CN1514833A - Novel tyrosine kinase inhibitors - Google Patents

Novel tyrosine kinase inhibitors Download PDF

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Publication number
CN1514833A
CN1514833A CNA028105168A CN02810516A CN1514833A CN 1514833 A CN1514833 A CN 1514833A CN A028105168 A CNA028105168 A CN A028105168A CN 02810516 A CN02810516 A CN 02810516A CN 1514833 A CN1514833 A CN 1514833A
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pyridin
hydroxyl
phenyl
ethylamino
radicals
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M��D����ά˹
M·D·维特曼
ղ���
N·巴拉苏布拉马尼安
ϣ
U·维拉帕特希
K·滋梅曼恩
M·G·索尼尔
�������ɭ
P·刘
���з�
X·尚
D·B·弗伦内森
K·M·斯托夫范
J·G·塔兰特
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Bristol Myers Squibb Co
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Bristol Myers Squibb Co
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Abstract

The present invention provides compounds of formula (I) and pharmaceutically acceptable salts thereof. The formula (I) compounds inhibit tyrosine kinase enzymes thereby making them useful as anti-cancer agents. The formula (I) compounds are also useful for the treatment of other diseases which can be treated by inhibiting tyrosine kinase enzymes.

Description

Novel tyrosine kinase inhibitor
Related application
According to 35U.S.C.Section 119 (e), the application requires the rights and interests of the U.S. Provisional Application number 60/279,327 of March 28 calendar year 2001 application.
Invention field
The present invention relates generally to and uses new small molecule to suppress Tyrosylprotein kinase.
Background of invention
Tyrosylprotein kinase is a class of enzymes, on the phenolic hydroxyl group of the terminal phosphate group-transfer of catalysis Triphosaden tyrosine residues in the target protein.Tyrosylprotein kinase has vital role (Plowman, G.D. in some cell functions signal transduction of (comprising propagation, canceration, apoptosis and the differentiation of cell); Ullrich, A.; Shawver, L.K.:Receptor Tyrosine KinaseAs Targets For Drug Intervention.DN&P(1994)7：334-339)。Therefore, the inhibitor of these enzymes can be used for treating or preventing to rely on the proliferative disease of these enzymes.EPDML strong evidence shows that the overexpression of receptor type protein tyrosine kinase or activation cause sending the important factor that composition mitogenesis signal is the continuous growth of human malignancies.The Tyrosylprotein kinase that relates to said process comprises Abl, CDK ' s, EGF, EMT, FGF, FAK, Flk-1/KDR, HER-2, IGF-1R, IR, LCK, MET, PDGF, Src and VEGF (Traxler, P.M.Protein Tyrosine Kinase Inhibitor in CancerTreatment.Exp.Opin.Ther Patents (1997) 7:571-588; Be attached to this paper by reference).Therefore, still need to develop the new compound that can be used for regulating or suppressing Tyrosylprotein kinase.
Summary of the invention
The present invention relates to suppress Tyrosylprotein kinase compound, comprise the compound compositions that suppresses Tyrosylprotein kinase and use treatment with tyrosine kinase inhibitors with the tyrosine kinase activity overexpression or on be adjusted to method (Powis, the G. of the disease (for example cancer, diabetes, restenosis, arteriosclerosis, psoriasis, vascularization disease and Immunological diseases) of feature; Workman, P.Signaling targets For The Development of Cancer Drugs.Anti-Cancer?Drug?Design(1994)，9：263-277；Merenmies，J.；Parada，L.F.；Henkemeyer，M.Receptor?Tyrosine?Kinase?Signaling?in?VascularDevelopment.Cell?Growth?Differ(1997)8：3-10；Shawver，L.K.；Lipsosn，K.E.；Fong，T.A.T.；McMahon，G.；Plowmnan，G.D.；Strawn，L.M.Receptor?Tyrosine?Kinase?As?Targets?For?Inhibition?ofAngiogenesis。Drug Discovery Today (1997) 2:50-63; All documents are attached to this paper by reference).
Except can be used as independent drug use, can also with standard treatment combined utilization known in the art, tyrosine kinase inhibitor can strengthen cytotoxicity or suppress the therapeutic activity of cell like this.
The present invention relates to have compound, its enantiomer, diastereomer, pharmacy acceptable salt, hydrate, prodrug and the solvate of following formula I structure:
Wherein
X is selected from N, C, C 1-C 3Alkyl, one or more R 7The C that replaces 1-C 3Alkyl and chemical bond;
Y is selected from O and S;
W is selected from N, C, O and S, and prerequisite is W when being O or S, then R 9Do not exist;
R 1, R 2, R 3, R 4, R 5, R 6, R 7, R 8, R 9Independently be selected from following group: H, C separately 1-6Alkyl, alkenyl, alkynyl group, cycloalkyl, Heterocyclylalkyl, halogen, amino, OR 60, NO 2, OH, SR 60, NR 60R 61, CN, CO 2R 60, CONR 60R 61, CO 2NR 60R 61, NR 62CONR 60R 61, NR 60SO 2R 61, SO 2NR 60R 61, C (NR 62) NR 60R 61, aryl, heteroaryl, (CH 2) nOR 60, (CH 2) nNR 60R 61, (CH 2) nSR 60, (CH 2) nAryl, (CH 2) nHeteroaryl, (CH 2) nHeterocyclylalkyl, NH-Z-aryl and NH-Z-heteroaryl;
Wherein n is 1-3;
Z is selected from C 1-C 4Alkyl group, alkenyl and alkynyl group; Z contains one or more hydroxyls, sulfydryl, alkoxyl group, thio alkoxy, amino, halogen, NR 60SO 2R 61Z is optional in conjunction with one or more following group: CO, CNOH, CNOR of being selected from 60, CNNR 60, CNNCOR 60And CNNSO 2R 60
R 60, R 61And R 62Independently be selected from following group: H, alkyl, alkenyl, alkynyl group, cycloalkyl, cycloalkylalkyl, hydroxyl, alkoxyl group, aryl, heteroaryl, heteroarylalkyl and alkyl-R 25, wherein
R 25For hydrogen, alkenyl, hydroxyl, sulfydryl, alkoxyl group, thio alkoxy, amino, alkylamino, dialkyl amido, aryl, heteroaryl, cyano group, halogen, sulfinyl, alkylsulfonyl ,-NR 30COOR 31,-NR 30C (O) R 31,-NR 30SO 2R 31,-C (O) NR 30R 31, heteroaryl or Heterocyclylalkyl;
R 30And R 31Independent is hydrogen, alkyl, cycloalkyl or alkyl-R 25
In preferred embodiments, R 1, R 7, R 8And R 9Be H;
R 2And R 4Be H or F;
Y is O;
X is selected from N and CH;
W is N;
R 5Be selected from H, methyl, ethyl, sec.-propyl, sec-butyl, cyclopropyl, F and CF 3
R 6Be selected from H, 2-aminomethyl pyridine, NHCH (CH 2OH) CH 2Ph, NHCH 2CH (OH) aryl and NHCH (CH 2OH) CH 2Aryl;
R 2Be selected from OR 60, C (NH) NHR 60, C (O) NHR 60Imidazoles, tetrahydroglyoxaline, tetrahydropyrimidine, piperazine, morpholine, high morpholine, piperidines, tetramethyleneimine, high piperazine and amino; Wherein
R 60Be selected from H, alkyl, cycloalkyl, Heterocyclylalkyl and alkyl-R 25, R wherein 25For hydrogen, alkenyl, hydroxyl, sulfydryl, thio alkoxy, alkoxyl group, thio alkoxy, halogen, cyano group, sulfinyl, alkylsulfonyl ,-NR 30COOR 31,-NR 30C (O) R 31,-NR 30SO 2R 31,-C (O) N 30R 31, heteroaryl or Heterocyclylalkyl;
R 30And R 31Independent is hydrogen, alkyl, cycloalkyl or alkyl-R 25
The present invention also provides medicinal compositions, and this medicinal compositions comprises the formula I compound and the pharmaceutically acceptable carrier of above definition.
The present invention further provides medicinal compositions, this medicinal compositions comprises formula I compound and pharmaceutically acceptable carrier and at least a optional other cancer therapy drug with the fixed dosage preparation of above definition.
The method of a kind of treatment with at least a Tyrosylprotein kinase diseases associated also is provided in addition, and this method comprises the formula I compound of the above definition of the Mammals treatment significant quantity that needs this treatment.In addition, the invention provides the method for a kind of treatment and at least a Tyrosylprotein kinase diseases associated, this method comprises formula I compound and at least a other cancer therapy drug that gives the above definition of Mammals.
Detailed Description Of The Invention
The invention provides the formula I compound of above definition, the medicinal compositions that uses described compound and the method for using described compound.
It below is the definition that is used to describe the various terms of The compounds of this invention.These terms in the whole specification sheets are to use separately or use all as the part of macoradical more to be suitable for give a definition (unless the restriction of other specific examples is arranged).
Unless other definition is arranged, uses separately herein or be meant that as the term " alkyl " of other group part alkane (hydrocarbon) deutero-comprises the univalent perssad of 1-12 carbon atom.Alkyl is optional straight chain, side chain or the cyclic saturated hydrocarbyl that replaces.When being substituted, alkyl can be replaced on any effective tie point by maximum four substituting groups (defined R).When relating to certain alkyl and replaced, replace and use " branched-chain alkyl " by alkyl.Exemplary not substituted alkyl comprises methyl, ethyl, propyl group, sec.-propyl, normal-butyl, the tertiary butyl, isobutyl-, amyl group, hexyl, isohexyl, heptyl, 4,4-dimethyl amyl group, octyl group, 2,2,4-tri-methyl-amyl, nonyl, decyl, undecyl, dodecyl etc.Exemplary substituting group includes but not limited to one or more following groups: hydroxyl, halogen (for example F, Cl, Br, I), haloalkyl (CCl for example 3Or CF 3), alkoxyl group, alkylthio, cyano group, carboxyl (COOH), alkyl-carbonyl (C (O) R), alkoxy carbonyl (OCOR), amino (NH 2), formamyl (NHCOOR-or-OCONHR-), urea (NHCONHR), sulfydryl (SH), sulfinyl, alkylsulfonyl, aryl, heteroaryl and Heterocyclylalkyl.The alkyl of definition can also comprise one or more carbon-carbon double bonds or one or more carbon carbon triple bond.Alkyl can also be by alkyl-R 25Expression.In preferred embodiments, alkyl is methyl, ethyl, propyl group or butyl, and comprises methyl, ethyl, propyl group or the butyl of replacement.
Use separately herein or be meant straight chain, side chain or the cyclic hydrocarbon group that comprises 2-12 carbon atom and at least one carbon-carbon double bond as the term " alkenyl " of other group part.Alkenyl can be substituted according to the same way as of abovementioned alkyl is optional.
Use separately herein or be meant and comprise 2-12 carbon atom and at least one carbon carbon triple-linked straight chain, side chain or cyclic hydrocarbon group as the term " alkynyl group " of other group part.Alkynyl group can be substituted according to the same way as of abovementioned alkyl is optional.
Use separately herein or as the term " alkoxyl group " of other group part be meant comprise 1-10 carbon atom and by Sauerstoffatom being covalently linked to the straight or branched alkyl of parent molecule, and term " C 1-6Alkoxyl group " and " lower alkoxy " be meant such group of 1-6 carbon atom, example includes but not limited to methoxyl group, oxyethyl group, propoxy-, isopropoxy, butoxy, tert.-butoxy etc.When using together with the substituting group of alkoxyl group, term " the optional replacement " is meant that maximum two hydrogen (preferably on different carbon atoms) are selected from following group replacement: low alkyl group, phenyl, cyano group, halogen, trifluoromethyl, nitro, hydroxyl, alkanoyloxy, amino, alkyl monosubstituted amino and dialkyl amido.Alkoxyl group can replace according to the identical replacement mode of abovementioned alkyl.
Use separately herein or be meant-SO and can being replaced by for example alkyl or aryl as the term " sulfinyl " of other group part.
Use separately herein or be meant-SO as the term " alkylsulfonyl " of other group part 2And can be replaced by alkyl or aryl.
Use separately herein or be meant-NH as the term " amino " of other group part 2" amino " can be chosen wantonly by one or two (identical or different) substituting group and replace for example following substituting group: alkyl, aryl, arylalkyl, alkenyl, alkynyl group, heteroaryl, heteroarylalkyl, Heterocyclylalkyl, Heterocyclylalkyl alkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl or alkylthio.Preferred substituted comprises alkylamino and dialkyl amido, for example methylamino, ethylamino, dimethylamino and diethylamino.Any substituting group of the alkyl or aryl that above-mentioned substituting group can be further limits by carboxylic acid or by this paper replaces.In addition, An Ji substituting group can constitute 1-pyrrolidyl, piperidino, 1-azepines base, 4-morpholinyl, 4-parathiazan base, 4-sulfinyl morpholine, 4-alkylsulfonyl morpholine, 1-piperazinyl, 4-alkyl-1-piperazinyl, 4-arylalkyl-1-piperazinyl, 4-alkyl diaryl-1-piperazinyl, the high piperazinyl of 1-, the high piperazinyl of 4-alkyl-1-, the high piperazinyl of 4-arylalkyl-1-, the high piperazinyl of 4-alkyl diaryl-1-together with coupled nitrogen-atoms; 1-pyrrolidyl, piperidino or 1-azepines base, optional by alkyl, alkoxyl group, alkylthio, halogen, trifluoromethyl or hydroxyl replacement.
Use separately herein or be meant monocycle or bicyclic aromatic ring (for example the phenyl of phenyl, replacement etc.) and condense group (for example naphthyl, phenanthryl etc.) as the term " aryl " of other group part.Aryl comprises at least one ring that contains 6 atoms, maximum 5 described rings, the ring maximum 22 atoms and contain alternately (resonance) two keys between adjacent carbons or suitable heteroatoms thus.Aryl can be chosen wantonly by one or more groups and replace, and described group includes but not limited to: halogen, alkyl, alkenyl, alkynyl group, alkoxyl group, hydroxyl, carboxyl, formamyl, alkoxy carbonyl, alkyl amino-carbonyl, nitro, trifluoromethyl, amino, cycloalkyl, cyano group, alkyl S (O) m(m=0,1 or 2) or sulfydryl.Aryl can also be replaced formation fused rings, for example dihydro benzo furyl, oxindole base, indyl, indolinyl, oxindole base, benzoxazole alkane ketone group, benzoxazole quinoline base and benzoxazole alkane ketone by Heterocyclylalkyl and heterocyclic aryl.
Use separately herein or be meant and contain 3-9 carbon atom, the preferred undersaturated hydrocarbon ring of complete saturated or part of 3-7 carbon atom as the term " cycloalkyl " of other group part.In addition, cycloalkyl can be substituted.The cycloalkyl that replaces is meant that described ring contains 1,2 or 3 (preferred 1) and is selected from following substituting group: the alkyl of halogen, alkyl, replacement, alkenyl, alkynyl group, nitro, cyano group, oxo (=O), hydroxyl, alkoxyl group, alkylthio ,-CO 2H ,-OC (=O) H, CO 2-alkyl-,-OC (=O) alkyl ,=N-OH ,=N-O-alkyl, aryl, heteroaryl, heterocyclic radical, 5 or 6 yuan of ketone acetals (promptly 1,3-dioxolane or 1,3-diox) ,-NR ' R " ,-C (=O) NR ' R " ,-OC (=O) NR ' R " ,-NR ' CO 2R " ,-NR ' C (=O) R " ,-SO 2NR ' R " and-NR ' SO 2R ", wherein " independently be selected from the alkyl and the cycloalkyl of hydrogen, alkyl, replacement separately, perhaps R ' and R " constitute heterocyclic radical or hetero-aromatic ring together for R ' and R.Cycloalkyl can also be replaced the formation Heterocyclylalkyl by heteroatoms (for example O, N and S).Preferred Heterocyclylalkyl comprises optional morpholine, high morpholine (7 yuan of rings), parathiazan, piperazine, high piperazine (7 yuan of rings) and the piperidines that replaces.
Use separately herein or be meant as the term " heteroaryl " of other group part to replace and unsubstituted 5-6 unit monocycle, 9-10 unit's dicyclo and 11-14 unit three cyclophane family groups, wherein at least one contains at least one heteroatoms (O, S or N) in encircling.Comprise heteroatomic each ring in the heteroaryl and can comprise one or two Sauerstoffatom or sulphur atom and/or 1-4 nitrogen-atoms, prerequisite is that heteroatoms adds up to below four or four and each encircles and contains at least one carbon atom in each ring.The fused rings that dicyclo or three rings constitute can only comprise carbon atom and can be saturated, fractional saturation or unsaturated group.Nitrogen-atoms and sulphur atom can be chosen wantonly oxidized, and nitrogen-atoms can be chosen wantonly by quaternized.Dicyclo or tricyclic heteroaryl must comprise at least one complete aromatic ring, and other fused rings or ring can be aromatics or non-aromatic ring.Heteroaryl can connect at any available nitrogen atom or the carbon atom of any ring.Hetero-aromatic ring system can comprise 0,1,2 or 3 and be selected from following substituting group: the alkyl of halogen, alkyl, replacement, alkenyl, alkynyl group, nitro, cyano group, hydroxyl, alkoxyl group, alkylthio ,-CO 2H ,-OC (=O) H ,-CO 2-alkyl ,-OC (=O) alkyl, phenyl, benzyl, phenylethyl, phenoxy group, thiophenyl, cycloalkyl, replacement cycloalkyl, heterocyclic radical, heteroaryl ,-NR ' R " ,-C (=O) NR ' R " ,-OC (=O) NR ' R " ,-NR ' CO 2R " ,-NR ' C (=O) R " ,-SO 2NR ' R " and-NR ' SO 2R ", wherein " independently be selected from the alkyl and the cycloalkyl of hydrogen, alkyl, replacement separately, perhaps R ' and R " constitute heterocyclic radical or hetero-aromatic ring together for R ' and R.
Exemplary bicyclic heteroaryl comprises pyrryl, pyrrolidyl, imidazolinyl, pyrazolyl, pyrazolinyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl group, isothiazolyl, furyl, thienyl, oxadiazole base, pyridyl, pyrazinyl, pyrimidyl, pyridazinyl, triazinyl etc.
Exemplary bicyclic heteroaryl comprises indyl, indolinyl, oxindole base benzoxazole alkane ketone group, benzothiazolyl, benzo dioxolyl benzoxazolyl, benzothienyl, quinolyl, tetrahydro isoquinolyl, isoquinolyl, benzimidazolyl-, benzopyranyl, the indolizine base, benzofuryl, the chromone base, the coumarin base, benzopyranyl, the cinnoline base, quinoxalinyl, indazolyl, pyrrolopyridinyl, the furo pyridyl, dihydro-iso indolyl, tetrahydric quinoline group etc.
Exemplary tricyclic heteroaryl comprises carbazyl, benzindole base, phenanthroline base, acridyl, phenanthridinyl, xanthenyl etc.
Use separately herein or be meant chlorine, bromine, fluorine or the iodine of selecting based on independent principle as term " halogen " or " halogen " of other group part.
Use separately herein or be meant-OH as the term " hydroxyl " of other group part.
Use separately herein or be meant the alkyl that is connected to parent molecule by sulphur atom as the term " thio alkoxy " of other group part.The example of thio alkoxy includes but not limited to sulfo-methoxyl group, thio ethoxy etc.
Abbreviation: " Ph " is phenyl; " Me " is methyl; " Et " is ethyl.
" cancer therapy drug " used herein comprises known anticancer therapy method for example radiotherapy or use cytostatics or cytotoxicity medicine, for example (but being not limited to) DNA active medicine, for example cis-platinum or Zorubicin; Topoisomerase II inhibitor, for example Etoposide; Topoisomerase I inhibitor, for example CPT-11 or Hycamtin; Tubulin medicine, for example taxol, docetaxel or esperamicin; Hormone drug, for example tamoxifen; Thymidylate synthase inhibitor, for example 5 FU 5 fluorouracil; Antimetabolite, for example methotrexate; Tyrosine kinase inhibitor, for example Iressa and OSI-774; Angiogenesis inhibitor; The EGF inhibitor; The VEGF inhibitor; The CDK inhibitor; The Her1/2 inhibitor; Directly at the monoclonal antibody of growth factor receptors, for example erbitux (EGF) and trastuzumab (herceptin) are (Her2).
When a functional group was defined as " protected ", this just meaned that described functional group is that its modified forms is to prevent in protected position unwanted side reaction taking place.Consider that art technology level and reference standard document [for example Greene, T.W. etc., Protective Groups inOrganic Synthesis, Wiley, N.Y. (1991)] just can select the blocking group of suitable The compounds of this invention from the application.
Work as C 1-6Alkyl, alkenyl, alkynyl group, when cycloalkyl is substituted, preferably replaced: hydroxyl, cyano group, formamyl, hydroxyl, alkoxyl group, sulfydryl, alkenyl, thio alkoxy, amino, alkylamino, amido, alkylsulfonyl, sulfinyl, sulfonamido, halogen, Heterocyclylalkyl, aryl or heteroaryl by one or more following groups.
When aryl or heteroaryl are substituted; preferably replaced: alkyl, alkenyl, alkynyl group, cyano group, formamyl, hydroxyl, alkoxyl group, thio alkoxy, amino, amido, sulfonamido, halogen or " replacement, wherein R ', R " formation and aryl-fused ring by R ' and R by one or more following groups.Work as CH 2When aryl or heteroaryl are substituted, preferably replaced: alkyl, alkenyl, alkynyl group, cyano group, formamyl, hydroxyl, alkoxyl group, thio alkoxy, amino, amido, sulfonamido or halogen by one or more following groups.
When NH-Z-aryl or NH-Z-heteroaryl are substituted, preferably replaced: alkyl, alkenyl, alkynyl group, hydroxyl, alkoxyl group, thio alkoxy, amino, halogen, nitro, itrile group, carboxylic acid ester groups, alkoxy carbonyl, formamyl, ester group, amide group, aryl or heteroaryl by one or more following groups.
The index number of symbol " C " back limits the carbonatoms that concrete group can comprise." C for example 1-6Alkyl " be meant the saturated carbon chains of the straight or branched of 1-6 carbon atom; The example comprises methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, sec-butyl, isobutyl-, the tertiary butyl, n-pentyl, sec.-amyl sec-pentyl secondary amyl, isopentyl and n-hexyl.Depend on context, " C 1-6Alkyl " also can refer to the C of two groups of bridge joint 1-6Alkylidene group; The example comprises propane-1,3-two bases, butane-1,4-two bases, 2-methyl-butane-1,4-two bases etc." C 2-6Alkenyl " be meant the straight or branched carbochain that contains at least one carbon-carbon double bond and 2-6 carbon atom; The example comprises vinyl, propenyl, pseudoallyl, butenyl, isobutenyl, pentenyl and hexenyl.Depend on context, " C 2-6Alkenyl " also can refer to the C of two groups of bridge joint 2-6Olefin 2 base; The example comprises ethene-1,2-two bases (vinylene), 2-methyl-2-butene-1,4-two bases, 2-hexene-1,6-two bases etc." C 2-6Alkynyl group " be meant the straight or branched carbochain that contains at least one carbon carbon triple bond and 2-6 carbon atom; The example comprises ethynyl, proyl, butynyl and hexin base.
Term " alkyl-R 25" comprise that the optional alkyl (for example methyl, ethyl, propyl group and butyl) that replaces is connected to R 25Group.R 25Generally include hydrogen, alkenyl, hydroxyl, sulfydryl, alkoxyl group, thio alkoxy, amino, alkylamino, dialkyl amido, aryl, heteroaryl, cyano group, halogen, sulfinyl, alkylsulfonyl ,-NHCOOH ,-NHC (O)-,-NHSO 2-,-C (O) NH 2, heteroaryl or Heterocyclylalkyl (for example morpholinyl) or group with following formula structure:
Figure A0281051600371
Figure A0281051600372
Or
Figure A0281051600373
Use separately herein or comprise the imidazoles of replacement and the tetrahydroglyoxaline of replacement as term " imidazoles " and " tetrahydroglyoxaline " of other group part.Similarly, term " tetrahydropyrimidine " comprises the tetrahydropyrimidine of replacement.Equally, term " piperazine ", " piperidines ", " morpholine ", " high piperazine ", " high morpholine " and " tetramethyleneimine " comprise the piperazine of replacement, the piperidines of replacement, the morpholine of replacement, the high morpholine of replacement and the tetramethyleneimine of replacement respectively.
The compounds of this invention is compound, its enantiomer, diastereomer, pharmacy acceptable salt, hydrate, prodrug and the solvate with following general formula I:
Figure A0281051600374
X is selected from N, C, C 1-C 3Alkyl, one or more R 7The C that replaces 1-C 3Alkyl and chemical bond;
Y is selected from O and S;
W is selected from N, C, O and S, and prerequisite is W when being O or S, then R 9Do not exist;
R 1, R 2, R 3, R 4, R 5, R 6, R 7, R 8, R 9Independently be selected from following group: H, C separately 1-6Alkyl, alkenyl, alkynyl group, cycloalkyl, Heterocyclylalkyl, halogen, amino, OR 60, NO 2, OH, SR 60, NR 60R 61, CN, CO 2R 60, CONR 60R 61, CO 2NR 60R 61, NR 62CONR 60R 61, NR 60SO 2R 61, SO 2NR 60R 61, C (NR 62) NR 60R 61, aryl, heteroaryl, (CH 2) nOR 60, (CH 2) nNR 60R 61, (CH 2) nSR 60, (CH 2) nAryl, (CH 2) nHeteroaryl, (CH 2) nHeterocyclylalkyl, NH-Z-aryl and NH-Z-heteroaryl;
Wherein n is 1-3;
Z is selected from C 1-C 4Alkyl group, alkenyl and alkynyl group; Z contains one or more hydroxyls, sulfydryl, alkoxyl group, thio alkoxy, amino, halogen, NR 60SO 2R 61Z is optional in conjunction with one or more following group: CO, CNOH, CNOR of being selected from 60, CNNR 60, CNNCOR 60And CNNSO 2R 60
R 60And R 61Independently be selected from following group: H, alkyl, alkenyl, alkynyl group, cycloalkyl, cycloalkylalkyl, hydroxyl, alkoxyl group, aryl, heteroaryl, heteroarylalkyl and alkyl-R 25, wherein
R 25For hydrogen, alkenyl, hydroxyl, sulfydryl, alkoxyl group, thio alkoxy, amino, alkylamino, dialkyl amido, aryl, heteroaryl, cyano group, halogen, sulfinyl, alkylsulfonyl ,-NR 30COOR 31,-NR 30C (O) R 31,-NR 30SO 2R 31,-C (O) NR 30R 31, heteroaryl or Heterocyclylalkyl;
R 30And R 31Independent is hydrogen, alkyl, cycloalkyl or alkyl-R 25
In certain embodiments of the invention, R 3For-OR 60, R 60For alkyl or-alkyl-R 25, R wherein 25For hydrogen, alkenyl, hydroxyl, sulfydryl, alkoxyl group, thio alkoxy, amino, halogen, cyano group, alkyl sulphinyl, alkyl sulphonyl ,-R 30COOR 31,-NR 30C (O) R 31,-NR 30SO 2R 31,-C (O) NR 30R 31, heteroaryl or Heterocyclylalkyl; R 30And R 31Independent is hydrogen, alkyl, cycloalkyl or alkyl-R 25In preferred embodiments, R 60For methyl ,-(CH 2) nCH 2OH or-(CH 2) nCH 2N (CH 2CH 2) 2O, n are 0,1 or 2.
In certain embodiments, R 3Be piperazine, high piperazine, 3-methylpiperazine or 3, the 5-lupetazin, and choose wantonly and be selected from following group in the 4-N position and replace: alkyl, aryl, cycloalkyl, cycloalkylalkyl, Heterocyclylalkyl, alkyl-R 25,-C (O)-R 15, OR-CO 2R 15, R wherein 15Be hydrogen, alkyl, aryl, alkyl-R 25, amino or aryl; R 25For hydrogen, alkenyl, hydroxyl, sulfydryl, alkoxyl group, thio alkoxy, amino, alkylamino, dialkyl amido, cyano group, halogen, sulfinyl, alkylsulfonyl, aryl sulfonyl ,-NR 30COOR 31,-NR 30C (O) R 31,-NR 30SO 2R 31,-C (O) NR 30R 31, heteroaryl or Heterocyclylalkyl; R 30And R 31Independent is hydrogen, alkyl, cycloalkyl or alkyl-R 25In preferred embodiments, piperazine is replaced by following group: Me, CH 2Cyclopropyl, CH 2CH 2NMe 2, CH 2CH 2NEt 2, CH 2CH 2NH 2, CH 2CH 2NHMe, CH 2CH 2NHEt, N-CH 2CH 2N (CH 2CH 2) 2O, (CH 2) nCH 2-R 25, R wherein 25Be OH, OMe, F, CN, CF 3, SOCH 3Or SO 2CH 3, wherein n is 0,1 or 2.
In certain embodiments, R 3Be amino.Preferred amino comprises NHCH 2CH 2OH, NMeCH 2CH 2OH, NEtCH 2CH 2OH, NHCH 2CH 2NH 2, NMeCH 2CH 2NH 2, NEtCH 2CH 2NH 2, NHCH 2CH 2NMe 2, NMeCH 2CH 2NMe 2, NEtCH 2CH 2NMe 2, NHCH 2CH 2NEt 2, NMeCH 2CH 2NEt 2, NEtCH 2CH 2NEt 2, NHCH 2CH 2N (CH 2CH 2) 2O, NMeCH 2CH 2N (CH 2CH 2) 2O, NEtCH 2CH 2N (CH 2CH 2) 2O.
In certain embodiments, R 3Be the optional piperidines that replaces.Preferred substituted is selected from hydroxyl, sulfydryl, amino, alkylamino, dialkyl amido, alkoxyl group, thio alkoxy, 1,3-dioxolane (OCHR 15) 2, 1,3-diox (OCHR 15CHR 15CHR 15O-)-NHC (O) R 15,-NHCO 2R 15, R wherein 15Be hydrogen, alkyl or alkyl-R 25, R wherein 25For hydrogen, alkenyl, hydroxyl, sulfydryl, alkoxyl group, thio alkoxy, amino, halogen, cyano group, alkyl sulphinyl, alkyl sulphonyl ,-NR 30COOR 31,-NR 30C (O) R 31,-NR 30SO 2R 31,-C (O) NR 30R 31, heteroaryl or Heterocyclylalkyl; R 30And R 31Independent is hydrogen, alkyl, cycloalkyl or alkyl-R 25
In certain embodiments, R 3Be the optional following group that replaces: morpholine, high morpholine, parathiazan, sulfinyl morpholine or alkylsulfonyl morpholine.Preferred substituted comprises hydroxyl, sulfydryl, amino, alkylamino, dialkyl amido, alkoxyl group, thio alkoxy, alkyl-R 25,-NHC (O) R 15,-NHCO 2R 15, R wherein 15Be hydrogen, alkyl or alkyl-R 25, R wherein 25For hydrogen, alkenyl, hydroxyl, sulfydryl, alkoxyl group, thio alkoxy, amino, halogen, cyano group, alkyl sulphinyl, alkyl sulphonyl ,-NR 30COOR 31,-NR 30C (O) R 31,-NR 30SO 2R 31,-C (O) NR 30R 31, heteroaryl or Heterocyclylalkyl; R 30And R 31Independent is hydrogen, alkyl, cycloalkyl or alkyl-R 25
In certain embodiments, R 3Be tetramethyleneimine.Preferred tetramethyleneimine comprises 3-hydroxyl pyrrolidine, 3-alkoxyl group tetramethyleneimine and 3-alkylamino tetramethyleneimine.
According to one embodiment of the invention, R 3Be optional N-tetrahydropyrimidine or the TMSIM N imidazole quinoline that replaces, wherein said substituting group preferred alkyl, hydroxyalkyl, alkoxyalkyl, haloalkyl, cyano group alkyl, carboxyl or methane amide.
In certain embodiments, R 6Be selected from H, 2-aminomethyl pyridine, NHCH 2CH (OH) aryl and NHCH (CH 2OH) CH 2Aryl, wherein aryl is optional is substituted.In preferred embodiments, described aryl is replaced by Br, Cl, F or methoxyl group.In certain embodiments, R 6Structure with one of following formula:
Or
R wherein 40Be hydrogen or alkyl, be preferably methyl, R 17Be hydrogen or halogen (for example Br, Cl or F).
Preferred The compounds of this invention has the structure of one of following formula:
Wherein
R 12And R 13Independent is hydrogen, alkyl or alkyl-R 25
R 15Be hydrogen, alkyl or alkyl-R 25
R 16Independent is hydrogen or methyl;
R 17, R 18And R 19Independent is hydrogen, halogen or alkoxyl group, or R 18And R 19Constitute Heterocyclylalkyl or heteroaryl together;
R 25For hydrogen, hydroxyl, sulfydryl, alkenyl, alkoxyl group, thio alkoxy, amino, halogen, cyano group, sulfinyl, alkylsulfonyl ,-NR 30COOR 31,-NR 30C (O) R 31,-NR 30SO 2R 31,-C (O) NR 30R 31, heteroaryl or Heterocyclylalkyl;
R 30And R 31Independent is hydrogen, alkyl, cycloalkyl or alkyl-R 25
In preferred embodiments, R 12Be hydrogen, methyl, methylol, methoxymethyl, CH 2F, CH 2CN, CO 2H or-CONR 30R 31, R wherein 30And R 31Independent is hydrogen or alkyl-R 25
R 13Be H;
R 17Be Br, Cl or F;
R 18Be halogen or methoxyl group;
R 19Be H.
The suitable example of the salt of The compounds of this invention comprises organic acid salt or inorganic acid salt.These salt include but not limited to hydrochloride, hydrobromate, vitriol, mesylate, maleate, fumarate, phosphoric acid salt and other pharmacy acceptable salt.Also comprise being not suitable for pharmaceutical use but the salt that can be used for other purposes, for example be used for separating or purification free formula I compound or its pharmacy acceptable salt.
No matter all steric isomers of The compounds of this invention are mixed form or respective pure form, or the substantially pure form all is included in the present invention.The definition of The compounds of this invention comprises its all possible steric isomer and their mixture.Especially comprise racemic form with specified activity and independent opticity isomer.Racemic form can be disassembled with physical method, for example fractional crystallization, fractionation or crystallization diastereomer derivative or separate with the chiral column chromatography.Independent opticity isomer can obtain according to ordinary method with racemic modification, for example generates the salt post crystallization with opticity acid.
Should be understood that the prodrug form that the present invention includes formula I compound.The various forms of prodrug is well known in the art.The example of described prodrug derivatives referring to:
(a) Design of Prodrugs, H.Bundgaard edits (Elsevier, 1985); Methods in Enzymology, the 42nd volume, pp.309-396, chief editors such as K.Widder, (Academic Press, 1985);
(b) A Textbook of Drug Design and Development, chief editor Krosgaard-Larsen and H.Bundgaard, the 5th chapter, " Design and Application of Prodrugs ", H.Bundgaard, pp.113-191 (1991);
(c)H.Bundgaard，Advanced?Drug?Deliver?Reviews，8，pp.1-38(1992)；
(d) H.Bundgaard etc., Journal ofPharmaceutical Sciences, 77,285 (1988);
(e) N.Kayeka etc., Chem.Phar.Bull., 32,692 (1984).
The present invention also provides medicinal compositions, and said composition comprises formula I compound and pharmaceutically acceptable carrier and at least a other cancer therapy drug with the fixed dosage preparation of above definition.Preferred cancer therapy drug is to be selected from following medicine: tamoxifen, toremifene, raloxifene, droloxifene, iodoxyfene, Magace, Anastrozole, letrozole, borazole, Exemestane, flutamide, Nilutamide, bicalutamide, cyproterone acetate, goserelin acetate, leuproside (luprolide), finasteride, trastuzumab, methotrexate, 5 FU 5 fluorouracil, cytosine arabinoside, Zorubicin, daunorubicin, epirubicin, idarubicin, Mitomycin-C, dactinomycin, mithramycin, cis-platinum, carboplatin, L-sarcolysin, Chlorambucil, busulfan, endoxan, ifosfamide, nitrosourea, thiotephan, vincristine(VCR), safe plain, taxotere, Etoposide, teniposide, amsacrine, irinotecan, Hycamtin, esperamicin; Tyrosine kinase inhibitor, for example Iressa or OSI-774; Angiogenesis inhibitor; The EGF inhibitor; The VEGF inhibitor; The CDK inhibitor; The HER1/2 inhibitor; Direct monoclonal antibody, for example erbitux (EGF) and trastuzumab (Her2) at growth factor receptors.
The present invention further provides a kind of method by at least a tyrosine-kinase enzyme treatment disease of adjusting, this method comprises the formula I compound of the above definition of the Mammals treatment significant quantity that needs this treatment.
In addition, it is a kind of by regulating the method for at least a tyrosine-kinase enzyme treatment disease that the present invention also provides, this method comprise the Mammals treatment significant quantity that needs this treatment above definition formula I compound and unite and give (while or sequential) at least a other cancer therapy drug.
The disease of described the inventive method preferred therapeutic is a cancer.In addition, Tyrosylprotein kinase includes, but is not limited to: Abl, CDK ' S, EGF, EMT, FGF, FAK, Flk-1/KDR, HER-2, IGF-1R, IP, LCK, MET, PDGF, Src and VEGF.
The present invention also provides the treatment method for cancer, and this method comprises at least a medicinal compositions with above definition of the Mammals treatment significant quantity that needs this treatment.
The present invention further provides a kind of method for the treatment of proliferative disease, this method comprises at least a medicinal compositions with above definition of the Mammals treatment significant quantity that needs this treatment.
Some compound of formula I usually can be according to following flow process and those skilled in the art's knowledge preparation.The solvate of formula I compound (for example hydrate) is also included within the scope of the invention.The solvation method is well-known in this area.Therefore, The compounds of this invention can be free form or hydrate forms, and can obtain by the illustrative methods of following flow process.
More particularly, the exemplary explanation of flow process I-VII the preparation method of the claimed compound of the present invention.Embodiment exemplary illustration The compounds of this invention subsequently can be used these flow preparation.Any substituting group that these flow processs are not subjected to listed embodiment or are used for illustrative purpose limits.
Flow process I has introduced the preparation method of benzimidazoles.Can be easy to obtain initial diamine 1 with literature method, also can be by commercially available acquisition.Then diamine and aldehyde 2 condensations are obtained benzoglyoxaline 3.Can further modify 3 benzoglyoxaline or the functional group on the heterocyclic aryl then.
Flow process I.
Perhaps; above-mentioned benzoglyoxaline can progressively prepare (referring to flow process II), and elder generation generates acid amides with 5 chloride of acid or any peptide coupler commonly used (for example DCC (dicyclohexylcarbodiimide), EDCI (1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride) etc.).In case generate acid amides 6, can adopt catalytic hydrogenation, transfer hydrogenation or chemical reduction method (SnCl for example 2Or iron powder) reduction nitro also can adopt other method that is used to reduce aromatic nitro known in the art.Again aniline just can be generated benzoglyoxaline with acid treatment.
Flow process II.
Figure A0281051600451
By way of example, flow process III graphic extension uses 4-iodo-2-methoxyl group-pyridine-3-formaldehyde 7 to obtain functionalized benzoglyoxaline 8.Adopt proton acidic conditions, TMSI (three silyl iodine), BBr 3Or known in the art other be used for hydrolysis methoxyl group under the condition of decomposition of methyl ether, will obtain haloperidid ketone 9.Add and contain the pyridone 10 that heteroatoms nucleophilic reagent amine, alcohol or mercaptan will obtain replacing.Other functional group can add in the above aldehyde cpd, comprise only be used for illustrative purpose above example.
Flow process III
Equally, can modify aromatic ring according to the benzoglyoxaline of flow process I or II preparation.The R on benzoglyoxaline for example 3Introducing cyano group makes and can prepare heterocycle such as imidazoles, tetrahydroglyoxaline, oxazoline, thiazoline, acid amides or amidine.Flow process IV illustrates such switching process.From the benzoglyoxaline 11 that cyano group replaces, its heterocycle can be modified according to flow process IV and obtain 12.Preferred ethanol and the acid generation imido-ester of using provides intermediate 13.Imido-ester 13 can followingly be converted into 14: generate tetrahydroglyoxaline with diamine; With amino alcohol Sheng oxazoline; Aminoacetal generates imidazoles; Amino mercapto generates thiazoline.Perhaps imido-ester also can be hydrolyzed to acid, utilizes then and appoints standard amide reaction reagent (DCC, EDCI etc.) that acid and amine coupling are generated acid amides 15.Imido-ester 13 also can be used as intermediate and amine prepared in reaction amidine 16.
Flow process IV
Figure A0281051600471
The further method for transformation of the benzoglyoxaline of flow process V graphic extension halogen atom-containing, utilize the palladium katalysis under the condition that Suzuki proposes, transform [Yang etc., Acta Chem.Scand. (1993) 221; Suzuki etc., Synth.Commun. (1981) 11:513] or under the condition that Buchwald/Hartwig proposes, transform [Buchwald etc., J.Am.Chem.Soc. (1994) 116:7901; Hartwig etc., J.Am.Chem.Soc. (1994) 116:5969; Hartwig. Angew.Chem., Int.Ed.Engl. (1998) 37:2046] and these method improvement conditions under carry out.Can predict the reactant that preparation bromo benzoglyoxaline 17 will be provided for the Suzuki coupling, it and aryl boric acid, vinyl boric acid and heterocyclic boronic acids coupling can obtain benzoglyoxaline 18.Equally, can begin from identical bromide and amine prepared in reaction amine and heterocycle (for example piperazine or morpholine derivative) 19 under its change condition of conditioned disjunction of Buchwald and Hartwig introduction.
Flow process V
Perhaps amine and Hete rocyclic derivatives for example 19 can use intermediate 6 prepare according to flow process II.R when 6 3During for halogen (preferred F), halogen can be by amine, alcohol, heterocyclic amine and other nitrogen heterocyclic ring (for example piperazine, piperidines, 4-amino piperidine, morpholine, imidazoles etc.) displacement (flow process VI).The terminal nitrogen atom of piperazine or 4-amino piperidine can be obtained alkyl derivative in alkylation under the standard alkylation conditions or in the reductive amination reaction with aldehyde reaction then.Perhaps, the terminal nitrogen atom of piperazine or 4-amino piperidine can be used the normal condition of much knowing organic synthesis field those of skill in the art by acidylate or carbamylization.According to the graphic extension of flow process II can preparation example as 19 compound.
Flow process VI.
Perhaps use R 3For halogen (preferred F) and halogen can be carried out the substitution reaction of nucleophilicity aromatics as initial feed by amine, alcohol, heterocyclic amine and other nitrogen heterocyclic ring (for example piperazine, piperidines, 4-amino piperidine, morpholine, imidazoles etc.) metathetical 20 can be with at R 3Introduce amine, heterocycle and alcohol (flow process VII).The terminal nitrogen atom of piperazine or 4-amino piperidine can be obtained alkyl derivative in alkylation under the standard alkylation conditions or in the reductive amination reaction with aldehyde reaction then.Perhaps, the terminal nitrogen atom of piperazine or 4-amino piperidine can be used the normal condition of much knowing organic synthesis field those of skill in the art by acidylate or carbamylization.The N-methyl-p-nitroaniline of gained can be reduced to diamine 21, and method is seen the graphic extension of flow process III.
Flow process VII.
The invention purposes
The compounds of this invention has medicinal property; Especially formula I compound is a tyrosine kinase inhibitor.Thus, the new compound of formula I can be used for treating various proliferative disease (including but not limited to that Tyrosylprotein kinase is diseases related), for example cancer, autoimmune disorder, virus disease, fungal disease, neurodegenerative disease and cardiovascular disorder.
More particularly, formula I compound can be used for treating various cancers, includes but not limited to following cancer:
A) cancer cancer comprises bladder cancer, breast cancer, colorectal carcinoma, kidney, liver cancer, lung cancer (comprising small cell lung cancer), the esophageal carcinoma, carcinoma of gallbladder, ovarian cancer, carcinoma of the pancreas, cancer of the stomach, cervical cancer, thyroid carcinoma, prostate cancer and skin carcinoma (comprising squamous cell carcinoma);
B) lymphatic system hematopoietic system cancer comprises leukemia, acute lymphoblastic leukemia, acute lymphoblastic leukemia, B cell lymphoma, t cell lymphoma, He Jiejin lymphomas, non_hodgkin lymphoma, hair cell lymphoma and burkitt's lymphoma;
C) medullary system hematopoietic system cancer comprises acute and chronic myelocytic leukemia, myelodysplastic syndrome and promyelocyte leukemia;
D) mesenchyme source tumour comprises fibrosarcoma and rhabdosarcoma;
E) maincenter and peripheral nervous system tumour comprise star-like glucagonoma, neuroblastoma, neurospongioma and schwannoma;
F) other tumour comprises sarcoma (sacroma), melanoma, spermocytoma, teratocarcinoma, osteosarcoma, xeroderma pitmentosum, keratoacanthoma, thyroid follcular carcinoma and Kaposi.
In general, because Tyrosylprotein kinase has vital role in regulating cell proliferation, so various inhibitor can be used as reversible cytostatics, it is all diseases of feature, for example benign prostatic hyperplasia unusually that described cytostatics can be used for treating with cell proliferation, familial adenomatosis polyposis, neurofibromatosis, atherosclerosis, pulmonary fibrosis, sacroiliitis, psoriatic, glomerulonephritis, vascular restenosis after angioplasty or the vascular operation, hypertrophic scar forms, inflammatory bowel, graft-rejection, endotoxin shock and fungi infestation.
But formula I compound cell death inducing.The apoptosis abnormal reaction is found in multiple human diseases.Formula I compound can be used for treating cancer (including but not limited to the above-mentioned type cancer) as apoptosis regulator, virus infection (includes but not limited to simplexvirus, poxvirus, Epstein-Barr virus, Sendai virus and adenovirus), stop the AIDS development of HIV infected patient, autoimmune disorder (includes but not limited to systemic lupus, erythema, the autoimmunity glomerulonephritis, rheumatoid arthritis, psoriatic, inflammatory bowel and autoimmune diabetes), neurodegenerative disease (includes but not limited to Alzheimer's, AIDS dependency dementia, Parkinson's disease, amyotrophic lateral sclerosis, retinitis pigmentosa, spinal muscular atrophy and cerebral degeneration), myelodysplastic syndrome, aplastic anemia, the local damage that myocardial infarction is followed, apoplexy and reperfusion injury, arrhythmia, atherosclerosis, toxin hepatopathy or alcoholic liver disease, blood disease (including but not limited to chronic anaemia and aplastic anemia), musculoskeletal system degenerative disease (including but not limited to osteoporosis and sacroiliitis), aspirin sensitive type sinusitis paranasal sinusitis, cystic fibrosis, multiple sclerosis, ephrosis and cancer pain.
Formula I compound can be regulated cell RNA and the synthetic level of DNA.Therefore, these compounds can be used for treating various virus infectiones (including but not limited to HIV, Human papilloma virus HPV, simplexvirus, poxvirus, Epstein-Barr virus, Sendai virus and adenovirus).
Formula I compound also can be used for the chemoprophylaxis cancer.Chemoprophylaxis is defined as by stoping initial mutagenesis or stoping existing unusual precancerous cell to suppress developing of invasive cancer or suppress tumor recurrence.
Formula I compound also can be used for suppressing tumor vessel to be formed and shifts.
The compounds of this invention also can be with known anti-cancer therapies combined utilization (medication or sequentially drug using), and for example radiotherapy or cytostatics or cytotoxic drug are such as but not limited to DNA active medicine (for example cis-platinum or Zorubicin); Topoisomerase II inhibitor (for example Etoposide); Topoisomerase I inhibitor (for example CPT-11 or Hycamtin); Tubulin medicine (for example taxol, docetaxel or esperamicin); Hormonal medicaments (for example tamoxifen); Thymidylate synthase inhibitor (for example 5 FU 5 fluorouracil); Antimetabolite (for example methotrexate); Tyrosine kinase inhibitor (for example Iressa and OSI-774); Angiogenesis inhibitor; The EGF inhibitor; The VEGF inhibitor; The CDK inhibitor; The Her1/2 inhibitor; Direct monoclonal antibody (for example erbitux (EGF) and trastuzumab (Her2)) at growth factor receptors.
If be mixed with fixed dosage, this mixing prod can use The compounds of this invention and interior other active medicine or the therapy of approval dosage range in the following dosage range.In the time can not being mixed with mixed preparation, formula I compound also can with known anticancer drugs or the sequential application of cytotoxic drug.The present invention does not limit the medication order; Formula I compound can give before or after known anticancer drugs or the cytotoxic drug giving.
The medicine that the further theme of the present invention relates to and have such use (comprising control cancer, inflammation and sacroiliitis), wherein comprise formula I compound or at least a its pharmaceutically-acceptable acid addition of at least a above definition, and the formula I compound that relates to above definition has purposes in the anti-active medicine of aforementioned proliferative disease (comprising cancer, inflammation and/or sacroiliitis) in preparation.
The pharmacological property of The compounds of this invention can confirm by a large amount of pharmacological evaluations.Following exemplary pharmacological evaluation method has been used for The compounds of this invention and salt thereof.
The biological assessment method
A.CDK 2/ cyclin E kinases is analyzed
The kinase reaction thing comprises GST-CDK2/ cyclin E mixture, 0.5 μ g GST-RB fusion rotein (the amino acid 776-928 of retinoblastoma protein), the 0.2 μ Ci of 5ng baculovirus expression 3350 μ L kinase buffer liquid (50mMHepes, pH8.0, the 10mM MgCl of P γ-ATP, 25 μ mATP 2, 1mM EGTA, 2mM DTT).At 30 ℃ of incubation 45min, adding cold trichoroacetic acid(TCA) (TCA) to final concentration is 15% stopped reaction with reactant.Use the general harvesting device of Filtermate (Packard InstrumentCo., Meriden, CT) the TCA precipitation is collected in (Packard Instrument Co. on the GF/Cunifilter plate, Meriden, CT), (PackardInstrument Co., Meriden CT) counts filter membrane with TopCount 96-hole liquid scintillation counter.Draw dose response curve to determine to suppress 50% kinase activity desired concn (IC 50).Compound is dissolved in methyl-sulphoxide (DMSO) with the concentration of 10mM, estimates the compound of 6 kinds of concentration in triplicate.The ultimate density of DMSO is 2% in the evaluation.IC 50Value is obtained by nonlinear regression analysis, and its variation coefficient (SD/ mean value, n=6)=14%.
The B.EMT kinases is analyzed
The phosphorylation that detects Gst-SLP76 by Gst-Emtk is a kind of kinases analytical procedure based on filter membrane, and it is used for the inhibition activity of detection compound to EMT.Kinase reaction is carrying out 15min under room temperature on the 96-orifice plate, add 100 μ L20% trichoroacetic acid(TCA) (TCA) termination reactions that contain the 0.1M trisodium phosphate then.Kinase reaction mixture (60 μ l) comprises 25mMHEPES, pH7.0,0.1mg/ml BSA, 5mM MgCl 2, 5mM MnCl 2, 8ng enzyme (Gst-Emtk), 5 μ g substrate proteins (Gst-SLP76), 1 μ M ATP, 0.4 μ Ci[γ-P 33] ATP and test-compound (a plurality of concentration are arranged).Behind the reaction terminating, albumen precipitates 1h in 4 ℃ in the presence of TCA.The albumen (UniFilter-96, GF/C, Packard Instrument) that is settled out with the filter plate results washs and removes excessive [γ-P then 33] ATP.Add 35 μ LMicroscint 20 (Packard Instrument) back TopCount NXT (PackardInstrument) detection of radioactive.
The C.FAK Tyrosylprotein kinase is analyzed
Analyze focal adhesion kinase with synthetic polymer poly (Glu/Tyr) (Sigma Chemicals) as phosphate acceptors (phosphoacceptor) substrate.Each reaction mixture cumulative volume is 50 μ L, comprise enzyme, 2 μ g poly-(Glu/Tyr), 1 μ M ATP and the 0.2 μ Ci[γ of 100ng baculovirus expression- 33P] ATP.Reaction mixture also comprises 40mM Tris.HCl, pH7.4,1mMMnCl 2, 0.5mM DTT and 0.1mg/ml bovine serum albumin.Reaction mixture was 26 ℃ of incubations 1 hour, and the radiophosphorus phosphate content that is transferred to poly-(Glu/Tyr) substrate by detection by quantitative is determined kinase activity.The following detection of keying action: add cold trichoroacetic acid(TCA) (TCA) and be settled out albumen, with the general harvesting device of Filtermate precipitation is collected in (Packard Instrument Co. on the GF/C unifilter plate, Meriden, CT), filter membrane TopCount 96-hole liquid scintillation counter (Packard Instrument Co., Meriden CT) counts.It is 10mM that compound is dissolved in methyl-sulphoxide (DMSO) to concentration, estimates the compound of 6 kinds of concentration in triplicate.The DMSO ultimate density that adds kinase assays is 0.5%, and verified this concentration is to not influence of kinase activity.IC 50Value is obtained by nonlinear regression analysis, and its variation coefficient (SD/ mean value, n=6)=16%.
The D.HER-1/HER-2 kinases is analyzed
GST-HER1,100ngHER2, the 100ng/ml poly-(Glu/Tyr) that the kinase reaction thing comprises the 10ng baculovirus expression (Sigma), 50 μ l kinase buffer liquid (50mM Tris, pH7.5, the 10mM MnCl of 0.2 μ Ci33P γ-ATP, 1 μ M ATP 2, 0.5mMDTT).Reactant at 27 ℃ of incubation 1h, is added cold trichoroacetic acid(TCA) (TCA) to final concentration and is 15% with termination reaction.Use the general harvesting device of Filtermate (Packard Instrument Co., Meriden, CT) the TCA precipitation is collected in (Packard InstrumentCo. on the GF/Cunifilter plate, Meriden, CT), (PackardInstrument Co., Meriden CT) counts filter membrane with TopCount 96-hole liquid scintillation counter.Draw dose response curve to determine to suppress 50% kinase activity desired concn (IC 50).Compound is dissolved in methyl-sulphoxide (DMSO) with the concentration of 10mM, estimates the compound of 6 kinds of concentration in triplicate.The ultimate density of DMSO is 1% in the evaluation.IC 50Value is obtained by nonlinear regression analysis, and its variation coefficient (SD/ mean value, n=6)=16%.
The E.IGF-receptor tyrosine kinase is analyzed
Analyze the IGF-1 receptor tyrosine kinase with synthetic polymer poly (Glu/Tyr) (Sigma Chemicals) as the phosphate acceptors substrate.Each reaction mixture cumulative volume is 50 μ L, comprise enzyme, 2.5 μ g poly-(Glu/Tyr), 25 μ M ATP and the 0.1 μ Ci[γ of 125ng baculovirus expression- 33P] ATP.Reaction mixture also comprises 20mM MOPS, pH7.0,0.5mM MnCl 2, 0.5mM DTT and 0.1mg/ml bovine serum albumin.Reaction mixture was 30 ℃ of incubations 45 minutes, and the radiophosphorus phosphate content that is transferred to poly-(Glu/Tyr) substrate by detection by quantitative is determined kinase activity.The following detection of keying action: add cold trichoroacetic acid(TCA) (TCA) and be settled out albumen, with the general harvesting device of Filtermate precipitation is collected in (PackardInstrument Co. on the GF/Cunifilter plate, Meriden, CT), filter membrane TopCount 96-hole liquid scintillation counter (Packard Instrument Co., Meriden CT) counts.It is 10mM that compound is dissolved in methyl-sulphoxide to concentration, estimates the compound of 6 kinds of concentration in triplicate.Adding the DMSO ultimate density of estimating in the kinases is 0.5%, and verified this concentration is to not influence of kinase activity.IC 50Value is obtained by nonlinear regression analysis, and its variation coefficient (SD/ mean value, n=6)=16%.
F. insulin receptor tyrosine kinase analysis
Analyze insulin receptor tyrosine kinase with synthetic polymer poly (Glu/Tyr) (Sigma Chemicals) as phosphate acceptors (Phosphoacceptor) substrate.Each reaction mixture cumulative volume is 50 μ l, comprise enzyme, 2.5 μ g poly-(Glu/Tyr), 25 μ M ATP and the 0.1 μ Ci[γ of 90ng baculovirus expression- 33P] ATP.Reaction mixture also comprises 20mM Tris.HCl, pH7.4,5mM MnCl 2, 0.5mM DTT and 0.1mg/ml bovine serum albumin.Reaction mixture was 26 ℃ of incubations 1 hour, and the radiophosphorus phosphate content that is transferred to poly-(Glu/Tyr) substrate by detection by quantitative is determined kinase activity.The following detection of keying action: add cold trichoroacetic acid(TCA) (TCA) and be settled out albumen, with the general harvesting device of Filtermate precipitation is collected in (Packard Instrument Co. on the GF/Cunifilter plate, Meriden, CT), filter membrane TopCount 96-hole liquid scintillation counter (Packard Instrument Co., Meriden CT) counts.It is 10mM that compound is dissolved in methyl-sulphoxide to concentration, estimates the compound of 6 kinds of concentration in triplicate.The DMSO that estimates in the adding kinases is finally dense to become 0.5%, and verified this concentration is to not influence of kinase activity.IC 50Value is obtained by nonlinear regression analysis, and its variation coefficient (SD/ mean value, n=6)=16%.
The G.LCK kinases is analyzed
The kinase reaction thing comprise 10ng GST-Lck, the 100ng/ml of 10ng baculovirus expression poly-(Glu/Tyr) (Sigma), 50 μ l kinase buffer liquid (50mM Tris, pH7.5, the 10mM MnCl of 0.2 μ Ci33P γ-ATP, 1 μ M ATP 2, 0.5mM DTT).Reactant at 27 ℃ of incubation 1h, is added cold trichoroacetic acid(TCA) (TCA) to final concentration and is 15% with termination reaction.Use the general harvesting device of Filtermate (Packard Instrument Co., Meriden, CT) the TCA precipitation is collected in (Packard Instrument Co. on the GF/C unifilter plate, Meriden, CT), (PackardInstrument Co., Meriden CT) counts filter membrane with TopCount 96-hole liquid scintillation counter.Draw dose response curve to determine to suppress 50% kinase activity desired concn (IC 50).Compound is dissolved in methyl-sulphoxide (DMSO) with the concentration of 10mM, estimates the compound of 6 kinds of concentration in triplicate.The ultimate density of DMSO is 1% in the evaluation.IC 50Value is obtained by nonlinear regression analysis, and its variation coefficient (SD/ mean value, n=6)=16%.
The H.MET kinases is analyzed
The kinase reaction thing comprise GST-Met, the 2.5 μ g of 10ng baculovirus expression poly-(Glu/Tyr) (Sigma), 50 μ l kinase buffer liquid (40mM Tris, pH7.5, the 1mM MnCl of 0.2 μ Ci33P γ-ATP, 10 μ M ATP 2, 0.50mM DTT).Reactant at 27 ℃ of incubation 1h, is added cold trichoroacetic acid(TCA) (TCA) to final concentration and is 3.5% with termination reaction.
Use the general harvesting device of Filtermate (Packard Instrument Co., Meriden, CT) the TCA precipitation is collected in (Packard Instrument Co. on the GF/C unifilter plate, Meriden, CT), (Packard Instrument Co., Meriden CT) counts filter membrane with TopCount 96-hole liquid scintillation counter.Draw dose response curve to determine to suppress 50% kinase activity desired concn (IC 50).Compound is dissolved in methyl-sulphoxide (DMSO) with the concentration of 10mM, estimates the compound of 7 kinds of concentration in triplicate.The ultimate density of DMSO is 1% in the evaluation.IC 50Value is obtained by nonlinear regression analysis, and its variation coefficient (SD/ mean value, n=6)=16%.
The I.PDGF receptor kinase is analyzed
The GST-PDGFbR, 0.3 μ g biotinylization poly-(Glu/Tyr) that the kinase reaction thing comprises the 70ng baculovirus expression (Sigma) and 50 μ l kinase buffer liquid (20mMHepes, pH7.5,0.7 μ M ATP, 10mM MnCl 2, 0.5mM DTT, 0.15mM NaCl, 0.1mg/ml BSA).With reactant incubation 30 minutes under room temperature, jolting, add 10 μ l 0.2MEDTA, the PH8.0 termination reaction.Add 150 μ LHTRF and detect damping fluid, at room temperature incubation is 1.5 hours.Carry out quantitative counting with Discovery HTRF Packard Instrument.
The analysis of J.VEGFR-2 (KDR) kinases
The kinase reaction thing comprise GST-KDR, the 1.5 μ g of 7.5ng baculovirus expression poly-(Glu/Tyr) (Sigma), 50 μ l kinase buffer liquid (25mM Tris, pH7.5, the 1.8mM MnCl of 0.04 μ Ci 33P γ-ATP, 2.5 μ M ATP 2, 0.0.625mM DTT).Reactant at 27 ℃ of incubation 1h, is added cold trichoroacetic acid(TCA) (TCA) to final concentration and is 15% with termination reaction.Use the general harvesting device of Filtermate (Packard Instrument Co., Meriden, CT) the TCA precipitation is collected in (Packard Instrument Co. on the GF/C unifilter plate, Meriden, CT), (PackardInstrument Co., Meriden CT) counts filter membrane with TopCount 96-hole liquid scintillation counter.Draw dose response curve to determine to suppress 50% kinase activity desired concn (IC 50).Compound is dissolved in methyl-sulphoxide (DMSO) with the concentration of 10 mM, estimates the compound of 6 kinds of concentration in triplicate.The ultimate density of DMSO is 1% in the evaluation.IC 50Value is obtained by nonlinear regression analysis, and its variation coefficient (SD/ mean value, n=6)=16%.
K. cytotoxicity analysis (HT-29-colon cancer cell; Colo205, the MCF-7-breast cancer cell)
Tumour cell ties up in McCoy ' s 5A substratum (GIBCO) and the 10% heat-inactivated foetal calf serum (GIBCO) and cultivates.Vitro cytotoxicity evaluation in tumour cell is undertaken by the colorimetry based on tetrazolium, this method is utilized MTS, and (3-(4,5-dimethylthiazole-2-yl)-5-(3-carboxyl p-methoxy-phenyl)-2-(4-sulfophenyl (sulphenyl)-2H-tetrazolium inner salt) (Promega) metabolic conversion is the reduction form of absorption 492nm (1) light.Behind the inoculating cell 24h, add medicine.At 37 ℃ of test-compound incubations with serial dilution after 72 hours, with MTS (Riss, T.L etc., Comparison of MTT, XTT, and a novel tetrazolium compound MTSfor in vitro proliferation and chemosensitivity assays., " Mol.Biol.Cell 3 (Suppl.): 184a, 1992) and electron pair mixture phenazine methosulfate add in the cell.Continue incubation 3h, obtain cell survival quantity with spectrophotometer in the absorbancy of 492nm detection substratum then with respect to control group.Results expression is cytotoxicity concentration median (IC 50Value).
Table 1-biologic activity (μ M); All compounds are to kinase whose kinase activity below one or more＜25 μ M:CDK, EMT, FAK, Her1, Her2, IGF, IR, LCK, MET, PDGF, VEGF in the table.HT-29 and Colo205 are people's colon tumor cell system, and MCF-7 is people's breast tumor cell system.
Embodiment ???HT-29 ???MCF-7 ??Colo205
???1 ????1.0
???3 ????2.0
???399 ????0.4 ????0.8
???400 ????0.8 ????0.9
???411 ????0.7 ????0.9
???517 ????0.3
???519 ????0.3 ????0.6
???520 ????0.6 ????0.2
???521 ????0.5
???522 ????0.7 ????0.1 ????0.1
???523 ????0.6
???524 ????0.6
???525 ????1.1
??526 ???1.4
??527 ???1.3 ????0.1 ????0.3
??534 ???0.4
??538 ???0.9
??544 ???0.3 ????0.6
??553 ???0.9 ????0.3 ????0.2
??554 ???0.7 ????0.2 ????0.3
??555 ???0.2 ????0.1 ????0.2
??559 ???0.6 ????0.3
??574 ???0.2
??581 ???0.2 ????0.3
??582 ???0.1 ????0.2
??583 ???0.1 ????0.2
??584 ???0.3 ????0.2
??585 ???0.7 ????0.3
??590 ???0.8 ????0.2 ????0.2
??593 ???0.7
The general step of preparation 2-hydroxyl-2-(phenyl of replacement)-ethamine:
Figure A0281051600581
1-(3-chloro-phenyl)-2-nitro-ethanol:
3-chloro-phenyl aldehyde (20g, add in Nitromethane 99Min. 0.142mol) (100mL) solution sal epsom (37.6g, 0.312mol) and tertbutylimido-three (pyrrolidyl) phosphorane (4.43g, 0.014mol).Reaction mixture is at room temperature stirred 2h.Behind the vacuum concentration, resistates obtains yellow-green colour oily title compound (26.4g, 100%) with flash chromatography purification (25%EtOAc/ hexane). 1H NMR (300MHz, DMSO-d 6) δ 7.53 (1H, s), 7.35-7.42 (3H, m), 6.23 (1H, broad peak s), 5.32-5.33 (1H, m), 4.90 (1H, dd, J=3.2,12.4Hz), 4.60 (1H, dd, J=1.2,12.4Hz).
[1-(3-chloro-phenyl)-2-nitro-oxyethyl group]-triethyl-silane:
1-(3-chloro-phenyl)-2-nitro-ethanol (26 g, add in DMF 0.14mol) (50mL) solution imidazoles (28.6g, 0.42mol) and the chloro triethyl silicane (25.3g, 0.17mol).Reaction mixture is at room temperature stirred 2h.After the water quencher, the mixture ethyl acetate extraction.Dried over sodium sulfate is used in the organic layer water and the salt water washing that merge, filters.Except that after desolvating, crude product obtains colorless oil title compound (37g, 91%) with flash chromatography purification (2%EtOAc/ hexane). 1H?NMR(300MHz，CDCl 3)δ7.40(1H，s)，7.27-7.32(3H，m)，5.40(1H，dd，J＝3.2，9.5Hz)，4.51(1H，dd，J＝9.5，12.1Hz)，4.36(1H，dd，J＝3.3，12.1Hz)，0.85(9H，t，J＝7.5Hz)，0.54(6H，q，J＝7.5Hz)。
2-(3-chloro-phenyl)-2-triethylsilyl oxygen base-ethamine:
Methanol wash 3 times are used in Raney nickel (1g) distilled water wash 5 times.With [1-(3-chloro-phenyl)-2-nitro-oxyethyl group]-triethyl-silane (10g, 0.032mol) and methyl alcohol (100mL) solution hydrogenation at room temperature (35psi) 14h of Raney nickel.Reaction mixture filters by Celite pad, uses washed with methanol.Concentrated filtrate obtains colorless oil title compound (5.6g, 62%) to doing, and it is directly used in next step need not to purify again. 1H?NMR(300MHz，CDCl 3)δ7.32(1H，s)，7.18-7.26(3H，m)，4.70(1H，t，J＝5.8Hz)，2.86(2H，m)，0.89(9H，t，J＝7.9Hz)，0.56(6H，q，J＝7.8Hz)。LRMS(M+H) +m/z286。
The general step of preparation 2-hydroxyl-2-(phenyl of replacement)-ethamine:
4-methoxyl group-3-bromophenyl chloroacetophenone:
At 0 ℃, aluminum chloride (13.4g, add in methylene dichloride 0.10mol) (40mL) suspension 2-bromoanisole (12.5mL, 0.10mol) and chloroacetyl chloride (8mL, solution 0.10mol).Solution was risen to room temperature 2 hours, be poured on ice, use dichloromethane extraction,, use dried over mgso then with saturated sodium bicarbonate solution, salt water washing.Filtering solution concentrates, and obtains white solid 15.37g with alcohol crystal.LRMS[M-H]-260.8；IR(KBr)1697，1048，1255cm -1； 1H?NMR(300MHz，CDCl 3)δ8.18(s，1H)，7.94(dd，J＝8.67Hz，1H)，6.96(d，J＝8.67Hz，1H)，4.62(s，2H)，3.98(s，3H)； 13C?NMR(CDCl 3，75.5Hz)δ188.8，160.3，134.1，129.9，128.2，112.4，111.3，56.6，45.3。
The general step that chiral reduction chloro ketone and ammonia are separated:
Figure A0281051600602
(S)-1-[4-methoxyl group-3-bromophenyl]-ethylene chlorhydrin:
(S)-and methyl-CBS-oxazole borine (toluene solution of 1M, 0.745mL, 0.745mmol) and BH 3(8mL adds BH to-THF simultaneously in solution 8mmol) 3-THF solution (19mL, 19mmol) and above chloro ketone (10.03g, 19mL THF solution 37.98mmol).Two kinds of solution dropwised in 30 minutes.With solution stirring 1h, slowly add methyl alcohol (50mL) quencher reaction.Concentrated solution, resistates is handled the transparent oily chloropharin that (1: 1 hexane/ethyl acetate) obtains quantitative output (10.0g) with chromatography on short silicagel column.IR(KBr)1053，1258，3406cm -1； 1H?NMR(300MHz，CDCl 3)δ7.59(s，1H)，7.30(dd，J＝2.16Hz，1H)，6.90(d，J＝8.46Hz，1H)，4.83(dd，J＝3.57Hz，1H)，3.90(s，3H)，3.64(ddd，J＝3.6，11.1，8.7，2H)，2.04(bs，1H)。 13CNMR(CDCl 3，75.5?MHz)δ155.9，133.5，131.1，126.3，111.9，73.1，60.4，56.3，50.7。
Figure A0281051600611
(S) 2-amino-1-[3-chloro-4-p-methoxy-phenyl] the ethylate hydrochlorate:
At-40 ℃, (10.0g adds 100g ammonia in 120mL methanol solution 37.9mmol) to above chloropharin.Solution is packaged in the pressure flask, rises to room temperature, stirs 48h.With solution cooling and unlimited.Boil off ammonia, concentrated solution.Resistates obtains 3.83g white solid (35%) with ethanol/ethyl acetate crystallization.Product and Boc 2O reacts in ethyl acetate and saturated sodium bicarbonate, analyzes and judge with chirality HPLC (chirality OJ post, elutriant 95% hexane/ethanol) to reach till the 98%ee.Collect product-2.96g and the 1.41g that obtains, total recovery 75% once more.LRMS[M+H]+246；IR(cm -1，KBr)1055，1261，3001，2948，3356； 1H?NMR(500MHz，DMSO)δ8.09(bs，2H)，7.58(s，1H)，7.36(dd，J＝2.05，6.45Hz，1H)，7.11(d，J＝8.5Hz，1H)6.10(s，1H)，4.80(m，1H)，3.84(s，3H)，3.00(ddd，J＝2.7，12.6，9.5Hz，2H)； 13C?NMR(DMSO，75.5MHz)δ154.8，135.4，130.4，126.6，112.4，110.4，67.9，56.2，45.4。
Figure A0281051600612
(S) 2-amino-1-[3-chloro-phenyl-] the ethylate hydrochlorate is according to the preparation of above-mentioned general step.LRMS[M+H]+172；IR(KBr，cm -1)3048，3351，2952； 1H?NMR(300MHz，MeOD)δ?7.48(s，1H)，7.35(m，3H)，3.31(ddd，J＝1.5，3.12，9.15Hz?2H)。
Figure A0281051600613
(S)-and 2-amino-1-[3-bromophenyl] the ethylate hydrochlorate is according to the preparation of above-mentioned general step.LRMS?[MH]+217.9；IR(KBr，cm -1)3025，3443，2891； 1H?NMR(50MHz，DMSO)δ7.93(bs，2H)，7.60(s，1H)，7.52(d，1H)，7.41(s，1H)，7.35(d，J＝7.7Hz，1H)，6.17(s，1H)，4.82(m，1H)，3.08(ddd，J＝2.6，12.7，9.6Hz，2H)； 13C?NMR(DMSO，75.5MHz)δ144.4，130.5，128.7，125.0，121.6，68.3，45.1。
Figure A0281051600621
(S)-and 2-amino-1-[3-chloro-4-methylthio group phenyl] the ethylate hydrochlorate is according to the preparation of above-mentioned general step.LRMS[M+H]+217.9；IR(KBr，cm -1)3007，3358； 1H?NMR(500MHz，DMSO)δ8.12(bs，2H)，7.46(s，1H)，7.37(s，1H)，7.35(d，1H)6.19(d，1H)，4.83(m，1H)，3.01(ddd，J＝3.2，12.8，9.3Hz，2H)； 13C?NMR?(DMSO，75.5MHz)δ139.6，136.5，129..8，126.6，125.4，68.0，45.2，14.2。
Figure A0281051600622
(S)-and 2-amino-1-[3-chloro-4-fluoro-phenyl] the ethylate hydrochlorate is according to the preparation of above-mentioned general step.LRMS[M+H]+189.9；IR(KBr，cm -1)1509，3008，3359； 1H?NMR(500MHz，DMSO)δ8.21(bs，2H)，7.61(d，J＝7.85Hz，1H)，7.42(m，2H)，6.29(s，1H)，4.88(m，1H)，3.03(ddd，J＝3.4，12.8，9.2Hz，2H)； 13C?NMR(DMSO，75.5MHz)δ157.5，155.5，139.7，128.1，126.7，119.3，116.7，109.0，67.8，45.2。
(S)-and 2-amino-1[3-chloro-4-p-methoxy-phenyl] the ethylate hydrochlorate is according to the preparation of above-mentioned general step.LRMS[M+H]+202; IR (KBr, cm -1) 3354,3003,2949,1288,1064; 1H NMR (500MHz, DMSO) δ 8.18 (brs, 3H), 7.43 (d, J=2.0Hz, 1H), 7.31 (dd, J=8.5,2.0Hz, 1H), 7.14 (d, J=5.1Hz, 1H), 6.11 (s, 1H), 4.81 (m, 1H), 3.84 (s, 3H), 2.99 (dd, J=13,3.5Hz, 1H), 2.83 (dd, J=12.5,9Hz, 1H); 13C NMR (DMSO, 125MHz) δ 153.9,135.0, and 127.3,125.8,120.8,112.6,68.0,56.1,45.5; C 9H 12ClNO 2The ultimate analysis calculated value of-HCl: C, 45.39; H, 5.50; N, 5.88.Measured value: C, 45.38; H, 5.43; N, 5.70.
Figure A0281051600631
(S)-2-amino-1-(7-bromo-2,3-Dihydrobenzofuranes-5-yl)-2-monoethanolamine hydrochloride is according to the preparation of above-mentioned general step.LRMS[M+H]+258; IR (KBr, cm -1) 3349,3006,2928,1485,1045,983; 1H NMR (500MHz, DMSO) δ 8.13 (brs, 3H), 7.29 (s, 1H), 7.23 (s, 1H), 6.08 (d, J=4Hz, 1H), 4.76 (m, 1H), 4.61 (t, J=9Hz, 2H), 3.29 (t, J=9Hz, 2H), 2.96 (dd, J=13,3.5Hz, 1H), 2.82 (dd, J=13,9.5Hz, 1H); 13C NMR (DMSO, 125MHz) δ 156.3,135.9, and 129.1,128.1,122.1,100.9,71.5,68.2,45.6,29.9; C 10H 12BrNO 2The ultimate analysis calculated value of-HCl: C, 40.77; H, 4.44; N, 4.75.
Measured value: C, 40.77; H, 4.63; N, 4.63.
The general step of preparation 2-amino-3-(replacement-phenyl)-propyl alcohol:
Figure A0281051600632
(S)-[2-(3-bromo-phenyl)-1-methylol-ethyl]-t-butyl carbamate:
(S)-3-(3-bromo-phenyl)-2-tert-butoxycarbonyl amino-propionic acid (500mg, add in THF 1.45mmol) (30mL) solution borine-tetrahydrofuran complex (1.0M solution) (4.35mL, 4.35mmol).Reaction mixture is at room temperature stirred 14h, with acetate (1mL) quencher.After removing most of solvent, resistates extracts with EtOAc, uses the salt water washing, uses dried over sodium sulfate.After concentrating, crude product (400mg, 83%) is directly used in next step and need not to purify again.LCMS(M+H)+m/z?330(t＝1.61min)
Figure A0281051600641
(S)-2-amino-3-(3-bromo-phenyl)-third-1-alcohol:
(S)-(400mg adds 4M HCl De dioxane solution (2mL, excessive) to [2-(3-bromo-phenyl)-1-methylol-ethyl]-t-butyl carbamate in methyl alcohol 1.21mmol) (30mL) solution.Reaction mixture is at room temperature stirred 14h.Behind the vacuum concentration, resistates is directly used in next step need not to purify again.LCMS(M+H) +m/z?230(t＝0.78min)
5-chloracetyl-7-chloro-indole ketone:
(13.4g adds 7-chloro-indole ketone (0.10mol) and chloroacetyl chloride (8mL, 0.10mol) solution in methylene dichloride 0.10mol) (40mL) suspension to aluminum chloride at 0 ℃.Solution is risen to room temperature 2h, be poured on ice, use dichloromethane extraction,, will obtain required chloro ketone with dried over mgso with saturated sodium bicarbonate solution, salt water washing.
Figure A0281051600643
(S)-7-chloro-5-(2-chloro-1-hydroxyl-ethyl)-2-oxindole:
(S)-and methyl-CBS-oxazole borine (the 1M toluene solution, 0.745mL, 0.745mmol) and BH 3(8mL adds BH to-THF simultaneously in solution 8mmol) 3-THF solution (19mL, 19mmol) and the 19mL THF solution of 5-chloracetyl-7-chloro-indole ketone (37.98mmol).Two kinds of solution all added in 30 minutes.With solution stirring 1h, slowly add methyl alcohol (50mL) quencher.Concentrated solution, resistates is by short silica gel column chromatography purification (1: 1 hexane/ethyl acetate).
(S)-2-amino-L-(7-chloro-indole ketone-5-yl)-ethylate hydrochlorate:
At-40 ℃, in the 120mL methanol solution of above chloropharin (37.9mmol), add 100g ammonia.Solution is encapsulated in the pressure flask and rises to room temperature, stirs 48h.Solution cooling back is opened wide.Boil off ammonia, concentrated solution obtains hydrochloride, it can be used ethanol/ethyl acetate crystallization.
Figure A0281051600652
6-chloracetyl-4-chloro-2-benzoxazolone:
At 0 ℃, (13.4g adds 4-chloro-2-benzoxazolone (0.10mol) and chloroacetyl chloride (8mL, solution 0.10mol) in methylene dichloride 0.10mol) (40mL) suspension to aluminum chloride.Solution is risen to room temperature 2h, be poured on ice, use dichloromethane extraction,, will obtain required chloro ketone with dried over mgso with saturated sodium bicarbonate solution, salt water washing.
(S)-6-(2-chloro-1-hydroxyl-ethyl)-4-chloro-2-benzoxazolone:
(S)-and methyl-CBS-oxazole borine (toluene solution of 1M, 0.745mL, 0.745mmol) and BH 3(8mL adds BH to-THF simultaneously in solution 8mmol) 3-THF solution (19mL, 19mmol) and the 19mL THF solution of 6-chloracetyl-4-chloro-2-benzoxazolone (37.98mmol).Two kinds of solution all dropwised in 30 minutes.With solution stirring 1h, slowly add methyl alcohol (50mL) quencher.Concentrated solution, resistates is by short silica gel column chromatography purification (1: 1 hexane/ethyl acetate).
(S)-2-amino-1-(4-chloro-2--benzoxazolone-6-yl)-ethylate hydrochlorate:
At-40 ℃, add 100g ammonia in the 120mL methanol solution of above chloropharin (37.9mmol).Solution is encapsulated in the pressure flask and rises to room temperature, stirs 48h.Solution cooling back is opened wide.Boil off ammonia, concentrated solution obtains hydrochloride, it can be used ethanol/ethyl acetate crystallization.
Figure A0281051600662
N-methyl-7-chlorine indoline:
In the 500mL acetone soln of 7-chlorine indoline (0.10mol), add K 2CO 3(0.15mol) and MeI (0.15mol), be back to initial feed and exhaust.Water and saturated sodium bicarbonate solution washing behind the filtering reaction thing obtains N-Me-7-chlorine indoline with dried over mgso.
N-methyl-5-chloro ethanoyl-7-chloro-indoline:
At 0 ℃, aluminum chloride (13.4g, and adding solution N-Me-7-chlorine indoline (0.10mol) and chloroacetyl chloride in methylene dichloride 0.10mol) (40mL) suspension (8mL, 0.10mol).Solution is risen to room temperature 2h, be poured on ice, use dichloromethane extraction,, obtain required chloro ketone with dried over mgso with saturated sodium bicarbonate solution, salt water washing.
Figure A0281051600671
(S)-N-methyl-5-(2-chloro-1-hydroxyethyl)-7-chloro-indoline:
(S)-and methyl-CBS-oxazole borine (toluene solution of 1M, 0.745mL, 0.745mmol) and BH 3(8mL adds BH to-THF simultaneously in solution 8mmol) 3-THF solution (19mL, 19mmol) and the 19mLTHF solution of N-methyl-5-chloro ethanoyl-7-chloro-indoline (37.98mmol).Two kinds of solution all dropwised in 30 minutes.With solution stirring 1h, slowly add methyl alcohol (50mL) quencher.Concentrated solution, resistates is by short silica gel column chromatography purification (1: 1 hexane/ethyl acetate).
Figure A0281051600672
(S)-2-amino-1-(7-chloro-N-methyl-indoline-5-yl)-ethylate hydrochlorate:
At-40 ℃, add 100g ammonia in the 120mL methanol solution of above chloropharin (37.9mmol).Solution is encapsulated in the pressure flask and rises to room temperature, stirs 48h.Solution cooling back is opened wide.Boil off ammonia, concentrated solution obtains hydrochloride, it can be used ethanol/ethyl acetate crystallization.
Figure A0281051600673
(S)-2-chloro-1-(7-chloro-N-methyl-indoles-5-yl)-ethanol:
(S)-the N-methyl-[the 100mL t-butyl methyl ether solution of 5-(2-chloro-1-hydroxyethyl)-7-chloro-indoline (0.10mmol) at room temperature uses adjacent tetrachlorobenzoquinone (0.10mmol) to handle.Concentrated solution, resistates obtains corresponding indoles with silica gel chromatography purification (1: 1 hexane/ethyl acetate).
(S)-2-amino-1-(7-chloro-N-methyl-indoles-5-yl)-ethylate hydrochlorate:
At-40 ℃, add 100g ammonia in the 120mL methanol solution of above chloropharin (37.9mmol).Solution is encapsulated in the pressure flask and rises to room temperature, stirs 48 h.Solution cooling back is opened wide.Boil off ammonia, concentrated solution obtains hydrochloride, it can be used ethanol/ethyl acetate crystallization.
Figure A0281051600682
4-chloro-2-methyl-benzoxazoles:
The 100mL aqueous solution that adds LiOH (0.20mol) in the 200mL ethanolic soln of 4-chloro-2-benzoxazolone (0.10mol).Reflux solution 8h, cooling then.Solution is used ethyl acetate extraction with 1N HCl neutralization, then uses dried over mgso.Concentrated solution is dissolved in 200mL toluene and 0.10mol acetate then.The solution 12h that refluxes in Dean Stark trap concentrates the back and purifies with flash chromatography.
Figure A0281051600683
6-chloracetyl-4-chloro-2-methyl-benzoxazoles:
At 0 ℃, (13.4g adds 2-methyl-4-chloro-benzoxazole (0.10mol) and chloroacetyl chloride (8mL, solution 0.10mol) to aluminum chloride in methylene dichloride 0.10mol) (40mL) suspension.Solution is risen to room temperature 2h, be poured on ice, use dichloromethane extraction,, will obtain required chloro ketone with dried over mgso with saturated sodium bicarbonate solution, salt water washing.
Figure A0281051600691
(S)-6-(2-chloro-1-hydroxyl-ethyl)-4-chloro-2-methyl-benzoxazoles:
(S)-and methyl-CBS-oxazole borine (toluene solution of 1M, 0.745mL, 0.745mmol) and BH 3(8mL adds BH to-THF simultaneously in solution 8mmol) 3-THF solution (19mL, 19mmol) and the 19mLTHF solution of 6-chloracetyl-4-chloro-2-methyl-benzoxazoles (37.98mmol).Two kinds of solution all dropwised in 30 minutes.With solution stirring 1h, slowly add methyl alcohol (50mL) quencher.Concentrated solution, resistates is by short silica gel column chromatography purification (1: 1 hexane/ethyl acetate).
(S)-2-amino-1-(4-chloro-2-methyl-benzoxazole-6-yl)-ethylate hydrochlorate:
At-40 ℃, add 100g ammonia in the 120mL methanol solution of above chloropharin (37.9mmol).Solution is encapsulated in the pressure flask and rises to room temperature, stirs 48h.Solution cooling back is opened wide.Boil off ammonia, concentrated solution obtains hydrochloride, it can be used ethanol/ethyl acetate crystallization.
Preparation 3-(6-imidazoles-1-base-4-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl)-4-iodo-1H-pyridin-2-ones:
Figure A0281051600693
1-(3-methyl-4-nitro-phenyl)-1H-imidazoles:
4-fluoro-2-methyl isophthalic acid-nitro-benzene (300mg, add in DMSO 1.84mmol) (2mL) solution KOH (20mg, 3.87mmol) and imidazoles (263mg, 3.88mmol).Reaction mixture is heated to 100 ℃ of 3.5h, is cooled to room temperature, dilute with ice cold water then.Leach the gained precipitation, with the ice cold water washing, then vacuum obtains yellow powdery title compound (310mg, 80%). 1H?NMR(300MHz，DMSO-d 6)δ8.46(1H，s)，8.16(1H，d，J＝8.9Hz)，7.90-7.92(2H，m)，7.78(1H，dd，J＝2.5，8.9Hz)，7.17(1H，s)，2.61(3H，s)。LRMS(M+H) +m/z?204。
Figure A0281051600701
4-imidazoles-1-base-2-methyl-aniline:
(200mg 0.98mmol) carries the methyl alcohol (3mL) that adds in the palladium (35mg) through the degassing with 10% carbon to 1-(3-methyl-4-nitro-phenyl)-1H-imidazoles.Suspension is inflated in proper order with emptying with hydrogen/vacuum and is operated.Suspension is stirring 14h (hydrogen jar) under nitrogen atmosphere, room temperature.The black reaction mixture filters by Celite pad, uses washed with methanol.Concentrated filtrate obtains title compound (166mg, 98%), it is directly used in next step need not to purify again. 1H NMR (300MHz, DMSO-d 6) δ 7.95 (1H, s), 7.48 (1H, s), 7.16 (1H, narrow peak d, J=2.5Hz), 7.09 (1H, dd, J=2.5,8.4Hz), 7.01 (1H, s), 6.67 (1H, d, J=8.4Hz), 5.03 (2H, broad peak s), 2,10 (3H, s).
N-(4-imidazoles-1-base-2-methyl-6-nitro-phenyl)-ethanamide:
At 0 ℃, (1g adds Ac in methylene dichloride 5.78mmol) (20mL) solution to 4-imidazoles-1-base-2-methyl-aniline 2O (0.7mL, 7.28mmol).Reaction mixture at room temperature stirs 14h, dilute with water.The water layer dichloromethane extraction, the organic layer of merging is used dried over sodium sulfate with saturated sodium bicarbonate and salt water washing, and vacuum concentration obtains white solid then.White solid is suspended in (15mL) in the vitriol oil.At 0 ℃ concentrated nitric acid (0.312mL) is added in the suspension.Reaction mixture is slowly risen to room temperature, at room temperature stir 4h.After being cooled to-10 ℃, reaction mixture neutralizes with ammonium hydroxide, uses ethyl acetate extraction.Dried over sodium sulfate is used in the organic layer salt water washing that merges, and concentrates then.Resistates was purified (1: 9: the 5MeOH/THF/ hexane) obtain title compound (0.61g, 41%) with flash chromatography. 1H?NMR(300MHz，CD 3OD)δ8.11(1H，s)，7.45-7.56(2H，m)，7.38(1H，dd，J＝2.4，8.4Hz)，7.14(1H，s)，2.33(3H，s)，2.18(3H，s)。
4-imidazoles-1-base-2-methyl-6-nitro-aniline:
(279mg adds 2N HCl (2mL) to N-(4-imidazoles-1-base-2-methyl-6-nitro-phenyl)-ethanamide in ethanol 1.07mmol) (3mL) suspension.Reaction mixture is heated to backflow 14h, is cooled to room temperature, neutralize with saturated sodium bicarbonate then.Leach gained bright orange solid, then vacuum-drying.Obtain orange solids title compound (179mg, 76%). 1HNMR(300MHz，CD 3OD)δ8.78(1H，s)，8.24(1H，s)，7.78(1H，s)，7.64(1H，s)，7.46(1H，s)，2.36(3H，s)。
Figure A0281051600712
5-imidazoles-1-base-3-methyl-benzene-1, the 2-diamines:
(350mg 1.61mmol) carries methyl alcohol (5mL) and the TFA (5) that adds in the palladium (40mg) through the degassing with 10% carbon to 4-imidazoles-1-base-2-methyl-6-nitro-aniline.Reaction mixture is inflated and the emptying operation in proper order with hydrogen/vacuum, stirs 14h (hydrogen jar) under nitrogen atmosphere, room temperature.The black reaction mixture filters by Celite pad, uses washed with methanol.Concentrated filtrate obtains resistates, with its dilute with water, uses ethyl acetate extraction.The organic layer that merges is used dried over sodium sulfate with saturated sodium bicarbonate, salt water washing.Be concentrated into to do and obtain solid title compound (275mg, 91%). 1H?NMR(300MHz，CD 3OD)δ7.87(1H，s)，7.34(1H，s)，7.05(1H，s)，6.72(1H，d，J＝2.4Hz)，6.65(1H，d，J＝2.4Hz)2.21(3H，s)。LCMS(M+H) +m/z?189(t＝0.23min)。
4-iodo-2-methoxyl group-pyridine-3-formaldehyde (WO95/29917):
5 liters three neck round-bottomed flasks dispose a unsettled mechanical stirrer under nitrogen atmosphere, the THF (1L) that packs in the flask is cooled to-78 ℃ then.-78 ℃ add in sleeve pipe solution under agitation tert-butyl lithium (pentane solution of 1.7M) (800mL, 1.36mol), then add the 2-methoxypyridine (132.2g, 1.21mol).Mixture stirs 1h at-78 ℃.In mixture, drip N-formyl radical-N at-78 ℃, N ', N '-trimethylammonium quadrol (176mL, 1.37mol).Reaction mixture at-78 ℃ of stir about 30min, is risen to-23 ℃ of stir about 30min then.In mixture, add glycol dimethyl ether (1L) at-23 ℃, then add n-Butyl Lithium (hexane solution of 2.5M) (800mL, 2.0mol).With gained mixture stir about 2h, reaction mixture becomes deep green during this period.Packing in 12-L4 neck round-bottomed flask, (571g, 2.25mol) and glycol dimethyl ether (2L), gained solution is cooled to-78 ℃ to iodine.By sleeve pipe the inclusion of 5-L flask is transferred to iodine and glycol dinitrate ether mixture in the 12-L flask at-78 ℃.Add finish after, at-78 ℃ with reaction mixture restir 1h.Remove cooling bath, mixture is risen to about 0 ℃, use 2L water and the acid treatment of 2L1N salt then.Add methyl tertiary butyl ether (2L), isolate each layer.Water layer extracts with 2 * 1L methyl tertiary butyl ether.The saturated Na of organic layer that merges 2S 2O 3(1.2L), salt solution (1.2L) washing, use dried over sodium sulfate.Behind the vacuum concentration, thick soup compound dilutes with hexane (1L).Mixture cools off about 30min with ice/water-bath.Leach post precipitation vacuum-drying and obtain the faint yellow solid title compound. 1H?NMR(300MHz，CDCl 3)δ10.22(s，1H)，7.86(1H，d，J＝5.3Hz)，7.54(1H，d，J＝5.3Hz)，4.06(3H，s)。LCMS(M+H) +m/z?364(t＝2.26min)。
6-imidazoles-1-base-2-(4-iodo-2-methoxyl group-pyridin-3-yl)-4-methyl isophthalic acid H-benzoglyoxaline:
At 0 ℃, 5-imidazoles-1-base-3-methyl-benzene-1, (175mg adds 4-iodo-2-methoxyl group-pyridine-3-formaldehyde (245mg, methyl alcohol 0.93mmol) (5mL) solution to the 2-diamines in methyl alcohol 0.93mmol) (8mL) solution.Reaction mixture stirs 1.5h at 0 ℃, at room temperature stirs 2h then.After concentrating, resistates is with the flash column chromatography (10%MeOH/CH that purifies 2Cl 2) acquisition title compound (291mg, 60%). 1H?NMR(300MHz，CD 3OD)δ8.13(1H，s)，7.98(1H，d，J＝5.4Hz)，7.62(1H，d，J＝5.4Hz)，7.59(2H，s)，7.33(1H，s)，7.16(1H，s)，3.90(3H，s)，2.67(3H，s)。LCMS(M+H) +m/z?432(t＝0.99min)。
Figure A0281051600731
3-(6-imidazoles-1-base-4-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl)-4-iodo-1H-pyridin-2-ones:
With 1N HCl (6mL) suspension of 6-imidazoles-1-base-2-(4-iodo-2-methoxyl group-pyridin-3-yl)-4-methyl isophthalic acid H-benzoglyoxaline be heated to 70 ℃ 3 days, be cooled to room temperature, dilute with ethyl acetate then.After the extraction, the salt water washing of the organic layer of merging concentrates then with dried over sodium sulfate.Resistates is with the flash chromatography (1%NH that purifies 4OH/10%MeOH/CH 2Cl 2) acquisition solid title compound (78mg, 81%). 1H?NMR(300MHz，CD 3OD)δ8.12(1H，s)，7.58(2H，s)，7.29-7.31(2H，m)，7.16(1H，s)，7.01(1H，J＝6.8Hz)，2.66(3H，s)。LCMS(M+H) +m/z?418(t＝0.75min)
Preparation 2-(4-chloro-2-oxo-1,2-dihydro-pyridin-3-yl)-7-methyl-3H-benzoglyoxaline-5-formonitrile HCN:
Figure A0281051600732
4-amino-3-methyl-cyanobenzene:
3-methyl-4-nitro-cyanobenzene (20g, add in HOAc 0.123mol) (200mL) solution iron powder (17.55g, 0.309mol).Behind the 10min, the reactant heat release also becomes black.Reaction mixture is at room temperature stirred 14h, use EtOAc (200mL) dilution then.The brown precipitation is filtered by Celite pad, and filter cake washes with EtOAc.Vacuum concentrated filtrate, resistates obtains title compound (15.3g, 92%) with flash chromatography purification (40%EtOAc/ hexane). 1H?NMR(300MHz，CDCl 3)δ7.30-7.34(2H，m)，6.64(1H，d，J＝8.7Hz)，2.16(3H，s)。LCMS(M+H) +m/z?133(t＝0.93min)。
Figure A0281051600741
N-(4-cyano group-2-methyl-6-nitro-phenyl)-2,2,2-three fluoro-ethanamides:
Disposable adding 4-amino-3-methyl-cyanobenzene in the ice-cold trifluoro-acetic anhydride (60mL) (14.33g, 0.108mol).Stir gained white soup compound 30min at 0 ℃.Add then ammonium nitrate (17.28g, 0.216mol).At 0 ℃ of stirred reaction mixture 1h, at room temperature stir 14h.After removing most of solvent, reaction mixture is with ice-cooled, and with the ice quencher.Leach yellow mercury oxide, use cold water washing, then vacuum-drying.Crude product (15.5g, 52% yield, about 80% purity) is directly used in next step and need not to purify again. 1H?NMR(300MHz，CD 3OD)δ8.05(1H，s)，7.74(1H，s)，2.30(3H，s)。LRMS(neg.ESI，(M-H)-)m/z?272。
Figure A0281051600742
4-amino-3-methyl-5-nitro-cyanobenzene:
With N-(4-cyano group-2-methyl-6-nitro-phenyl)-2,2,2-three fluoro-ethanamides (5g, 18.3mmol) and the mixture heating up of the methyl alcohol of 2M ammonia (80mL) to the 14h that refluxes, be cooled to room temperature then.Behind the vacuum concentration, resistates obtains title compound (3.24g, 100%, about 80% purity) with flash chromatography purification (20% EtOAc/ hexane). 1H NMR (300MHz, CDCl 3) δ 8.40 (1H, s), 7.47 (1H, s), 6.6-6.8 (2H, broad peak s), 2.89 (3H, s).
Figure A0281051600743
3,4-diamino-5-methyl-cyanobenzene:
4-amino-3-methyl-5-nitro-cyanobenzene (3.24g, and adding tin chloride dihydrate in ethanol 18.3mmol) (80mL) solution (8.67g, 49.75mmol).Reaction mixture is heated to backflow 14h, is cooled to room temperature then, again vacuum concentration.Resistates is handled with triethylamine (20nL) with ethyl acetate (100mL) dilution.The gained soup compound filters by Celite pad, and filter cake washes three times with ethyl acetate (50mL).Filtrate is used dried over sodium sulfate then with saturated sodium bicarbonate, water and salt water washing, refilters.Except that after desolvating, resistates obtains faint yellow solid title compound (2.17g, 81%) with flash chromatography on silica gel method purification (30%-50%EtOAc/ hexane). 1H?NMR(300?MHz，CDCl 3)δ6.94(1H，s)，6.85(1H，s)，2.16(3H，s)。LCMS(M+H) +m/z?148(t＝0.67min)。
2-(4-iodo-2-methoxyl group-pyridin-3-yl)-7-methyl-3H-benzoglyoxaline-5-formonitrile HCN:
At 0 ℃, 3, (2.00g adds 4-iodo-2-methoxyl group-pyridine-3-formaldehyde (3.6g, MeOH 13.6mmol) (20mL) solution to 4-diamino-5-methyl-cyanobenzene in MeOH 13.6mmol) (40mL) solution.The gained soup compound stirs 1h at 0 ℃.At 0 ℃, (1.73g, MeOH 8.8mmol) (10mL) solution is added drop-wise in the reaction mixture with dropping funnel with iodine.Reaction mixture is at room temperature stirred 14h.After removing MeOH, the saturated Na of resistates 2S 2O 3Dilution extracts with EtOAc.Dried over sodium sulfate is used in the organic layer water and the salt water washing that merge.Crude product is with the flash column chromatography (3%MeOH/CH that purifies 2Cl 2) acquisition title compound (1.81g, 46%). 1H?NMR(300MHz，CDCl 3)δ7.90(1H，s)，7.49(1H，d，J＝5.4Hz)，7.46(1H，s)，7.41(1H，d，J＝5.3Hz)，3.78(3H，s)，2.68(3H，s)。LCMS(M+H) +m/z?391(t＝1.27min)。
2-(4-chloro-2-oxo-12-dihydro-pyridin-3-yl)-7-methyl-3H-benzoglyoxaline-5-formonitrile HCN:
(1.8g, 4M HCl diox (40mL) suspension 4.63mmol) is heated to 80 ℃ of 6h, is cooled to room temperature then with 2-(4-iodo-2-methoxyl group-pyridin-3-yl)-7-methyl-3H-benzoglyoxaline-5-formonitrile HCN.Leach the post precipitation drying.Crude product (1.08g, 82%) is directly used in next step and need not to purify again.LRMS(neg.ESI，(M-H) -)m/z?283。
Preparation (S)-4-(1-benzyl-2-trityl oxygen base-ethylamino)-3-(6-bromo-4-methyl isophthalic acid H-benzo Imidazoles-2-yl)-the 1H-pyridin-2-ones:
5-bromo-3-methyl-benzene-1, the 2-diamines:
4-bromo-2-methyl-6-nitro-aniline (20g, and adding tin chloride dihydrate in ethanol 0.086mol) (200mL) suspension (49.2g, 0.258mol).Reaction mixture is heated to backflow 14h, is cooled to room temperature, then vacuum concentration.Resistates is handled with triethylamine (40mL) with ethyl acetate (150mL) dilution.The gained soup compound filters by Celite pad, and filter cake washes with three parts of ethyl acetate (50mL).Filtrate is used the dried over sodium sulfate after-filtration with saturated sodium bicarbonate, water and salt water washing.Except that after desolvating, resistates is purified with the flash chromatography on silica gel method, and (the 30%EtOAc/ hexane is used 5%MeOH/CH then 2Cl 2) acquisition yellow oily title compound (10.26g, 59%). 1H?NMR(300MHz，CDCl 3)δ6.77(1H，d，J＝2.0Hz)，6.74(1H，d，J＝2.0Hz)，2.16(3H，s)。LCMS(M+H) +m/z201。(t＝0.83min)。
6-bromo-2-(4-iodo-2-methoxyl group-pyridin-3-yl)-4-methyl isophthalic acid H-benzoglyoxaline:
At 0 ℃, 5-bromo-3-methyl isophthalic acid, (4g drips 4-iodo-2-methoxyl group-pyridine-3-formaldehyde (5.23g, methyl alcohol 19.9mmol) (20mL) solution to the 2-phenylenediamine in methyl alcohol 19.9mmol) (80mL) solution.The gained soup compound at room temperature stirred 30 minutes.Add iodine (2.53g, methyl alcohol 9.95mmol) (20mL) solution by dropping funnel then.Behind 14h, the vacuum concentration reaction mixture is used 5%Na 2S 2O 3Ethyl acetate extraction is used in dilution.Dried over sodium sulfate is used in the organic layer water, the salt water washing that merge.Except that after desolvating, carefully resistates is handled (20%EtOAc/ hexane) with flash chromatography and obtain yellow spumescence title compound (4.05g, 46%). 1H NMR (300 MHz, CDCl 3) δ 7.86 (1H, d, J=5.31Hz), 7.53 (1H, d, J=5.3Hz), 7.26 (2H, broad peak s), 3.91 (3H, s), 2.63 (3H, s).LCMS(M+H) +m/z?444(t＝1.39min)。
3-(6-bromo-4-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl)-4-chloro-1H-pyridin-2-ones:
(4g 9.03mmol) He in the 60mL 4M HCl De diox suspension is heated to 80 ℃ of 6h to 6-bromo-2-(4-iodo-2-methoxyl group-pyridin-3-yl)-4-methyl isophthalic acid H-benzoglyoxaline, is cooled to room temperature then.Leach the dry brown powder shape title compound (3.0g, 100%) that obtains of post precipitation.Crude product is directly used in next step and need not to purify again. 1H?NMR(300MHz，CD 3OD)δ7.55(1H，s)，7.42(1H，d，J＝6.0Hz)，7.17(1H，s)，6.91(1H，d，J＝6.0Hz)，2.55(3H，s)。LCMS(M+H) +m/z?338(t＝1.33min)。
Figure A0281051600772
(S)-4-(1-benzyl-2-hydroxyl-ethylamino)-3-(6-bromo-4-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl)-the 1H-pyridin-2-ones:
3-(6-bromo-4-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl)-4-chloro-1H-pyridin-2-ones (1.42g, add in DMF 3.78mmol) (15mL) solution (S)-(-)-2-amino-3-phenyl-1-propyl alcohol (1.43g, 9.45mmol) and N-methylmorpholine (1.5mL).Reaction mixture is heated to 80 ℃ of 6h, is cooled to room temperature then.High vacuum is removed and to be desolvated, and resistates is with the flash chromatography (5%MeOH/CH that purifies 2Cl 2) acquisition yellow spumescence title compound (1.26g, 74%). 1HNMR(300MHz，CDCl 3)δ6.9-7.2(8H，m)，5.86(1H，d，J＝7.1Hz)，3.7-3.9(3H，m)，2.9-3.1(2H，m)，2.57(3H，s)。LCMS(M+H) +m/z?453(t＝2.03min)。
Figure A0281051600781
(S)-4-(1-benzyl-2-trityl oxygen base-ethylamino)-3-(6-bromo-4-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl)-the 1H-pyridin-2-ones:
(S)-and 4-(1-benzyl-2-hydroxyl-ethylamino)-3-(6-bromo-4-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl)-(0.9g adds Cs in THF 1.98mmol) (30mL) solution to the 1H-pyridin-2-ones 2CO 3(1.29g, 3.96mmol), then add trityl group chlorine (1.10g, 3.96mmol).Reaction mixture is heated to backflow 14h under nitrogen atmosphere, is cooled to room temperature then.Except that after desolvating, resistates dilutes with ethyl acetate, washes with water.The aqueous solution is partly used ethyl acetate extraction, and dried over sodium sulfate is used in the organic layer water of merging and salt water washing.Behind the vacuum concentration, resistates obtains white solid title compound (1g, 73%) with flash column chromatography purification (30%EtOAc/ hexane). 1H NMR (300MHz, DMSO-d 6) δ 11.77 (1H, broad peak s), 11.73 (1H, d, J=5.2Hz), 11.46 (1H, broad peak s), 7.13-7.54 (23H, m), 5.87 (1H, d, J=4.5Hz), 4.09-4.14 (1H, m), 3.07-3.42 (4H, m), 2.54 (3H, s).LCMS(M+H) +m/z?695(t＝2.79min)。
Preparation 3-[6-(4-ethanoyl-piperazine-1-yl)-4-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl]-4-chloro-1H- Pyridin-2-ones:
1-[4-(4-amino-3-methyl-5-nitro-phenyl)-piperazine-1-yl]-ethyl ketone:
With 4-bromo-2-methyl-6-nitro-aniline (5g; 21.64mmol), 1-ethanoyl piperazine (4.2g; 32.46mmol), palladium (244mg; 1.08mmol), tri-butyl phosphine (440mg; 2.16mmol) and sodium tert-butoxide (4.2g, toluene 43.29mmol) (70mL) mixture is heated to 100 ℃ of 14h under nitrogen atmosphere.Reaction mixture is cooled to room temperature, dilutes with EtOAc.After the extraction, dried over sodium sulfate is used in the organic layer water of merging, salt water washing.Concentrate to obtain light brown resistates, with it with the flash column chromatography (10%MeOH/CH that purifies 2Cl 2) acquisition title compound (4.21g, 70%). 1H?NMR(400MHz，CD 3OD)δ7.42(1H，d，J＝2.8Hz)，7.23(1H，d，J＝2.8Hz)，3.71(2H，t，J＝5.1Hz)，3.67(2H，t，J＝5.1Hz)，3.04(2H，t，J＝5.2Hz)，2.98(2H，t，J＝5.2Hz)，2.24(3H，s)，2.13(3H，s)。LCMS(M+H) +m/z?279(t＝1.46min)。
1-[4-(3,4-diamino-5-methyl-phenyl)-piperazine-1-yl]-ethyl ketone:
Under nitrogen atmosphere, to 1-[4-(4-amino-3-methyl-5-nitro-phenyl)-piperazine-1-yl]-(4.5g 16.2mmol) carries adding methyl alcohol (50mL) and acetate (5mL) in the palladium (400mg) with 10% carbon to ethyl ketone.Reaction mixture (hydrogen jar) under nitrogen atmosphere is stirred 14h.Filter dark solution, filter cake methanol wash by Celite pad.Concentrated filtrate obtains title compound (4.00g, 100%), it is directly used in next step need not to purify again.LCMS(M+H) +m/z?207(t＝0.41min)。
1-{4-[2-(4-iodo-2-methoxyl group-pyridin-3-yl)-7-methyl-3H-benzoglyoxaline-5-yl]-piperazine-1-yl }-ethyl ketone:
1-[4-(3,4-diamino-5-methyl-phenyl)-piperazine-1-yl]-ethyl ketone (4.00g, and adding 4-iodo-2-methoxyl group-pyridine-3-formaldehyde in methyl alcohol 16.18mmol) (100mL) solution (4.25g, 16.18mmol).Reaction mixture is at room temperature stirred 14h.After concentrating, resistates is with the flash column chromatography (10%MeOH/CH that purifies 2Cl 2) acquisition title compound (5.25g, 66%). 1H?MR(400MHz，CD 3OD)δ7.81(1H，d，J＝5.4Hz)，7.48(1H，d，J＝5.4Hz)，7.26(1H，s)，6.85(1H，s)，3.85(3H，s)，3.78(2H，t，J＝5.0Hz)，3.64(2H，t，J＝5.0Hz)，3.16(2H，t，J＝5.2Hz)，3.11(2H，t，J＝5.2Hz)，2.62(3H，s)，2.13(3H，s)。LCMS(M+H) +m/z?492(t＝1.71min)。
Figure A0281051600802
3-[6-(4-ethanoyl-piperazine-1-yl)-4-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl]-4-chloro-1H-pyridin-2-ones:
1-{4-[2-(4-iodo-2-methoxyl group-pyridin-3-yl)-7-methyl-3H-benzoglyoxaline-5-yl]-piperazine-1-yl }-(5.2g 10.6mmol) adds entry (5mL) to ethyl ketone in diox (60mL) solution of 4M HCl.Reaction mixture is at room temperature stirred 14h.Concentrated reaction mixture obtains title compound (4.02g, 100%), it is directly used in next step need not to purify again.LCMS(M+H) +m/z?486(t＝1.55min)。
Preparation (S)-4-(1-methylol-2-phenyl-ethylamino)-3-(4-methyl-6-piperazine-1-base-1H-benzene And imidazoles-2-yl)-the 1H-pyridin-2-ones:
(S)-3-[6-(4-ethanoyl-piperazine-1-yl)-4-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl]-4-(1-methylol-2-phenyl-ethylamino)-1H-pyridin-2-ones:
3-[6-(4-ethanoyl-piperazine-1-yl)-4-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl]-4-chloro-1H-pyridin-2-ones (1g; 2.6mmol) DMF (10mL) solution in add (S)-(-)-2-amino-3-phenyl-propyl alcohol (0.78mg, 5.2mmol) and N-methylmorpholine (2mL).Reaction mixture is heated to 80 ℃ of 12h, is cooled to room temperature, high vacuum concentrates then.Resistates is with the flash column chromatography (10%MeOH/CH that purifies 2Cl 2) acquisition title compound (0.90g, 69%). 1H?NMR(400MHz，CD 3OD)δ7.36(1H，s)，7.02-7.23(6H，m)，6.80(1H，s)，5.98(1H，d，J＝7.5Hz)，4.10-4.12(3H，m)，3.67-3.78(6H，m)，3.06-3.11(3H，m)，2.90(1H，dd，J＝7.8，13.6Hz)，2.54(3H，s)，2.12(3H，s)。LCMS(M+H) +m/z?501(t＝1.30min)。
Figure A0281051600812
(S)-4-(1-methylol-2-phenyl-ethylamino)-3-(4-methyl-6-piperazine-1-base-1H-benzimidazolyl-2 radicals-yl)-the 1H-pyridin-2-ones:
(S)-3-[6-(4-ethanoyl-piperazine-1-yl)-4-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl]-(900mg 18mmol) adds entry (1mL) to 4-(1-methylol-2-phenyl-ethylamino)-1H-pyridin-2-ones in diox (10mL) solution of 4M HCl.Reaction mixture is heated to 80 ℃ of 14h, is cooled to room temperature then.High vacuum concentrates and obtains title compound (0.83g, 100%), it is directly used in next step need not to purify again.LCMS(M+H) +m/z?459(t＝1.13min)。
Preparation 2-(4,6-two chloro-pyrimidine-5-yl)-6-imidazoles-1-base-4-methyl isophthalic acid H-benzoglyoxaline:
4,6-two chloro-pyrimidine-5-formaldehydes:
At 0 ℃, (7mL 0.09mol) adds POCl with DMF 3(21mL, 0.23mol) in.Reaction mixture is at room temperature stirred 0.5h.Be divided into the aliquot amount and add 4, and 6-dihydroxyl-pyrimidine-5-formaldehyde (5g, 0.045mol).Reaction mixture is heated to 90 ℃ of 6h, is cooled to room temperature then.Under ice bath, a large amount of excessive trash ices are slowly joined in the reaction mixture.The mixture dichloromethane extraction.Dried over sodium sulfate is used in the organic layer water, the salt water washing that merge.After concentrating, resistates obtains title compound (4g, 50%) with column chromatography purification (20%EtOAc/ hexane). 1H?NMR(400MHz，CDCl 3)δ8.91(1H，s)，7.87(1H，s)。LRMS(M+H) +m/z?177。
Figure A0281051600822
2-(4,6-two chloro-pyrimidine-5-yl)-6-imidazoles-1-base-4-methyl isophthalic acid H-benzoglyoxaline:
5-imidazoles-1-base-3-methyl-benzene-1, (180mg adds 4 in methyl alcohol 0.96mmol) (4mL) solution to the 2-diamines, 6-two chloro-pyrimidine-5-formaldehydes (183mg, methyl alcohol 0.96mmol) (1mL) solution.Reaction mixture is at room temperature stirred 14h.After concentrating, resistates is with flash column chromatography (5% methyl alcohol/CH of purifying 2Cl 2) acquisition title compound (180mg, 55%).LCMS(M+H) +m/z?344(t＝1.31min)。
The step of preparation 2-amino-4-fluoro-6-methyl oil of mirbane:
2-(3,5-two fluoro-2-nitro-phenyl)-propanedioic acid di tert butyl carbonate:
0 ℃ to NaH (54.6g, 60%, (118g 0.546mol), stirs 30min to add the propanedioic acid di tert butyl carbonate in 600mL DMF suspension 1.365mol).Add 2,4 in 3h, (75g, 0.42mol) solution at room temperature stir 12h with solution to the 400mL DMF of 6-trifluoronitrobenzene.Reaction mixture is extracted with ethyl acetate (3 times).Dried over mgso is used in ethyl acetate water (3 times) and salt water washing, concentrates then to obtain the 62g crude product.LCMS[M+Na]-396； 1H?NMR(500MHz，DMSO)δ7.81(m，1H)，7.27(m，1H)，5.00(s，1H)，1.41(m，18H)。
2-(3-amino-5-fluoro-2-nitro-phenyl)-propanedioic acid di tert butyl carbonate:
(62g 0.42mol) joins the methanol solution of the 700mL 2M ammonia that is contained in the pressure flask to rough 2-(3,5-two fluoro-2-nitro-phenyl)-propanedioic acid di tert butyl carbonate.Sealed vessel post-heating to 85 ℃ 18h.With the reaction mixture cooling, carefully open container, methanol solution is concentrated obtain the 140g raw product.LCMS[M+Na]-393； 1H?NMR(500MHz，DMSO)δ6.76(dd，J＝10.82.8Hz，1H)，6.29(dd，J＝10.8，2.8Hz，1H)，4.99(brs，2H)，4.80(s，1H)，1.40(m，18H)。
Figure A0281051600833
3-amino-5-fluoro-2-nitrophenyl acetate:
In 500mL4N HCl De dioxane solution, add 50mL water to 2-(3-amino-5-fluoro-2-nitro-phenyl)-propanedioic acid di tert butyl carbonate (140g), be heated to 40 ℃ 2 days.Solution ethyl acetate extraction (3 times), acetic acid ethyl acetate extract water (3 times) and salt water washing.The organic moiety dried over mgso, and concentrated acquisition 78g raw product (66% purity, LC/MS); 1H NMR (500MHz, DMSO) δ 12.40 (brs, 1H), 7.04 (s, 2H), 6.68 (dd, J=10.9,2.8Hz, 1H), 6.47 (dd, J=10.9,2.8Hz, 1H), 3.80 (s, 2H).
Figure A0281051600841
2-amino-4-fluoro-6-methyl oil of mirbane:
To rough 3-amino-5-fluoro-2-nitrophenyl acetate (3.6g, 16.8mmol) the middle Cu that adds 2(10.1g, 120mL acetonitrile 70.6mmol) add 50 μ l methyl alcohol, backflow suspension 12h to O simultaneously.By diatomite filtration, Celite pad water and ethyl acetate are washed with reaction mixture.Filtrate is used ethyl acetate extraction, and dried over sodium sulfate is used in water and salt water washing, concentrate then to obtain the 2.95g product, by 1It is 80% purity that H NMR detects.ESIMS[M+Na]-193； 1H?NMR(500MHz，DMSO)δ6.67(s，2H)，6.56(dd，J＝11，2.8Hz，1H)，6.39(dd，J＝11，2.8Hz，1H)，2.50(s，3H)。
Preparation 4-chloro-3-(4-methyl-6-morpholine-4-base-1H-benzimidazolyl-2 radicals-yl)-1H-pyridin-2-ones and The 4-iodo-3-(step of 4-methyl-6-morpholine-4-base-1H-benzimidazolyl-2 radicals-yl)-1H-pyridin-2-ones
2-methyl-4-morpholine-4-base-6-nitro-aniline:
In the 800ml pressure flask, add three (dibenzalacetones), two palladiums (2.64g, 2.88mmol), 2-(two-tertiary butyl phosphino-) biphenyl (1.42g, 4.75mmol) and sodium tert-butoxide (17.5g, 182mmol).Add then anhydrous THF (500mL), 4-bromo-2-methyl-6-N-methyl-p-nitroaniline (30.0g, 130mmol) and morpholine (34ml, 390mmol).Argon gas is fed 1min in the solution, sealed flask.Reaction mixture was stirred 3 days at 85 ℃.Vacuum boils off THF, and silicagel column upper end is transferred to it in crude product silicon-dioxide preabsorption then.With hexane-ethyl acetate (gradient: 6: 4 to 4: 6 to 0: 1) wash-out, after boiling off solvent, obtain title compound (15.2g sorrel solid, 49.3%).LCMS(M+H) +m/z?238(t＝0.64min)。 1H NMR (500MHz, DMSO-d 6) δ 7.32 (1H, s), 7.22 (1H, s), 6.96 (2H, s), 3.72 (4H, broad peak s), 2.96 (4H, broad peak s), 2.21 (3H, s).
2-(4-iodo-2-methoxyl group-pyridin-3-yl)-4-methyl-6-morpholine-4-base-1H-benzoglyoxaline:
(15.2g 64mmol) is suspended in methyl alcohol (200ml) in the PARR flask with 2-methyl-4-morpholine-4-base-6-nitro-aniline.Adding carbon carries palladium, and (1.0g 10%Pd), spends the night suspension jolting under the 60psi nitrogen atmosphere.Mixture passes through diatomite filtration (under the argon atmospher) in 3 neck flasks, the diatomite washed with methanol, and filtrate is diluted to cumulative volume 500ml with methyl alcohol, is cooled to 0 ℃ then.In 3 hours, slowly add 4-iodo-2-methoxyl group-pyridine-3-formaldehyde (14.6g, methyl alcohol 55.5mmol) (500ml) solution.After adding about 1/4 solution, system opened wide contact, stirred weekend, reach room temperature thus with air.The vacuum concentration reaction mixture filters (elutriant: methylene dichloride-ethyl acetate-methyl alcohol 55-40-5), use the ethyl acetate crystallization then by the silicon-dioxide pad.Isolate brown solid title compound (12.68g, 51%).Mother liquor is handled the 2.90g product (12%) of reentrying through flash chromatography.[be full of chromatographic column with methylene dichloride, use methylene dichloride-ethyl acetate 6-4, methylene dichloride-ethyl acetate-methyl alcohol 58-40-2 wash-out compound successively].LCMS(M+H) +m/z?451(t＝1.03min)。 1H NMR (500MHz, CDCl 3) δ 7.76 (1H, d, J=5.3Hz)), 7.42 (1H, d, J=5.3Hz), 6.85 (1H, broad peak s), 6.82 (1H, s), 3.86 (4H, t, J=4.5Hz), 3.79 (3H, s), 3.12 (4H, t, J=4.5Hz), 2.60 (3H, s), 2.21 (3H, s).
Figure A0281051600861
4-chloro-3-(4-methyl-6-morpholine-4-base-1H-benzimidazolyl-2 radicals-yl)-1H-pyridin-2-ones and 4-iodo-3-(4-methyl-6-morpholine-4-base-1H-benzimidazolyl-2 radicals-yl)-the 1H-pyridin-2-ones:
(15.58g 34.6mmol) is suspended in 1, in the 4-diox (300mL), adds concentrated hydrochloric acid aqueous solution (50ml) with 2-(4-iodo-2-methoxyl group-pyridin-3-yl)-4-methyl-6-morpholine-4-base-1H-benzoglyoxaline.Mixture at room temperature stirs and spends the night, and stirs 3h at 50 ℃ then.Cooling mixture is to room temperature, and (67g 0.8mol), filters in the ice-cold solution of impouring sodium bicarbonate.The water ethyl acetate extraction.Solid product is dissolved in the methylene dichloride that contains part methyl alcohol, between water and methylene dichloride, extracts then.The organic layer dried over sodium sulfate that merges, vacuum concentration obtains the inextricable mixture of 4-chloro-and 4-iodo-title compound then.Product directly uses and need not to purify again.LCMS (M+H) +M/z 437 and m/z 345 (t is 0.92min).
Preparation 4-[2-(4-chloro-2-oxo-1,2-dihydro-pyridin-3-yl)-7-methyl-3H-benzoglyoxaline-5- Base]-piperazine-1-t-butyl formate and 4-[2-(4-iodo-2-oxo-1,2-dihydro-pyridin-3-yl)-7-first Base-3H-benzoglyoxaline-5-yl]-step of piperazine-1-t-butyl formate
Figure A0281051600862
4-(3-amino-5-methyl-4-nitro-phenyl)-piperazine-1-t-butyl formate:
Under nitrogen atmosphere, (10g, (39g is 209.4mmol) with 4-methylmorpholine (25.9mL) to add the BOC-piperazine in anhydrous NMP (160mL) solution 58.79mmol) for the 3-fluoro-5-amino-6-nitrotoluene under stirring.The gained dark solution is heated to backflow 72h, is cooled to room temperature, use ethyl acetate (4000mL) dilution then.The organic layer water (8 * 1500mL), salt solution (1 * 1500mL) washing, use dried over sodium sulfate, vacuum-evaporation.Gained dark oil thing is dissolved in the ebullient dehydrated alcohol (800mL), and being concentrated into cumulative volume is 400mL, is allowed to condition at standing over night under the room temperature.Solution further is cooled to-20 ℃ of 5h, leaches the gained solid, vacuum-drying obtains light yellow solid 16.3g (83%). 1H?NMR(500MHz，CDCl 3)δ6.16(brs，1H)，6.04(brs，1H)，3.70-3.60(m，4H)，3.38-3.25(m，4H)，2.53(s，3H)，1.48(s，9H)；LCMS(M+H) +m/z?337。
4-(3,4-diamino-5-methyl-phenyl)-piperazine-1-t-butyl formate:
(15g adds 20%Pd (OH) in methyl alcohol 44.6mmol) (2200mL) solution to 4-(3-amino-5-methyl-4-nitro-phenyl)-piperazine-1-t-butyl formate under stirring 2/ C (1.6g) fully feeds nitrogen in the suspension, then feed hydrogen.Gained suspension is stirred spend the night (about 1atm) under room temperature, nitrogen atmosphere.Gained suspension filters by Celite pad under nitrogen atmosphere, with methyl alcohol (400-500mL) washing.Use products therefrom immediately.LCMS(M+H) +m/z?307。
Figure A0281051600872
4-[2-(4-iodo-2-methoxyl group-pyridin-3-yl)-7-methyl-3H-benzoglyoxaline-5-yl]-piperazine-1-t-butyl formate:
Under 0 ℃, nitrogen atmosphere, with the 4-(3 of addition funnel under stirring, 4-diamino-5-methyl-phenyl)-methyl alcohol (about 2700mL) solution of piperazine-1-t-butyl formate (44.6mmol-hypothesis in previous step 100% transform) in slow adding (2h) 4-iodo-2-methoxyl group-pyridine-3-formaldehyde (15.0g, anhydrous methanol 57.1mmol) (225mL) solution.Gained solution is at 0 ℃ of following restir 30min.Remove cooling bath, reaction mixture is stirred 72h in the presence of room temperature, air.Vacuum concentration gained solution is dissolved in methylene dichloride (1500mL) final vacuum with resistates and removes desolvate (repeating 3 times).High vacuum dry gained black spumescence solid. 1H?NMR(500MHz，CDCl 3)δ7.82(d，1H，J＝5.4Hz)，7.50(d，1H，J＝5.4Hz)，6.98(brs，1H)，6.90(brs，1H)，4.05(s，3H)，3.67-3.58(m，4H)，3.18-3.09(m，4H)，2.63(s，3H)，1.49(s，9H)；。LCMS(M+H) +m/z?550。
Figure A0281051600881
4-iodo-3-(4-methyl-6-piperazine-1-base-1H-benzimidazolyl-2 radicals-yl)-the 1H-pyridin-2-ones:
4-[2-(4-iodo-2-methoxyl group-pyridin-3-yl)-7-methyl-3H-benzoglyoxaline-5-yl under stirring]-piperazine-1-t-butyl formate solution (24g, 43.7mmol) middle adding 1, the 4-diox (750mL) and the 6N HCl aqueous solution (30mL) ℃ spend the night mixture heating up to 75.Cooling solution is to room temperature, incline and supernatant liquor, (3 * 500mL) wash gained black gumminess solid with anhydrous diethyl ether, vacuum-drying obtains 17.7g (93%) black solid title compound, it is used to prepare 4-[2-(4-chloro-2-oxo-1 according to explanation, 2-dihydro-pyridin-3-yl)-7-methyl-3H-benzoglyoxaline-5-yl]-piperazine-1-t-butyl formate and 4-[2-(4-iodo-2-oxo-1,2-dihydro-pyridin-3-yl)-7-methyl-3H-benzoglyoxaline-5-yl]-piperazine-1-t-butyl formate; LCMS (M+H) +M/z436.(explain: the small peak of LC/MS (4-chloro-pyridin-2-ones) shows m/z 344,346).
4-[2-(4-chloro-2-oxo-1,2-dihydro-pyridin-3-yl)-7-methyl-3H-benzoglyoxaline-5-yl]-piperazine-1-t-butyl formate and 4-[2-(4-iodo-2-oxo-1,2-dihydro-pyridin-3-yl)-7-methyl-3H-benzoglyoxaline-5-yl]-piperazine-1-t-butyl formate:
4-iodo-3-under stirring (4-methyl-6-piperazine-1-base-1H-benzimidazolyl-2 radicals-yl)-1H-pyridin-2-ones (17.7g, 40.7mmol) methylene dichloride (750mL) suspension in add tert-Butyl dicarbonate (9.8g, 44.8mmol) and triethylamine (67.4mL, 483.6mmol).Mixture is at room temperature stirred 30min, purify with the flash chromatography on silica gel method.After using methylene dichloride, 2.5% methanol/ethyl acetate wash-out successively, merge uniform parts, the partial vacuum evaporation obtains yellow solid product, then filters (8.9g, about 41%, 2 output). 1H?NMR(500MHz，CD 3OD)δ7.25(d，1H，J＝6.9Hz)，6.97(d，1H，J＝6.9Hz)，6.97(brs，1H)，6.89(brs，1H)，3.65-3.56(m，4H)，3.16-3.07(m，4H)，2.55(s，3H)，1.49(s，9H)；LCMS(M+H) +m/z?536。(explain: the small peak of LC/MS (4-chloro-pyridin-2-ones) shows m/z 444,446).
Preparation 3-[6-(4-amino-piperadine-1-yl)-4-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl]-4-iodo-1H-pyrrole Pyridine-2-ketone and 3-[6-(4-amino-piperadine-1-yl)-4-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl]-the 4-chloro- The 1H-pyridin-2-ones
Figure A0281051600891
[1-(3-amino-5-methyl-4-nitro-phenyl)-piperidin-4-yl]-t-butyl carbamate:
Merge 5-fluoro-3-methyl-2-nitro-aniline (0.97g, 5.7mmol), the 4-N-BOC-amino piperidine (1.60g, 8.0mmol), diisopropylethylamine (2.5mL, 14mmol) and DMSO (10ml), at 85 ℃ of stirring 3h.Reaction mixture is poured in the saturated sodium bicarbonate aqueous solution, uses ethyl acetate extraction.Dried over sodium sulfate is used in organic layer water (3x) and salt water washing, concentrates then.The silicon-dioxide flash column chromatography (eluent: hexane-ethyl acetate-triethylamine 50-50-1, use 33-66-1 then) acquisition yellow solid title compound.(1.57g，79％)。LCMS(M+H) +m/z?351(t＝1.55min)。 1H NMR (500MHz, CD 3OD) δ 6.70 (1H, broad peak s), 6.22 (1H, d, J=2.5Hz)), 6.13 (1H, d, J=2.5Hz), 3.88 (2H, d, J=13.3Hz), 3.58 (1H, broad peak s), 2.98 (2H, t, J=11.8Hz), 2.48 (3H, s), 1.92 (2H, d, J=11.3Hz), 1.48 (2H, m), 1.45 (9H, s).
Figure A0281051600892
1-[2-(4-iodo-2-methoxyl group-pyridin-3-yl)-7-methyl-3H-benzoglyoxaline-5-yl]-piperidin-4-yl }-t-butyl carbamate:
(1.54g 4.4mmol) is dissolved in methyl alcohol (100ml) with [1-(3-amino-5-methyl-4-nitro-phenyl)-piperidin-4-yl]-t-butyl carbamate.Add carbon and carry palladium (0.3g, 10% Pd), suspension vigorous stirring under nitrogen atmosphere is spent the night.Mixture filters (under argon atmospher) in 3 neck flasks by Celite pad, the diatomite washed with methanol, and filtrate is cooled to 0 ℃.Slowly add 4-iodo-2-methoxyl group-pyridine-3-formaldehyde (1.21g, methyl alcohol 4.6mmol) (50mL) solution (in the 2h).Mixture at room temperature stirs in the air and spends the night, then vacuum concentration.(elutriant: hexane-ethyl acetate-methyl alcohol 5-4-1) purification obtains title compound to the silicon-dioxide flash column chromatography.(0.79g，32％)。LCMS(M+H) +m/z?564(t＝1.31min)。
3-[6-(4-amino-piperadine-1-yl)-4-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl]-4-iodo--1H-pyridin-2-ones and 3-[6-(4-amino-piperadine-1-yl)-4-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl]-4-chloro-1H-pyridin-2-ones:
Will 1-[2-(4-iodo-2-methoxyl group-pyridin-3-yl)-7-methyl-3H-benzoglyoxaline-5-yl]-piperidin-4-yl }-t-butyl carbamate (330mg, 0.59mmol) be suspended in and contain 1 of 4M HCl, in 4-diox (20ml) solution, add entry (3mL) (thermopositive reaction).Mixture at room temperature stirs and spends the night, and vacuum concentration obtains the inextricable mixture of 4-chloro-and 4-iodo-title compound then.Product directly uses and need not to purify again.LCMS (M+H) +M/z 450 and m/z 358 (t is 0.69min).
Figure A0281051600902
3-methyl-5-(2-morpholine-4-oxyethyl group)-2-nitro-aniline:
Under ice bath, add in THF (30mL) solution of 2-morpholine-4-base-ethanol (5g, excessive) in batches NaH (0.21g, 8.82mmol).Reaction mixture is at room temperature stirred 30min.Add 5-fluoro-3-methyl-2-nitro-aniline then.Reaction mixture is heated to backflow 6h, is cooled to room temperature, concentrate then.Residue diluted with water extracts with EtOAc.Dried over sodium sulfate is used in the organic layer water, the salt water washing that merge.After concentrating, resistates obtains title compound (0.70g, 85%) with column chromatography purification (20%EtOAc/ hexane). 1H?NMR(400MHz，CD 3OD)δ6.10(1H，s)，6.09(1H，s)，4.38-4.42(2H，m)，3.92-4.08(4H，m)，3.72(1H，d，J＝12Hz)，3.53-3.56(2H，m)，3.05-3.10(2H，m)，2.48(3H，s)。LCMS(M+H) +m/z?282(t＝0.73min)。
(S)-7-bromo-2-{4-[2-(3-chloro-phenyl)-2-hydroxyl-ethylamino]-2-oxo-1,2-dihydro-pyridin-3-yl }-3H-benzoglyoxaline-5-formaldehyde:
At-78 ℃, (S)-7-bromo-2-{4-[2-(3-chloro-phenyl)-2-hydroxyl-ethylamino]-2-oxo-1,2-dihydro-pyridin-3-yl }-(150mg adds DIBAL-H (1M toluene solution in THF 0.31mmol) (50mL) solution to 3H-benzoglyoxaline-5-formonitrile HCN, 1.55mL, 1.55mmol).Reaction mixture is stirred 10h at-40 ℃, be cooled to-78 ℃ then.Add EtOAc (0.5mL).Reaction mixture is stirred 30min at-78 ℃, add entry (1mL) then.Reaction mixture is risen to room temperature, concentrate.Make resistates pass through little Celite pad.Concentrated filtrate obtains title compound (67mg, 43%) with the preparation HPLC purification. 1H NMR (400MHz, CD 3OD) δ 9.45 (1H, s), 7.62 (1H, s), 7.56 (1H, narrow peak d, J=1.6Hz), 7.44 (1H, narrow peak d, J=1.0Hz), 7.32-7.42 (2H, m), 7.24-7.30 (3H, m), 6.24 (1H, d, J=7.6Hz), 5.01 (1H, m), 3.65-3.76 (2H, m).LCMS(M+H) +m/z?487(t＝1.76min)。
Figure A0281051600921
5-(1,4,5,6-tetrahydropyrimidine-1-yl)-3-methyl-2-N-methyl-p-nitroaniline:
5-fluoro-3-methyl-2-N-methyl-p-nitroaniline (2.0g under stirring, 11.76mmol) 10mLDMSO solution add 1,4,5,6-tetrahydropyrimidine (1.2g, 14.11mmol) and salt of wormwood (2.43g, 17.64mmol), mixture at 100 ℃ of heating 10h, is cooled off, dilute with water is with the ethyl acetate extraction that contains 5% methyl alcohol.Dried over sodium sulfate is used in the organic extract liquid water, the salt water washing that merge.Boil off solvent and obtain resistates, it is handled (methanol solution of 20% 2M ammonia and methylene dichloride) with chromatography obtain red solid product 1.85g (67%). 1H?NMR(400MHz，CD 3OD)δ7.89(1H，s)，6.53(1H，d，J＝2.57Hz)，6.44((1H，d，J＝2.1Hz)，7.04(1H，d，J＝2.1Hz)，3.70(2H，t，J＝6.0Hz)，3.41(2H，t，J＝5.65Hz)，2.43(3H，s)，2.05(2H，m)LCMS(M+H) +m/z?235(t＝0.78min)。
Embodiment 1 (general step of embodiment 1-21)
(S)-4-(2-hydroxyl-1-phenyl-ethylamino)-3-(6-imidazoles-1-base-4-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl)-the 1H-pyridin-2-ones:
3-(6-imidazoles-1-base-4-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl)-4-iodo-1H-pyridin-2-ones (30mg, add in DMF 0.072mmol) (1mL) solution (S)-(-)-2-phenyl glycinol (26mg, 0.18mmol) and N-methylmorpholine (0.1mL).Reaction mixture is heated to 80 ℃ of 6h, is cooled to room temperature then.Solvent removed in vacuo, resistates are purified with preparation HPLC and are obtained title compound (16mg, 52%). 1H NMR (300MHz, CD 3OD) δ 8.07 (1H, narrow peak t, J=1.7Hz), 7.76 (2H, s), 7.27-7.48 (7H, m), 7.21 (1H, d, J=7.5Hz), 6.11 (1H, d, J=7.5Hz), 4.92 (1H, m), 4.03 (1H, dd, J=4.5,11.2Hz), 3.95 (1H, dd, J=6.2,11.2Hz), 2.75 (3H, s).LCMS(M+H) +m/z?427(t＝1.44min)
Embodiment 2
(±)-4-[2-hydroxyl-2-(3-iodo-phenyl)-ethylamino]-3-(6-imidazoles-1-base-4-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl)-the 1H-pyridin-2-ones: 1H NMR (300MHz, CD 3OD) δ 9.41 (1H, s), 8.06 (1H, s), 7.88 (1H, s), 7.76 (1H, s), 7.71 (1H, s), 7.59 (1H, d, J=7.8Hz), 7.47 (1H, d, J=7.8Hz) 7.32 (1H, and s) 7.29 (1H, d, J=7.6Hz), 7.09 (1H, t, J=7.8Hz), 6.24 (1H, d, J=7.6Hz), 4.97 (1H, dd, J=5.0,6.0Hz), 3.75 (1H, dd, J=5.0,13.5Hz), 3.67 (1H, dd, J=6.0,13.5Hz), 2.68 (3H, s).LCMS(M+H) +m/z?553(t＝1.43min)。
Embodiment 3
Figure A0281051600932
(±)-4-[2-(3-chloro-phenyl)-2-hydroxyl-ethylamino]-3-(6-imidazoles-1-base-4-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl)-the 1H-pyridin-2-ones: 1H NMR (300MHz, CD 3OD) δ 9.39 (1H, narrow peak T, J=1.4Hz), 8.04 (1H, narrow peak t, J=1.7Hz), 7.76 (1H, narrow peak t, J=1.7Hz), 7.69 (1H, narrow peak d, J=1.9Hz), 7.55 (1H, s), 7.23-7.42 (5H, m), 6.25 (1H, d, J=7.6Hz), 5.01 (1H, dd, J=4.8,6.4Hz), 3.76 (1H, dd, J=4.8,13.4Hz), 3.66 (1H, dd, J=6.4,13.4Hz), 2.67 (3H, s).LCMS(M+H) +m/z?461(t＝1.46min)。
Embodiment 4
Figure A0281051600941
(±)-4-[2-(3-bromo-phenyl)-2-hydroxyl-ethylamino]-3-(6-imidazoles-1-base-4-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl)-the 1H-pyridin-2-ones: 1H NMR (300MHz, CD 3OD) δ 9.38 (1H, s), 8.02 (1H, s), 7.74 (1H, s), 7.69 (1H, s), 7.66 (1H, narrow peak d, J=1.4Hz), and 7.20-7.48 (5H, m), 6.21 (1H, d, J=7.6Hz), 4.99 (1H, dd, J=4.8,6.3Hz), 3.73 (1H, dd, J=4.8,13.5Hz), 3.64 (1H, dd, J=6.3,13.5Hz), 2.65 (3H, s).LCMS(M+H) +m/z?505(t＝1.47min)。
Embodiment 5
(±)-N-(2-chloro-4-{1-hydroxyl-2-[3-(6-imidazoles-1-base-4-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl)-2-oxo-1,2-dihydro-pyridin-4-yl amino]-ethyl }-phenyl)-Toluidrin: 1H NMR (300MHz, CD 3OD) δ 9.39 (1H, s), 8.05 (1H, s), 7.76 (1H, s), 7.68 (1H, s), 7.62 (1H, narrow peak d, J=1.5Hz), 7.52 (1H, s), 7.42-7.49 (2H, m), 7.31 (1H, s), 7.30 (1H, d, J=7.6Hz), 6.26 (1H, d, J=7.6Hz) 5.01 (1H, dd, J=5.0,5.6Hz), 3.76 (1H, d, J=5.0,13.4Hz), 3.74 (1H, dd, J=5.6,13.4Hz), 2.98 (3H, s), 2.68 (3H, s).LCMS(M+H) +m/z?554(t＝1.11min)。
Embodiment 6
N-3-bromo-benzoyl N '-[3-(6-imidazoles-1-base-4-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl)-2-oxo-1,2-dihydro-pyridin-4-yl]-hydrazine: 1H NMR (300MHz, CD 3OD) δ 9.40 (1H, narrow peak t, J=1.4Hz), 8.14 (1H, narrow peak t, J=1.7Hz), 8.05 (1H, narrow peak t, J=1.7Hz), 7.95 (1H, d, and J=7.9Hz) 7.81 (1H, d, J=7.9Hz), 7.74-7.77 (2H, m), 7.49 (1H, t, J=7.9Hz), 7.41 (1H, d, J=7.4Hz), 7.34 (1H, s), 6.38 (1H, d, J=7.4Hz), 2.70 (3H, s).LCMS(M+H) +m/z?504(t＝1.44min)
Embodiment 7
Figure A0281051600961
N-4-amino-benzoyl N '-[3-(6-imidazoles-1-base-4-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl)-2-oxo-1,2-dihydro-pyridin-4-yl]-hydrazine: 1H NMR (300MHz, CD 3OD) δ 9.41 (1H, s), 8.06 (1H, s), 7.76-7.79 (4H, m), 7.39 (1H, d, J=7.4Hz), 7.36 (1H, s), 6.81 (2H, d, J=8.6Hz), 6.36 (1H, d, J=7.4Hz), 2.70 (3H, s).LCMS(M+H) +m/z?441(t＝0.96min)。
Embodiment 8
Figure A0281051600962
(S)-4-[2-(2-chloro-phenyl)-1-methylol-ethylamino]-3-(6-imidazoles-1-base-4-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl)-the 1H-pyridin-2-ones: 1H NMR (300MHz, CD 3OD) δ 9.41 (1H, s), 8.05 (1H, narrow peak t, J=1.7Hz), 7.76 (1H, narrow peak t, J=1.7Hz), 7.72 (1H, narrow peak d, J=1.9Hz), 7.08-7.36 (6H, m), 6.10 (1H, d, J=7.7Hz), 3.98-4.24 (1H, m), (3.84 1H, dd, J=4.4,11.2 Hz), 3.79 (1H, dd, J=4.8,11.2Hz), 3.35 (1H, dd, J=5.4,13.6Hz), 3.09 (1H, dd, J=7.8,13.6Hz), 2.72 (3H, s).LCMS(M+H) +m/z?475(t＝1.56min)。
Embodiment 9
(S)-4-[2-(3-chloro-phenyl)-1-methylol-ethylamino]-3-(6-imidazoles-1-base-4-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl)-the 1H-pyridin-2-ones: 1H NMR (300MHz, CD 3OD) δ 9.42 (1H, s), 8.07 (1H, narrow peak t, J=1.7Hz), 7.75-7.78 (2H, m), 7.14-7.37 (6H, m), 6.18 (1H, d, J=7.7Hz), 4.07-4.11 (1H, m), 3.76-3.77 (2H, m), 3.17 (1H, dd, J=5.1,13.7Hz), 2.98 (1H, dd, J=8.2,13.7Hz), 2.71 (3H, s).LCMS(M+H) +m/z?475(t＝1.57min)。
Embodiment 10
Figure A0281051600972
(S)-4-[2-(4-chloro-phenyl)-1-methylol-ethylamino]-3-(6-imidazoles-1-base-4-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl)-the 1H-pyridin-2-ones: 1H NMR (300MHz, CD 3OD) δ 9.42 (1H, s), 8.07 (1H, narrow peak t, J=1.6Hz), 7.77 (1H, narrow peak t, J=1.6Hz), 7.73 (1H, narrow peak d, J=1.9Hz), and 7.16-7.37 (6H, m), 6.19 (1H, d, J=7.7Hz), and 4.06-4.10 (1H, m), 3.72-3.77 (2H, m), 3.14 (1H, dd, J=5.3,13.8Hz), 2.98 (1H, dd, J=7.8,13.8Hz), 2.69 (3H, s).LCMS(M+H) +m/z?475(t＝1.61min)
Embodiment 11
Figure A0281051600981
(S)-4-[2-(2-bromo-phenyl)-1-methylol-ethylamino]-3-(6-imidazoles-1-base-4-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl)-the 1H-pyridin-2-ones: 1H NMR (300MHz, CD 3OD) δ 9.41 (1H, s), 8.06 (1H, s), 7.75-7.77 (2H, m), (7.52 1H, dd, J=1.5,7.5 Hz), 7.36 (1H, d, J=1.9 Hz), 7.34 (1H, s), 7.03-7.16 (3H, m), 6.09 (1H, d, J=7.7Hz), 4.15-4.27 (1H, m), 3.82 (2H, m), 3.35 (1H, dd, J=5.0,13.6Hz), 3.10 (1H, dd, J=9.0,13.6Hz), 2.74 (3H, s).LCMS(M+H) +m/z?519(t＝1.56min)。
Embodiment 12
(S)-4-[2-(3-bromo-phenyl)-1-methylol-ethylamino]-3-(6-imidazoles-1-base-4-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl)-the 1H-pyridin-2-ones: 1H NMR (300MHz, CD 3OD) δ 9.41 (1H, s), 8.06 (1H, s), 7.74-7.77 (2H, m), 7.47 (1H, s), 7.24-7.31 (4H, m), 7.11 (1H, d, J=7.7Hz) 6.16 (1H, d, J=7.7Hz), 4.05-4.11 (1H, m), 3.76 (2H, m), 3.15 (1H, dd, J=5.0,13.6Hz), 2.96 (1H, dd, J=8.3,13.6Hz), 2.70 (3H, s).LCMS(M+H) +m/z?519(t＝1.54min)。
Embodiment 13
Figure A0281051600991
(±)-4-(1-methylol-2-pentafluorophenyl group-ethylamino)-3-(6-imidazoles-1-base-4-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl)-the 1H-pyridin-2-ones: 1H NMR (300 MHz, CD 3OD) δ 9.40 (1H, s), 8.06 (1H, narrow peak t, J=1.8 Hz), 7.77 (1H, narrow peak t, J=1.7Hz), 7.74 (1H, narrow peak d, J=1.8Hz), 7.35 (1H, s), 7.29 (1H, d, J=7.6Hz), 6.22 (1H, d, J=7.6Hz), 4.24 (1H, m), 3.82 (2H, dd, J=2.6,4.5Hz), 3.23 (2H, t, J=6.5Hz), 2.70 (3H, s).LCMS(M+H) +m/z?531(t＝1.61min)。
Embodiment 14
Figure A0281051600992
(S)-4-(1-methylol-2-pyridin-4-yl-ethylamino)-3-(6-imidazoles-1-base-4-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl)-the 1H-pyridin-2-ones: 1H NMR (400MHz, CD 3OD) δ 9.42 (1H, s), 8.67 (2H, d, J=6.6 Hz), 8.07 (2H, d, J=6.6Hz), 8.06 (1H, s), 7.77 (2H, s), 7.36 (1H, s), 7.28 (1H, d, J=7.6Hz), 6.24 (1H, d, J=7.6Hz), 4.35 (1H, m), 3.82 (2H, d, J=4.4Hz), 3.50 (1H, dd, J=4.4,13.6Hz), 3.40 (1H, dd, J=8.7,13.6Hz), 2.71 (3H, s).LCMS(M+H) +m/z?442(t＝0.96min)。
Embodiment 15
Figure A0281051601001
(S)-4-(1-methylol-2-naphthalene-2-base-ethylamino)-3-(6-imidazoles-1-base-4-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl)-the 1H-pyridin-2-ones: 1H NMR (300MHz, CD 3OD) δ 7.99 (1H, narrow peak t, J=1.7Hz), 7.26-7.75 (11H, m), 7.15 (1H, d, J=7.6Hz), 6.19 (1H, d, J=7.6Hz), 4.16-4.20 (1H, m), 3.75-3.86 (2H, m), 3.30 (1H, dd, J=5.4,13.6Hz), 3.15 (1H, dd, J=7.6,13.6Hz), 2.60 (3H, s).LCMS(M+H) +m/z?491(t＝1.71min)。
Embodiment 16
Figure A0281051601002
(S)-4-(2-cyclohexyl-1-methylol-ethylamino)-3-(6-imidazoles-1-base-4-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl)-the 1H-pyridin-2-ones: 1H NMR (300MHz, CD 3OD) δ 9.40 (1H, s), 8.06 (1H, narrow peak t, J=1.7Hz), 7.76 (1H, narrow peak t, J=1.7Hz), 7.73 (1H, narrow peak d, J=1.7Hz), 7.34 (1H, d, J=7.6Hz), 7.33 (1H, s), 6.34 (1H, d, J=7.6Hz), 3.89-3.94 (1H, m), 3.68 (2H, d, J=4.9Hz), 2.68 (3H, s), and 1.62-1.83 (7H, m), 0.95-1.26 (6H, m) LCMS (M+H) +M/z 447 (t=1.71min)
Embodiment 17
Figure A0281051601011
(3S, 4R)-4-(3-hydroxyl-2,2-dimethyl-chroman-4-base is amino)-3-(6-imidazoles-1-base-4-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl)-the 1H-pyridin-2-ones: 1H NMR (300MHz, CD 3OD) δ 9.36 (1H, s), 8.02 (1H, narrow peak t, J=1.7Hz), 7.73 (1H, narrow peak t, J=1.7Hz), 7.69 (1H, narrow peak d, J=2.0Hz), 7.37 (1H, d, J=7.6Hz), 7.18-7.30 (3H, m), 6.89 (1H, t, J=7.6Hz), 6.85 (1H, d, J=8.4Hz), 6.61 (1H, d, J=7.6Hz), 4.93 (1H, d, J=8.2Hz), 3.80 (1H, d, J=8.2Hz), 2.46 (3H, s), 1.48 (3H, s), 1.35 (3H, s).LCMS(M+H) +m/z?483(t＝1.70min)。
Embodiment 18
3-(6-imidazoles-1-base-4-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl)-4-(2-thiophene-2-base-ethylamino)-1H-pyridin-2-ones: 1H NMR (500MHz, DMSO-d 6) δ 13.17 (1H, broad peak s), 11.32 (1H, broad peak s), 11.03 (1H, broad peak s), 9.59 (1H, broad peak s), 8.22 (1H, broad peak s), 7.91 (1H, s), 7.82 (1H, d, J=2.0Hz), 7.41 (1H, t, J=6.9Hz), 7.36 (1H, dd, J=1.0,5.1Hz), 7.30-7.40 (1H, m), 7.05 (1H, broad peak s), 7.01 (1H, t, J=4.2Hz), 6.23 (1H, d, J=7.5Hz), 3.74 (2H, t, J=6.5Hz), 3.25 (2H, t, J=6.5Hz), 2.58 (3H, s).
Embodiment 19
Figure A0281051601021
3-(6-imidazoles-1-base-4-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl)-4-[2-(1H-indol-3-yl)-ethylamino]-the 1H-pyridin-2-ones: 1H NMR (500MHz, DMSO-d 6) δ 13.17 (1H, broad peak s), 11.27 (broad peak s, 1H), 11.00 (1H, broad peak s), 10.89 (1H, s), 9.58 (1H, broad peak s), (8.30 1H, broad peak s), 7.91 (1H, s), 7.80 (1H, s), 7.63 (1H, d, J=7.9Hz), 7.40 (1H, t, J=6.9Hz), 7.34 (1H, d, J=8.0Hz), and 7.30-7.40 (2H, m), 7.07 (1H, t, J=7.5Hz), 6.99 (1H, t, J=7.6Hz), 6.23 (1H, dd, J=0.8,7.2Hz), 3.76 (2H, broad peak s), 3.17 (2H, t, J=6.7Hz), 2.50 (3H, s).
Embodiment 20
Figure A0281051601022
3-(6-imidazoles-1-base-4-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl)-4-(pyridine-2-ylmethoxy)-1H-pyridin-2-ones:
3-(6-imidazoles-1-base-4-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl)-4-iodo-1H-pyridin-2-ones (25mg, add in DMF 0.06mmol) (2mL) solution piconol (26mg, 0.24mmol) and cesium fluoride (36mg, 0.24mmol).Reaction mixture is heated to 130 ℃ of 14h, is cooled to room temperature then.Behind the vacuum concentration, resistates is purified with preparation HPLC and is obtained title compound (8.2mg, 34%). 1H NMR (300MHz, CD 3OD) δ 9.58 (1H, narrow peak d, J=1.2Hz), 8.92 (1H, d, J=4.9Hz), 8.19 (1H, narrow peak T, J=1.2Hz), 8.12 (1H, s), 7.97-8.02 (2H, m), 7.85 (1H, narrow peak t, J=1.8Hz), 7.81 (1H, narrow peak t, J=1.0Hz), 7.63 (1H, d, J=7.9Hz), 7.54 (1H, t, J=6.2Hz), 6.81 (1H, J=7.5Hz), 5.86 (2H, s), 2.86 (3H, s).LCMS(M+H) +m/z?399(t＝1.07min)
Embodiment 21
(±)-4-[2-(3-bromo-phenyl)-2-fluoro-ethylamino]-3-(6-imidazoles-1-base-4-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl)-the 1H-pyridin-2-ones: 1H NMR (300MHz, CD 3OD) δ 9.40 (1H, t, J=1.4Hz), 8.06 (1H, t, J=1.9Hz), 7.76 (1H, t, J=1.7Hz), 7.72 (1H, d, J=1.9Hz), 7.66 (1H, s), and 7.27-7.50 (5H, m), 6.29 (1H, d, J=7.6Hz), 5.75-5.94 (1H, m), 3.86-4.06 (2H, m), 2.64 (3H, s).LCMS(M+H) +m/z?507(t＝1.70min)。
Embodiment 22 (general step of embodiment 22-28)
Figure A0281051601032
(S)-and 2-[4-(1-methylol-2-phenyl-ethylamino)-2-oxo-1,2-dihydro-pyridin-3-yl]-7-methyl-3H-benzoglyoxaline-5-formonitrile HCN:
2-(4-chloro-2-oxo-1,2-dihydro-pyridin-3-yl)-7-methyl-3H-benzoglyoxaline-5-formonitrile HCN (0.7g, 2.19mmol) DMF (15mL) solution in add N-methylmorpholine (0.66g, 6.57mmol) and (S)-(-)-2-amino-3-phenyl-1-propyl alcohol (0.40g, 2.63mmol).Reaction mixture is heated to 80 ℃ of 6h, is cooled to room temperature then.Behind the vacuum concentration, resistates is with flash chromatography (3% MeOH/CH that purifies 2Cl 2) acquisition yellow spumescence title compound (0.59g, 68%). 1H?NMR(400MHz，CD 3OD)δ7.74(1H，s)，7.63(1H，s)，7.12-7.27(6H，m)，6.07(1H，d，J＝7.5Hz)，3.97(1H，m)，3.74(2H，t，J＝5Hz)，3.14(1H，dd，J＝5.5，14.0Hz)，2.94(1H，dd，J＝7.9，14.0Hz)，2.60(3H，s)。LCMS(M+H) +m/z?400(t＝1.71min)。
Embodiment 23
(±)-2-{4-[2-(3-chloro-phenyl)-2-hydroxyl-ethylamino]-2-oxo-1,2-dihydro-pyridin-3-yl }-7-methyl-3H-benzoglyoxaline-5-formonitrile HCN: 1H NMR (300MHz, DMSO-d 6) δ 7.92 (1H, s), 7.59 (1H, s), 7.28-7.47 (5H, m), 6.19 (1H, d, J=7.3Hz), 4.92-4.96 (1H, m), 3.53-3.73 (2H, m), 2.58 (3H, s).LCMS(M+H) +m/z?420(t＝1.99min)
Embodiment 24
Figure A0281051601051
(S)-2-{4-[2-(3-chloro-phenyl)-1-methylol-ethylamino]-2-oxo-1,2-dihydro-pyridin-3-yl }-7-methyl-3H-benzoglyoxaline-5-formonitrile HCN: 1H MR (400MHz, CD 3OD) δ 7.86 (1H, s), 7.10-7.33 (6H, m), 6.12 (1H, d, J=7.6Hz), 4.01-4.05 (1H, m), 3.75 (2H, d, J=4.09Hz), 3.15 (1H, dd, J=4.9,13.5Hz), 2.86-3.00 (1H, m), 2.63 (3H, s).LCMS(M+H) +m/z?434(t＝1.81min)。
Embodiment 25
Figure A0281051601052
(±)-2-{4-[2-(3-bromo-4-methoxyl group-phenyl)-2-hydroxyl-ethylamino]-2-oxo-1,2-dihydro-pyridin-3-yl }-7-methyl-3H-benzoglyoxaline-5-formonitrile HCN: 1H NMR (300MHz, CD 3OD) δ 7.86 (1H, s), 7.75 (1H, s), 7.67 (1H, s), 728-7.40 (2H, m), 6.95 (1H, d, J=8.5Hz), 6.24 (1H, d, J=7.4 Hz), 4.93 (1H, m), 3.65-3.97 (2H, m), 3.82 (3H, s), 2.57 (3H, s).LCMS(M+H) +m/z494(t＝2.10min)。
Embodiment 26
(±)-2-{4-[2-(3-fluoro-phenyl)-2-hydroxyl-ethylamino]-2-oxo-1,2-dihydro-pyridin-3-yl }-7-methyl-3H-benzoglyoxaline-5-formonitrile HCN: 1H NMR (400MHz, CD 3OD) δ 7.70 (1H, s), 7.49 (1H, s), 7.22-7.32 (4H, m), 6.92 (1H, d, J=8.9Hz), 6.17 (1H, d, J=7.2 Hz), 4.92 (1H, t, J=6.3Hz), 3.66 (2H, d, J=5.9Hz), 2.56 (3H, s).LCMS(M+H) +m/z?404(t＝1.65min)。
Embodiment 27
Figure A0281051601062
(±)-2-{4-[2-(3-bromo-phenyl)-2-hydroxyl-ethylamino]-2-oxo-1,2-dihydro-pyridin-3-yl }-7-methyl-3H-benzoglyoxaline-5-formonitrile HCN: 1H NMR (300MHz, CD 3OD) δ 7.92 (1H, s), 7.72 (1H, s), 7.26-7.50 (5H, m), 6.19 (1H, d, J=7.1Hz), 4.93 (1H, t, J=4.3Hz), 3.47-3.73 (2H, m), 2.58 (3H, s).LCMS(M+H) +m/z?464(t＝2.00min)
Embodiment 28
(S)-and 2-[4-(2-hydroxyl-2-phenyl-ethylamino)-2-oxo-1,2-dihydro-pyridin-3-yl]-7-methyl-3H-benzoglyoxaline-5-formonitrile HCN: 1H NMR (400MHz, CD 3OD) δ 8.04 (1H, s), 7.74 (1H, s), 7.24-7.51 (6H, m), 6.22 (1H, d, J=7.5Hz), 5.00 (1H, m), 3.64-3.74 (2H, m), 2.60 (3H, s).LCMS(M+H) +m/z?386(t＝1.65min)。
The preparation method that embodiment 29-35 introduces according to flow process the III diamine of buying or the diamine for preparing easily and 4-iodo-2-methoxyl group-pyridine-3-formaldehyde condensation preparation.
Embodiment 29
(±)-4-[2-(3-bromo-4-methoxyl group-phenyl)-2-hydroxyl-ethylamino]-3-(4,5,6-three fluoro-1H-benzimidazolyl-2 radicals-yl)-the 1H-pyridin-2-ones: 1H NMR (500MHz, CD 3COCD 3) δ 13.26 (1H, broad peak s), 10.93 (1H, broad peak s), 10.27 (1H, broad peak s), 7.76 (1H, s), 7.54-7.56 (2H, m), 7.41-7.42 (1H, m), 7.06 (1H, d, J=8.2 Hz), 6.29 (1H, d, J=7.5Hz), 5.05-5.07 (1H, m), 3.87 (3H, s), 3.74-3.79 (1H, m), 3.65-3.69 (1H, m).
Embodiment 30
Figure A0281051601081
(±)-4-[2-(3-bromo-4-methoxyl group-phenyl)-2-hydroxyl-ethylamino]-3-(4,6-two bromo-1H-benzimidazolyl-2 radicals-yl)-the 1H-pyridin-2-ones: 1H NMR (500MHz, CD 3COCD 3) δ 13.18 (1H, broad peak s), 11.18 (1H, broad peak s), 10.20 (1H, broad peak s), 7.92 (1H, s), 7.78 (1H, s), 7.52-7.55 (3H, m), 7.03 (1H, d, J=8.5 Hz), 6.28 (1H, d, J=7.4 Hz), 5.06-5.08 (1H, m), 3.86 (3H, s), 3.73-3.77 (1H, m), 3.66-3.70 (1H, m).
Embodiment 31
Figure A0281051601082
(±)-4-[2-(3-bromo-4-methoxyl group-phenyl)-2-hydroxyl-ethylamino]-3-(5,6-two chloro-1H-benzimidazolyl-2 radicals-yl)-the 1H-pyridin-2-ones: 1H NMR (500MHz, CD 3COCD 3) δ 7.79 (3H, m), 7.53 (1H, dd, J=2.0,8.4Hz), 7.41-7.44 (1H, m), 7.08 (1H, d, J=8.4Hz), 6.29 (1H, d, J=7.5Hz), 5.05-5.08 (1H, m), 3.89 (3H, s), 3.74-3.78 (1H, m), 3.70-3.72 (1H, m).
Embodiment 32
Figure A0281051601091
(±)-3-(the 1H-benzimidazolyl-2 radicals-yl)-4-[2-(3-bromo-phenyl)-2-hydroxyl-ethylamino]-the 1H-pyridin-2-ones: 1H NMR (500MHz, CD 3COCD 3) δ 7.80 (1H, s), 7.64-7.69 (2H, m), 7.60 (1H, d, J=7.7Hz), and 7.46-7.48 (2H, m), 7.33 (1H, t, J=7.8Hz), and 7.19-7.22 (2H, m), 6.59 (1H, d, J=4.5Hz), and 5.12-5.14 (1H, m), 5.13 (1H, dd, J=4.5,7.2Hz), 3.82 (1H, dd, J=4.5,13.6Hz), 3.71 (1H, dd, J=7.2,13.6Hz).
Embodiment 33
3-(the 1H-benzimidazolyl-2 radicals-yl)-4-[(pyridine-2-ylmethyl)-amino]-the 1H-pyridin-2-ones: 1H NMR (500MHz, CD 3COCD 3) δ 8.96-8.98 (1H, m), 8.46-8.49 (1H, m), 8.03 (1H, d, J=8.0Hz), 7.93 (1H, t, J=6.4Hz), 7.69-7.73 (2H, m), 7.53 (1H, d, J=7.5Hz), 7.28-7.32 (2H, s), 6.34 (1H, d, J=7.5Hz), 5.29 (2H, m).
Embodiment 34
Figure A0281051601101
(S)-3-(the 1H-benzimidazolyl-2 radicals-yl)-4-(1-methylol-2-phenyl-ethylamino)-1H-pyridin-2-ones: 1H NMR (500MHz, CD 3COCD 3) δ 7.67-7.69 (2H, m), 7.15-7.44 (8H, m), 6.31 (1H, d, J=7.5Hz), 4.10-4.13 (1H, m), 3.76-3.82 (2H, m), 3.23 (1H, dd, J=5.6,13.7Hz), 3.04 (1H, dd, J=8.1,13.7Hz).
Embodiment 35
Figure A0281051601102
(±)-3-(the 1H-benzimidazolyl-2 radicals-yl)-4-[2-(3-bromo-4-methoxyl group-phenyl)-2-hydroxyl-ethylamino]-the 1H-pyridin-2-ones: 1H NMR (500MHz, CD 3COCD 3) δ 7.78 (1H, s), 7.68 (2H, s), 7.50-7.55 (2H, m), and 7.21-7.24 (2H, m), 7.06 (1H, d, J=8.4Hz), 6.44 (1H, d, J=7.5Hz), 5.08 (1H, dd, J=4.6,7.2Hz), 3.87 (3H, s), 3.79 (1H, dd, J=4.6,13.4Hz), 3.71 (1H, dd, J=7.2,13.4Hz).
Embodiment 36-43 prepares according to flow process V.
Embodiment 36 (general step of embodiment 36-43)
Figure A0281051601111
(S)-and 4-{2-[4-(1-methylol-2-phenyl-ethylamino)-2-oxo-1,2-dihydro-pyridin-3-yl]-7-methyl-3H-benzoglyoxaline-5-yl }-piperazine-1-(N-sec.-propyl-methane amide):
(S)-and 4-(1-methylol-2-phenyl-ethylamino)-3-(4-methyl-6-piperazine-1-base-1H-benzimidazolyl-2 radicals-yl)-(30mg adds isocyanic acid isopropyl esters (2) to the 1H-pyridin-2-ones in methyl alcohol 0.063mmol) (2mL) solution.Reaction mixture is at room temperature stirred 5min.Concentrate and obtain resistates, it is purified with preparation HPLC obtains title compound (23.8mg, 69%). 1H NMR (400MHz, CD 3OD) δ 7.55 (1H, s), 7.14-7.28 (7H, m), 6.12 (1H, d, J=7.8Hz), 4.01-4.03 (1H, m), 3.92 (quintet, J=6.6Hz), 3.80 (4H, m), 3.76 (1H, dd, J=4.8,11.2Hz), 3.70 (1H, dd, J=5.2,11.2Hz), 3.61-3.64 (4H, m), 3.09 (1H, dd, J=5.6,13.7Hz), 2.91 (1H, dd, J=8.0,13.7Hz), 2.64 (3H, s), 1.19 (6H, d, J=6.8Hz).LCMS(M+H) +m/z?545(t＝1.99min)。
Embodiment 37
Figure A0281051601112
(S)-and 4-{2-[4-(1-methylol-2-phenyl-ethylamino)-2-oxo-1,2-dihydro-pyridin-3-yl]-7-methyl-3H-benzoglyoxaline-5-yl }-piperazine-1-(N-ethyl-methane amide): 1H NMR (400MHz, CD 3OD) δ 7.55 (1H, s), 7.12-7.28 (7H, m), 6.12 (1H, d, J=7.8Hz), 4.01-4.05 (1H, m), 3.62-3.81 (10H, m), 3.24 (2H, q, J=7.2Hz), 3.08 (1H, dd, J=5.6,13.7Hz), 2.91 (1H, dd, J=8.0,13.7Hz), 2.65 (3H, s), 1.14 (3H, t, J=7.2Hz).LCMS(M+H) +m/z?531(t＝1.93min)。
Embodiment 38
(S)-4-(1-methylol-2-phenyl-ethylamino)-3-{4-methyl-6-[4-(1-phenyl-formyl radical)-piperazine-1-yl]-1H-benzimidazolyl-2 radicals-yl }-the 1H-pyridin-2-ones:
(S)-and 4-(1-methylol-2-phenyl-ethylamino)-3-(4-methyl-6-piperazine-1-base-1H-benzimidazolyl-2 radicals-yl)-(30mg adds Benzoyl chloride (1) to the 1H-pyridin-2-ones in methyl alcohol 0.063mmol) (2mL) solution.Reaction mixture is stirred 5min, concentrate then.Resistates is purified with preparation HPLC and is obtained title compound (11mg, 33%). 1H?NMR(400MHz，CD 3OD)δ7.48-7.54(5H，m)，7.37(1H，s)，7.13-7.26(7H，m)，6.08(1H，d，J＝7.7Hz)，3.79-4.02(5H，m)，3.76(1H，dd，J＝4.7，11.2Hz)，3.67(1H，dd，J＝5.7，11.2Hz)，3.54(4H，m)，3.03(1H，dd，J＝5.7，13.7Hz)，2.89(1H，dd，J＝8.0，13.7Hz)，2.62(3H，s)。LCMS(M+H) +m/z?563(t＝2.19min)。
Embodiment 39
(S)-4-(1-methylol-2-phenyl-ethylamino)-3-[6-(4-sec.-propyl-piperazine-1-yl)-4-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl]-the 1H-pyridin-2-ones:
(S)-and 4-(1-methylol-2-phenyl-ethylamino)-3-(4-methyl-6-piperazine-1-base-1H-benzimidazolyl-2 radicals-yl)-(25mg adds acetone (0.25mL) and 1M NaCNBH in methyl alcohol 0.054mmol) (0.5mL) solution to the 1H-pyridin-2-ones 3THF solution (0.2mL).Reaction mixture is at room temperature stirred 1h, vacuum concentration then.Resistates is purified with preparation HPLC and is obtained title compound (12mg, 44%). 1H?NMR(400MHz，CD 3OD)δ7.10-7.24(6H，m)，7.08(1H，s)，7.06(1H，s)，6.06(1H，d，J＝7.9Hz)，3.58-4.01(10H，m)，3.34(1H，m)，3.14(1H，m)，2.98(1H，dd，J＝5.9，13.7Hz)，2.83(1H，dd，J＝7.9，13.7Hz)，2.60(3H，s)，1.44(6H，d，J＝6.7Hz)。LCMS(M+H) +m/z?501(t＝1.80min)。
Embodiment 40
(S)-3-[6-(4-benzyl-piperazine-1-yl)-4-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl]-4-(1-methylol-2-phenyl-ethylamino)-1H-pyridin-2-ones: 1H NMR (400MHz, CD 3OD) δ 7.50-7.57 (6H, m), 7.04-7.27 (7H, m), 6.07 (1H, d, J=7.8Hz), 4.22 (2H, s), 3.97-4.00 (1H, m), 3.34-3.77 (2H, m), 2.82-3.04 (10H, m), 2.58 (3H, s).LCMS(M+H) +m/z?549(t＝1.93min)。
Embodiment 41
Figure A0281051601141
(±)-3-[6-(4-ethanoyl-piperazine-1-yl)-4-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl]-4-[2-(3-chloro-phenyl)-2-hydroxyl-ethylamino]-the 1H-pyridin-2-ones: 1H NMR (400MHz, CD 3OD) δ 7.50 (1H, s), 7.25-7.49 (5H, m), 7.20 (1H, s), 6.25 (1H, d ,=8.0Hz), 4.94 (1H, dd, J=4.6,7.1Hz), 3.88-3.92 (4H, m), 3.50-3.65 (6H, m), 2.62 (3H, s), 2.20 (3H, s).LCMS(M+H) +m/z?521(t＝2.13min)。
Embodiment 42
Figure A0281051601142
(±)-4-[2-(3-chloro-phenyl)-2-hydroxyl-ethylamino]-3-(4-methyl-6-piperazine-1-base-1H-benzimidazolyl-2 radicals-yl)-the 1H-pyridin-2-ones: 1H NMR (400MHz, CD 3OD) δ 7.47 (1H, s), 7.25-7.38 (4H, m), 7.07 (2H, s), 6.25 (1H, d, J=7.6Hz), 4.90 (1H, m), 3.42-3.66 (10H, m), 2.59 (3H, s).LCMS?(M+H) +m/z479(t＝1.90min)。
Embodiment 43
Figure A0281051601151
(±)-4-[2-(3-chloro-phenyl)-2-hydroxyl-ethylamino]-3-[6-(4-sec.-propyl-piperazine-1-yl)-4-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl]-the 1H-pyridin-2-ones: 1H NMR (400MHz, CD 3OD) δ 7.47 (1H, s), 7.25-7.38 (4H, m), 7.06 (2H, s), 6.26 (1H, d, J=7.6Hz), and 4.91-4.93 (1H, m), 3.89-3.92 (2H, m), and 3.51-3.64 (5H, m), 3.31-3.37 (2H, m), and 3.09-3.30 (2H, m), 2.59 (3H, s), 1.44 (6H, d, J=6.6Hz).LCMS(M+H) +m/z?521(t＝1.95min)。
Embodiment 44
(S)-6-(1-methylol-2-phenyl-ethylamino)-5-(6-imidazoles-1-base-4-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl)-the 3H-pyrimidin-4-one:
(S)-2-[6-chloro-5-(6-imidazoles-1-base-4-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl)-pyrimidine-4-base is amino]-3-phenyl-third-1-alcohol:
2-(4,6-two chloro-pyrimidine-5-yl)-6-imidazoles-1-base-4-methyl isophthalic acid H-benzoglyoxaline (40mg, add in Virahol 0.16mmol) (5mL) solution (S)-(-)-2-amino-3-phenyl-propyl alcohol (35mg, 0.23mmol) and triethylamine (0.5mL).Reaction mixture is heated to 80 ℃ of 4h, is cooled to room temperature, high vacuum concentrates then.Crude product is directly used in next step and need not to purify again.LCMS(M+H) +m/z?460(t＝2.13min)。
(S)-6-(1-methylol-2-phenyl-ethylamino)-5-(6-imidazoles-1-base-4-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl)-the 3H-pyrimidin-4-one:
(S)-2-[6-chloro-5-(6-imidazoles-1-base-4-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl)-pyrimidine-4-base is amino]-the 4N HCl (0.5mL) of 3-phenyl-third-1-alcohol and acetate (0.5mL) solution in adding 2 drip.Reaction mixture is heated to 100 ℃ of 8h, is cooled to room temperature, the methanol solution with ammonia neutralizes then.After concentrating, resistates is purified with preparation HPLC and is obtained title compound (26mg, 37%, two step). 1H NMR (400MHz, CD 3OD) δ 9.41 (1H, narrow peak t, J=1.5Hz), 8.06 (1H, narrow peak dd, J=1.6,1.9Hz), 7.9391H, s), 7.77 (1H, narrow peak dd, J=1.6,1.8Hz), 7.73 (1H, narrow peak d, J=1.9Hz), 7.11-7.21 (6H, m), 4.70-4.74 (1H, m), 3.74 (2H, d, J=4.7Hz), 3.11 (1H, dd, J=6.1,13.5Hz), 3.00 (1H, dd, J=7.8,13.5Hz), 2.70 (3H, s).LCMS(M+H) +m/z?442(t＝2.17min)。
Embodiment 45-383 prepares according to above-mentioned general method (flow process III)
The LCMS condition:
A) YMC C18 S5 4.6 * 50mm; The 0-100% gradient, 4min *Flow velocity 4mL/min
B) YMC ODS-A C18 S7 3.0 * 50mm; The 0-100% gradient, 2min *Flow velocity 5mL/min
C) YMC C18 S5 4.5 * 50mm; The 0-100% gradient, 8min *Flow velocity 2.5mL/min
D) YMC C18 S7 3.0 * 50mm; The 0-100% gradient, 3min *Flow velocity 5mL/min
E) YMC ODSA S3 6.0 * 150mm; The 0-100% gradient, 5min *Flow velocity 1.5mL/min
F) PHS-PRIMESPHERE C18 4.6 * 30mm; The 0-100% gradient, 2min *Flow velocity 5mL/min
G) YMC C18 S7 3.0 * 50mm; The 0-100% gradient, 4min *Flow velocity 5mL/min
H) YMC ODS-A C18 S7 3.0 * 50mm; The 0-100% gradient, 2min *Flow velocity 5mL/min
I) YMC ODS-A C18 S7 3.0 * 50mm; The 0-100% gradient, 1.5min *Flow velocity 5mL/min
J) YMC Xterra C18 S7 3.0 * 50mm; The 0-100% gradient, 2min *Flow velocity 5mL/min
K) YMC Pro-0DS C18 S5 4.6 * 33mm; The 0-100% gradient, 3min *Flow velocity 4mL/min
1) YMC ODS-A C18 S7 3.0 * 50mm; The 0-100% gradient, 4min *Flow velocity 4mL/min
*Gradient finishes with 90% methyl alcohol/10% water (0.1%TFA) since 10% methyl alcohol/90% water (0.1%TFA)
Embodiment # title
Figure A0281051601181
Figure A0281051601201
Figure A0281051601221
Figure A0281051601301
Figure A0281051601311
Figure A0281051601321
Figure A0281051601331
Figure A0281051601341
Figure A0281051601361
Figure A0281051601371
Figure A0281051601381
Figure A0281051601391
Figure A0281051601401
Figure A0281051601411
Figure A0281051601421
Figure A0281051601441
Figure A0281051601461
Figure A0281051601471
Figure A0281051601501
Figure A0281051601511
Figure A0281051601521
Figure A0281051601531
Figure A0281051601561
Figure A0281051601571
Figure A0281051601581
Figure A0281051601591
Figure A0281051601621
Figure A0281051601631
Figure A0281051601641
Generate intermediate imido-ester (flow process IV, 13)
(S)-and 2-[4-(1-methylol-2-phenyl-ethylamino)-2-oxo-1,2-dihydro-pyridin-3-yl]-7-methyl-3H-benzoglyoxaline-5-first imido acid ethyl ester:
At 0 ℃ to (S)-2-[4-(1-methylol-2-phenyl-ethylamino)-2-oxo-1,2-dihydro-pyridin-3-yl]-7-methyl-3H-benzoglyoxaline-5-formonitrile HCN (0.8g, 2.0mmol) ethanol (anhydrous, 80mL) feed HCl (anhydrous) in the suspension until saturated.Feed after several minutes, mixture becomes settled solution, and solution is at room temperature stirred 14h.Behind the vacuum concentration, crude product (0.89g, 100%) directly uses and need not to purify again.LCMS(M+H) +m/z?446(t＝1.55min)。
Figure A0281051601662
(±)-2-{4-[2-(3-chloro-phenyl)-2-hydroxyl-ethylamino]-2-oxo-1,2-dihydro-pyridin-3-yl }-7-methyl-3H-benzoglyoxaline-5-first imido acid ethyl ester:
Title compound is according to the general step preparation that generates imido-ester.LCMS(M+H) +m/z?466(t＝1.43min)。
General step-generation the tetrahydroglyoxaline (flow process IV, 14) that is used for embodiment 384-397
Embodiment 384
(S)-3-[6-(4,5-dihydro-1H-imidazoles-2-yl)-4-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl]-4-(1-methylol-2-phenyl-ethylamino)-1H-pyridin-2-ones:
Rough imido-ester (60mg, 0.135mmol) with methyl alcohol dilution, then add quadrol (24mg, 0.40mmol).Reaction mixture is heated to backflow 6h.Behind the vacuum concentration, resistates is purified with preparation HPLC and is obtained title compound (37mg, 62%). 1H?NMR(300MHz，CD 3OD)δ7.94(1H，s)，7.50(1H，s)，7.12-7.30(6H，m)，6.16(1H，d，J＝7.7Hz)，4.04-4.10(5H，m)，3.75-3.77(2H，m)，3.15(1H，dd，J＝5.2，13.6Hz)，2.96(1H，dd，J＝8.1，13.6Hz)，2.67(3H，s)。LCMS(M+H) +m/z?443(t＝1.50min)。
Embodiment 385
(±)-4-[2-(3-chloro-phenyl)-2-hydroxyl-ethylamino]-3-[6-(4,5-dihydro-1H-imidazoles-2-yl)-4-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl]-the 1H-pyridin-2-ones:
1H?NMR(300MHz，CD 3OD)δ7.93(1H，s)，7.54(1H，s)，7.23-7.45(5H，m)，6.26(1H，d，J＝7.6Hz)，5.01(1H，t，J＝6.3Hz)，4.01(4H，s)，3.78(1H，dd，J＝4.7，13.5Hz)，3.67(1H，dd，J＝6.6，13.5Hz)，2.66(3H，s)。LCMS(M+H) +m/z?463(t＝1.54min)
Embodiment 386
Figure A0281051601681
4-[2-(3-chloro-phenyl)-2R-hydroxyl-ethylamino]-3-[4-methyl-6-(4S-methyl-4,5-dihydro-1H-imidazoles-2-yl)-1H-benzimidazolyl-2 radicals-yl]-1H-pyridin-2-ones and 4-[2-(3-chloro-phenyl)-2S-hydroxyl-ethylamino]-3-[4-methyl-6-(4S-methyl-4,5-dihydro-1H-imidazoles-2-yl)-1H-benzimidazolyl-2 radicals-yl]-the 1H-pyridin-2-ones:
1H?NMR(300MHz，CD 3OD)δ7.90(2H，s)，7.53(2H，s)，7.22-7.47(10H，m)，6.23(2H，d，J＝7.5Hz)，5.00(2H，t，J＝6.4Hz)，4.49-4.57(2H，m)，4.21(2H，t，J＝11.0Hz)，3.61-3.78(6H，m)，2.63(6H，s)，1.48(6H，d，J＝6.3Hz)。LCMS(M+H) +m/z?477(t＝1.71min)。
Embodiment 387
Figure A0281051601682
(±)-4-[2-(3-chloro-phenyl)-2-hydroxyl-ethylamino]-3-[4-methyl-6-(1-methyl-4,5-dihydro-1H-imidazoles-2-yl)-1H-benzimidazolyl-2 radicals-yl]-the 1H-pyridin-2-ones:
1H?NMR(300MHz，CD 3OD)δ7.94(1H，s)，7.57(1H，s)，7.23-7.52(5H，m)，6.22(1H，d，J＝7.5Hz)，4.99(1H，m)，4.00-4.15(2H，m)，3.57-3.75(4H，m)，2.77(3H，s)，2.61(3H，s)。LCMS(M+H) +m/z477(t＝1.60min)。
Embodiment 388
Figure A0281051601691
(±)-4-[2-(3-chloro-phenyl)-2-hydroxyl-ethylamino]-3-[6-(4,4-dimethyl-4,5-dihydro-1H-imidazoles-2-yl)-4-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl]-the 1H-pyridin-2-ones:
1H?NMR(300MHz，CD 3OD)δ7.89(1H，s)，7.52(1H，s)，7.22-7.45(5H，m)，6.19(1H，d，J＝7.4Hz)，4.99(1H，t，J＝6.2Hz)，3.84(2H，s)，3.78(1H，dd，J＝4.4，13.4Hz)，3.60(1H，dd，J＝6.7，13.4Hz)，2.61(3H，s)，1.55(6H，s)。LCMS(M+H) +m/z?491(t＝1.73min)。
Embodiment 389
2-(2-{4-[2-(3-chloro-phenyl)-2R-hydroxyl-ethylamino]-2-oxo-1,2-dihydro-pyridin-3-yl }-7-methyl-3H-benzoglyoxaline-5-yl)-4,5-dihydro-1H-imidazoles-4S-formic acid and 2-(2-{4-[2-(3-chloro-phenyl)-2S-hydroxyl-ethylamino]-2-oxo-1,2-dihydro-pyridin-3-yl }-7-methyl-3H-benzoglyoxaline-5-yl)-4,5-dihydro-1H-imidazoles-4S-formic acid:
1H?NMR(300MHz，CD 3OD)δ7.88(2H，s)，7.52(2H，s)，7.22-7.44(10H，m)，6.17(2H，d，J＝7.4Hz)，5.05(2H，m)，4.23-4.38(4H，m)，3.56-3.72(6H，m)，2.58(6H，s)。LCMS(M+H) +m/z?507(t＝1.64min)。
Embodiment 390
Figure A0281051601701
(±)-4-[2-(3-chloro-phenyl)-2-hydroxyl-ethylamino]-3-[4-methyl-6-(1,4,5,6-tetrahydrochysene-pyrimidine-2-base)-1H-benzimidazolyl-2 radicals-yl]-the 1H-pyridin-2-ones:
1H?NMR(300MHz，CD 3OD)δ7.90(1H，s)，7.53(1H，s)，7.22-7.47(5H，m)，6.23(1H，d，J＝7.6Hz)，5.00(1H，t，J＝6.3Hz)，4.49-4.57(1H，m)，3.60-3.77(5H，m)，3.24-3.34(2H，m)，2.63(3H，s)。LCMS(M+H) +m/z?477(t＝1.59min)。
Embodiment 391
Figure A0281051601702
(±)-4-[2-(3-chloro-4-methoxyl group-phenyl)-2-methoxyl group-ethylamino]-3-[6-(4,5-dihydro-1H-imidazoles-2-yl)-4-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl]-the 1H-pyridin-2-ones:
1H?NMR(300MHz，CD 3OD)δ7.88(1H，s)，7.46(1H，s)，7.44(1H，s)，7.31(1H，d，J＝6.4Hz)，7.28(1H，d，J＝5.6?Hz)，7.01(1H，d，J＝6.4Hz，6.19(1H，d，J＝5.6Hz)，4.49(1H，dd，J＝3.4，5.0Hz)，4.09(4H，s)，3.82(3H，s)，3.36(3H，s)，3.63-3.67(2H，m)，2.62(3H，s)。LCMS(M+H) +m/z?507(t＝1.72min)。
Embodiment 392
(±)-4-[2-(3-bromo-4-methoxyl group-phenyl)-2-hydroxyl-ethylamino]-3-[6-(4,5-dihydro-1H-imidazoles-2-yl)-4-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl]-the 1H-pyridin-2-ones:
Hydrolysis benzylic type muriate is that oxy-compound prepares title compound. 1H?NMR(400MHz，CD 3OD)δ7.90(1H，s)，7.67(1H，s)，7.48(1H，s)，7.38(1H，dd，J＝2.0，8.5Hz)，7.31(1H，d，J＝7.6Hz)，6.95(1H，d，J＝8.5Hz)，6.26(1H，d，J＝7.6Hz)，4.94(1H，m)，4.10(4H，s)，3.80(3H，s)，3.62-3.74(2H，m)，2.62(3H，s)。LCMS(M+H) +m/z?537(t＝1.49min)。
Embodiment 393
Figure A0281051601712
(S)-3-[6-(4,4-dimethyl-4,5-dihydro-1H-imidazoles-2-yl)-4-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl]-4-(1-methylol-2-phenyl-ethylamino)-1H-pyridin-2-ones:
1H?NMR(300MHz，CD 3OD)δ7.94(1H，s)，7.50(1H，s)，7.12-7.30(6H，m)，6.15(1H，dd，J＝7.7?Hz)，4.02-4.10(1H，m)，3.85(2H，s)，3.75-3.77(2H，m)，2.96-3.17(2H，m)，2.67(3H，s)，1.56(6H，s)。LCMS(M+H) +m/z?471(t＝1.62min)。
Embodiment 394
Figure A0281051601721
(S)-and 2-{2-[4-(1S-methylol-2-phenyl-ethylamino)-2-oxo-1,2-dihydro-pyridin-3-yl]-7-methyl-3H-benzoglyoxaline-5-yl }-4,5-dihydro-1H-imidazoles-4S-formic acid
1H?NMR(300MHz，CD 3OD)δ8.03(1H，s)，7.60(1H，s)，7.11-7.29(6H，m)，6.15(1H，d，J＝7.3Hz)，5.07(1H，dd，J＝6.9，11.8Hz)，4.25-4.41(2H，m)，4.05-4.07(1H，m)，3.70-3.82(2H，m)，3.12(1H，dd，J＝5.5，13.6Hz)，2.95(1H，dd，J＝8.0，13.6Hz)，2.69(3H，s)。LCMS(M+H) +m/z?487(t＝1.35min)。
Embodiment 395
Figure A0281051601722
(S)-4-(1-methylol-2-phenyl-ethylamino)-3-[4-methyl-6-(1,4,5,6-tetrahydrochysene-pyrimidine-2-base)-1H-benzimidazolyl-2 radicals-yl]-the 1H-pyridin-2-ones:
1H?NMR(300MHz，CD 3OD)δ7.76(1H，s)，7.32(1H，s)，7.09-7.29(6H，m)，6.15(1H，d，J＝7.6Hz)，4.02-4.07(1H，m)，3.71-3.79(2H，m)，3.61(4H，t，J＝5.6Hz)，3.14(1H，dd，J＝5.3，13.6Hz)，2.95(1H，dd，J＝8.1，13.6Hz)，2.65(3H，s)，2.09-2.16(2H，m)。LCMS(M+H) +m/z?457(t＝1.49min)。
Embodiment 396
(S)-4-(1-methylol-2-phenyl-ethylamino)-3-[4-methyl-6-(1-methyl-4,5-dihydro-1H-imidazoles-2-yl)-1H-benzimidazolyl-2 radicals-yl]-the 1H-pyridin-2-ones:
1H?NMR(300MHz，CD 3OD)δ7.77(1H，s)，7.10-7.30(7H，m)，6.16(1H，d，J＝7.6Hz)，3.97-4.20(5H，m)，3.73-3.77(2H，m)，3.26(3H，s)，3.15(1H，dd，J＝5.3，13.6Hz)，2.96(1H，dd，J＝8.0，13.6Hz)，2.68(3H，s)。LCMS(M+H) +m/z?457(t＝1.53min)
Embodiment 397
Figure A0281051601732
(S)-3-[6-(4,5-dihydro-1H-imidazoles-2-yl)-4-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl]-4-(2-hydroxyl-2-phenyl-ethylamino)-1H-pyridin-2-ones:
1H?NMR(400MHz，CD 3OD)δ7.91(1H，s)，7.50(1H，s)，7.48(2H，s)，7.24-7.35(4H，m)，6.25(1H，d，J＝7.6Hz)，5.01(1H，dd，J＝4.6，7.0Hz)，4.10(4H，s)，3.65-3.76(2H，m)，2.64(3H，s)。LCMS(M+H) +m/z?429(t＝1.48min)。
Embodiment 398
Figure A0281051601741
(S)-4-(1-methylol-2-phenyl-ethylamino)-3-[6-(1H-imidazoles-2-yl)-4-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl]-the 1H-pyridin-2-ones:
Imido-ester (150mg, and adding aminoacetaldehyde diethyl acetal in methyl alcohol 0.31mmol) (10mL) solution (97mg, 0.93mmol).Mixture is at room temperature stirred 14h.Solvent removed in vacuo, resistates 60%HClO 4(5mL) at room temperature handle 14h.Then reaction mixture is neutralized with dense ammonium hydroxide.Leach inorganic salt.Concentrated filtrate obtains white solid title compound (37mg, 27%) with the preparation HPLC purification. 1H NMR (300MHz, CD 3OD) δ 7.94 (1H, narrow peak d, J=1.3Hz), 7.58 (2H, s), 7.53 (1H, narrow peak d, J=0.6Hz), 7.12-7.31 (6H, m), 6.16 (1H, d, J=7.7Hz), 4.04-4.08 (1H, m), 3.76-3.79 (2H, m), 3.16 (1H, dd, J=54,13.6Hz), 3.97 (1H, dd, J=8.1,13.6Hz), 2.69 (3H, s).LCMS(M+H) +m/z?441(t＝1.60min)。
The general step of preparation amidine, embodiment 399-412 (flow process IV, 16)
Embodiment 399
Figure A0281051601742
(S)-and 2-[4-(1-methylol-2-phenyl-ethylamino)-2-oxo-1,2-dihydro-pyridin-3-yl]-7, N-dimethyl-3H-benzoglyoxaline-5-carbonamidine:
(60mg 0.135mmol) with methyl alcohol (10mL) dilution, adds methylamine (methanol solution of 2.0M, 0.5mL, excessive) in the solution rough imido-ester then.After stirring 2h, concentrated reaction mixture obtains white solid title compound (32mg, 55%) with the preparation HPLC purification. 1H?NMR(300MHz，CD 3OD)δ7.82(1H，s)，7.38(1H，s)，7.10-7.30(6H，m)，6.15(1H，J＝7.7?Hz)，4.03-4.07(1H，m)，4.72-4.76(2H，m)，3.06-3.18(1H，m)，3.12(3H，s)，2.96(1H，dd，J＝8.0，13.5?Hz)，2.67(3H，s)。LCMS?(M+H) +m/z?431(t＝1.34min)。
Embodiment 400
(±)-2-{4-[2-(3-chloro-phenyl)-2-hydroxyl-ethylamino]-2-oxo-1,2-dihydro-pyridin-3-yl }-7, N-dimethyl-3H-benzoglyoxaline-5-carbonamidine:
1H?NMR(300MHz，CD 3OD)δ7.81(1H，s)，7.54(1H，s)，7.23-7.54(5H，m)，6.26(1H，d，J＝7.6Hz)，5.01(1H，t，J＝4.8Hz)，3.77(1H，dd，J＝4.5，13.4Hz)，3.67(1H，dd，J＝6.6，13.4Hz)，3.12(3H，s)，2.66(3H，s)。LCMS(M+H) +m/z?451(t＝1.32min)。
Embodiment 401
Figure A0281051601752
(±)-2-{4-[2-(3-chloro-phenyl)-2-hydroxyl-ethylamino]-2-oxo-1,2-dihydro-pyridin-3-yl }-7-methyl-3H-benzoglyoxaline-5-carbonamidine:
1H?NMR(300MHz，CD 3OD)δ7.90(1H，s)，7.26-7.57(6H，m)，6.25(1H，d，J＝7.6Hz)，5.01(1H，t，J＝6.4Hz)，3.75(1H，dd，J＝4.8，13.4Hz)，3.66(1H，dd，J＝6.7，13.4Hz)，2.62(3H，s)。LCMS(M+H) +m/z?437(t＝1.59min)。
Embodiment 402
Figure A0281051601761
(±)-2-{4-[2-(3-chloro-phenyl)-2-hydroxyl-ethylamino]-2-oxo-1,2-dihydro-pyridin-3-yl }-7, N, N-trimethylammonium-3H-benzoglyoxaline-5-carbonamidine:
1H?NMR(300MHz，CD 3OD)δ7.63(1H，s)，7.54(1H，s)，7.18-7.41(5H，m)，6.26(1H，d，J＝7.6Hz)，5.01(1H，t，J＝6.3Hz)，3.77(1H，dd，J＝4.7，13.5Hz)，3.67(1H，dd，J＝6.6，13.5Hz)，3.34(6H，s)，2.66(3H，s)。LCMS(M+H) +m/z?465(t＝1.57min)。
Embodiment 403
(±)-2-{4-[2-(3-chloro-phenyl)-2-hydroxyl-ethylamino]-2-oxo-1,2-dihydro-pyridin-3-yl }-N-cyclopropyl-7-methyl-3H-benzoglyoxaline-5-carbonamidine:
1H?NMR(300MHz，CD 3OD)δ7.78(1H，s)，7.54(1H，s)，7.22-7.41(5H，m)，6.25(1H，d，J＝7.6Hz)，5.01(1H，t，J＝6.4Hz)，3.76(1H，dd，J＝4.7，13.5Hz)，3.67(1H，dd，J＝6.6，13.5Hz)，2.77-2.83(1H，m)，2.65(3H，s)，1.03-1.10(2H，m)，0.86-0.92(2H，m)。LCMS(M+H) +m/z?477(t＝1.43min)。
Embodiment 404
(±)-2-{4-[2-(3-chloro-4-methoxyl group-phenyl)-2-methoxyl group-ethylamino]-2-oxo-1,2-dihydro-pyridin-3-yl }-7, N-dimethyl-3H-benzoglyoxaline-5-carbonamidine:
1H NMR (300MHz, CD 3OD) δ 7.79 (1H, narrow peak d, J=1.0Hz), 7.45 (1H, narrow peak d, J=1.5Hz), 7.38 (1H, s), 7.28-7.31 (2H, m), 7.02 (1H, d, J=6.4Hz), 6.22 (1H, d, J=5.7Hz), 4.52 (1H, t, J=5.9Hz), 3.83 (3H, s), 3.60-3.71 (2H, m), 3.36 (3H, s), 3.13 (3H, s), 2.65 (3H, s).LCMS(M+H) +m/z?495(t＝1.64min)。
Embodiment 405
(±)-2-{4-[2-(3-chloro-4-methoxyl group-phenyl)-2-hydroxyl-ethylamino]-2-oxo-1,2-dihydro-pyridin-3-yl }-7, N-dimethyl-3H-benzoglyoxaline-5-carbonamidine:
2-{4-[2-(3-chloro-4-methoxyl group-phenyl)-2-methoxyl group-ethylamino]-2-oxo-1,2-dihydro-pyridin-3-yl }-7, N-dimethyl-3H-benzoglyoxaline-5-carbonamidine (40mg, 0.08mmol) methyl alcohol (5mL) solution in add 2N NaOH (0.5mL), reaction mixture is at room temperature stirred 14h.Behind the vacuum concentration, resistates is purified with preparation HPLC and is obtained oily title compound (7.2mg, 19%). 1H NMR (300MHz, CD 3OD) δ 7.78 (1H, narrow peak d, J=1.6Hz), 7.52 (1H, narrow peak d, J=2.1Hz), and 7.30-7.36 (3H, m), 6.99 (1H, d, J=8.5Hz), 6.27 (1H, d, J=7.6Hz), 4.94 (1H, t, J=5.9Hz), 3.82 (3H, s), 3.68-3.72 (2H, m), 3.13 (3H, s), 2.63 (3H, s).LCMS(M+H) +m/z?481(t＝1.44min)
Embodiment 406
Figure A0281051601781
(±)-2-{4-[2-(3-bromo-4-methoxyl group-phenyl)-2-hydroxyl-ethylamino]-2-oxo-1,2-dihydro-pyridin-3-yl]-7, N-dimethyl-3H-benzoglyoxaline-5-carbonamidine:
1H?NMR(400MHz，CD 3OD)δ7.77(1H，s)，7.67(1H，s)，7.29-7.39(3H，m)，6.95(1H，d，J＝8.4Hz)，6.23(1H，d，J＝4.4Hz)，4.92(1H，m)，3.80(3H，s)，3.69(2H，m)，3.13(3H，s)，2.61(3H，s)。LCMS(M+H) +m/z?525(t＝1.44min)。
Embodiment 407
Figure A0281051601791
(S)-and N-cyclopropyl-2-[4-(1-methylol-2-phenyl-ethylamino)-2-oxo-1,2-dihydro-pyridin-3-yl]-7-methyl-3H-benzoglyoxaline-5-carbonamidine:
1H?NMR(300MHz，CD 3OD)δ7.81(1H，s)，7.37(1H，s)，7.10-7.30(6H，m)，6.16(1H，d，J＝7.6Hz)，4.03-4.08(1H，m)，3.74-3.76(2H，m)，3.15(1H，dd，J＝5.3，13.6Hz)，2.96(1H，dd，J＝8.1，13.6Hz)，2.78-2.84(1H，m)，2.67(3H，s)，1.03-1.10(2H，m)，0.87-0.92(2H，m)。LCMS(M+H) +m/z?457(t＝1.51min)。
Embodiment 408
Figure A0281051601792
(S)-and N-ethyl-2-[4-(1-methylol-2-phenyl-ethylamino)-2-oxo-1,2-dihydro-pyridin-3-yl]-7-methyl-3H-benzoglyoxaline-5-carbonamidine:
1H?NMR(400MHz，CD 3OD)δ7.82(1H，s)，7.38(1H，s)，7.12-7.30(6H，m)，6.15(1H，d，J＝7.8Hz)，4.04-4.07(1H，m)，3.75-3.77(2H，m)，3.51(2H，q，J＝7.3Hz)，3.15(1H，dd，J＝5.4，13.7Hz)，2.96(1H，dd，J＝8.1，13.7Hz)，2.67(3H，s)，1.40(3H，t，J＝7.3Hz)。LCMS(M+H) +m/z?445(t＝1.44min)。
Embodiment 409
Figure A0281051601801
(S)-2-{4-[2-(3-chloro-phenyl)-1-methylol-ethylamino]-2-oxo-1,2-dihydro-pyridin-3-yl }-7, N-dimethyl-3H-benzoglyoxaline-5-carbonamidine:
1HNMR(400MHz，CD 3OD)δ7.83(1H，s)，7.38(1H，s)，7.31(1H，s)，7.10-7.24(4H，m)，6.16(1H，d，J＝7.6?Hz)，4.06-4.09(1H，m)，3.72-3.77(2H，m)，3.16(3H，s)，3.15(1H，m)，2.96(1H，dd，J＝8.2，13.7Hz)，2.67(3H，s)。LCMS(M+H) +m/z?465(t＝1.49min)。
Embodiment 410
Figure A0281051601802
(S)-2-{4-[2-(2-chloro-phenyl)-1-methylol-ethylamino]-2-oxo-1,2-dihydro-pyridin-3-yl }-7, N-dimethyl-3H-benzoglyoxaline-5-carbonamidine:
1H?NMR(400MHz，CD 3OD)δ7.84(1H，s)，7.41(1H，s)，7.32-7.35(2H，m)，7.06-7.18(3H，m)，6.10(1H，d，J＝7.5Hz)，4.20-4.24(1H，m)，3.76-3.85(2H，m)，3.30-3.34(1H，m)，3.06-3.14(1H，m)，3.13(3H，s)，2.64(3H，s)。LCMS(M+H) +m/z?465(t＝1.48min)。
Embodiment 411
Figure A0281051601811
(±)-2-{4-[2-(3-bromo-phenyl)-2-hydroxyl-ethylamino]-2-oxo-1,2-dihydro-pyridin-3-yl }-7, N-dimethyl-3H-benzoglyoxaline-5-carbonamidine:
1H?NMR(300MHz，CD 3OD)δ7.80(1H，s)，7.69(1H，s)，7.20-7.45(5H，m)，6.25(1H，d，J＝7.3Hz)，5.00(1H，t，J＝5.9Hz)，3.64-3.80(2H，m)，3.12(3H，s)，2.66(3H，s)。LCMS(M+H) +m/z?495(t＝1.49min)。
Embodiment 412
Figure A0281051601812
(S)-and 2-[4-(2-hydroxyl-2-phenyl-ethylamino)-2-oxo-1,2-dihydro-pyridin-3-yl]-7, N-dimethyl-3H-benzoglyoxaline-5-carbonamidine:
1H?NMR(400MHz，CD 3OD)δ7.78(1H，s)，7.24-7.49(7H，m)，6.21(1H，d，J＝7.0Hz)，4.00-5.05(1H，m)，3.61-3.74(2H，m)，3.12(3H，s)，2.63(3H，s)。LCMS(M+H) +m/z?417(t＝1.28min)。
Figure A0281051601831
Figure A0281051601841
Figure A0281051601881
Figure A0281051601891
The preparation acid amides
Intermediate is synthetic
Figure A0281051601902
(±)-2-{4-[2-(3-chloro-phenyl)-2-hydroxyl-ethylamino]-2-oxo-1,2-dihydro-pyridin-3-yl }-7-methyl-3H-benzoglyoxaline-5-ethyl formate:
(±)-2-{4-[2-(3-chloro-phenyl)-2-hydroxyl-ethylamino-]-2-oxo-1,2-dihydro-pyridin-3-yl }-7-methyl-3H-benzoglyoxaline-5-first imido acid ethyl ester solution (400mg, 0.90mmol) with 2N HCl (20mL) solution dilution, mixture is at room temperature stirred 14h.Be concentrated into do after, crude product (419mg, 100%) is directly used in next step and need not to purify again.Low amounts of product is purified with preparation HPLC and is obtained title compound. 1H?NMR(300MHz，CD 3OD)δ8.11(1H，s)，7.74(1H，s)，7.25-7.54(5H，m)，6.25(1H，d，J＝7.6Hz)，4.99(1H，t，J＝7.2Hz)，4.38(2H，q，J＝7.1Hz)，3.61-3.76(2H，m)，2.61(3H，s)，1.42(3H，q，J＝7.1Hz)。LCMS(M+H) +m/z?467(t＝2.23min)。
Figure A0281051601911
(±)-2-{4-[2-(3-chloro-phenyl)-2-hydroxyl-ethylamino]-2-oxo-1,2-dihydro-pyridin-3-yl }-7-methyl-3H-benzoglyoxaline-5-formic acid:
Above ethyl ester (419mg 0.90mmol) dilutes with methyl alcohol (15mL) and water (5mL), then add sodium hydroxide (180mg, 4.5mmol).Mixture at room temperature stirs 14h.After removing methyl alcohol, resistates neutralizes with 2N HCl solution.Filter the gained soup compound, wash with ice cold water.Collect solid after the high vacuum dry.Crude product (395mg, 100% yield, 80% purity) is directly used in next step and need not to purify again. 1NMR(300MHz，CD 3OD)δ8.20(1H，s)，7.92(1H，s)，7.27-7.47(5H，m)，6.27(1H，d，J＝7.6Hz)，4.85(1H，m)，3.63(2H，m)，2.67(3H，s)。LCMS(M+H) +m/z?439(t＝1.88min)。
Embodiment 475
Figure A0281051601921
(S)-and 2-[4-(1-methylol-2-phenyl-ethylamino)-2-oxo-1,2-dihydro-pyridin-3-yl]-7-methyl-3H-benzoglyoxaline-5-ethyl formate:
(30mg 0.067mmol) with methyl alcohol (10mL) dilution, adds two and drips imido-ester then.Reaction mixture is at room temperature stirred 20h.Behind the vacuum concentration, resistates is purified with preparation HPLC and is obtained white solid title compound (18.2mg, 61%). 1H MR (300MHz, CD 3OD) δ 7.74 (1H, s), 7.11-7.30 (7H, m), 6.10 (1H, d, J=6.9Hz), 4.37 (2H, q, J=6.6Hz), (4.02 1H, broad peak s), and 3.69-3.81 (2H, m), 3.10 (1H, dd, J=4.8,13.5Hz), 2.93 (1H, dd, J=7.8,13.5Hz), 2.62 (3H, s), 1.41 (3H, J=6.6Hz).LCMS(M+H) +m/z?447(t＝1.95min)。
With (±)-2-{4-[2-(3-chloro-phenyl)-2-hydroxyl-ethylamino]-2-oxo-1,2-dihydro-pyridin-3-yl }-7-methyl-3H-benzoglyoxaline-5-formic acid begins to prepare acid amides, embodiment 476-504, flow process IV, 15
Embodiment 476
Figure A0281051601922
(±)-2-{4-[2-(3-chloro-phenyl)-2-hydroxyl-ethylamino]-2-oxo-1,2-dihydro-pyridin-3-yl]-7-methyl-3H-benzoglyoxaline-5-formic acid methyl nitrosourea:
Acid (50mg, add in DMF 0.11mmol) (5mL) solution diphenyl phosphate azide (38mg, 0.14mmol).Mixture is stirred 5min.Add then methylamine (the THF solution of 2.0M) (0.11mL, 0.22mmol).Mixture is at room temperature stirred 14h.After high vacuum was removed DMF, resistates was purified with preparation HPLC and is obtained white solid title compound (18mg, 36%). 1H?NMR(300MHz，CD 3OD)δ7.89(1H，s)，7.18-7.53(6H，m)，6.23(1H，d，J＝7.6Hz)，4.98(1H，m)，3.70(1H，dd，J＝4.7，13.5Hz)，3.61(1H，dd，J＝7.0，13.5Hz)，2.94(3H，s)，2.61(3H，s)。LCMS(M+H) +m/z?452(t＝1.57min)
Embodiment 477
(±)-2-{4-[2-(3-chloro-phenyl)-2-hydroxyl-ethylamino]-2-oxo-1,2-dihydro-pyridin-3-yl }-7-methyl-3H-benzoglyoxaline-5-(N, dinethylformamide):
1H?NMR(300MHz，CD 3OD)δ7.52(1H，s)，7.24-7.40(5H，m)，7.15(1H，s)，6.25(1H，d，J＝7.6Hz)，4.98(1H，dd，J＝5.0，6.9Hz)，3.70(1H，dd，J＝4.8，13.5Hz)，3.62(1H，dd，J＝7.0，13.5Hz)，3.3(3H，s)，3.08(3H，s)，2.62(3H，s)。LCMS(M+H) +m/z?466(t＝1.84min)。
Embodiment 478
(±)-2-{4-[2-(3-chloro-phenyl)-2-hydroxyl-ethylamino]-2-oxo-1,2-dihydro-pyridin-3-yl }-7-methyl-3H-benzoglyoxaline-5-(N-tert-butylformamide):
1H?NMR(300MHz，CD 3OD)δ7.82(1H，s)，7.53(1H，s)，7.48(1H，s)，7.24-7.40(4H，m)，6.25(1H，d，J＝7.6Hz)，5.00(1H，m)，3.64-3.70(2H，m)，2.62(3H，s)，1.49(9H，s)。LCMS(M+H) +m/z?494(t＝1.79min)。
Embodiment 479
(±)-2-{4-[2-(3-chloro-phenyl)-2-hydroxyl-ethylamino]-2-oxo-1,2-dihydro-pyridin-3-yl }-7-methyl-3H-benzoglyoxaline-5-(N-butyl N-methyl-methane amide):
1H?NMR(300MHz，CD 3OD)δ7.51(1H，s)，7.48(1H，s)，7.24-7.39(4H，m)，7.13(1H，s)，6.22(1H，d，J＝7.6Hz)，4.95(1H，m)，3.55-3.70(3H，m)，3.34(1H，m)，3.05(3H，s)，2.62(3H，s)，0).79-1.69(7H，m)。LCMS(M+H) +m/z?508(t＝1.88min)。
Embodiment 480
(±)-2-{4-[2-(3-chloro-phenyl)-2-hydroxyl-ethylamino]-2-oxo-1,2-dihydro-pyridin-3-yl }-7-methyl-3H-benzoglyoxaline-5-[N-(2-morpholine-4-base-ethyl)-methane amide]:
1H?NMR(300MHz，CD 3OD)δ7.58(1H，s)，7.52(1H，s)，7.05-7.42(5H，m)，6.22(1H，d，J＝7.6Hz)，4.97(1H，dd，J＝4.9，6.7Hz)，2.60-4.07(14H，m)，2.61(3H，s)。LCMS(M+H) +m/z?551(t＝1.49min)。
Embodiment 481
Figure A0281051601952
(±)-4-[1-(2-{4-[2-(3-chloro-phenyl)-2-hydroxyl-ethylamino]-2-oxo-1,2-dihydro-pyridin-3-yl }-7-methyl-3H-benzoglyoxaline-5-yl)-formyl radical]-piperazine-1-t-butyl formate:
1H?NMR(300MHz，CD 3OD)δ7.52(1H，s)，7.50(1H，s)，7.24-7.38(4H，m)，7.18(1H，m)，6.22(1H，d，J＝7.6Hz)，4.97(1H，m)，3.49-3.69(10H，m)，2.62(3H，s)，1.47(9H，s)。LCMS(M+H) +m/z?607(t＝1.90min)。
Embodiment 482
(±)-4-[2-(3-chloro-phenyl)-2-hydroxyl-ethylamino]-3-[4-methyl-6-(1-piperazine-1-base-formyl radical)-1H-benzimidazolyl-2 radicals-yl]-the 1H-pyridin-2-ones:
(±)-4-[1-(2-{4-[2-(3-chloro-phenyl)-2-hydroxyl-ethylamino]-2-oxo-1; 2-dihydro-pyridin-3-yl }-7-methyl-3H-benzoglyoxaline-5-yl)-formyl radical]-piperazine-1-t-butyl formate (40mg; 0.06mmol) methyl alcohol (5mL) solution in add 4.0M HCl De dioxane solution (0.1mL, excessive).Reaction mixture is at room temperature stirred 14h.After concentrating, resistates is purified with preparation HPLC and is obtained white foam shape title compound (16mg, 63%). 1H NMR (300MHz, CD 3OD) δ 7.56 (1H, s), 7.53 (1H, s), 7.23-7.41 (4H, m), 7.17 (1H, m), 6.26 (1H, d, J=7.6Hz), 4.99 (1H, dd, J=4.7,6.4Hz), (3.91 4H, broad peak s), 3.74 (1H, dd, J=4.7,13.5Hz), 3.65 (1H, dd, J=6.4,13.5Hz), (3.31 4H, broad peak s), 2.63 (3H, s).LCMS(M+H) +m/z507(t＝1.38min)。
Embodiment 483
Figure A0281051601962
(±)-2-{4-[2-(3-chloro-phenyl)-2-hydroxyl-ethylamino]-2-oxo-1,2-dihydro-pyridin-3-yl }-7-methyl-3H-benzoglyoxaline-5-(N-cyclopropyl carboxamide):
1H?NMR(300MHz，CD 3OD)δ7.80(1H，s)，7.21-7.53(6H，m)，6.22(1H，d，J＝7.6Hz)，4.99(1H，t，J＝6.4Hz)，3.59-3.76(2H，m)，2.83-2.90(1H，m)，2.60(3H，s)，0.81-0.89(2H，m)，0.64-0.73(2H，m)。LCMS(M+H) +m/z?478(t＝1.60min)
Embodiment 484
Figure A0281051601971
(±)-2-{4-[2-(3-chloro-phenyl)-2-hydroxyl-ethylamino]-2-oxo-1,2-dihydro-pyridin-3-yl }-7-methyl-3H-benzoglyoxaline-5-(N-cyclopentyl methane amide):
1H?NMR(300MHz，CD 3OD)δ7.97(1H，s)，7.16-7.60(6H，m)，6.22(1H，d，J＝7.6Hz)，4.35(1H，m)，3.58-3.68(2H，m)，2.62(3H，s)，1.29-2.07(9H，m)。LCMS(M+H) +m/z?506(t＝1.86min)。
Embodiment 485
Figure A0281051601972
(±)-4-[2-(3-chloro-phenyl)-2-hydroxyl-ethylamino]-3-[4-methyl-6-(1-piperidines-1-base-formyl radical)-1H-benzimidazolyl-2 radicals-yl]-the 1H-pyridin-2-ones:
1H?NMR(300MHz，CD 3OD)δ7.53(1H，s)，7.46(1H，s)，7.18-7.41(4H，m)，7.07(1H，s)，6.23(1H，d，J＝7.6Hz)，4.98(1H，dd，J＝4.8，6.6Hz)，3.60-3.74(5H，m)，3.18-3.24(1H，m)，2.60(3H，m)，1.43-1.7(6H，m)。LCMS(M+H) +m/z?506(t＝1.78min)。
Embodiment 486
Figure A0281051601981
(±)-2-{4-[2-(3-chloro-phenyl)-2-hydroxyl-ethylamino 1-2-oxo-1,2-dihydro-pyridin-3-yl }-7-methyl-3H-benzoglyoxaline-5-(N-cyclohexyl methane amide):
1H?NMR(300MHz，CD 3OD)δ7.88(1H，s)，7.54(1H，s)，7.52(1H，s)，7.16-7.40(4H，m)，6.22(1H，J＝7.6?Hz)，4.97(1H，dd，J＝4.7，6.9Hz)，3.89(H，m)，3.69(1H，dd，J＝4.7，13.5Hz)，3.61(1H，dd，J＝6.9，13.5Hz)，2.61(3H，s)，1.19-2.00(10H，m)。LCMS(M+H) +m/z?520(t＝1.93min)。
Embodiment 487
(±)-4-[2-(3-chloro-phenyl)-2-hydroxyl-ethylamino]-3-{4-methyl-6-[1-(4-methyl-piperidines-1-yl)-formyl radical]-1H-benzimidazolyl-2 radicals-yl }-the 1H-pyridin-2-ones:
1H?NMR(300MHz，CD 30D)δ7.51(1H，s)，7.49(1H，s)，7.21-7.39(4H，m)，7.14(1H，s)，6.24(1H，d，J＝7.6Hz)，4.96(1H，dd，J＝4.7，7.0Hz)，3.68(1H，dd，J＝4.7，13.6Hz)，3.60(1H，dd，J＝7.0，13.6Hz)，2.62(3H，s)，1.93-1.72(9H，m)，1.00(3H，d，J＝6.3Hz)。LCMS(M+H) +m/z?520(t＝1.97min)。
Embodiment 488
Figure A0281051601991
(±)-4-[2-(3-chloro-phenyl)-2-hydroxyl-ethylamino]-3-[6-(4,5-dihydro-thiazol-2-yl)-4-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl]-the 1H-pyridin-2-ones:
(±)-2-{4-[2-(3-chloro-phenyl)-2-hydroxyl-ethylamino]-2-oxo-1,2-dihydro-pyridin-3-yl }-7-methyl-3H-benzoglyoxaline-5-formonitrile HCN (100mg, 0.24mmol) methyl alcohol (20mL) solution in add 2-amino-ethyl sulfydryl hydrochloride (41mg, 0.36mmol) and triethylamine (0.1mL, excessive).Reaction mixture is heated to backflow 14h, is cooled to room temperature then.After concentrating, resistates is purified with preparation HPLC and is obtained yellow solid title compound (76mg, 66%). 1H?NMR(300MHz，CD 3OD)δ8.10(1H，s)，7.71(1H，s)，7.66(1H，s)，7.25-7.53(4H，m)，6.33(1H，d，J＝7.6Hz)，5.01(1H，dd，J＝4.2，7.0Hz)，4.58(2H，t，J＝8.6Hz)，3.91(2H，t，J＝8.6Hz)，3.73(1H，dd，J＝4.2，13.7Hz)，3.63(1H，dd，J＝7.0)，13.7Hz)，2.64(3H，s)。LCMS(M+H) +m/z?480(t＝1.70min)。
Embodiment 489
(±)-2-{4-[2-(3-chloro-phenyl)-2-hydroxyl-ethylamino]-2-oxo-1,2-dihydro-pyridin-3-yl }-7-methyl-3H-benzoglyoxaline-5-formaldehyde:
Under-78 ℃, nitrogen atmosphere, to (±)-2-{4-[2-(3-chloro-phenyl)-2-hydroxyl-ethylamino]-2-oxo-1,2-dihydro-pyridin-3-yl }-7-methyl-3H-benzoglyoxaline-5-formonitrile HCN (76mg, 0.18mmol) toluene (anhydrous, 20mL) add in the suspension diisobutyl aluminum (1.4M toluene solution) (0.65mL, 0.97mmol).Mixture is stirred 6h at-78 ℃.Add ethyl acetate (1mL) then, then add entry (0.5mL).Mixture at room temperature stirs 20min.Make mixture pass through Celite pad, concentrated filtrate then.Crude product is purified with preparation HPLC and is obtained brown solid title compound (4mg, 2.5%). 1H?NMR(300MHz，CD 3OD)δ7.65(1H，s)，7.57(1H，s)，7.24-7.50(5H，m)，6.26(1H，d，J＝7.6Hz)，5.49(1H，s)，4.96(1H，m)，3.53-3.79(2H，m)，2.62(3H，s)。LCMS(M+H) +m/z?423(t＝1.79min)
Embodiment 490
Figure A0281051602001
(±)-4-[2-(3-chloro-phenyl)-2-hydroxyl-ethylamino]-3-[6-(1-hydroxyl-1-methyl-ethyl)-4-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl]-the 1H-pyridin-2-ones:
Under-78 ℃, nitrogen atmosphere, to (±)-2-{4-[2-(3-chloro-phenyl)-2-hydroxyl-ethylamino]-2-oxo-1,2-dihydro-pyridin-3-yl }-7-methyl-3H-benzoglyoxaline-5.-ethyl formate (40mg, 0.08mmol) THF (5mL) solution in add lithium methide (1.4M THF solution, 0.57mL, 0.8mmol).Reaction mixture is risen to ambient temperature overnight gradually.After the water quencher, mixture distributes between ethyl acetate and water.Organic layer salt water washing is used dried over sodium sulfate, then vacuum concentration.Resistates is purified with preparation HPLC and is obtained colorless oil title compound (13mg, 36%). 1H?NMR(300MHz，CD 3OD)δ7.66(1H，s)，7.47(1H，s)，7.26-7.41(5H，m)，6.26(1H，d，J＝7.6Hz)，4.92(1H，m)，3.54-3.61(2H，m)，2.62(3H，s)，1.60(6H，s)。LCMS(M+H) +m/z?453(t＝1.46min)。
Embodiment 491
Figure A0281051602011
(±)-3-(6-amino methyl-4-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl)-4-[2-(3-chloro-phenyl)-2-hydroxyl-ethylamino]-the 1H-pyridin-2-ones:
(±)-2-{4-[2-(3-chloro-phenyl)-2-hydroxyl-ethylamino]-2-oxo-1,2-dihydro-pyridin-3-yl }-7-methyl-3H-benzoglyoxaline-5-methane amide (20mg, 0.046mmol) THF (1mL) solution in add borine-tetrahydrofuran complex (1M solution) (0.45mL, 0.45mmol).Reaction mixture is at room temperature stirred 10h, with acetate (2) quencher.After removing most of solvent, resistates extracts with EtOAc, uses the salt water washing, uses dried over sodium sulfate.After concentrating, crude product is purified with preparation HPLC and is obtained title compound (11.5mg, 60%). 1H?NMR(400MHz，CD 3OD)δ7.53(1H，s)，7.50(1H，s)，7.39(1H，d，J＝7.5Hz)，7.24-7.32(3H，m)，7.13(1H，s)，6.26(1H，d，J＝7.5Hz)，4.99(1H，dd，J＝4.8，6.8Hz)，4.19(2H，s)，3.72(1H，dd，J＝4.8，13.6Hz)，3.64(1H，dd，J＝6.8，13.6Hz)，2.62(3H，s)。LCMS(M+H) +m/z424(t＝2.10min)。
Embodiment 492
Figure A0281051602012
(±)-4-[2-(3-chloro-phenyl)-2-hydroxyl-ethylamino]-3-(6-methylol-4-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl)-the 1H-pyridin-2-ones:
At-20 ℃ to (±)-2-{4-[2-(3-chloro-phenyl)-2-hydroxyl-ethylamino]-2-oxo-1,2-dihydro-pyridin-3-yl }-3H-benzoglyoxaline-5-ethyl formate (25mg, 0, add NaBH in methyl alcohol 054mmol) (2mL) and acetate (1mL) solution 4(10mg, 0.27mmol).Reaction mixture is stirred 30min at-20 ℃.With Virahol (5) quencher.After removing most of solvent, resistates extracts with EtOAc, and dried over sodium sulfate is used in water and salt water washing.After concentrating, crude product is purified with preparation HPLC and is obtained title compound (18mg, 62%). 1H?NMR(300MHz，CD 3OD)δ7.50(1H，s)，7.48(1H，s)，7.25-7.38(4H，m)，7.22(1H，s)，6.25(1H，d，J＝7.6Hz)，4.89-4.94(1H，m)，4.76(2H，s)，3.51-3.62(2H，m)，2.62(3H，s)。LCMS(M+H) +m/z?425(t＝1.64min)。
Figure A0281051602031
The general step of Suzuki coupling, embodiment 505-509 (flow process V, 18)
Embodiment 505
(S)-4-(1-benzyl-2-hydroxyl-ethylamino)-3-(4-methyl-6-phenyl-1H-benzimidazolyl-2 radicals-yl)-the 1H-pyridin-2-ones:
(S)-4-(1-benzyl-2-trityl oxygen base-ethylamino)-3-[6-bromo-4-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl]-the 1H-pyridin-2-ones (50mg, 0.072mmol), phenyl-boron dihydroxide (13mg, 0.11mmol) and 2M K 2CO 3(0.108mL adds Pd (PPh in THF 0.22mmol) (5mL) solution 3) 4(8.3mg, 0.007mmol).With mixture heating up to the 14h that refluxes.After the cooling, reaction mixture dilutes with methylene dichloride, with the saturated sodium bicarbonate washing, uses dried over sodium sulfate, then vacuum concentration.Resistates is directly used in next step and need not to purify again.LCMS(M+H) +m/z693(t＝2.82min)。Crude product is at room temperature handled 6h with 4N HCl De dioxane solution (5mL).Behind the vacuum concentration, resistates is purified with preparation HPLC and is obtained white solid title compound (17mg, 34%). 1H?NMR(300MHz，CD 3OD)δ7.13-7.67(13H，m)，6.15(1H，d，J＝7.4Hz)，3.99-4.11(1H，m)，3.74-3.77(2H，m)，3.16(1H，dd，J＝5.4，13.6Hz)，2.97(1H，dd，J＝7.8，13.6Hz)，2.69(3H，s)。LCMS(M+H) +m/z?451(t＝2.04min)。
Embodiment 506
(S)-4-(1-benzyl-2-hydroxyl-ethylamino)-3-(4-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl)-the 1H-pyridin-2-ones:
1H?NMR(300MHz，CD 3OD)δ6.98-7.46(9H，m)，6.15(1H，d，J＝7.5Hz)，3.99-4.04(1H，m)，3.75(2H，d，J＝5.1Hz)，3.16(1H，dd，J＝5.1，13.6Hz)，2.95(1H，dd，J＝8.1，13.6Hz)，2.61(3H，s)。LCMS(M+H) +m/z?375(t＝1.72min)。
Embodiment 507
(S)-4-(1-benzyl-2-hydroxyl-ethylamino)-3-[6-(2-methoxyl group-phenyl)-4-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl]-the 1H-pyridin-2-ones:
1H?NMR(300NHz，CD 3OD)δ6.99-7.59(12H，m)，6.16(1H，d，J＝7.5Hz)，4.04(1H，m)，3.81(3H，s)，3.76(2H，d，J＝4.1Hz)，2.96-3.20(2H，m)，2.66(3H，s)。LCMS(M+H) +m/z?481(t＝2.00min)。
Embodiment 508
(S)-4-(1-benzyl-2-hydroxyl-ethylamino)-3-[6-(4-fluoro-phenyl)-4-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl]-the 1H-pyridin-2-ones:
1H?NMR(300MHz，CD 3OD)δ7.10-7.66(12H，m)，6.13(1H，d，J＝7.6Hz)，3.99-4.04(1H，m)，3.76(2H，d，J＝5.0Hz)，3.16(1H，dd，J＝5.0，13.6Hz)，2.96(1H，dd，J＝8.1，13.6Hz)，2.65(3H，s)。LCMS(M+H) +m/z?469(t＝2.07min)。
Embodiment 509
Figure A0281051602071
(S)-4-(1-benzyl-2-hydroxyl-ethylamino)-3-[6-(4-methoxyl group-phenyl)-4-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl]-the 1H-pyridin-2-ones:
1H?NMR(300MHz，CD 3OD)δ6.97-7.65(12H，m)，6.14(1H，d，J＝7.6Hz)，4.00-4.04(1H，m)，3.83(3H，s)，3.76(2H，d，J＝5.0Hz)，2.95-3.19(2H，m)，2.67(3H，s)。LCMS(M+H) +m/z?481(t＝2.01min)。
The general step of Buchwald coupling, embodiment 510-516 flow process V, 19
Embodiment 510
Figure A0281051602072
(S)-4-(1-benzyl-2-hydroxyl-ethylamino)-3-(4-methyl-6-morpholine-4-base-1H-benzimidazolyl-2 radicals-yl)-the 1H-pyridin-2-ones:
Under nitrogen atmosphere, with (S)-4-(1-benzyl-2-trityl oxygen base-ethylamino)-3-[6-bromo-4-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl]-1H-pyridin-2-ones (150mg, 0.216mmol), morpholine (28.2mg, 0.324mmol), palladium (2.4mg, 0.01mmol), tri-butyl phosphine (4.4mg, 0.02mmol) and sodium tert-butoxide (104mg, toluene 1.08mmol) (5mL) mixture heating up to 100 ℃ 14h.Reaction mixture is cooled to room temperature, dilutes with EtOAc.After the extraction, dried over sodium sulfate is used in the organic layer water of merging, salt water washing.Concentrate and obtain little brown resistates, it is at room temperature handled 6h with 4N HCl De dioxane solution (3mL).Except that after desolvating, resistates is purified with preparation HPLC and is obtained title compound (18mg, 18%). 1H?NMR(400MHz，CD 3OD)δ7.59(1H，s)，7.12-7.28(7H，m)，6.12(1H，d，J＝7.6Hz)，4.01-4.08(5H，m)，3.76(1H，dd，J＝4.8，11.1Hz)，3.71(1H，dd，J＝5.2，11.1Hz)，3.32-3.10(4H，m)，3.09(1H，dd，J＝5.6，13.7Hz)，2.92(1H，dd，J＝8.0，13.7Hz)，2.65(3H，s)。LCMS(M+H) +m/z?460(t＝1.30min)。
Embodiment 511
(±)-4-[2-(3-chloro-phenyl)-2-hydroxyl-ethylamino]-3-(4-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl)-the 1H-pyridin-2-ones:
1H?NMR(300MHz，CD 3OD)δ7.17-7.64(8H，m)，6.23(1H，d，J＝10.2Hz)，4.94(1H，m)，3.61(1H，dd，J＝4.8，13.8Hz)，3.54(1H，dd，J＝7.4，13.8Hz)，2.61(3H，s)。LCMS(M+H) +m/z?395(t＝1.65min)。
Embodiment 512
Figure A0281051602082
(±)-4-[2-(3-chloro-phenyl)-2-hydroxyl-ethylamino]-3-(4-methyl-6-pyridin-3-yl-1H-benzimidazolyl-2 radicals-yl)-the 1H-pyridin-2-ones:
1H?NMR(300MHz，CD 3OD)δ9.14(1H，s)，8.88(1H，d，J＝8.2Hz)，8.72(1H，d，J＝5.4Hz)，8.08(1H，dd，J＝5.8，8.2Hz)，7.82(1H，s)，7.56(1H，s)，7.24-7.45(5H，m)，6.26(1H，d，J＝7.6Hz)，5.02(1H，dd，J＝5.0，6.5Hz)，3.77(1H，dd，J＝5.0，13.5Hz)，3.68(1H，dd，J＝6.5，13.5Hz)，2.68(3H，s)。LCMS(M+H) +m/z?472(t＝1.66min)。
Figure A0281051602091
Following examples 517-519 is according to flow process VII and III preparation.
Embodiment 517
Figure A0281051602101
(S)-4-[2-(3-chloro-phenyl)-2-hydroxyl-ethylamino]-3-(4-methyl-6-piperazine-1-base-1H-benzimidazolyl-2 radicals-yl)-the 1H-pyridin-2-ones:
1H?NMR(500MHz，CD 3OD)δ7.54(brs，1H)，7.40-7.20(m，4H)，7.03(brs，1H)，6.84(brs，1H)，6.25(d，1H，J＝7.60Hz)，5.01-4.91(m，1H)，3.73(dd，1H)，3.65(dd，1H)，3.45-3.25(m，8H)，2.56(s，3H)；LCMS(M+H) +m/z?479，481。
Embodiment 518
Figure A0281051602102
(±)-4-[2-(3-chloro-4-methylthio group-phenyl)-2-hydroxyl-ethylamino]-3-(4-methyl-6-piperazine-1-base-1H-benzimidazolyl-2 radicals-yl)-the 1H-pyridin-2-ones:
1H?NMR(500MHz，CD 3OD)δ7.47(brs，1H)，7.38-7.29(m，2H)，7.19(d，1H，J＝8.3Hz)，7.03(brs，1H)，6.98(brs，1H)，6.26(d，1H，J＝7.7Hz)，4.90-4.81(m，1H)，3.65-3.35(m，10H)，2.56(s，3H)，2.42(s，3H)；LCMS(M+H) +m/z?525，527。
Embodiment 519
Figure A0281051602111
(S)-4-[2-(3-chloro-4-fluoro-phenyl)-2-hydroxyl-ethylamino]-3-(4-methyl-6-piperazine-1-base-1H-benzimidazolyl-2 radicals-yl)-the 1H-pyridin-2-ones:
1H?NMR(500MHz，CD 3OD)δ7.61(dd，1H，J＝2.1，7.2Hz)，7.40(ddd，1H)，7.28(d，1H，J＝7.5Hz)，7.17(dd，1H，J＝8.9，8.8Hz)，7.02(brs，1H)，6.87(brs，1H)，6.25(d，1H，J＝7.6Hz)，4.99-4.90(m，1H)，3.73-3.60(m，2H)，3.45-3.30(m，8H)，2.54(s，3H)；LCMS(M+H) +m/z?497，499。
Following embodiment (520-522) illustrates preparation according to flow process VIII and III and to bridged piperazine derivatives is alkylating.
Embodiment 520 (general step that is used for embodiment 520-522)
Figure A0281051602112
(S)-3-[4-(2-{4-[2-(3-chloro-phenyl)-2-hydroxyl-ethylamino]-2-oxo-1,2-dihydro-pyridin-3-yl }-7-methyl-3H-benzoglyoxaline-5-yl)-the piperazine Qin-1-yl]-propionitrile:
4-[2-(3-chloro-phenyl)-2-hydroxyl-ethylamino under stirring]-3-(4-methyl-6-piperazine-1-base-1H-benzimidazolyl-2 radicals-yl)-(17mg, anhydrous methanol 0.021mmol) (1mL) solution adds Hunigs alkali (36 μ L) to the 1H-pyridin-2-ones.Gained solution is cooled to 0 ℃, adds vinyl cyanide (5 μ L) in batches and react completely until the LCMS judgement.Reactant is risen to room temperature, vacuum evaporating solvent.The gained resistates is with anti-phase preparation HPLC purify (methanol of gradient/0.1% trifluoroacetic acid).Evaporate the trifluoroacetate (12.1mg) that suitable part obtains title compound: 1H NMR (500MHz, CD 3OD) δ 7.49 (brs, 1H), 7.39-7.23 (m, 4H), 7.15 (brs, 1H), 7.06 (brs, 1h), 6.25 (d, 1H, J=7.7Hz), 4.97-4.88 (m, 1H), 3.70-3.40 (m, 12H), 3.06 (t, 2H, J=7.0Hz), 2.59 (s, 3H); LCMS (M+H) +M/z 532,534.The trifluoroacetate of pure title compound is dissolved in methyl alcohol, handles with Varian Mega Bond-Elute SCX packed column.Use methanol-eluted fractions, use 2.0 M NH then 3/ MeOH wash-out obtains free alkali.Product is suspended in MeOH, adds the 1.00N HCl aqueous solution (2 equivalent).Gained solution filters by 45 μ m strainers, and evaporation obtains the dihydrochloride of title compound then: 1H NMR (300MHz, CD 3OD) δ 7.50-7.25 (m, 5H), 7.16 (brs, 1H), 7.13 (brs, 1H), 6.27 (d, 1H, J=7.7Hz), 4.95-4.87 (m, 1H), 3.70-3.40 (m, 12H), 3.13 (t, 2H, J=7.0Hz), 2.62 (s, 3H); LCMS (M+H) +M/z 532,534.
Embodiment 521
Figure A0281051602121
(S)-4-[2-(3-chloro-phenyl)-2-hydroxyl-ethylamino]-3-{6-[4-(2-methylsulfonyl-ethyl)-piperazine-1-yl]-4-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl }-the 1H-pyridin-2-ones:
1H?NMR(500MHz，CD 3OD)δ7.53(brs，1H)，7.41-7.20(m，4H)，7.13(brs，1H)，6.92(brs，1H)，6.24(d，1H，J＝7.6Hz)，5.00-4.92(m，1H)，3.80-3.25(m，14H)，3.13(s，3H)，2.57(s，3H)；LCMS(M+H) +m/z?585，587。
Embodiment 522
Figure A0281051602131
(S)-3-[4-(2-{4-[2-(3-bromo-4-methoxyl group-phenyl)-2-hydroxyl-ethylamino]-2-oxo-1,2-dihydro-pyridin-3-yl }-7-methyl-3H-benzoglyoxaline-5-yl)-piperazine-1-yl]-propionitrile:
1H?NMR(500MHz，CD 3OD)δ7.59(brs，1H)，7.41(d，1H，J＝7.5Hz)，7.34(dd，1H，J＝2.0，8.5Hz)，7.17(brs，1H)，7.12(brs，1H)，7.00(d，1H，J＝8.5Hz)，6.25(d，1H，J＝7.5Hz)，4.85-4.76(m，1H)，3.85(s，3H)，3.80-3.30(m，12H)，3.16(t，2H，J＝7.0Hz)，2.55(s，3H)；LCMS(M+H) +m/z?606，608。
Following examples (523-528) are according to flow process VII and III and to the preparation that illustrates of the carbamylization of bridged piperazine derivatives
Embodiment 523 (general step of embodiment 523-528)
(S)-4-(2-{4-[2-(3-chloro-phenyl)-2-hydroxyl-ethylamino]-2-oxo-1,2-dihydro-pyridin-3-yl }-7-methyl-3H-benzoglyoxaline-5-yl)-piperazine-1-formic acid 2-fluoro-ethyl ester:
At 0 ℃ of 4-[2-(3-chloro-phenyl)-2-hydroxyl-ethylamino under stirring]-3-(4-methyl-6-piperazine-1-base-1H-benzimidazolyl-2 radicals-yl)-1H-pyridin-2-ones (～2TFA salt, 80mg,～0.1mmol) methyl alcohol (2mL) solution adds N, N-diisopropylethylamine (170 μ L) and chloroformic acid 2-fluorine ethyl ester (37mg).Remove cooling bath, solution is at room temperature stirred 30min, stir the back and finish with LC/MS analysis demonstration reaction.Then with reaction mixture with anti-phase preparation HPLC purify (methanol of gradient/0.1% trifluoroacetic acid).The evaporation corresponding section obtains the trifluoroacetate of title compound, and it is dissolved in methyl alcohol, uses Varian Mega Bond-Elute SCX packed column to handle.Use methanol-eluted fractions, then use 2.0M NH 3/ MeOH wash-out obtains free alkali (46.2mg).This product is suspended in MeOH, adds the 1.00N HCl aqueous solution (1 equivalent).Gained solution filters by 45 μ m strainers, and evaporation obtains the mono-hydrochloric salts (46 mg) of title compound then: 1H NMR (500MHz, CD 3OD) δ 7.50 (brs, 1H), 7.45-7.20 (m, 6H), 6.26 (d, 1H, J=7.7Hz), 4.98-4.91 (m, 1H), 4.64 (dm, 2H, J=47.9Hz), 4.39 (dm, 2H, J=29Hz), 3.95-3.50 (m, 10H), 2.63 (s, 3H); LCMS(M+H) +m/z?569，571。
Embodiment 524
(S)-4-(2-{4-[2-(3-chloro-phenyl)-2-hydroxyl-ethylamino]-2-oxo-1,2-dihydro-pyridin-3-yl }-7-methyl-3H-benzoglyoxaline-5-yl)-piperazine-1-formic acid 2-methoxyl group-ethyl ester:
1H?NMR(500MHz，CD 3OD)δ7.53-7.22(m，7H)，6.26(d，1H，J＝7.6Hz)，4.96(dd，1H，J＝7.0，4.6Hz)，4.31-4.27(m，2H)，4.05-3.55(m，12H)，3.39(s，3H)，2.64(s，3H)；LCMS(M+H) +m/z?581，583。
Embodiment 525
Figure A0281051602151
(S)-4-(2-{4-[2-(3-chloro-phenyl)-2-hydroxyl-ethylamino]-2-oxo-1,2-dihydro-pyridin-3-yl }-7-methyl-3H-benzoglyoxaline-5-yl)-piperazine-1-t-butyl formate:
1H?NMR(500MHz，CD 3OD)δ7.51(brs，1H)，7.40-7.22(m，6H)，6.26(d，1H，J＝7.7Hz)，4.96-4.90(m，1H)，3.90-3.30(m，10H)，2.64(s，3H)，1.51(s，9H)；LCMS(M+H) +m/z?579，581。
Embodiment 526
Figure A0281051602152
(S)-4-(2-{4-[2-(3-chloro-phenyl)-2-hydroxyl-ethylamino]-2-oxo-1,2-dihydro-pyridin-3-yl }-7-methyl-3H-benzoglyoxaline-5-yl)-piperazine-1-formic acid Propargyl ester:
1H?NMR(500MHz，CD 3OD)δ7.50(brs，1H)，7.43-7.20(m，5H)，7.19(brs，1H)，6.25(d，1H，J＝7.6Hz)，4.98-4.90(m，1H)，4.78(d，2H，J＝2.5Hz)，3.95-3.30(m，10H)，2.97(t，1H，J＝2.5Hz)，2.62(s，3H)；LCMS(M+H)+m/z?561，563。
Embodiment 527
(S)-4-(2-{4-[2-(3-bromo-4-methoxyl group-phenyl)-2-hydroxyl-ethylamino]-2-oxo-1,2-dihydro-pyridin-3-yl }-7-methyl-3H-benzoglyoxaline-5-yl)-piperazine-1-t-butyl formate:
1H?NMR(300MHz，CD 3OD)δ7.65(brs，1H)，7.48-7.28(m，3H)，7.25(brs，1H)，6.97(d，1H，J＝8.5Hz)，6.25(d，1H，J＝7.7Hz)，4.94-4.86(m，1H)，3.90-3.45(m，10H)，3.82(s，3H)，2.61(s，3H)，1.52(s，9H)；LCMS(M+H) +?m/z?653，655。
Embodiment 528
Figure A0281051602162
(S)-4-(2-{4-[2-(3-bromo-4-methoxyl group-phenyl)-2-hydroxyl-ethylamino]-2-oxo-1,2-dihydro-pyridin-3-yl }-7-methyl-3H-benzoglyoxaline-5-yl)-piperazine-1-ethyl formate:
1H NMR (400MHz, CD 3OD) δ 7.80 (1H, s), 7.63 (1H, narrow peak d, J=1.8Hz), 7.52 (1H, s), 7.42 (1H, d, J=7.5Hz), 7.37 (1H, dd, J=1.8,8.4Hz), 7.00 (1H, d, J=8.4Hz), 6.31 (1H, d, J=7.5Hz), 4.89 (1H, m), 4.22 (2H, q, J=7.1Hz), 3.98 (4H, brs), 3.84 (3H, s), 3.70-3.72 (4H, m), 3.59-3.60 (2H, m), 2.67 (3H, s), 1.31 (3H, t, J=7.1Hz).LCMS(M+H) +m/z?625(t＝1.45min)。
Following embodiment (529-540) is according to the preparation that illustrates of other alkylation of flow process VII and III and bridged piperazine derivatives.
Embodiment 529 (general step of embodiment 529-540)
Figure A0281051602171
(S)-4-[2-(3-chloro-4-methoxyl group-phenyl)-2-hydroxyl-ethylamino]-3-{6-[4-(3-fluoro-propyl group)-piperazine-1-yl]-4-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl }-the 1H-pyridin-2-ones:
4-[2-(3-chloro-4-methoxyl group-phenyl)-2-hydroxyl-ethylamino under stirring]-3-(4-methyl-6-piperazine-1-base-1H-benzimidazolyl-2 radicals-yl)-1H-pyridin-2-ones (100mg, 0.162mmol) 1, add N in 4-diox (4.0mL), ethanol (0.8mL), methyl alcohol (0.8mL) solution, N-diisopropylethylamine (0.30mL) and 1-bromo-3-fluoro-propane (85 μ l).Reactant is at 80 ℃ of heating 12h.Then reaction mixture is purified with anti-phase preparation HPLC (methanol of gradient/0.1% trifluoroacetic acid).The evaporation corresponding section obtains the trifluoroacetate of title compound, and it is dissolved in methyl alcohol, uses Varian Mega Bond-Elute SCX packed column to handle.Use methanol-eluted fractions, then use 2.0M NH 3/ MeOH wash-out obtains free alkali (39.3mg).This product is suspended in MeOH, adds the 1.00N HCl aqueous solution (2 equivalent).Gained solution filters by 45 μ m strainers, and evaporation obtains the dihydrochloride (43.5mg) of title compound then: 1H NMR (400MHz, CD 3OD) δ 7.43-7.37 (m, 2H), 7.28 (dd, 1H, J=2.0,8.6Hz), 7.16 (brs, 1H), 7.08 (d, 1H, J=1.7Hz), 7.01 (d, 1H, J=8.5Hz), 6.24 (d, 1H, J=7.7Hz), 4.84-4.78 (m, 1H), 4.60 (dt, 2H, J=5.7,47.1Hz), 3.95-3.88 (m, 2H), 3.83 (s, 3H), 3.78-3.71 (m, 2H), 3.53-3.14 (m, 8H), 2.59 (s, 3H), 2.31-2.16 (m, 2H); LCMS (M+H) +M/z 569,571.
Embodiment 530
(S)-4-[2-(3-chloro-phenyl)-2-hydroxyl-ethylamino]-3-{6-[4-(2-fluoro-ethyl)-piperazine-1-yl]-4-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl }-the 1H-pyridin-2-ones:
1H?NMR(400MHz，CD 3OD)δ7.45-7.20(m，5H)，7.16(brs，1H)，7.09(brs，1H)，6.25(d，1H，J＝7.6Hz)，5.00-4.92(m，1H)，4.92-4.78(m，2H)，3.98-3.15(m，12H)，2.60(s，3H)；LCMS(M+H) +m/z?525，527。
Embodiment 531
Figure A0281051602182
(S)-4-[2-(3-chloro-4-fluoro-phenyl)-2-hydroxyl-ethylamino]-3-{6-[4-(3-fluoro-propyl group)-piperazine-1-yl]-4-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl }-the 1H-pyridin-2-ones:
1H?NMR(400MHz，CD 3OD)δ7.52(dd，1H，J＝2.1，7.2Hz)，7.40(d，1H，J＝7.6Hz)，7.35-7.12(m，3H)，7.08(d，1H，J＝1.7Hz)，6.25(d，1H，J＝7.7Hz)，4.90-4.82(m，1H)，4.60(dt，2H，J＝5.4，47.1Hz)，3.96-3.10(m，12H)，2.60(s，3H)，2.28-2.13(m，2H)；LCMS(M+H) +m/z?557，559。
Embodiment 532
(S)-4-[2-(3-bromo-4-methoxyl group-phenyl)-2-hydroxyl-ethylamino]-3-{6-[4-(3-fluoro-propyl group)-piperazine-1-yl]-4-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl }-the 1H-pyridin-2-ones:
1H?NMR(400MHz，CD 3OD)δ7.58(d，1H，J＝2.0Hz)，7.43(d，1H，J＝7.6Hz)，7.34(dd，1H，J＝2.0，8.5Hz)，7.19(brs，1H)，7.1?1(brs，1H)，7.00(d，1H，J＝8.5Hz)，6.26(d，1H，J＝7.7Hz)，5.90-4.82(m，1H)，4.61(dt，2H，J＝5.4，47.1Hz)，3.95-3.12(m，12H)，3.85(s，3H)，2.62(s，3H)，2.30-2.14(m，2H)；LCMS(M+H) +m/z?613，615。
Embodiment 533
Figure A0281051602192
(S)-4-[2-(3-chloro-phenyl)-2-hydroxyl-ethylamino]-3-{4-methyl-6-[4-(3,3,3-three fluoro-propyl group)-piperazine-1-yl]-1H-benzimidazolyl-2 radicals-yl }-the 1H-pyridin-2-ones:
1H?NMR(300MHz，CD 3OD)δ7.50-7.10(m，7H)，6.26(d，1H，J＝7.5Hz)，4.96-4.88(m，1H)，4.00-3.15(m，12H)，3.00-2.82(m，2H)，2.61(s，3H)；LCMS(M+H) +m/z?575，577。
Embodiment 534
Figure A0281051602201
(S)-4-[2-(3-chloro-phenyl)-2-hydroxyl-ethylamino]-3-{6-[4-(3-fluoro-propyl group)-piperazine-1-yl]-4-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl }-the 1H-pyridin-2-ones:
1H?NMR(300MHz，CD 3OD)δ7.46-7.25(m，5H)，7.19(brs，1H)，7.11(brs，1H)，6.27(d，1H，J＝7.7Hz)，4.95-4.86(m，1H)，4.62(dt，2H，J＝5.4，47.1Hz)，3.98-3.15(m，12H)，2.62(s，3H)，2.35-2.12(m，2H)；LCMS(M+H) +m/z?539，541。
Embodiment 535
Figure A0281051602202
(S)-4-[2-(3-chloro-phenyl)-2-hydroxyl-ethylamino]-3-{4-methyl-6-[4-(3,4,4-three fluoro-fourth-3-thiazolinyl)-piperazine-1-yl]-1H-benzimidazolyl-2 radicals-yl }-the 1H-pyridin-2-ones:
LCMS(M+H) +m/z?587，589。
Embodiment 536
Figure A0281051602211
4-[2-(3-chloro-phenyl)-2 (S)-hydroxyl-ethylaminos]-3-{6-[4-(3-fluoro-2-hydroxyl-propyl group)-piperazine-1-yl]-4-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl }-the 1H-pyridin-2-ones:
LCMS(M+H) +m/z?555，557。
Embodiment 537
(S)-4-[2-(3-chloro-phenyl)-2-hydroxyl-ethylamino]-3-{6-[4-(2-hydroxy-2-methyl-propyl group)-piperazine-1-yl]-4-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl }-the 1H-pyridin-2-ones:
1H?NMR(400MHz，CD 3OD)δ7.44-7.22(m，5H)，7.15(brs，1H)，7.08(brs，1H)，6.25(d，1H，J＝7.6Hz)，4.88-4.80(m，1H)，3.86-3.81(m，4H)，3.55-3.32(m，6H)，3.28(s，2H)，2.60(s，3H)，1.38(s，6H)；LCMS(M+H) +m/z?551，553。
Embodiment 538
(S)-4-[2-(3-chloro-phenyl)-2-hydroxyl-ethylamino]-3-{6-[4-(2-hydroxyl-ethyl)-piperazine-1-yl]-4-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl }-the 1H-pyridin-2-ones:
1H?NMR(400MHz，CD 3OD)δ7.50(1H，s)，7.25-7.35(4H，m)，7.04(1H，s)，6.97(1H，s)，6.22(1H，d，J＝6.8Hz)，4.93-4.95(1H，m)，3.21-3.96(14H，m)，2.57(3H，s)。LCMS(M+H) +m/z?523(t＝1.11min)。
Embodiment 539
Figure A0281051602222
(S)-4-[2-(3-bromo-4-methoxyl group-phenyl)-2-hydroxyl-ethylamino]-3-{6-[4-(2-hydroxyl-ethyl)-piperazine-1-yl]-4-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl }-the 1H-pyridin-2-ones:
1H NMR (400MHz, CD 3OD) δ 7.60 (1H, narrow peak d, J=2.0Hz), 7.40 (1H, d, J=7.6Hz), 7.35 (1H, dd, J=2.0,8.4Hz), 7.13 (1H, s), 7.09 (1H, s), 6.99 (1H, d, J=8.4Hz), 6.25 (1H, d, J=7.6Hz), 4.82-4.87 (1H, m), 3.76-3.97 (6H, m), 3.84 (3H, s), 3.24-3.52 (8H, m), 2.60 (3H, s).LCMS(M+H) +m/z?597(t＝1.09min)。
Embodiment 540
(S)-[4-(2-{4-[2-(3-chloro-phenyl)-2-hydroxyl-ethylamino]-2-oxo-1,2-dihydro-pyridin-3-yl }-7-methyl-3H-benzoglyoxaline-5-yl)-piperazine-1-yl]-acetonitrile:
1H?NMR(400MHz，CD 3OD)δ7.50-7.25(m，7H)，6.28(d，1H，J＝8.0Hz)，4.95-4.88(m，1H)，4.32(s，2H)，3.75-3.62(m，4H)，3.60-3.35(m，6H)，2.63(s，3H)；LCMS(M+H) +m/z?518，520。
Following embodiment (541-553) is according to the preparation that illustrates of the acidylate of flow process VII and III and bridged piperazine derivatives.
Embodiment 541 (general step of embodiment 541-553)
Figure A0281051602232
(S)-4-[2-(3-chloro-phenyl)-2-hydroxyl-ethylamino]-3-{6-[4-(4-fluoro-butyryl radicals)-piperazine-1-yl]-4-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl }-the 1H-pyridin-2-ones:
4-[2-(3-chloro-phenyl)-2-hydroxyl-ethylamino under stirring]-3-(4-methyl-6-piperazine-1-base-1H-benzimidazolyl-2 radicals-yl)-1H-pyridin-2-ones (70mg, 0.136mmol) anhydrous N, dinethylformamide (750 μ L) solution adds 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (112mg, 0.584mmol), I-hydroxybenzotriazole hydrate (59mg, 0.438mmol), N-methylmorpholine (0.048mL, 0.438mmol) and 4-fluorine butyric acid (31mg, 0.291mmol; Referring to O ' Hagan, D., J.Fluorine chem., 43, (1989), and 371-377), with mixture heating up to 80 ℃ 3h.Then reaction mixture is purified with anti-phase preparation HPLC (methanol of gradient/0.1% trifluoroacetic acid).The evaporation corresponding section obtains the trifluoroacetate of title compound, and it is dissolved in methyl alcohol, uses Varian Mega Bond-Elute SCX packed column to handle.Use methanol-eluted fractions, then use 2.0M NH 3/ MeOH wash-out obtains free alkali (35.9mg).This product is suspended in MeOH, adds the 1.00N HCl aqueous solution (2 equivalent).Gained solution filters by 45 μ m strainers, and evaporation obtains the dihydrochloride (37.6mg) of title compound then: 1H NMR (400MHz, CD 3OD) δ 7.61 (brs, 1H), 7.47 (brs, 1H), 7.44-7.20 (m, 5H), 6.27 (d, 1H, J=7.6Hz), 4.92 (dd, 1H, J=4.4,7.3Hz), 4.50 (dt, 2H, J=5,9,47.3Hz), 4.05-3.40 (m, 10H), 2.64 (s, 3H), 2.63 (t, 2H, J=7.6Hz), 2.09-1.95 (m, 2H); LCMS (M+H) +M/z 567,569.
Embodiment 542
(S)-4-[2-(3-chloro-phenyl)-2-hydroxyl-ethylamino]-3-{6-[4-(2,2-two fluoro-ethanoyl)-piperazine-1-yl]-4-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl }-the 1H-pyridin-2-ones:
LCMS(M+H) +m/z?557，559。
Embodiment 543
(S)-4-[2-(3-chloro-phenyl)-2-hydroxyl-ethylamino]-3-{6-[4-(2-methylsulfonyl-ethanoyl)-piperazine-1-yl]-4-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl }-the 1H-pyridin-2-ones:
LCMS(M+H) +m/z?599，601。
Embodiment 544
(S)-3-[6-(4-ethanoyl-piperazine-1-yl)-4-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl]-4-[2-(3-chloro-phenyl)-2-hydroxyl-ethylamino]-the 1H-pyridin-2-ones:
1H?NMR(500MHz，CD 3OD)δ7.57(brs，1H)，7.49(brs，1H)，7.40-7.20(m，5H)，6.29(d，1H，J＝7.6Hz)，4.98-4.90(m，1H)，4.02-3.91(m，4H)，3.70-3.50(m，6H)，2.66(s，3H)，2.21(s，3H)；LCMS(M+H) +m/z?521，523。
Embodiment 545
Figure A0281051602261
(S)-4-[2-(3-chloro-phenyl)-2-hydroxyl-ethylamino]-3-(4-methyl-6-{4-[2-(1-oxo-1-parathiazan-4-yl)-ethanoyl]-piperazine-1-yl }-the 1H-benzimidazolyl-2 radicals-yl)-the 1H-pyridin-2-ones:
LCMS(M+H) +m/z?638，640。
Embodiment 546
Figure A0281051602262
(S)-4-[2-(3-chloro-phenyl)-2-hydroxyl-ethylamino]-3-(6-{4-[2-(1,1-dioxo-1-parathiazan-4-yl)-ethanoyl]-piperazine-1-yl }-4-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl)-the 1H-pyridin-2-ones:
LCMS(M+H) +m/z?654，656。
Embodiment 547
Figure A0281051602263
(S)-4-[2-(3-chloro-phenyl)-2-hydroxyl-ethylamino]-3-{4-methyl-6-[4-(2-parathiazan-4-base-ethanoyl)-piperazine-1-yl]-1H-benzimidazolyl-2 radicals-yl }-the 1H-pyridin-2-ones:
LCMS(M+H)＝m/z?622，624。
Embodiment 548
4-[2-(3-chloro-phenyl)-2 (S)-hydroxyl-ethylaminos]-3-{6-[4-(2-methanesulfinyl-ethanoyl)-piperazine-1-yl]-4-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl }-the 1H-pyridin-2-ones:
LCMS(M+H) +m/z?583，585。
Embodiment 549
(S)-4-[2-(3-chloro-phenyl)-2-hydroxyl-ethylamino]-3-{6-[4-(2-methoxyl group-ethanoyl)-piperazine-1-yl]-4-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl }-the 1H-pyridin-2-ones:
1H?NMR(500MHz，CD 3OD)δ7.49(brs，1H)，7.40-7.18(m，6H)，6.26(d，1H，J＝7.7Hz)，4.98-4.90(m，1H)，4.25(s，2H)，3.95-3.46(m，10H)，3.44(s，3H)，2.63(s，3H)；LCMS(M+H) +m/z?551，553。
Embodiment 550
Figure A0281051602281
(S)-4-[2-(3-chloro-phenyl)-2-hydroxyl-ethylamino]-3-{4-methyl-6-[4-(2-methylthio group-ethanoyl)-piperazine-1-yl]-1H-benzimidazolyl-2 radicals-yl }-the 1H-pyridin-2-ones:
1H?NMR(500MHz，CD 3OD)δ7.49(brs，1H)，7.45-7.20(m，6H)，6.26(d，1H，J＝7.60Hz)，4.98-4.90(m，1H)，3.97-340(m，12H)，2.63(s，3H)，2.20(s，3H)；LCMS(M+H) +m/z?567，569。
Embodiment 551
Figure A0281051602282
(S)-3-{6-[4-(2-chloro-ethanoyl)-piperazine-1-yl]-4-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl }-4-[2-(3-chloro-phenyl)-2-hydroxyl-ethylamino]-the 1H-pyridin-2-ones:
1H?NMR(500MHz，CD 3OD)δ7.49(brs，1H)，7.38-7.20(m，5H)，7.15(brs，1H)，6.25(d，1H，J＝7.6Hz)，4.98-4.90(m，1H)，4.35(s，2H)，3.90-3.80(m，4H)，3.66-3.30(m，6H)，2.61(s，3H)；LCMS(M+H) +m/z?555，557。
Embodiment 552
(S)-4-(2-{4-[2-(3-bromo-4-methoxyl group-phenyl)-2-hydroxyl-ethylamino]-2-oxo-1,2-dihydro-pyridin-3-yl }-7-methyl-3H-benzoglyoxaline-5-yl)-piperazine-1-formaldehyde:
1H NMR (400MHz, CD 3OD) δ 8.18 (1H, s), 7.65 (1H, s), 7.61 (1H, narrow peak d, J=2.0Hz), 7.46 (1H, s), 7.43 (1H, d, J=7.6Hz), 7.36 (1H, dd, J=2.0,8.5Hz), 7.00 (1H, d, J.=8.5Hz), 6.32 (1H, d, J=7.6Hz), 4.86-4.89 (1H, m), 3.91-3.96 (4H, m), 3.84 (3H, s), 3.57-3.67 (7H, m), 2.66 (3H, s).LCMS(M+H) +m/z?581(t＝1.24?min)。
Embodiment 553
Figure A0281051602292
(S)-4-(2-{4-[2-(3-chloro-phenyl)-2-hydroxyl-ethylamino]-2-oxo-1,2-dihydro-pyridin-3-yl }-7-methyl-3H-benzoglyoxaline-5-yl)-piperazine-1-formaldehyde:
1H?NMR(400MHz，CD 3OD)δ8.12(1H，s)，7.50(1H，s)，7.24-7.38(6H，m)，6.23(1H，d，J＝7.6Hz)，4.93-4.96(1H，m)，3.54-3.79(10H，m)，2.58(3H，s)。LCMS(M+H) +m/z?507(t＝1.29min)。
Following examples (554-575) are according to flow process VII and III preparation
Embodiment 554
Figure A0281051602301
(S)-4-[2-(3-chloro-phenyl)-2-hydroxyl-ethylamino]-3-(4-methyl-6-morpholine-4-base-1H-benzimidazolyl-2 radicals-yl)-the 1H-pyridin-2-ones:
4-chloro-3-(4-methyl-6-morpholine-4-base-1H-benzimidazolyl-2 radicals-yl)-1H-pyridin-2-ones and corresponding iodo compound 4-iodo-3-(4-methyl-6-morpholine-4-base-1H-benzimidazolyl-2 radicals-yl)-1H-pyridin-2-ones (4.43g, add triethylamine (7.0ml in～11mmol) acetonitrile (100mL) suspension, 50mmol) and 2-(S)-2-(3-chloro-phenyl)-2-hydroxyl-ethylamine hydrochloride (2.55g, 12.2mmol).Mixture spends the night 85 ℃ of stirrings.LCMS shows remainder initial feed pyridone.Add 2-(S)-2-(3-chloro-phenyl)-2-hydroxyl-ethylamine hydrochloride (0.22g, 1.06mmol), with mixture at 85 ℃ of restir 24h.Add Cs after boiling off fugitive constituent 2CO 3The aqueous solution (200mL, 10%), suspension ultrasonication 5min stirs then and spends the night.Leach product, wash with water, with methyl alcohol-chloroform recrystallization.Isolate the yellow crystal title compound.(3.951g，75％)。LCMS(M+H) +m/z?480(t＝1.31min)。HPLCt=4.93min, YMC-Pack ODS-A 3.0 * 50mm; The 0-100% gradient, 8min; Flow velocity 2.5mL/min.Mono-hydrochloric salts 1H NMR (500MHz, DMSO-d 6) δ 13.3 (1H, broad peak s), 11.22 (1H, s), 10.9 (1H, broad peak s), 7.65 (1H, broad peak s), 7.60 (1H, s), 7.45 (d, J=7.6Hz), 7.38-7.30 (4H, m), 6.19 (1H, d, J=7.5Hz), 4.92 (1H, t, J=5.3Hz), (4.00 6H, broad peak), 3.67 (1H, m), 3.52 (5H, m), 2.58 (3H, s).
The general step of preparation mono-hydrochloric salts and dihydrochloride:
The methanol solution or the suspension of free alkali are handled with the normal 1.00NHCl aqueous solution of 1.00 (or 2.00resp.).If have a large amount of compounds to keep insoluble, then add isopyknic methylene dichloride and improve solubleness.Mixture is filtered, then vacuum concentration.With spiece evaporation as for, and the most of sample concentration that is used for research body in leaches then until the acquisition compound crystal.
Embodiment 555
Figure A0281051602311
(S)-4-[2-(3-bromo-4-methoxyl group-phenyl)-2-hydroxyl-ethylamino]-3-(4-methyl-6-morpholine-4-base-1H-benzimidazolyl-2 radicals-yl)-the 1H-pyridin-2-ones:
1H?NMR(300MHz，CD 3OD)δ7.68-7.60(m，2H)，7.43-7.28(m，3H)，6.98(d，1H，J＝8.50Hz)，6.26(d，1H，J＝7.7Hz)，4.97-4.89(m，1H)，4.18-4.04(m，4H)，3.82(s，3H)，3.73-3.55(m，6H)，2.63(s，3H)；LCMS(M+H) +m/z?554，556。
Embodiment 556
Figure A0281051602312
(S)-4-[2-(3-chloro-4-fluoro-phenyl)-2-hydroxyl-ethylamino]-3-(4-methyl-6-morpholine-4-base-1H-benzimidazolyl-2 radicals-yl)-the 1H-pyridin-2-ones:
1H?NMR(300MHz，CD 3OD)δ7.65-7.50(m，2H)，7.43-7.20(m，3H)，7.18(dd，1H，J＝8.9，8.8Hz)，6.27(d，1H，J＝7.6Hz)，5.00-4.91(m，1H)，4.15-4.02(m，4H)，3.75-3.60(m，6H)，2.64(s，3H)；LCMS(M+H) +m/z?498，500。
Embodiment 557
Figure A0281051602321
(S)-4-[2-(3-chloro-4-methoxyl group-phenyl)-2-hydroxyl-ethylamino]-3-(4-methyl-6-morpholine-4-base-1H-benzimidazolyl-2 radicals-yl)-the 1H-pyridin-2-ones:
1H?NMR(400MHz，CD 3OD)δ7.67(brs，1H)，7.45(brs，1H)，7.40-7.28(m，3H)，7.00(d，1H，J＝8.4Hz)，6.27(d，1H，J＝7.6Hz)，4.95-4.84(m，1H)，4.15-4.05(m，4H)，3.82(s，3H)，3.75-3.55(m，6H)，2.64(s，3H)；LCMS(M+H) +m/z?510，512。
Embodiment 558
(S)-4-[2-(7-bromo-2,3-dihydro-cumarone-5-yl)-2-hydroxyl-ethylamino]-3-(4-methyl-6-morpholine-4-base-1H-benzimidazolyl-2 radicals-yl)-the 1H-pyridin-2-ones:
1H?NMR(400MHz，CD 3OD)δ7.54(brs，1H)，7.35-7.30(m，2H)，7.27(brs，1H)，7.22(brs，1H)，6.27(d?1H，J＝7.6Hz)，4.95-4.87(m，1H)，4.60-4.50(m，2H)，4.10-4.00(m，4H)，3.75-3.60(m，6H)，3.25-3.13(m，2H)，2.62(s，3H)；LCMS(M+H) +m/z?566，568。
Embodiment 559
4-[2-(3-chloro-phenyl)-2 (S)-hydroxyl-ethylaminos]-3-[4-methyl-6-[2 (S), 6 (R)-dimethyl-morpholines-4-yl]-1H-benzimidazolyl-2 radicals-yl]-the 1H-pyridin-2-ones.
1H?NMR(400MHz，CD 3OD)δ7.23-7.57(7H，-m)，6.22(1H，d，J＝7.6Hz)，4.97(1H，m)，4.06(2H，m)，3.62-3.68(4H，m)，3.20-3.34(2H，m)，2.63(3H，s)，1.30(6H，d，J＝6.28Hz)，LCMS(M+H) +m/z?508(t＝2.12min)
Embodiment 560
Figure A0281051602332
4-[2-(3-bromo-4-methoxyl group-phenyl)-2 (S)-hydroxyl-ethylaminos]-3-[4-methyl-6-[2 (S), 6 (R)-dimethyl-morpholines-4-yl]-1H-benzimidazolyl-2 radicals-yl]-the 1H-pyridin-2-ones.
1H?NNR(400MHz，CD 3OD)δ7.73(1H-s)，7.63(1H，s)，7.42(1H，s)，7.34(2H，m)，6.96(1H，d，J＝8.48Hz)，6.21(1H，d，J＝7.48Hz)，4.87(1H，m)，4.23(2H，m)，3.57-3.67(4H，m)，3.34(3H，s)3.30-3.32(2H，m)，2.60(1H，s)，1.30(6H，d，J＝6.2Hz)LCMS(M+H) +m/z?582(t＝2.03min)
Embodiment 561
Figure A0281051602341
4-[2-(3-chloro-phenyl)-(S)-2-hydroxyl-ethylamino]-3-{6-[(R)-2-methyl fluoride-morpholine-4-yl]-4-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl }-1H-pyridin-2-ones and 4-[2-(3-chloro-phenyl)-(S)-2-hydroxyl-ethylamino]-3-{6-[(S)-2-methyl fluoride-morpholine-4-yl]-4-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl }-the 1-pyridin-2-ones:
1H?NMR(400MHz，CD 3OD)δ7.47(1H，s)，7.23-7.43(6H，m)，6.22(1H，d，J＝7.2Hz)，4.87-4.94(1H，m)，4.60(1H，d，J＝3.4Hz)，4.48(1H，d，J＝3.4Hz)，4.04-4.15(3H，m)，3.28-3.62(6H，m)，2.56(3H，s)。LCMS(M+H) +m/z?512(t＝1.35min)。
Embodiment 562
Figure A0281051602351
4-[2-(3-bromo-4-methoxyl group-phenyl)-(S)-2-hydroxyl-ethylamino]-3-{6-[(R)-2-methyl fluoride-morpholine-4-yl]-4-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl }-1H-pyridin-2-ones and 4-[2-(3-bromo-4-methoxyl group-phenyl)-(S)-2-hydroxyl-ethylamino]-3-{6-[(S)-2-methyl fluoride-morpholine-4-yl]-4-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl }-the 1H-pyridin-2-ones:
1H NMR (400MHz, CD 3OD) δ 7.60 (1H, narrow peak d, J=2.0Hz), 7.56 (1H, s), 7.39 (1H, brs), 7.34 (1H, dd, J=2.0,8.4Hz), 6.97 (1H, d, J8.4Hz), 6.27 (1H, d, J=6.4Hz), 4.86 (1H, m), 4.61 (1H, m), 4.50 (1H, m), 4.77-4.19 (3H, m), 3.82 (3H, s), 3.38-3.74 (8H, m), 2.63 (3H, s).LCMS(M+H) +m/z?586(t＝1.31min)。
Embodiment 563
Figure A0281051602352
4-[2-(3-chloro-4-methoxyl group-phenyl)-(S)-2-hydroxyl-ethylamino]-3-{6-[(R)-2-methyl fluoride-morpholine-4-yl]-4-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl }-1H-pyridin-2-ones and 4-[2-(3-chloro-4-methoxyl group-phenyl)-(S)-2-hydroxyl-ethylamino]-3-{6-[(S)-2-methyl fluoride-morpholine-4-yl]-4-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl }-the 1H-pyridin-2-ones:
1H?NMR(400MHz，CD 3OD)δ7.45(1H，s)，7.28-7.30(3H，m)，7.10(1H，s)，6.97(1H，d，J＝8.0Hz)，6.20(1H，d，J＝6.4Hz)，4.85(1H，m)，4.58(1H，brs)，4.46(1H，brs)，3.93-4.10(3H，m)，3.80(3H，s)，3.59(4H，m)，3.07-3.29(2H，m)，2.55(3H，s)。LCMS(M+H) +m/z542(t＝1.28min)
Embodiment 564
Figure A0281051602361
4-[2-(7-bromo-2,3-dihydro-cumarone-5-yl)-(S)-2-hydroxyl-ethylamino]-3-{6-[(R)-2-methyl fluoride-morpholine-4-yl]-4-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl }-1H-pyridin-2-ones and 4-[2-(7-bromo-2,3-dihydro-cumarone-5-yl)-(S)-2-hydroxyl-ethylamino]-3-{6-[(S)-2-methyl fluoride-morpholine-4-yl]-4-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl }-the 1H-pyridin-2-ones:
1H?NMR(400MHz，CD 3OD)δ7.26-7.40(4H，m)，7.19(1H，s)，6.24(1H，d，J＝7.6Hz)，4.81-4.82(1H，m)，4.49-4.61(4H，m)，3.18-4.18(11H，m)，2.59(3H，s)。LCMS(M+H) +m/z?598(t＝1.32min)。
Embodiment 565
4-[2-(3-chloro-phenyl)-(S)-2-hydroxyl-ethylamino]-3-{6-[(R)-2-methylol-morpholine-4-yl]-4-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl }-1H-pyridin-2-ones and 4-[2-(3-chloro-phenyl)-(S)-2-hydroxyl-ethylamino]-3-{6-[(S)-2-methylol-morpholine-4-yl]-4-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl }-the 1H-pyridin-2-ones:
1H?NMR(400MHz，CD 3OD)δ7.49(1H，s)，7.23-7.37(6H，m)，7.10(1H，s)，6.24(1H，d，J＝7.6Hz)，4.95-4.96(1H，m)，4.19(1H，m)，3.94-4.80(2H，m)，3.59-3.71(8H，m)，2.63(3H，s)。LCMS(M+H) +m/z?510(t＝1.21min)。
Embodiment 566
Figure A0281051602372
4-[2-(3-bromo-4-methoxyl group-phenyl)-(S)-2-hydroxyl-ethylamino]-3-{6-[(R)-2-methylol-morpholine-4-yl]-4-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl }-1H-pyridin-2-ones and 4-[2-(3-bromo-4-methoxyl group-phenyl)-(S)-2-hydroxyl-ethylamino]-3-{6-[(S)-2-methylol-morpholine-4-yl]-4-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl }-the 1H-pyridin-2-ones:
1H NMR (400MHz, CD 3OD) δ 7.62 (1H, narrow peak d, J=2.0Hz), 7.54 (1H, s), 7.29-7.36 (3H, m), 6.95 (1H, d, J=8.4Hz), 6.23 (1H, d, J=7.6Hz), 4.88-4.89 (1H, m), 3.56-4.19 (11H, m), 3.80 (3H, s), 2.60 (3H, s).LCMS(M+H) +m/z?584(t＝1.16min)。
Embodiment 567
Figure A0281051602381
4-[2-(3-chloro-4-methoxyl group-phenyl)-(S)-2-hydroxyl-ethylamino]-3-{6-[(R)-2-methylol-morpholine-4-yl]-4-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl }-1H-pyridin-2-ones and 4-[2-(3-chloro-4-methoxyl group-phenyl)-(S)-2-hydroxyl-ethylamino]-3-{6-[(S)-2-methylol-morpholine-4-yl]-4-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl }-the 1H-pyridin-2-ones:
1H?NMR(400MHz，CD 3OD)δ7.68(1H，s)，7.54(1H，s)，7.45(1H，s)，7.39(1H，s)，7.30-7.32(2H，m)，6.98(1H，d，J＝8.4Hz)，6.22(1H，d，J＝7.6Hz)，4.89(1H，m)，4.11-4.19(3H，m)，3.80(3H，s)，3.49-3.72(8H，m)，2.60(3H，s)。LCMS(M+H) +m/z?540(t＝1.09min)。
Embodiment 568
Figure A0281051602391
4-[2-(3-chloro-phenyl)-(S)-2-hydroxyl-ethylamino]-3-{6-[(R)-2-methyl-morpholine-4-yl]-4-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl }-1H-pyridin-2-ones and 4-[2-(3-chloro-phenyl)-(S)-2-hydroxyl-ethylamino]-3-{6-[(S)-2-methyl-morpholine-4-yl]-4-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl }-the 1H-pyridin-2-ones:
1H?NMR(400MHz，CD 3OD)δ?7.75(1H，s)，7.48(1H，s)，7.42(1H，s)，7.23-7.37(4H，m)，6.24(1H，d，J＝7.2?Hz)，4.94-4.97(1H，m)，4.11-4.16(3H，m)，3.61-3.68(5H，m)，3.38(1H，m)，2.64(3H，s)，1.29(3H，d，J＝6.4Hz)。LCMS(M+H) +m/z?494(t＝1.32min)。
Embodiment 569
4-[2-(3-bromo-4-methoxyl group-phenyl)-(S)-2-hydroxyl-ethylamino]-3-{6-[(R)-2-methyl-morpholine-4-yl]-4-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl }-1H-pyridin-2-ones and 4-[2-(3-bromo-4-methoxyl group-phenyl)-(S)-2-hydroxyl-ethylamino]-3-{6-[(S)-2-methyl-morpholine-4-yl]-4-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl }-the 1H-pyridin-2-ones:
1H?NMR(400MHz，CD 3OD)δ7.63(1H，s)，7.62(1H，s)，7.30-7.61(3H，m)，6.95(1H，d，J＝8.4Hz)，6.22(1H，d，J＝7.6Hz)，4.88-4.90(1H，m)，4.08-4.18(3H，m)，3.80(3H，s)，3.61-3.67(5H，m)，3.32-3.34(1H，m)，2.60(3H，s)，1.28(3H，d，J＝6.0Hz)。LCMS(M+H) +m/z?568(t＝1.31min)。
Embodiment 570
Figure A0281051602401
4-[2-(3-chloro-4-methoxyl group-phenyl)-(S)-2-hydroxyl-ethylamino]-3-{6-[(R)-2-methyl-morpholine-4-yl]-4-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl }-1H-pyridin-2-ones and 4-[2-(3-chloro-4-methoxyl group-phenyl)-(S)-2-hydroxyl-ethylamino]-3-{6-[(S)-2-methyl-morpholine-4-yl]-4-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl }-the 1H-pyridin-2-ones:
1H NMR (400MHz, CD 3OD) δ 7.48 (1H, narrow peak d, J=2.0Hz), 7.40 (1H, brs), 7.31 (1H, narrow peak d, J=2.0Hz), 7.29 (1H, narrow peak d, J=2.0Hz), 6.97 (1H, d, J=8.4Hz), 6.22 (1H, d, J=7.6Hz), 4.87-4.90 (1H, m), 4.11 (1H, m), 3.95-4.01 (2H, m), 3.80 (3H, s), 3.47 (4H, m), 332 (1H, m), 3.25 (1H, m), 2.57 (3H, s), 1.27 (3H, d, J=6.4Hz).LCMS(M+H) +m/z?525(t＝1.27min)。
Embodiment 571
4-[2-(3-chloro-phenyl)-(S)-2-hydroxyl-ethylamino]-3-{6-[(R)-2-methoxymethyl-morpholine-4-yl]-4-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl }-1H-pyridin-2-ones and 4-[2-(3-chloro-phenyl)-(S)-2-hydroxyl-ethylamino]-3-{6-[(S)-2-methoxyl group-methyl-morpholine-4-yl]-4-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl }-the 1H-pyridin-2-ones:
1H NMR (400MHz, CD 3OD) δ 7.49 (1H, narrow peak d, J=2.0Hz), 7.23-7.36 (6H, m), 6.22 (1H, d, J=7.2Hz), 4.93-4.96 (1H, m), 4.08-4.21 (11H, m), 3.38 (3H, s), 2.60 (3H, s), 1.27 (3H, d, J=6.4Hz).LCMS(M+H) +m/z?524(t＝1.35min)
Embodiment 572
Figure A0281051602412
4-[2-(3-bromo-4-methoxyl group-phenyl)-(S)-2-hydroxyl-ethylamino]-3-{6-[(R)-2-methoxymethyl-morpholine-4-yl]-4-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl }-1H-pyridin-2-ones and 4-[2-(3-bromo-4-methoxyl group-phenyl)-(S)-2-hydroxyl-ethylamino]-3-{6-[(S)-2-methoxymethyl-morpholine-4-yl]-4-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl }-the 1H-pyridin-2-ones:
1H MR (400MHz, CD 3OD) δ 7.63 (1H, narrow peak d, J=2.0Hz), 7.40 (1H, brs), 7.30-7.36 (3H, m), 7.19 (1H, brs), 6.95 (1H, d, J=8.4Hz), 6.23 (1H, d, J=7.2Hz), 4.87-4.89 (1H, m), 4.18 (1H, m), 3.97-4.03 (3H, m), 3.80 (3H, s), 3.54-3.66 (7H, m), 3.39 (3H, s), 2.59 (3H, s).LCMS(M+H) +m/z?598(t＝1.31min)。
Embodiment 573
Figure A0281051602421
4-[2-(3-chloro-4-methoxyl group-phenyl)-(S)-2-hydroxyl-ethylamino]-3-{6-[(R)-2-methoxymethyl-morpholine-4-yl]-4-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl }-1H-pyridin-2-ones and 4-[2-(3-chloro-4-methoxyl group-phenyl)-(S)-2-hydroxyl-ethylamino]-3-{6-[(S)-2-methoxymethyl-morpholine-4-yl]-4-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl }-the 1H-pyridin-2-ones:
1H NMR (400MHz, CD 3OD) δ 7.52 (1H, s), 7.46 (1H, narrow peak d, J=1.6Hz), 7.29-7.34 (3H, m), 6.99 (1H, d, J=8.4Hz), 6.24 (1H, d, J=7.2Hz), 4.89 (1H, m), 4.06-4.17 (3H, m), 3.81 (3H, s), 3.54-3.68 (8H, m), 3.38 (3H, s), 2.60 (3H, s).LCMS(M+H) +m/z?554(t＝1.28min)。
Embodiment 574
4-[2-(3-chloro-phenyl)-2 (S)-hydroxyl-ethylaminos]-3-[4-methyl-6-(4-methyl-piperazine-1-yl)-1H-benzimidazolyl-2 radicals-yl]-the 1H-pyridin-2-ones.
1H?NMR(400MHz，CD 3OD)δ7.46(1H，s)，7.24-7.36(m，4H)，7.04(2H，s)，6.22(1H，d，J＝7.64Hz)，4.89(1H，m)，3.30-3.82(10H，m)2.97(3H，s)，2.57(3H，-s)。LCMS(M+H) +m/z?493(t＝1.56min)
Embodiment 575
Figure A0281051602432
4-[2-(3-bromo-4-methoxyl group-phenyl)-2 (S)-hydroxyl-ethylaminos]-3-[4-methyl-6-(4-methyl-piperazine-1-yl)-1H-benzimidazolyl-2 radicals-yl]-the 1H-pyridin-2-ones.
1H?NMR(400MHz，CD 3OD)δ7.61(1H，d，J＝2.0Hz)，7.32-7.37(2H，m)，7.05(2H，s)，6.97(1H，d，J＝8.52Hz)，6.24(1H，d，J＝7.64Hz)，4.82(1H，m)，3.82(3H，s)3.30-3.64(10H，m)，2.98(3H，s)，2.56(3H，s)LCMS(M+H) +m/z?567(t＝1.53min)
Following embodiment (576-581) is according to flow process VII and III and to the preparation that illustrates of 4-amino-piperadine derivatives acidylate.
Embodiment 576 (general step of embodiment 576-581)
4-[2-(3-chloro-phenyl)-2-hydroxyl-ethylamino]-3-{6-[4-(kharophen)-piperidines-1-yl]-4-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl }-the 1H-pyridin-2-ones:
The 5ml MeOH solution of (～50-100 μ mol) of 4-amino-piperadine compound is cooled to 0 ℃.Add then～10 equivalent Huenigs alkali and～3 equivalent chloride of acid.The jolting bottle is allowed to condition under the room temperature and leaves standstill 1h immediately.Obtain 4-acyl group-amino piperidine compound with the preparation HPLC purification after boiling off fugitive constituent. 1H?NMR(500MHz，CD 3OD)δ8.06(1H，s)，7.68(1H，s)，7.49(1H，s)，7.44(1H，d，J＝7.6)，7.27-7.38(4H，m)，6.333(1H，d，J＝7.6Hz)，4.96(1H，dd，J＝4.1，7.6Hz)，4.17(1H，m)，3.87(4H，m)，3.65(1H，dd，J＝4.2，14Hz)，3.58(1H，dd，J＝7.8，13.8Hz)，2.72(3H，s)，2.31(2H，m)，2.19(2H，m)，2.02(3H，s)。LCMS (M+H) +M/z 535 (t=1.03min, YMC Xterra C18 S7 3.0 * 50mm; The 0-100% gradient, 1.5min; Flow velocity 5mL/min).
Embodiment 577
4-[2-(3-chloro-phenyl)-2-hydroxyl-ethylamino]-3-{6-[4-(2-glycoloyl amino)-piperidines-1-yl]-4-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl }-the 1H-pyridin-2-ones:
LCMS(M+H) +m/z?551(t＝1.27min)。HPLCt=5.01min, WatersXterra C18 S5 4.6 * 30mm; The 0-100% gradient, 12min; Flow velocity 5mL/min.
Embodiment 578
4-[2-(3-chloro-phenyl)-2-hydroxyl-ethylamino]-3-{6-[4-(2-acetyl fluoride amino)-piperidines-1-yl]-4-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl }-the 1H-pyridin-2-ones:
LCMS(M+H) +m/z?597(t＝1.31min)。HPLC t=6.90min, YMC-Pack ODS-A 3.0 * 50mm, 0-100% gradient, 12min; Flow velocity 2.5mL/min.
Embodiment 579
4-[2-(3-bromo-4-methoxyl group-phenyl)-2-hydroxyl-ethylamino]-3-{6-[4-(kharophen)-piperidines-1-yl]-4-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl }-the 1H-pyridin-2-ones:
LCMS(M+H) +m/z?609(t＝1.27min)。HPLCt=5.00min, WatersXterra C18 S5 4.6 * 30mm; The 0-100% gradient, 12min; Flow velocity 5mL/min.
Embodiment 580
4-[2-(3-bromo-phenyl)-2-hydroxyl-ethylamino]-3-{6-[4-(2-glycoloyl amino)-piperidines-1-yl]-4-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl }-the 1H-pyridin-2-ones:
LCMS(M+H) +m/z?595(t＝1.30min)。HPLCt=5.09min, WatersXterra C18 S5 4.6 * 30mm; The 0-100% gradient, 12min; Flow velocity 5mL/min.
Embodiment 581
Figure A0281051602462
4-[2-(3-chloro-phenyl)-2-hydroxyl-ethylamino]-3-{6-[4-(2-acetyl fluoride amino)-piperidines-1-yl]-4-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl }-the 1H-pyridin-2-ones:
LCMS (M+H) +M/z 553 (t=1.35min) .HPLCt=5.90min, YMC-Pack ODS-A 3.0 * 50mm; The 0-100% gradient, 10min; Flow velocity 2.5mL/min.Following embodiment (582-584) is according to flow process VII and III and to the preparation that illustrates of 4-amino-piperadine derivatives carbamylization.
The general step of embodiment 582-584
The 5ml MeOH solution of (～50-100 μ mol) of 4-amino-piperadine compound is cooled to 0 ℃.Add then～10 equivalent Huenigs alkali and～3 equivalent urea chlorides.The jolting bottle is allowed to condition at standing over night under the room temperature immediately.Obtain 4-formamido group-amino piperidine compound with the preparation HPLC purification after boiling off fugitive constituent.
Embodiment 582
4-[2-(3-chloro-phenyl)-2-hydroxyl-ethylamino]-3-{6-[4-(2-methoxy ethoxy formamido group)-piperidines-1-yl]-4-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl }-the 1H-pyridin-2-ones:
1H?NMR(500MHz，CD 3OD)δ7.90(1H，s)，7.26-7.52(6H，m)，6.29(1H，d，J＝7.5Hz)，4.97(1H，dd，J＝4.1，7.0Hz)，4.20(2H，m)，3.93(1H，m)，3.60-3.84(8H，m)，3.37(3H，s)，2.69(3H，s)，2.33(2H，m)，2.13(2H，m)。LCMS (M+H) +M/z 595 (t=1.09min, YMC Xterra C18 S7 3.0 * 50mm; The 0-100% gradient, 1.5min; Flow velocity 5mL/min).
Embodiment 583
4-[2-(3-chloro-phenyl)-2-hydroxyl-ethylamino]-3-{6-[4-(methoxy methyl amido)-piperidines-1-yl]-4-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl }-the 1H-pyridin-2-ones:
1H?NMR(500MHz，CD 3OD)δ8.00(1H，s)，7.63(1H，s)，7.26-7.49(5H，m)，6.32(1H，d，J＝7.6Hz)，4.96(1H，dd，J＝4.2，7.6Hz)，3.93(1H，m)，3.79-3.88(4H，m)，3.67(3H，s)，3.56-3.65(2H，m)，2.71(3H，s)，2.32(2H，m)，2.17(2H，m)。LCMS (M+H) +M/z 551 (t=1.07min, YMC Xterra C18 S7 3.0 * 50mm; The 0-100% gradient, 1.5min; Flow velocity 5mL/min).
Embodiment 584
4-[2-(3-chloro-phenyl)-2-hydroxyl-ethylamino]-3-{6-[4-(2-fluorine (ethoxymethyl) amido)-piperidines-1-yl]-4-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl }-the 1H-pyridin-2-ones:
1H NMR (500MHz, CD 3OD) δ 7.92 (1H, s), 7.26-7.54 (6H, m), 6.3 (1H, d, J=7.5Hz), 4.97 (1H, dd, J=4.5,7.5Hz), 4.63 (1H, broad peak s), 4.53 (1H, d, J=2.5Hz), 4.32 (1H, broad peak s), 4.27 (1H, broad peak s), 3.93 (1H, m), 3.79-3.85 (4H, m), 3.58-3.72 (2H, m), 2.70 (3H, s), 2.33 (2H, m), 2.15 (2H, m).LCMS (M+H) +M/z 583 (t=1.29min, YMC Xterra C18 S7 3.0 * 50mm; The 0-100% gradient, 2min; Flow velocity 5mL/min).
Following embodiment (585-590) according among flow process VII and III and the flow process VII with the pure preparation that illustrates as nucleophilic reagent.
Embodiment 585 (general step of embodiment 585-590)
(S)-4-[2-(3-chloro-phenyl)-2-hydroxyl-ethylamino]-3-[4-methyl-6-(2-morpholine-4-base-oxyethyl group)-1H-benzimidazolyl-2 radicals-yl]-the 1H-pyridin-2-ones:
1H?NMR(400MHz，CD 3OD)δ7.53(1H，s)，7.37-7.39(1H，m)，7.23-7.30(3H，m)，7.01(1H，s)，6.75(1H，s)，6.21(1H，d，J＝7.2Hz)，4.98(1H，t，J＝5.6Hz)，4.40(2H，br?s)，3.97(4H，br?s)，3.45-3.73(8H，m)，2.54(3H，s)。LCMS(M+H) +m/z?524(t＝1.24min)。
Embodiment 586
Figure A0281051602491
(S)-4-[2-(3-bromo-4-methoxyl group-phenyl)-2-hydroxyl-ethylamino]-3-[4-methyl-6-(2-morpholine-4-base-oxyethyl group)-1H-benzimidazolyl-2 radicals-yl]-the 1H-pyridin-2-ones:
1H NMR (400MHz, CD 3OD) δ 7.67 (1H, narrow peak d, J=1.6Hz), 7.36 (1H, dd, J=1.6,8.4Hz), 7.25 (1H, d, J=7.2Hz), 6.98 (1H, s), 6.92 (1H, d, J=8.4Hz), 6.75 (1H, s), (6.22 1H, d, J=7.2 Hz), and 4.89-4.92 (1H, m), 4.41 (2H, brs), 3.97 (4H, brs), 3.79 (3H, s), 3.34-3.66 (8H, m), 2.51 (3H, s).LCMS(M+H) +m/z?598(t＝1.22min)。
Embodiment 587
Figure A0281051602492
(S)-4-[2-(3-chloro-phenyl)-2-hydroxyl-ethylamino]-3-[4-methyl-6-(2-methoxyl group-oxyethyl group)-1H-benzimidazolyl-2 radicals-yl]-the 1H-pyridin-2-ones:
1H?NMR(400MHz，CD 3OD)δ7.48(1H，s)，7.25-7.36(4H，m)，6.96(1H，s)，6.81(1H，s)，6.20(1H，d，J＝7.4?Hz)，4.90-4.93(1H，m)，4.13-4.14(2H，m)，3.76-3.77(2H，m)，3.50-3.61(2H，m)，3.43(3H，s)，2.53(3H，s)。LCMS(M+H) +m/z?469(t＝1.52min)。
Embodiment 588
Figure A0281051602501
(S)-4-[2-(3-chloro-phenyl)-2-hydroxyl-ethylamino]-3-[4-methyl-6-(2-hydroxyl-oxyethyl group)-1H-benzimidazolyl-2 radicals-yl]-the 1H-pyridin-2-ones:
1H NMR (400MHz, CD 3OD) δ 7.43-7.45 (2H, m), 7.27-7.34 (3H, m), 7.08 (1H, s), 7.04 (1H, narrow peak d, J=1.0Hz), 6.28 (1H, d, J=7.6Hz), 4.87 (1H, m), 4.13 (2H, t, J=4.6Hz), 3.92 (2H, t, J=4.6Hz), 3.45-3.54 (2H, m), 2.60 (3H, s).LCMS(M+H) +m/z?455(t＝1.35min)。
Embodiment 589
Figure A0281051602502
(S)-4-[2-(3-bromo-4-methoxyl group-phenyl)-2-hydroxyl-ethylamino]-3-[4-methyl-6-(3-morpholine-4-base-propoxy-)-1H-benzimidazolyl-2 radicals-yl]-the 1H-pyridin-2-ones:
1HNMR(400MHz，CD 3OD)δ7.66(1H，s)，7.35(1H，dd，J＝1.6，7.9Hz)，7.25(1H，brs)，6.93(1H，s)，6.91(1H，s)，6.68(1H，s)，6.19(1H，brs)，4.86(1H，m)，4.05-4.10(4H，brs)，3.79(3H，s)，3.17-3.73(12H，m)，2.50(3H，s)。LCMS(M+H) +m/z?612(t＝1.16min)。
Embodiment 590
(S)-4-[2-(3-chloro-phenyl)-2-hydroxyl-ethylamino]-3-[4-methyl-6-(3-morpholine-4-base-propoxy-)-1H-benzimidazolyl-2 radicals-yl]-the 1H-pyridin-2-ones:
1H?NMR(400MHz，CD 3OD)δ?7.52(1H，s)，7.36-7.38(1H，m)，7.23-7.30(3H，m)，6.92(1H，s)，6.67(1H，s)，6.18(1H，d，J＝6.9Hz)，4.96(1H，t，J＝5.9Hz)，4.04-4.08(4H，m)，3.82(2H，m)，3.56-3.65(8H，m)，3.15-3.18(2H，m)，2.52(3H，s)。LCMS(M+H) +m/z?538(t＝1.19min)。
Following embodiment (591-593) is according to flow process VII and III preparation, and wherein cyano group (flow process IV) is converted into aldehyde, and aldehyde and amine are carried out reductive amination.
Embodiment 591 (general method of embodiment 591-593)
Figure A0281051602521
(S)-3-(4-bromo-6-morpholine-4-ylmethyl-1H-benzimidazolyl-2 radicals-yl)-4-[2-(3-chloro-phenyl)-2-hydroxyl-ethylamino]-the 1H-pyridin-2-ones:
(S)-7-bromo-2-{4-[2-(3-chloro-phenyl)-2-hydroxyl-ethylamino]-2-oxo-1,2-dihydro-pyridin-3-yl }-(130mg adds morpholine (0.2mL, excessive) to 3H-benzoglyoxaline-5-formaldehyde in methyl alcohol 0.27mmol) (60mL) solution.Reaction mixture is at room temperature stirred 1h.Add NaCNBH then 3(1M THF solution, 1.35mL, 1.35mmol).Reaction mixture at room temperature stirred spend the night, then vacuum concentration.Resistates is purified with preparation HPLC and is obtained title compound (68mg, 45%). 1H?NMR(400MHz，CD 3OD)δ7.83(1H，s)，7.69(1H，s)，7.68(1H，s)，7.24-7.54(4H，m)，6.30(1H，d，J＝7.6Hz)，4.89-5.02(1H，m)，4.50(2H，s)，3.66-3.71(4H，m)，3.17-3.43(6H，m)。LCMS(M+H) +m/z?558(t＝1.41min)。
Embodiment 592
(S)-3-[4-bromo-6-(4-methyl-piperazine-1-ylmethyl)-1H-benzimidazolyl-2 radicals-yl]-4-[2-(3-chloro-phenyl)-2-hydroxyl-ethylamino]-the 1H-pyridin-2-ones:
1H?NMR(400MHz，CD 3OD)δ7.70(1H，s)，7.55(2H，s)，7.42(1H，d，J＝7.6Hz)，7.24-7.32(3H，m)，6.22(1H，d，J＝7.6Hz)，5.01(1H，t，J＝6.2Hz)，4.35(2H，brs)，3.48-3.71(10H，m)，2.98(3H，s)。LCMS(M+H) +m/z?571(t＝1.37min)。
Embodiment 593
Figure A0281051602531
(S)-4-[2-(3-chloro-phenyl)-2-hydroxyl-ethylamino]-3-[4-methyl-6-(4-methyl-piperazine-1-ylmethyl)-1H-benzimidazolyl-2 radicals-yl]-the 1H-pyridin-2-ones:
(S)-3-[4-bromo-6-(4-methyl-piperazine-1-ylmethyl)-1H-benzimidazolyl-2 radicals-yl in being loaded on bottle]-4-[2-(3-chloro-phenyl)-2-hydroxyl-ethylamino]-1H-pyridin-2-ones (80mg, 0.14mmol, tin tetramethide (2.5mL, excessive), PdCl 2(PPh 3) 4(10mg, 0.014mmol) and KF (40mg feeds nitrogen in DMF 0.7mmol) (2mL) mixture, the sealing, be heated to then 100 ℃ 2 days.Make reaction mixture pass through the diatomite pulvinulus.After concentrating, resistates is purified with preparation HPLC and is obtained title compound (34mg, 48%). 1H?NMR(400MHz，CD 3OD)δ7.53(1H，s)，7.45(1H，s)，7.24-7.40(4H，m)，7.09(1H，s)，6.22(1H，d，J＝7.6Hz)，4.99(1H，t，J＝6.4Hz)，4.04(2H，brs)，3.61-3.74(2H，m)，2.98-3.34(8H，m)，2.80(3H，s)，2.58(3H，s)。LCMS(M+H) +m/z?507(t＝1.29min)。
Following embodiment (594-595) is according to flow process VIII and III and use tetrahydropyrimidine to do the preparation that illustrates of nucleophilic reagent in flow process VII.
Embodiment 594
4-[2-(3-chloro-phenyl)-2 (S)-hydroxyl-ethylaminos]-3-[4-methyl-6-(1,4,5,6-tetrahydropyrimidine-1-yl)-1H-benzimidazolyl-2 radicals-yl]-the 1H-pyridin-2-ones:
1H?NMR(400MHz，CD 3OD)δ8.38(1H，s)，7.52(1H，s)，7.21-7.41(5H，m)，7.04(1H，d，J＝1.2Hz)，6.21(1H，d，J＝7.6Hz)，4.97(1H，t，J＝4.9Hz)3.97(2H，m)3.60-3.73(2H，m)，3.52(2H，t，J＝5.74Hz)2.60(3H，s)，2.25(2H，m)LCMS(M+H) +m/z?477(t＝1.79min)
Embodiment 595
Figure A0281051602542
4-[2-(4-methoxyl group-3-chloro-phenyl)-2 (S)-hydroxyl-ethylaminos]-3-[4-methyl-6-(1,4,5,6-tetrahydropyrimidine-1-yl)-1H-benzimidazolyl-2 radicals-yl]-the 1H-pyridin-2-ones:
1H?NMR(400MHz，CD 3OD)δ8.37(1H，s)，7.52(1H，s)，7.04-7.52(4H，m)，7.04(1H，d，J＝1.2Hz)，6.21(1H，d，J＝7.6Hz)，4.98(1H，t，J＝4.92Hz)，3.97(5H，m)，3.60-3.73(2H，m)，3.52(2H，t，J＝5.74Hz)，2.60(3H，s)，2.26(2H，m)。LCMS(M+H) +m/z?507(t＝1.67min)
Should be understood that the foregoing description never limits the scope of the present invention, but exemplary illustration.All reference that this paper quotes all are attached to this paper by reference.

Claims (58)

1. a following formula I compound, its enantiomer, diastereomer, pharmacy acceptable salt, hydrate, prodrug and solvate:
Figure A0281051600021
Wherein
X is selected from N, C, C 1-C 3Alkyl, one or more R 7The C that replaces 1-C 3Alkyl and chemical bond;
Y is selected from O and S;
W is selected from N, C, O and S, and prerequisite is W when being O or S, then R 9Do not exist;
R 1, R 2, R 3, R 4, R 5, R 6, R 7, R 8, R 9Independently be selected from following group: H, C separately 1-6Alkyl, alkenyl, alkynyl group, cycloalkyl, Heterocyclylalkyl, halogen, amino, OR 60, NO 2, OH, SR 60, NR 60R 61, CN, CO 2R 60, CONR 60R 61, OCONR 60R 61, NR 62CONR 60R 61, NR 60SO 2R 61, SO 2NR 60R 61, C (NR 62) NR 60R 61, aryl, heteroaryl, (CH 2) nOR 60, (CH 2) nNR 60R 61, (CH 2) nSR 60, (CH 2) nAryl, (CH 2) nHeteroaryl, (CH 2) nHeterocyclylalkyl, NH-Z-aryl and NH-Z-heteroaryl;
Wherein n is 1-3;
Z is selected from C 1-C 4Alkyl group, alkenyl and alkynyl group; Z contains one or more hydroxyls, sulfydryl, alkoxyl group, thio alkoxy, amino, halogen, NR 60SO 2R 61Z is optional in conjunction with one or more following group: CO, CNOH, CNOR of being selected from 60, CNNR 60, CNNCOR 60And CNNSO 2R 60
R 60And R 61Independently be selected from following group: H, alkyl, alkenyl, alkynyl group, cycloalkyl, cycloalkylalkyl, hydroxyl, alkoxyl group, aryl, heteroaryl, heteroarylalkyl and alkyl-R 25, wherein
R 25For hydrogen, alkenyl, hydroxyl, sulfydryl, alkoxyl group, thio alkoxy, amino, alkylamino, dialkyl amido, aryl, heteroaryl, cyano group, halogen, sulfinyl, alkylsulfonyl ,-NR 30COOR 31,-NR 30C (O) R 31,-NR 30SO 2R 31,-C (O) NR 30R 31, heteroaryl or Heterocyclylalkyl;
R 30And R 31Independent is hydrogen, alkyl, cycloalkyl or alkyl-R 25
2. the compound of claim 1, wherein
R 1, R 7, R 8And R 9Be H;
R 2And R 4Be H or F;
Y is O;
X is selected from N and CH;
W is N;
R 5Be selected from H, methyl, ethyl, sec.-propyl, sec-butyl, cyclopropyl, F and CF 3
R 6Be selected from H, 2-aminomethyl pyridine, NHCH 2CH (OH) Ph,
NHCH 2CH(OH)(3-Cl-Ph)、NHCH 2CH(OH)(3-Br-Ph)、
NHCH 2CH(OH)(3-Br-4-OMe-Ph)、NHCH(CH 2OH)CH 2Ph、
NHCH 2CH (OH) aryl and NHCH (CH 2OH) CH 2Aryl;
R 3Be selected from OR 60, C (NH) NHR 60, C (O) NHR 60Imidazoles, tetrahydroglyoxaline, tetrahydropyrimidine, piperazine, morpholine, high morpholine, piperidines, tetramethyleneimine, high piperazine and amino; Wherein
R 60Be selected from H, alkyl, cycloalkyl, Heterocyclylalkyl and alkyl-R 25, R wherein 25For hydrogen, alkenyl, hydroxyl, sulfydryl, thio alkoxy, alkoxyl group, thio alkoxy, halogen, cyano group, sulfinyl, alkylsulfonyl ,-NR 30COOR 31,-NR 30C (O) R 31,-NR 30SO 2R 31,-C (O) NR 30R 31, heteroaryl or Heterocyclylalkyl;
R 30And R 31Independent is hydrogen, alkyl, cycloalkyl or alkyl-R 25
3. the compound of claim 2, wherein R 3For-OR 60, R 60For alkyl or-alkyl-R 25, wherein
R 25For hydrogen, alkenyl, hydroxyl, sulfydryl, alkoxyl group, thio alkoxy, amino, halogen, cyano group, sulfinyl, alkylsulfonyl ,-NR 30COOR 31,-NR 30C (O) R 31,-NR 30SO 2R 31,-C (O) NR 30R 31, heteroaryl or Heterocyclylalkyl;
R 30And R 31Independent is hydrogen, alkyl, cycloalkyl or alkyl-R 25
4. the compound of claim 3, wherein R 60For methyl ,-(CH 2) nCH 2OH or-(CH 2) nCH 2N (CH 2CH 2) 2O, n are 0,1 or 2.
5. the compound of claim 3, wherein R 25For morpholine,
Figure A0281051600041
Or
Figure A0281051600043
R wherein 33Alkyl for hydrogen, alkyl or replacement.
6. the compound of claim 2, wherein R 3Be piperazine, high piperazine, 3-methylpiperazine or 3, the 5-lupetazin, and choose wantonly and be selected from following group in the 4-N position and replace: alkyl, cycloalkyl, cycloalkylalkyl, alkyl-R 25,-C (O)-R 15Or-CO 2R 15, R wherein 15Be hydrogen, alkyl, aryl, alkyl-R 25, amino or aryl;
R 25For hydrogen, alkenyl, hydroxyl, sulfydryl, alkoxyl group, thio alkoxy, amino, alkylamino, dialkyl amido, cyano group, halogen, sulfinyl, alkylsulfonyl, aryl sulfonyl ,-NR 30COOR 31,-NR 30C (O) R 31,-NR 30SO 2R 31,-C (O) NR 30R 31, heteroaryl or Heterocyclylalkyl;
R 30And R 31Independent is hydrogen, alkyl, cycloalkyl or alkyl-R 25
7. the compound of claim 6, wherein said piperazine is replaced by following group: methyl, ethyl, CH 2-cyclopropyl, hydroxyethyl, 2-dimethyl aminoethyl, 2-diethylamino ethyl, 2-amino-ethyl, 2-methylamino ethyl, 2-ethylamino ethyl, methoxy ethyl, ethoxyethyl group, morpholine and morpholinyl ethyl.
8. the compound of claim 2, wherein R 3For being selected from following amino: hydroxyalkyl amino, aminoalkyl group amino, dialkyl aminoalkyl amino and Heterocyclylalkyl alkylamino.
9. the compound of claim 8, wherein said amino is selected from following group:
NHCH 2CH 2OH、NMeCH 2CH 2OH、NEtCH 2CH 2OH、NHCH 2CH 2NH 2、
NMeCH 2CH 2NH 2、NEtCH 2CH 2NH 2、NHCH 2CH 2NMe 2、
NMeCH 2CH 2NMe 2、NEtCH 2CH 2NMe 2、NHCH 2CH 2NEt 2、
NMeCH 2CH 2NEt 2、NEtCH 2CH 2NEt 2、NHCH 2CH 2N(CH 2CH 2) 2O、
NMeCH 2CH 2N (CH 2CH 2) 2O and NEtCH 2CH 2N (CH 2CH 2) 2O.
10. the compound of claim 2, wherein R 3Be piperidines, and optional replaced by following group: hydroxyl, sulfydryl, amino, alkylamino, dialkyl amido, alkoxyl group, thio alkoxy, 1,3-dioxolane, 1, the 3-diox ,-NHC (O) R 15,-NHCO 2R 15, R wherein 15Be hydrogen, alkyl, aryl or alkyl-R 25, R wherein 25For hydrogen, alkenyl, hydroxyl, sulfydryl, alkoxyl group, thio alkoxy, amino, halogen, cyano group, sulfinyl, alkylsulfonyl ,-NR 30COOR 31,-NR 30C (O) R 31,-NR 30SO 2R 31,-C (O) NR 30R 31, heteroaryl or Heterocyclylalkyl;
R 30And R 31Independent is hydrogen, alkyl, cycloalkyl or alkyl-R 25
11. the compound of claim 2, wherein R 3Be morpholine, parathiazan, sulfinyl morpholine, alkylsulfonyl morpholine or high morpholine, perhaps following group: morpholine, parathiazan, sulfinyl morpholine, alkylsulfonyl morpholine or high morpholine for replacing.
12. the compound of claim 11, wherein said morpholine, parathiazan, sulfinyl morpholine, alkylsulfonyl morpholine or high morpholine are replaced by following group: hydroxyl, sulfydryl, amino, alkylamino, dialkyl amido, alkoxyl group, thio alkoxy, alkyl-R 25,-NHC (O) R 15,-NHCO 2R 15, R wherein 15Be hydrogen, alkyl, aryl or alkyl-R 25, R wherein 25For hydrogen, alkenyl, hydroxyl, sulfydryl, alkoxyl group, thio alkoxy, amino, halogen, cyano group, sulfinyl, alkylsulfonyl ,-NR 30COOR 31,-NR 30C (O) R 31,-NR 30SO 2R 31,-C (O) NR 30R 31, heteroaryl or Heterocyclylalkyl;
R 30And R 31Independent is hydrogen, alkyl, cycloalkyl or alkyl-R 25
13. the compound of claim 2, wherein R 3Be (CH 2) n-morpholine or (CH 2) n-piperazine, wherein n is 1-3.
14. the compound of claim 2, wherein R 3Be optional N-tetrahydropyrimidine or the TMSIM N imidazole quinoline that replaces.
15. the compound of claim 14, wherein at least one described substituting group is alkyl, hydroxyalkyl, alkoxyalkyl, haloalkyl, cyano group alkyl, carboxyl or methane amide.
16. the compound of claim 2, wherein R 3Be tetramethyleneimine.
17. the compound of claim 2, wherein said tetramethyleneimine are selected from 3-hydroxyl pyrrolidine, 3-alkoxyl group tetramethyleneimine, 3-alkylamino tetramethyleneimine and 3-dialkyl amido tetramethyleneimine.
18. the compound of claim 2, wherein R 6Be selected from H, 2-aminomethyl pyridine, NHCH 2CH (OH) aryl and NHCH (CH 2OH) CH 2Aryl.
19. the compound of claim 18, wherein said aryl is the optional phenyl that replaces.
20. the compound of claim 19, wherein said phenyl is replaced by following group: Br, Cl, F, alkoxyl group or-NHSO 2CH 3
21. the compound of claim 19, wherein said substituting group are 3-Br, 3-Cl or 3-F.
22. the compound of claim 19, wherein said substituting group are 4-F or 4-methoxyl group.
23. the compound of claim 19, wherein R 6For
Figure A0281051600061
Or
R wherein 17Be H, Br, Cl or F, R 40Be H or alkyl.
24. compound with following formula structure:
Figure A0281051600071
R wherein 12And R 13Independent is hydrogen, alkyl or alkyl-R 25, wherein
R 25For hydrogen, hydroxyl, sulfydryl, alkenyl, amino, alkoxyl group, thio alkoxy, halogen, cyano group, sulfinyl, alkylsulfonyl ,-CO 2H ,-C (O) NR 30R 31,-NR 30SO 2R 31,-NR 30C (O) R 31,-NR 30C (O) OR 31, heteroaryl or Heterocyclylalkyl;
R 17, R 18And R 19Independent is hydrogen, halogen or alkoxyl group, perhaps R 18And R 19Constitute Heterocyclylalkyl or heteroaryl together;
R 30And R 31Independent is hydrogen, alkyl or alkyl-R 25
25. the compound of claim 24, wherein R 25For morpholine,
Figure A0281051600072
Or
Figure A0281051600074
R wherein 33Alkyl for hydrogen, alkyl or replacement.
26. the compound of claim 24, wherein R 12Be hydrogen, methyl, methylol, methoxymethyl, CH 2F, CH 2CN, CO 2H or-CONR 30R 31, R wherein 30And R 31Independent is hydrogen or alkyl-R 25
27. the compound of claim 24, described compound connects following side chain:
Figure A0281051600082
Or
Figure A0281051600083
R wherein 40Be hydrogen or alkyl, and R 70Be hydrogen or halogen.
28. the compound of claim 24, wherein R 12And R 13Be H; R 17For Br, F or Cl; R 18Be methoxyl group or fluorine; R 19Be H; Perhaps R 18And R 19Constitute 4-O together, 5-dihydrofuran base.
29. the compound of claim 24, wherein R 12And R 13Be methyl; R 17Be Br, F or Cl; R 18Be hydrogen or methoxyl group; R 19Be H.
30. compound with following formula structure:
R wherein 15For hydrogen, alkyl, aryl or-alkyl-R 25, wherein
R 25For hydrogen, hydroxyl, sulfydryl, alkenyl, amino, alkoxyl group, thio alkoxy, halogen, cyano group, sulfinyl, alkylsulfonyl ,-NR 30COOR 31,-NR 30C (O) R 31,-NR 30SO 2R 31,-C (O) NR 30R 31, heteroaryl or Heterocyclylalkyl;
R 16Independent separately is hydrogen or methyl;
R 17, R 18And R 19Independent is hydrogen, halogen or alkoxyl group; Perhaps R 18And R 19Constitute Heterocyclylalkyl or heteroaryl together; R 30And R 31Independent is hydrogen, alkyl or alkyl-R 25
31. the compound of claim 30, wherein R 25For morpholine, parathiazan,
Figure A0281051600091
Or
Figure A0281051600093
32. the compound of claim 30, described compound connects following side chain:
Figure A0281051600094
Figure A0281051600095
Or
Figure A0281051600096
R wherein 40Be hydrogen or alkyl, R 17Hydrogen or halogen.
33. the compound of claim 30, wherein R 15Be hydrogen, methyl, ethyl or (CH 2) nCH 2-R 25, R wherein 25Be OH, OMe, F, CN, CF 3, SOCH 3Or SO 2CH 3, wherein n is 0 or 1.
34. the compound of claim 30, wherein R 15Be cyano ethyl, hydroxyethyl, CH 2CH 2SOCH 3, CH 2CH 2CH 2F, CH 2CH 2CH 2CN or CH 2CH 2CF 3R 16And R 19Be H; R 17Be Br or Cl; R 18Be hydrogen or methoxyl group.
35. compound with following formula structure:
Wherein
R 15Be hydrogen, alkyl, aryl or alkyl-R 25
R 25For hydrogen, hydroxyl, sulfydryl, alkenyl, alkoxyl group, thio alkoxy, amino, halogen, cyano group, sulfinyl, alkylsulfonyl ,-NR 30COOR 31,-NR 30C (O) R 31,-NR 30SO 2R 31,-C (O) NR 30R 31, heteroaryl or Heterocyclylalkyl;
R 16Independent separately is hydrogen or methyl;
R 17, R 18And R 19Independent is hydrogen, halogen or alkoxyl group, perhaps R 18And R 19Constitute Heterocyclylalkyl or heteroaryl together;
R 30And R 31Independent is hydrogen, alkyl, cycloalkyl or alkyl-R 25
36. the compound of claim 35, wherein R 25For morpholine, parathiazan,
Or
Figure A0281051600104
R wherein 33Alkyl for hydrogen, alkyl or replacement.
37. the compound of claim 35, described compound connects following side chain:
Figure A0281051600111
Or
Figure A0281051600113
R wherein 40Be hydrogen or alkyl, R 17Be hydrogen or halogen.
38. the compound of claim 35, wherein R 15Be hydrogen or methyl; R 17Be bromine, chlorine or fluorine; R 18Be hydrogen or methoxyl group; R 19Be hydrogen.
39. compound with following formula structure:
Figure A0281051600114
Wherein
R 15For hydrogen, alkyl or-alkyl-R 25
R 25For hydrogen, hydroxyl, sulfydryl, alkenyl, alkoxyl group, thio alkoxy, amino, halogen, cyano group, sulfinyl, alkylsulfonyl ,-NR 30COOR 31,-NR 30C (O) R 31,-NR 30SO 2R 31,-C (O) NR 30R 31, heteroaryl or Heterocyclylalkyl;
R 16Independent separately is hydrogen or methyl;
R 17, R 18And R 19Independent is hydrogen, halogen or alkoxyl group; Perhaps R 18And R 19Constitute heterocyclic radical or heteroaryl together;
R 30And R 31Independent is hydrogen, alkyl, cycloalkyl or alkyl-R 25
40. the compound of claim 39, described compound connects following side chain:
Or
Figure A0281051600123
R wherein 40Be hydrogen or alkyl, R 17Be hydrogen or halogen.
41. the compound of claim 39, wherein R 15For hydrogen, methyl, ethyl or-(CH 2) nCH 2-R 25, wherein n is 0,1 or 2; R 25Be OH, OMe, F, CN, CF 3, SOCH 3Or SO 2CH 3,-NR 30COR 31,-NR 30COOR 31,-NR 30SO 2R 31,-C (O) NR 30R 31, or the group with following formula structure:
Figure A0281051600124
Figure A0281051600125
Or
Figure A0281051600126
R wherein 33Alkyl for hydrogen, alkyl or replacement.
42. the compound of claim 39, wherein R 15Be ethyl, methoxy ethyl, CH 2CH 2F or CH 2CH 2CN; R 17Be bromine or chlorine; R 18Be methoxyl group or hydrogen; R 19Be hydrogen.
43. compound with following formula structure:
Wherein
R 16For hydrogen, alkyl, aryl or-alkyl-R 25
R 25For hydrogen, hydroxyl, sulfydryl, alkenyl, alkoxyl group, thio alkoxy, amino, halogen, cyano group, sulfinyl, alkylsulfonyl ,-NR 30COOR 31,-NR 30C (O) R 31,-NR 30SO 2R 31,-C (O) NR 30R 31, heteroaryl or Heterocyclylalkyl;
R 17, R 18And R 19Independent is hydrogen, halogen or alkoxyl group; Perhaps R 18And R 19Constitute heterocyclic radical or heteroaryl together;
R 30And R 31Independent is hydrogen, alkyl, cycloalkyl or alkyl-R 25
44. the compound of claim 43, wherein R 15For-(CH 2) nCH 2R 25, n is 0,1,2 or 3, R 25Be OH, OMe, F, CN, CF 3, SOCH 3Or SO 2CH 3,-NR 30COOR 31,-NR 30C (O) R 31,-NR 30SO 2R 31,-C (O) NR 31R 32Or have a following formula structure:
Or
Figure A0281051600134
R wherein 33Alkyl for hydrogen, alkyl or replacement.
45. the compound of claim 43, wherein R 15Be methyl, ethyl, CH 2F, methoxy ethyl, CH 2CH 2F or CH 2CH 2CH 2SOCH 3R 17Be bromine; R 18Be hydrogen, methoxyl group or fluorine; R 19Be H.
46. the compound of claim 45, described compound connects following side chain:
Figure A0281051600142
Or
R wherein 40Be hydrogen or alkyl, R 17Be hydrogen or halogen.
47. compound with following formula structure:
Figure A0281051600144
Or
Figure A0281051600145
Each R wherein 15Independent be hydrogen, alkyl, aryl or-alkyl-R 25
R 25For hydrogen, hydroxyl, sulfydryl, alkenyl, alkoxyl group, thio alkoxy, amino, halogen, cyano group, sulfinyl, alkylsulfonyl ,-NR 30COOR 31,-N 30C (O) R 31,-NR 30SO 2R 31,-C (O) NR 30R 31, heteroaryl or Heterocyclylalkyl;
R 17, R 18And R 19Independent is hydrogen, halogen or alkoxyl group; Perhaps R 18And R 19Constitute heterocyclic radical or heteroaryl together;
R 30And R 31Independent is hydrogen, alkyl, cycloalkyl or alkyl-R 25
48. the compound of claim 1, described compound is selected from following compound:
1 (S)-4-(2-hydroxyl-1-phenyl-ethylamino)-3-(6-imidazoles-1-base-4-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl)-the 1H-pyridin-2-ones;
2 (±)-4-[2-hydroxyl-2-(3-iodo-phenyl)-ethylamino]-3-(6-imidazoles-1-base-4-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl)-the 1H-pyridin-2-ones;
3 (±)-4-[2-(3-chloro-phenyl)-2-hydroxyl-ethylamino]-3-(6-imidazoles-1-base-4-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl)-the 1H-pyridin-2-ones;
4 (±)-4-[2-(3-bromo-phenyl)-2-hydroxyl-ethylamino]-3-(6-imidazoles--1-base-4-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl)-the 1H-pyridin-2-ones;
5 (S)-4-[2-(2-chloro-phenyl)-1-methylol-ethylamino]-3-(6-imidazoles-1-base-4-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl)-the 1H-pyridin-2-ones;
6 (S)-4-[2-(3-chloro-phenyl)-1-methylol-ethylamino]-3-(6-imidazoles-1-base-4-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl)-the 1H-pyridin-2-ones;
7 (S)-4-[2-(4-chloro-phenyl)-1-methylol-ethylamino]-3-(6-imidazoles-1-base-4-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl)-the 1H-pyridin-2-ones;
8 (S)-4-[2-(2-bromo-phenyl)-1-methylol-ethylamino]-3-(6-imidazoles-1-base-4-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl)-the 1H-pyridin-2-ones;
9 (S)-4-[2-(3-bromo-phenyl)-1-methylol-ethylamino]-3-(6-imidazoles-1-base-4-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl)-the 1H-pyridin-2-ones;
10 (±)-4-(1-methylol-2-pentafluorophenyl group-ethylamino)-3-(6-imidazoles-1-base-4-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl)-the 1H-pyridin-2-ones;
11 (S)-4-(1-methylol-2-pyridin-4-yl-ethylamino)-3-(6-imidazoles-1-base-4-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl)-the 1H-pyridin-2-ones;
12 (S)-4-[1-methylol-2-(2-naphthyl)-ethylaminos]-3-(6-imidazoles-1-base-4-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl)-the 1H-pyridin-2-ones;
133-(6-imidazoles-1-base-4-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl)-4-(pyridine-2-ylmethoxy)-1H-pyridin-2-ones;
14 (±)-4-[2-(3-bromo-phenyl)-2-fluoro-ethylamino]-3-(6-imidazoles-1-base-4-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl)-the 1H-pyridin-2-ones;
15 (S)-2-[4-(1-methylol-2-phenyl-ethylamino)-2-oxo-1,2-dihydro-pyridin-3-yl]-7-methyl-3H-benzoglyoxaline-5-formonitrile HCN;
16 (±)-2-{4-[2-(3-chloro-phenyl)-2-hydroxyl-ethylamino]-2-oxo-1,2-dihydro-pyridin-3-yl }-7-methyl-3H-benzoglyoxaline-5-formonitrile HCN;
17 (S)-2-{4-[2-(3-chloro-phenyl)-1-methylol-ethylamino]-2-oxo-1,2-dihydro-pyridin-3-yl }-7-methyl-3H-benzoglyoxaline-5-formonitrile HCN;
18 (±)-2-{4-[2-(3-bromo-4-methoxyl group-phenyl)-2-hydroxyl-ethylamino]-2-oxo-1,2-dihydro-pyridin-3-yl }-7-methyl-3H-benzoglyoxaline-5-formonitrile HCN;
19 (±)-2-{4-[2-(3-fluoro-phenyl)-2-hydroxyl-ethylamino]-2-oxo-1,2-dihydro-pyridin-3-yl }-7-methyl-3H-benzoglyoxaline-5-formonitrile HCN;
20 (±)-2-{4-[2-(3-bromo-phenyl)-2-hydroxyl-ethylamino]-2-oxo-1,2-dihydro-pyridin-3-yl }-7-methyl-3H-benzoglyoxaline-5-formonitrile HCN;
21 (S)-2-[4-(2-hydroxyl-2-phenyl-ethylamino)-2-oxo-1,2-dihydro-pyridin-3-yl]-7-methyl-3H-benzoglyoxaline-5-formonitrile HCN;
22 (±)-3-(the 1H-benzimidazolyl-2 radicals-yl)-4-[2-(3-bromo-phenyl)-2-hydroxyl-ethylamino]-the 1H-pyridin-2-ones;
23 (S)-3-(the 1H-benzimidazolyl-2 radicals-yl)-4-(1-methylol-2-phenyl-ethylamino)-1H-pyridin-2-ones;
24 (±)-3-(the 1H-benzimidazolyl-2 radicals-yl)-4-[2-(3-bromo-4-methoxyl group-phenyl)-2-hydroxyl-ethylamino]-the 1H-pyridin-2-ones;
25 (S)-4-{2-[4-(1-methylol-2-phenyl-ethylamino)-2-oxo-1,2-dihydro-pyridin-3-yl]-7-methyl-3H-benzoglyoxaline-5-yl }-piperazine-1-(N-sec.-propyl-methane amide);
26 (S)-4-{2-[4-(1-methylol-2-phenyl-ethylamino)-2-oxo-1,2-dihydro-pyridin-3-yl]-7-methyl-3H-benzoglyoxaline-5-yl }-piperazine-1-(N-ethyl-methane amide);
27 (S)-4-(1-methylol-2-phenyl-ethylamino)-3-{4-methyl-6-[4-(1-phenyl-formyl radical)-piperazine-1-yl]-1H-benzimidazolyl-2 radicals-yl }-the 1H-pyridin-2-ones;
28 (S)-4-(1-methylol-2-phenyl-ethylamino)-3-[6-(4-sec.-propyl-piperazine-1-yl)-4-methyl-H-benzimidazolyl-2 radicals-yl]-the 1H-pyridin-2-ones;
29 (S)-3-[6-(4-benzyl-piperazine-1-yl)-4-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl]-4-(1-methylol-2-phenyl-ethylamino)-1H-pyridin-2-ones;
30 (±)-3-[6-(4-ethanoyl-piperazine-1-yl)-4-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl]-4-[2-(3-chloro-phenyl)-2-hydroxyl-ethylamino]-the 1H-pyridin-2-ones;
31 (±)-4-[2-(3-chloro-phenyl)-2-hydroxyl-ethylamino]-3-(4-methyl-6-piperazine-1-base-1H-benzimidazolyl-2 radicals-yl)-the 1H-pyridin-2-ones;
32 (±)-4-[2-(3-chloro-phenyl)-2-hydroxyl-ethylamino]-3-[6-(4-sec.-propyl-piperazine-1-yl)-4-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl]-the 1H-pyridin-2-ones;
33 (S)-6-(1-methylol-2-phenyl-ethylamino)-5-(6-imidazoles-1-base-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl)-the 3H-pyrimidin-4-one;
34 (S)-2-[6-chloro-5-(6-imidazoles-1-base-4-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl)-pyrimidine-4-base is amino]-3-phenyl-third-1-alcohol;
35 (S)-4-(2-hydroxyl-2-phenyl-ethylamino)-3-(6-imidazoles-1-base-4-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl)-the 1H-pyridin-2-ones;
36 (R)-4-(2-hydroxyl-2-phenyl-ethylamino)-3-(6-imidazoles-1-base-4-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl)-the 1H-pyridin-2-ones;
37 (1S, 2R)-4-(1-hydroxyl-indane-2-base is amino)-3-(6-imidazoles-1-base-4-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl)-the 1H-pyridin-2-ones;
38 (±)-4-[2-hydroxyl-2-(3-hydroxyl-phenyl)-ethylamino]-3-(6-imidazoles-1-base-4-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl)-the 1H-pyridin-2-ones;
39 (S)-4-(2-hydroxyl-2-pyridine-2-base-ethylamino)-3-(6-imidazoles-1-base-4-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl)-the 1H-pyridin-2-ones;
40 (±)-N-(3-{1-hydroxyl-2-[3-(6-imidazoles-1-base-4-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl)-2-oxo-1,2-dihydro-pyridin-4-yl amino]-ethyl }-phenyl)-Toluidrin;
41 (±)-4-[2-(3-fluoro-phenyl)-2-hydroxyl-ethylamino]-3-(6-imidazoles-1-base-4-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl)-the 1H-pyridin-2-ones;
42 (±)-4-[2-(3-chloro-4-fluoro-phenyl)-2-hydroxyl-ethylamino]-3-(6-imidazoles-1-base-4-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl)-the 1H-pyridin-2-ones;
43 (S)-4-[2-(3-fluoro-phenyl)-1-methylol-ethylamino]-3-(6-imidazoles-1-base-4-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl)-the 1H-pyridin-2-ones;
44 (±)-4-[2-(3-chloro-phenyl)-2-hydroxyl-ethylamino]-3-(6-imidazoles-1-base-1H-benzimidazolyl-2 radicals-yl)-the 1H-pyridin-2-ones;
45 (±)-4-[2-(3-bromo-4-methoxyl group-phenyl)-2-hydroxyl-ethylamino]-3-(6-imidazoles-1-base-4-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl)-the 1H-pyridin-2-ones;
46 (S)-4-[2-(3-bromo-phenyl)-2-hydroxyl-ethylamino]-3-(6-imidazoles-1-base-4-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl)-the 1H-pyridin-2-ones;
47 (S)-4-[2-(3-chloro-phenyl)-2-hydroxyl-ethylamino]-3-(6-imidazoles-1-base-4-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl)-the 1H-pyridin-2-ones;
48 (R)-4-[2-(3-chloro-phenyl)-2-hydroxyl-ethylamino]-3-(6-imidazoles-1-base-4-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl)-the 1H-pyridin-2-ones;
49 (±)-4-[2-(3-chloro-4-methoxyl group-phenyl)-2-hydroxyl-ethylamino]-3-(6-imidazoles-1-base-4-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl)-the 1H-pyridin-2-ones;
50 (±)-(2-chloro-4-{1-hydroxyl-2-[3-(6-imidazoles-1-base-4-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl)-2-oxo-1,2-dihydro-pyridin-4-yl amino]-ethyl }-phenyl)-Urethylane;
51 (S)-4-(1-methylol-2-phenyl-ethylamino)-3-[4-methyl-6-(4-methyl-piperazine-1-yl)-1H-benzimidazolyl-2 radicals-yl]-the 1H-pyridin-2-ones;
52 (S)-4-(1-methylol-2-phenyl-ethylamino)-3-[4-methyl-6-(4-normal-butyl-piperazine-1-yl)-1H-benzimidazolyl-2 radicals-yl]-the 1H-pyridin-2-ones;
53 (S)-3-{6-[4-(2-hydroxyl-ethyl)-piperazine-1-yl]-4-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl }-4-(1-methylol-2-phenyl-ethylamino)-1H-pyridin-2-ones;
54 (S)-4-{2-[4-(1-methylol-2-phenyl-ethylamino)-2-oxo-1,2-dihydro-pyridin-3-yl]-7-methyl-3H-benzoglyoxaline-5-yl }-piperazine-1-methane amide;
55 (±)-4-[2-(3-chloro-phenyl)-2-hydroxyl-ethylamino]-3-(4-methyl-6-piperazine-1-base-1H-benzimidazolyl-2 radicals-yl)-the 1H-pyridin-2-ones;
56 (±)-4-[2-(3-chloro-phenyl)-2-hydroxyl-ethylamino]-3-[6-(4-ethyl-piperazine-1-yl)-4-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl]-the 1H-pyridin-2-ones;
57 (±)-4-[2-(3-chloro-phenyl)-2-hydroxyl-ethylamino]-3-{6-[4-(2-hydroxyl-ethyl) piperazine-1-yl]-4-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl }-the 1H-pyridin-2-ones;
58 (±)-4-[2-(3-chloro-phenyl)-2-hydroxyl-ethylamino]-3-(4-methyl-6-morpholine-4-base-1H-benzimidazolyl-2 radicals-yl)-the 1H-pyridin-2-ones;
59 (±)-4-[2-(3-bromo-phenyl)-2-hydroxyl-ethylamino]-3-(4-methyl-6-morpholine-4-base-1H-benzimidazolyl-2 radicals-yl)-1H-;
60 (±)-4-[2-(3-bromo-4-methoxyl group-phenyl)-2-hydroxyl-ethylamino]-3-(4-methyl-6-morpholine-4-base-1H-benzimidazolyl-2 radicals-yl)-the 1H-pyridin-2-ones;
61 (±)-4-[2-(3-bromo-phenyl)-2-hydroxyl-ethylamino]-3-{6-[4-(2-hydroxyl-ethyl)-piperazine-1-yl]-4-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl }-the 1H-pyridin-2-ones;
62 (±)-4-[2-(3-bromo-phenyl)-2-hydroxyl-ethylamino]-3-(4-methyl-6-piperazine-1-base-1H-benzimidazolyl-2 radicals-yl }-the 1H-pyridin-2-ones;
63 (±)-4-[2-(3-bromo-phenyl)-2-hydroxyl-ethylamino]-3-(4-methyl-6-piperazine-1-base-1H-benzimidazolyl-2 radicals-yl }-the 1H-pyridin-2-ones;
64 (±)-3-[6-(4-ethanoyl-piperazine-1-yl)-4-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl]-4-[2-(3-bromo-phenyl)-2-hydroxyl-ethylamino]-1 H-pyridin-2-ones;
65 (S)-4-(1-methylol-2-phenyl-ethylamino)-3-[4-methyl-6-(2-morpholine-4-base-ethylamino)-1H-benzimidazolyl-2 radicals-yl]-the 1H-pyridin-2-ones;
66 (±)-6-[2-(3-chloro-phenyl)-2-hydroxyl-ethylamino]-5-(6-imidazoles-1-base-4-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl)-the 3H-pyrimidin-4-one;
67 (±)-4-[2-(3-chloro-phenyl)-2-hydroxyl-ethylamino]-3-[6-(1-hydroxyl-1-methyl-ethyl)-4-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl]-the 1H-pyridin-2-ones;
68 (±)-3-(6-amino methyl-4-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl)-4-[2-(3-chloro-phenyl)-2-hydroxyl-ethylamino]-the 1H-pyridin-2-ones;
69 (±)-4-[2-(3-chloro-phenyl)-2-hydroxyl-ethylamino]-3-(6-methylol-4-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl)-the 1H-pyridin-2-ones;
70 (S)-4-(1-benzyl-2-hydroxyl-ethylamino)-3-(4-methyl-6-morpholine-4-base-1H-benzimidazolyl-2 radicals-yl)-the 1H-pyridin-2-ones;
71 (S)-4-(1-benzyl-2-hydroxyl-ethylamino)-3-(4-methyl-6-piperidines-1-base-1H-benzimidazolyl-2 radicals-yl)-the 1H-pyridin-2-ones.
49. the compound of claim 1, described compound is selected from following compound:
1 (S)-4-(1-benzyl-2-hydroxyl-ethylamino)-3-(4-methyl-6-piperidines-1-base-1H-benzimidazolyl-2 radicals-yl)-the 1H-pyridin-2-ones;
24-[2-(3-chloro-4-methylthio group-phenyl)-2-hydroxyl-ethylamino]-3-(4-methyl-6-piperazine-1-base-1H-benzimidazolyl-2 radicals-yl)-the 1H-pyridin-2-ones;
34-[2-(3-chloro-4-fluoro-phenyl)-2-hydroxyl-ethylamino]-3-(4-methyl-6-piperazine-1-base-1H-benzimidazolyl-2 radicals-yl)-the 1H-pyridin-2-ones;
43-[4-(2-{4-[2-(3-chloro-phenyl)-2-hydroxyl-ethylamino]-2-oxo-1,2-dihydro-pyridin-3-yl }-7-methyl-3H-benzoglyoxaline-5-yl)-piperazine-1-yl]-propionitrile;
54-[2-(3-chloro-phenyl)-2-hydroxyl-ethylamino]-3-{6-[4-(2-methylsulfonyl-ethyl)-piperazine-1-yl]-4-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl }-the 1H-pyridin-2-ones;
63-[4-(2-{4-[2-(3-bromo-4-methoxyl group-phenyl)-2-hydroxyl-ethylamino]-2-oxo-1,2-dihydro-pyridin-3-yl }-3H-benzoglyoxaline-5-yl)-7-methyl-piperazine-1-yl]-propionitrile;
74-(2-{4-[2-(3-chloro-phenyl)-2-hydroxyl-ethylamino]-2-oxo-1,2-dihydro-pyridin-3-yl }-7-methyl-3H-benzoglyoxaline-5-yl)-piperazine-1-formic acid 2-fluoro-ethyl ester;
84-(2-{4-[2-(3-chloro-phenyl)-2-hydroxyl-ethylamino]-2-oxo-1,2-dihydro-pyridin-3-yl }-7-methyl-3H-benzoglyoxaline-5-yl)-piperazine-1-formic acid 2-methoxyl group-ethyl ester;
94-(2-{4-[2-(3-chloro-phenyl)-2-hydroxyl-ethylamino]-2-oxo-1,2-dihydro-pyridin-3-yl }-7-methyl-3H-benzoglyoxaline-5-yl)-piperazine-1-t-butyl formate;
104-(2-{4-[2-(3-chloro-phenyl)-2-hydroxyl-ethylamino]-2-oxo-1,2-dihydro-pyridin-3-yl }-7-methyl-3H-benzoglyoxaline-5-yl)-piperazine-1-formic acid Propargyl ester;
114-(2-{4-[2-(3-bromo-4-methoxyl group-phenyl)-2-hydroxyl-ethylamino]-2-oxo-1,2-dihydro-pyridin-3-yl }-7-methyl-3H-benzoglyoxaline-5-yl)-piperazine-1-t-butyl formate;
12 (S)-4-(2-{4-[2-(3-bromo-4-methoxyl group-phenyl)-2-hydroxyl-ethylamino]-2-oxo-1,2-dihydro-pyridin-3-yl }-7-methyl-3H-benzoglyoxaline-5-yl)-piperazine-1-ethyl formate;
134-[2-(3-chloro-4-methoxyl group-phenyl)-2-hydroxyl-ethylamino]-3-{6-[4-(3-fluoro-propyl group)-piperazine-1-yl]-4-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl }-the 1H-pyridin-2-ones;
144-[2-(3-chloro-phenyl)-2-hydroxyl-ethylamino]-3-{6-[4-(2-fluoro-ethyl)-piperazine-1-yl]-4-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl }-the 1H-pyridin-2-ones;
154-[2-(3-chloro-4-fluoro-phenyl)-2-hydroxyl-ethylamino]-3-{6-[4-(3-fluoro-propyl group)-piperazine-1-yl]-4-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl }-the 1H-pyridin-2-ones;
164-[2-(3-bromo-4-methoxyl group-phenyl)-2-hydroxyl-ethylamino]-3-{6-[4-(3-fluoro-propyl group)-piperazine-1-yl]-4-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl }-the 1H-pyridin-2-ones;
174-[2-(3-chloro-phenyl)-2-hydroxyl-ethylamino]-3-{4-methyl-6-[4-(3,3,3-three fluoro-propyl group)-piperazine-1-yl]-1H-benzimidazolyl-2 radicals-yl }-the 1H-pyridin-2-ones;
184-[2-(3-chloro-phenyl)-2-hydroxyl-ethylamino]-3-{6-[4-(3-fluoro-propyl group)-piperazine-1-yl]-4-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl }-the 1H-pyridin-2-ones;
194-[2-(3-chloro-phenyl)-2-hydroxyl-ethylamino]-3-{4-methyl-6-[4-(3,4,4-three fluoro-fourth-3-thiazolinyl)-piperazine-1-yl]-1H-benzimidazolyl-2 radicals-yl }-the 1H-pyridin-2-ones;
204-[2-(3-chloro-phenyl)-2-hydroxyl-ethylamino]-3-{6-[4-(3-fluoro-2-hydroxyl-propyl group)-piperazine-1-yl]-4-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl }-the 1H-pyridin-2-ones;
214-[2-(3-chloro-phenyl)-2-hydroxyl-ethylamino]-3-{6-[4-(2-hydroxy-2-methyl-propyl group)-piperazine-1-yl]-4-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl }-the 1H-pyridin-2-ones;
22 (S)-4-[2-(3-chloro-phenyl)-2-hydroxyl-ethylamino]-3-{6-[4-(2-hydroxyl-ethyl)-piperazine-1-yl]-4-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl }-the 1H-pyridin-2-ones;
23 (S)-4-[2-(3-bromo-4-methoxyl group-phenyl)-2-hydroxyl-ethylamino]-3-{6-[4-(2-hydroxyl-ethyl)-piperazine-1-yl]-4-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl }-the 1H-pyridin-2-ones;
24[4-(2-{4-[2-(3-chloro-phenyl)-2-hydroxyl-ethylamino]-2-oxo-1,2-dihydro-pyridin-3-yl }-7-methyl-3H-benzoglyoxaline-5-yl)-piperazine-1-yl]-acetonitrile;
254-[2-(3-chloro-phenyl)-2-hydroxyl-ethylamino]-3-{6-[4-(4-fluoro-butyryl radicals)-piperazine-1-yl]-4-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl }-the 1H-pyridin-2-ones;
264-[2-(3-chloro-phenyl)-2-hydroxyl-ethylamino]-3-{6-[4-(2,2-two fluoro-ethanoyl)-piperazine-1-yl]-4-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl }-the 1H-pyridin-2-ones;
274-[2-(3-chloro-phenyl)-2-hydroxyl-ethylamino]-3-{6-[4-(2-methylsulfonyl-ethanoyl)-piperazine-1-yl]-4-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl }-the 1H-pyridin-2-ones;
283-[6-(4-ethanoyl-piperazine-1-yl)-4-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl]-4-[2-(3-chloro-phenyl)-2-hydroxyl-ethylamino]-the 1H-pyridin-2-ones;
294-[2-(3-chloro-phenyl)-2-hydroxyl-ethylamino]-3-(4-methyl-6-{-4-[2-(1-oxo-114-parathiazan-4-yl)-ethanoyl]-piperazine-1-yl }-the 1H-benzimidazolyl-2 radicals-yl)-the 1H-pyridin-2-ones;
304-[2-(3-chloro-phenyl)-2-hydroxyl-ethylamino]-3-(6-{4-[2-(1,1-dioxo-116-parathiazan-4-yl)-ethanoyl]-piperazine-1-yl }-4-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl)-the 1H-pyridin-2-ones;
314-[2-(3-chloro-phenyl)-2-hydroxyl-ethylamino]-3-{4-methyl-6-[4-(2-parathiazan-4-base-ethanoyl)-piperazine-1-yl]-1H-benzimidazolyl-2 radicals-yl }-the 1H-pyridin-2-ones;
324-[2-(3-chloro-phenyl)-2-hydroxyl-ethylamino]-3-{6-[4-(2-methanesulfinyl-ethanoyl)-piperazine-1-yl]-4-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl }-the 1H-pyridin-2-ones;
334-[2-(3-chloro-phenyl)-2-hydroxyl-ethylamino]-3-{6-[4-(2-methoxyl group-ethanoyl)-piperazine-1-yl]-4-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl }-the 1H-pyridin-2-ones;
344-[2-(3-chloro-phenyl)-2-hydroxyl-ethylamino]-3-{4-methyl-6-[4-(2-methylthio group-ethanoyl)-piperazine-1-yl]-1H-benzimidazolyl-2 radicals-yl }-the 1H-pyridin-2-ones;
353-{6-[4-(2-chloro-ethanoyl)-piperazine-1-yl]-4-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl }-4-[2-(3-chloro-phenyl)-2-hydroxyl-ethylamino]-the 1H-pyridin-2-ones;
36 (S)-4-(2-{4-[2-(3-bromo-4-methoxyl group-phenyl)-2-hydroxyl-ethylamino]-2-oxo-1,2-dihydro-pyridin-3-yl }-7-methyl-3H-benzoglyoxaline-5-yl)-piperazine-1-formaldehyde;
37 (S)-4-(2-{4-[2-(3-chloro-phenyl)-2-hydroxyl-ethylamino]-2-oxo-1,2-dihydro-pyridin-3-yl }-7-methyl-3H-benzoglyoxaline-5-yl)-piperazine-1-formaldehyde;
38 (S)-4-[2-(3-chloro-phenyl)-2-hydroxyl-ethylamino]-3-(4-methyl-6-morpholine-4-base-1H-benzimidazolyl-2 radicals-yl)-the 1H-pyridin-2-ones;
394-[2-(3-bromo-4-methoxyl group-phenyl)-2-hydroxyl-ethylamino]-3-(4-methyl-6-morpholine-4-base-1H-benzimidazolyl-2 radicals-yl)-the 1H-pyridin-2-ones;
404-[2-(3-chloro-4-fluoro-phenyl)-2-hydroxyl-ethylamino]-3-(4-methyl-6-morpholine-4-base-1H-benzimidazolyl-2 radicals-yl)-the 1H-pyridin-2-ones;
414-[2-(3-chloro-4-methoxyl group-phenyl)-2-hydroxyl-ethylamino]-3-(4-methyl-6-morpholine-4-base-1H-benzimidazolyl-2 radicals-yl)-the 1H-pyridin-2-ones;
424-[2-(7-bromo-2,3-dihydro-cumarone-5-yl)-2-hydroxyl-ethylamino]-3-(4-methyl-6-morpholine-4-base-1H-benzimidazolyl-2 radicals-yl)-the 1H-pyridin-2-ones;
434-[2-(3-chloro-phenyl)-2 (S)-hydroxyl-ethylaminos]-3-[4-methyl-6-[2 (S), 6 (R)-dimethyl-morpholines-4-yl]-1H-benzimidazolyl-2 radicals-yl]-the 1H-pyridin-2-ones;
444-[2-(3-bromo-4-methoxyl group-phenyl)-2 (S)-hydroxyl-ethylaminos]-3-[4-methyl-6-[2 (S), 6 (R)-dimethyl-morpholines-4-yl]-1H-benzimidazolyl-2 radicals-yl]-the 1H-pyridin-2-ones;
454-[2-(3-chloro-phenyl)-(S)-2-hydroxyl-ethylamino]-3-{6-[(R)-2-methyl fluoride-morpholine-4-yl]-4-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl }-the 1H-pyridin-2-ones;
464-[2-(3-chloro-phenyl)-(S)-2-hydroxyl-ethylamino]-3-{6-[(S)-2-methyl fluoride-morpholine-4-yl]-4-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl }-the 1H-pyridin-2-ones;
474-[2-(3-bromo-4-methoxyl group-phenyl)-(S)-2-hydroxyl-ethylamino]-3-{6-[(R)-2-methyl fluoride-morpholine-4-yl]-4-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl }-the 1H-pyridin-2-ones;
484-[2-(3-bromo-4-methoxyl group-phenyl)-(S)-2-hydroxyl-ethylamino]-3-{6-[(S)-2-methyl fluoride-morpholine-4-yl]-4-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl }-the 1H-pyridin-2-ones;
494-[2-(3-chloro-4-methoxyl group-phenyl)-(S)-2-hydroxyl-ethylamino]-3-{6-[(R)-2-methyl fluoride-morpholine-4-yl]-4-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl }-the 1H-pyridin-2-ones;
504-[2-(3-chloro-4-methoxyl group-phenyl)-(S)-2-hydroxyl-ethylamino]-3-{6-[(S)-2-methyl fluoride-morpholine-4-yl]-4-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl }-the 1H-pyridin-2-ones;
514-[2-(7-bromo-2,3-dihydro-cumarone-4-yl)-(S)-2-hydroxyl-ethylamino]-3-{6-[(R)-2-methyl fluoride-morpholine-4-yl]-4-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl }-the 1H-pyridin-2-ones;
524-[2-(7-bromo-2,3-dihydro-cumarone-4-yl)-(S)-2-hydroxyl-ethylamino]-3-{6-[(S)-2-methyl fluoride-morpholine-4-yl]-4-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl }-the 1H-pyridin-2-ones;
534-[2-(3-chloro-phenyl)-(S)-2-hydroxyl-ethylamino]-3-{6-[(R)-2-methylol-morpholine-4-yl]-4-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl }-the 1H-pyridin-2-ones;
544-[2-(3-chloro-phenyl)-(S)-2-hydroxyl-ethylamino]-3-{6-[(S)-2-methylol-morpholine-4-yl]-4-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl }-the 1H-pyridin-2-ones;
554-[2-(3-bromo-4-methoxyl group-phenyl)-(S)-2-hydroxyl-ethylamino]-3-{6-[(R)-2-methylol-morpholine-4-yl]-4-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl }-the 1H-pyridin-2-ones;
564-[2-(3-bromo-4-methoxyl group-phenyl)-(S)-2-hydroxyl-ethylamino]-3-{6-[(S)-2-methylol-morpholine-4-yl]-4-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl }-the 1H-pyridin-2-ones;
574-[2-(3-chloro-4-methoxyl group-phenyl)-(S)-2-hydroxyl-ethylamino]-3-{6-[(R)-2-methylol-morpholine-4-yl]-4-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl }-the 1H-pyridin-2-ones;
584-[2-(3-chloro-4-methoxyl group-phenyl)-(S)-2-hydroxyl-ethylamino]-3-{6-[(S)-2-methylol-morpholine-4-yl]-4-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl }-the 1H-pyridin-2-ones;
594-[2-(3-chloro-phenyl)-(S)-2-hydroxyl-ethylamino]-3-{6-[(R)-2-methyl-morpholine-4-yl]-4-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl }-the 1H-pyridin-2-ones;
604-[2-(3-chloro-phenyl)-(S)-2-hydroxyl-ethylamino]-3-{6-[(S)-2-methyl-morpholine-4-yl]-4-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl }-the 1H-pyridin-2-ones;
614-[2-(3-bromo-4-methoxyl group-phenyl)-(S)-2-hydroxyl-ethylamino]-3-{6-[(R)-2-methyl-morpholine-4-yl]-4-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl }-the 1H-pyridin-2-ones;
624-[2-(3-bromo-4-methoxyl group-phenyl)-(S)-2-hydroxyl-ethylamino]-3-{6-[(S)-2-methyl-morpholine-4-yl]-4-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl }-the 1H-pyridin-2-ones;
63 4-[2-(3-chloro-4-methoxyl group-phenyl)-(S)-2-hydroxyl-ethylamino]-3-{6-[(R)-2-methyl-morpholine-4-yl]-4-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl }-the 1H-pyridin-2-ones;
644-[2-(3-chloro-4-methoxyl group-phenyl)-(S)-2-hydroxyl-ethylamino]-3-{6-[(S)-2-methyl-morpholine-4-yl]-4-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl }-the 1H-pyridin-2-ones;
654-[2-(3-chloro-phenyl)-(S)-2-hydroxyl-ethylamino]-3-{6-[(R)-2-methoxymethyl-morpholine-4-yl]-4-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl }-the 1H-pyridin-2-ones;
664-[2-(3-chloro-phenyl)-(S)-2-hydroxyl-ethylamino]-3-{6-[(S)-2-methoxymethyl-morpholine-4-yl]-4-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl }-the 1H-pyridin-2-ones;
674-[2-(3-bromo-4-methoxyl group-phenyl)-(S)-2-hydroxyl-ethylamino]-3-{6-[(R)-2-methoxymethyl-morpholine-4-yl]-4-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl }-the 1H-pyridin-2-ones;
684-[2-(3-bromo-4-methoxyl group-phenyl)-(S)-2-hydroxyl-ethylamino]-3-{6-[(S)-2-methoxymethyl-morpholine-4-yl]-4-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl }-the 1H-pyridin-2-ones;
694-[2-(3-chloro-4-methoxyl group-phenyl)-(S)-2-hydroxyl-ethylamino]-3-{6-[(R)-2-methoxymethyl-morpholine-4-yl]-4-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl }-the 1H-pyridin-2-ones;
704-[2-(3-chloro-4-methoxyl group-phenyl)-(S)-2-hydroxyl-ethylamino]-3-{6-[(S)-2-methoxymethyl-morpholine-4-yl]-4-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl }-the 1H-pyridin-2-ones;
714-[2-(3-chloro-phenyl)-2 (S)-hydroxyl-ethylaminos]-3-[4-methyl-6-(4-methyl-piperazine-1-yl)-1H-benzimidazolyl-2 radicals-yl]-the 1H-pyridin-2-ones;
724-[2-(3-bromo-4-methoxyl group-phenyl)-2 (S)-hydroxyl-ethylaminos]-3-[4-methyl-6-(4-methyl-piperazine-1-yl)-1H-benzimidazolyl-2 radicals-yl]-the 1H-pyridin-2-ones;
734-[2-(3-chloro-phenyl)-2-hydroxyl-ethylamino]-3-{6-[4-(kharophen)-piperidines-1-yl]-4-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl }-the 1H-pyridin-2-ones;
744-[2-(3-chloro-phenyl)-2-hydroxyl-ethylamino]-3-{6-[4-(2-glycoloyl amino)-piperidines-1-yl]-4-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl }-the 1H-pyridin-2-ones;
754-[2-(3-chloro-phenyl)-2-hydroxyl-ethylamino]-3-{6-[4-(2-fluoro kharophen)-piperidines-1-yl]-4-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl }-the 1H-pyridin-2-ones;
764-[2-(3-bromo-4-methoxyl group-phenyl)-2-hydroxyl-ethylamino]-3-{6-[4-(kharophen)-piperidines-1-yl]-4-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl }-the 1H-pyridin-2-ones;
774-[2-(3-bromo-phenyl)-2-hydroxyl-ethylamino]-3-{6-[4-(2-glycoloyl amino)-piperidines-1-yl]-4-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl }-the 1H-pyridin-2-ones;
784-[2-(3-chloro-phenyl)-2-hydroxyl-ethylamino]-3-{6-[4-(2-fluoro kharophen)-piperidines-1-yl]-4-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl }-the 1H-pyridin-2-ones;
794-[2-(3-chloro-phenyl)-2-hydroxyl-ethylamino]-3-{6-[4-(2-methoxy ethoxy formamido group)-piperidines-1-yl]-4-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl }-the 1H-pyridin-2-ones;
804-[2-(3-chloro-phenyl)-2-hydroxyl-ethylamino]-3-{6-[4-(methoxy methyl amido)-piperidines-1-yl]-4-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl }-the 1H-pyridin-2-ones;
814-[2-(3-chloro-phenyl)-2-hydroxyl-ethylamino]-3-{6-[4-(2-fluoro (ethoxymethyl) amido)-piperidines-1-yl]-4-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl }-the 1H-pyridin-2-ones;
82 (S)-4-[2-(3-chloro-phenyl)-2-hydroxyl-ethylamino]-3-[4-methyl-6-(2-morpholine-4-base-oxyethyl group)-1H-benzimidazolyl-2 radicals-yl]-the 1H-pyridin-2-ones;
83 (S)-4-[2-(3-bromo-4-methoxyl group-phenyl)-2-hydroxyl-ethylamino]-3-[4-methyl-6-(2-morpholine-4-base-oxyethyl group)-1H-benzimidazolyl-2 radicals-yl]-the 1H-pyridin-2-ones;
84 (S)-4-[2-(3-chloro-phenyl)-2-hydroxyl-ethylamino]-3-[4-methyl-6-(2-methoxyl group-oxyethyl group)-1H-benzimidazolyl-2 radicals-yl]-the 1H-pyridin-2-ones;
85 (S)-4-[2-(3-chloro-phenyl)-2-hydroxyl-ethylamino]-3-[4-methyl-6-(2-hydroxyl-oxyethyl group)-1H-benzimidazolyl-2 radicals-yl]-the 1H-pyridin-2-ones;
86 (S)-4-[2-(3-bromo-4-methoxyl group-phenyl)-2-hydroxyl-ethylamino]-3-[4-methyl-6-(2-morpholine-4-base-propoxy-)-1H-benzimidazolyl-2 radicals-yl]-the 1H-pyridin-2-ones;
87 (S)-4-[2-(3-chloro-phenyl)-2-hydroxyl-ethylamino]-3-[4-methyl-6-(2-morpholine-4-base-propoxy-)-1H-benzimidazolyl-2 radicals-yl]-the 1H-pyridin-2-ones;
88 (S)-3-(4-bromo-6-morpholine-4-ylmethyl-1H-benzimidazolyl-2 radicals-yl)-4-[2-(3-chloro-phenyl)-2-hydroxyl-ethylamino]-the 1H-pyridin-2-ones;
89 (S)-3-[4-bromo-6-(4-methyl-piperazine-1-ylmethyl-1H-benzimidazolyl-2 radicals-yl)-4-[2-(3-chloro-phenyl)-2-hydroxyl-ethylamino]-the 1H-pyridin-2-ones;
90 (S)-4-[2-(3-chloro-phenyl)-2-hydroxyl-ethylamino]-3-[4-methyl-6-(4-methyl-piperazine-1-ylmethyl)-1H-benzimidazolyl-2 radicals-yl]-the 1H-pyridin-2-ones;
914-[2-(3-chloro-phenyl)-2 (S)-hydroxyl-ethylaminos]-3-[4-methyl-6-(1,4,5,6-tetrahydropyrimidine-1-yl)-1H-benzimidazolyl-2 radicals-yl]-the 1H-pyridin-2-ones;
924-[2-(4-methoxyl group-3-chloro-phenyl)-2 (S)-hydroxyl-ethylaminos]-3-[4-methyl-6-(1,4,5,6-tetrahydropyrimidine-1-yl)-1H-benzimidazolyl-2 radicals-yl]-the 1H-pyridin-2-ones.
50. a medicinal compositions, said composition comprise the compound and the pharmaceutically acceptable carrier of claim 1.
51. the medicinal compositions of claim 50, said composition also comprise at least a other cancer therapy drug with the fixed dosage preparation.
52. the medicinal compositions of claim 51, wherein said cancer therapy drug is selected from following medicine: tamoxifen, toremifene, raloxifene, droloxifene, iodoxyfene, Magace, Anastrozole, letrozole, borazole, Exemestane, flutamide, Nilutamide, bicalutamide, cyproterone acetate, goserelin acetate, leuproside, finasteride, trastuzumab, methotrexate, 5 FU 5 fluorouracil, cytosine arabinoside, Zorubicin, daunorubicin, epirubicin, idarubicin, Mitomycin-C, dactinomycin, mithramycin, cis-platinum, carboplatin, L-sarcolysin, Chlorambucil, busulfan, endoxan, ifosfamide, nitrosourea, thiotephan, vincristine(VCR), safe plain, taxotere, Etoposide, teniposide, amsacrine, irinotecan, Hycamtin, esperamicin, Iressa, OSI-774; Angiogenesis inhibitor, EGF inhibitor, VEGF inhibitor, CDK inhibitor, Her1 and Her2 inhibitor and monoclonal antibody.
53. the method for a treatment and at least a Tyrosylprotein kinase diseases associated, this method comprise the compound of the claim 1 that needs the Mammals of this treatment significant quantity.
54. the method for claim 53, wherein said Tyrosylprotein kinase are Abl, CDK ' s, EGF, EMT, FGF, FAK, Flk-1/KDR, HER-2, IGF-1R, IR, LCK, MET, PDGF, Src or VEGF.
55. the method for claim 53, this method comprise also that described compound and at least a other cancer therapy drug are united and give described Mammals.
56. the method for claim 53, wherein said disease are cancer.
57. a treatment method for cancer, this method comprise the claim 50 of the Mammals treatment significant quantity that needs this treatment or 51 composition.
58. a method for the treatment of proliferative disease, this method comprise the claim 50 of the Mammals treatment significant quantity that needs this treatment or 51 composition.
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