hydrogen or R independently b; Each R c1and R c5be hydrogen or R independently c; Each C ring, R b, R cand R ethe structure having and preferred structure are with defined identical for any molecular formula above.
In certain embodiments, each R in molecular formula (III) or molecular formula (IIIa) bindependently selected from C 1-3aliphatic group, C 1-3fluoride fat family group and R 2b, each R cindependently selected from C 1-3aliphatic group, C 1-3fluoride fat family group and R 2c.In some such embodiment, each R 2band R 2cindependently selected from halogen radical ,-NO 2,-C (R 5)=C (R 5) 2,-C ≡ C-R 5,-OR 5and-N (R 4) 2.
In certain embodiments, the present invention is relevant with the compound of molecular formula (IIIa) representative, wherein R ehydrogen; Each R b2and R b3independently selected from hydrogen, halogen radical, C 1-3aliphatic group, C 1-3fluoride fat family group and-OR 5, R wherein 5hydrogen or C 1-3aliphatic group.Each R c1and R c5independently selected from hydrogen, halogen radical, C 1-3aliphatic group, C 1-3fluoride fat family group and-OR 5, R wherein 5hydrogen or C 1-3aliphatic group.In certain embodiments, each R b3and R c1independently selected from halogen radical, C 1-3aliphatic group, C 1-3fluoride fat family group and-OR 5, R wherein 5hydrogen or C 1-3aliphatic group.In some such embodiment, R b2hydrogen, R c5be selected from hydrogen, halogen radical, C 1-3aliphatic group, C 1-3fluoride fat family group and-OR 5, each Rb 3and R c1independently selected from halogen radical, C 1-3aliphatic group, C 1-3fluoride fat family group and-OR 5, R wherein 5hydrogen or C 1-3aliphatic group.In certain embodiments, R b2hydrogen, R c2hydrogen, chlorine, fluorine, bromine, methyl, trifluoromethyl or methoxyl group, each R b3and R c1independently selected from chlorine, fluorine, bromine, methyl, trifluoromethyl or methoxyl group.
Certain embodiments of the present invention are relevant with the subgenus material of molecular formula (A) representative material, and these subgenus materials are defined by molecular formula (IV):
Wherein:
A ring is by 0-2 R binstitute replaces;
B ring is aryl or the heteroaryl of single ring architecture or twin nuclei, and by 0-2 independently selected from R cwith 0-3 independently selected from R 2cor C 1-6aliphatic substituting group optionally replaces;
R ehydrogen or by R 3or R 7the optional C replacing 1-3aliphatic group;
R gbe selected from hydrogen, C 1-6aliphatic group and R 2d; And
Each R hand R khydrogen or R independently d.
In some such embodiment, the present invention is relevant with the compound of molecular formula (IV) representative, wherein:
R dor R 2din each R 4hydrogen, C 1-3aliphatic group or 5 yuan of-6 yuan of aromatic yl groups or heteroaryl groups, or two R on same nitrogen-atoms 4form the heteroaryl groups of 5 yuan-6 yuan of optional replacement or the heterocyclic radical group of 4 yuan-8 yuan together with this nitrogen-atoms, wherein these heteroaryl groups and heterocyclic radical group also contain 0-2 heteroatoms that is selected from nitrogen, oxygen, sulphur except this nitrogen-atoms in ring structure;
R dor R 2din each R 5hydrogen, C 1-3aliphatic group or 5 yuan of-6 yuan of aromatic yl groups or heteroaryl groups.
In some such embodiment, at R dor R 2din two R on same nitrogen-atoms 4form piperidines cyclic group, piperazine cyclic group, the morpholine cyclic group of optional replacement together with this nitrogen-atoms.
In certain embodiments, the present invention is relevant with the compound of molecular formula (IV) representative, wherein:
A ring is through 0-2 R breplace, wherein each R bindependently selected from C1-3 aliphatic group, R 2b, R 7b,-T 1-R 2band-T 1-R 7b; T wherein 1it is C1-3 alkene chain;
B ring is 5 yuan of single ring architecture or 6 yuan of aryl or heteroaryl, and by 0-2 independently selected from R csubstituting group replace, each R wherein cindependently selected from C1-3 aliphatic group, R 2c, R 7c,-T 1-R 2c,-T 1-R 7c, T wherein 1it is C1-3 alkene chain; And
R ehydrogen.
In some this class embodiment, each R bindependently selected from C1-3 aliphatic group, R 2band-T 1-R 2b, each R cindependently selected from C1-3 aliphatic group, R 2cand-T 1-R 2c.In certain embodiments, each R 2bindependently selected from halogen radical ,-NO 2,-C (R 5)=C (R 5) 2,-C ≡ C-R 5,-OR 5and-N (R 4) 2; Each R 2cindependently selected from halogen radical ,-NO 2,-C (R 5)=C (R 5) 2,-C ≡ C-R 5,-OR 5and-N (R 4) 2.
In certain embodiments, the present invention is relevant with the compound of molecular formula (IV) representative, wherein R hand R kin one be R 7d.In certain embodiments, R ghydrogen, R 7dit is tetrazyl.
In certain embodiments, the present invention is relevant with the compound of molecular formula (IV) representative, wherein R ghydrogen, R hand R kin the molecular formula of be-T 2-R 2dor-T 2-R 7d, R hand R kin another be selected from hydrogen, halogen radical, C1-3 aliphatic group and-OR 5, R wherein 5hydrogen or C1-3 aliphatic group.In certain embodiments, T 2c1-6 alkene chain, and insertion-C (O) N (R optionally in this alkene chain 4)-or-N (R 4) C (O)-.
In certain embodiments, the present invention is relevant with the compound of molecular formula (IV) representative, wherein R ghydrogen, R hand R kin the molecular formula of be-V-T 3-R 2d, R hand R kin another be selected from hydrogen, halogen radical, C 1-3aliphatic group and-OR 5, R wherein 5hydrogen or C 1-3aliphatic group.In some this class embodiment, V is-C (O) N (R 4)-, T 3the alkene chain with 2-4 carbon atom, R 2dbe-N (R 4) 2, each R wherein 4be hydrogen or C independently 1-3aliphatic group, or-N (R 4) 2be the optional heteroaryl groups of 5 yuan-6 yuan replacing or the heterocyclic radical group of 4 yuan-8 yuan, wherein these heteroaryl groups and heterocyclic radical group also contain 0-2 heteroatoms that is selected from nitrogen, oxygen, sulphur except this nitrogen-atoms in ring structure.In some such embodiment ,-N (R 4) 2be the optional heterocyclic group replacing, be selected from piperidyl, piperazinyl, morpholinyl.At some in other such embodiments ,-N (R 4) 2be the optional heterocyclic radical replacing, be selected from pyrrolidyl, azetidinyl.
At some, in other embodiment, the present invention is relevant with the compound of molecular formula (IV) representative, wherein R ghydrogen, R hand R kin the molecular formula of be-V-T 3-R 7d, R hand R kin another be selected from hydrogen, halogen radical, C 1-3aliphatic group and-OR 5, R wherein 5hydrogen or C 1-3aliphatic group.In some such embodiment, V is-C (O) N (R 4)-, T 3the alkene chain with 2-4 carbon atom, R 7dthe optional heterocyclic radical group of 4 yuan-8 yuan replacing or the optional heteroaryl groups of 5 yuan-6 yuan replacing.In some such embodiment, R 7dbe the optional heteroaryl replacing, be selected from pyridyl, pyridazinyl, pyrimidyl, pyrazinyl, pyrryl, oxazolyl, imidazolyl and pyrazolyl.At some in other such embodiments, R 7dit is the bridging bicyclic heterocyclic group of 6 yuan-8 yuan.
In certain embodiments, the present invention is relevant with the compound of molecular formula (IV) representative, wherein R ghydrogen, R hand R kin at least one be selected from-CO 2r 5,-C (O) N (R 4) 2,-C (=NR 4) N (R 4) 2,-C (O) N (R 4) C (=NR 4)-N (R 4) 2,-N (R 4) C (=NR 4)-N (R 4)-C (O) R 5or-NR 4c (O) R 5.In certain embodiments, R hand R kin at least one be-CO 2r 5, R wherein 5hydrogen or C 1-6aliphatic group.In certain embodiments, each R gand R khydrogen, R hbe-CO 2r 5.
In certain embodiments, R ghydrogen, R hand R kin one be-C (O)-N (R 4) 2or-C (=NR 4) N (R 4) 2, wherein-N (R 4) 2be the optional heterocyclic group replacing, be selected from piperidyl, piperazinyl, morpholinyl, pyrrolidyl, azetidinyl.In some such embodiment, R hand R kin a molecular formula having be a kind of in defined molecular formula D-i to D-v below.In some such embodiment, R hand R kin the molecular formula of be a kind of in molecular formula D-1 to D-51, or the molecular formula on corresponding position in compound shown in table 3 below.
Certain embodiments of the present invention are relevant to the subgenus material of molecular formula (A) representative material, and these subgenus materials are defined by molecular formula (C):
Wherein:
A ring is 5 yuan of-6 yuan of aryl, heteroaryl, alicyclic radical or heterocyclic radicals through replacing or process does not replace;
B ring by 0-2 independently selected from R cwith 0-3 independently selected from R 2cor C1-6 aliphatic group replaces;
C ring by 0-2 independently selected from R dwith 0-3 independently selected from R 2dor C1-6 aliphatic group replaces; And
Each R e, R xand R ythe structure having and preferred structure are with defined identical above.
In certain embodiments, the present invention is relevant with the subgenus material of molecular formula (C) representative material, and these subgenus materials are defined by molecule formula V:
Wherein:
R ehydrogen; Or by R 3or R 7the optional C replacing 1-3aliphatic group;
A ring is by 0-3 R breplace;
B ring by 0-2 independently selected from R cwith 0-2 independently selected from R 2cor C 1-6aliphatic group replaces; And
C ring is through replacing or not process replacement.
In certain embodiments, the compound of molecule formula V representative is defined by molecular formula (Va):
Wherein:
R ehydrogen;
Each R b2and R b3independently selected from hydrogen, halogen radical, C 1-3aliphatic group, C 1-3fluoride fat family group and-OR 5, R wherein 5hydrogen or C 1-3aliphatic group;
Each R c1and R c5independently selected from hydrogen, halogen radical, C 1-3aliphatic group, C 1-3fluoride fat family group and-OR 5, R wherein 5hydrogen or C 1-3aliphatic group;
R gbe selected from hydrogen, halogen radical, C 1-6aliphatic group and R 2d; And
Each R h, R khydrogen or R independently d.
In certain embodiments, the present invention is relevant with the compound of molecular formula (Va) representative, wherein R hand R kin at least one molecular formula be-V-T 3-R 2dor-V-T 3-R 7d, wherein:
V is-C (O) N (R 4)-;
T 3c 2-4alkene chain;
R 2dbe-N (R 4) 2, R wherein 4hydrogen or C 1-3aliphatic group, or two R on same nitrogen-atoms 4form the heterocyclic radical group of 4 yuan-8 yuan of optional replacement or the heteroaryl groups of 5 yuan-6 yuan together with this nitrogen-atoms, wherein these heteroaryl groups and heterocyclic radical group also contain 0-2 heteroatoms that is selected from nitrogen, oxygen, sulphur except this nitrogen-atoms in ring structure; And
R 7dthe optional heterocyclic radical group of 4 yuan-8 yuan replacing or the optional heteroaryl groups of 5 yuan-6 yuan replacing.
In certain embodiments, the present invention is relevant with the compound of molecular formula (Va) representative, wherein R ghydrogen, R hand R kin at least one be selected from-CO 2r 5,-C (O) N (R 4) 2,-C (=NR 4) N (R 4) 2,-C (O) N (R 4) C (=NR 4)-N (R 4) 2,-N (R 4) C (=NR 4)-N (R 4)-C (O) R 5or-NR 4c (O) R 5.
In certain embodiments, the present invention is relevant with the compound of molecular formula (Va) representative, wherein:
R e, R b2, R gand R keach is hydrogen naturally;
R b3and R c1be selected from independently of one another halogen radical, C 1-3aliphatic group, C 1-3fluoride fat family group and-OR 5, R wherein 5hydrogen or C 1-3aliphatic group;
R c5be selected from hydrogen, halogen radical, C 1-3aliphatic group, C 1-3fluoride fat family group and-OR 5, R wherein 5hydrogen or C 1-3aliphatic group; And
R hbe-CO 2h ,-C (O) N (R 4) 2,-C (=NR 4) N (R 4) 2,-C (O) N (R 4) C (=NR 4)-N (R 4) 2, or-N (R 4) C (=NR 4)-N (R 4)-C (O) R 5; R wherein 5it is the optional nitrogen heterocycle group of 4 yuan-8 yuan replacing;-N (R 4) 2be the optional heterocyclic radical group of 4 yuan-8 yuan replacing, except nitrogen-atoms, also in ring structure, contain 0-2 heteroatoms that is selected from nitrogen, oxygen, sulphur.
The preferred thing of these variable groups as herein described is combining rear formed compound all within the scope of the present invention.
Table 3 has provided the specific examples of molecule formula V representative material.
Table 3 aurora kinase inhibitors
In table 3, the chemical name of compound is as follows:
The chloro-7-of I-1:4-[9-(the fluoro-phenyl of 2-)-5 hydrogen-benzo [c] Kui Linpyrimido quinoline [4,5-e] azepine-2 base-amino]-N-(2-methylamino-ethyl)-benzamide
The chloro-7-of I-2:N-(2-amino-ethyl)-4-[9-(the fluoro-phenyl of 2-)-5 hydrogen-benzo [c] Kui Linpyrimido quinoline [4,5-e] azepine-2-base is amino]-N-methyl-benzamide
The chloro-7-of I-3:4-[9-(the fluoro-phenyl of 2-)-5 hydrogen-benzo [c] Kui Linpyrimido quinoline [4,5-e] azepine-2 base is amino]-N-methyl-N-(2-methylamino-ethyl)-benzamide
The chloro-7-of I-4:4-[9-(the fluoro-phenyl of 2-)-5 hydrogen-benzo [c] Kui Linpyrimido quinoline [4,5-e] azepine-2-base is amino]-N-(2-dimethylamino-ethyl)-benzamide
The chloro-7-of I-5:4-[9-(the fluoro-phenyl of 2-)-5 hydrogen-benzo [c] Kui Linpyrimido quinoline [4,5-e] azepine-2 base is amino]-N-(2-dimethylamino-ethyl)-N-methyl-benzamide
The chloro-7-of I-6:4-[9-(the fluoro-phenyl of 2-)-5 hydrogen-benzo [c] Kui Linpyrimido quinoline [4,5-e] azepine-2 base is amino]-N-(3-dimethylamino-propyl group) benzamide
The chloro-7-of I-7:4-[9-(the fluoro-phenyl of 2-)-5 hydrogen-benzo [c] Kui Linpyrimido quinoline [4,5-e] azepine-2 base is amino]-N-(3-dimethylamino-propyl group)-N-methyl-benzamide
The chloro-7-of I-8:{4-[9-(the fluoro-phenyl of 2-)-5 hydrogen-benzo [c] Kui Linpyrimido quinoline [4,5-e] azepine-2 base is amino]-phenyl }-piperazine-1-base-ketone
The chloro-7-of I-9:{4-[9-(the fluoro-phenyl of 2-)-5 hydrogen-benzo [c] Kui Linpyrimido quinoline [4,5-e] azepine-2 base is amino]-phenyl }-(4-methyl-piperazine-1-yl)-ketone
The chloro-7-of I-10:{4-[9-(the chloro-phenyl of 2-)-5 hydrogen-benzo [c] Kui Linpyrimido quinoline [4,5-e] azepine-2 base is amino]-phenyl }-(4-methyl-piperazine-1-yl)-ketone
The chloro-7-o-of I-11:{4-[9-tolyl-5 hydrogen-benzos [c] Kui Linpyrimido quinolines [4,5-e] azepine-2 base is amino]-phenyl }-(4-methyl-piperazine-1-yl)-ketone
The chloro-7-of I-12:{4-[9-(2-methoxyl group-phenyl)-5 hydrogen-benzo [c] Kui Linpyrimido quinoline [4,5-e] azepine-2 base is amino]-phenyl }-(4-methyl-piperazine-1-yl)-ketone
The chloro-7-of I-13:{4-[9-(the fluoro-phenyl of 4-)-5 hydrogen-benzo [c] Kui Linpyrimido quinoline [4,5-e] azepine-2 base is amino]-phenyl }-(4-methyl-piperazine-1-yl)-ketone
I-14:{4-[7-(the fluoro-phenyl of 2-)-9-methyl-5 hydrogen-benzos [c] Kui Linpyrimido quinolines [4,5-e] azepine-2 base is amino]-phenyl }-(4-methyl-piperazine-1-yl)-ketone
The chloro-7-of I-15:2-{3-[9-(the fluoro-phenyl of 2-)-5 hydrogen-benzo [c] Kui Linpyrimido quinoline [4,5-e] azepine-2 base is amino]-phenyl }-(4-methyl-piperazine-1-yl)-ketone
The chloro-7-of I-16:4-[9-(the fluoro-phenyl of 2-)-5 hydrogen-benzo [c] Kui Linpyrimido quinoline [4,5-e] azepine-2 base is amino]-N-piperidin-4-yl-benzamide
I-17:(4-amino-piperadine-1-base-and the chloro-7-of 4-[9-(the fluoro-phenyl of 2-)-5 hydrogen-benzo [c] Kui Linpyrimido quinoline [4,5-e] azepine-2 base is amino]-benzene }-ketone
The chloro-7-of I-18:{4-[9-(the fluoro-phenyl of 2-)-5 hydrogen-benzo [c] Kui Linpyrimido quinoline [4,5-e] azepine-2 base is amino]-phenyl }-(4-dimethyl-piperidin-1-yl)-ketone
The chloro-7-of I-19:4-[9-(the fluoro-phenyl of 2-)-5 hydrogen-benzo [c] Kui Linpyrimido quinoline [4,5-e] azepine-2 base is amino]-N-[3-(4-methyl-piperazine-1-yl)-propyl group]-benzamide
The chloro-7-of I-20:4-[9-(the chloro-phenyl of 2-)-5 hydrogen-benzo [c] Kui Linpyrimido quinoline [4,5-e] azepine-2 base is amino]-N-[3-(4-methyl-piperazine-1-yl)-propyl group]-benzamide
I-21:4-(the chloro-7-o-of 9-tolyl-5 hydrogen-benzos [c] Kui Linpyrimido quinolines [4,5-e] azepine-2 base is amino)-N-[3-(4-methyl-piperazine-1-yl)-propyl group]-benzamide
The chloro-7-of I-22:4-[9-(2-methoxyl group-phenyl)-5 hydrogen-benzo [c] Kui Linpyrimido quinoline [4,5-e] azepine-2 base is amino]-N-[3-(4-methyl-piperazine-1-yl)-propyl group]-benzamide
The chloro-7-of I-23:4-[9-(the fluoro-phenyl of 4-)-5 hydrogen-benzo [c] Kui Linpyrimido quinoline [4,5-e] azepine-2 base is amino]-N-[3-(4-methyl-piperazine-1-yl)-propyl group]-benzamide
I-24:4-[7-(the fluoro-phenyl of 2-)-9-methyl-5 hydrogen-benzos [c] Kui Linpyrimido quinolines [4,5-e] azepine-2 base is amino]-N-[3-(4-methyl-piperazine-1-yl)-propyl group]-benzamide
The chloro-7-of I-25:2-{3-[9-(the fluoro-phenyl of 2-)-5 hydrogen-benzo [c] Kui Linpyrimido quinoline [4,5-e] azepine-2 base is amino]-phenyl }-N-[3-(4-methyl-piperazine-1-yl)-propyl group]-benzamide
The chloro-7-of I-26:{4-[9-(the fluoro-phenyl of 2-)-5 hydrogen-benzo [c] Kui Linpyrimido quinoline [4,5-e] azepine-2 base is amino]-phenyl }-morpholine-4-base-ketone
I-27:4-[9-chloro-(the fluoro-phenyl of 2-)-5 hydrogen-benzo [c] Kui Linpyrimido quinoline [4,5-e] azepine-2 base is amino]-N, N-bis--(2-hydroxyl-ethyl)-benzamide
I-28:{4-[9-chloro-(the chloro-phenyl of 2-)-5 hydrogen-benzo [c] Kui Linpyrimido quinoline [4,5-e] azepine-2 base is amino]-phenyl }-morpholine-4-base-ketone
I-29:4-[9-chloro-(the fluoro-phenyl of 2-)-5 hydrogen-benzo [c] Kui Linpyrimido quinoline [4,5-e] azepine-2 base is amino]-N-(2-morpholine-4-base-ethyl)-benzamide
I-30:4-[9-chloro-(the fluoro-phenyl of 2-)-5 hydrogen-benzo [c] Kui Linpyrimido quinoline [4,5-e] azepine-2 pyridinylamino]-N-(2-morpholine-4-base-ethyl)-benzamide
I-31:4-(the chloro-7-o-of 9-tolyl-5 hydrogen-benzos [c] Kui Linpyrimido quinolines [4,5-e] azepine-2 base is amino)-N-(2-morpholine-4-base-ethyl)-benzamide
Chloro-7 (2-methoxyl group-phenyl)-5 hydrogen-benzo [c] Kui Linpyrimido quinoline [4,5-e] azepine-2 bases of I-32:4-[9-are amino]-N-(3-morpholine-4-base-ethyl)-benzamide
The chloro-7-of I-33:4-[9-(the fluoro-phenyl of 4-)-5 hydrogen-benzo [c] Kui Linpyrimido quinoline [4,5-e] azepine-2 base is amino]-N-(2-morpholine-4-base-ethyl)-benzamide
The chloro-7-of I-34:4-[9-(the chloro-phenyl of 2-)-5 hydrogen-benzo [c] Kui Linpyrimido quinoline [4,5-e] azepine-2 base is amino]-2-hydroxy-n-(2-morpholine-4-base-ethyl)-benzamide
The chloro-7-of I-35:[9-(the chloro-phenyl of 2-)-5 hydrogen-benzo [c] Kui Linpyrimido quinoline [4,5-e] azepine-2-yl]-pyridine-2-base-amine
The chloro-7-of I-36:[9-(the fluoro-phenyl of 2-)-5 hydrogen-benzo [c] Kui Linpyrimido quinoline [4,5-e] azepine-2-yl]-(the chloro-phenyl of 3,5-bis-)-amine
The chloro-7-of I-37:[9-(the fluoro-phenyl of 2-)-5 hydrogen-benzo [c] Kui Linpyrimido quinoline [4,5-e] azepine-2-yl]-(4-methoxyl group-phenyl)-amine
The chloro-7-of I-38:[9-(the fluoro-phenyl of 2-)-5 hydrogen-benzo [c] Kui Linpyrimido quinoline [4,5-e] azepine-2-yl]-(4-oxyethyl group-phenyl)-amine
The chloro-7-of I-39:[9-(the fluoro-phenyl of 2-)-5 hydrogen-benzo [c] Kui Linpyrimido quinoline [4,5-e] azepine-2-yl]-(3-methoxyl group-phenyl)-amine
The chloro-7-of I-40:[9-(the fluoro-phenyl of 2-)-5 hydrogen-benzo [c] Kui Linpyrimido quinoline [4,5-e] azepine-2-yl]-(2-methoxyl group-phenyl)-amine
The chloro-7-of I-41:[9-(the fluoro-phenyl of 2-)-5 hydrogen-benzo [c] Kui Linpyrimido quinoline [4,5-e] azepine-2-yl]-(the chloro-phenyl of 4-)-amine
The chloro-7-of I-42:[9-(the chloro-phenyl of 2-)-5 hydrogen-benzo [c] Kui Linpyrimido quinoline [4,5-e] azepine-2-yl]-(the chloro-phenyl of 4-)-amine
The chloro-7-of I-43:[9-(the fluoro-phenyl of 2-)-5 hydrogen-benzo [c] Kui Linpyrimido quinoline [4,5-e] azepine-2-yl]-(the chloro-phenyl of 3-)-amine
The chloro-7-of I-44:[9-(the fluoro-phenyl of 2-)-5 hydrogen-benzo [c] Kui Linpyrimido quinoline [4,5-e] azepine-2-yl]-(the chloro-phenyl of 2-)-amine
The chloro-7-of I-45:4-[9-(the chloro-phenyl of 2-)-5 hydrogen-benzo [c] Kui Linpyrimido quinoline [4,5-e] azepine-2 base is amino]-phenol
The chloro-7-of I-46:[9-(the fluoro-phenyl of 2-)-5 hydrogen-benzo [c] Kui Linpyrimido quinoline [4,5-e] azepine-2-yl]-(4-morpholine-4 base-phenyl)-amine
The chloro-7-of I-47:[9-(the fluoro-phenyl of 2-)-5 hydrogen-benzo [c] Kui Linpyrimido quinoline [4,5-e] azepine-2-yl]-[4-(4-methyl-piperazine-1 base)-phenyl]-amine
The chloro-7-of I-48:[9-(the fluoro-phenyl of 2-)-5 hydrogen-benzo [c] Kui Linpyrimido quinoline [4,5-e] azepine-2-yl]-(4-pyridine-4 base-methyl-phenyl)-amine
The chloro-7-of I-49:4-[9-(the fluoro-phenyl of 2-)-5 hydrogen-benzo [c] Kui Linpyrimido quinoline [4,5-e] azepine-2 base is amino]-phenyl cyanide
The chloro-7-of I-50:[9-(the fluoro-phenyl of 2-)-5 hydrogen-benzo [c] Kui Linpyrimido quinoline [4,5-e] azepine-2-yl]-(4-nitro-phenyl)-amine
I-51:4-[7-(the fluoro-phenyl of 2-)-5 hydrogen-benzo [c] Kui Linpyrimido quinoline [4,5-e] azepine-2 base is amino]-phenylformic acid
The chloro-7-of I-52:4-[9-(the fluoro-phenyl of 2-)-5 hydrogen-benzo [c] Kui Linpyrimido quinoline [4,5-e] azepine-2 base is amino]-phenylformic acid
The chloro-7-of I-53:4-[9-(the chloro-phenyl of 2-)-5 hydrogen-benzo [c] Kui Linpyrimido quinoline [4,5-e] azepine-2 base is amino]-phenylformic acid
I-54:4-(the chloro-7-o-of 9-tolyl-5 hydrogen-benzos [c] Kui Linpyrimido quinolines [4,5-e] azepine-2 base is amino)-phenylformic acid
The chloro-7-of I-55:4-[9-(2-methoxyl group-phenyl)-5 hydrogen-benzo [c] Kui Linpyrimido quinoline [4,5-e] azepine-2 base is amino]-phenylformic acid
The chloro-7-of I-56:4-[9-(the fluoro-phenyl of 4-)-5 hydrogen-benzo [c] Kui Linpyrimido quinoline [4,5-e] azepine-2 base is amino]-phenylformic acid
The fluoro-7-of I-57:4-[9-(the fluoro-phenyl of 2-)-5 hydrogen-benzo [c] Kui Linpyrimido quinoline [4,5-e] azepine-2 base is amino]-phenylformic acid
I-58:4-[-7-(the fluoro-phenyl of 2-)-9-methyl-5 hydrogen-benzos [c] Kui Linpyrimido quinolines [4,5-e] azepine-2 base is amino]-phenylformic acid
The fluoro-7-of I-59:4-[10-(the fluoro-phenyl of 2-)-5 hydrogen-benzo [c] Kui Linpyrimido quinoline [4,5-e] azepine-2 base is amino]-phenylformic acid
The chloro-7-of I-60:4-[10-(the fluoro-phenyl of 2-)-5 hydrogen-benzo [c] Kui Linpyrimido quinoline [4,5-e] azepine-2 base is amino]-phenylformic acid
The bromo-7-of I-61:4-[10-(the fluoro-phenyl of 2-)-5 hydrogen-benzo [c] Kui Linpyrimido quinoline [4,5-e] azepine-2 base is amino]-phenylformic acid
I-62:4-[7-(the fluoro-phenyl of 2-)-10-methoxyl group-5 hydrogen-benzos [c] Kui Linpyrimido quinolines [4,5-e] azepine-2 base is amino]-phenylformic acid
The chloro-7-of I-63:4-[9-(the chloro-phenyl of 2-)-5 hydrogen-benzo [c] Kui Linpyrimido quinoline [4,5-e] azepine-2 base is amino]-benzamide
The chloro-7-of I-64:3-[9-(the chloro-phenyl of 2-)-5 hydrogen-benzo [c] Kui Linpyrimido quinoline [4,5-e] azepine-2 base is amino]-benzamide
The chloro-7-of I-65:{3-4-[9-(the chloro-phenyl of 2-)-5 hydrogen-benzo [c] Kui Linpyrimido quinoline [4,5-e] azepine-2 base is amino]-phenyl }-acetic acid
The chloro-7-of I-66:2-{3-4-[9-(the chloro-phenyl of 2-)-5 hydrogen-benzo [c] Kui Linpyrimido quinoline [4,5-e] azepine-2 base is amino]-phenyl }-ethanamide
The chloro-7-of I-67:4-[9-(the fluoro-phenyl of 2-)-5 hydrogen-benzo [c] Kui Linpyrimido quinoline [4,5-e] azepine-2 base is amino]-Phenylsulfonic acid
The chloro-7-of I-68:4-[9-(the fluoro-phenyl of 2-)-5 hydrogen-benzo [c] Kui Linpyrimido quinoline [4,5-e] azepine-2 base is amino]-benzsulfamide
The chloro-7-of I-69:4-[9-(the chloro-phenyl of 2-)-5 hydrogen-benzo [c] Kui Linpyrimido quinoline [4,5-e] azepine-2 base is amino]-N-(5-methyl-isoxazole-3 bases)-benzsulfamide
The chloro-7-of I-70:[9-(the fluoro-phenyl of 2-)-5 hydrogen-benzo [c] Kui Linpyrimido quinoline [4,5-e] azepine-2-yl]-(4-trifluoromethanesulfonic acid base-phenyl)-amine
The chloro-7-of I-71:[9-(the fluoro-phenyl of 2-)-5 hydrogen-benzo [c] Kui Linpyrimido quinoline [4,5-e] azepine-2-yl]-(3,4-dimethoxy-phenyl)-amine
The chloro-7-of I-72:[9-(the fluoro-phenyl of 2-)-6,7-dihydro-5 hydrogen-benzos [c] Kui Linpyrimido quinolines [4,5-e] azepine-2-yl]-(3,4-dimethoxy-phenyl)-amine
The chloro-7-of I-73:[9-(the chloro-phenyl of 2-)-5 hydrogen-benzo [c] Kui Linpyrimido quinoline [4,5-e] azepine-2-yl]-(3,4-dimethoxy-phenyl)-amine
The chloro-7-o-of I-74:(9-tolyl-5 hydrogen-benzos [c] Kui Linpyrimido quinolines [4,5-e] azepine-2-yl)-(3,4-dimethoxy-phenyl)-amine
I-75:(3,4-dimethoxy-phenyl)-[7-(the fluoro-phenyl of 2-)-9-methyl-5 hydrogen-benzos [c] Kui Linpyrimido quinolines [4,5-e] azepine-2-yl]-amine
I-76:(3,4-dimethoxy-phenyl)-[7-(the fluoro-phenyl of 2-)-9-sec.-propyl-5 hydrogen-benzos [c] Kui Linpyrimido quinolines [4,5-e] azepine-2-yl]-amine
I-77:(3,4-dimethoxy-phenyl)-[10 fluoro-7-(the fluoro-phenyl of 2-)-5 hydrogen-benzo [c] Kui Linpyrimido quinoline [4,5-e] azepine-2-yl]-amine
The bromo-7-of I-78:[10-(the fluoro-phenyl of 2-)-5 hydrogen-benzo [c] Kui Linpyrimido quinoline [4,5-e] azepine-2-yl]-(3,4-dimethoxy-phenyl)-amine
I-79:(3,4-dimethoxy-phenyl)-[7-(the fluoro-phenyl of 2-)-10-trifluoromethyl-5 hydrogen-benzos [c] Kui Linpyrimido quinolines [4,5-e] azepine-2-yl]-amine
I-80:(3,4-dimethoxy-phenyl)-[7-(the fluoro-phenyl of 2-)-10-methyl-5 hydrogen-benzos [c] Kui Linpyrimido quinolines [4,5-e] azepine-2-yl]-amine
I-81:(3,4-dimethoxy-phenyl)-[7-(the fluoro-phenyl of 2-)-10-methoxyl group-5 hydrogen-benzos [c] Kui Linpyrimido quinolines [4,5-e] azepine-2-yl]-amine
I-82:(3,4-dimethoxy-phenyl)-[7-(the fluoro-phenyl of 2-)-11-methyl-5 hydrogen-benzos [c] Kui Linpyrimido quinolines [4,5-e] azepine-2-yl]-amine
The chloro-7-of I-83:[9-(the fluoro-phenyl of 2-)-5 hydrogen-benzo [c] Kui Linpyrimido quinoline [4,5-e] azepine-2-yl]-(2,3-dihydro-benzo [Isosorbide-5-Nitrae] dioxin-6-yl)-amine
The chloro-7-of I-84:[9-(the fluoro-phenyl of 2-)-5 hydrogen-benzo [c] Kui Linpyrimido quinoline [4,5-e] azepine-2-yl]-(the fluoro-3-methoxyl group-phenyl of 4-)-amine
The chloro-7-of I-85:4-[9-(the fluoro-phenyl of 2-)-5 hydrogen-benzo [c] Kui Linpyrimido quinoline [4,5-e] azepine-2 base is amino]-2-hydroxy-benzoic acid
The chloro-7-of I-86:4-[9-(the chloro-phenyl of 2-)-5 hydrogen-benzo [c] Kui Linpyrimido quinoline [4,5-e] azepine-2 base is amino]-2-hydroxy-benzoic acid
The chloro-7-of I-87:[9-(the chloro-phenyl of 2-)-5 hydrogen-benzo [c] Kui Linpyrimido quinoline [4,5-e] azepine-2-yl]-(the chloro-phenyl of 3,4-bis-)-amine
The chloro-7-of I-88:[9-(the chloro-phenyl of 2-)-5 hydrogen-benzo [c] Kui Linpyrimido quinoline [4,5-e] azepine-2-yl]-(3,5-dimethoxy-phenyl)-amine
The chloro-7-of I-89:[9-(the fluoro-phenyl of 2-)-5 hydrogen-benzo [c] Kui Linpyrimido quinoline [4,5-e] azepine-2-yl]-(3,5-dimethyl-phenyl)-amine
The chloro-7-of I-90:[9-(the fluoro-phenyl of 2-)-5 hydrogen-benzo [c] Kui Linpyrimido quinoline [4,5-e] azepine-2-yl]-phenyl-amine
The chloro-7-of I-91:4-[9-(the fluoro-phenyl of 2,5-bis-)-5 hydrogen-benzo [c] Kui Linpyrimido quinoline [4,5-e] azepine-2 base is amino]-phenylformic acid
The chloro-7-of I-92:4-[9-(the fluoro-phenyl of 2,3-bis-)-5 hydrogen-benzo [c] Kui Linpyrimido quinoline [4,5-e] azepine-2 base is amino]-phenylformic acid
I-93:(3-dimethylamino-pyrrolidin-1-yl)-4-[7-(the fluoro-phenyl of 2-)-9-methoxyl group-5 hydrogen-benzos [c] Kui Linpyrimido quinolines [4,5-e] azepine-2 base is amino]-phenyl }-ketone
The chloro-7-of I-94:4-[9-(2,5-dimethoxy-phenyl)-5 hydrogen-benzo [c] Kui Linpyrimido quinoline [4,5-e] azepine-2 base is amino]-phenylformic acid
I-95:4-[7-(the fluoro-phenyl of 2-)-9-methoxyl group-5 hydrogen-benzos [c] Kui Linpyrimido quinolines [4,5-e] azepine-2 base is amino]-N, N-bis--(2-hydroxyl-ethyl) benzamide
The chloro-7-of I-96:4-[9-(the fluoro-phenyl of 2,4-bis-)-5 hydrogen-benzo [c] Kui Linpyrimido quinoline [4,5-e] azepine-2 base is amino]-phenylformic acid
The chloro-7-of I-97:4-[9-(2,4-dimethoxy-phenyl)-7 hydrogen-benzo [c] Kui Linpyrimido quinoline [4,5-e] azepine-2 base is amino]-phenylformic acid
The chloro-7-of I-98:{4-[9-(the fluoro-phenyl of 2-)-5 hydrogen-benzo [c] Kui Linpyrimido quinoline [4,5-e] azepine-2 base is amino]-phenyl }-(3-dimethylamino-azepine-1-yl)-ketone
The chloro-7-of I-99:4-[9-(the fluoro-phenyl of 2-)-5 hydrogen-benzo [c] Kui Linpyrimido quinoline [4,5-e] azepine-2 base is amino]-N-methyl-N-(1-methyl-pyrrolidin-3-yl)-benzamide
The chloro-7-of I-100:{4-[9-(the fluoro-phenyl of 2-)-5 hydrogen-benzo [c] Kui Linpyrimido quinoline [4,5-e] azepine-2 base is amino]-phenyl }-(3-dimethylamino-pyrrolidin-1-yl)-ketone
The chloro-7-of I-101:4-[9-(2,4-dimethoxy-phenyl)-5 hydrogen-benzo [c] Kui Linpyrimido quinoline [4,5-e] azepine-2 base is amino]-phenylformic acid
The chloro-7-of I-102:{4-[9-(the fluoro-phenyl of 2-)-5 hydrogen-benzo [c] Kui Linpyrimido quinoline [4,5-e] azepine-2 base is amino]-phenyl }-(3-methylamino-tetramethyleneimine-1 base)-ketone
I-103:(3-amino-tetramethyleneimine-1 base)-the chloro-7-of 4-[9-(the fluoro-phenyl of 2-)-5 hydrogen-benzo [c] Kui Linpyrimido quinoline [4,5-e] azepine-2 base is amino]-phenyl }-ketone
The chloro-7-of I-104:4-[9-(the fluoro-phenyl of 2,3-bis-)-5 hydrogen-benzo [c] Kui Linpyrimido quinoline [4,5-e] azepine-2 base is amino]-methyl benzoate
The chloro-7-of I-105:4-[9-(the fluoro-phenyl of 2,5-bis-)-5 hydrogen-benzo [c] Kui Linpyrimido quinoline [4,5-e] azepine-2 base is amino]-methyl benzoate
The chloro-7-of I-106:{4-[9-(the fluoro-phenyl of 2-)-5 hydrogen-benzo [c] Kui Linpyrimido quinoline [4,5-e] azepine-2 base is amino]-phenyl } phosphoric acid
The chloro-7-of I-107:N-{4-[9-(the fluoro-phenyl of 2-)-5 hydrogen-benzo [c] Kui Linpyrimido quinoline [4,5-e] azepine-2 base is amino]-phenyl }-Toluidrin
The chloro-7-of I-108:N-{4-[9-(the fluoro-phenyl of 2-)-5 hydrogen-benzo [c] Kui Linpyrimido quinoline [4,5-e] azepine-2 base is amino]-phenyl }-N-methyl-ethanamide
The chloro-7-of I-109:2-{4-[9-(the fluoro-phenyl of 2-)-5 hydrogen-benzo [c] Kui Linpyrimido quinoline [4,5-e] azepine-2 base is amino]-benzoyl }-succinic acid
The chloro-7-of I-110:[9-(the fluoro-phenyl of 2-)-4-methyl-5 hydrogen-benzos [c] Kui Linpyrimido quinolines [4,5-e] azepine-2-yl]-(3,4-dimethoxy-phenyl)-amine
The chloro-7-of I-111:{4-[9-(the fluoro-phenyl of 2-)-5 hydrogen-benzo [c] Kui Linpyrimido quinoline [4,5-e] azepine-2 base is amino]-phenyl }-(3,5-dimethyl-piperazine-1-yl)-ketone
The chloro-7-of I-112:1-{4-[9-(the fluoro-phenyl of 2-)-5 hydrogen-benzo [c] Kui Linpyrimido quinoline [4,5-e] azepine-2 base is amino]-benzoyl }-pyrrolidin-2-yl-carboxylic acid
The chloro-7-of I-113:{4-[9-(the fluoro-phenyl of 2-)-5 hydrogen-benzo [c] Kui Linpyrimido quinoline [4,5-e] azepine-2 base is amino]-phenyl }-(3-methyl-piperazine-1-yl)-ketone
The chloro-7-of I-114:[9-(the fluoro-phenyl of 2-)-5 hydrogen-benzo [c] Kui Linpyrimido quinoline [4,5-e] azepine-2-yl]-[4-(2-hydrogen-tetrazolium-5 base)-phenyl]-amine
The chloro-7-of I-115:N-{4-[9-(the fluoro-phenyl of 2-)-5 hydrogen-benzo [c] Kui Linpyrimido quinoline [4,5-e] azepine-2 base is amino]-phenyl-ethanamide
The chloro-7-of I-116:5-[9-(the fluoro-phenyl of 2-)-5 hydrogen-benzo [c] Kui Linpyrimido quinoline [4,5-e] azepine-2 base is amino] the fluoro-phenylformic acid of-2-
The chloro-7-of I-117:N-(3-amino-propyl group)-4-[9-(the fluoro-phenyl of 2-)-5 hydrogen-benzo [c] Kui Linpyrimido quinoline [4,5-e] azepine-2 base is amino]-N-methyl-benzamide
The chloro-7-of I-118:2-{4-[9-(the fluoro-phenyl of 2-)-5 hydrogen-benzo [c] Kui Linpyrimido quinoline [4,5-e] azepine-2 base is amino]-benzoyl }-propionic acid
The chloro-7-of I-119:5-[9-(the fluoro-phenyl of 2-)-5 hydrogen-benzo [c] Kui Linpyrimido quinoline [4,5-e] azepine-2 base is amino]-pyrimidyl-2-carboxylic acid
The chloro-7-of I-120:2-{4-[9-(the fluoro-phenyl of 2-)-5 hydrogen-benzo [c] Kui Linpyrimido quinoline [4,5-e] azepine-2 base is amino]-phenyl }-N-(2-morpholine-4-base-ethyl)-ethanamide
The chloro-7-of I-121:5-[9-(the fluoro-phenyl of 2-)-5 hydrogen-benzo [c] Kui Linpyrimido quinoline [4,5-e] azepine-2 base is amino]-2-methoxyl group-phenylformic acid
The chloro-7-of I-122:5-[9-(the fluoro-phenyl of 2-)-5 hydrogen-benzo [c] Kui Linpyrimido quinoline [4,5-e] azepine-2 base is amino]-2-methyl-phenylformic acid
The chloro-7-of I-123:6-[9-(the fluoro-phenyl of 2-)-5 hydrogen-benzo [c] Kui Linpyrimido quinoline [4,5-e] azepine-2 base is amino]-Nicotinicum Acidum
The chloro-7-of I-124:4-[9-(the fluoro-phenyl of 2-)-5 hydrogen-benzo [c] Kui Linpyrimido quinoline [4,5-e] azepine-2 base is amino]-N-(2-morpholine-4 base-ethyl)-methoxyl group-benzsulfamide
The chloro-7-of the chloro-5-[9-of I-125:2-(the fluoro-phenyl of 2-)-5 hydrogen-benzo [c] Kui Linpyrimido quinoline [4,5-e] azepine-2 base is amino]-phenylformic acid
The chloro-7-of I-126:4-[9-(the fluoro-phenyl of 2-)-5 hydrogen-benzo [c] Kui Linpyrimido quinoline [4,5-e] azepine-2 base is amino]-phenyl-acetic acid
The chloro-7-of I-127:4-[9-(the fluoro-phenyl of 2-)-5 hydrogen-benzo [c] Kui Linpyrimido quinoline [4,5-e] azepine-2 base is amino]-2-trifluoromethyl-phenylformic acid
The chloro-7-of I-128:4-[9-(the fluoro-phenyl of 2-)-5 hydrogen-benzo [c] Kui Linpyrimido quinoline [4,5-e] azepine-2 base is amino]-N-methyl-N-(1-methyl-piperidin-4-yl)-benzamide
The chloro-7-of I-129:N-(3-amino-propyl group)-4-[9-(the fluoro-phenyl of 2-)-5 hydrogen-benzo [c] Kui Linpyrimido quinoline [4,5-e] azepine-2 pyridinylamino]-benzamide
The chloro-7-of I-130:4-[9-(the fluoro-phenyl of 2-)-5 hydrogen-benzo [c] Kui Linpyrimido quinoline [4,5-e] azepine-2 pyridinylamino]-N-(3-methylamino-propyl group)-benzamide
The chloro-7-of I-131:N-(2-amino-2-methyl-propyl group)-4-[9-(the fluoro-phenyl of 2-)-5 hydrogen-benzo [c] Kui Linpyrimido quinoline [4,5-e] azepine-2 base is amino]-benzamide
I-132:2-(3,4-dimethoxy-phenyl amino)-7-(the fluoro-phenyl of 2-)-5 hydrogen-benzo [c] Kui Linpyrimido quinoline [4,5-e] azepine-10-carboxylic acid
The chloro-7-of I-133:4-[9-(the fluoro-phenyl of 2-)-5 hydrogen-benzo [c] Kui Linpyrimido quinoline [4,5-e] azepine-2 base is amino]-2-methyl-phenylformic acid
The chloro-7-of the chloro-4-[9-of I-134:2-(the fluoro-phenyl of 2-)-5 hydrogen-benzo [c] Kui Linpyrimido quinoline [4,5-e] azepine-2 base is amino]-phenylformic acid
The chloro-7-of I-135:4-[9-(the fluoro-phenyl of 2,6-bis-)-5 hydrogen-benzo [c] Kui Linpyrimido quinoline [4,5-e] azepine-2 base is amino]-phenylformic acid
The chloro-7-of I-136:4-[9-(the fluoro-phenyl of 2-)-5 hydrogen-benzo [c] Kui Linpyrimido quinoline [4,5-e] azepine-2 base is amino] the fluoro-phenylformic acid of-2-
I-137:4-[-7-(the fluoro-phenyl of 2-)-9-methoxyl group-5 hydrogen-benzos [c] Kui Linpyrimido quinolines [4,5-e] azepine-2 base is amino]-phenylformic acid
I-138:(3,4-dimethyl-phenyl)-[7-(the fluoro-phenyl of 2-)-9-methoxyl group-5 hydrogen-benzos [c] Kui Linpyrimido quinolines [4,5-e] azepine-2-yl]-amine
I-139:[9, the chloro-7-of 10-bis-(the fluoro-phenyl of 2-)-5 hydrogen-benzo [c] Kui Linpyrimido quinoline [4,5-e] azepine-2-yl]-(3,4-dimethoxy-phenyl)-amine
I-140:4-[9, the chloro-7-of 10-bis-(the fluoro-phenyl of 2-)-5 hydrogen-benzo [c] Kui Linpyrimido quinoline [4,5-e] azepine-2 base is amino]-phenylformic acid
The chloro-7-of I-141:4-[9-(the fluoro-phenyl of 2-)-5 hydrogen-benzo [c] Kui Linpyrimido quinoline [4,5-e] azepine-2 base is amino]-2-methoxyl group-phenylformic acid
The chloro-7-of I-142:N-(2-amino-ethyl)-4-[9-(the fluoro-phenyl of 2-)-5 hydrogen-benzo [c] Kui Linpyrimido quinoline [4,5-e] azepine-2 base is amino]-benzamide
I-143:4-(the chloro-7-of 9-phenyl-5 hydrogen-benzos [c] Kui Linpyrimido quinolines [4,5-e] azepine-2 base is amino)-phenylformic acid
I-144:[7-(the bromo-phenyl of 2-) the chloro-5 hydrogen-benzo of-9-[c] Kui Linpyrimido quinoline [4,5-e] azepine-2-yl]-(3,4-dimethoxy-phenyl)-amine
The chloro-7-of I-145:2-{4-[9-(the fluoro-phenyl of 2-)-5 hydrogen-benzo [c] Kui Linpyrimido quinoline [4,5-e] azepine-2 base is amino]-phenyl-1-(4-methyl-piperazine-1-yl)-ethyl ketone
The chloro-7-of I-146:3-[9-(the fluoro-phenyl of 2-)-5 hydrogen-benzo [c] Kui Linpyrimido quinoline [4,5-e] azepine-2 base is amino]-phenylformic acid
The chloro-7-of I-147:4-[9-(the fluoro-phenyl of 2-)-5 hydrogen-benzo [c] Kui Linpyrimido quinoline [4,5-e] azepine-2 base is amino]-N-[2-(1 hydrogen-imidazol-4 yl)-ethyl]-benzamide
I-148:4-[7-(the fluoro-phenyl of 2-)-9-methyl-5 hydrogen-benzos [c] Kui Linpyrimido quinolines [4,5-e] azepine-2 base is amino]-N-(2-morpholine-4-base-ethyl)-benzamide
The chloro-7-of I-149:{3-[9-(the fluoro-phenyl of 2-)-5 hydrogen-benzo [c] Kui Linpyrimido quinoline [4,5-e] azepine-2 base is amino]-phenyl-acetic acid
The chloro-7-of I-150:4-[9-(the fluoro-phenyl of 2-)-5 hydrogen-benzo [c] Kui Linpyrimido quinoline [4,5-e] azepine-2 base is amino]-N-(2-pyridin-4-yl)-ethyl]-benzamide
The chloro-7-of I-151:4-[9-(the fluoro-phenyl of 2-)-5 hydrogen-benzo [c] Kui Linpyrimido quinoline [4,5-e] azepine-2 base is amino]-N-(2-pyridin-3-yl)-ethyl]-benzamide
The chloro-7-of I-152:(9-phenyl-5 hydrogen-benzos [c] Kui Linpyrimido quinolines [4,5-e] azepine-2 base])-(3,4-dimethoxy-phenyl)-amine
I-153:4-[7-(the fluoro-phenyl of 2-)-10-methyl-5 hydrogen-benzos [c] Kui Linpyrimido quinolines [4,5-e] azepine-2 base is amino]-phenylformic acid
I-154:(3,4-dimethyl-phenyl)-[7-(the fluoro-phenyl of 2-)-9-methoxyl group-5 hydrogen-benzos [c] Kui Linpyrimido quinolines [4,5-e] azepine-2-yl]-amine
The chloro-7-of I-155:4-[9-(4-methoxyl group-phenyl)-5 hydrogen-benzo [c] Kui Linpyrimido quinoline [4,5-e] azepine-2 base is amino]-phenylformic acid
The chloro-7-of I-156:4-[9-(3-methoxyl group-phenyl)-5 hydrogen-benzo [c] Kui Linpyrimido quinoline [4,5-e] azepine-2 base is amino]-phenylformic acid
The chloro-7-of I-157:4-[9-(the fluoro-phenyl of 3-)-5 hydrogen-benzo [c] Kui Linpyrimido quinoline [4,5-e] azepine-2 base is amino]-N-[3-(4-methyl-piperazine-1 base)-propyl group]-benzamide
The chloro-7-of I-158:4-[9-(the fluoro-phenyl of 3-)-5 hydrogen-benzo [c] Kui Linpyrimido quinoline [4,5-e] azepine-2 base is amino]-N-(2-morpholine-4-base-ethyl)-benzamide
The chloro-7-of I-159:{4-[9-(the fluoro-phenyl of 3-)-5 hydrogen-benzo [c] Kui Linpyrimido quinoline [4,5-e] azepine-2 base is amino]-phenyl }-(4-methyl-piperazine-1-yl)-ketone
The chloro-7-of I-160:4-[9-(the fluoro-phenyl of 2-)-5 hydrogen-benzo [c] Kui Linpyrimido quinoline [4,5-e] azepine-2 base is amino]-N-methyl-N-(2-pyridine-2-base-ethyl)-benzamide
The chloro-7-of I-161:4-[9-(the fluoro-phenyl of 2-)-5 hydrogen-benzo [c] Kui Linpyrimido quinoline [4,5-e] azepine-2 base is amino]-N-(2-pyridine-2-base-ethyl)-benzamide
The chloro-7-of I-162:4-[9-(the fluoro-phenyl of 3-)-5 hydrogen-benzo [c] Kui Linpyrimido quinoline [4,5-e] azepine-2 base is amino]-phenylformic acid
The chloro-7-of I-163:{3-[9-(the fluoro-phenyl of 2-)-5 hydrogen-benzo [c] Kui Linpyrimido quinoline [4,5-e] azepine-2 base is amino]-phenyl }-(4-methyl-piperazine-1-yl)-ketone
The chloro-7-of I-164:9-(2-fluorophenyl)-N-{4-[(4-pyridine-2-base piperazine-1-yl) carbonyl] phenyl }-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2-amine
The chloro-7-of I-165:9-(2-fluorophenyl)-N-(4-{[4-(2-morpholine-4-base-2-oxoethyl) piperazine-1-yl] carbonyl } phenyl)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2-amine
The chloro-7-of I-166:9-(2-fluorophenyl-N-(4-{[4-(2-furancarbonyl) piperazine-1-yl] carbonyl } phenyl)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2-amine
I-167: phenmethyl-4-(the chloro-7-of 4-{[9-(2-fluorophenyl)-5 hydrogen-Kui Linpyrimido quinoline-[5,4-d] [2] phenyl azepine-2-yl] amino } benzoyl) piperazine-1-carboxylate
I-168: ethyl-4-(the chloro-7-of 4-{[9-(2-fluorophenyl)-5 hydrogen-Kui Linpyrimido quinoline-[5,4-d] [2] phenyl azepine-2-yl] amino } benzoyl) piperazine-1-carboxylate
I-169:2-[4-(the chloro-7-of 4-{[9-(2-fluorophenyl)-5 hydrogen-Kui Linpyrimido quinoline-[5,4-d] [2] phenyl azepine-2-yl] amino } benzoyl) piperazine-1-yl] phenylformic acid
I-170:2-[4-(the chloro-7-of 4-{[9-(2-fluorophenyl)-5 hydrogen-Kui Linpyrimido quinoline-[5,4-d] [2] phenyl azepine-2-yl] amino } benzoyl) piperazine-1-yl]-N-sec.-propyl ethanamide
The chloro-7-of I-171:9-(2-fluorophenyl-N-(4-{[4-(2-tetramethyleneimine-1 base ethyl) piperazine-1-yl] carbonyl } phenyl)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2-amine
I-172:N-[2-(aminocarboxyl) phenyl] the chloro-7-of-4-{[9-(2-fluorophenyl)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2-yl] amino } benzamide
The chloro-7-of I-173:9-(2-fluorophenyl-N-{4-[(4-pyrimidine-2 base piperazine-1-yl) carbonyl] phenyl }-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2-amine
The chloro-7-of I-174:4-[9-(the chloro-6-fluorophenyl of 2-)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] azepine-2-yl] amino } phenylformic acid
The chloro-7-of I-175:9-(2,6-difluorophenyl-N-{4-[(3,5-lupetazin-1-yl) carbonyl] phenyl }-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2-amine
The chloro-7-of I-176:9-(2,6-difluorophenyl)-N-(4-{[3-(dimethylamino) tetramethyleneimine-1 base] carbonyl } phenyl)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2-amine
The chloro-N-{4-[(3 of I-177:9-, 5-lupetazin-1-yl) carbonyl] phenyl }-7-(the fluoro-6-p-methoxy-phenyl of 2-)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2-amine
The chloro-N-of I-178:9-(4-{[3-(dimethylamino) pyrrolidin-1-yl] carbonyl } phenyl)-7-(the fluoro-6-p-methoxy-phenyl of 2-)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2-amine
The chloro-N-of I-179:9-(4-{[3-(dimethylamino) azetidine-1-yl] carbonyl } phenyl)-7-(the fluoro-6-p-methoxy-phenyl of 2-)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2-amine
The chloro-7-of I-180:9-(2,6-difluorophenyl)-N-(4-{[3-(dimethylamino) azetidine-1-yl] carbonyl } phenyl)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2-amine
The chloro-7-of I-181:{4-[9-(the fluoro-phenyl of 2-)-5 hydrogen-benzo [c] Kui Linpyrimido quinoline [4,5-e] phenyl azepine-2 base is amino]-phenyl }-[4-(3-piperidin-1-yl-propyl group) piperazine-1-yl]-ketone
The chloro-7-of I-182:{4-[9-(the fluoro-phenyl of 2-)-5 hydrogen-benzo [c] Kui Linpyrimido quinoline [4,5-e] phenyl azepine-2 base is amino]-phenyl }-[4-(2-piperidin-1-yl-ethyl) piperazine-1-yl]-ketone
The chloro-7-of I-183:{4-[9-(the fluoro-phenyl of 2,6-bis-)-5 hydrogen-benzo [c] Kui Linpyrimido quinoline [4,5-e] phenyl azepine-2 base is amino]-phenyl }-(4-dimethylamino-piperidin-1-yl)-ketone
The chloro-7-of I-184:{4-[9-(the fluoro-phenyl of 2,6-bis-)-5 hydrogen-benzo [c] Kui Linpyrimido quinoline [4,5-e] phenyl azepine-2 base is amino]-phenyl }-(4-methyl-piperazine-1-yl)-ketone
The chloro-7-of I-185:4-[9-(the fluoro-phenyl of 2,6-bis-)-5 hydrogen-benzo [c] Kui Linpyrimido quinoline [4,5-e] phenyl azepine-2 base is amino]-phenyl }-N-(3-dimethylamino-propyl group)-N-methyl-benzamide
The chloro-7-of I-186:{4-[9-(the fluoro-6-methoxyl group-phenyl of 2-)-5 hydrogen-benzo [c] Kui Linpyrimido quinoline [4,5-e] phenyl azepine-2 base is amino]-phenyl }-(4-dimethylamino-piperidin-1-yl)-ketone
The chloro-7-of I-187:{4-[9-(the fluoro-phenyl of 2-)-5 hydrogen-benzo [c] Kui Linpyrimido quinoline [4,5-e] phenyl azepine-2 base is amino]-phenyl }-[4-(2-dipropyl amino-ethyl) piperazine-1-yl]-ketone
The chloro-7-of I-188:{4-[9-(the fluoro-phenyl of 2-)-5 hydrogen-benzo [c] Kui Linpyrimido quinoline [4,5-e] phenyl azepine-2 base is amino]-phenyl }-[4-(3-tetramethyleneimine-1 base-propyl group) piperazine-1 base]-ketone
The chloro-7-of I-189:{4-[9-(the fluoro-phenyl of 2-)-5 hydrogen-benzo [c] Kui Linpyrimido quinoline [4,5-e] phenyl azepine-2 base is amino]-phenyl }-[4-(2-morpholine-4 base-ethyl) piperazine-1-yl]-ketone
The chloro-7-of I-190:4-[9-(the fluoro-6-methoxyl group-phenyl of 2-)-5 hydrogen-benzo [c] Kui Linpyrimido quinoline [4,5-e] phenyl azepine-2 base is amino]-phenylformic acid
The chloro-7-of I-191:{4-[9-(the fluoro-phenyl of 2,6-bis-)-5 hydrogen-benzo [c] Kui Linpyrimido quinoline [4,5-e] phenyl azepine-2 base is amino]-phenyl }-(3 (S)-methyl-piperazine-1-yl)-ketone
I-192:(3-amino-azetidine-1 base)-the chloro-7-of 4-[9-(the fluoro-phenyl of 2-)-5 hydrogen-benzo [c] Kui Linpyrimido quinoline [4,5-e] phenyl azepine-2 base is amino]-phenyl }-ketone
The chloro-7-of I-193:{4-[9-(the fluoro-phenyl of 2-)-5 hydrogen-benzo [c] Kui Linpyrimido quinoline [4,5-e] phenyl azepine-2 base is amino]-phenyl }-(3-dimethylaminomethyl-azetidine-1 base)-ketone
The chloro-7-of I-194:{4-[9-(the fluoro-phenyl of 2,6-bis-)-5 hydrogen-benzo [c] Kui Linpyrimido quinoline [4,5-e] phenyl azepine-2 base is amino]-phenyl }-(3 (R)-methyl-piperazine-1-pyridyl)-ketone
The chloro-7-of I-195:{4-[9-(the fluoro-phenyl of 2,6-bis-)-5 hydrogen-benzo [c] Kui Linpyrimido quinoline [4,5-e] phenyl azepine-2 base is amino]-phenyl }-piperazine-1-pyridyl-ketone
I-196:(3-amino-tetramethyleneimine-1 base)-the chloro-7-of 4-[9-(the fluoro-phenyl of 2,6-bis-)-5 hydrogen-benzo [c] Kui Linpyrimido quinoline [4,5-e] phenyl azepine-2 base is amino]-phenyl }-ketone
The chloro-7-of I-197:{4-[9-(the fluoro-phenyl of 2,6-bis-)-5 hydrogen-benzo [c] Kui Linpyrimido quinoline [4,5-e] phenyl azepine-2 base is amino]-phenyl }-(3-methylamino-pyrrolidin-1-yl)-ketone
The chloro-7-of I-198:{4-[9-(the fluoro-phenyl of 2,6-bis-)-5 hydrogen-benzo [c] Kui Linpyrimido quinoline [4,5-e] phenyl azepine-2 base is amino]-N-methyl-N-(3-methylamino-propyl group)-benzamide
The chloro-7-of I-199:{4-[9-(the fluoro-6-methoxyl group-phenyl of 2-)-5 hydrogen-benzo [c] Kui Linpyrimido quinoline [4,5-e] phenyl azepine-2 base is amino]-phenyl }-(3-methylamino-pyrrolidin-1-yl)-ketone
The chloro-7-of I-200:4-[9-(the fluoro-phenyl of 2-)-5 hydrogen-benzo [c] Kui Linpyrimido quinoline [4,5-e] phenyl azepine-2 base is amino]-phenyl }-cyclohexyl carboxylic acid
The chloro-N-of I-201:9-(4-{[4-(2-p-methoxy-phenyl) piperazine-1-yl] carbonyl } phenyl)-7-(2-fluorophenyl)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2-amine
Amino (imido grpup) methyl of I-202:N-[] the chloro-7-of-4-{[9-(2,6-difluorophenyl)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2-yl] amino } benzamide
The chloro-7-of I-203:3-[9-(2,6-difluorophenyl)-5 hydrogen-benzo [c] Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2-yl] amino } phenylformic acid
The chloro-7-of I-204:9-(2,6-difluorophenyl)-N-(3-{[3-(dimethylamino) azetidine-1-yl] carbonyl } phenyl)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2-amine
The chloro-7-of I-205:9-(2,6-difluorophenyl)-N-(3-{[4-(dimethylamino) piperidin-1-yl] carbonyl } phenyl)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2-amine
The chloro-7-of I-206:9-(2,6-difluorophenyl)-N-(3-{[3-(dimethylamino) pyrrolidin-1-yl] carbonyl } phenyl)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2-amine
I-207:N-[2-(amino methyl)-1,3 benzoxazole-5-yl] the chloro-7-of-9-(2,6-difluorophenyl)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2-amine
The chloro-N-[4-of I-208:9-(4-[3-(diethylamino) propyl group] and piperazine-1-yl } carbonyl) phenyl]-7-(2-fluorophenyl)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2-amine
The chloro-N-[4-of I-209:9-(4-[2-(diethylamino) ethyl] and piperazine-1-yl } carbonyl) phenyl]-7-(2-fluorophenyl)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2-amine
The chloro-N-[4-of I-210:9-(4-[3-(dimethylamino) propyl group] and piperazine-1-yl } carbonyl) phenyl]-7-(2-fluorophenyl)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2-amine
The chloro-7-of I-211:9-(2-fluorophenyl)-N-[4-(4-[(1-methyl piperidine-3-yl) and methylpiperazine-1-yl } carbonyl) phenyl]-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2-amine
The chloro-7-of I-212:9-(2,6-difluorophenyl)-N-(4-nitrophenyl)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2-amine
The chloro-N-of I-213:9-(the chloro-4-{[4-of 3-(2-pyrrolidin-1-yl ethyl) piperazine-1-yl] carbonyl } phenyl)-7-(2-fluorophenyl)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2-amine
The chloro-N-of I-214:9-(the chloro-4-[(3-methylpiperazine-1-yl of 3-) carbonyl] phenyl)-7-(2-fluorophenyl)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2-amine
The chloro-N-of I-215:9-(the chloro-4-{[3-of 3-(dimethylamino) pyrrolidin-1-yl] carbonyl } phenyl)-7-(2,6-difluorophenyl)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2-amine
The chloro-4-{[(3-methylpiperazine-1-yl of the chloro-N-{3-of I-216:9-)] carbonyl } phenyl)-7-(2,6-difluorophenyl)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2-amine
The chloro-7-of I-217:N-[9-(2,6-difluorophenyl)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2-yl]-Isosorbide-5-Nitrae phenylenediamine
I-218: the chloro-7-of the chloro-4-{[9-of methyl 2-(2,6-difluorophenyl)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2-yl] amino }-benzoic ether
I-219:1-(the chloro-7-of 4-{[9-(2,6-difluorophenyl)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2-yl] amino } benzoyl)-piperazine-2 yl carboxylic acid
The chloro-7-2 of I-220:9-, 6-difluorophenyl)-N-(sting-1-of 4-{[4-(methylamino)-piperazine yl]-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2-amine
Amino sting-the 1-of piperazine of I-221:N-{4-[(3-yl) carbonyl] phenyl } the chloro-7-of-9-(2,6-difluorophenyl)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2-amine
The chloro-7-of I-222:9-(2,6-difluorophenyl)-N-{3-[(3,5-dimethylamino piperazine-1-yl) carbonyl] phenyl }-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2-amine
The chloro-7-of I-223:4-{[9-(2,6-difluorophenyl)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2-yl] amino } sting-1-of-N-[[4-(dimethylamino) piperazine yl] (imido grpup) methyl] benzamide
The chloro-7-of I-224:4-{[9-(2,6-difluorophenyl)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2-yl] amino }-N-[imido grpup (piperazine-1-yl) methyl] benzamide
The chloro-7-of I-225:4-{[9-(the fluoro-6-p-methoxy-phenyl of 2-)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2-yl] amino }-N-[3-(dimethylamino) propyl group]-N-methyl-benzamide
The chloro-7-of I-226:3-{[9-(the fluoro-6-p-methoxy-phenyl of 2-)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2-yl] amino }-N-[3-(dimethylamino) propyl group]-N-methyl-benzamide
The chloro-N-of I-227:9-(3-{[3-(dimethylamino) azetidine-1-yl] carbonyl } phenyl)-7-(the fluoro-6-p-methoxy-phenyl of 2-)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2-amine
The chloro-N-{3-[(3 of I-228:9-, 5-lupetazin-1-yl)] carbonyl phenyl)-7-(the fluoro-6-p-methoxy-phenyl of 2-)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2-amine
The chloro-N-of I-229:9-(sting-1-of 3-{[(4-(dimethylamino) piperazine yl] carbonyl } phenyl)-7-(the fluoro-6-p-methoxy-phenyl of 2-)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2-amine
I-230:N-(4-{[3-(amino methyl) azetidine-1-yl] carbonyl } phenyl) the chloro-7-of-9-(2-fluorophenyl)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2-amine
The chloro-N-of I-231:9-(3-{[(3-(dimethylamino) pyrrolidin-1-yl] carbonyl } phenyl)-7-(the fluoro-6-p-methoxy-phenyl of 2-)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2-amine
The chloro-7-of I-232:9-(the fluoro-6-p-methoxy-phenyl of 2-)-N-{4-[(3-methylpiperazine-1-yl) carbonyl] phenyl } 5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2-amine
The chloro-7-of I-233:9-(the fluoro-6-p-methoxy-phenyl of 2-)-N-{4-[(4-methylpiperazine-1-yl) carbonyl] phenyl } 5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2-amine
The chloro-7-of I-234:9-(2,6-difluorophenyl)-N-(4-{[3-(dimethylamino) azetidine-1-yl] carbonyl } phenyl)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2-amine
The chloro-7-of I-235:9-(the fluoro-6-p-methoxy-phenyl of 2-)-N-(4-{[3-(methylamino) azetidine-1-yl] carbonyl } phenyl)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2-amine
The chloro-7-of I-236:4-{[9-(2,6-difluorophenyl)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2-yl] amino } phenyl cyanide
The chloro-7-of I-237:4-{[9-(2,6-difluorophenyl)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2-yl] amino }-N-[[3-(dimethylamino) pyrrolidin-1-yl] (imido grpup) methyl] benzamide
The chloro-7-of I-238:4-{[9-(2,6-difluorophenyl)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2-yl] amino }-N-[(3,5-lupetazin-1-yl) (imido grpup) methyl] benzamide
I-239:N-{4-[(4-(sting-1-of amino piperazine yl) carbonyl] phenyl } the chloro-7-of-9-(2,6-difluorophenyl)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2-amine
I-240:N-{4-[(3-(amino-pyrrolidine-1-yl) carbonyl] phenyl } the chloro-7-of-9-(the fluoro-6-p-methoxy-phenyl of 2-)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2-amine
I-241:N-{4-[(4-(sting-1-of amino piperazine yl) carbonyl] phenyl } the chloro-7-of-9-(the fluoro-6-p-methoxy-phenyl of 2-)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2-amine
The chloro-7-of I-242:9-(the fluoro-6-p-methoxy-phenyl of 2-)-N-(4-{[4-(sting-1-of methylamino piperazine yl] carbonyl } phenyl)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2-amine
The chloro-7-of I-243:9-(the fluoro-6-p-methoxy-phenyl of 2-)-N-[4-(piperazine-1-base carbonyl) phenyl]-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2-amine
Sting-1-of the chloro-7-of I-244:9-(2,6-difluorophenyl)-N-{4-[[4-(dimethylamino) piperazine yl] (imido grpup) methyl] phenyl }-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2-amine
I-245:N-(the chloro-7-of 4-{[9-(2,6-difluorophenyl)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2-yl] amino } phenyl } guanidine
The chloro-7-of I-246:4-{[9-(2,6-difluorophenyl)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2-yl] amino }-N-[2-(methylamino) ethyl] benzamide
The chloro-7-of I-247:4-{[9-(2,6-difluorophenyl)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2-yl] amino }-N-[2-(dimethylamino) ethyl]-N-methyl-benzamide
I-248: methyl 4-(the chloro-7-of 4-{[9-(2,6-difluorophenyl)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2-yl] amino } benzoyl)-piperazine-2-carboxylate
I-249:2-[(4-carbonyl phenyl) amino]-7-(2-fluorophenyl)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-9-carboxylic acid
The chloro-7-of I-250:9-(2,6-difluorophenyl)-N-{4-[[3-(dimethylamino) pyrrolidin-1-yl] (imido grpup) methyl] phenyl }-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2 amine
The chloro-7-of I-251:9-(2,6-difluorophenyl)-N-{4-[(3,5-lupetazin-1-yl) (imido grpup) methyl] phenyl }-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2 amine
I-252:N-(2-aminoethyl)-4-{[9-chloro-7-(2,6-difluorophenyl)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2-yl] amino }-N-methyl-benzamide
The chloro-7-of I-253:9-(2,6-difluorophenyl)-N-(4-{[3-(dimethylamino) piperidin-1-yl] carbonyl } phenyl)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2 amine
The chloro-7-of I-254:4-{[9-(the fluoro-6-p-methoxy-phenyl of 2-)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2-yl] amino }-N-[2-(methylamino) ethyl] benzamide
The chloro-7-of I-255:4-{[9-(the fluoro-6-p-methoxy-phenyl of 2-)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2-yl] amino }-N-[2-(dimethylamino) ethyl]-N-methyl-benzamide
I-256:7-(2-fluorophenyl)-2-[(3-p-methoxy-phenyl) amino]-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-9-carboxylic acid
I-257:N-(3-aminopropyl)-4-{[9-chloro-7-(2,6-difluorophenyl)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2-yl] amino }-N-methyl-benzamide
The chloro-7-of the chloro-5-{[9-of I-258:2-(2,6-difluorophenyl)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2-yl] amino } phenylformic acid
The chloro-7-of I-259:4-{[9-(2,6-difluorophenyl)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2-yl] amino }-N-[[3-(dimethylamino) azetidine-1-yl] (imido grpup) methyl] benzamide
I-260:N-(amino-2 methyl-propyls of 2-) the chloro-7-of-4-{[9-(2,6-difluorophenyl)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2-yl] amino } benzamide
The chloro-7-of I-261:4-{[9-(the fluoro-6-p-methoxy-phenyl of 2-)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2-yl] amino }-N-methyl-N-[3-(methylamino) propyl group] benzamide
I-262:N-{4-[(3-amino piperidine-1 base) carbonyl] phenyl } the chloro-7-of-9-(the fluoro-6-p-methoxy-phenyl of 2-)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2-amine
The chloro-7-of I-263:9-(the fluoro-6-p-methoxy-phenyl of 2-)-N-(4-{[3-(methylamino) piperidin-1-yl] carbonyl } phenyl)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2-amine
The chloro-7-of I-264:N-(3-aminopropyl)-4-{[9-(the fluoro-6-p-methoxy-phenyl of 2-)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2-yl] amino }-N-methyl-benzamide
The chloro-7-of I-265:N-(2-aminopropyl)-4-{[9-(the fluoro-6-p-methoxy-phenyl of 2-)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2-yl] amino }-N-methyl-benzamide
I-266:4-(the chloro-7-of 4-{[9-(2,6-difluorophenyl)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2 base] amino } benzoyl) piperazine-2-carboxylic acid
The chloro-7-of I-267:9-(2,6-difluorophenyl)-N-{4-[[3-(dimethylamino) azetidine-1 base] (imido grpup) methyl] phenyl)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2-amine
The chloro-7-of I-268:9-(2,6-difluorophenyl)-N-(4-{ imido grpup [3-(methylamino) tetramethyleneimine-1 base] methyl } phenyl)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2-amine
The chloro-N-of I-269:9-(the chloro-3-{[4-of 4-(dimethylamino) piperidines-1 base] carbonyl } phenyl)-7-(2,6-difluorophenyl)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2-amine
The chloro-7-of I-270:9-(2,6-difluorophenyl)-N-[4-(5,5-dimethyl-4, hydrogen-imidazoles-2,5-dihydro-1 base) phenyl]-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2-amine
The chloro-7-of I-271:N-[9-(2,6-difluorophenyl)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2 base]-N '-pyrimidine-2 base benzene-Isosorbide-5-Nitrae diamines
I-272:4-{[9-(the amino 1-of 3-proyl-1 base)-7-(2,6-difluorophenyl)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2 base] amino } phenylformic acid
The bromo-7-of I-273:9-(2,6-difluorophenyl)-N-(3-p-methoxy-phenyl)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2-amine
The bromo-7-of I-274:4-{[9-(2,6-difluorophenyl)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2 base] amino } phenylformic acid
I-275:7-(2,6-difluorophenyl)-N-(3-p-methoxy-phenyl)-9-(3-tetramethyleneimine-1 base propyl alcohol base-1-yl)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2-amine
I-276:9-(the amino 1-of 3-proyl-1 base)-7-(2,6-difluorophenyl)-N-(3-p-methoxy-phenyl)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2-amine
I-277:4-(the chloro-7-[2-of 9-(trifluoromethyl) phenyl] and-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2 base } amino) phenylformic acid
The amino chloro-7-[2-of azetidine (trifluoromethyl) phenyl of I-278:N-{4-[(3-]-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2 base } amino) phenylformic acid
I-279:4-[(9-chloro-7-pyridine-2 base-5 hydrogen-Kui Linpyrimido quinolines [5,4-d] [2] phenyl azepine-2 base) amino] phenylformic acid
I-280:N-(the chloro-7-of 4-{[9-(2,6-difluorophenyl)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2 base] amino } phenyl)-4-methylpiperazine-1-carboxylic amine
The chloro-N-of I-281:9-(the chloro-3-{[3-of 4-(methylamino) tetramethyleneimine-1 base] carbonyl } phenyl)-7-(2,6-difluorophenyl)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2-amine
The chloro-N-of I-282:9-(the chloro-3-{[4-of 4-(methylamino) piperidines-1 base] carbonyl } phenyl)-7-(2,6-difluorophenyl)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2-amine
The chloro-7-of the chloro-5-{[9-of I-283:2-(2,6-difluorophenyl)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2 base] amino }-N-methyl-N-[2-(methylamino) ethyl] benzamide
I-284:N-{4-[(3-amino-pyrrolidine-1 base) (imido grpup) methyl] phenyl } the chloro-7-of-9-(2,6-difluorophenyl)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2-amine
I-285:2-(the chloro-7-of 4-{[9-(2,6-difluorophenyl)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2 base] amino } phenyl)-Isosorbide-5-Nitrae, 5,6-tetrahydropyrimidine-5 alcohol
I-286:N-{4-[(3-aminoazaheterocycles butane-1 base) carbonyl] phenyl } the chloro-7-of-9-(the fluoro-6-p-methoxy-phenyl of 2-)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2-amine
I-287:N-{4-[(4-amino piperidine-1 base) carbonyl] phenyl } the chloro-7-[2-of-9-(trifluoromethyl) phenyl]-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2-amine
The chloro-N-of I-288:9-(4-{[4-(methylamino) piperidines-1 base] carbonyl } phenyl)-7-[2-(trifluoromethyl) phenyl]-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2-amine
I-289:N-{4-[(3-amino-pyrrolidine-1 base) carbonyl] phenyl } the chloro-7-[2-of-9-(trifluoromethyl) phenyl]-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2-amine
The chloro-N-of I-290:9-(4-{[3-(methylamino) tetramethyleneimine-1 base] carbonyl } phenyl)-7-(2-trifluoromethyl) phenyl]-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2-amine
The chloro-N-of I-291:9-(the chloro-3-{[3-of 4-(methylamino) azetidine-1 base] carbonyl } phenyl)-7-(2,6-difluorophenyl)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2-amine
I-292:N-{3-[(4-amino piperidine-1 base) carbonyl]-4-chloro-phenyl-} the chloro-7-[2-of-9-(difluorophenyl) phenyl]-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2-amine
The chloro-7-[2-of I-293:9-(difluorophenyl)-N-(4-{[3-(dimethylamino) piperidines-1 base] carbonyl } phenyl)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2-amine
I-294: methyl 4-amino-1-(the chloro-7-of 4-{[9-(2,6-difluorophenyl)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2 base] amino } benzoyl)-piperidines-4-carboxylicesters
I-295:4-amino-1-(the chloro-7-of 4-{[9-(2,6-difluorophenyl)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2 base] amino } benzoyl)-piperidines-4-carboxylic acid
I-296:N-{4-[(3-aminoazaheterocycles butane-1 base) carbonyl] phenyl } the chloro-7-[2-of-9-(trifluoromethyl) phenyl]-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2-amine
The chloro-N-of I-297:9-(4-{[3-(methylamino) azetidine-1 base] carbonyl } phenyl)-7-(2-trifluoromethyl) phenyl]-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2-amine
I-298:N-{4-[(4-amino piperidine-1 base) carbonyl] phenyl }-9-chloro-7-pyridine-2 base-5 hydrogen-Kui Linpyrimido quinolines [5,4-d] [2] phenyl azepine-2-amine
I-299:N-{4-[(3-amino-pyrrolidine-1 base) carbonyl] phenyl }-9-chloro-7-pyridine-2 base-5 hydrogen-Kui Linpyrimido quinolines [5,4-d] [2] phenyl azepine-2-amine
I-300: the chloro-7-of ethyl 2-amino-4-[(4-{[9-(2,6-difluorophenyl)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2 base] amino } benzoyl) amino] butyric ester
The chloro-7-of I-301:4-{[9-(3-fluorine pyridine-2 base)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2 base] amino } phenylformic acid
I-302:9-{[3-(dimethylamino) azetidine-1 base] carbonyl }-7-(2-fluorophenyl)-N-(3-p-methoxy-phenyl)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2-amine
I-303:7-(2-fluorophenyl)-2-[(3-p-methoxy-phenyl) amino]-N-methyl-N-[3-(3-methylamino) propyl group]-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-9-carboxylic acid amides
I-304:N-{4-[(4-amino piperidine-1 base) carbonyl] phenyl } the chloro-7-of-9-(3 fluorine pyridine-2 base)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2-amine
I-305:N-{4-[(3-amino-pyrrolidine-1 base) carbonyl] phenyl } the chloro-7-of-9-(3 fluorine pyridine-2 base)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2-amine
I-306:2-(the chloro-7-[2-of 4-{[9-(difluorophenyl)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2 base] amino } phenyl)-4,5-dihydro-1 hydrogen-imidazole-5-carboxylic acid
I-307:N-(the chloro-7-of 4-{[9-(2,6-difluorophenyl)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2 base] amino } phenyl)-2-(dimethylamino) ethanamide
I-308:2-amino-N-(the chloro-7-of 4-{[9-(2,6-difluorophenyl)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2 base] amino } phenyl)-2-methyl propanamide
I-309: ethyl (2R)-4-amino-2-[(4-{[9-chloro-7-(2,6-difluorophenyl)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2 base] amino } benzoyl) amino] butyric ester
The chloro-7-of I-310:4-[(4-{[9-(2,6-difluorophenyl)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2 base] amino } benzoyl)-N methyl piperazine-2-carboxylic acid amides
I-311:7-(2-fluorophenyl)-2-[(3-p-methoxy-phenyl) amino]-N-(3-morpholine-4 base propyl group)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-9-carboxylic acid amides
I-312:9-[(3,5-lupetazin-1 base) carbonyl]-7-[(2-fluorophenyl)-N-(3-p-methoxy-phenyl)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2-amine
The chloro-N-of I-313:9-(the chloro-4-{[4-of 3-(dimethylamino) piperidines-1 base] carbonyl } phenyl)-7-(2,6-difluorophenyl)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2-amine
I-314: ethyl-2-(the chloro-7-of 4-{[9-(2,6-difluorophenyl)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2 base] amino } phenyl)-4,5-dihydro-1 hydrogen-imidazole-5-carboxylic acid ester
The chloro-N-of I-315:9-(4-{[3-(methylamino) tetramethyleneimine-1 base] carbonyl } phenyl)-7-(base-5, pyridine-2 hydrogen-Kui Linpyrimido quinolines [5,4-d] [2] phenyl azepine-2-amine
The chloro-N-of I-316:9-(4-{[4-(methylamino) piperidines-1 base] carbonyl } phenyl)-7-(base-5, pyridine-2 hydrogen-Kui Linpyrimido quinolines [5,4-d] [2] phenyl azepine-2-amine
I-317:4-(the chloro-7-of 4-{[9-(2,6-difluorophenyl)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2 base] amino } benzoyl) piperazine-2-carboxylic acid amides
I-318:N-{4-[(3-amino-pyrrolidine-1 base) carbonyl]-3-chloro-phenyl-} the chloro-7-of-9-(2,6-difluorophenyl)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2-amine
I-319:N-(the chloro-7-of 4-{[9-(2,6-difluorophenyl)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2 base] amino } phenyl) piperidines-4-carboxylic acid amides
The chloro-7-of I-320:4-{[9-(the fluoro-6-{ methyl of 2-[2-(methylamino) ethyl] amino } phenyl)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2 base] amino } phenylformic acid
The chloro-7-of I-321:9-(2,4 difluorobenzene base)-N-{4-[(3,5-lupetazin-1 base) carbonyl] phenyl }-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2-amine
The chloro-7-of I-322:9-(2,4-Dimethoxyphenyl)-N-{4-[(3,5-lupetazin-1 base) carbonyl] phenyl }-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2-amine
The chloro-7-of I-323:9-(the chloro-6-fluorophenyl of 2-)-N-{4-[(3,5-methylpiperazine-1 base) carbonyl] phenyl }-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2-amine
The chloro-7-of I-324:9-(the chloro-6-fluorophenyl of 2-)-N-{4-[(3,5-lupetazin-1 base) carbonyl] phenyl }-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2-amine
The chloro-7-of I-325:9-(the chloro-6-fluorophenyl of 2-)-N-{4-[(4-(methylamino) piperazine-1 base) carbonyl] phenyl }-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2-amine
The chloro-7-of I-326:9-(the chloro-6-fluorophenyl of 2-)-N-{4-[(3-(methylamino) piperazine-1 base) carbonyl] phenyl }-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2-amine
The chloro-7-of I-327:9-(the chloro-6-fluorophenyl of 2-)-N-{4-[(3-(methylamino) tetramethyleneimine-1 base) carbonyl] phenyl }-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2-amine
The chloro-N-of I-328:9-(3,4-Dimethoxyphenyl)-7-{2-[(dimethylamino) methyl] phenyl }-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2-amine
The chloro-7-of I-329:9-(2-p-methoxy-phenyl)-N-{4-[(3-methylpiperazine-1 base) carbonyl] phenyl }-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2-amine
The chloro-N-{4-[(3 of I-330:9-, 5-lupetazin-1 base) carbonyl] phenyl }-7-(2-p-methoxy-phenyl)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2-amine
The chloro-7-of I-331:9-(2-p-methoxy-phenyl)-N-{4-[(4-methylamino) piperazine-1 base] carbonyl } phenyl)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2-amine
The chloro-7-of I-332:9-(2-p-methoxy-phenyl)-N-{4-[(3-methylamino) tetramethyleneimine-1 base] carbonyl } phenyl)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2-amine
The chloro-7-of I-333:9-(2-p-methoxy-phenyl)-N-{4-[(3-methylamino) piperidines-1 base] carbonyl } phenyl)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2-amine
The chloro-7-of I-334:4-{[9-(2,6-difluorophenyl)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2 base] amino }-N-methyl-benzamide
The chloro-7-of I-335:4-{[9-(the fluoro-6-{ methyl of 2-[3-(methylamino) propyl group] amino } phenyl)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2 base] amino } phenylformic acid
The chloro-7-of I-336:4-{[9-(the fluoro-6-{ methyl of 2-[3-(methylamino) propyl group] amino } phenyl)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2 base] amino }-N-methyl-benzamide
I-337:1-(the chloro-7-of 4-{[9-(2,6-difluorophenyl)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2 base] amino } phenyl) ethyl ketone
I-338:N-[3-(the amino 1-of 3-propine-1 base) phenyl] the chloro-7-of-9-(2,6-difluorophenyl)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2-amine
The fluoro-6-[(2-hydroxyethyl of the chloro-7-{2-of I-339:4-[(9-) amino] phenyl }-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2 base) amino]-N-methyl-benzamide
I-340:4-[(7-{2-[(2-amino-ethyl) amino]-6-fluorophenyl } the chloro-5 hydrogen-Kui Linpyrimido quinoline of-9-[5,4-d] [2] phenyl azepine-2 base) amino]-N-methyl-benzamide
I-341:4-amino-1-(the chloro-7-of 4-{[9-(2,6-difluorophenyl)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2 base] amino } benzoyl)-N-methyl piperidine-4-carboxylicesters
The chloro-7-{2-[4-of I-342:4-[(9-(dimethylamino) piperidines-1 base]-6-fluorophenyl }-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2 base) amino]-N-methyl-benzamide
The chloro-7-of I-343:9-(2,6-difluorophenyl)-N-{3-[(3-dimethylamino) 1-propine-1 base] phenyl }-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2-amine
The chloro-7-of I-344:9-(2,6-difluorophenyl)-N-(3-iodophenyl)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2-amine
The chloro-7-of I-345:4-{[9-(2-{[2-(dimethylamino) ethyl] amino }-6-fluorophenyl)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2 base) amino]-N-methyl-benzamide
The chloro-7-{2-[[2-of I-346:4-{[9-(dimethylamino) ethyl] (methyl) amino]-6-fluorophenyl }-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2 base) amino]-N-methyl-benzamide
The chloro-7-of I-347:4-{[9-(the fluoro-6-{ methyl of 2-[2-(methylamino) ethyl] amino } phenyl)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2 base] amino }-N-methyl-benzamide
I-348:4-(7-[2-(4-amino piperidine-1 base)-6-fluorophenyl] and the chloro-5 hydrogen-Kui Linpyrimido quinoline of-9-[5,4-d] [2] phenyl azepine-2 base } amino)-N-methyl-benzamide
I-349:7-(2-fluorophenyl)-2-[(3-methoxyl group) amino]-N-methyl-N-[2-(methylamino) ethyl]-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-9-carboxylic acid amides
I-350:4-amino-1-(the chloro-7-of 4-{[9-(2,6-difluorophenyl)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2 base] amino } benzoyl) piperidines-4-carboxylic acid amides
The chloro-7-of I-351:9-(the chloro-6-fluorophenyl of 2-)-N-(4-{[3-(methylamino) azetidine-1 base] carbonyl } phenyl)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2-amine
The chloro-7-of I-352:9-(2,6-difluorophenyl)-N-(4-methyl isophthalic acid, 3-thiazole-2 base)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2-amine
I-353:7-(2,6-difluorophenyl)-2-[(3-p-methoxy-phenyl) amino]-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-9-carboxylic acid
I-354:4-(the fluoro-6-of the chloro-7-[2-of 9-(methylamino) phenyl] and-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2 base } amino)-N-methyl-benzamide
The chloro-7-of I-355:2-{[9-(2,6-difluorophenyl)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2 base] amino }-N-methyl isophthalic acid, 3-thiazole-4-carboxylic acid amides
I-356:N-1 hydrogen-benzimidazolyl-2 radicals base-9-chloro-7-(2,6-difluorophenyl)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2-amine
I-357:7-(2,6-difluorophenyl)-2-[(4-methyl isophthalic acid, 3-thiazole-2 base) amino]-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-9-carboxylic acid
I-358:3-amino-1-(the chloro-7-of 3-{[9-(2,6-difluorophenyl)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2 base] amino } phenyl) acetone-1
I-359:1-(the chloro-7-of 3-{[9-(2,6-difluorophenyl)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2 base] amino } phenyl)-3-(methylamino) acetone-1
The chloro-7-of I-360:2-{[9-(2,6-difluorophenyl)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2 base] amino }-1,3-thiazoles-4-carboxylic acid
I-361: the chloro-7-of ethyl 2-{[9-(2,6-difluorophenyl)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2 base] amino }-1,3-thiazoles-4-carboxylicesters
The chloro-7-of I-362:9-(2,6-difluorophenyl)-N-{4-[(3,5-lupetazin-1 base) carbonyl]-1,3-thiazoles-2 base }-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2-amine
I-363: the chloro-7-of ethyl 2-{[9-(2,6-difluorophenyl)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2 base] amino }-1,3-oxazole-5-carboxylicesters
The chloro-7-of I-364:2-{[9-(2,6-difluorophenyl)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2 base] amino }-1,3-thiazoles-5-carboxylic acid
The chloro-7-of I-365:9-(2,6-difluorophenyl)-N-(4-{[(3R)-3-methylpiperazine-1 base] carbonyl }-1,3-thiazoles-2 base)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2-amine
The chloro-7-of I-366:9-(2,6-difluorophenyl)-N-(4-{[(2R)-2-methylpiperazine-1 base] carbonyl } phenyl)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2-amine
The chloro-7-of I-367:9-(2,6-difluorophenyl)-N-(4-{[3-(methylamino) tetramethyleneimine-1 base] carbonyl }-1,3-thiazoles-2 base)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2-amine
The chloro-7-of I-368:2-{[9-(2,6-difluorophenyl)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2 base] amino }-1,3-thiazoles-4-carboxylic acid
The chloro-7-of I-369:9-(2,6-difluorophenyl)-N-{5-[(3,5-lupetazin-1 base) carbonyl]-1,3-thiazoles-2 base }-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2-amine
The chloro-7-of I-370:9-(2,6-difluorophenyl)-N-(5-{[3-(methylamino) tetramethyleneimine-1 base] carbonyl }-1,3-oxazole-2 base)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2-amine
The chloro-7-of I-371:4-{[9-(2,6-difluorophenyl)-5-methyl-5 hydrogen-Kui Linpyrimido quinolines [5,4-d] [2] phenyl azepine-2 base] amino } phenylformic acid
The chloro-7-of I-372:9-(2,6-difluorophenyl)-N-(3-{[3-(methylamino) propyl group] phenyl }-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2-amine
I-373:N-[3-(3-(aminopropyl) phenyl] the chloro-7-of-9-(2,6-difluorophenyl)-5-methyl-5 hydrogen-Kui Linpyrimido quinolines [5,4-d] [2] phenyl azepine-2-amine
The chloro-7-of I-374:9-(2,6-difluorophenyl)-N-{4-[(3,5-lupetazin-1 base) carbonyl]-1,3-oxazole-2 base }-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2-amine
The chloro-7-of I-375:9-(2,6-difluorophenyl)-N-(4-{[3-(methylamino) tetramethyleneimine-1 base] carbonyl }-1,3-oxazole-2 base)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2-amine
I-376:7-(2,6-difluorophenyl)-2-(4-[(3,5-lupetazin-1 base) and carbonyl] phenyl } amino)-N-methyl-5 hydrogen-Kui Linpyrimido quinolines [5,4-d] [2] phenyl azepine-2-amine
I-377:2-{[4-(aminocarboxyl) phenyl] amino }-7-(2,6-difluorophenyl)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-9-carboxylic acid
I-378:1-(the chloro-7-of 4-{[9-(2,6-difluorophenyl)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2 base] amino } benzoyl)-N-methyl-4-(methylamino) piperidines-4-carboxylic acid amides
I-379:N-{4-[(3-amino-3-methylpyrrolidin-1 base) carbonyl] phenyl } the chloro-7-of-9-(2,6-difluorophenyl)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2-amine
The chloro-7-of I-380:9-(2,6-difluorophenyl)-N-(4-{[3-methyl-3-(methylamino) tetramethyleneimine-1 base] carbonyl } phenyl)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2-amine
I-381:1-(the chloro-7-of 4-{[9-(2,6-difluorophenyl)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2 base] amino } benzoyl)-4-(methylamino) piperidines-4-carboxylic acid amides
The chloro-7-of I-382:9-(2,6-difluorophenyl)-N-{4-[(3,3,5-tri methyl piperazine-1 base) carbonyl] phenyl }-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2-amine
I-383:N-1-azabicyclo [2.2.2] octane-3 base-4-{[9-chloro-7-(2,6-difluorophenyl)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2 base] amino }-N-methyl-benzamide
I-384:N-1-azabicyclo [2.2.2] octane-3 base-4-{[9-chloro-7-(2,6-difluorophenyl)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2 base] amino } benzamide
The chloro-7-of I-385:4-{[9-(2,6-difluorophenyl)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2 base] amino }-N-hydroxybenzamide
I-386:N-{4-[(aminooxy) carbonyl] phenyl } the chloro-7-of-9-(2,6-difluorophenyl)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2-amine
The chloro-7-of I-387:4-{[9-(2,6-difluorophenyl)-7 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2 base] amino } phenylformic acid
The chloro-7-of I-388:4-{[9-(2,3-difluorophenyl)-7 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2 base] amino } phenylformic acid
I-389:3-amino-1-(the chloro-7-of 4-{[9-(2,6-difluorophenyl)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2 base] amino } benzoyl)-N-methylpyrrolidin-3-carboxylic acid amides
I-390:3-amino-1-(the chloro-7-of the chloro-4-{[9-of 2-(2,6-difluorophenyl)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2 base] amino } benzoyl) tetramethyleneimine-3-carboxylic acid amides
The chloro-7-of I-391:9-(2,6-difluorophenyl)-N-{4-[(3,3-lupetazin-1 base) carbonyl] phenyl }-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2-amine
The chloro-7-of I-392:4-{[9-(2,6-difluorophenyl)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2 base] amino }-N-(8-methyl-8-azabicyclo [3,2,1] octane-3-yl) benzamide
The chloro-7-of I-393:9-(2,6-difluorophenyl)-N-(4-{[3-(dimethylamino)-3-methylpyrrolidin-1 base] carbonyl } phenyl)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2-amine
The chloro-7-of I-394:9-(2,6-difluorophenyl)-N-(3-methyl isophthalic acid hydrogen-pyrazoles-5 base]-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2-amine
The chloro-7-of the chloro-4-{[9-of I-395:2-(2,6-difluorophenyl)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2 base] amino } phenylformic acid
I-396:4-amino-1-(the chloro-7-of the chloro-4-{[9-of 2-(2,6-difluorophenyl)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2 base] amino } benzoyl)-N-methyl piperidine-4-carboxylic acid amides
I-397:4-amino-1-(the chloro-7-of the chloro-4-{[9-of 2-(2,6-difluorophenyl)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2 base] amino } benzoyl)-N, N-lupetidine-4-carboxylic acid amides
I-398:4-[(9-methoxyl group-7-oxo-6,7-dihydro-5 hydrogen-Kui Linpyrimido quinolines [5,4-d] [2] phenyl azepine-2 base) amino] phenylformic acid
I-399:2-(4-[(3,5-lupetazin-1 base) and carbonyl] phenyl } amino)-9-methoxyl group-5,6-dihydro-7 hydrogen-Kui Linpyrimido quinolines [5,4-d] [2] phenyl azepine-7-ketone
I-400:9-methoxyl group-2-[(4-{[3-(methylamino) tetramethyleneimine-1 base] carbonyl } phenyl) amino }--5,6-dihydro-7 hydrogen-Kui Linpyrimido quinolines [5,4-d] [2] phenyl azepine-7-ketone
I-401:4-[(8-methyl-7-oxo-5,6,7,8-tetrahydropyrimidine is [5,4-c] pyrrolo-[3,2-e] azepine-2 base also) amino] phenylformic acid
I-402:2-(4-[(3,5-lupetazin-1 base) and carbonyl] phenyl } amino)-8-methyl-5,8-dihydro-pyrimidin is [5,4-c] pyrrolo-[3,2-e] azepine-7 (6 hydrogen)-one also
I-403:2-[(3-p-methoxy-phenyl) amino]-8-methyl-5,8-dihydro-pyrimidin is [5,4-c] pyrrolo-[3,2-e] azepine-7 (6 hydrogen)-one also
The chloro-2-[(3 of I-404:9-, 4-Dimethoxyphenyl) amino]-5,6-dihydro-7 hydrogen-Kui Linpyrimido quinolines [5,4-d] [2] phenyl azepine-7-ketone
The chloro-7-of I-405:4-{[4-amino-9-(2,6-difluorophenyl)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2 base] amino } phenylformic acid
The chloro-N-of I-406:9-(the chloro-4-{[4-of 3-(methylamino) piperidines-1 base] carbonyl } phenyl)-7-(2,6-difluorophenyl)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2-amine
The chloro-N-of I-407:9-(the chloro-4-{[4-of 3-(methylamino) piperidines-1 base] carbonyl } phenyl)-7-(the fluoro-6-p-methoxy-phenyl of 2-)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2-amine
The chloro-7-of I-408:4-{[9-(the fluoro-hydroxy phenyl of 2-)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2 base] amino } phenylformic acid
The chloro-N-[4-of I-409:9-(1,7 phenodiazine spiral shell [4.4] ninth of the ten Heavenly Stems-7 base carbonyl) phenyl]-7-(2,6-difluorophenyl)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2-amine
The chloro-7-of I-410:9-(2,6-difluorophenyl)-N-(4-{[2-(methylamino)-7-azabicyclo [2,2,1] heptan-7 base] carbonyl } phenyl)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2-amine
I-411:1-(the chloro-7-of 4-{[9-(2,6-difluorophenyl)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2 base] amino } benzoyl)-N-methyl-3-(methylamino) tetramethyleneimine-3-carboxylic acid amides
I-412:1-(the chloro-7-of 4-{[9-(2,6-difluorophenyl)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2 base] amino } benzoyl)-3-(methylamino) tetramethyleneimine-3-carboxylic acid amides
I-413:1-(the chloro-7-of the chloro-4-{[9-of 2-(2,6-difluorophenyl)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2 base] amino } benzoyl)-N-methyl-3-(methylamino) tetramethyleneimine-3-carboxylic acid amides
The chloro-7-of I-414:9-(2,6-difluorophenyl)-N-(4-{[3-methyl-3-(methylamino) piperidines-1 base] carbonyl } phenyl)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2-amine
The chloro-7-of I-415:9-(the fluoro-6-p-methoxy-phenyl of 2-)-N-(4-{[3-methyl-3-(methylamino) piperidines-1 base] carbonyl } phenyl)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2-amine
The chloro-7-of the chloro-4-[9-of I-416:{2-(the fluoro-6-methoxyl group-phenyl of 2-)-5 hydrogen-phenylpropyl alcohol [c] Kui Linpyrimido quinoline [4,5-e] phenyl azepine-2 base is amino] phenyl }-(3-methyl-3-methylamino piperidines-1 base)-ketone
The chloro-7-of I-417:9-(2,6-difluorophenyl)-N-(4-{[4-methyl-4-(methylamino) piperidines-1 base] carbonyl } phenyl)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2-amine
The chloro-7-of I-418:9-(2,6-difluorophenyl)-N-(4-{[4-(dimethylamino)-4-methyl piperidine-1 base] carbonyl } phenyl)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2-amine
I-419:N-{4-[(4-amino-4-methyl piperidine-1 base) carbonyl] phenyl } the chloro-7-of-9-(2,6-difluorophenyl)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2-amine
The chloro-N-of I-420:9-(the chloro-4-{[4-methyl-4-of 3-(methylamino) piperidines-1 base] carbonyl } phenyl)-7-(2,6-difluorophenyl)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2-amine
The chloro-7-of I-421:9-(the fluoro-6-methoxyl group-phenyl of 2-)-N-(4-{[4-methyl-4-(methylamino) piperidines-1 base] carbonyl } phenyl)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2-amine
The chloro-7-of the chloro-4-[9-of I-422:2-(the fluoro-6-methoxyl group-phenyl of 2-)-5 hydrogen-benzo [c] Kui Linpyrimido quinoline [4,5-e] azepine-2 base is amino]-phenyl }-(4-methyl-4-methylamino-piperidines-1 base)-ketone
The chloro-7-of I-423:9-(the fluoro-6-methoxyl group-phenyl of 2-)-N-(the fluoro-4-{[4-methyl-4-of 3-(methylamino) piperidines-1 base] carbonyl } phenyl)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2-amine
The chloro-4-[(3 of the chloro-N-{3-of I-424:9-, 3,5,5-tetramethyl-piperazine-1 base) carbonyl] phenyl }-7-(the fluoro-6-methoxyl group-phenyl of 2-)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2-amine
The chloro-7-of I-425:N-1-azabicyclo [2,2,2] pungent-3 bases-4-{[9-(the fluoro-6-methoxyl group-phenyl of 2-)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2 base] amino } the fluoro-N-methyl-benzamide of-2-
The chloro-7-of I-426:N-1-azabicyclo [2,2,2] pungent-3 bases-4-{[9-(the fluoro-6-methoxyl group-phenyl of 2-)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2 base] amino }-N-methyl-benzamide
I-427:N-8-azabicyclo [3,2,1] pungent-3 bases-4-{[9-chloro-7-(2,6-difluorophenyl)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2 base] amino }-N-methyl-benzamide
The chloro-7-of I-428:9-(2,6-difluorophenyl)-N-(pungent-8 bases of 4-{[3-(methylamino)-8-azabicyclo [3,2,1]] carbonyl } phenyl)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2-amine
The chloro-7-of I-429:9-(the fluoro-6-methoxyl group-phenyl of 2-)-N-(pungent-8 bases of 4-{[3-(methylamino)-8-azabicyclo [3,2,1]] carbonyl } phenyl)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2-amine
I-430:4-{[7-(2,6-difluorophenyl)-9-methyl-5 hydrogen-Kui Linpyrimido quinolines [5,4-c] thieno-s [2,3-e] azepine-2 base] amino } phenylformic acid
I-431:7-(2,6-difluorophenyl)-N-{4-[(3,3,5,5-tetrahydrochysene piperazine-1 base) carbonyl] phenyl }-5 hydrogen-Kui Linpyrimido quinoline [5,4-c] thieno-[2,3-e] azepine-2-amine
I-432:N-{4-[(3-amino-3-methylpyrrolidin-1 base) carbonyl] phenyl }-7-(2,6-difluorophenyl)-10-methyl-5,10 dihydro-pyrimidins are [5,4-c] pyrrolo-[2,3-e] azepine-2-amine also
I-433:7-(2,6-difluorophenyl)-9-methyl-N-(4-{[3-(methylamino) tetramethyleneimine-1 base] carbonyl } phenyl)-5 hydrogen-furo [2,3-c] Kui Linpyrimido quinoline [4,5-e] azepine-2-amine
I-434:4-(2,6-difluorophenyl)-2-methyl-N-(4-{[3-methyl-3-(methylamino) tetramethyleneimine-1 base] carbonyl } phenyl)-6 hydrogen-Kui Linpyrimido quinoline [5,4-c] [1,3] thiazole is [4,5-e] azepine-9-amine also
I-435:N-{4-[(3-amino-3-methylpyrrolidin-1 base) carbonyl] phenyl }-7-(the fluoro-6-methoxyl group-phenyl of 2-)-5,9-dihydro-pyrimidin is [5,4-c] [1,3] pyrrolo-[3,4-e] azepine-2-amine also
I-436:4-{[4-(2,6-difluorophenyl)-1-methyl isophthalic acid, 6-dihydro-pyrazolo [4,3-c] Kui Linpyrimido quinoline [4,5-e] azepine-9 base] amino } phenylic acid
I-437:1-{4-[4-(the fluoro-phenyl of 2,6-bis-)-hydrogen-3-sulfo--5,2-methyl-6,8,10 three nitrogen-benzos [e] Azulene-9 base is amino]-benzoyl }-4-dimethylamino-piperidines-4-carboxylic acid methyl acid amides
I-438:4-(4-{[7-(2,6-difluorophenyl)-5 hydrogen-furo [3,2-c] Kui Linpyrimido quinoline [4,5-e] azepine-2 base] amino } benzoyl)-N methyl piperazine-2-carbonyl acid amides
I-439:4-(4-{[4-(2,6-difluorophenyl)-6 hydrogen-isoxazoles are [4,5-c] Kui Linpyrimido quinoline [4,5-e] azepine-9 base also] amino } benzoyl)-N methyl piperazine-2-carbonyl acid amides
I-440:4-(2,6-difluorophenyl)-9-[4-{[3-methyl-3-(methylamino) tetramethyleneimine-1 base] carbonyl } phenyl) amino]-3,6-glyoxalidine is [4,5-c] Kui Linpyrimido quinoline [4,5-e] azepine-2 (1 hydrogen)-one also
I-441:2-amino-N-(3-{[7-(2,6-difluorophenyl)-8,10-dimethyl-5 hydrogen-Kui Linpyrimido quinolines [5,4-c] thieno-s [3,2-e] azepine-2 base] amino } phenyl)-N, 2-dimethyl propylene acid amides
The chloro-7-of I-442:9-(2,6-difluorophenyl)-N-{3-[(2,2,6,6-tetramethyl piperidine also-4 bases) oxo] phenyl }-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2-amine
I-443:4-(the chloro-7-of 4-{[9-(2,6-difluorophenyl)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2 base] amino } phenyl)-N-methyl isophthalic acid-(methylamino) hexanaphthene carboxylic acid amides
I-444:7-(3-{[7-(2 fluoro-p-methoxy-phenyl)-9-methoxyl group-5 hydrogen-Kui Linpyrimido quinolines [5,4-d] [2] phenyl azepine-2 base] amino } phenyl)-1,7 phenodiazine spiral shell [4.4] ninth of the ten Heavenly Stems-6 ketone
The chloro-N-[4-of I-445:9-(pungent-3 bases of 3,8-diaza-bicyclo [3,2,1]) phenyl]-7-(2,6-difluorophenyl)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2-amine
I-446:1-(the chloro-7-of 3-{[9-(2,6-difluorophenyl)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2 base] amino } phenyl)-3,3,5-tri methyl piperazine-2-ketone
The chloro-N-[4-of I-447:9-(lupetidine-4 base) phenyl]-7-(the fluoro-6-methoxyl group-phenyl of 2-)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2-amine
I-448:N-[4-(1-amino-1-methylethyl) the chloro-7-of-9-(2,6-difluorophenyl)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2-amine
I-449:N-[4-(pungent-2 base carbonyls of 2,5-phenodiazine spiral shell [3.4]) phenyl]-7-(2,6-difluorophenyl)-10-methyl-5 hydrogen-isothiazole [5,4-c] Kui Linpyrimido quinoline [4,5-e] azepine-2-amine also
I-450:4-(2,6-difluorophenyl)-1-methyl-9-[(4-{[4-methyl-4-(methylamino) piperazine-1 base] carbonyl } phenyl) amino]-1,6-dihydro-2 hydrogen-Kui Linpyrimido quinolines [5,4-c] [1,3] thiazole is [4,5-e] azepine-2-ketone also
I-451:4-(2,6-difluorophenyl)-N-[4-(1 hydrogen-imidazoles-2 base) phenyl]-1 methyl isophthalic acid, 6-glyoxalidine is [4,5-c] Kui Linpyrimido quinoline [4,5-e] azepine-9-amine also
I-452:4-{[7-(2,6-difluorophenyl)-5 hydrogen-[1] cumarone is [2,3-c] Kui Linpyrimido quinoline [4,5-e] azepine-2 base also] amino } phenylformic acid
I-453:7-(2,6-difluorophenyl)-N-{4-[(3,3,5,5-tetramethyl-piperazine-1 base) carbonyl] phenyl }-8,9,10,11-tetrahydrochysene-5 hydrogen-pyrido [4 ', 3 ': 4,5] thieno-s [3,2-c] Kui Linpyrimido quinolines [4,5-e] azepine-2-amine
The bromo-7-of I-454:9-(2-fluorophenyl)-N-(4-{[3-(methylamino) tetramethyleneimine-1 base] carbonyl } phenyl)-5,8-dihydro-Kui Linpyrimido quinoline [5,4-c] pyrrolo-[3,2-e] azepine-2-amine
I-455:7-(2-fluorophenyl)-N-(3-methyl isophthalic acid hydrogen-indazole-6 base)-5,12-dihydro-pyrimidin is [4 ', 5 ': 5,6] azepines [4,3-b] indoles-2-amine also
I-456:1-(4-{[7-(2,6-difluorophenyl)-9,10-dimethyl-5,8-dihydro-Kui Linpyrimido quinoline [5,4-c] pyrrolo-[3,2-e] azepine-2 base] amino } benzoyl)-3-(methylamino) tetramethyleneimine-3-carboxylic acid amides
The chloro-7-of I-457:{3-[9-(the fluoro-6-methoxyl group-phenyl of 2-)-5 hydrogen-benzo [c] Kui Linpyrimido quinoline [4,5-e] azepine-2 base is amino]-phenyl }-(4-methyl-piperazine-1 base)-ketone
The chloro-7-of I-458:[9-(the fluoro-phenyl of 2,6-bis-)-5 hydrogen-benzo [c] Kui Linpyrimido quinoline [4,5-e] azepine-2 base]-(2-methylamino methyl-benzothiazole-6 base)-amine
The chloro-7-of I-459:4-[9-(2-isopropoxy-phenyl)-5 hydrogen-benzo [c] Kui Linpyrimido quinoline [4,5-e] azepine-2 base]-(2-methylamino methyl-benzothiazole-6 base)-amine
The chloro-7-of I-460:4-[9-(the fluoro-6-isopropoxy-phenyl of 2-)-5 hydrogen-benzo [c] Kui Linpyrimido quinoline [4,5-e] azepine-2 base is amino]-phenylformic acid
The chloro-7-of I-461:4-[9-(2-oxyethyl group-phenyl)-5 hydrogen-benzo [c] Kui Linpyrimido quinoline [4,5-e] azepine-2 base is amino]-phenylformic acid
The chloro-7-of I-462:4-[9-(the fluoro-phenyl of 2-oxyethyl group-6-)-5 hydrogen-benzo [c] Kui Linpyrimido quinoline [4,5-e] azepine-2 base is amino]-phenylformic acid
The chloro-7-of I-463:4-[9-(the fluoro-6-methyl-phenyl of 2-)-5 hydrogen-benzo [c] Kui Linpyrimido quinoline [4,5-e] azepine-2 base is amino]-phenylformic acid
The chloro-7-of I-464:4-[9-(2-trifluoromethoxy-phenyl)-5 hydrogen-benzo [c] Kui Linpyrimido quinoline [4,5-e] azepine-2 base is amino]-phenylformic acid
The chloro-7-of I-465:4-[9-(the fluoro-6-trifluoromethoxy-phenyl of 2-)-5 hydrogen-benzo [c] Kui Linpyrimido quinoline [4,5-e] azepine-2 base is amino]-phenylformic acid
The chloro-7-of I-466:4-[9-(the fluoro-2-trifluoromethoxy-phenyl of 3-)-5 hydrogen-benzo [c] Kui Linpyrimido quinoline [4,5-e] azepine-2 base is amino]-phenylformic acid
The chloro-7-of I-467:4-[9-(2,3-dimethoxy-phenyl)-5 hydrogen-benzo [c] Kui Linpyrimido quinoline [4,5-e] azepine-2 base is amino]-phenylformic acid
The chloro-7-of I-468:4-[9-(2-isobutyl--phenyl)-5 hydrogen-benzo [c] Kui Linpyrimido quinoline [4,5-e] azepine-2 base is amino]-phenylformic acid
The chloro-5 hydrogen-benzo of I-469:4-[7-cumarone-2 base-9-[c] Kui Linpyrimido quinoline [4,5-e] azepine-2 base is amino]-phenylformic acid
The chloro-7-of I-470:4-[9-(1-methyl isophthalic acid hydrogen-pyrroles-2 base)-5 hydrogen-benzo [c] Kui Linpyrimido quinoline [4,5-e] azepine-2 base is amino]-phenylformic acid
The chloro-7-of I-471:4-[9-(1-methyl isophthalic acid hydrogen-imidazoles-2 base)-5 hydrogen-benzo [c] Kui Linpyrimido quinoline [4,5-e] azepine-2 base is amino]-phenylformic acid
I-472:4-(9-chloro-7-thiophene-2 base-5 hydrogen-benzos [c] Kui Linpyrimido quinolines [4,5-e] azepine-2 base is amino)-phenylformic acid
The chloro-7-of I-473:4-[9-(2 hydrogen-pyrazoles-3 base)-5 hydrogen-benzo [c] Kui Linpyrimido quinoline [4,5-e] azepine-2 base is amino]-phenylformic acid
The chloro-7-of I-474:4-[9-(2-ethynyl-phenyl)-5 hydrogen-benzo [c] Kui Linpyrimido quinoline [4,5-e] azepine-2 base is amino]-phenylformic acid
The I-475:4-[7-chloro-5 hydrogen-benzo of (2-amino methyl-phenyl)-9-[c] Kui Linpyrimido quinoline [4,5-e] azepine-2 base is amino]-phenylformic acid
The chloro-7-of I-476:4-[9-(the fluoro-2-methoxyl group-phenyl of 5-)-5 hydrogen-benzo [c] Kui Linpyrimido quinoline [4,5-e] azepine-2 base is amino]-phenylformic acid
The chloro-7-of I-477:4-[9-(3-methoxyl group-pyridine-2 base)-5 hydrogen-benzo [c] Kui Linpyrimido quinoline [4,5-e] azepine-2 base is amino]-phenylformic acid
The fluoro-7-of I-478:4-[8-(the fluoro-phenyl of 2-)-5 hydrogen-benzo [c] Kui Linpyrimido quinoline [4,5-e] azepine-2 base is amino]-phenylformic acid
The chloro-7-of I-479:4-[8-(the fluoro-phenyl of 2-)-5 hydrogen-benzo [c] Kui Linpyrimido quinoline [4,5-e] azepine-2 base is amino]-phenylformic acid
The fluoro-7-of I-480:4-[11-(the fluoro-phenyl of 2-)-5 hydrogen-benzo [c] Kui Linpyrimido quinoline [4,5-e] azepine-2 base is amino]-phenylformic acid
The chloro-7-of I-481:4-[11-(the fluoro-phenyl of 2-)-5 hydrogen-benzo [c] Kui Linpyrimido quinoline [4,5-e] azepine-2 base is amino]-phenylformic acid
The chloro-7-of I-482:6-[9-(the fluoro-phenyl of 2-)-5 hydrogen-benzo [c] Kui Linpyrimido quinoline [4,5-e] azepine-2 base is amino]-Pyridazine 3 carboxylic acid
The chloro-7-of I-483:2-[9-(the fluoro-phenyl of 2-)-5 hydrogen-benzo [c] Kui Linpyrimido quinoline [4,5-e] azepine-2 base is amino]-1 hydrogen-imidazoles-4-carboxylic acid
The chloro-7-of I-484:4-[9-(the fluoro-phenyl of 2-)-4-methyl-5 hydrogen-benzos [c] Kui Linpyrimido quinolines [4,5-e] azepine-2 base is amino]-1 hydrogen-imidazoles-4 benzoic acid
The chloro-7-of I-485:4-[4-amino methyl-9-(the fluoro-phenyl of 2-)-5 hydrogen-benzo [c] Kui Linpyrimido quinoline [4,5-e] azepine-2 base is amino]-phenylformic acid
The chloro-7-of I-486:4-[9-amino methyl-9-phenyl-5 hydrogen-benzos [c] Kui Linpyrimido quinolines [4,5-e] azepine-2 base is amino]-phenylformic acid
The chloro-7-of I-487:9-(2-fluorophenyl)-N-{4-[(2-methylpiperazine-1 base) carbonyl] phenyl }-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2-amine
The chloro-7-of I-488:4-{[9-(the fluoro-phenyl of 2-)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2 base] amino }-N-[{3-[(dimethylamino) methyl] azetidine-1 base } (imido grpup) methyl]-4-benzamide
The chloro-7-of I-489:4-{[9-(2-fluorophenyl)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2 base] amino }-N-[imido grpup (piperazine-1 base) methyl] benzamide
The chloro-7-of I-490:4-{[9-(2-fluorophenyl)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2 base] amino }-N-[imido grpup (3-methylpiperazine-1 base) methyl] benzamide
The chloro-7-of I-491:4-{[9-(2-fluorophenyl)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2 base] amino }-N-[[3-(dimethylamino) methyl] tetramethyleneimine-1 base] (imido grpup) methyl] benzamide
The chloro-7-of I-492:4-{[9-(2-fluorophenyl)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2 base] amino }-N-[imido grpup (4-methylpiperazine-1 base) methyl] benzamide
The chloro-7-of I-493:4-{[9-(2-fluorophenyl)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] azepine-2 base] amino }-N-[(3,5-lupetazin-1 base) (imido grpup) methyl] benzamide
The chloro-7-of I-494:1-[[(4-{[9-(2-fluorophenyl)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2 base] amino } benzoyl) amino] (imido grpup) methyl] tetramethyleneimine-3-carboxylic acid amides
The chloro-7-of I-495:1-[[(4-{[9-(2-fluorophenyl)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2 base] amino } benzoyl) amino] (imido grpup) methyl] piperidines-3-carboxylic acid amides
The chloro-7-of I-496:4-{[9-(2-fluorophenyl)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2 base] amino }-N-[{4-[(cyclopropyl carbonyl) amino] piperidines-1 base } (imido grpup) methyl] benzamide
The chloro-7-of I-497:4-{[9-(2-fluorophenyl)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2 base] amino }-N-[(dimethylamino) (imido grpup) methyl] benzamide
The chloro-7-of I-498:N-[[(4-{[9-(2-fluorophenyl)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2 base] amino } phenyl) amino] (imido grpup) methyl] cyclopropane carboxamide
The chloro-7-of I-499:N-[[(4-{[9-(2-fluorophenyl)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2 base] amino } phenyl) amino] (imido grpup) methyl]-3-(dimethylamino) pentamethylene carboxylic acid amides
I-500:4-(the fluoro-6-of the chloro-7-[2-of 9-(trifluoroethyl) phenyl] and-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2 base } amino) phenylformic acid
The chloro-7-of I-501:4-{[9-(2,6-dichlorophenyl)-5 hydrogen >-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2 bases] amino } phenylformic acid
The chloro-7-of I-502:4-{[9-(fluoro-6 aminomethyl phenyls of 2-)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2 base] amino } phenylformic acid
I-503:4-{[7-(bromo-6 chloro-phenyl-s of 2-) the chloro-5 hydrogen-Kui Linpyrimido quinoline of-9-[5,4-d] [2] phenyl azepine-2 base] amino } phenylformic acid
The chloro-7-of I-504:9-(2,6-difluorophenyl)-N-{4-[(3,5-lupetazin-1 base) carbonyl]-3-fluorophenyl }-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2-amine
The chloro-7-of I-505:4-{[9-(2,6-difluorophenyl)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2 base] amino }-N-[(3,5-lupetazin-1 base) (imido grpup) methyl]-N-methyl-benzamide
The chloro-7-of I-506:4-{[9-(2,6-difluorophenyl)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2 base] amino }-N-[[3-(dimethylamino) azetidine-1 base] (imido grpup) methyl]-N-methyl-benzamide
The chloro-7-of I-507:3-{[9-(2,6-difluorophenyl)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2 base] amino }-N-[(3,5-lupetazin-1 base) (imido grpup) methyl] benzamide
The chloro-7-of I-508:3-{[9-(2,6-difluorophenyl)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2 base] amino }-N-[[3-(dimethylamino) tetramethyleneimine-1 base] (imido grpup) methyl] methyl benzamide
The chloro-7-of I-509:9-(2,6-difluorophenyl)-N-{3-[(3,5-lupetazin-1 base) carbonyl]-4-fluorophenyl }-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2-amine
The chloro-7-of I-510:N-[[(4-{[9-(2,6-difluorophenyl)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2 base] amino } phenyl) amino] (imido grpup) methyl]-3-(dimethylamino) pentamethylene carboxylic acid amides
The chloro-7-of I-511:N-[[(4-{[9-(2,6-difluorophenyl)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2 base] amino }-2 fluorophenyls) amino] (imido grpup) methyl]-3-(dimethylamino) pentamethylene carboxylic acid amides
The chloro-7-of I-512:N-[[(5-{[9-(2,6-difluorophenyl)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2 base] amino }-2 fluorophenyls) amino] (imido grpup) methyl]-3-(dimethylamino) pentamethylene carboxylic acid amides
I-5] and 3:N-(the chloro-7-of 4-{[9-(2,6-difluorophenyl)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2 base] amino } phenyl)-3,5-lupetazin-1-imide
The chloro-7-of I-514:4-{[9-(2,6-difluorophenyl)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2 base] amino }-N-[[3-(dimethylamino) tetramethyleneimine-1 base] (imido grpup) methyl]-N-methyl-benzamide
I-515:N-(the chloro-7-(2 of 3-{[9-, 6-difluorophenyl)-5<i> hydrogen </i>-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2 base] amino } phenyl)-3,5-lupetazin-1-imide
I-516:N-(the chloro-7-of 3-{[9-(2,6-difluorophenyl)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2 base] amino } phenyl)-N, 3,5-tri methyl piperazine-1-imide
The chloro-7-of I-517:3-{[9-(2,6-difluorophenyl)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2 base] amino }-N-[[3-(dimethylamino) azetidine-1 base] (imido grpup) methyl] benzamide
I-518:N-(the chloro-7-of 5-{[9-(2,6-difluorophenyl)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2 base] amino }-2 fluorophenyls)-N, 3,5-tri methyl piperazine-1-imide
The chloro-7-of I-519:N-[[3-{[9-(2,6-difluorophenyl)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2 base] amino } phenyl) amino] (imido grpup) methyl]-3-(dimethylamino) pentamethylene carboxylic acid amides
The chloro-7-of I-520:9-(2,6-difluorophenyl)-N-{3-[(3,5-lupetazin-1 base) (imido grpup) methyl] phenyl }-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2-amine
I-521:N-(the chloro-7-of 4-{[9-(2,6-difluorophenyl)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2 base] amino } phenyl)-N, 3,5-tri methyl piperazine-1-imide
I-522:N-(the chloro-7-of 4-{[9-(2,6-difluorophenyl)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2 base] amino }-2-fluorophenyl)-3,5-lupetazin-1-imide
The chloro-7-of I-523:9-(2,6-difluorophenyl)-N-{4-[(3,5-lupetazin-1 base) (imido grpup) methyl]-3-fluorophenyl }-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2-amine
The chloro-7-of I-524:5-{[9-(2,6-difluorophenyl)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2 base] amino }-2-(lupetidine-4 base)-1 hydrogen-isoindole-1,3 (2 hydrogen)-diketone
I-525:N-[2-(amino methyl)-1 hydrogen-benzoglyoxaline-6 base] the chloro-7-of-9-(2-fluorophenyl)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2-amine
The chloro-7-of I-526:9-(2-fluorophenyl)-N-{2-[(methylamino) methyl]-1 hydrogen-benzoglyoxaline-6 base]-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2-amine
The chloro-N-{2-[(methylamino of I-527:9-) methyl]-1 hydrogen-benzoglyoxaline-6 base]-7-(2-fluorophenyl)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2-amine
The chloro-7-of I-528:9-(2-fluorophenyl)-N-{2-[(methylamino) methyl]-1,3-benzothiazole-6 base]-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2-amine
The chloro-7-of I-529:9-(2,6-difluorophenyl)-N-{2-[(methylamino) methyl]-1 hydrogen-benzoglyoxaline-6 base]-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2-amine
The chloro-7-of I-530:9-(2,6-difluorophenyl)-N-{2-[(methylamino) methyl]-1,3-benzoxazole-6 base]-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2-amine
The chloro-7-of I-531:9-(2-fluorophenyl)-N-{2-[(methylamino) methyl]-1,3-benzoxazole-6 base]-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2-amine
The chloro-7-of I-532:9-(2,6-difluorophenyl)-N-{3-[(3,5-lupetazin-1 base) (imido grpup) methyl]-4-fluorophenyl }-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2-amine
The chloro-7-of I-533:9-(2,6-difluorophenyl)-N-{2-[(methylamino) methyl]-1,3-benzothiazole-6 base]-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2-amine
The chloro-7-of I-534:{3-[9-(2,6-difluorophenyl)-5 hydrogen-benzo [c] Kui Linpyrimido quinoline [4,5-e] azepine-2 base is amino]-phenyl }-(4-methyl-piperazine-1 base)-ketone
The chloro-7-of I-535:3-[9-(2,6-difluorophenyl)-5 hydrogen-benzo [c] Kui Linpyrimido quinoline [4,5-e] azepine-2 base is amino]-N-methyl-N-(4-methyl-phenyl)-benzamide
In a certain embodiment, the present invention relates to be selected from the compound of following material:
The chloro-7-of I-52:4-[9-(the fluoro-phenyl of 2-)-5 hydrogen-benzo [c] Kui Linpyrimido quinoline [4,5-e] azepine-2 base is amino] phenylformic acid
The chloro-7-of I-135:4-[9-(the fluoro-phenyl of 2,6-bis-)-5 hydrogen-benzo [c] Kui Linpyrimido quinoline [4,5-e] azepine-2 base is amino] phenylformic acid
The chloro-7-of I-174:4-{[9-(the chloro-6-fluorophenyl of 2-)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] phenyl azepine-2 base] amino } phenylformic acid
The chloro-7-of I-175:9-(2,6-difluorophenyl)-N-{4-[(3,5-lupetazin-1 base) carbonyl] phenyl }-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2-amine
The chloro-N-{4-[(3 of I-177:9-, 5-lupetazin-1 base) carbonyl] phenyl }-7-(the fluoro-6-p-methoxy-phenyl of 2-)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2-amine
The chloro-N-of I-179:9-(4-{[3-(dimethylamino) azetidine-1 base] carbonyl } phenyl)-7-(the fluoro-6-p-methoxy-phenyl of 2-)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2-amine
The chloro-7-of I-183:{4-[9-(the fluoro-phenyl of 2,6-bis-)-5 hydrogen-benzo [c] Kui Linpyrimido quinoline [4,5-e] azepine-2 base is amino]-phenyl }-(4-dimethylamino-piperidines-1 base) ketone
The chloro-7-of I-190:4-[9-(the fluoro-6-methoxyl group-phenyl of 2-)-5 hydrogen-benzo [c] Kui Linpyrimido quinoline [4,5-e] azepine-2 base is amino]-phenylformic acid
The chloro-7-of I-191:{4-[9-(the fluoro-phenyl of 2,6-bis-)-5 hydrogen-benzo [c] Kui Linpyrimido quinoline [4,5-e] azepine-2 base is amino]-phenyl }-(3 (s)-methyl-piperazine-1 base)-ketone
I-196:(3-amino-tetramethyleneimine-1 base)-the chloro-7-of 4-[9-(the fluoro-phenyl of 2,6-bis-)-5 hydrogen-benzo [c] Kui Linpyrimido quinoline [4,5-e] azepine-2 base is amino]-phenyl }-ketone
The chloro-7-of I-197:{4-[9-(the fluoro-phenyl of 2,6-bis-)-5 hydrogen-benzo [c] Kui Linpyrimido quinoline [4,5-e] azepine-2 base is amino]-phenyl }-(3-methylamino-tetramethyleneimine-1 base)-ketone
The chloro-7-of I-199:{4-[9-(the fluoro-6-methoxyl group-phenyl of 2-)-5 hydrogen-benzo [c] Kui Linpyrimido quinoline [4,5-e] azepine-2 base is amino]-phenyl }-(3-methylamino-tetramethyleneimine-1 base)-ketone
The chloro-7-of I-220:9-(2,6-difluorophenyl)-N-(4-{[4-(methylamino) piperidines-1 base] carbonyl } phenyl)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2-amine
The chloro-7-of I-232:9-(the fluoro-6-p-methoxy-phenyl of 2-)-N-{4-[(3-methylpiperazine-1 base) carbonyl] phenyl }-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2-amine
The chloro-7-of I-234:9-(2,6-difluorophenyl)-N-(4-{[3-(methylamino) azetidine-1 base] carbonyl } phenyl)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2-amine
The chloro-7-of I-235:9-(the fluoro-6-p-methoxy-phenyl of 2-)-N-(4-{[3-(methylamino) azetidine-1 base] carbonyl } phenyl)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2-amine
I-240:N-{4-[(3-amino-pyrrolidine-1 base) carbonyl] phenyl } the chloro-7-of-9-(the fluoro-6-p-methoxy-phenyl of 2-)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2-amine
I-241:N-{4-[(4-amino piperidine-1 base) carbonyl] phenyl } the chloro-7-of-9-(the fluoro-6-p-methoxy-phenyl of 2-)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2-amine
The chloro-7-of I-242:9-(the fluoro-6-p-methoxy-phenyl of 2-)-N-(4-{[4-(methylamino) piperidines-1 base] carbonyl } phenyl)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2-amine
The chloro-7-of I-263:9-(the fluoro-6-p-methoxy-phenyl of 2-)-N-(4-{[3-(methylamino) piperidines-1 base] carbonyl } phenyl)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2-amine
I-286:N-{4-[(3-aminoazaheterocycles butane-1 base) carbonyl] phenyl } the chloro-7-of-9-(the fluoro-6-p-methoxy-phenyl of 2-)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2-amine
The chloro-7-of I-293:9-(2,6-difluorophenyl)-N-(4-{[3-(dimethylamino) piperidines-1 base] carbonyl } phenyl)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2-amine
I-310:4-(the chloro-7-of 4-{[9-(2,6-difluorophenyl)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2 base] amino } benzoyl)-N methyl piperazine-2-carboxylic acid amides
I-318:N-{4-[(3-amino-pyrrolidine-1 base) carbonyl]-3-chloro-phenyl-} the chloro-7-of-9-(2,6-difluorophenyl)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2-amine
The chloro-7-of I-326:9-(the chloro-6-fluorophenyl of 2-)-N-(4-{[3-(dimethylamino) piperidines-1 base] carbonyl } phenyl)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2-amine
I-341:4-amino-1-(the chloro-7-of 4-{[9-(2,6-difluorophenyl)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2 base] amino } benzoyl)-N-methyl piperidine-4-carboxylic acid amides
I-383:N-1-azabicyclo [2.2.2] oct-3-yl-4-{[9-chloro-7-(2,6-difluorophenyl)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2 base] amino }-N-methyl-benzamide
The chloro-7-of I-380:9-(2,6-difluorophenyl)-N-(4-{[3-methyl-3-(methylamino) tetramethyleneimine-1 base] carbonyl } phenyl)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2-amine
I-396:4-amino-1-(the chloro-7-of the chloro-4-{[9-of 2-(2,6-difluorophenyl)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2 base] amino } benzoyl)-N-methyl piperidine-4-carboxylic acid amides
Compound in the present invention can be prepared by the method known to those of ordinary skills, and/or is prepared with reference to the synthetic route shown in flow process 1, flow process 2 and flow process 3 below.Those of ordinary skill in the art will recognize that, below reaction conditions in illustrated each reaction can change; Comprise the variation of solvent, reactant, catalyzer and temperature of reaction.Other synthetic route is also available.
Shown in flow process 1 is the general synthetic route of preparation molecular formula (I) representative compound, wherein can select, and A ring and B ring can be replaced by phenyl ring.Those of ordinary skill in the art will recognize that, by selecting suitable ketone to start material in method G, some compound of molecular formula (I) representative can be prepared by the synthetic route similar to route shown in flow process 1; Wherein, in these compounds, a kind of or A ring and B ring in A ring or B ring are not phenyl ring.
The method of the ketone of dimethylamino methylene-benzo [c] azepine-5-shown in synthetic molecules formula v (seeing flow process 1) is the 3rd, and the 947,585, the 4th, the 022,801 and the 4th, in 028, No. 381 United States Patent (USP), have illustrated.The method that compound shown in molecular formula v is converted into Kui Linpyrimido quinoline [5,4-d] [2] the phenyl azepine that there is no C ring substituent is known, and the 4th, 318, No. 854 and the 4th, has illustrated in 547, No. 581 United States Patent (USP)s.Shown in flow process 1, the compound (molecular formula IIa) that contains C ring in the present invention can be reacted and be prepared with aryl or heteroaryl guanidine by the compound shown in molecular formula v.
Flow process 1: the general routes outlined of synthetic N-aryl-(7-phenyl-5 hydrogen-benzos [C] pyrido-[4,5-e] azepine-2 base)-amine
Shown in synthetic molecules formula (i), the method for the amino two aryl ketones that replace is known, and concrete building-up process will describe in example.As shown in method G, the diazotization by amine and iodide replace can be realized compound shown in molecular formula (i) and to the iodine shown in molecular formula (ii), replace the conversion of two aryl ketones.According to method I, by fragrant iodide and shielded propargyl amine, carry out cross-coupling reaction and can prepare compound (iii) from compound (ii).In flow process 1, two aryl ketones and N-tert-butoxycarbonyl propargyl amine generation coupling that iodine replaces, but those skilled in the art will appreciate that, two aryl ketones of other halogens replacements and other shielded propargyl amine also can be used.In addition, cross-coupling reaction also can be used various catalyzer, alkaloids, solvent; And carry out under differing temps.For the compound that is not phenyl for B ring, also can prepare compound (iii) by method J, in method J, Weinreb 2-iodo-benzoic acid acid amides and N-tert-butoxycarbonyl propargyl amine carry out coupling, then carry out coupling with the B ring of lithiumation.According to method K, by the Mercury bisulfate that uses in order (II) hydrochloric acid/diox and N, N-diisopropyl ethyl amine is processed the compound that can make the compound of molecular formula (iii) representative progressively change into molecular formula (iv) representative to the compound of molecular formula (iii) representative.Another approach is, according to method L, use hydration liquid and the sodium carbonate of hydrochloric acid/diox to carry out subsequent treatment, thereby the compound of the molecular formula of making (iii) representative to change into the compound of molecular formula (iv) representative.Those of ordinary skill in the art will appreciate that, arylalkyne class material can form hydrations with multiple other strong acid, such as forming hydration with trifluoroacetic acid and sulfuric acid.
Use N, dinethylformamide dimethylacetal solution is processed the compound that can obtain molecular formula (v) representative to the compound of molecular formula (iv) representative, N wherein, dinethylformamide dimethylacetal dissolves in multi-solvents, and this treating processes can be carried out at different temperature.Example 11 has shown that molecular formula at 80 ℃ (iv) is converted into molecular formula (V) in methylbenzene.Use aryl or heteroaryl guanidine to process and can make the compound of molecule formula V representative change into compound (IIa) the compound of molecule formula V representative.According to method Q, to molecule formula V representative compound, aryl or heteroaryl guanidine and N, the mixed reactant of N-diisopropyl ethyl amine in dimethyl formamide carries out microwave radiation processing can complete this reaction.In addition, rear a kind of reaction can have salt of wormwood to exist according to method R; And carry out the in the situation that of alcohol reflux.
In certain embodiments, can also prepare compound (IIa) according to method S, wherein first with Guanidinium hydrochloride, the compound of molecule formula V representative is processed, thereby prepare 5 hydrogen-benzo [C] Kui Linpyrimido quinoline [4,5-e] azepine-2-amine, then this amine substance carries out cross-coupling reaction with heteroaryl amine, thereby forms compound (IIa), and C ring is wherein heteroaryl.
Flow process 2: the general synthetic route of synthetic molecules formula (A-1) representative compound
What flow process 2 showed is the general synthetic route of preparation molecular formula (A-1) representative compound, wherein can select, and A ring can be 5 yuan of-6 yuan of aryl, heteroaryl or heterocyclic radicals through replacing; B ring can be aryl, heterocyclic radical, alicyclic radical or the heterocyclic radical through replacing; C ring is aryl, heteroaryl, heterocyclic radical or the alicyclic radical through replacing or be unsubstituted.
Some document is illustrated the beta-keto nitrile synthetic method of the heterocyclic substituted of molecular formula (vi) representative, such as seeing the article (2003) 68 (12) of the people such as Katritzky on < < JOC > >, 4932-4934; And the article (2004) of the people such as Berg man on the synthetic > > of < <, 16,2760-2765.Use is dissolved in the DMF dimethylacetal of different solvents compound (vi) is processed and can be obtained intermediate product ketones with Enamino-esters (vii); Treating processes can be carried out at different temperature, and the synthetic method of 00/78731 pair of intermediate ketones with Enamino-esters of PCP International Application No. WO (vii) has been done further instruction.
As shown in flow process 2, use the guanidine processing ketones with Enamino-esters (vii) of monosubstitution can prepare cyanopyrimidine (viii).This reaction can reflux and realize the reaction mixture that contains guanidine ethanolic soln in the situation that salt of wormwood exists.The method of the middle pyrimidine product of the involutory one-tenth molecular formula of PCT International Application No. WO 00/78731 (viii) representative has been done further instruction.
As shown in step 3, at Raney Ni metal catalyst, exist in situation, by hydrogenation reaction, compound (viii) can be reduced into amine substance (ix), the explanation of relevant Raney Ni metal catalyst, is shown in the article 68:766-9 (1946) of the people such as Price on < < Journal of the American Chemical Society > >.In addition, this reduction reaction also can be passed through such as LiAlH 4such reductive agent is realized; Relevant LiAlH 4explanation, see the people such as Thurkauf at < < the article 13 (17) on biological and doctor's malignant boil chemical communication > >: 2921-2924, (2003).
Under the condition existing at certain alkali, compound (ix) is reacted with acid chloride and amine substance (ix) can be changed into amide substance (x), or in the situation that coupling agent exists, make compound (ix) and carboxylic acid reaction, thereby amine substance (ix) is changed into amide substance (x).Then by amide substance (x) with such as polyphosphoric acid, Vanadium Pentoxide in FLAKES, methylsulfonic acid, phosphoryl chloride or phosphinylidyne/zinc chloride (IV) such cyclodehydration agent together heat and amide substance (X) can be changed into the required compound of molecular formula (A-1) representative.
Other routes of flow process 3 synthetic molecules formula (A-1) representative compounds
Shown in flow process 3 is the general synthetic route of another kind of preparation molecular formula (A-1) representative compound, wherein can select, and A ring is 5 yuan of-6 yuan of aryl, heteroaryl or heterocyclic radicals through replacing; B ring can be aryl, heterocyclic radical, alicyclic radical or the heterocyclic radical through replacing; C ring is aryl, heteroaryl, heterocyclic radical or the alicyclic radical through replacing or process does not replace.
The method of the heterocyclic substituted carboxylic acid of synthetic molecules formula (xii) representative is known, and extensively has explanation in the literature.Use β-alanine to carry out condensation to compound (xii) and can make acid amides (xiii).In the middle of synthetic molecules formula (xiii) representative, the method for amide substance has further instruction in the literature, such as seeing that the people such as Protevin are at < < tetrahedron communication > > (44 (52): the people such as the article 9263-9265 (2003)) and E-Nagger are at the < < India chemistry magazine > > of association (59 (6): the article 783-6 (1982)).
By using the dilute aqueous solution of alkali metal hydroxide to process ester (xiii), acid (xiv) can be prepared, such as using the dilute aqueous solution of sodium hydroxide or lithium hydroxide to process ester (xiii), acid (xiv) can be prepared.The example of this conversion people such as Portevin at < < tetrahedron communication > > (44 (52): have illustrated in the article 9263-9265 (2003)).
Using the such cyclodehydration agent of polyphosphoric acid to process compound (xiv) can make compound (xiv) that cyclic action occurs, thereby generate azepine diketone (xv), the people such as Annoura are at < < tetrahedron communication > > (36 (3): the article 413-16 (1995)) is illustrated polyphosphoric acid.
Use DMF dimethylacetal to process and can prepare ketones with Enamino-esters (xvi) compound (xv).This reaction can be carried out in different temperature and different solvent.
Use the guanidine processing ketones with Enamino-esters (xvi) of monosubstitution can prepare Kui Linpyrimido quinoline azepine ketone (xvii).This reaction can realize by the ethanolic soln mixture that contains compound (xvi) and guanidine is carried out to reflow treatment, has salt of wormwood to exist in this reaction process.
By compound (xvii), reacted can be made Kui Linpyrimido quinoline azepine ketone (xvii) change into chlorination imide (xviii) with chlorizating agent, typical chlorizating agent is POCl 3or SOCl 2.Then according to people such as Nadin at < < organic chemistry magazine > > (68 (7), 2844-2852 (2003)) method in article, with palladium catalyst, make compound (xviii) and organic boronic carry out cross-coupling reaction, thereby generate azatropylidene (xi).
Compound in the present invention is aurora kinase inhibitors.Can by body or analyzed in vitro determine the binding ability of these compounds and aurora kinase and/or suppress the ability of aurora kinase.Analyzed in vitro comprises that measuring these compounds makes the inhibition degree of stromatin or peptide generation phosphorylation ability to aurora kinase.Analyzed in vitro also comprises the binding ability of these compounds and aurora kinase is carried out to quantitative test.Before the combination of inhibitor and aurora kinase, inhibitor is carried out to radioactive tracer processing; And then the amount that radioactive tracer associative key was separated and measured to inhibitor/aurora kinase binding substances can be measured to the binding ability of inhibitor and aurora kinase.In addition, the binding ability of inhibitor and aurora kinase can also be measured by competition experiments, in competition experiments, uses the aurora kinase having combined with known radioligand to cultivate new inhibitor.Can also analyze the ability of these compounds affect cell functions or physiological function, cell function wherein and physiological function are that the activity by aurora kinase mediates.The analysis of these performances describes the form with example and/or is known in the art.
Therefore, on the other hand, the invention provides and suppress aurora kinase in the method for intracellular reactive, the method comprises makes the aurora kinase inhibitors of molecular formula (I) representative contact with cell, and wherein, in this cell, aurora kinase need to be suppressed.In certain embodiments, in aurora kinase inhibitors and cell, all members of aurora kinase family interact, and reduce all aurora kinase family members' activity.In certain other embodiments, aurora kinase suppresses to interact with the part member of the interior aurora kinase of cell family, and reduces the activity of this part of aurora kinase.In some preferred embodiment, aurora kinase inhibitors suppresses the activity of a kind of aurora kinase in cell selectively.
In the preferred case, the method in the present invention can suppress the breeding of aurora kinase inhibitors institute exposing cell.Phrase " inhibition cell proliferation " refers to for the cell not contacting with respect to aurora kinase inhibitors, the inhibition ability of aurora kinase inhibitors to the quantity of its exposing cell and Growth of Cells.Use cell counter cell quantity to be added up or can be assessed the breeding of cell by cytoactive analysis, for example, by MTT, XTT or WST, analyze the breeding situation of determining cell.When cell is during in entity vegetative period (such as solid tumor or organ), can use calipers to measure the size of entity grower, and by the grower size to aurora kinase institute exposing cell and the grower size of exposing cell not, compare to evaluate the breeding situation of cell.
In the preferred case, compare with the cell that aurora kinase inhibitors is not contacted, the extent of growth of aurora kinase institute exposing cell at least slows down 50%.Compare with not contacted cell, in different embodiments, the extent of growth of aurora kinase institute exposing cell at least slows down approximately 75%, or at least slows down approximately 90%, or at least slows down approximately 95%.In certain embodiments, phrase " inhibition cell proliferation " comprises that the cell not contacting with aurora kinase inhibitors compares, and aurora kinase inhibitors can reduce the quantity of its exposing cell.Therefore, because aurora kinase inhibitors can suppress the breeding of its exposing cell, so aurora kinase inhibitors can slow down the growth of its exposing cell; The cell generation cessation of growth cessation that it is contacted; Make the cell generating program dead (being natural death of cerebral cells) of its contact; Or make necrocytosis.
On the other hand, the invention provides a kind of pharmaceutical composition, in this pharmaceutical composition, contain the compound of defined molecular formula (A) representative above, or contain the carrier of accepting in salt that these compounds accept in pharmacology and pharmacology.
If compound acceptable salts substances in pharmacology use the present invention in these compositions in, preferably mineral acid or organic acid derivative of these salts substances, or the derivative of mineral alkali or organic bases.Relevant applicable salts substances, ask for an interview < < medical science that the article (66:1-19 (1977)) of the people such as Berge on < < medical science magazine > > and Remington show and method > > (the 20th edition, A.Gennaro edits, Lippincott Williams & Wilkins press publishes, 2000).
Applicable non-limiting bisalt material comprises: acetate, adipate, alginates, aspartate, benzoate, benzene sulfonate, bisulfate, butyrates, Citrate trianion, camphorate, camsilate, cyclopentane propionate, two grape hydrochlorates, dodecyl sulfate, esilate, fumarate, light conversion enanthate, phosphoglyceride, Hemisulphate, enanthate, hexanoate, hydrogenchloride, hydrogen bromide, hydrogen iodide, 2-isethionate, lactic acid salt, maleic acid salt, mesylate, 2-naphthalenesulfonate, nicotine hydrochlorate, oxalate, two tea salicylates, pectin salt, persulphate, 3-phenyl-propionic salt, picrate, pivalate, propionic salt, succinate, tartrate, thiocyanate-, tosylate and undecylate.
Applicable alkaline salt material comprises: ammonium salt, an alkali metal salt; Such as sodium salt and sylvite, alkaline earth salt; Such as calcium salt and magnesium salts, organic alkali salt, such as dicyclohexyl amine, N-methyl D-glucosamine, t-aminobutane, quadrol, thanomin and choline and with amino acid whose salts such as arginine, Methionins; But applicable alkaline species material is not limited to these materials.For example, the compound of molecular formula (v) representative can be prepared into corresponding sodium salt, C ring process-CO wherein 2h replaces.
Equally, use following reactant can make nitrogenous basic group quaternized, such reactant comprises such as the such low-carbon alkyl halogenide of the muriate of methyl, ethyl, propyl group and butyl, bromide and iodide, such as dimethyl, diethyl, dibutyl and the such dialkylsulfates of three amyl group sulfuric esters, such as the such long-chain halogenide of muriate, bromide and iodide of decyl, lauryl and hard ester acyl, such as phenmethyl and such aralkyl halogenide and other materials of phenethyl bromide compound.Can obtain so water-soluble, oil soluble, water dispersible or oil-dispersing property product.
Term used herein " acceptable carrier in pharmacology " refers to acceptor compatible and active agents can be sent to the material of object point position in the situation that not destroying medicament activity mutually, in preferable case, this material is compatible mutually with Mammals, more preferably compatible mutually with human body.Both made this carrier there is toxic side effect, but in the preferred case, these toxic side effect also by reasonable risk/benefit that active agents intended purpose had compare make up.
Pharmaceutical composition in the present invention can be manufactured by methods known in the art, such as the processes such as the granulation by traditional, mixing, dissolving, encapsulate, lyophilization or emulsification are prepared.These compositions can be made into various forms, comprising granule, precipitation agent, microgranules, dry powder doses, amorphous dry powder doses, tablet, capsule, syrup, injection, emulsifying agent, elixir, suspension agent or solution, wherein dry powder doses comprises lyophilize dry powder doses, Rotary drying dry powder doses or jet drying dry powder doses.Can select, these formulations can contain the mixture of stablizer, PH properties-correcting agent, tensio-active agent, bioactive modification agent and these materials.
These pharmaceutical preparations can be used liquid to be prepared into liquid suspension or solution, such as using the mixed solution of oily substance, water, alcohols thing or these materials that these pharmaceutical preparations are made to liquid suspension or solution, but operable liquid does not limit to these materials above ground.For oral administration or drug administration by injection, also can in medicament, add tensio-active agent, suspension agent or the emulsifying agent that is suitable for pharmacy.Suspension agent comprises oily substance; Such as peanut oil, sesame oil, Oleum Gossypii semen, Semen Maydis oil and sweet oil, but oily substance is not limited to these materials.Suspension agent preparation also can contain such as ethyl oleate, Isopropyl myristate, glycerin fatty acid ester and the such fatty acid ester of acetylize glycerin fatty acid ester.Suspension agent preparation can contain alcohols material, and such as containing ethanol, Virahol, cetyl alcohol, glycerol and ethylene glycol, but contained alcohols material is not limited to these alcohols.In suspension agent preparation, also can contain ether material, hydrocarbon and water; Ether material is such as being PEG; But ether material is not limited to this; Hydrocarbon is such as being mineral oil and vaseline oil.
These compositions can be used acceptable carrier in pharmacology, these carriers comprise ion-exchanger, aluminum oxide, aluminum foil stearate, Yelkin TTS, serum protein, such as serum human albumen, such as phosphoric acid salt, glycine, Sorbic Acid, the buffer substance that potassium sorbate is such, the partial glyceride mixture of saturated vegetable fatty acid, water, such as protamine sulfate, Sodium phosphate dibasic, potassium hydrogen phosphate, sodium-chlor, the salts substances that zinc salt is such or ionogen, silica gel, Magnesium Trisilicate, polyvinylpyrrolidone, cellulosic material, polyoxyethylene glycol, Xylo-Mucine, polypropylene ester, wax, polyethylene-polypropylene abaculus polymkeric substance, polyoxyethylene glycol and lanolin, but in pharmacology, acceptable carrier is not limited to above-mentioned these materials.
According to the preferred embodiments of the invention, the composition in the present invention can be made into the formulation that is applicable to Mammals administration, especially makes the formulation that is suitable for mankind's administration.Pharmaceutical composition in the present invention can carry out oral administration, drug administration by injection, injection inhalation, topical, rectal administration, intranasal administration, orally administering, vagina administration or carry out administration by implanted reservoir.Term used herein " injection " comprises injection in injection in subcutaneous injection, intravenous injection, intramuscular injection, joint injection, synovia, breastbone inner injection, film, injection into liver, internal injury injection and intracranial injection or drop.In the preferred case, these compositions carry out administration by oral, intravenous injection or subcutaneous injection mode.Medicament in the present invention can be made into fugitive medicament, quick release medicine or long-acting medicament.In addition, these compounds can carry out topical, but not whole body administration, such as tumor sites being carried out to administration (as carried out administration by injection system).
In the present invention, the sterilization injection type of composition can be hydration suspension or oleagenous suspension.According to the suitable dispersion agent of utilization known in the art, wetting agent and suspension agent, can prepare the composition of suspending agent type.The injection type of sterilization can also be injection solution or the suspension of sterilization, and solution wherein or suspension are arranged in acceptable thinner or solvent in nontoxic injection, such as being arranged in 1,3 butylene glycol.In the present invention, the used carrier accepted comprises water, Ringer solution and isotonic sodium chlorrde solution.In addition, the fixedly oil through sterilization is also conventional solvent and the suspension medium using.At this on the one hand, any bland fixedly oil all can be used, comprising synthetic single glyceride or double glyceride.Such as the such lipid acid of oleic acid and glyceride derivative thereof, can be used for preparing injection type, in pharmacology, acceptable natural oils material also can be used for preparing injection type, such as sweet oil or Viscotrol C, especially the polyoxyethylene compound of these oily substances can be used for preparing injection type.These oily solutions or suspension also can contain long-chain alcohols thinner or dispersion agent, and such as carboxymethyl cellulose or similar dispersion agent, these materials are generally used for preparing acceptable formulation in pharmacology, comprising emulsification formulation and suspending agent type.According to the needs of formulation, the tensio-active agent that other are conventional, such as Tweens material, spans material and other emulsifying agent or biological activity toughener also can be used for preparing acceptable solid dosage in pharmacology, liquid dosage form or other formulations.Compound in the present invention can be made into the injection type that carries out administration by the mode of injecting or continuous drop mode.The unit dose drug of injection can be placed in ampoule, or is placed in the container of multiple doses.
Pharmaceutical composition in the present invention can carry out oral administration according to acceptable oral dosage form, and wherein oral dosage form comprises capsule, tablet, hydration suspension agent or solution, but oral dosage form is not limited to these formulations.For oral tablet, conventional carrier comprises lactose and cereal starch.In oral tablet, conventionally also add such as the such lubricant of Magnesium Stearate.For oral capsule, available thinner comprises lactose and dry cereal starch.When hydration suspension is used for oral administration, active ingredient combines with emulsifying agent and suspension agent.If need, also can add sweeting agent, seasonings or tinting material in medicament.
In addition, the pharmaceutical composition in the present invention can also carry out rectal administration with suppository form.These suppositorys can be by mixing medicine to make with applicable non-irritating excipient mutually, and wherein vehicle is at room temperature solid-state, but is liquid under rectal temperature, so vehicle dissolves in rectum, thereby discharge medicine.Vehicle comprises theobroma oil, beeswax and polyoxyethylene glycol.
Pharmaceutical composition in the present invention can also carry out topical, and especially, when the target location for the treatment of is local application very easily when region or organ, this is comprising treatment illness in eye, tetter or lower intestinal tract disease.Be applicable to these regions or organ topical agent is very easily prepared.
Topical agent for lower intestinal tract can adopt rectal suppository form (seing above face) or adopt applicable bowel lavage formulation.Local skin note formulation also can be used.For local application, pharmaceutical composition can also be made suitable finish form, wherein in finish, contains and suspends or be dissolved in the active ingredient in one or more carriers.In the present invention, compound carrier used when topical comprises mineral oil, liquid Vaseline, white vaseline, propylene glycol, polyoxyethylene, polyoxyethylene compound, emulsifying wax and water, but topical carrier used is not limited to these materials.In addition, the pharmaceutical composition in the present invention can also be made applicable lotion or creme, contains and suspend or be dissolved in the active ingredient that can accept carrier in one or more pharmacology in these lotions or creme.Applicable carrier comprises mineral oil, sorbitan monostearate, poly-Sorbic Acid acid 60, spermaceti ester type waxes, hexadecanol, 2-octyl dodecanol, phenylcarbinol and water, but applicable carrier is not limited to these materials.
For ophthalmic administration, pharmaceutical composition in the present invention can be made into macro suspension, and this macro suspension is the isotonic saline solution suspension through sterilization and pH value adjusting, or, in the preferred case, the pharmaceutical composition in the present invention is made the normal isotonic saline solution through sterilization and PH adjusting; Wherein in salt aqeous suspension and salt brine solution, can be added with the such sanitas of benzalkonium muriate, also can not add sanitas.In addition,, for ophthalmic administration, the pharmaceutical composition in the present invention also can be made into such as the such finish of Vaseline.
Pharmaceutical composition in the present invention can also with aerosol or and the form of inhalation carry out administration.The technology that this based composition can be known altogether according to pharmacy field is prepared, and uses phenylcarbinol or other applicable sanitass, strengthens bioactive absorption enhancer, fluorocarbon and/or other conventional stablizer or dispersion agent can be made salt brine solution by the pharmaceutical composition in the present invention.
Pharmaceutical composition in the present invention is particularly useful for treating the disease of aurora kinase mediation.As used herein, term " aurora kinase mediation disease " comprises any expression by aurora kinase or active disorder, disease or the illness causing, any expression of take aurora kinase or active as feature or need disorder, disease and the illness of aurora kinase activity.Term " disorder of aurora kinase mediation " also comprises any disorder, disease and illness; But the activity that suppresses aurora kinase in these disorders, disease and illness is useful.The disease of aurora kinase mediation comprises proliferative disease.Nonrestrictive proliferative disease example comprises chronic inflammatory proliferative disease, such as psoriasis and rheumatic arthritis, and eye proliferative disease, such as diabetes type retinopathy, optimum hyperplasia, such as vascular tumor, and cancer.
In the preferred case, composition in the present invention can be made into various preparations, thereby for the disease mediated patient of aurora kinase, or for likely suffering from the disease mediated patient of aurora kinase, or for the disease mediated patients with recurrent of aurora kinase, in this article, term " patient " refers to animal, preferably refer to Mammals, more preferably refer to the mankind.In the preferred case, the pharmaceutical composition in the present invention is made into be suitable for oral, intravenous injection or hypodermic preparation.Yet above-mentioned any formulation containing dose therapeutically effective the compounds of this invention is all within routine test scope, so these formulations all within the scope of the present invention.In certain embodiments, the pharmaceutical composition in the present invention also contains other treatment medicament.In the preferred case, these other treatment medicaments are medicines of at present institute's disease that takes a disease or the normal use of illness for the treatment of patient.
Term " dose therapeutically effective " refers to that the amount of medicament is enough to make the activity of aurora kinase to occur perceptible reduction, or alleviates significantly the disease mediated severity of aurora kinase.Required aurora kinase inhibitors consumption depends on inhibitor to the effect of particular cell types and treats the required time of this disease.It should be understood that, for concrete patient's concrete consumption and concrete treatment plan, be certainly taken at many factors, this comprising the activity of used particular compound, the severity of patient's age, body weight, general health situation, sex, patient's diet situation, the time of administration, defecation frequency, compatibility of drugs, doctor's diagnosis and the disease for the treatment of.In the present invention, in composition, other contained pharmaceutical quantities can not surpass the amount of unique a kind of active medicine contained in composition conventionally.In the preferred case, the content of other drug is about unique a kind of 50%-100% with therapeutic activity chemical content in composition.
On the other hand, the invention provides to aurora kinase the disease mediated patient method for the treatment of, and provide to likely become aurora kinase disease mediated patient or the disease mediated patients with recurrent of the aurora kinase method for the treatment of.The method comprises uses compound or the pharmaceutical composition in the present invention to patient.Just as previously described, the compound in the present invention or pharmaceutical composition can be obtained useful result for the treatment of or preventive effect with it proliferative disease patient.Compound in the present invention and pharmaceutical composition are particularly useful for treating cancer.
As used herein, term " cancer " refers to cellularity disease, and the feature of this cellularity disease is that the out of control or imbalance of cell proliferation, cytodifferentiation reduce, cell is abnormal and/or cell is abnormal in the newborn ability of ectopic sites to the ability of crowding into of surrounding tissue.Term " cancer " comprises noumenal tumour and the raw tumour of blood, but is not limited to the tumour of these kinds.Term " cancer " comprises dermatosis, tissue disease, organ disease, skeletal diseases, cartilaginous tissue disease, hematologic disease and vascular disease.Term " cancer " also comprises primary carcinoma disease and metastatic cancer.
In available the present invention, the non-limiting noumenal tumour of method treatment comprises carcinoma of the pancreas; Bladder cancer; Colorectal carcinoma; Breast cancer, wherein breast cancer comprises transitivity breast cancer; Prostate cancer, wherein prostate cancer comprises male hormone relationship type prostate cancer and non-male hormone relationship type predecesor's merit gland cancer; Kidney, its carcinoma mesonephric comprises metastatic renal cell cancer; Liver cancer; Lung cancer, wherein lung cancer comprises nonsmall-cell lung cancer (NSCLC), bronchovesicular cancer (BAC) and adenocarcinoma of lung; Ovarian cancer, wherein ovarian cancer comprises carrying out property epithelial cancer and Primary peritoneal carcinoma; Cervical cancer; Cancer of the stomach; Esophagus cancer; Head term cancer, wherein head and neck cancer comprises Head and neck squamous cell carcinoma; Melanoma; Neuroendocrine carcinoma, wherein neuroendocrine carcinoma comprises transitivity neuroendocrine tumor; The cancer of the brain, wherein the cancer of the brain comprises neurospongioma, degeneration oligodendroglioma, glioblastoma multiforme; Osteocarcinoma and soft tissue sarcoma.
In certain other embodiments, cancer is hematologic malignancies.The limiting examples of hematologic malignancies comprises acute myeloid leukemia (AML); Chronic granulocytic leukemia (CML), wherein chronic granulocytic leukemia comprises acceleration chronic granulocytic leukemia and chronic granulocytic leukemia stage of attack (CML-BP); Acute lymphoblastic leukemia (ALL); Lymphocytic leukemia (CLL); Hodgkin's disease (HD); Non_hodgkin lymphoma (NHL), wherein non_hodgkin lymphoma comprises follicular lymphoma and lymphoma mantle cell; B cell lymphoma; T cell lymphoma; Multiple myeloma (MM); Walden Si Telunshi macroglobulinemia; Hyperosteogeny abnormal syndrome (MDS), wherein hyperosteogeny abnormal syndrome comprises refractory anemia (RA), RARS (RARS), RAEB (RAEB) and transformant RAEB (RAEB-T); Myelosis syndromes.
In certain embodiments, the compound in the present invention or composition are used to treat the cancer that aurora kinase is exaggerated.In certain embodiments, compound in the present invention or composition are used to treat cancer patients, the state of an illness likely develops into patient and the cancer return patient of cancer, and cancer species wherein comprises colorectal carcinoma, ovarian cancer, breast cancer, cancer of the stomach, prostate cancer and carcinoma of the pancreas.In certain embodiments, the kind of cancer is breast cancer, colorectal carcinoma and carcinoma of the pancreas.
In certain embodiments, the aurora kinase inhibitors in the present invention and other treatment Drug combination.Other treatment medicine also can be suppressed aurora kinase or be played a role by different mechanism.In certain embodiments, other treatment medicine is the medicine that the current disease for the treatment of patient is normally used.Aurora kinase inhibitors in the present invention can be with identical formulation and other treatment Drug combination, also can be with different formulations and other treatment Drug combination.When adopting different formulations, other treatment medicine is used before or after aurora kinase inhibitors in the present invention, also can use simultaneously.
In certain embodiments, the aurora kinase inhibitors in the present invention and the Drug combination that is selected from cytotoxic drug, radiopharmaceuticals and immunotherapy medicaments.Applicable non-limiting cytotoxic drug of combining use with aurora kinase inhibitors in the present invention comprises: antimetabolite, wherein antimetabolite comprises capecitabine, 2,2-difluoro deoxycytidine, 5 FU 5 fluorouracil or 5 FU 5 fluorouracil/folinic acid, fludarabine, cytosine arabinoside, mercaptopurine, sulphur island purine, pentostatin and Rheumatrex; Topoisomerase enzyme inhibitor, wherein topoisomerase enzyme inhibitor comprises Zuyeyidal, teniposide, camptothecine, Hycamtin, Rinotecan, Zorubicin and daunorubicin; Vinca alkaloids, wherein vinca alkaloids comprises vincristine(VCR) and vinealeucoblastine(VLB); Taxane substances, wherein taxane substances comprises taxol and Docetaxel; Platinum agent, wherein platinum agent comprises cis-platinum, Carboplatin and oxaliplatin; Microbiotic, wherein microbiotic comprises the Mycocet of dactinomycin, bleomycin, ametycin, Zorubicin, daunorubicin, IDA, Pegylation; Alkylating agent, such as melphalan, Chlorambucil, busulfan, Thiotepa, ifosfamide, carmustine, Lomustine, Semustine, streptozocin, decarbazine and endoxan; Phthalein Paraperidide and relevant analogue, wherein neurosedyn and analogue thereof comprise CC-5013 and CC-4074; Protein tyrosine kinase inhibitor, wherein protein tyrosine kinase inhibitor comprises imatinib mesylate and Ai Ruisha; Antibody, wherein antibody comprises trastuzumab, Mabthera, Cetuximab and rhuMAb-VEGF; Mitoxantrone hydrochloride; Dexamethasone; Prednisone and Temozolomide.
For the present invention is more fully understood, below Preparation Example and test implementation example are described.These embodiment have shown how to prepare or test concrete compound, and these examples should not be considered to scope of the present invention to form any restriction.
Implementation column
Definition
AcOH acetic acid
ATP Triphosaden
BSA bovine serum albumin
Uncle Boc-butoxy carbonyl
DMF DMF
DTT dithiothreitol (DTT)
EDTA ethylenediamine tetraacetic acid (EDTA)
EtOAc ethyl acetate
Et 2o ether
MeOH methyl alcohol
MTT MTT salt
XTT 2,3-bis-(2-methoxyl group-4-nitro-5-sulfur phenenyl)-2 hydrogen-tetrazolium salts
-5-formylaniline inner salt
WST (4-[3-(4-iodophenyl)-2-(4-nitrophenyl)-2 hydrogen-5-tetrazolium
And]-1,3-benzene disulfonic acid sodium
PKA cAMP-dependent kinases
PPA polyphosphoric acid
TBTU O-benzotriazole-1-N, N, N ', N '-tetramethyl-urea a tetrafluoro borate
THF tetrahydrofuran (THF)
H hour
Min minute
M/z mass/charge
MS mass spectrum
HRMS high resolution mass spectrum
embodiment 1: the method (seeing flow process 1) of synthetic molecules formula (i) representative compound:
(2-amino-4-methoxyl-phenyl)-(the fluoro-phenyl of 2-)-ketone (1h)
At 0 ℃, 3-anisidine is added drop-wise to the BCl being stirred 3(the CH that concentration is 1M in solution 2cl 2solution, 8.8 milliliters, 8.8 mmoles).Add AlCl 3(1.15 grams, 8.8 mmoles), then add 2-fluorophenyl cyanogen (1.6 milliliters, 16.0 mmoles).This mixture is carried out to the reflow treatment of 16 hours, be then cooled to 0 ℃.Add hydrochloric acid (2N, 30 milliliters), then mixture is heated to 80 ℃, and strong stirring 30 minutes.After cool to room temperature.Use CH 2cl 2(3 * 50 milliliters) extract mixture.Use salt solution to wash the organic phase of chemical combination, with magnesium sulfate, be dried, filter and evaporate under vacuum condition.Use chromatographic column (silica gel, hexane: EtOAc is 4: 1) to purify to the brown oily product obtaining, thereby make compound 1h (1.1 grams, productive rate is 56%), MS m/z=246 (M+H).
(2-amino-3-methyl-phenyl)-(the fluoro-phenyl of 2-)-ketone (1b)
According to prepare compound 1h described in the similar method of method, O-Tolylamine and 2-fluorophenyl cyanogen are converted to compound 1b (productive rate is 20%), MS m/z=230 (M+H).
(the fluoro-phenyl of 2-amino-4-)-(the fluoro-phenyl of 2-)-ketone (1c)
According to prepare compound 1h described in the similar method of method, the fluoro-aniline of 3-and 2-fluorophenyl cyanogen are converted to compound 1c (productive rate is 25%), MS m/z=234 (M+H).
(the bromo-phenyl of 2-amino-4-)-(the fluoro-phenyl of 2-)-ketone (1e)
According to prepare compound 1h described in the similar method of method, the bromo-aniline of 3-and 2-fluorophenyl cyanogen are converted to compound 1e (productive rate is 15%), MS m/z=294/296 (M+H).
(2-amino-4-methyl-phenyl)-(the fluoro-phenyl of 2-)-ketone (1g)
According to prepare compound 1h described in the similar method of method, m-Tolylamine and 2-fluorophenyl cyanogen are converted to compound 1g (productive rate is 44%), MS m/z=230 (M+H).
(2-amino-4, the chloro-phenyl of 5-bis-)-(the fluoro-phenyl of 2-)-ketone (1ad)
According to prepare compound 1h described in the similar method of method, 3,4-DCA and 2-fluorophenyl cyanogen are converted to compound 1ad (productive rate is 17%), MS m/z=284 (M+H).
(2-amino-5-sec.-propyl-phenyl)-(the fluoro-phenyl of 2-)-ketone (1ag)
According to prepare compound 1h described in the similar method of method, 4-isopropyl aniline and 2-fluorophenyl cyanogen are converted to compound 1ag (productive rate is 22%), MS m/z=258 (M+H).
the method B of embodiment 2 synthetic molecules formula (i) representative compounds
(2-amino-5-methyl-phenyl)-(the fluoro-phenyl of 2-)-ketone (1af)
2-iodine fluorobenzene (2.0 milliliters, 17 mmoles) is dissolved in anhydrous THF (20 milliliters) under ar gas environment, and is cooled to-20 ℃.Slowly add isopropylmagnesium chloride solution (8.5 milliliters, 17.0 mmoles), and to solution stirring 20 minutes.Then in THF, add 2-nitro-5-tolyl aldehyde (2.7 grams, 16.5 mmoles), and mixture is carried out the stirring of 20 minutes at-20 ℃, then with saturated aqueous ammonium chloride solution, carry out quenching.Mixture be distributed in EtOAc (100 milliliters) Xiang Heshui (100 milliliters) mutually in, collect organic phase, with magnesium sulfate, be dried, filter also and evaporate under vacuum condition.By this material dissolution at anhydrous CH 2cL 2in (80 milliliters).Then add silica gel (20.3 grams) and pyridinium chlorochromate (5.4 grams, 25 mmoles), at room temperature to this suspension agitation 3 hours.Then with silica gel, mixture is filtered.Filtrate concentrates under vacuum condition, uses chromatographic column (silica gel, hexane: EtOAc is 3: 2) to purify to resulting residue, thereby obtains 2-nitro-benzophenone (3.7 grams, 14 mmoles).This benzophenone is dissolved in Glacial acetic acid (50 milliliters), methyl alcohol (50 milliliters) and deionized water (10 milliliters).The in the situation that of strong stirring, add iron powder (10 microns of <, 1.0 grams), and suspension is heated to 60 ℃.After 20 minutes, then add iron powder (2.0 grams), and at 60 ℃, stir 3 hours.After cooling, add silica gel (12.5 grams), and remove volatile constituent under vacuum condition.The powder suspension obtaining, in EtOAc (100 milliliters), and is carefully processed with the sodium hydroxide of 1N concentration, until liquid becomes alkalescence while detecting with reindeer moss.Suspended substance is filtered, thereby organic phase is separated, use salt solution to wash, with magnesium sulfate, be dried, filter and evaporate under vacuum condition.Use chromatographic column (silica gel, hexane: EtOAc is 1: 3) to purify to the residue obtaining, thereby obtain compound 1af (3.1 grams, productive rate is 94%), MS m/z=230 (M+H).
(2-amino-4-trifluoromethyl-phenyl)-(the fluoro-phenyl of 2-)-ketone (1f)
According to prepare compound 1af described in the similar method of method, 2-nitro-4-trifluoromethyl-phenyl aldehyde is converted to compound 1f (productive rate is 46%), MS m/z=230 (M+H).
(2-amino-5-fluorine-phenyl)-(the fluoro-phenyl of 2-)-ketone (1j)
According to prepare compound 1af described in the similar method of method, the fluoro-2-nitro-phenyl aldehyde of 5-is converted to compound 1j (productive rate is 60%), MS m/z=234 (M+H).
(2-amino-5-methoxyl group-phenyl)-(the fluoro-phenyl of 2-)-ketone (1ah)
According to prepare compound 1af described in the similar method of method, 5-methoxyl group-2-nitro-phenyl aldehyde is converted to compound 1ah (productive rate is 62%), MS m/z=246 (M+H).
embodiment 3: the method C of synthetic molecules formula (i) representative compound
(the chloro-phenyl of 2-amino-5-)-(2-methyl-phenyl)-ketone (1m)
In the THF suspension of sodium carbonate (3.8 grams, 36 mmoles) and the chloro-phenylformic acid of 2-amino-5-(3.1 grams, 18 mmoles), drip Benzoyl chloride (5.3 milliliters, 45 mmoles).This mixture is stirred 16 hours, then add water (200 milliliters).The throw out obtaining is collected and filtered, use methanol/water (1/1,100 milliliter) to wash, then under vacuum condition, be dried, thereby obtain the chloro-2-phenyl-benzo of 6-[d] [1,3] oxazine-4 ketone (4.3 grams, productive rate is 92%).At-78 ℃, to the CH of benzoxazine (5.0 grams, 19 mmoles) 2cl 2in (100 milliliters) suspension, drip O-tolyl chlorination magnesium (the THF solution of 2M concentration, 48 mmoles).This mixture is heated to-30 ℃, and stirs 1 hour.Then the hydrochloric acid that adds 1N concentration.Collect organic phase, and use CH 2cl 2(2 * 50 milliliters) washing water.Use the sodium hydroxide (2 * 50 milliliters) of 0.1N to wash the organic phase of combination; with magnesium sulfate, be dried; filter and concentrate under vacuum condition; thereby obtain the chloro-2-of N-[4-(2-methyl-benzoyl)-phenyl]-benzamide (6.3 grams, productive rate is 93%).Amino-the benzophenone of acrylated (3.5 grams, 10 mmoles) is dissolved in the methyl alcohol that contains potassium hydroxide (3M, 30 mmoles), and refluxes 16 hours.Then by solution cool to room temperature, and water (50 milliliters) and EtOAc (100 milliliters) are diluted.Collect organic phase, and water (3 * 50 milliliters) washs, with magnesium sulfate, be dried, filter also and evaporate under vacuum condition, thereby obtain compound 1m (2.4 grams, productive rate is 98%), MS m/z=246 (M+H).
(the chloro-phenyl of 2-amino-5-)-(2-methoxyl group-phenyl)-ketone (1n)
Use the method similar with preparation method described in compound 1m, by the chloro-2-phenyl-benzo of 6-[d], [1,3] oxazine-4 ketone is converted into compound 1n (productive rate is 84%), MSm/z=262 (M+H).
(the chloro-phenyl of 2-amino-5-)-(2-dimethylamino methyl-phenyl)-ketone (1q)
At the chloro-2-of N-[4-(2-methyl-benzoyl)-phenyl] (5.1 grams of-benzamide; 14.6 mmoles) and (2.85 grams of N-bromo-succinimides; 16 mmoles) in tetrachloromethane (150 milliliters) solution, add 2; 2 '-azo diisobutyl nitrile (0.2 gram, 1.5 mmoles).This solution is carried out to the reflow treatment of 4 hours.Then by solution cool to room temperature.And use CH 2cl 2(150 milliliters) dilute and water (3 * 50 milliliters) washs.Use sodium sulfate to be dried organic phase, and be evaporated to absolutely dried condition under vacuum condition, thereby obtain the chloro-phenyl of N-[2-(2-brooethyl-benzoyl)-4-]-benzamide (4.6 grams, productive rate is 74%).CH with dimethylamine paraphenylene terephthalamide (2.3 grams, 5.4 mmoles) 2cl 2(50 milliliters) solution carries out saturated processing, stirs 16 hours, and be evaporated to absolutely dried condition under vacuum condition.The resistates obtaining is dissolved in methyl alcohol (50 milliliters), and adds water (5 milliliters) solution of potassium hydroxide (0.9 gram, 16 mmoles).This solution is carried out to the reflow treatment of 24 hours.Under vacuum condition, this solution is concentrated, then use EtOAc (150 milliliters) and water (50 milliliters) to dilute.Water (3 * 50 milliliters) washs organic phase, is dried, with chromatographic column (silica gel, methyl alcohol: CH with sodium sulfate 2cl 2: NHOH=18: 80: 2) purify, thereby obtain compound 1q (0.9 gram, productive rate is 53%), MS m/z=289 (M+H).
(the chloro-phenyl of 2-amino-5-)-(the fluoro-phenyl of 3-)-ketone (1r)
Use the method similar with preparation method described in compound 1m, by the chloro-2-phenyl-benzo of 6-[d], [1,3] oxazine-4 ketone is converted into compound 1r (productive rate is 36%), MSm/z=250 (M+H).
(the chloro-phenyl of 2-amino-5-)-(3-methoxyl group-phenyl)-ketone (1s)
Use the method similar with preparation method described in compound 1m, by the chloro-2-phenyl-benzo of 6-[d], [1,3] oxazine-4 ketone is converted into compound 1s (productive rate is 64%), MSm/z=262 (M+H).
(the chloro-phenyl of 2-amino-5-)-(2,4-dimethoxy-phenyl)-ketone (1x)
Use the method similar with preparation method described in compound 1m, by the chloro-2-phenyl-benzo of 6-[d], [1,3] oxazine-4 ketone is converted into compound 1x (productive rate is 63%), MSm/z=292 (M+H).
(the chloro-phenyl of 2-amino-5-)-(2,5-dimethoxy-phenyl)-ketone (1z)
Use the method similar with preparation method described in compound 1m, by the chloro-2-phenyl-benzo of 6-[d], [1,3] oxazine-4 ketone is converted into compound 1z (productive rate is 62%), MSm/z=292 (M+H).
embodiment 4: the method D of synthetic molecules formula (i) representative compound
(the chloro-phenyl of 2-amino-5-)-(the fluoro-6-methoxyl group-phenyl of 2-)-ketone (1ac)
At-78 ℃, to butyllithium hexane (62 milliliters, the 155 mmoles) solution that drips 2.5M in THF (180 milliliters) solution of the fluoro-3-methoxyl group-benzene of 1-(19.6 grams, 155 mmoles).At-78 ℃, to this solution stirring 3 hours, then, at-20 ℃, this solution is joined to the chloro-2-phenyl-benzo of 6-[d] [in THF (280 milliliters) suspension of 1,3] oxazine-4 ketone (38.8 grams, 150 mmoles).This mixture is progressively heated, until this liquid becomes homogeneous liquid.Adding concentration is the hydrochloric acid (150 milliliters) of 1N, then adds EtOAc (250 milliliters), and this solution is heated to room temperature.Collect organic phase, and water (250 milliliters), saturated sodium bicarbonate solution (2 * 250 milliliters) and water (250 milliliters) wash.Then with sodium sulfate, organic phase is dried, and is evaporated to absolutely dried condition under vacuum condition, thereby obtain the chloro-2-of N-[4-(the fluoro-6-methoxyl group-benzoyl of the 2-)-phenyl of orange solid state]-benzamide (42.7 grams).At the chloro-2-of N-[4-(the fluoro-6-methoxyl group-benzoyl of 2-)-phenyl] (42.7 grams of-benzamide; 110 mmoles) water (100 milliliters) solution that adds potassium hydroxide (56.4 grams, 1 mole) in methyl alcohol (540 milliliters) solution.This solution is carried out to the reflow treatment of 16 hours.Then by this solution cool to room temperature, and by filtering, the throw out of generation is removed.Under vacuum condition, filtrate is concentrated, and dilute with EtOAc (250 milliliters), then water (3 * 100 milliliters) washs.Use sodium sulfate to be dried organic phase, under vacuum condition, concentrate, then use chromatographic column (silica gel, the EtOAc/ hexane of 0-15%) purify, thereby obtain compound 1ac (19.6 grams, productive rate is 47%), MS m/z=280 (M+H).
embodiment 5: the method E of synthetic molecules formula (i) representative compound
(the chloro-phenyl of 2-amino-5-)-(the fluoro-phenyl of 4-)-ketone (1t)
In the time of 10 minutes, to being heated in the p-fluorobenzoyl chloride (49.7 grams, 314 mmoles) of 120 ℃, add p-chloroaniline (17.8 grams, 139 mmoles).This mixture is heated to 180 ℃, and in 10 minutes, adds zinc dichloride (23.8 grams, 174 mmoles).The mixture obtaining is heated 2 hours at 205 ℃.After being cooled to 120 ℃, slowly adding the hydrochloric acid (2 * 125 milliliters) of 3N, and mixture is kept 1 hour at 120 ℃.Then hot water is carried out to decant processing, and use hot 3N hydrochloric acid (2 * 125 milliliters) to wash remaining residue.Residue is poured on ice face, and uses CH 2cL 2(3 * 100 milliliters) extract.Use the hydrochloric acid (2 * 50 milliliters) of 3N, the sodium hydroxide (2 * 50 milliliters) of 5N and water (3 * 50 milliliters) wash the organic phase of combination; and be dried with magnesium sulfate; then filter; and concentrate under vacuum condition; thereby obtain the chloro-2-of N-[4-(the fluoro-benzoyl of the 4-)-phenyl of 15 grams (productive rate is 29%)] the fluoro-benzamide of-4-, this product is dark yellow powder.In the flask that fills acrylated amino-benzophenone (6.7 grams, 18 mmoles), adding concentration ratio is hydrochloric acid and the acetic acid (700 milliliters) of 1: 1, the mixture of generation is heated to 105 ℃, and stirs 16 hours.By mixture cool to room temperature, and concentrate under vacuum condition.Resistates is poured on ice face, and uses CH 2cL 2(3 * 50 milliliters) extract.Use sodium hydroxide (2 * 50 milliliters) and the water (3 * 50 milliliters) of 5N to wash, then with magnesium sulfate, be dried, then filter, and concentrate under vacuum condition.Use chromatographic column (silica gel, 5-25%EtOAc/ hexane) to purify to the residue generating, and carry out recrystallize processing with hexane, thereby row is to compound 1t (3.4 grams, productive rate is 76%), MS m/z=250 (M+H).
(the chloro-phenyl of 2-amino-5-)-(4-methoxyl group-phenyl)-ketone (1u)
To preparing the compound 1s process chloro-2-of N-[4-used (the fluoro-benzoyl of 4-)-phenyl] add the sodium hydroxide (50 milliliters) of 5N in methyl alcohol (400 milliliters) solution of-fluoro-benzamide of 4-, and the solution generating is carried out to the reflow treatment of 16 hours.By solution cool to room temperature, and concentrate under vacuum condition.Use CH 2cL 2(2 * 100 milliliters) extract water.Water (3 * 50 milliliters) is washed the organic phase of combination, and be dried with magnesium sulfate, then filter, under vacuum condition, concentrate.Use chromatographic column (silica gel, 5-25%EtOAc/ hexane) residue generating is purified, and carry out recrystallize processing with methyl alcohol, thereby obtain (3.5 grams of the compound 1u of pale yellow powder shape, productive rate is 83%), MS m/z=262 (M+H).
(2-amino-5-methyl-phenyl)-(the fluoro-phenyl of 2,6-bis-)-ketone (1aj)
Use the method similar with preparation method described in compound 1t, p-Tolylamine and 2,6-difluoro benzoyl chloride are converted into compound 1aj (productive rate is 16%), MS m/z=248 (M+H).
embodiment 6: the method F for preparing molecular formula (i) representative compound
(the chloro-phenyl of 2-amino-5-)-(the fluoro-phenyl of 2,6-bis-)-ketone (1aa)
Under ar gas environment, the chloro-uncle N--butoxy carbonyl-aniline of 4-is dissolved in not containing in the anhydrous tetrahydro furan (40 milliliters) of inhibitor, and this solution is cooled to-78 ℃.In dry ice/acetone cooling tank, t-Buli (the 1.7M solution in pentane, 20 milliliters, 34 mmoles) is cooling, then in 20 minutes, by intubate, t-Buli is joined in uncle-butoxy carbonyl-aniline solution.At-78 ℃, this yellow solution is stirred 30 minutes, then with 2.5 hours, this solution is heated to-30 ℃, and then is cooled to-78 ℃.Under ar gas environment, 2,6-difluoro benzoyl chloride (2.8 grams, 16 mmoles) is dissolved in anhydrous THF (30 milliliters), and is cooled to-78 ℃.Then in 30 minutes, by intubate, 0-lithiumation aniline is joined in this acidic chloride solution.Before the hydrochloric acid (50 milliliters) that uses 1N carries out quenching to this solution stirring 20 minutes.With EtOAc, this solution is diluted, organic phase is separated, use magnesium sulfate to be dried, and concentrate under vacuum condition, until complete drying.Use chromatographic column (silica gel, hexane: EtOAc=4: 1) the orange oily mater obtaining is purified, thereby obtain amino-benzophenone (3.3 grams, productive rate is 60%) that uncle-butoxy carbonyl is protected.Uncle N--butoxy carbonyl-Uvinul A Plus is dissolved in to anhydrous CH 2cl 2in (50 milliliters), and add trifluoroacetic acid (50 milliliters).After 1 hour stirs, this solution is evaporated to absolutely dried condition under vacuum condition.The residue obtaining is dissolved in the EtOAc (100 milliliters) and water (100 milliliters) that contains sodium bicarbonate.Use saturated sodium bicarbonate aqueous solution to wash organic phase, with magnesium sulfate, be dried, under vacuum condition, concentrate, until absolutely dried condition, thereby obtain the compound 1aa of some amount, MSm/z=268 (M+H).
(the chloro-phenyl of 2-amino-5-)-(the fluoro-phenyl of 2,3-bis-)-ketone (1v)
According to the similar method of method described in allied compound 1aa explanation above, 4-chloro-N-tert-butoxycarbonyl aniline and 2,3-difluoro benzoyl chloride are converted into compound 1v (productive rate is 14%), MS m/z=268 (M+H).
(the chloro-phenyl of 2-amino-5-)-(the fluoro-phenyl of 2,4-bis-)-ketone (1w)
According to the similar method of method described in allied compound 1aa explanation above, 4-chloro-N-tert-butoxycarbonyl aniline and 2,4 difluorobenzene formyl chloride are converted into compound 1w (productive rate is 20%), MS m/z=268 (M+H).
(the chloro-phenyl of 2-amino-5-)-(the fluoro-phenyl of 2,5-bis-)-ketone (1y)
According to the similar method of method described in allied compound 1aa explanation above, 4-chloro-N-tert-butoxycarbonyl aniline and 2,4 difluorobenzene formyl chloride are converted into compound 1y (productive rate is 10%), MS m/z=268 (M+H).
(the chloro-phenyl of 2-amino-5-)-(the fluoro-phenyl of the chloro-6-of 2-)-ketone (1ab)
According to the similar method of method described in allied compound 1aa explanation above, 4-chloro-N-tert-butoxycarbonyl aniline and the fluoro-Benzoyl chloride of the chloro-6-of 2-are converted into compound 1ab (productive rate is 42%), MS m/z=284 (M+H).
(2-amino-5-chloro-phenyl-)-(2-(trifluoromethyl) phenyl) ketone (1o)
According to the similar method of method described in allied compound 1aa explanation above, 4-chloro-N-tert-butoxycarbonyl aniline and 2-(trifluoromethyl) Benzoyl chloride are converted into compound 1o (productive rate is %), MS m/z=(M+H).
embodiment 7: the method G of synthetic molecules formula (ii) representative compound and method H (seeing flow process 1)
(the iodo-phenyl of the chloro-2-of 5-)-(the fluoro-phenyl of 2,6-bis-)-ketone (2aa)
Method G: (the chloro-phenyl of 2-amino-5-)-(the fluoro-phenyl of 2,6-bis-)-ketone (1aa) (2.6 grams, 9.7 mmoles) is dissolved in acetic acid (10 milliliters) and concentrated hydrochloric acid (4 milliliters), and this solution is cooled to 0 ℃.Water (6 milliliters) solution of Sodium Nitrite (0.7 gram, 10.7 mmoles) is added drop-wise in solution above, temperature is maintained between 0-5 ℃.Then at 0 ℃, reaction mixture is stirred 30 minutes.Then drip cold EtOAc (20 milliliters), and to solution stirring 20 minutes.And then water (10 milliliters) solution of dropping iodine (1.5 grams, 5.8 mmoles) and potassiumiodide (1.9 grams, 11.6 mmoles), and mixture is heated to room temperature, and stir 1 hour.Use EtOAc (200 milliliters) to dilute reaction mixture, and use the saturated aqueous solution (4 * 100 milliliters) of Sulfothiorine to wash reaction mixture.With EtOAc (3 * 50 milliliters), the water of combination is extracted.Then use saturated aqueous solution (3 * 50 milliliters) and the water (2 * 50 milliliters) of sodium bicarbonate to wash the organic phase of combination, with sodium sulfate, be dried, then filter, and concentrate under vacuum condition, thereby obtain (3.3 grams of compound 2aa, productive rate is 90%), compound 2aa is flaxen solid.
4-(the fluoro-benzoyl of 2-) the iodo-methyl benzoate of-3-(2i)
Method H: add potassium permanganate (3.8 grams, 24 mmoles) in the trimethyl carbinol (25 milliliters) of compound 2g (1 gram, 3 mmoles) and water (25 milliliters) solution.This solution is carried out to the reflow treatment of 18 hours.Add THF (50 milliliters), and solution is refluxed 30 minutes, after cool to room temperature, filter.Under vacuum condition, filtrate is concentrated, use methyl alcohol (20 milliliters) to dilute, and carry out acidification with concentrated hydrochloric acid.Water (10 milliliters) dilutes solution, collects the throw out generating, thereby obtains 4-(the fluoro-benzoyl of 2-) the iodo-phenylformic acid of-3-(1 gram, productive rate is 92%) of white solid.At 140 ℃, methyl alcohol (6 milliliters) solution of the 4-that contains concentrated hydrochloric acid (100 microlitre) (the fluoro-benzoyl of 2-) the iodo-phenylformic acid of-3-(0.5 gram, 1.4 mmoles) is carried out to the microwave radiation processing (300 watts) of 30 minutes.Collect the throw out generating, thereby obtain compound 2i (0.4 gram, productive rate is 79%), MS m/z=385 (M+H); Compound 2i is white solid.
2-(the iodo-benzoyl of the chloro-2-of 5-)-benzoic acid methyl ester (2p)
According to the similar method of method described in allied compound 2i explanation above, compound 2m is converted into compound 2p (productive rate is 81%), MS m/z=401 (M+H).
3-(2-fluoro benzoyl)-4-iodo-benzoic acid methyl ester (2ai)
According to the similar method of method described in allied compound 2i explanation above, compound 2af is converted into compound 2ai (productive rate is 60%), MS m/z=385 (M+H).
3-(2,6-difluoro benzoyl)-4-iodo-benzoic acid methyl ester (2ak)
According to the similar method of method described in allied compound 2i explanation above, compound 2aj is converted into compound 2ak (productive rate is 58%), MS m/z=403 (M+H).
In table 4, the compound of listed molecular formula 2 representatives can be prepared according to the mode similar with mode shown in method H to method G, has the description of method G and method H above in the explanation of allied compound 2aa and compound 2i.
Table 4: the illustrative embodiment of molecular formula 1-5 representative compound
embodiment 8: the method I (seeing flow process 1) of synthetic molecules formula iii representative compound
The chloro-2-of 3-[4-(the fluoro-benzoyl of 2,6-bis-)-phenyl] and 2-propynyl }-t-butyl carbamate (3aa)
By (the iodo-phenyl of the fluoro-2-of 5-)-(the fluoro-phenyl of 2,6-bis-)-ketone (2aa) (5.5 grams, 14.5 mmoles), 2-propynyl-t-butyl carbamate (2.5 grams, 16 mmoles), PdCl 2(PPh 3) 2(0.6 gram, 0.9 mmole) and Cu (I) I (0.2 gram, 0.9 mmole) are suspended in anhydrous CH 2cL 2in (50 milliliters), and with nitrogen to this mixture bubbling 30 minutes.Add diethylamine (8 milliliters), and at room temperature to solution stirring 16 hours.Under vacuum condition, solution is carried out to concentration, by chromatographic column (silica gel, 0-15%EtOAc/ hexane), the residue generating is purified, thereby obtain compound 3aa (3.6 grams, productive rate is 61%), MS m/z=406 (M+H); Compound 3aa is white solid.
In table 4, the compound of listed molecular formula 3 representatives can be prepared according to the mode similar to mode shown in method I, has the description of method I in the explanation of compound 3aa.
embodiment 9: the method J (seeing flow process 1) of synthetic molecules formula iii representative compound
Tert-butyl 3-(the chloro-2-picolinyl of 4-) 2-propynyl carbamate (3a1)
The chloro-2-iodo-benzoic acid of 5-(2.8 grams, 10 mmoles) is dissolved in anhydrous methylene chloride (80 milliliters), then adds DMF (50 microlitres, catalyzer), then add thionyl chloride (2.4 grams, 20 mmoles).In the situation that stirring, this mixture is refluxed 12 hours, cool to room temperature then, and concentrate under vacuum condition.Residue and toluene (2 * 10 milliliters) carry out azeotropic, and use in the situation that further not purifying.The chloro-2-iodobenzene of 5-formyl chloride (10 mmole) is dissolved in anhydrous methylene chloride (50 milliliters), and adds N, O-dimethyl hydroxylamine (1.1 grams, 11 mmoles).This mixture is cooled to 0 ℃, and adds pyridine (2.4 grams, 30 mmoles).This mixture is heated to room temperature, stirs 12 hours, then use saturated brine (20 milliliters) to carry out quenching.Organic phase is separated, and used methylene dichloride (2 * 10 milliliters) to extract water.Use anhydrous magnesium sulfate to be dried the organic extract of combination, then filter, and concentrate under vacuum condition.Use flash chromatography method to purify to residue, wherein flash chromatography method is carried out on silica gel (50 grams), and take methylene dichloride as eluent; Thereby obtain the iodo-N-methoxyl group-N-methyl-benzamide of the chloro-2-of 5-(3.1 grams, productive rate is 95%), MSm/z=326 (M+H).
According to method H; (3.1 grams of Weinreb acid amides; 9.5 mmoles) and (2.9 grams of 2-propynyl carboxylamine tertiary butyl ester; 9 mmoles) there is coupling; thereby form (2.7 grams of 3-(the chloro-2-of 4-(methoxyl group (methyl) formamyl) phenyl) 2-propynyl carboxylamine tertiary butyl ester; productive rate is 80%), MS m/z=353 (M+H).This product is dissolved in anhydrous THF (40 milliliters), and is cooled to-78 ℃, add lithiumation pyridine; Wherein lithiumation pyridine is by the anhydrous THF solution preparation of 2-bromopyridine (4.2 grams, 26.6 mmoles) and n-butyllithium (the 1.6M hexane solution of 14.3 milliliters, 22.8 mmoles) and obtain under-78 ℃ and ar gas environment.The time of 1 hour, progressively the mixture of generation is heated to-40 ℃, then uses salt solution (20 milliliters) to carry out chilling.After being heated to room temperature, use ethyl acetate (3 * 20 milliliters) to extract mixture.Use magnesium sulfate to be dried organic extract, then filter and concentrate.Use silica gel (100 grams) flash chromatography method to purify to residue, thereby obtain compound 3a1 (2.14 grams, productive rate is 76%), MS m/z=371 (M+H); Wherein, in flash chromatography method, the dichloromethane solution of methylene dichloride and 10% ethyl acetate is as eluent.
embodiment 10: the method K of synthetic molecules formula iv representative compound and method L (seeing flow process 1)
The chloro-1-of 8-(the fluoro-phenyl of 2-)-3,4-dihydro-benzo [C] azepine-5 ketone (4K)
Method K: methylene dichloride (100 milliliters) solution that will contain { the chloro-2-of 3-[4-(the fluoro-benzoyl of 2-)-phenyl] 2-propynyl } carboxylamine tertiary butyl ester (9.2 grams, 23 mmoles) of formic acid (9.18 milliliters) is cooled to 0 ℃.Add Mercury bisulfate (II) (2.1 grams, 7.1 mmoles), and at 0 ℃, reaction is stirred 2 hours.Water (20 milliliters) and ammonium hydroxide (20 milliliters) are diluted this mixture.Collect organic phase, and with EtOAc (3 * 100 milliliters), water is extracted.Water washs the organic phase of combination; with magnesium sulfate, be dried; after filtering; under vacuum condition, solvent is evaporated, thereby obtains [the chloro-2-of 3-[4-(2-fluoro benzoyl)-phenyl]-3-oxopropyl of brown solid shape] 8.9 grams of-carboxylamine tertiary butyl ester (productive rate is 95%).This product (8.9 grams, 22 mmoles) is dissolved in to hydrochloric acid (4N dioxane solution, 185 milliliters), and at room temperature stirs 30 minutes.Under vacuum condition, this solution is evaporated.Resistates is dissolved in methylene dichloride (250 milliliters), and adds diisopropylethylamine (18 milliliters).At room temperature to this solution stirring 2 hours, under vacuum condition, this solution is evaporated, use chromatographic column (silica gel, 10-50%EtOAc/ hexane) residue is purified, thereby obtain (2.9 grams of the compound 4K of brown solid shape, productive rate is 46%), MS m/z=288 (M+H).
The chloro-1-of 8-(the chloro-phenyl of 2,6-bis-)-3,4-dihydro-benzo [c] azepine-5 ketone (4aa)
Method L: { the chloro-2-of 3-[4-(the fluoro-benzoyl of 2,6-bis-)-phenyl] 2-propynyl }-carboxylamine tertiary butyl ester (5.6 grams, 15 mmoles) is dissolved in diox (200 milliliters).The hydrochloric acid (aqueous solution) (200 milliliters) that adds 5N in this solution, at room temperature to this solution stirring 14 hours, then at 60 ℃, stir again 2 hours, with methylene dichloride (200 milliliters), this solution is diluted, add sodium carbonate, until this solution is alkalescence while checking with reindeer moss.This mixture is stirred 2 hours.Organic phase is separated, and with methylene dichloride (2 * 100 milliliters), water is extracted.Water (3 * 50 milliliters) washs the organic phase of combination, uses sodium sulfate to be dried, and after filtering, under vacuum condition, concentrates, thereby obtains compound 4aa (4.2 grams, productive rate is 100%), MSm/z=306 (M+H).
According to the similar method of method shown in compound 4K and compound 4aa explanation, can prepare the compound of listed molecular formula 4 representatives of table 4.
embodiment 11: the method M (seeing flow process 1) of synthetic molecules formula V representative compound
The chloro-4-dimethylamino of 8-methylene-1-(the fluoro-phenyl of 2,6-bis-)-3,4-dihydro-benzo [c] azepine-5 ketone (5aa)
By the chloro-1-(2 of 8-, the fluoro-phenyl of 6-bis-)-3,4-dihydro-benzo [c] azepine-5 ketone (4aa) (4.2 grams, 15 mmoles) are dissolved in toluene (100 milliliters) and N, in dinethylformamide dimethylacetal (19 milliliters), and at 80 ℃, heat 2 hours.Under vacuum condition, concentrate, use chromatographic column (silica gel, 0-75%EtOAc/ hexane) to purify to the residue generating, thereby obtain compound 5aa (2.6 grams, productive rate is 78%), MSm/z=361 (M+H); Wherein compound 5aa is light brown solid.
According to the similar approach of method shown in compound 5aa explanation, can prepare the compound of listed molecular formula 5 representatives of table 4.
embodiment 12: by method N, method O or method P, prepare aryl guanidine or heteroaryl guanidine
N-(3,4-dimethoxy-phenyl)-guanidine
Method N: in 0 ℃ and strong stirring situation, drip nitric acid (concentration is 69%, 9.0 milliliter, 0.1 mole) in EtOH (60 milliliters) solution of 3,4-dimethoxyaniline (15.3 grams, 0.1 mole).Water (8.5 milliliters) solution that adds cyanamide (4.6 grams, 0.1 mole) in this solution, and in backflow situation, this solution is heated 3 hours.Use EtOH (50 milliliters) to dilute this mixture, and be cooled to 4 ℃.Collect the golden needle-like product generate, and be dried under vacuum condition, thereby obtain the nitrate (14.7 grams, productive rate is 57%) of N-(3,4-dimethoxy-phenyl)-guanidine, MS m/z=196 (M+H).
N-pyridine-3 base-guanidine
Method O: in 3-aminopyridine (1.0 grams, 10.6 mmoles), 1,3-bis-(tert-butoxycarbonyl)-2-methyl-2-sulfo-pseudo-urea (4.0 grams, 13.8 mmoles) and Et 3in methylene dichloride (100 milliliters) solution mixture of N (15 milliliters), add mercury chloride (4.0 grams, 14.8 mmoles).Under room temperature and nitrogen environment, the mixture generating is stirred 16 hours, during churning in mixture, can generate white depositions.Use mixture is filtered, and use Et 2o washs.Filtrate to combination under vacuum condition is dried; until complete drying is used chromatographic column (silica gel, 15%EtOAc/ hexane) to purify to the white solid obtaining; thereby obtain the guanidine (3.1 grams, productive rate is 88%) of two-uncle-butoxy carbonyl protection.In methyl alcohol (2 milliliters) solution of this material, add hydrochloric acid (the Yan Suan dioxane solution of 4N, 60 milliliters).The solution obtaining is carried out to the backflow of 16 hours, after cool to room temperature with Et 2o develops, thereby obtains the hydrochloride (1.2 grams, productive rate is 74%) of N-pyridine-3 base guanidine, MS m/z=173 (M+H).
Guanidinobenzoic acid tertiary butyl ester, hydrochloride
Method P: add (1,3-benzyloxy carbonyl)-2-methyl-2-sulfo-pseudo-urea (5.6 grams, 15.5 mmoles), Et in methylene dichloride (20 milliliters) solution of PABA tertiary butyl ester (2.0 grams, 10.3 mmoles) 3n (5.0 milliliters, 36 mmoles) and mercury chloride (3.37 grams, 12.4 mmoles).At room temperature this reaction mixture is carried out the stirring at a night.Use reaction mixture is filtered, under vacuum condition, filtrate is concentrated, and use the chromatographic column (methylene dichloride of the dichloromethane/hexane to 100% of 1: 1, then be 10%EtOAc/ methylene dichloride) purify, thereby obtain 4-(2,3-bis-(benzyloxycarbonyl) guanidine radicals) phenylformic acid tertiary butyl ester (3.9 grams, productive rate is 75%).On carbon in pressurized bottle (2 grams), add 20% palladium hydroxide, then add EtOAc (80 milliliters) solution of 4-(2,3-bis-(benzyloxycarbonyl) guanidine radicals) phenylformic acid tertiary butyl ester (3.9 grams, 7.7 mmoles).Under the hydrogen environment and room temperature of 50psi pressure, mixture is carried out to the stirring at a night.Use solution is filtered, and make filtrate evaporation under vacuum condition, thereby obtain guanidinobenzoic acid tertiary butyl ester (1.8 grams, productive rate is 100%).The hydrochloric acid Et that adds 2M in the EtOAc (50 milliliters) of this guanidine class material (855 milligrams, 3.6 mmoles) solution 2o (1.9 milliliters, 3.8mM) solution.This solution is concentrated, by filtering collecting precipitation thing, use Et 2o washs, and is dried under vacuum condition, thereby obtains hydrochloride (840 milligrams, productive rate is 85%).
embodiment 13: method Q, method R and the method S of synthetic molecules formula (I) representative compound
The chloro-7-of 4-[9-(the fluoro-phenyl of 2-)-5 hydrogen-benzo [c] Kui Linpyrimido quinoline [4,5-e] azepine-2 base is amino]-phenylformic acid (I-52)
Method Q: at 250 ℃, to the chloro-4-dimethylamino of 8-methylene-1-(the fluoro-phenyl of 2-)-3, (0.22 gram of 4-dihydro-benzo [c] azepine-5 ketone (5K), 0.64 mmole), 4-guanidine radicals-benzoate hydrochloride is (0.15 gram, 0.70 mmole) and (0.23 milliliter of diisopropylethylamine (I-Pr2EtN), 1.32 mmoles) DMF (2,5 milliliters) solution carries out the microwave radiation processing (300 watts) of 300 seconds.After thing to be mixed is cooling, mixture is poured in water (100 milliliters).The hydrochloric acid that drips 1N when stirring, makes pH value reach 3, then adds EtOAc (50 milliliters).The throw out of collecting generation by filtration is dried under vacuum condition, thereby obtains the compound (I-52) (0.13 gram, productive rate is 47%) of brown solid shape.
The chloro-7-of 4-[9-(the fluoro-phenyl of 2,6-bis-)-5 hydrogen-benzo [c] Kui Linpyrimido quinoline [4,5-e] azepine-2 base is amino]-phenylformic acid (I-135)
Method R: to the chloro-4-dimethylaminomethylene-1-(2 of 8-, the fluoro-phenyl of 6-bis-)-3, (2.6 grams of 4-dihydro-benzo [c] azepine-5 ketone (5aa), 7.1 mmoles), 4-guanidine radicals-benzoate hydrochloride is (1.7 grams, 7.8 mmoles) and EtOH (50 milliliters) solution of 15 aqueous carbonate potassium (2.6 grams, 15.6 mmoles) carry out the backflow of 14 hours.This mixture is poured in water (400 milliliters) after cooling.The hydrochloric acid that drips 1N when stirring, makes pH value reach 3.Then add EtOAc (400 milliliters), water (2 * 100 milliliters) washs organic phase, with sodium sulfate, be dried, and dry until absolutely dried condition under vacuum condition.Resistates is suspended in methylene dichloride, and filters.Solid matter is dissolved in EtOAc, uses silica gel to filter, under vacuum condition, concentrate and be dried, thereby obtain the compound (I-135) (1.4 grams, productive rate is 42%) of white solid.
In water (1.2 milliliters) solution of ethanol (8.86 milliliters), add the chloro-7-(2 of 4-[9-, the fluoro-phenyl of 6-bis-)-5 hydrogen-benzo [c] Kui Linpyrimido quinoline [4,5-e] azepine-2 base is amino] (1.5 grams ,-phenylformic acid (I-135), 2.95 moles), and this mixture is heated to 50 ℃.In mixture, add aqueous sodium hydroxide solution (0.02458 grams per milliliter), make the pH value of solution reach 11.6.In solution, add water, adding water inventory is 4.26 mls/g of anacidity things again.The slurries of formation are heated to 70 ℃, and carry out fast filtering, solution is maintained between 65-70 ℃.Add hot ethanol (9.15 milliliters, 7.21 grams), this solution is cooled to 65 ℃.The sodium salt crystal seed of compound (I-135) (7.1 milligrams, 0.014 mole) is joined in this solution with slurry form, and wherein the slurry of this crystal seed is that the ethanol of this crystal seed 10% (weight) adds the aqueous solution, and the ratio of second alcohol and water is 75: 25.This mixture maintains 1 hour at 65 ℃, then with the cooling rate of 12 ℃/h, is cooled to 35 ℃.At 35 ℃, then add ethanol.With the cooling rate of 12 ℃/h, this mixture is cooled to 0 ℃ again, and at 0 ℃, keeps 1 hour.The dense thick slurry generating is filtered, use cold ethanol (5.52 grams, 7 milliliters) to wash wet cake, thereby obtain the sodium salt of Compound I-135; Productive rate is 72%, and this sodium salt is hydrate.
The chloro-7-of 2-[9-(the fluoro-phenyl of 2,6-bis-)-5 hydrogen-benzo [c] Kui Linpyrimido quinoline [4,5-e] azepine-2 base is amino]-oxazole-5 carboxylic acid (I-364)
Method S: by the chloro-4-dimethylaminomethylene-1-(2 of 8-, 6-difluorophenyl)-3, (3.6 grams of 4-dihydrobenzo [c] azepine-5 ketone (5aa), 10 mmoles), Guanidinium hydrochloride is (1.06 grams, 11 mmoles), salt of wormwood is (4.6 grams, 33 mmoles) and ethanol (100 milliliters) capacity of being blended in be in the round-bottomed flask of 100 milliliters, and stir 3 hours in the situation that refluxing.In the situation that stirring, reaction mixture is poured in 500 ml waters.Use ethyl acetate (4 * 200 milliliters) to extract this mixture.Use salt solution to there being phase extract to wash, use sodium sulfate to be dried, then through filtering and evaporation and obtain the solid of brown.This solid is mixed mutually with diethyl ether, with ether, wash after filtering, then under vacuum condition, be dried, thereby the 9-that obtains filbert solid state is chloro-7-(2, the fluoro-phenyl of 6-bis-)-5 hydrogen-benzo [c[Kui Linpyrimido quinoline [4,5-e] azepine-2 base amine (3.16 grams, productive rate is 89%), MS m/z=357 (M+H).By (0.2 gram of this amine substance, 5.6 mmoles), methylene iodide is (7.7 grams, 28.6 mmoles), cupric iodide (I) is (1.1 grams, 5.6 mmoles), anhydrous tetrahydro furan (40 milliliters) and isopentyl nitric ether are (2.0 grams, 16.8 mmoles) be blended in round-bottomed flask, and stir 1 hour in backflow situation.By this mulberry solution cool to room temperature, then transfer in the separatory funnel that contains 1N hydrochloric acid (250 milliliters) and ethyl acetate (150 milliliters).Organic phase is separated, by ethyl acetate (100 milliliters), water is extracted.Organic extraction is mixed mutually, and use ammonium hydroxide (3%), saturated ammonium chloride and saturated brine to wash, then with sodium sulfate, be dried, obtain furvous oil body after filtration and after concentrated.Use chromatographic column (silica gel, the dichloromethane solution of methylene dichloride to 10% ethyl acetate) purify, thereby obtain the chloro-7-of 9-(the fluoro-phenyl of 2,6-bis-) the iodo-5 hydrogen-benzo of-2-[c] Kui Linpyrimido quinoline [4 of light yellow solid shape, 5-e] azatropylidene, MSm/z=468 (M+H).
At 145 ℃, to the chloro-7-(2 of 9-, the fluoro-phenyl of 6-bis-) the iodo-5 hydrogen-benzo of-2-[c] Kui Linpyrimido quinoline [4,5-e] (200 milligrams of azatropylidenes, 0.43 mmole), ethyl 2-An Ji oxazole-5-carboxylate salt (81.2 milligrams, 0.52 mmole), three (dibenzalacetone) two palladiums (0) (Pd 2(dba) 3) mixture of (935 milligrams, 0.034 mmole), Xantphos (30 milligrams, 0.052 mmole), efflorescence potassiumphosphate (183 milligrams, 0.86 mmole) and degassed toluene carries out the microwave radiation (300 watts) of 20 minutes.By this mixture cool to room temperature, then evaporate, finally leave the solid matter of brown, use chromatographic column (silica gel, the diethyl ether dichloromethane solution of methylene dichloride to 50% concentration) to purify, thereby obtain the chloro-7-(2 of 2-[9-of yellow powder shape, the fluoro-phenyl of 6-bis-)-5 hydrogen-benzo [c] Kui Linpyrimido quinoline [4,5-e] azepine-2 base amino]-oxazoles-5-carboxylic acid, ethyl ester (103 milligrams, productive rate is 48%), MS m/z=496 (M+H).At room temperature, to the chloro-7-(2 of 2-[9,6-difluoro)-phenyl]-5 hydrogen-benzo [c] Kui Linpyrimido quinoline [4,5-e] azepine-2 base is amino] (91 milligrams of-oxazoles-5-carboxylic acid, ethyl esters, 0.18 mmole), the lithium hydroxide (3.7 milliliters, 3.7 mmoles) of methyl alcohol (1 milliliter), tetrahydrofuran (THF) (3 milliliters) and 1N stirs 3 hours.In the situation that stirring, add water (50 milliliters), by slowly adding the hydrochloric acid of 1N to carry out acidifying to this clear thorough yellow solution.In this solution, can generate yellow throw out.Add diethyl ether (10 milliliters), by filtering collecting precipitation thing, water and diethyl ether are washed to throw out, then under vacuum condition, be dried, thereby obtain Compound I-364 (78 milligrams, productive rate is 93%) of yellow powder shape, MS m/z=468 (M+H).
embodiment 14: the method T of synthetic molecules formula (I) representative compound
The chloro-7-of 4-[9-(the fluoro-phenyl of 2-)-5 hydrogen-benzo [c] Kui Linpyrimido quinoline [4,5-e] azepine-2 base is amino] and-phenyl }-(4-methyl-piperazine-1 base)-ketone (I-9)
(0.1 gram, 0.2 mmole), TBTU (0.08 gram, 0.2 mmole) and Et in Compound I-52 3in DMF (5 milliliters) solution of N (0.06 milliliter, 0.4 mmole), add 1-methyl-piperazine (0.03 milliliter, 0.3 mmole).To this solution stirring 30 minutes, then use the sodium hydroxide (50 milliliters) of 0.1N and EtOAc (50 milliliters) to dilute.Organic phase is carried out to separation, with sodium sulfate, be dried, and concentrate under vacuum condition.Use chromatographic column (silica gel, methylene dichloride: methyl alcohol: ammonium hydroxide=94: 5: 1) to purify to the residue generating, thereby obtain Compound I-9 (0.07 gram, productive rate is 47%).
embodiment 15: the method U of synthetic molecules formula (I) representative compound
The chloro-7-of 4-[9-(2,6-difluorophenyl)-5 hydrogen-benzo [c] Kui Linpyrimido quinoline [4,5-e] azepine-2 pyridinylamino]-N-[(3-dimethylamino-tetramethyleneimine-1 base)-imido grpup-methyl]-benzamide (I-237)
Mixture to Compound I-135 (4.8 grams, 10 mmoles) and DMF (100 milliliters) stirs.Add fluoro-N, N, N ', N '-tetramethyl-methane amide hexafluorophosphate (2.9 grams, 11 mmoles), then adds diisopropylethylamine (3.9 grams, 30 mmoles).At room temperature this mixture is stirred 10 minutes.Then add false arteries and veins vitriol (3.2 grams, the 11 mmoles) solid of 2-methyl-2-sulfo-, at room temperature this reaction mixture is stirred to a night.Use salt solution to carry out quenching to this reaction; by filtration, collect cream-coloured throw out; water washs throw out; and be dried under vacuum condition; thereby the 1-{4-[9-that obtains light yellow solid shape is chloro-7-(the fluoro-phenyl of 2,6-bis-)-5 hydrogen-benzo [c] Kui Linpyrimido quinoline [4,5-e] azepine-2 pyridinylamino]-benzoyl } (5.81 grams of-2-methyl-isothioureas; productive rate is 100%), MS m/z=549 (M+H).
Under stirring state, to (250 milligrams of benzoyl-methyl-isothioureas, 0.5 mmole), (58 milligrams of 3-dimethylamino tetramethyleneimine, 0.5 mmole), (50 milligrams of triethylamines, 0.5 mmole) and the solution of toluene (10 milliliters) carry out the backflow of 8 hours, then under vacuum condition, remove volatile constituent, use chromatographic column (silica gel, the ammonia ethanol/methylene liquid of 1% 7N ammonia ethanol/methylene to 5%) residue of brown is purified, thereby obtain (154 milligrams of Compound I-237 of yellow solid shape, productive rate is 54%), MS m/z=615 (M+H).
embodiment 16: the method V of synthetic molecules formula (I) representative compound
Kui Linpyrimido quinoline [4,5-e] azepine-2 base]-4-[(3,5-dimethyl-piperazine-1 base) and-imido grpup-methyl]-phenyl }-amine (I-251)
At 0 ℃, to Compound I-236, in dehydrated alcohol (75 milliliters) suspension of (1.9 grams, 4.4 mmoles), add anhydrous hydrogen chloride gas, until form the solution of homogeneous phase.This solution is heated to room temperature, and places 3 days.Add diethyl ether (100 milliliters), by filtration, collect the throw out generating, with diethyl ether, throw out is washed, and be dried under vacuum condition, thereby obtain (2.4 grams of the chloro-7-of the pulverous 4-[9-of glassy yellow (the fluoro-phenyl of 2,6-bis-)-5 hydrogen-benzo [c] Kui Linpyrimido quinoline [4,5-e] azepine-2 base amino-benzo imido acid ethyl ester hydrochlorides, productive rate is 94%), MS m/z=504 (M+H).
At 120 ℃, the mixture of benzo imido acid ethyl ester (100 milligrams, 0.17 mmole), 2,6-dimethyl-piperizine (200 milligrams, 8.8 mmoles) and dehydrated alcohol (1 milliliter) is carried out to the microwave radiation (300 watts) of 7.5 minutes.By this reaction soln cool to room temperature, and slowly pour in the salt brine solution (10 milliliters) being stirred.Collect formed throw out, and use chromatographic column (silica gel, 0.25% ammonium hydroxide/2 methyl alcohol/97.75% methylene dichloride to 2.5% ammonium hydroxide/20% methyl alcohol/77.5% methylene dichloride) purify, thereby obtain Compound I-251 (30 milligrams, productive rate is 30%) of faint yellow solid shape.
embodiment 17: the method W of synthetic molecules formula (I) representative compound
4-methyl-piperazine-1-carboxylic acid the chloro-7-of 4-[9-(the fluoro-phenyl of 2,6-bis-)-5 hydrogen-benzo [c] Kui Linpyrimido quinoline [4,5-e] azepine-2 base is amino] and-phenyl }-acid amides (I-280)
To (I-212,500 milligrams, 1.05 mmoles), stannous chloride dihydrate is (1.42 grams, 6.3 mmoles) and the mixture of ethyl acetate (15 milliliters) carry out the backflow of 28 hours, then cool to room temperature, and place a night, in the situation that stirring, the reaction mixture of this mustard seed yellow is poured on the trash ice of approximately 50 grams, and places for some time.Add sodium hydrogen carbonate solution, pH value is adjusted to 8.By ethyl acetate, this mixture is extracted to (3 * 100 milliliters).Extract is mixed, and be dried with sodium sulfate, under vacuum condition, evaporate after filtering, thereby the N-[9-that obtains orange/yellow solid shape is chloro-7-(2, the fluoro-phenyl of 6-bis-)-5 hydrogen-benzo [c] Kui Linpyrimido quinoline [4,5-e] azepine-2 base] (500 milligrams of-benzene-Isosorbide-5-Nitrae-diamines, productive rate 100%), MS m/z=448 (M+H).At 160 ℃, to (50 milligrams of this products, (89 milligrams of 0.1 mmole) diox (0.5 milliliter) solution, 4-methylpiperazine-1-carbonyl chlorides, (142 milligrams of 0.6 mmole) dioxane solution and diisopropylethylamine, 1.1 mmole) dioxane solutions carry out the microwave radiation (300 watts) of 60 minutes, by this reaction soln cool to room temperature, and be poured into lentamente in the salt brine solution (10 milliliters) being stirred.By the throw out filtering forming, collect, water washs, with RP-HPLC (C 18, CH 3cN is at 0.1HCO 2concentration in H aqua liquid is 0-100%) purify, thus obtain Compound I-280 (6 milligrams, productive rate is 10%) of faint yellow solid shape, MS m/z=574 (M+H).
embodiment 18: the method X of synthetic molecules formula (I) representative compound
4-[(7-{2-[(2-amino-ethyl) amino]-6-fluorophenyl } the chloro-5 hydrogen-Kui Linpyrimido quinoline of-9-[5,4-d] [2] benzo-aza-2 base) amino]-N-methyl-benzamide (I-340)
At 140 ℃, quadrol (200 microlitre) solution of Compound I-334 (49 milligrams, 0.1 mmole) is carried out to the microwave radiation (300 watts) of 20 minutes.By reaction soln cool to room temperature, and be slowly poured in the salt brine solution (10 milliliters) being stirred.By filtration, collect generated throw out, water washs, use chromatographic column (silica gel, 1% ammonium hydroxide 12% methyl alcohol/97% methylene dichloride to 2.5% ammonium hydroxide/20% methyl alcohol/77.5% methylene dichloride) purify, thereby obtain (46 milligrams of Compound I-340 of faint yellow solid shape, productive rate is 87%), MS m/z=530 (M+H).
Some particular compound in the present invention is prepared to method X by method Q, the process of using with above to the similar process described in Compound I-52, I-135, I-236, I-237, I-280 and I-340.Use time-of-flight mass spectrometer is collected HRMS data, and wherein this mass spectrograph is connected with Agilent HPLC.In table 5, provided through testing (M+H) of some definite compound +, the deviation of these experimental values and calculated value is within 10ppm.
embodiment 19: the method Y of synthetic molecules formula (I) representative compound
Kui Linpyrimido quinoline [4,5-e] azepine-2 base]-(3,4-dimethoxy-phenyl)-amine (I-72)
[the chloro-7-of 9-(the fluoro-phenyl of 2-)-5 hydrogen-benzo [c] Kui Linpyrimido quinoline [4,5-e] azepine-2 base]-(3,4-dimethoxy-phenyl)-amine (I-71,49 milligrams, 0.10 mmole) is dissolved in methylene dichloride (1.8 milliliters).In this solution, add acetic acid, then stir, and be cooled to 0 ℃.Then add zinc powder (20 milligrams, 0.31 mmole), at 0 ℃, this mixture is stirred 1 hour, be then heated to room temperature, then stir 4 hours.Add again zinc powder (10 milligrams, 0.15 mmole), add acetic acid (0.22 milliliter), and at room temperature this mixture is stirred 20 hours.With methylene dichloride, this reaction mixture is diluted.Organic phase is separated, with sodium hydroxide and the salt solution of 1N, washed, and be dried with magnesium sulfate, under vacuum condition, concentrate after filtering.Use chromatographic column (silica gel, ethyl acetate) to purify to yellow powder, thereby obtain [the chloro-7-of 9-(the fluoro-phenyl of 2-)-6 of orange solid state, 7-dihydro-5 hydrogen-benzos [c] Kui Linpyrimido quinoline [4,5-e] azepine-2 base]-(3,4-dimethoxy-phenyl)-amine (I-72), (32 milligrams, productive rate is 65%), MSm/z=477.
embodiment 20: the method Z of synthetic molecules formula (I) representative compound
The chloro-7-of 4-[9-(the fluoro-phenyl of 2,6-bis-)-7 hydrogen-benzo [c] Kui Linpyrimido quinoline [4,5-e] azepine-2 pyridinylamino]-phenylformic acid (I-387)
In Compound I-135, in THF (20 milliliters) solution of (1.0 grams, 2.1 mmoles), add tert.-butoxy potassium (the THF solution of 1M, 20 mmoles).To this solution stirring 1 hour, and with the hydrochloric acid of 1N, pH value is adjusted to 3.Then water (100 milliliters) dilutes this solution, and extracts with EtOAc (3 * 50 milliliters).With sodium sulfate, organic phase is dried, and concentrates under vacuum condition, use RP-HPLC (C18, the CH of 0-100% 3the CN aqueous solution, contains 0.1% formic acid in this aqueous solution) the brown oil matter generating is purified, after lyophilize, obtain Compound I-387 (0.3 gram, productive rate is 30%).
The high resolution mass spectrum of the exemplary compound of table 5. molecular formula (A) representative
Compound High resolution mass spectrum Compound High resolution mass spectrum Compound High resolution mass spectrum
I-1： 515.1739 I-128： 569.221 I-254： 559.2009
I-2： 515.1775 I-129： 515.1759 I-255： 573.2187
I-3： 529.1881 I-130： 529.1927 I-256： 455.1499
I-4： 529.1889 I-131： 529.1929 I-257： 547.1803
I-5： 543.2054 I-132： 485.1637 I-258： 511.0542
I-6： 543.2066 I-134： 493.0633 I-259： 601.2042
I-7： 557.2233 I-135： 477.0955 I-260： 547.1813
I-8： 527.1769 I-136： 477.0929 I-261： 573.2173
I-9： 541.1910 I-137： 455.1529 I-262： 571.2009
I-10： 557.1613 I-138： 471.1842 I-263： 585.2164
I-11： 537.2175 I-139： 509.0987 I-264： 559.2041
I-12： 553.2114 I-140： 493.0648 I-265： 545.1858
I-13： 541.1881 I-141： 489.1129 I-266： 589.1555
I-14： 521.2463 I-142： 501.1594 I-267： 558.1969
I-15： 555.2072 I-143： 441.1137 I-268： 558.1982
I-16： 541.1897 I-144： 535.0517 I-269： 621.1760
I-17： 541.1908 I-145： 554.2076 I-270： 529.1733
I-18： 569.2207 I-146： 459.1021 I-271： 526.1345
I-19： 598.2473 I-147： 552.1697 I-272： 496.1588
I-20： 614.2190 I-148： 551.2548 I-273： 507.0622
I-21： 594.2742 I-150： 563.1742 I-274： 521.0448
I-22： 610.2708 I-151： 563.175 I-275： 536.2267
I-23： 598.2503 I-152： 457.1424 I-276： 482.1776
I-24： 578.3039 I-153： 439.1575 I-277： 509.0967
I-25： 612.2655 I-154： 441.1735 I-278： 531.1524
I-26： 528.1619 I-155： 471.1229 I-279： 442.1091
I-27： 546.1722 I-156： 471.1243 I-280： 574.1943
I-28： 544.1313 I-157： 598.2497 I-281： 593.1419
I-29： 571.2018 I-158： 571.2015 I-282： 607.1584
I-30： 587.1709 I-159： 541.1905 I-283： 581.1453
I-31： 567.2256 I-160： 577.1898 I-284： 544.1826
I-32： 597.2367 I-161： 563.1744 I-285： 531.1529
I-33： 571.2046 I-162： 459.1019 I-286： 543.1704
I-34： 603.1674 I-163： 541.1911 I-287： 591.1867
I-35： 432.0783 I-164： 604.2055 I-288： 605.2016
Compound High resolution mass spectrum Compound High resolution mass spectrum Compound High resolution mass spectrum
I-36： 483.0332 I-165： 654.2409 I-289： 577.1710
I-37： 445.1213 I-166： 621.1838 I-290： 591.1900
I-38： 459.1367 I-167： 661.2162 I-291： 579.1263
I-39： 445.1213 I-168： 599.2003 I-292： 593.1439
I-40： 445.1215 I-169： 647.1998 I-293： 587.2139
I-41： 449.0731 I-170： 626.2448 I-294： 617.1853
I-42： 465.0443 I-171： 624.2685 I-295： 603.1746
I-43： 449.0728 I-172： 577.1576 I-296： 563.1593
I-44： 449.0727 I-173： 605.2002 I-297： 577.1714
I-45： 447.0789 I-174： 493.0656 I-298： 524.1949
I-46： 500.1630 I-175： 573.1983 I-299： 510.1813
I-47： 513.1947 I-176： 573.1986 I-300： 605.1879
I-48： 506.1558 I-177： 585.2192 I-301： 460.0978
I-49： 440.1073 I-178： 585.2203 I-302： 537.2438
I-50： 460.0966 I-179： 571.2037 I-303： 539.2562
I-51： 425.1431 I-180： 559.1851 I-304： 542.1863
I-52： 459.1014 I-181： 652.2994 I-305： 528.1737
I-53： 475.0752 I-182： 638.2822 I-306： 545.1308
I-54： 455.1261 I-183： 587.2117 I-307： 533.1642
I-55： 471.1210 I-184： 559.1845 I-308： 533.1680
I-56： 459.1027 I-185： 575.2131 I-309： 605.1894
I-57： 443.1332 I-186： 599.2348 I-310： 602.1863
I-58： 439.1550 I-187： 654.3136 I-311： 581.2652
I-59： 443.1286 I-188： 638.2832 I-312： 551.2576
I-60： 459.1016 I-189： 640.2628 I-313： 621.1731
I-61： 503.0516 I-190： 489.1142 I-314： 573.1610
I-62： 455.1496 I-191： 559.1845 I-315： 524.1979
I-63： 474.0871 I-192： 513.1625 I-316： 538.2110
I-64： 474.0879 I-193： 555.2103 I-317： 588.1727
I-65： 489.0889 I-194： 559.1843 I-318： 579.1300
I-66： 488.1034 I-195： 545.1683 I-319： 559.1850
I-67： 495.0690 I-196： 545.1693 I-320： 545.1876
I-68： 494.0832 I-197： 559.1814 I-321： 573.1971
I-69： 591.0810 I-198： 561.2004 I-322： 597.2403
I-70： 547.0605 I-199： 571.2047 I-323： 575.1523
I-71： 475.1339 I-200： 465.1514 I-324： 589.1704
I-72： 477.1491 I-201： 647.2340 I-325： 589.1678
I-73： 491.1031 I-202： 518.1331 I-326： 589.1680
I-74： 471.1579 I-203： 477.0943 I-327： 575.1517
I-75： 455.1873 I-204： 559.1814 I-328： 514.1995
I-76： 483.2202 I-205： 587.2156 I-329： 553.2092
I-77： 459.1602 I-206： 573.2001 I-330： 567.2287
I-78： 519.0851 I-207： 503.1197 I-331： 567.2301
I-79： 509.1604 I-208： 640.2953 I-332： 553.2124
I-80： 455.1873 I-209： 626.2832 I-333： 567.2288
I-81： 471.1830 I-210： 612.2649 I-334： 490.1270
I-82： 455.1872 I-211： 638.2782 I-335： 559.2007
Compound High resolution mass spectrum Compound High resolution mass spectrum Compound High resolution mass spectrum
I-83： 473.1168 I-212： 478.0905 I-336： 572.2352
I-84： 463.1152 I-213： 658.2264 I-337： 475.1144
I-85： 475.1000 I-214： 575.1556 I-338： 486.1287
I-86： 491.0677 I-215： 607.1598 I-339： 531.1727
I-87： 483.0331 I-216： 593.1427 I-340： 530.1895
I-88： 491.1035 I-217： 448.1154 I-341： 616.2019
I-89： 443.1442 I-218： 525.0715 I-342： 598.2501
I-90： 477.093 I-219： 589.1588 I-343： 514.1631
I-91： 477.0928 I-220： 573.1994 I-344： 558.9984
I-92： 551.2557 I-221： 559.1807 I-345： 558.2185
I-93： 501.1302 I-222： 573.1989 I-346： 572.2341
I-94： 542.2212 I-223： 629.2331 I-347： 558.2203
I-95： 477.0929 I-224： 587.1893 I-348： 570.2169
I-96： 477.0931 I-225： 587.2358 I-349： 525.2404
I-97： 541.1928 I-226： 587.2364 I-350： 602.1911
I-98： 555.2058 I-227： 571.2031 I-351： 561.1395
I-99： 555.208 I-228： 585.2198 I-352： 454.0727
I-100： 501.134 I-229： 599.2352 I-353： 473.1430
I-101： 541.1905 I-230： 527.1765 I-354： 501.1626
I-102： 527.1755 I-231： 585.2195 I-355： 497.0780
I-103： 491.1094 I-232： 571.2033 I-356： 473.1106
I-104： 477.1084 I-233： 571.2028 I-357： 464.1012
I-105： 495.0789 I-234： 545.1676 I-358： 504.1412
I-106： 508.105 I-235： 557.1849 I-359： 532.1712
I-107： 486.1508 I-236： 458.0994 I-360： 484.0467
I-108： 574.1296 I-237： 615.2217 I-361： 512.0783
I-109： 489.1484 I-238： 615.2214 I-362： 580.1487
I-110： 555.2063 I-239： 559.1851 I-363： 496.0996
I-111： 556.1545 I-240： 557.1880 I-364： 468.0686
I-112： 541.1925 I-241： 571.2035 I-365： 566.1355
I-113： 483.1249 I-242： 585.2169 I-366： 559.1852
I-114： 472.1352 I-243： 557.1893 I-367： 566.1333
I-115： 477.0961 I-244： 586.2295 I-368： 468.0684
I-116： 529.1913 I-245： 490.1365 I-369： 564.1728
I-117： 530.1387 I-246： 547.1831 I-370： 550.1549
I-118： 585.217 I-247： 561.2004 I-371： 491.1096
I-119： 489.1156 I-248： 603.1714 I-372： 518.1921
I-120： 473.1179 I-249： 469.1317 I-373： 490.1603
I-121： 460.0964 I-250： 572.2137 I-374： 564.1736
I-122： 607.1699 I-251： 572.2140 I-375： 550.1579
I-123： 493.0631 I-252： 533.1689 I-376： 596.2613
I-124： 473.1161 I-253： 573.1966 I-377： 486.1401
I-378： 630.2207 I-385： 492.106 I-392： 599.2152
I-379： 559.1829 I-386： 492.1055 I-393： 587.2156
I-380： 573.1978 I-387： 477.095 I-394： 437.1107
I-381： 616.2039 I-388： 477.0948 I-395： 511.0564
I-382： 587.2132 I-389： 602.1900 I-396： 650.1655
Compound High resolution mass spectrum Compound High resolution mass spectrum Compound High resolution mass spectrum
I-383： 599.2158 I-390： 588.1738 I-397： 664.1835
I-384： 585.1999 I-301： 573.1996
embodiment 21: the expression of aurora kinase and purification
The expression of BTAK and purification
The baculovirus vector of use standard and insect cell expression system ( invitrogen company product) the recombined small-mouse BTAK (Histidine-BTAK) with aminoterminal hexahistidine tag is expressed.
According to the explanation of manufacturers, use Ni-NTA (Qiagen company product) agarose to purify to picking up from the solubility restructuring mouse property BTAK of insect cell, then use S-75 size exclusion post (Amersham medical biotechnology company product) to do further purification.
The expression of aurora kinase B and purification
The baculovirus vector of use standard and insect cell expression system ( invitrogen company product) the recombined small-mouse aurora kinase B with aminoterminal hexahistidine tag (Histidine-aurora kinase B) is expressed.
According to the explanation of manufacturers, use Ni-NTA (Qiagen company product) agarose to purify to picking up from the solubility restructuring mouse property aurora kinase B of insect cell, then use S-75 size exclusion post (Amersham medical biotechnology company product) to do further purification.
embodiment 22: aurora kinase analysis
BTAK analyze
The reactant of mouse property BTAK amounts to 25 microlitres, wherein contains the magnesium dichloride, 0.05% the Sodium Fluoride of Surfact-AMPS-20,5mM of 25mM Tutofusin tris hydrochloric acid (pH value is 8.5), 2.5mM, the peptide matrix (vitamin H-Beta-alanine-QTRRKSTGGKAPR-NH2) of the ATP of the DTT of 5mM, 250 μ M, 10 μ M and the recombined small-mouse BTAK of 500pM.In this aurora kinase reaction mixture, can contain aurora kinase inhibitors, also can not contain aurora kinase inhibitors, before the stop buffer (ethylenediamine tetraacetic acid (EDTA) of 1% BSA, 0.05 Surfact-AMPS-20 and 100mM) that uses 100 microlitres stops, at room temperature this reaction mixture is cultivated 15 minutes.The reaction mixture that amounts to 100 microlitres is transferred in the hole of the coated plate (Pierce) of 96 hole Neutravidin, and at room temperature cultivated 30 minutes.With lavation buffer solution (25mM Tutofusin tris, 150mM sodium-chlor with 0.1% polysorbas20), hole is washed and washed, and with the antibody response mixture of 100 microlitres, carry out the cultivation of 1 hour, wherein antibody response mixture contains 1% BSA, 0.05%Surfact-AMPS-20, anti-phosphoric acid protein kinase rabbit polyclonal antibody (1: 2000, New England biology laboratory is produced) and the anti-rabbit property immunoglobulin G (1: 2000, Perkin Elmer company product) of europium mark.Hole is washed, then use the reinforced solution (Perkin Elmer company product) of 100 microlitres to discharge combined europium.Use Wallac tMenVision (Petkin Elmer company product) carries out quantitative analysis to europium.
In this is analyzed, Compound I-1 is to I-12, I-14 to I-32, I-34, I-37, I-39, I-45, I-52 to I-55, I-57 to I-59, I-63 to I-69, I-73 to I-75, I-80, I-86, I-91, I-93 to I-96, I-98 to I-103, I-109, I-111 to I-113, I-117, I-118, I-120, I-126, I-128 to I-131, I-134 to I-138, I-142, I-145, I-147 to I-151, I-157, I-160 to I-163, I-165, I-166, I-168 to I-171, I-173 to I-199, I-202 to I-211, I-213 to I-217, I-219 to I-235, I-237 to I-301, I-304 to I-310, I-313 to I-327, I-329 to I-335, I-337 to I-341, I-343, I-350 to I-355, the IC that I-357 to I-360 and I-362 to I-376 express 50value is less than or equal to 1.0 μ M.
In this is analyzed, Compound I-1 is to I-12, I-14 to I-22, I-24 to I-32, I-52 to I-55, I-57, I-58, I-63, I-65 to I-67, I-69, I-73, I-86, I-93, I-98 to I-100, I-102, I-103, I-111 to I-113, I-117, I-128, I-130, I-135, I-145, I-147, I-148, I-160, I-161, I-163, I-171, I-174 to I-199, I-204 to I-206, I-208 to I-211, I-213 to I-217, I-219 to I-229, I-231 to I-235, I-237 to I-244, I-246 to I-257, I-259 to I-270, I-272, I-274, I-277, I-278, I-280 to I-301, I-304 to I-310, I-313 to I-319, I-321, I-323 to I-327, I-329 to I-334, I-337, I-338, I-341, I-343, I-350, I-351, I-353, I-355, I-357, I-359, I-362, the IC that I-365 to I-368 and I-371 to I-376 express 50value is less than or equal to 100nM.
Aurora kinase B analyze
The reactant of mouse property BTAK amounts to 25 microlitres, wherein contains magnesium dichloride, 0.025% Surfact-AMPS-20,1% glycerol, the DTT of 1mM, the peptide matrix (vitamin H-Beta-alanine-QTRRKSTGGKAPR-NH2) of the ATP of 250 μ M, 3 μ M and the recombined small-mouse aurora kinase B of 20nM of 25mM Tutofusin tris hydrochloric acid (pH value is 8.5), 2.5mM.In this aurora kinase reaction mixture, can contain aurora kinase inhibitors, also can not contain aurora kinase inhibitors, before the stop buffer (ethylenediamine tetraacetic acid (EDTA) of 1% BSA, 0.05 Surfact-AMPS-20 and 100mM) that uses 100 microlitres stops, at room temperature this reaction mixture is cultivated 3 hours.The reaction mixture that amounts to 100 microlitres is transferred in the hole of the coated plate (Pierce) of 96 hole Neutravidin, and at room temperature cultivated 30 minutes.With lavation buffer solution (25mM Tutofusin tris, 150mM sodium-chlor with 0.1% polysorbas20), hole is washed and washed, and with the antibody response mixture of 100 microlitres, carry out the cultivation of 1 hour, wherein antibody response mixture contains 1% BSA, 0.05%Surfact-AMPS-20, anti-phosphoric acid protein kinase rabbit polyclonal antibody (1: 2000, New England biology laboratory is produced) and the anti-rabbit property immunoglobulin G (1: 2000, Perkin Elmer company product) of europium mark.Hole is washed, then use the reinforced solution (Perkin Elmer company product) of 100 microlitres to discharge combined europium.Use Wallac tMenVision (Petkin Elmer company product) carries out quantitative analysis to europium.
embodiment 23: cell analysis
Aurora kinase phosphorylation is analyzed
By determining the reduction degree of aurora kinase zymolyte phosphorylation, can determine BTAK or aurora kinase B activity repressed situation in whole cell system.For example, Serine 10 is a kind of aurora kinase zymolytes, by determining that histone H 3 can measure to the reduction degree of serine phosphorylation effect the situation that the activity of aurora kinase B is suppressed at whole cell system.In addition, similarly in analytical method, can assess with the zymolyte of any known aurora kinase B the suppressed degree of aurora kinase B activity.
In specific examples, the implanted 96 porocyte culture plates (10 * 10 of HeLa cell 3individual cells/well) in, and cultivate a night at 37 ℃.At 37 ℃, use aurora kinase inhibitors to cultivate cell, then mix 10 minutes with 4% paraformaldehyde, then use the PBS solution of 0.5%TritonX-100 to penetrate.At room temperature, use the anti-p histone H 3 of mouse property (1: 120, Cell Signaling Technology, Inc.'s product) and rabbit property antimitotic marker (1: 120, Millennium drugmaker product) antibody to cell cultures 1 hour.After using PBS to wash, at room temperature use anti-rabbit property immunoglobulin G Alexa 488 (1: 180, molecular probe company product) and anti-mouse property immunoglobulin G Alexa 594 (1: 180) to dye to cell.Then use Hoechst solution (2 mcg/ml) to dye to thymus nucleic acid.Use Discovery I and MetaMorph (global imaging company product) to carry out quantitatively the per-cent of p histone H 3 and antimitotic positive cell.By calculating the minimizing degree of p histone H 3 positive cell, determine the active downtrod degree of aurora kinase B.
Antiproliferative is analyzed
The foetal calf serum of use 10% supplements being arranged in HCT-116 (1000) or other tumour cells of the corresponding cell culture medium of 100 microlitre, these cells is implanted in the hole of 96 porocyte culture plates, and is cultivated a night at 37 ℃.In these culture hole, add aurora kinase inhibitors, and cultivate 96 hours at 37 ℃.In each culture hole, add MTT or WST reagent (10 microlitres, Roche company product), the explanation of Bing An manufacturers is cultivated 4 hours at 37 ℃.For MTT, according to the explanation of manufacturers (Roche company), the dyestuff of metabolism dissolved night.Under 595 nanometers (substantially) and 690 nanometers (reference) wavelength, read the optical density(OD) of each MTT culture hole, for the situation of using WST, use spectrophotometer (molecule equipment company product) to read the optical density(OD) of each culture hole.For the situation of MTT, from the optical density value of fundamental wavelength, deduct the reference point of optical density(OD).Using DMSO correlative value as 100%, thereby calculate inhibition percentage ratio.
embodiment 24: activity in vivo analysis
Live body in-vivo tumour efficiency Model
Under aseptic condition, use 23-ga syringe needle, 100 microlitres are contained to HCT-116 (1 * 10 6) or the phosphate buffered salt solution of other tumour cells be expelled in the female nude mice of CD-1 (5-8 week is large, CR company product) right side, back subcutaneous.The 7th day from implantation tumour cell starts, and the use vernier callipers weekly size of twice pair of tumour is measured.Use standard method (0.5 * (long * wide) 2) calculating gross tumor volume.When gross tumor volume reaches 200 cubic millimeters of left and right, the vein by afterbody is to injected in mice aurora kinase inhibitors (100 microlitre), and it is different wherein injecting consumption and inject time.All contrast mouse are only accepted vector injection.Weekly the tumor size of mouse and body weight are carried out to mensuration twice, when the tumour of contrast mouse reaches 2000 cubic millimeters of left and right, finish research.
Although above the present invention is had been described in detail, these describe in detail is the object for clarification and understanding, and these specific embodiments are illustrative, and nonrestrictive.By reading herein, it should be appreciated by those skilled in the art, can make various modifications to form of the present invention and details without departing from the present invention, scope of the present invention is limited by the appended claim of this paper, but not is limited by these specific embodiments.
Institute's referenced patents and the contained knowledge of scientific and technical literature are that those skilled in the art are operable herein.Unless another indicates, otherwise that under technical term used herein and scientific and technical terminology and the present invention, in field, technician understands jointly is consistent.Even if having by situation specific or that quote as proof separately, issue patent, patent application and the reference quoted are herein incorporated to herein by quoting as proof to be unified at this.When there is inconsistent situation, all with herein, comprise described in definition and being as the criterion.

Claims (50)

1. the compound of molecular formula (A) representative:
Or this compound acceptable salts substances pharmaceutically;
Wherein:
R f1hydrogen, or R f1and R f2form key;
R f2hydrogen, or R f2with R f1or Rx forms key;
Each R xand R yhydrogen independently; Or R xand R f2form key;
G is B ring;
A ring is phenyl, and wherein, A ring is optionally independently selected from R bsubstituting group replace;
R bselect free C 1-6alkyl, C 1-6thiazolinyl, C 1-6alkynyl, C 1-6fluoro-alkyl, C 1-6fluoro thiazolinyl, C 1-6fluoro alkynyl, R 2bwith-T 1-R 2bin the group forming;
T 1c 1-6alkene chain;
R2b selects free halogen radical ,-C ≡ C-R 5,-OR 5,-N (R 4) 2,-CO 2r 5or-C (O) N (R 4) 2in the group forming;
B ring is 5 yuan of-6 yuan of aryl or 5 yuan of-6 yuan of heteroaryls; B ring is by 0-2 the independent R selecting cinstitute replaces;
R cindependently selected from C 1-6alkyl, C 1-6thiazolinyl, C 1-6alkynyl, R 2 cwith-T 1-R 2c;
R 2cbe selected from halogen radical ,-C ≡ C-R 5,-OR 5,-N (R 4) 2;
C ring is 5 yuan of single ring architecture or 6 yuan of aryl or heteroaryl, and by the R of 0-2 independent selection dwith 0-2 be independently selected from R 2dor C 1-6alkyl, C 1-6thiazolinyl, C 1-6alkynyl replaces
Each R dindependently select free C 1-6alkyl, C 1-6thiazolinyl, C 1-6alkynyl, R 2d, R 7d,-T 2-R 2d,-T 2-R 7d,-V-T 3-R 2d, and-V-T 3-R 7din the group forming;
T 2unsubstituted or by one or two C 1-3alkyl, C 1-3thiazolinyl, C 1-3the C of alkynyl substituted 1-6alkene chain, wherein, optionally can insert in alkene chain-C ≡ C-,-N (R 4)-,-N (R 4) C (O)-,-C (O) N (R 4)-or-C (O)-, T wherein 2or T 2the optional part that forms 3 yuan of-7 rings of certain part;
T 3unsubstituted or by one or two C 1-3alkyl, C 1-3thiazolinyl, C 1-3the C of alkynyl substituted 1-4alkene chain, wherein, optionally can insert in alkene chain-NR 4c (O)-,-C (O)-, T wherein 3or T 3the optional part that forms 3 yuan of-7 rings of certain part;
V is-N (R 4)-,-C (O) N (R 4)-;
R 2dhalogen radical ,-NO 2,-CN ,-OR 5,-SO 2r 6,-SO 3r 5,-SO 2n(R 4) 2,-N (R 4) 2,-NR 4c (O) R 5,-CO 2r 5,-C (O) R 5,-C (O) N (R 4) 2,-C (O) N (R 4) C (=NR 4)-N (R 4) 2,-N (R 4) C (=NR 4)-N (R 4)-C (O) R 5,-C (=NR 4)-N (R 4) 2,-N (R 4) C (=NR 4)-N (R 4) 2,-N (R 4) SO 2r 6, or-P (O) (OR 5) 2;
Each R 7d3 yuan of-7 yuan of monocyclic heterocycles bases, 5 yuan of-6 yuan of heteroaryl groups independently; Selected free C1-3 alkyl ,-OR that it is optional 5, or-C (O) R 5the substituting group of the group forming replaces;
R ahydrogen;
R ehydrogen ,-N (R 4) 2, or quilt-N (R 4) 2the optional C replacing 1-3alkyl;
Each R 4hydrogen independently, or C 1-6alkyl, C 1-6thiazolinyl, C 1- 6alkynyl, C 6-10aryl, 5 yuan of-6 yuan of heteroaryls or 3 yuan of-7 yuan of monocyclic heterocycles bases; Or two R on same nitrogen-atoms 4form the heteroaryl of 5 yuan-6 yuan of optional replacement or 4 yuan of-8 yuan of heterocyclic radicals of optional replacement with this nitrogen-atoms, except this nitrogen-atoms, this heteroaryl or heterocyclic radical also contain 0-2 heterocyclic atom that is selected from nitrogen, oxygen or sulphur;
Each R 5hydrogen independently, or C 1-6alkyl, C 1-6thiazolinyl, C 1-6alkynyl, aryl, heteroaryl or heterocyclic radical;
Each R 6c independently 1-6alkyl, C 1-6thiazolinyl, C 1-6alkynyl or C 6-10aryl.
2. the compound in claim 1, has molecular formula (A-1):
3. the compound in claim 2 has molecular formula (C):
4. the compound in claim 2, has molecular formula (B):
5. the compound in claim 1, has molecular formula (I):
Or this compound acceptable salts substances pharmaceutically; Wherein:
R ehydrogen, each R f1and R f2hydrogen, or R f1and R f2form key.
6. the compound in claim 5 has molecular formula (II):
7. as the compound in claim 6, wherein B ring is aromatic yl group or the heteroaryl groups of single ring architecture or twin nuclei, be selected from furyl, thienyl, pyrryl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl group, phenyl, pyridyl, pyridazinyl, pyrimidyl, pyrazinyl and triazinyl, the R being selected by 0-2 independence that it is optional cinstitute replaces.
8. as the compound in claim 7, wherein B ring is optional by 0-2 the R being independently selected from cthe phenyl ring replacing or pyridyl.
9. the compound in claim 8, has molecular formula (IIa):
Wherein:
A ring is by 0-2 the independent R selecting binstitute replaces;
B ring is by 0-2 the independent R selecting cinstitute replaces.
10. the compound in claim 9, has at least one feature in following characteristics:
(a) each R bindependently selected from C 1-3alkyl, C 1-3thiazolinyl, C 1-3alkynyl and R 2b, each R wherein 2bindependently selected from halogen radical ,-C ≡ C-R 5,-OR 5,-N (R 4) 2,-CO 2r 5, and-C (O) N (R 4) 2; With
(b) each R cindependently selected from C 1-3alkyl, C 1-3thiazolinyl, C 1-3alkynyl and R 2c, each R wherein 2cindependently selected from halogen radical ,-C ≡ C-R 5,-OR 5, and-N (R 4) 2.
Compound in 11. claims 10, has molecular formula (III):
Compound in 12. claims 10, has molecular formula (IIIa):
Wherein:
Each R b2and R b3hydrogen or R independently b;
R bbe selected from C 1-3alkyl, C 1-3thiazolinyl, C 1-3alkynyl, C 1-3fluoro-alkyl, C 1-3fluoro thiazolinyl, C 1-3fluoro alkynyl and R 2b;
R 2bbe selected from halogen radical ,-C ≡ C-R 5,-OR 5,-N (R 4) 2,-CO2R 5, and-C (O) N (R 4) 2;
Each R c1and R c5hydrogen or R independently c;
R cbe selected from C 1-3alkyl, C 1-3thiazolinyl, C 1-3alkynyl, C 1-3fluoro-alkyl, C 1-3fluoro thiazolinyl, C 1-3fluoro alkynyl and R 2c; And
R 2cbe selected from halogen radical ,-C ≡ C-R 5,-OR 5and-N (R 4) 2.
13. as the compound in claim 12, wherein:
Each R b2and R b3independently selected from hydrogen, halogen, C 1-3alkyl, C 1- 3thiazolinyl, C 1-3alkynyl, C 1-3fluoro-alkyl, C 1-3fluoro thiazolinyl, C 1-3fluoro alkynyl and-OR 5, wherein, R 5hydrogen or C 1-3alkyl, C 1-3thiazolinyl, C 1-3alkynyl; And
Each R c1and R c5independently selected from hydrogen, halogen, C 1-3alkyl, C 1- 3thiazolinyl, C 1-3alkynyl, C 1-3fluoro-alkyl, C 1-3fluoro thiazolinyl, C 1-3fluoro alkynyl, and-OR 5, wherein, R 5hydrogen or C 1-3alkyl, C 1-3thiazolinyl, C 1-3alkynyl.
14. as the compound in claim 13, wherein each R b3and R c1independently selected from halogen radical, C 1-3alkyl, C 1-3thiazolinyl, C 1-3alkynyl, C 1-3fluoro-alkyl, C 1-3fluoro thiazolinyl, C 1-3fluoro alkynyl and-OR 5, R in base 5hydrogen or C 1-3alkyl, C 1-3thiazolinyl, C 1-3alkynyl.
15. as the compound in claim 14, each R in base b3and R c1chlorine, fluorine, bromine, methyl, trifluoromethyl or methoxyl group independently.
16. as the compound in claim 15, wherein:
C ring is aryl, the heteroaryl of monocycle or twin nuclei, and by 0-2 independently selected from R dwith 0-2 independently selected from R 2dor C 1-6alkyl, C 1-6thiazolinyl, C 1-6alkynyl replaces.
17. as the compound in claim 16, wherein C ring is phenyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, triazolyl, oxazolyl, benzimidazolyl-, benzothiazolyl, benzoxazolyl and phthalimidine, and by 0-2 independently selected from R dwith 0-2 independently selected from R 2dor C 1-6alkyl, C 1-6thiazolinyl, C 1-6alkynyl replaces.
18. as the compound in claim 17, wherein;
Each R dindependently selected from C 1-3alkyl, C 1-3thiazolinyl, C 1-3alkynyl, R 2d, R 7d,-T 2-R 2d,-T 2-T 7d,-V-T 3-R 2dand-V-T 3-R 7d; And
Each R 2dindependently selected from halogen radical ,-OR 5,-CO 2r 5,-C (O) N (R 4) 2-SO 2n(R 4) 2,-C (=NR 4) N (R 4) 2,-C (O) N (R 4) C (=NR 4) 2,-N (R 4) C (=NR 4)-N (R 4)-C (O) R 5, and-NR 4c (O) R 5.
19. as the compound in claim 18, and wherein C ring is through at least one R 7dreplacement, R wherein 7dbe selected from:
The R being selected by 0-2 independence on any commutable ring carbon atom or theheterocyclic nitrogen atom that these groups are optional dwith 0-2 the independent R selecting 2dor C 1-6alkyl, C 1-6thiazolinyl, C 1-6alkynyl replaces.
20. as the compound in claim 18, wherein C ring by least one-T 2-R 2 dor-T 2-R 7dreplace, wherein:
T 2can be C 1-6alkene chain, wherein T 2middle insertion-C ≡ C-,-C (O)-,-N (R 4) C (O)-or-N (R 4)-; And
R 2dbe selected from halogen radical ,-OR 5,-N (R 4) 2,-N (R 4) C (O)-,-CO 2r 5,-C (O) N (R 4) 2,-S (O) 2n(R 4) 2,-C (O) N (R 4) C (=NR 4)-(=NR 4) 2, and-N (R 4) C (=NR 4)-N (R 4)-C (O) R 5.
21. as the compound in claim 20, and wherein C ring is by one-T 2-R 2dor-T 2-R 7dreplace, and another substituting group optionally replaces, this substituting group is selected from hydrogen, halogen radical, C 1-3alkyl, C 1-3thiazolinyl, C 1-3alkynyl and-OR 5, R wherein 5hydrogen or C 1-3alkyl, C 1-3thiazolinyl, C 1-3alkynyl.
22. as the compound in claim 18, wherein C ring by least one-V-T 3-R 2dor-V-T 3r 7dreplace, wherein:
V is-N (R 4)-or-C (O) N (R 4)-;
T 3c 1-4alkene chain, and
R 2dbe selected from halogen radical ,-OR 5,-N (R 4) 2,-NR 4c (O) R 5,-CO 2r 5,-C (O) N (R 4) 2, and-SO 2n(R 4) 2.
23. as the compound in claim 22, and wherein C ring is by one-V-T 3-R 2dor-V-T 3-R 7dreplace, and another substituting group optionally replaces, substituting group is selected from hydrogen, halogen radical, C 1-3alkyl, C 1-3thiazolinyl, C 1-3alkynyl and-OR 5, R wherein 5hydrogen or C 1-3alkyl, C 1-3thiazolinyl, C 1-3alkynyl.
24. as the compound in claim 23, wherein:
V is-C (O) N (R 4)-;
T 3c 2-4alkene chain;
R 2dbe-N (R 4) 2, R wherein 4hydrogen or C independently 1-3alkyl, C 1- 3thiazolinyl, C 1-3alkynyl, or-N (R 4) 2by C 1-35 yuan of-6 yuan of heteroaryls that alkyl replaces or the heterocyclic radical of 4 yuan-8 yuan, this heteroaryl or heterocyclic radical, except nitrogen-atoms, also contain 0-2 heterocyclic atom that is selected from nitrogen, oxygen and sulphur, and
R 7dunsubstituted 4 yuan of-8 yuan of heterocyclic radical groups, unsubstituted 5 yuan of-6 yuan of heteroaryl groups.
25. as the compound in claim 24, wherein:
R 2dbe-N (R 4) 2, and-N (R 4) 2by C 1-3the optional heterocyclic radical replacing of alkyl, this heterocyclic radical is selected from piperidyl, piperazinyl, morpholinyl, pyrrolidyl and azetidinyl; And
R 7dbe unsubstituted heteroaryl, this heteroaryl is selected from pyridyl, pyridazinyl, pyrimidyl, pyrazinyl, pyrryl, oxazolyl, imidazolyl and pyrazolyl.
26. as the compound in claim 18, and wherein by one or two, the substituting group independently selected from lower group replaces C ring: C 1-3alkyl, C 1-3thiazolinyl, C 1 -3alkynyl, halogen radical ,-OR 5,-CO 2r 5,-C (O) N (R 4) 2,-SO 2n(R 4) 2,-C (=NR 4) N (R 4) 2,-C (O) N (R 4) C (=NR 4)-N (R 4) 2,-N (R 4) C (=NR 4)-N (R 4)-C (O) R 5, and-NR 4c (O) R 5.
27. as the compound in claim 26, and the substituting group that wherein C ring is selected from lower group by least one replaces :-CO 2r 5,-C (O) N (R 4) 2,-C (=NR 4) N (R 4) 2,-C (O) N (R 4) C (=NR 4)-N (R 4) 2,-N (R 4) C (=NR 4)-N (R 4)-C (O) R 5, and-NR 4c (O) R 5.
28. as the compound in claim 26, wherein C ring by least one-CO 2r 5replace, wherein R 5hydrogen or C 1-6alkyl, C 1-6thiazolinyl, C 1-6alkynyl.
29. as compound in claim 26, wherein:
C ring by least one-C (O) N (R 4) 2,-C (=NR 4) N (R 4) 2or-NR 4c (O) R 5replace; Wherein
-N (R 4) 2by C 1-3optional 4 yuan of-8 yuan of heterocyclic radicals that replace of alkyl, this heterocyclic radical, except nitrogen-atoms, also contains 0-2 heterocyclic atom that is selected from nitrogen, oxygen and sulphur; And
R 5it is the nitrogen heterocycle of 4 yuan-8 yuan.
30. as the compound in claim 29, wherein C ring by least one-C (O) N (R 4) 2or-C (=NR 4) N (R 4) 2replace, and-N (R 4) 2be the optional heterocyclic radical replacing, this heterocyclic radical is selected from piperidyl, piperazinyl, morpholinyl, pyrrolidyl and azetidinyl, and described heterocyclic radical is by C 1-3alkyl optionally replaces.
31. as the compound in claim 30, and wherein C ring is replaced by the substituting group of at least one following molecular formula representative:
Wherein:
D ring is selected from by one or two that following substituting group replaces: C 1-3alkyl, C 1-3thiazolinyl, C 1-3alkynyl ,-CO 2r 5,-N (R 4) 2, and-T 5-R m, T wherein 5a kind of C 1-3alkene chain and R mbe-N (R 4) 2or-CO 2r 5; ;
X is oxygen or NH;
W 1hydrogen, C 1-6alkyl, C 1-6thiazolinyl, C 1-6alkynyl or, 4 to 8 former aryl, heteroaryl or heterocyclic radical group, it is optional by C 1-3alkyl or-OR5.
32. as the compound in claim 30, and wherein C ring is replaced by the substituting group of at least one following molecular formula representative:
Wherein:
The optional substituting group that is selected from the following group forming by one or two of D ring replaces: C 1-3alkyl, C 1-3thiazolinyl, C 1-3alkynyl ,-CO 2r 5,-N (R 4) 2, and-T 5-R m, T wherein 5a kind of C 1-3alkene chain and R mbe-N (R 4) 2or-CO 2r 5; ;
X is oxygen or NH;
W 2r nor-T 6-R n;
T 6c 1-3alkene chain, and by R 3or R 3breplace; And
R nbe-N (R 4) 2or-C (O) N (R 4) 2; And
R zhydrogen ,-CO 2r 5,-C (O) N (R 4) 2,-C (O) R 5or by R 3or R 7the optional C replacing 1-3alkyl, C 1-3thiazolinyl, C 1-3alkynyl; Or R zand W 2and the carbon atom that they connect forms the heterocyclic radical of 4 yuan-7 yuan together.
33. as the compound in claim 30, and wherein at least one substituting group on C ring is selected from following group:
Middle X is O or NH.
34. as the compound in claim 30, and wherein at least one substituting group on C ring is selected from following group:
Wherein X is O or NH, and each R4z is hydrogen or methyl independently.
35. as the compound in claim 29, and wherein at least one substituting group on C ring is selected from following group:
Wherein X is O or NH, and each R4z is hydrogen or methyl independently.
36. as the compound in claim 30, wherein C ring by least one-C (O) N (R 4) 2or-C (=NH) N (R 4) 2replace one of them R 4hydrogen or C 1-3alkyl, another R 4unsubstituted or by C 1-3alkyl and-C (O) N (R 4) 24 yuan of-8 yuan of heterocyclic radicals or Heterocyclylalkyls replacing.
37. as the compound in claim 36, and wherein C ring is replaced by least one substituting group, and this substituting group is selected from following group:
Wherein X is O or NH.
38. as the compound in claim 36, and wherein C ring is replaced by least one substituting group; This substituting group is selected from following group:
Wherein X is O or NH, and each R 4zhydrogen or methyl independently.
39. as the compound in claim 6, and this compound has molecular formula (IV):
Wherein:
A ring is by 0-2 R breplace;
B ring is 5-6 unit's aryl or 5 to 10 yuan of heteroaryls, and by 0-2 the independent R selecting cinstitute replaces, and R cbe selected from R 2cor C 1-6alkyl, C 1-6thiazolinyl, C 1-6alkynyl;
R ehydrogen;
R gbe selected from hydrogen, C 1-6alkyl, C 1-6thiazolinyl, C 1-6alkynyl and R 2 d;
Each R hand R khydrogen or R independently d;
Each R dindependently selected from C 1-3alkyl, C 1-3thiazolinyl, C 1-3alkynyl, R 2d, R 7d,-T 2-R 2d,-T 2-R 7d,-V-T 3-R 2d, and-V-T 3-R 7d; And
Each R 2dindependently selected from halogen radical ,-OR 5,-CO 2r 5,-C (O) N (R 4) 2,-SO 2n(R 4) 2,-C (=NR 4) N (R 4) 2,-C (O) N (R 4) C (=NR 4)-N (R 4) 2,-N (R 4) C (=NR 4)-N (R 4)-C (O) R 5, and-NR 4c (O) R 5.
40. as the compound in claim 39, wherein each R gand R khydrogen, and R hbe ,-CO 2r 5,-C (O) N (R 4) 2,-C (=NR 4) N (R 4) 2, or-N (R 4) C (O) R 5.
Compound in 41. claims 6, has molecule formula V:
Wherein:
A ring is by 0-2 R breplace;
B ring is by 0-2 the independent R selecting creplace, and R cbe selected from R 2cor C 1-6alkyl, C 1-6thiazolinyl, C 1-6alkynyl;
C ring by 0-2 independently selected from R dwith 0-2 independently selected from R 2dor C 1-6alkyl, C 1-6thiazolinyl, C 1-6alkynyl substituted.
42. as the compound in claim 41, wherein:
A ring is by 0-2 R breplace, wherein each R bindependently selected from C 1-3alkyl, C 1-3thiazolinyl, C 1-3alkynyl, R 2b,-T 1-R 2b;
B ring by 0-2 independently selected from R csubstituting group replace, each R cindependently selected from C 1-3alkyl, C 1-3thiazolinyl, C 1-3alkynyl, R 2c,-T 1-R 2c;
T 1c 1-3alkene chain;
R 2bn (R 4) 2;
R 2cbe-N (R 4) 2; And
R ehydrogen.
Compound in 43. claims 42, has molecular formula (Va):
Wherein:
R ehydrogen;
Each R b2and R b3independently selected from hydrogen, halogen radical, C 1-3alkyl, C 1-3thiazolinyl, C 1-3alkynyl, C 1-3fluoro-alkyl, C 1-3fluoro thiazolinyl, C 1- 3fluoro alkynyl and-OR 5, R wherein 5hydrogen or C 1-3alkyl, C 1-3thiazolinyl, C 1-3alkynyl;
Each R c1and R c5independently selected from hydrogen, halogen radical, C 1-3alkyl, C 1-3thiazolinyl, C 1-3alkynyl, C 1-3fluoro-alkyl, C 1-3fluoro thiazolinyl, C 1- 3fluoro alkynyl and-OR 5, R wherein 5hydrogen or C 1-3alkyl, C 1-3thiazolinyl, C 1-3alkynyl;
R gbe selected from hydrogen, C 1-6alkyl, C 1-6thiazolinyl, C 1-6alkynyl and R 2d; And
Each R hand R khydrogen or R independently d.
44. as the compound in claim 40, wherein each R g, R hand R kindependently selected from hydrogen, C 1-3alkyl, C 1-3thiazolinyl, C 1-3alkynyl, halogen radical ,-OR 5,-CO 2r 5,-C (O) N (R 4) 2,-SO 2n(R 4) 2,-C (=NR 4) N (R 4) 2,-C (O) N (R 4) C (=NR 4)-N (R 4) 2,-N (R 4) C (=NR 4)-N (R 4)-C (O) R 5, and-N (R 4) C (O) R 5.
45. as the compound in claim 44, wherein R hand R kin at least one be selected from-CO 2r 5,-C (O) N (R 4) 2,-C (=NR 4) N (R 4) 2,-C (O) N (R 4) C (=NR 4)-N (R 4) 2,-N (R 4) C (=NR 4)-N (R 4)-C (O) R 5, and-N (R 4) C (O) R 5.
46. as the compound in claim 43, wherein:
R e, R b2, R g, and R keach is hydrogen naturally;
R b3and R c1be selected from independently of one another halogen radical, C 1-3alkyl, C 1- 3thiazolinyl, C 1-3alkynyl, C 1-3fluoro-alkyl, C 1-3fluoro thiazolinyl, C 1-3fluoro alkynyl and-OR 5, R wherein 5hydrogen or C 1-3alkyl, C 1-3thiazolinyl, C 1-3alkynyl;
R c5be selected from hydrogen, halogen, C 1-3alkyl, C 1-3thiazolinyl, C 1-3alkynyl, C 1-3fluoro-alkyl, C 1-3fluoro thiazolinyl, C 1-3fluoro alkynyl and-OR 5, R wherein 5hydrogen or C 1-3alkyl, C 1-3thiazolinyl, C 1-3alkynyl; And
R hbe-CO 2h ,-C (O) N (R 4) 2,-C (=NR 4) N (R 4) 2,-C (O) N (R 4) C (=NR 4)-N (R 4) 2, or-N (R 4) C (=NR 4)-N (R 4)-C (O) R 5, R wherein 54 yuan of-8 member heterocyclic ring containing nitrogen bases ,-N (R 4) 2be optional 4 yuan of-8 yuan of heterocyclic radicals that replace, this heterocyclic radical also contains 0-2 heteroatoms that is selected from nitrogen, oxygen except nitrogen-atoms.
Compound in 47. claims 1, is selected from lower group:
The chloro-7-of 4-[9-(the fluoro-phenyl of 2-)-5 hydrogen-benzo [c] Kui Linpyrimido quinoline [4,5-e] azepine 2 bases-amino]-phenylformic acid;
The chloro-7-of 4-[9-(the fluoro-phenyl of 2,6-bis-)-5 hydrogen-benzo [c] Kui Linpyrimido quinoline [4,5-e] azepine 2 bases-amino]-phenylformic acid;
The chloro-7-of 4-{[9-(the chloro-6-fluorophenyl of 2-)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] azepine 2 bases] amino }-phenylformic acid;
The chloro-7-of 9-(2,6-difluorophenyl)-N-{4-[(3,5-lupetazin-1 base) carbonyl] phenyl }-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2-amine;
The chloro-N-{4-[(3 of 9-, 5-lupetazin-1 base) carbonyl] phenyl }-7-(the fluoro-6-p-methoxy-phenyl of 2-)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2-amine;
The chloro-N-of 9-(4-{[3-(dimethylamino) azetidine-1 base] carbonyl } phenyl)-7-(the fluoro-6-p-methoxy-phenyl of 2-)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2-amine;
The chloro-7-of 4-[9-(the fluoro-phenyl of 2,6-bis-)-5 hydrogen-benzo [c] Kui Linpyrimido quinoline [4,5-e] azepine 2 bases-amino] and-phenyl }-(4-dimethylamino-piperidines-1 base)-ketone;
The chloro-7-of 4-[9-(the fluoro-6-methoxyl group-phenyl of 2-)-5 hydrogen-benzo [c] Kui Linpyrimido quinoline [4,5-e] azepine 2 bases-amino]-phenylformic acid;
The chloro-7-of 4-[9-(the fluoro-phenyl of 2,6-bis-)-5 hydrogen-benzo [c] Kui Linpyrimido quinoline [4,5-e] azepine 2 bases-amino] and-phenyl }-(3 (S)-methyl-piperazine-1 base)-ketone;
(3-amino-tetramethyleneimine-1 base)-and the chloro-7-of 4-[9-(the fluoro-phenyl of 2,6-bis-)-5 hydrogen-benzo [c] Kui Linpyrimido quinoline [4,5-e] azepine 2 bases-amino]-phenyl }-ketone;
The chloro-7-of 4-[9-(the fluoro-phenyl of 2,6-bis-)-5 hydrogen-benzo [c] Kui Linpyrimido quinoline [4,5-e] azepine 2 bases-amino] and-phenyl }-(3-methylamino-tetramethyleneimine-1 base)-ketone;
The chloro-7-of 4-[9-(the fluoro-6-methoxyl group-phenyl of 2-)-5 hydrogen-benzo [c] Kui Linpyrimido quinoline [4,5-e] azepine 2 bases-amino] and-phenyl }-(3-methylamino-tetramethyleneimine-1 base)-ketone;
The chloro-7-of 9-(the fluoro-phenyl of 2,6-bis-)-N-(4-{[4-(methylamino) piperidines-1 base] carbonyl }-phenyl)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2-amine;
The chloro-7-of 9-(the fluoro-6-p-methoxy-phenyl of 2-)-N-{[(3-methylpiperazine-1 base) carbonyl]-phenyl }-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2-amine;
The chloro-7-of 9-(the fluoro-phenyl of 2,6-bis-)-N-(4-{[3-(methylamino) azetidine-1 base] carbonyl } phenyl)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2-amine;
The chloro-7-of 9-(the fluoro-6-p-methoxy-phenyl of 2-)-N-(4-{[3-(methylamino) azetidine-1 base] carbonyl } phenyl)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2-amine;
N-{4-[(3-amino-pyrrolidine-1 base) carbonyl] phenyl } the chloro-7-of-9-(the fluoro-6-p-methoxy-phenyl of 2-)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2-amine;
N-{4-[(4-amino piperidine-1 base) carbonyl] phenyl } the chloro-7-of-9-(the fluoro-6-p-methoxy-phenyl of 2-)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2-amine;
The chloro-7-of 9-(the fluoro-6-p-methoxy-phenyl of 2-)-N-(4-{[4-(methylamino) piperidines-1 base] carbonyl } phenyl)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2-amine;
The chloro-7-of 9-(the fluoro-6-p-methoxy-phenyl of 2-)-N-(4-{[3-(methylamino) piperidines-1 base] carbonyl } phenyl)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2-amine;
N-{4-[(3-aminoazaheterocycles butane-1 base) carbonyl] phenyl } the chloro-7-of-9-(the fluoro-6-p-methoxy-phenyl of 2-)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2-amine;
The chloro-7-of 9-(2,6-difluorophenyl)-N-(4-{[3-(methylamino) piperidines-1 base] carbonyl } phenyl)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2-amine;
4-(the chloro-7-of 4-{[9-(2,6-difluorophenyl)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] phenyl azepine-2 base] amino } benzoyl)-N methyl piperazine-2-carboxylic acid amides;
N-{4-[(3-methylpyrrolidin-1 base) carbonyl]-3-chloro-phenyl-} the chloro-7-of-9-(2,6-difluorophenyl)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2-amine;
The chloro-7-of 9-(the chloro-6-fluorophenyl of 2-)-N-(4-{[3-(methylamino) piperidines-1 base] carbonyl } phenyl)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2-amine;
4-amino-1-(the chloro-7-of 4-{[9-(2,6-difluorophenyl)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] phenyl azepine-2 base] amino } benzoyl)-N-methyl piperidine-4-carboxylic acid amides;
N-1-azabicyclo [2.2.2] is pungent-the chloro-7-of 3 bases-4-{[9-(2,6-difluorophenyl)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] phenyl azepine-2 base] and amino }-N-methyl-benzamide;
The chloro-7-of 9-(2,6-difluorophenyl)-N-(4-{[3-methyl-3-(methylamino) tetramethyleneimine-1 base] carbonyl } phenyl)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] [2] phenyl azepine-2-amine;
4-amino-1-(the chloro-7-of the chloro-4-{[9-of 2-(2,6-difluorophenyl)-5 hydrogen-Kui Linpyrimido quinoline [5,4-d] phenyl azepine-2 base] amino } benzoyl)-N-methyl piperidine-4-carboxylic acid amides;
Or these compounds acceptable salts substances pharmaceutically.
48. 1 kinds are used for the treatment of the disease mediated pharmaceutical composition of aurora kinase, it comprises the compound in claim 1, the disease that wherein aurora kinase mediates is Hepatocellular cancer, lung cancer, nonsmall-cell lung cancer (NSCLC), head and neck cancer, melanoma, neuroendocrine cancer, neurospongioma, soft tissue sarcoma, acute myelogenous leukemia (AML), Fei Huojin lymphomas (N HL), follicular lymphoma, lymphoma mantle cell, B cell lymphoma, t cell lymphoma, multiple myeloma (MM), Waldenstrom macroglobulinemia, colorectal carcinoma, ovarian cancer, mammary cancer, cancer of the stomach, prostate cancer, and carcinoma of the pancreas.
49. as the pharmaceutical composition in claim 48, and cancer is wherein colorectal carcinoma, ovarian cancer, breast cancer, cancer of the stomach, prostate cancer and carcinoma of the pancreas.
50. as the pharmaceutical composition in claim 49, and cancer is wherein breast cancer, colorectal carcinoma and carcinoma of the pancreas.
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