CN103534252B - Benzomorpholine derivatives and its preparation method and application - Google Patents
Benzomorpholine derivatives and its preparation method and application Download PDFInfo
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- CN103534252B CN103534252B CN201280012517.1A CN201280012517A CN103534252B CN 103534252 B CN103534252 B CN 103534252B CN 201280012517 A CN201280012517 A CN 201280012517A CN 103534252 B CN103534252 B CN 103534252B
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- 0 CC(C1)(C=CC(OCC2)=C1N2c(c1c2)ncnc1ccc2[N+]([O-])=O)c(cc1[n]2)cnc1*(C)s2(-c(ccc(F)c1)c1F)=O Chemical compound CC(C1)(C=CC(OCC2)=C1N2c(c1c2)ncnc1ccc2[N+]([O-])=O)c(cc1[n]2)cnc1*(C)s2(-c(ccc(F)c1)c1F)=O 0.000 description 5
- GXMMIEPSFDECFD-UHFFFAOYSA-N COC(C(NS(c(c(F)c1)ccc1F)(=O)=O)=C1)NC=C1c(cc12)ccc1OCCN2c1c(cc(cc2)N)c2ncn1 Chemical compound COC(C(NS(c(c(F)c1)ccc1F)(=O)=O)=C1)NC=C1c(cc12)ccc1OCCN2c1c(cc(cc2)N)c2ncn1 GXMMIEPSFDECFD-UHFFFAOYSA-N 0.000 description 1
- BVMHCEYXMOSWAR-UHFFFAOYSA-N COc(c(NS(c(c(F)c1)ccc1F)(=O)=O)c1)ncc1-c1ccc2OCCN(c3ccncc3)c2c1 Chemical compound COc(c(NS(c(c(F)c1)ccc1F)(=O)=O)c1)ncc1-c1ccc2OCCN(c3ccncc3)c2c1 BVMHCEYXMOSWAR-UHFFFAOYSA-N 0.000 description 1
- VBMSNYDEDCQGEF-UHFFFAOYSA-N COc(c(NS(c(ccc(F)c1)c1F)(=O)=O)c1)ncc1-c(cc12)ccc1OCCN2c1ncncc1 Chemical compound COc(c(NS(c(ccc(F)c1)c1F)(=O)=O)c1)ncc1-c(cc12)ccc1OCCN2c1ncncc1 VBMSNYDEDCQGEF-UHFFFAOYSA-N 0.000 description 1
- SSSYZSOPEUVIAM-UHFFFAOYSA-N COc(ncc(-c(cc1)cc(Nc2ccncc2)c1O)c1)c1NS(c(c(F)c1)ccc1F)(=O)=O Chemical compound COc(ncc(-c(cc1)cc(Nc2ccncc2)c1O)c1)c1NS(c(c(F)c1)ccc1F)(=O)=O SSSYZSOPEUVIAM-UHFFFAOYSA-N 0.000 description 1
- LVILGAOSPDLNRM-UHFFFAOYSA-N Cc1ccncn1 Chemical compound Cc1ccncn1 LVILGAOSPDLNRM-UHFFFAOYSA-N 0.000 description 1
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- 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
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/04—Ortho-condensed systems
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
- C07D495/14—Ortho-condensed systems
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Abstract
The invention discloses lower formula (I) Benzomorpholine derivatives and the pharmaceutical composition containing described derivant and their preparation method, R in formula1、R2And R3Definition identical with description.Described formula (I) Benzomorpholine derivatives is phosphatidylinositols 3 kinases (PI3K) inhibitor, has good PI3K inhibitory action and cancer cell multiplication inhibitory action, thus can be used as treating the therapeutic agent of tumor.
Description
Technical field
The present invention relates to Benzomorpholine derivatives and preparation method thereof, the pharmaceutical composition containing described derivant and they
As the application in terms of preparing medicine and prevention and/treatment disease of phosphatidyl-inositol 3-kinase (PI3K) inhibitor.
Background technology
Phosphatidylinositols (phosphotidylinositol, PI) is in the multiple phospholipid found in cell membrane
Kind, play an important role in intracellular signal transduction.Phosphatidyl-inositol 3-kinase (Phosphoinositide 3-kinases,
PI3Ks) it is the enzyme of 3 phosphorylations of the inositol ring making phosphatidylinositols.PI3K catalysis phosphatidylinositols forms 3,4-diphosphonic acid
Phosphatidylinositols (phosphatidylinositol 3,4bisphosphate, PI (3,4) P2) and 3,4,5-triphosphoric acid phospholipid
Acyl inositol (phosphatidylinositol 3,4,5trisphosphate, PI (3,4,5) P3), causes the work of Protein kinase C
Change and intracellular calcium mobilisation (M.J.Berridge et al, Nature, 1984,312:315-320；Y.Nishizuka,
Science, 1984,225:1365-1370).PI (3,4) P2 and PI (3,4,5) P3 enters at a series of cells as second message,second messenger
Journey (as cell grow, break up, migrate, hypertrophy, survival) in play an important role (Carlos Garc í a-Echeverr í a
Et al., Purinergic Signalling, 2009,5:117-125).
PI3K can be divided into I, II and type III according to physiologic substrate specificity.Type I is by p110 catalytic sub-units and p85
The heterodimer of regulation subunit composition.This family is further split into type Ia based on regulation partner and regulation mechanism
(p110 α, p110 β, p110 δ) and type Ib (p110 γ) enzyme.Type Ia is activated by tyrosine-kinase enzyme system, and type Ib is by G egg
The receptor activation of white coupling.Type II includes PI3KC2a, C2 β and C2 γ hypotype, it is characterized by contain C2 domain at C-terminal,
Known PI and PI (4) P is the substrate of II class PI3K.Group III PI3K substrate only has PI.In PI3K hypotype, research carries out the most extensive
Be type Ia.Type Ia is that the regulator subunit of the catalytic subunit by 110kDa and 85/55kDa is constituted.Regulation is sub-single
Position containing SH2 domain, can by with growth factor receptors or the cheese of oncoprotein phosphorylation with tyrosine kinase activity
Histidine residue combines, the PI3K activity of induction p110 catalytic subunit (making its lipid substrate phosphorylation).It has been demonstrated that,
Ia class PI3K enzyme have in various human cancers directly or indirectly tumorigenicity (Vivanco and Sawyers et al.,
NatureReviews Cancer, 2002,2:489-501).Other hypotype of PI3K and cardiovascular and the generation of immunosuppressant disease
Relevant (Emilio Hirsch et al., Cardiovascular Research, 2009,82:262-271；Anne
FOUGERAT et al., Clinical Science, 2009,116:791-804).
Therefore, PI3K inhibitor can be used as anticarcinogen and receives much attention, and becomes the big study hotspot of tumor area one.
The LY294002 that Wortmannin (Alexandre et al., Biochem.J, 1993,296:297-301) and following formula represent
(C.J.Vlahos et al., J Biol Chem, 1994,269:5241-5248) is two known first generation wide spectrum PI3K
Inhibitor.They subtype-selectives each to PI3K are little, and toxicity is big.The most numerous compounds with PI3K as target spot enter one after another
Clinical research, a portion is PI3K selective depressant, as entered GDC-0941 (the Class I PI3K of clinical I phase
Inhibitor, Institute of Cancer Research UK), XL-147 (ClaSS I PI3K inhibitor,
Exelixis Inc), and PX-866 (PI3K α, δ and γ isoforms inhibitor, Oncothyreon)；Also has part
For PI3K/mTOR double inhibitor, as entered BEZ235 and BGT226 (Novartis AG) of clinical II phase, enter the clinical I phase
SF-1126 (Semafore Pharmaceuticals Inc) and XL-765 (Exelixis Inc) (Jeffrey
A.Engelman et al., NATURE REVIEWS CANCER, 2009,9:550-562；Zhao et al., NATURE
REVIEWS Drug Discovery, 2009,6:627-644).
International patent application WO 2008/144463 A1 discloses structure quinoline as shown in following formula (a),
Point out that they have suppression PI3K enzymatic activity, be used for treating autoimmune disease, inflammatory diseases, cardiovascular disease, nerve move back
Row disease, allergy, asthma, pancreatitis, multiple organ dysfunction syndrome, kidney disease, platelet aggregation, cancer, motility of sperm, shifting
Plant rejection, transplant rejection and injury of lung.
International patent application WO 2008/157191 A2 disclose a class have suppression PI3K enzymatic activity structure the most following
Quinazoline compound shown in formula (b), for autoimmune disease, platelet aggregation, cancer, motility of sperm, transplanting row
Scold reaction, transplant rejection and injury of lung.
International patent application WO 2009/055418 A1 discloses the most following formula (c) of structure of suppression PI3K enzymatic activity
Shown sulfapyridine derivant, is used for treating autoimmune disease, inflammatory diseases, cardiovascular disease, nervus retrogression disease
Disease, allergy, asthma, pancreatitis, multiple organ failure, MOF, kidney disease, platelet aggregation, cancer, motility of sperm, transplant rejection are anti-
Should, transplant rejection and injury of lung.
International patent application WO 2009/039140 A1 describes the most following formula (d) of the structure as PI3K inhibitor
Shown Pyridopyrimidine derivatives, can be used for treating autoimmune disease, inflammatory diseases, cardiovascular disease, neurological
Property disease, allergy, asthma, pancreatitis, multiple organ failure, MOF, kidney disease, platelet aggregation, cancer, motility of sperm, transplant rejection
Reaction, transplant rejection and injury of lung.
Therefore, PI3K path is that oncotherapy provides the biggest opportunity.PI3K target spot is carried out micromolecular inhibitor research,
New hope will be brought for mankind's antineoplaston.
Summary of the invention
Therefore, the invention provides lower formula (I) benzo morpholinium compound, or its pharmaceutically acceptable salt,
Wherein:
R1Selected from following one group of group: hydrogen, halogen, acyl group, amino, hydroxyl, sulfydryl, cyano group, nitro, carboxyl, C1～C6Alkane
Epoxide and substituted or unsubstituted C1～C6Alkyl；
R2Selected from following one group of group: amino, substituted or unsubstituted C1～C6Alkyl, substituted or unsubstituted aryl, take
Generation or unsubstituted heteroaryl, substituted or unsubstituted C3～C7Cycloalkyl and substituted or unsubstituted 3～7 yuan of Heterocyclylalkyls；
R3Selected from 0～5 such as 0,1,2,3,4 or 5 selected from the aryl of substituent group of A group group, heteroaryl or
Condensed heteroaryl or R3For-CO-R4, wherein R4For with 0～5 such as 0,1,2,3,4 or 5 replacements selected from A group group
The aryl of base, heteroaryl or condensed heteroaryl；And
A group group is selected from following one group: halogen, hydroxyl, sulfydryl, cyano group, nitro, carboxyl, C1～C6Alkoxyl, C1～C6
Alkane sulfydryl, substituted or unsubstituted C1～C6Alkyl, substituted or unsubstituted C3～C7Cycloalkyl, substituted or unsubstituted 3～7
Unit Heterocyclylalkyl ,-NRR ' ,-SO2R、-CONRR′、-NHSO2R and-NHCOR, R and R ' therein are separately hydrogen, take
Generation or unsubstituted C1～C6Alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted
C3～C7Cycloalkyl or substituted or unsubstituted 3～7 yuan of Heterocyclylalkyls.
The present invention also provides for pharmaceutical composition, and it contains the invention described above and leads to formula (I) compound or it is pharmaceutically acceptable
Salt, and pharmaceutically acceptable carrier, excipient or diluent.
The present invention also provides for logical formula (I) compound or its pharmaceutically acceptable salt medicine in preparation suppression PI3K enzymatic activity
Application in terms of thing.
The present invention also provides for logical formula (I) compound or its pharmaceutically acceptable salt in preparation for the medicine treating tumor
The application of aspect.
The present invention also provides for the Therapeutic Method of a kind of disease, described disease can by suppression PI3K activity and be alleviated or
Treatment, leads to formula (I) compound or its pharmaceutically acceptable salt including using the described present invention to the individuality needing this treatment
Step.
The present invention also provides for the preparation method of logical formula (I) compound, and described method comprises the following steps: to work as R3For aryl,
When heteroaryl or fused-aryl,
Method one:
With 2-amino-4-bromophenol as initiation material, with Formulas I a compound generation nucleophilic substitution, obtain Formulas I b chemical combination
Thing, Formulas I b compound and glycol dibromide generation ring-closure reaction, obtain Formulas I c compound, deposit at conventional transition metal catalyst
Under the conditions, Formulas I c compound with connection boric acid pinacol ester generation coupling reaction, production Id compound, Formulas I d compound with
N-[5-X-2-R1Pyridin-3-yl]-R2There is coupling reaction in-sulfonamide under conventional transition metal catalyst, obtains formula
(I) compound；Or
Method two:
With 2-amino-4-bromophenol as initiation material, with connection boric acid pinacol in the presence of conventional transition metal catalyst
Ester generation coupling reaction, obtains 3-amino-4-hydroxylphenyl boric acid pinacol ester, then makes it at conventional transition metal catalyst
With N-[5-X-2-R under conditions of existence1Pyridin-3-yl]-R2-sulfonamide generation coupling reaction, obtains compound Ie, compound
Ie Yu Ia compound generation nucleophilic substitution, obtains Formulas I f compound, Formulas I f compound and glycol dibromide generation closed loop
Reaction, obtains logical formula (I) compound；
Work as R3For-CO-R4Time,
With 6-bromo-3,4-dihydro-2H-benzo [b] [Isosorbide-5-Nitrae]Piperazine is initiation material, deposits at conventional transition metal catalyst
In lower and connection boric acid pinacol ester generation coupling reaction, obtain Compound Ig per, in the condition that conventional transition metal catalyst exists
Under, Compound Ig per and N-[5-X-2-R1Pyridin-3-yl]-R2-sulfonamide generation coupling reaction, obtains compound Ih, compound Ih
With carboxylic acid halides (X-CO-R4) there is acylation reaction, obtain Formulas I i compound, Formulas I i compound reacts in the basic conditions, is led to
Formula (I) compound；
In above-mentioned reaction process, R1、R2、R3And R4As defined hereinabove；Ia is the R of halo3, the preferably R of chloro3；With
And X represents halogen, preferably bromine.
In the described present invention leads to the preparation method of formula (I) compound, described " transition-metal catalyst " is that this area is even
The conventional transition metal catalyst that connection reaction is conventional, includes, but not limited to the most double (triphenyl phosphorus) palladium chloride, four (triphens
Base phosphorus) palladium, 1,1 '-two (diphenylphosphine) ferrocene palladium chloride, palladium etc.；Described " alkaline " condition can be by reaction
Adding conventional inorganic or organic base in system to be formed, described conventional inorganic or organic base includes, but not limited to such as hydrogen
Sodium oxide, potassium hydroxide, potassium carbonate, sodium carbonate, potassium acetate, pyridine, triethylamine etc..
In the present invention, term " halogen " refers to fluorine, chlorine, bromine or iodine.
In the present invention, term " C1～C6Alkyl " refer to the alkyl containing 1 to 6 carbon atom, including such as C1～C4Alkane
Base etc.；Include but not limited to such as methyl, ethyl, propyl group, isopropyl, butyl, isobutyl group, sec-butyl or the tert-butyl group, amyl group, oneself
Base etc.；Preferably methyl, ethyl, propyl group, isopropyl and butyl.
In the present invention, term " C1～C6Alkoxyl " refer to " C1～C6Alkyl-O-" group, wherein " C1～C6Alkyl " as
Upper definition, including such as C1～C4Alkoxyl etc.；Include but not limited to such as methoxyl group, ethyoxyl, propoxyl group, isopropoxy, fourth
Epoxide, isobutoxy, sec-butoxy, tert-butoxy, amoxy, hexyloxy etc.；Preferably methoxyl group, ethyoxyl, propoxyl group, isopropyl
Epoxide and butoxy.
In the present invention, term " C3～C7Cycloalkyl " refer to the cycloalkyl containing 3～7 carbon atoms, including such as C4~
C7Cycloalkyl, C5～C6Cycloalkyl etc., include but not limited to such as cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, suberyl and ring
Octyl group；Preferably cyclopropyl, cyclobutyl, cyclopenta and cyclohexyl.
In the present invention, term " 3～7 yuan of Heterocyclylalkyls " refers to containing 1～4 selected from heteroatomic the 3～7 of N, S and O
Unit's cycloalkyl, including such as 4～6 yuan of Heterocyclylalkyls, 5～6 yuan of Heterocyclylalkyls etc., the most such as Oxyranyle, oxolane
Base, tetrahydro-thienyl, THP trtrahydropyranyl, piperidyl, pyrrolidinyl, morpholinyl etc..
In the present invention, term " aryl " refers to that aromatic cyclic hydrocarbon group that carbon number is 6～14 or aromatic series condense
Hydrocarbon cyclic base, including such as C6～10Aryl etc.；Preferably phenyl, naphthyl, anthryl and phenanthryl, more preferably phenyl.
In the present invention, term " heteroaryl " refers to containing 1～4 heteroatomic 5～6 yuan of monocycle selected from N, S and O miscellaneous
Aryl, it can be fractional saturation.Here, it is preferred that heteroaryl be pyrimidine radicals, furyl, thienyl, pyrrole radicals, imidazoles
Base, pyrazolyl, thiazolyl, isothiazolyl,Oxazolyl, differentOxazolyl, triazolyl, tetrazole radical, thiadiazolyl group, pyridine radicals, pyridazine
Base, pyrazinyl；As the heteroaryl of fractional saturation, include but not limited to such as Isosorbide-5-Nitrae-dihydropyridine etc.；Wherein it is more preferably
Pyrimidine radicals and pyridine radicals.
In the present invention, term " condensed heteroaryl " refers to containing 1～4 heteroatomic 5～6 yuan of list selected from N, S and O
Dicyclic that ring heteroaryl is fused to each other or condenses with phenyl ring or three-ring type condensed heteroaryl, it can be fractional saturation
's.Here, as dicyclic condensed heteroaryl, preferably benzo pyrimidine radicals, Thienopyrimidine base, Furanopyrimidines base, benzo thiophene
Fen base, diazosulfide base, benzothiazolyl, benzimidazolyl, indyl, isoindolyl, indazolyl, quinolyl, isoquinolin
Base, quinazolyl；Particularly preferably benzo pyrimidine radicals, Thienopyrimidine base.As the dicyclic condensed heteroaryl of fractional saturation, bag
Include but be not limited to such as 1,2,3,4-tetrahydric quinoline groups etc..As three-ring type condensed heteroaryl, preferably benzothiophene pyrimidine radicals,
Pyrazine bithiophene phenyl, pyrazine bithiophene pyrimidine radicals, pyrazine Furanopyrimidines base, benzofuran pyrimidine radicals, pyrazine
And furo phenyl, benzothiophene pyridine radicals, pyrazine bithiophene pyridine radicals, benzofuran pyridine radicals, pyrazine furan
And pyridine radicals, particularly preferred pyrazine bithiophene pyrimidine radicals.
In the present invention, the R of logical formula (I)1、R2With " substituted or unsubstituted C described in A and R and R ' definition1～C6Alkane
Base ", " substituted or unsubstituted aryl ", " substituted or unsubstituted heteroaryl ", " substituted or unsubstituted C3～C7Cycloalkyl " with
And the term " substituted " in " substituted or unsubstituted 3～7 yuan of Heterocyclylalkyls " refers both to by halogen, cyano group, amino, hydroxyl, nitre
Base or carboxyl substituent are substituted；Such as, described " substituted or unsubstituted C1～C6Alkyl " refer to " by halogen, cyano group, amino,
The substituted or unsubstituted C of hydroxyl, nitro or carboxyl substituent1～C6Alkyl ".
In the present invention leads to a preferred embodiment of formula (I) compound, R1Selected from following one group of group: hydrogen, halogen
Element, hydroxyl, C1～C6Alkyl and C1～C6Alkoxyl.
In the present invention leads to a preferred embodiment of formula (I) compound, R1Selected from hydrogen, C1～C4Alkyl and C1～C4
Alkoxyl, more preferably methoxyl group and ethyoxyl.
In the present invention leads to a preferred embodiment of formula (I) compound, R2Selected from C1～C6Alkyl or halogen take
The C in generation6～10Aryl, 5～6 yuan of heteroaryls or 5～6 yuan of heterocyclic radicals, the particularly substituted phenyl of halogen such as fluorine or chlorine, more preferably
2,4-difluoro-benzene bases and 2,4-dichloro-phenyl.
In the present invention leads to a preferred embodiment of formula (I) compound, R3For being selected from A group group with 0～4
The C of substituent group6～14Aryl, preferably phenyl, naphthyl, anthryl or phenanthryl, more preferably phenyl；A group substituent group is selected from: halogen, ammonia
Base, hydroxyl, sulfydryl, cyano group, nitro, carboxyl, C1～C6Alkoxyl, C1～C6Alkane sulfydryl and substituted or unsubstituted C1～C6Alkane
Base.
In the present invention leads to a preferred embodiment of formula (I) compound, R3For being selected from A group group with 0～4
Substituent group containing 1～4 heteroatomic 5～6 yuan of bicyclic heteroaryl selected from N, S and O, wherein preferably pyrimidine radicals, pyridine
Base, pyridazinyl and pyrazinyl, more preferably pyrimidine radicals and pyridine radicals；A group group is selected from: halogen, hydroxyl, sulfydryl, cyano group, nitre
Base, carboxyl, C1～C6Alkoxyl, C1～C6Alkane sulfydryl, substituted or unsubstituted C1～C6Alkyl ,-NRR ' ,-NHCOR and-SO2R,
R and R ' therein is separately hydrogen, substituted or unsubstituted C1-C6Alkyl, substituted or unsubstituted C3-C7Cycloalkyl, takes
Generation or unsubstituted C3-C7Heterocyclylalkyl.
In the present invention leads to a preferred embodiment of formula (I) compound, R3For being selected from A group group with 0～4
Being fused to each other containing 1～4 heteroatomic 5～6 yuan of bicyclic heteroaryl selected from N, S and O or condense with phenyl ring of substituent group
Dicyclic or three-ring type condensed heteroaryl, wherein it is preferred that benzo pyrimidine radicals, Thienopyrimidine base, Furanopyrimidines
Base, benzothienyl, diazosulfide base, benzothiazolyl, benzimidazolyl, indyl, isoindolyl, indazolyl, quinoline
Base, isoquinolyl, quinazolyl, benzothiophene pyrimidine radicals, pyrazine bithiophene phenyl, pyrazine bithiophene pyrimidine radicals, pyrrole
Piperazine Furanopyrimidines base, benzofuran pyrimidine radicals, pyrazine furo phenyl, benzothiophene pyridine radicals, pyrazine thiophene
Fen pyridine radicals, benzofuran pyridine radicals and pyrazine furopyridyl, the most more preferably benzo pyrimidine radicals, thiophene
And pyrimidine radicals and pyrazine bithiophene pyrimidine radicals；A group substituent group is selected from: halogen, hydroxyl, sulfydryl, cyano group, nitro, carboxyl, C1~
C6Alkoxyl, C1～C6Alkane sulfydryl, substituted or unsubstituted C1～C6Alkyl ,-NRR ' ,-NHCOR and-SO2R, wherein R and R ' point
Not independently be hydrogen or substituted or unsubstituted C1～C6Alkyl or C3～C6Cycloalkyl.
In the present invention leads to a preferred embodiment of formula (I) compound, R3For-CO-R4, wherein R4For with 0～
4 aryl selected from the substituent group of A group group or heteroaryl.Preferably R4For phenyl, naphthyl, anthryl, phenanthryl, pyrimidine radicals, pyridine
Base, pyridazinyl or pyrazinyl, more preferably R4For phenyl and pyridine radicals；A group substituent group is selected from: halogen, amino, hydroxyl, sulfydryl, cyanogen
Base, nitro, carboxyl, C1～C6Alkoxyl, C1-C6Alkane sulfydryl and substituted or unsubstituted C1～C6Alkyl.
In the present invention leads to another preferred embodiment of formula (I) compound:
R1Selected from following one group of group: hydrogen, halogen, hydroxyl, C1～C6Alkyl and C1～C6Alkoxyl；And/or
R2Selected from C1～C6Alkyl or the C of halogen substiuted6～14Aryl, 5～6 yuan of heteroaryls or 5～6 yuan of heterocyclic radicals；With/
Or
R3For with 0～4 C selected from the substituent group of A group group6～14Aryl, containing 1～4 miscellaneous selected from N, S and O
5～6 yuan of bicyclic heteroaryls of atom or mutual containing 1～4 heteroatomic 5～6 yuan of bicyclic heteroaryl selected from N, S and O
The dicyclic condensed or condense with phenyl ring or three-ring type condensed heteroaryl, or R3For-CO-R4, R therein4For with 0
～4 C selected from the substituent group of A group group6～14Aryl or containing 1～4 heteroatomic 5～6 yuan of heteroaryl selected from N, S and O
Base；Described A group substituent group is selected from halogen, amino, hydroxyl, sulfydryl, cyano group, nitro, carboxyl, C1～C6Alkoxyl, C1～C6Alkane
Sulfydryl, substituted or unsubstituted C1～C6Alkyl ,-NRR ' ,-NHCOR and-SO2R, R and R ' therein are separately hydrogen, take
Generation or unsubstituted C1-C6Alkyl, substituted or unsubstituted C3-C6Cycloalkyl or substituted or unsubstituted C3-C6Heterocyclylalkyl.
In the present invention leads to a preferred embodiment of formula (I) compound, R3For with 0～3 taking selected from A group
The C of Dai Ji6～14Aryl, preferably phenyl, naphthyl, anthryl and phenanthryl；Or for containing with 0～3 substituent group selected from A group
1～3 hetero atom 5 selected from N, S, O～6 yuan of bicyclic heteroaryls, 5～6 yuan of monocycle heteroaryls especially with 1～3 atom N
Base, preferably comprise 6 yuan of bicyclic heteroaryls of 1～2 atom N, preferably pyrimidine radicals, pyridine radicals, pyridazinyl, pyrazinyl；Or it is
With 0～3 selected from A group substituent group containing 1～3 be selected from N, S and O heteroatomic 5～6 yuan of bicyclic heteroaryls mutual
The dicyclic condensed or condense with phenyl ring or three-ring type condensed heteroaryl, the wherein said preferred benzene of dicyclic condensed heteroaryl
And pyrimidine radicals, Thienopyrimidine base, Furanopyrimidines base, benzothienyl, diazosulfide base, benzothiazolyl, benzo miaow
Oxazolyl, indyl, isoindolyl, indazolyl, quinolyl, isoquinolyl and quinazolyl, wherein said three-ring type condenses heteroaryl
The preferred benzothiophene of base pyrimidine radicals, pyrazine bithiophene phenyl, pyrazine bithiophene pyrimidine radicals, pyrazine Furanopyrimidines
Base, benzofuran pyrimidine radicals, pyrazine furo phenyl, benzothiophene pyridine radicals, pyrazine bithiophene pyridine radicals, benzo
Furopyridyl and pyrazine furopyridyl；Or R3For-CO-R4, R therein4For being selected from A group base with 0～3
The C of the substituent group of group6～10Aryl, preferably phenyl and naphthyl；Or for containing with 0～3 substituent group selected from A group group
5～6 yuan of bicyclic heteroaryls of 1～3 atom N, preferably pyrimidine radicals, pyridine radicals, pyridazinyl and pyrazinyl；Wherein said A group
Substituent group is selected from halogen, amino, hydroxyl, sulfydryl, cyano group, nitro, carboxyl, C1～C4Alkoxyl, C1～C4Alkane sulfydryl, C1～C4Alkane
Base ,-NRR ' ,-NHCOR and-SO2R, R and R ' therein are separately hydrogen, C1～C4Alkyl, C3～C6Cycloalkyl or 3～6
Unit's Heterocyclylalkyl.
In the present invention leads to a preferred embodiment of formula (I) compound, R3For with 0～2 selected from halogen,
C1～4Alkyl or C1～4The phenyl of the substituent group of alkoxyl.
In the present invention leads to a preferred embodiment of formula (I) compound, R3For being selected from halogen, ammonia with 0～2
Base, hydroxyl, sulfydryl, cyano group, nitro, carboxyl, C1～C4Alkoxyl, C1～C4Alkane sulfydryl, C1～C4Alkyl ,-NRR ' ,-NHCOR
With-SO2The pyrimidine radicals of the substituent group of R, pyridine radicals, pyridazinyl or pyrazinyl.
In the present invention leads to a preferred embodiment of formula (I) compound, R3For being selected from halogen, ammonia with 0～3
Base, hydroxyl, sulfydryl, cyano group, nitro, carboxyl, C1～C4Alkoxyl, C1～C4Alkane sulfydryl, C1～C4Alkyl ,-NRR ' ,-NHCOR
With-SO2The benzo pyrimidine radicals of the substituent group of R, Thienopyrimidine base, Furanopyrimidines base, quinolyl, isoquinolyl, quinazoline
Base, benzothiophene pyrimidine radicals, pyrazine bithiophene phenyl, pyrazine bithiophene pyrimidine radicals or pyrazine Furanopyrimidines base,
Wherein R and R ' is separately hydrogen, C1～C4Alkyl or C3～C6Cycloalkanes.
In the present invention leads to a preferred embodiment of formula (I) compound, R3For-CO-R4, R therein4For with 0
～2 selected from halogen, C1～C4Alkoxyl or C1～C4The phenyl of the substituent group of alkyl, pyridine radicals or pyrimidine radicals.
In the present invention, the most logical concrete formula (I) compound includes following compounds and they are pharmaceutically acceptable
Salt:
2,4-bis-fluoro-N-{2-methoxyl group-5-[4-(pyrazine also [3 ', 2 ': 4,5] thieno [3,2-d] pyrimidine-4-yl)-
3,4-dihydro-2H-1,4-benzo [b] [Isosorbide-5-Nitrae]Piperazine-6-base] pyridin-3-yl } benzsulfamide；
2,4-bis-fluoro-N-{2-methoxyl group-5-[4-(thieno [3,2-d] pyrimidine-4-yl)-3,4-dihydro-2H-1,4-benzene
And [b] [Isosorbide-5-Nitrae]Piperazine-6-base] pyridin-3-yl } benzsulfamide；
2,4-bis-fluoro-N-{2-methoxyl group-5-[4-(6-nitro-quinazoline-4-base)-3,4-dihydro-2H-1,4-benzo [b]
[Isosorbide-5-Nitrae]Piperazine-6-base] pyridin-3-yl } benzsulfamide；
2,4-bis-fluoro-N-{2-methoxyl group-5-[4-(6-acetamido quinazoline 4-yl)-3,4-dihydro-2H-1,4-benzo
[b] [Isosorbide-5-Nitrae]Piperazine-6-base] pyridin-3-yl } benzsulfamide；
2,4-bis-fluoro-N-{2-methoxyl group-5-[4-(pyrimidine-4-yl)-3,4-dihydro-2H-1,4-benzo [b] [Isosorbide-5-Nitrae]
Piperazine-6-base] pyridin-3-yl } benzsulfamide；
2,4-bis-fluoro-N-{2-methoxyl group-5-[4-(2-aminopyrimidine-4-base)-3,4-dihydro-2H-1,4-benzo [b]
[Isosorbide-5-Nitrae]Piperazine-6-base] pyridin-3-yl } benzsulfamide；
2,4-bis-fluoro-N-{2-methoxyl group-5-[4-(6-(mesyl) thieno [3,2-d] pyrimidine-4-yl)-3,4-bis-
Hydrogen-2H-1,4-benzo [b] [Isosorbide-5-Nitrae]Piperazine-6-base] pyridin-3-yl } benzsulfamide；
2,4-bis-fluoro-N-{2-methoxyl group-5-[4-(2-ring propyl formamide yl pyrimidines-4-base)-3,4-dihydro-2H-1,4-
Benzo [b] [Isosorbide-5-Nitrae]Piperazine-6-base] pyridin-3-yl } benzsulfamide；
2,4-bis-fluoro-N-{2-methoxyl group-5-[4-(2-acetamido pyrimidine-4-yl)-3,4-dihydro-2H-1,4-benzo
[b] [Isosorbide-5-Nitrae]Piperazine-6-base] pyridin-3-yl } benzsulfamide；
2,4-bis-fluoro-N-{2-methoxyl group-5-[4-(nicotinoyl)-3,4-dihydro-2H-1,4-benzo [b] [Isosorbide-5-Nitrae]Piperazine-
6-yl] pyridin-3-yl } benzsulfamide；
2,4-bis-fluoro-N-{2-methoxyl group-5-[4-(6-isopropoxy nicotinoyl)-3,4-dihydro-2H-1,4-benzo [b]
[Isosorbide-5-Nitrae]Piperazine-6-base] pyridin-3-yl } benzsulfamide；
2,4-bis-fluoro-N-{2-methoxyl group-5-[4-(the different nicotinoyl of 2-isopropoxy)-3,4-dihydro-2H-1,4-benzo
[b] [Isosorbide-5-Nitrae]Piperazine-6-base] pyridin-3-yl } benzsulfamide；
2,4-bis-fluoro-N-{2-methoxyl group-5-[4-(2-amino-6-methylpyrimidine-4-base)-3,4-dihydro-2H-1,4-benzene
And [b] [Isosorbide-5-Nitrae]Piperazine-6-base] pyridin-3-yl } benzsulfamide；With
2,4-bis-fluoro-N-{2-methoxyl group-5-[4-(pyridin-4-yl)-3,4-dihydro-2H-1,4-benzo [b] [Isosorbide-5-Nitrae]
Piperazine-6-base] pyridin-3-yl } benzsulfamide.
The compounds of this invention, according to the kind of substituent group, occasionally there are geometric isomer and tautomer, bag of the present invention
Include these isomers separated or their mixture；The compounds of this invention occasionally there are chiral carbon atom, therefore there is base
In the optical isomer of chiral carbon atom, the present invention includes all possible optical isomer and mixture thereof.
Present invention additionally comprises the logical the most acceptable salt of formula (I) compound.Term " pharmaceutically acceptable salt " is
Refer to that the present invention of relative nontoxic leads to acid-addition salts or the base addition salts of formula (I) compound.Described acid-addition salts is formula (I) compound
The salt formed with suitable mineral acid or organic acid, these salt can be prepared in the last separation of compound and purification process,
Or make the compound of purification react with suitable organic acid or mineral acid with its free alkali form, then the salt that will be formed
Separate and prepare.Representative acid-addition salts includes, but not limited to such as hydrobromate, hydrochlorate, sulfate, sulphite, second
Hydrochlorate, oxalates, valerate, oleate, palmitate, stearate, laruate, borate, benzoate, lactate,
Phosphate, toluate, citrate, maleate, fumarate, succinate, tartrate, benzoate, first sulphur
Hydrochlorate, tosilate, gluconate, Lactobionate and lauryl sulfonate etc..
The salt that described base addition salts is formula (I) compound to be formed with suitable inorganic base or organic base, including such as with
Alkali metal, alkaline-earth metal, quaternary ammonium cation formed salt, as sodium salt, lithium salts, potassium salt, calcium salt, magnesium salt, tetramethyl quaternary ammonium salt, four
Hydroxyethyl quaternary ammonium salt etc.；Amine salt, including with ammonia (NH3), the salt that formed of primary amine, secondary amine or tertiary amine, such as: methylamine salt, dimethylamine salt, three
Methylamine salt, triethylamine salt, ethylamine salt etc..
The present invention leads to formula (I) compound and pharmaceutically acceptable salt can deliver medicine to mammal such as people, can adopt
With oral, the administration of rectum, parenteral (intravenous, intramuscular or subcutaneous), topical (such as with powder, ointment or drop
Etc. dosage form) etc. mode.
The present invention leads to formula (I) compound and pharmaceutically acceptable salt may be formulated for the solid formulation of oral administration
Type, includes, but not limited to such as capsule, tablet, pill, powder and granule etc..In these solid dosage formss, the present invention
Compound or its pharmaceutically acceptable salt mix with at least one conventional inert excipients (or carrier), as with sodium citrate or
Dicalcium phosphate mixes, or mixes with following compositions: (a) filler or bulking agent, such as, and starch, lactose, sucrose, glucose, manna
Alcohol and silicic acid etc.；(b) binding agent, such as, hydroxymethyl cellulose, alginate, gelatin, polyvinyl pyrrolidone, sucrose and Ah
Draw primary glue etc.；(c) wetting agent, such as, glycerol etc.；(d) disintegrating agent, such as, agar, calcium carbonate, potato starch or para arrowroot
Powder, alginic acid, some composition silicate and sodium carbonate etc.；(e) retarding solvent, such as paraffin etc.；F () absorbs accelerator, such as, quaternary ammonium
Compound etc.；(g) wetting agent, such as spermol and glyceryl monostearate etc.；(h) adsorbent, such as, Kaolin etc.；And/or
(i) lubricant, such as, Talcum, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulphate, or its mixture
Deng.In capsule, tablet and pill, it is possible to comprise buffer agent.
Described solid dosage forms such as tablet, sugar pill, capsule, pill and granule can use coating and shell material, such as casing and
Prepared by other material well known in the art.They can comprise opacifying agent, and, in this compositions, reactive compound releases
Put and can in a delayed fashion the part of certain in digestive tract discharge.Adoptable embedded material include such as polymeric material and
Wax.If desired, the compounds of this invention or its pharmaceutically acceptable salt also can be with the one in above-mentioned excipient or many
Plant and form microencapsulation form.
The present invention leads to formula (I) compound and pharmaceutically acceptable salt may be formulated for the liquid agent of oral administration
Type, includes, but not limited to the most pharmaceutically acceptable emulsion, solution, suspension, syrup and tincture etc..Except as activity
The present invention of compound is led to outside formula (I) compound or its pharmaceutically acceptable salt, and liquid dosage form also can comprise in this area normal
The inert diluent that rule use, such as water or other solvent, solubilizing agent and/or emulsifying agent, such as, ethanol, isopropanol, ethylene
Ester, ethyl acetate, propylene glycol, 1,3 butylene glycol, dimethylformamide or oil, particularly Oleum Gossypii semen, Oleum Arachidis hypogaeae semen, corn germ
Oil, olive oil, Oleum Ricini or Oleum sesami or the mixture etc. of these materials.
In addition to these inert diluents, these dosage forms also can comprise auxiliary agent, as wetting agent, emulsifying agent and suspending agent,
Sweeting agent, correctives and/or spice etc..
In addition to the present invention leads to formula (I) compound or its pharmaceutically acceptable salt, suspension can comprise suspending agent, example
As, ethoxylation isooctadecane alcohol, polyoxyethylene sorbitol, Isosorbide Dinitrate, microcrystalline Cellulose, aluminium methoxide, agar or this
The mixture etc. of a little materials.
The present invention leads to formula (I) compound and pharmaceutically acceptable salt may be formulated for the agent of parenteral injection
Type, includes, but not limited to the most physiologically acceptable sterile, aqueous or anhydrous solution, dispersion liquid, suspension or emulsion, and
For being again dissolved into the sterilized powder etc. of aseptic Injectable solution or dispersion liquid.Suitable aqueous and nonaqueous carrier, dilution
Agent, solvent or excipient include water, ethanol, polyhydric alcohol and suitable mixture etc. thereof.
The present invention leads to formula (I) compound and pharmaceutically acceptable salt may be formulated for the dosage form of topical,
Including ointment, powder, propellant and inhalant etc..The present invention leads to formula (I) compound or its pharmaceutically acceptable salt is permissible
Aseptically with physiologically acceptable carrier and any preservative, buffer agent, or the propellant that may need if desired
Etc. being mixed together.
Present invention also offers pharmaceutical composition, it contain 0.05-1000mg such as 1mg, 5mg, 10mg, 50mg,
The above-mentioned logical formula (I) compound of 100mg, 150mg, 200mg, 250mg, 300mg, 500mg, 800mg or 1000mg equal size or
Its pharmaceutically acceptable salt, and pharmaceutically acceptable carrier, excipient or diluent.
Pharmaceutical composition of the present invention can use conventional method, by the present invention is led to formula (I) compound or its pharmaceutically
Acceptable salt mixes with pharmaceutically acceptable carrier, excipient or diluent and prepares.
Present invention also offers a kind of method treating disease, described disease can be alleviated by suppression PI3K activity
Or treatment, such as tumor, use formula (I) compound or its medicine of 0.05-50mg/kg body weight/day including the patient to needs treatment
The step of acceptable salt on.In preferred embodiments, described disease is tumor.
The present invention leads to formula (I) compound or its pharmaceutically acceptable salt can be individually dosed, or with other pharmaceutically
Acceptable therapeutic agent is administered, and particularly uses with other antitumor combination.Described therapeutic agent includes but not limited to
Such as: act on the antineoplastic agent such as cisplatin of DNA chemical constitution, the antitumor drug such as methotrexate of nucleic acid synthesis is affected
(MTX), 5-fluorouracil (5FU) etc., affect the antitumor drug such as amycin, epirubicin of transcribed nucleic acid, aklavine,
Mithramycin etc., act on antitumor drug such as paclitaxel, the vinorelbine etc. of tubulin synthesis, and arimedex is such as
Aminoglutethimide, Lan Telong, letrozole, auspicious Ningde etc., cell-signaling pathways inhibitor such as epidermal growth factor receptor inhibitor she
Imatinib (Imatinib), gefitinib (Gefitinib), erlotinib (Erlotinib) etc..The described each one-tenth being applied in combination
Dividing and can simultaneously or in a sequence give, the form with unitary agent form or with separate preparation gives.Described combination not only includes
The compounds of this invention and the combination of other activating agent a kind of, and other is lived to include the compounds of this invention and two or more
The combination of property agent.
It is demonstrated experimentally that the compounds of this invention has cancer cell multiplication inhibitory action, can be used for the medicine of preparation treatment cancer.
The drug effect of the compounds of this invention anticancer propagation can measure by conventional method, and a kind of preferably evaluation methodology is
Sulforhodamine B (Sulforhodamine B, SRB) protein staining method: SRB is a kind of protein-binding stain, can be big with biology
Basic amino acid in molecule combines, and it is good linear relationship at optical density (OD) reading and the protein content of 510nm, therefore can
Quantitative as cell number, calculates medicine pair by the change of produced absorbance value after measuring medicine and acting on cancerous cell
The suppression ratio of cancer cell multiplication.
Suppression ratio (%)=(OD compares-OD inhibitor-OD blank)/(OD compares-OD blank) × 100%
OD compares: refer to the OD value not having the hole of the cell of medicine effect normal growth.
OD inhibitor: refer to add the OD value in the hole of the cell of compound effects positive or to be screened.
OD blank: refer to the OD value not having the parallel control hole of inoculating cell.
Half inhibitor concentration (IC50) value is calculated by software GraphPad Prism 5.
Below in conjunction with specific embodiment, the present invention is expanded on further.Should be understood that these embodiments are only used for illustrating this
Invention rather than restriction the scope of the present invention.The experimental technique of unreceipted actual conditions in the following example, generally according to often
Rule condition, or according to the condition proposed by manufacturer.Unless otherwise indicated, otherwise parts and percentages are weight portion and weight
Percentage ratio.
Detailed description of the invention
I. the compounds of this invention prepares embodiment
Embodiment 1:2, [(pyrazine also [3 ', 2 ': 4,5] thieno [3,2-d] is phonetic for 4-for 4-bis-fluoro-N-{2-methoxyl group-5-
Pyridine-4-base)-3,4-dihydro-2H-1,4-benzo [b] [Isosorbide-5-Nitrae]
Piperazine-6-base] pyridin-3-yl } synthesis of benzsulfamide
3-aminothiophene [2,3-b] pyrazine-2-methyl formate (20mmol) is refluxed overnight in appropriate Methanamide, obtains
Intermediate A (15mmol).This intermediate A (15mmol) is refluxed 3 hours in 15mL phosphorus oxychloride, obtains compound Ia-1
(10mmol).2-amino-4-bromophenol (5mmol) and compound Ia-1 (5mmol) is made to reflux 2 hours in appropriate isopropanol,
Obtain compound Ib-1 (4.4mmol).By Ib-1 (4.4mmol), glycol dibromide (8.8mmol) and potassium carbonate
(9.0mmol) stir 5 hours in 60 DEG C in DMF, obtain compound Ic-1 (3.1mmol).By compound Ic-1
(3.1mmol), connection boric acid pinacol ester (3.4mmol), [1,1 '-bis-(diphenylphosphino) ferrocene] palladium chloride
(0.3mmol) joining in 20mL Isosorbide-5-Nitrae-dioxane with potassium acetate (6.2mmol), backflow overnight, obtains Id-1
(3.1mmol).By compound Id-1 (1.5mmol), N-[5-bromo-2-methoxypyridine-3-base]-2,4 difluorobenzene sulfonamide
(1.6mmol), double (triphenylphosphine) palladium chlorides (0.2mmol) and 2M wet chemical (0.3mL) are added sequentially to 15mL
In Isosorbide-5-Nitrae-dioxane, in 100 DEG C of reactions overnight.By gained mixture concentrating under reduced pressure, add 10mL water, with dichloromethane repeatedly
Extract 3 times, merge organic facies, after washing 3 times with saturated common salt and be dried with anhydrous sodium sulfate, separate (first through silica gel column chromatography
Alcohol/dichloromethane: 0～50%), obtain yellow solid title compound (I)-1 (0.79mmol, yield is 52%).
ESI (+) m/z:620.
Embodiment 2:2,4-bis-fluoro-N-{2-methoxyl group-5-[4-(thieno [3,2-d] pyrimidine-4-yl)-3,4-dihydro-
2H-1,4-benzo [b] [Isosorbide-5-Nitrae]
Piperazine-6-base] pyridin-3-yl } synthesis of benzsulfamide
By 2-amino-4-bromophenol (5mmol) with compound 4-chloro thieno [3,2-d] pyrimidine (Ia-2,5mmol) suitable
Amount isopropanol refluxes 2 hours, obtains compound Ib-2 (3.8mmol).By Ib-2 (3.8mmol), glycol dibromide
(7.6mmol) stir 5 hours in 60 DEG C in DMF with potassium carbonate (8.1mmol), obtain compound Ic-2 (2.8mmol).Generalization
Compound Ic-2 (2.8mmol), connection boric acid pinacol ester (3.1mmol), [1,1 '-bis-(diphenylphosphino) ferrocene] palladium chloride
(0.27mmol) joining in 20mL Isosorbide-5-Nitrae-dioxane with potassium acetate (5.6mmol), backflow overnight, obtains Id-2
(2.7mmol).By compound Id-2 (1.5mmol), N-[5-bromo-2-methoxypyridine-3-base]-2,4 difluorobenzene sulfonamide
(1.6mmol), double (triphenylphosphine) palladium chlorides (0.2mmol) and 2M wet chemical (0.3mL) are added sequentially to
In 15mL Isosorbide-5-Nitrae-dioxane, in 100 DEG C of reactions overnight.By gained mixture concentrating under reduced pressure, add 10mL water, use dichloromethane
Alkane extracts 3 times repeatedly, merges organic facies, divides through silica gel column chromatography after washing 3 times with saturated common salt and be dried with anhydrous sodium sulfate
From (ethanol/methylene: 0～50%), obtain white solid title compound (I)-2 (0.71mmol, yield is 47%).
ESI (+) m/z:568.
Embodiment 3:2,4-bis-fluoro-N-{2-methoxyl group-5-[4-(6-nitro-quinazoline-4-base)-3,4-dihydro-2H-1,
4-benzo [b] [Isosorbide-5-Nitrae]
Piperazine-6-base] pyridin-3-yl } synthesis of benzsulfamide
By 2-amino-4-bromophenol (30mmol), connection boric acid pinacol ester (36mmol), [1,1 '-bis-(diphenylphosphino)
Ferrocene] palladium chloride (3.0mmol) and potassium acetate (90mmol) join in 120mL Isosorbide-5-Nitrae-dioxane, backflow overnight,
Obtain 3-amino-4-hydroxylphenyl pinacol borate (28.8mmol).By 3-amino-4-hydroxylphenyl pinacol borate
(28.8mmol), N-[5-bromo-2-methoxypyridine-3-base]-2,4 difluorobenzene sulfonamide (24mmol), double (triphenylphosphine) two
Palladous chloride. (2.1mmol), potassium acetate (72mmol) and 3mL water are added sequentially in 120mL Isosorbide-5-Nitrae-dioxane, anti-in 90 DEG C
Overnight should obtain compound Ie-3 (15mmol).By compound Ie-3 (0.71mmol) and 4-chloro-6-nitro-quinazoline
(0.71mmol) reflux 3 hours in appropriate isopropanol, obtain compound If-3 (0.69mmol).By compound If-3
(0.69mmol), glycol dibromide (0.71mmol) and potassium carbonate (0.71mmol) are added sequentially in DMF (10mL), in 60
DEG C reaction 4 hours.Add 20mL water, repeatedly extract with dichloromethane 3 times, merge organic facies, wash 3 times with saturated common salt and use
Anhydrous sodium sulfate is dried, separates (ethanol/methylene: 0～50%) through silica gel column chromatography, obtains yellow solid titled
Compound (I)-3 (0.29mmol, yield is 42%).
H1-NMR(CDCl3): δ 9.05 (s, 1H), δ 8.95 (s, 1H), δ 8.60 (d, 1H), δ 8.18 (d, 1H), δ 7.78 (s,
1H), δ 7.62 (m, 1H), δ 7.58 (s, 1H), δ 7.22-7.12 (m, 3H), δ 6.95-6.84 (m, 3H), δ 4.60 (m, 2H), δ
4.38 (m, 2H), δ 3.88 (s, 3H).
ESI (+) m/z:608.
Embodiment 4:2,4-bis-fluoro-N-{2-methoxyl group-5-[4-(6-acetamido quinazoline-4-base)-3,4-dihydro-
2H-1,4-benzo [b] [Isosorbide-5-Nitrae]
Piperazine-6-base] pyridin-3-yl } synthesis of benzsulfamide
Compound (I)-3 (0.2mmol) and reduced iron powder (1mmol) are joined backflow 2 hours in acetic acid (8mL),
To intermediate B (0.11mmol).Intermediate B (0.11mmol), acetic anhydride (0.13mmol) and sodium acetate (0.13mmol) are added
Enter in 15mL dichloromethane, be stirred overnight under room temperature.In reactant liquor, add 10mL water, repeatedly extract with dichloromethane 3 times,
Merge organic facies, wash 3 times with saturated common salt and dried with anhydrous sodium sulfate, separate (methanol/dichloromethane through silica gel column chromatography
Alkane: 0～50%), obtain solid, shaped title compound (I)-4 (0.041mmol, yield is 37%).
ESI (+) m/z:619.
ESI (-) m/z:617.
Embodiment 5:2,4-bis-fluoro-N-{2-methoxyl group-5-[4-(pyrimidine-4-yl)-3,4-dihydro-2H-1,4-benzo [b]
[Isosorbide-5-Nitrae]
Piperazine-6-base] pyridin-3-yl } synthesis of benzsulfamide
By the compound Ie-3 (0.71mmol) for preparing in embodiment 3 and the chloro-pyrimidine hydrochloride of 4-(Ia-5,
0.71mmol), triethylamine (0.71mmol) together in appropriate isopropanol reflux 36 hours, obtain compound If-5
(0.15mmol).Compound If-5 (0.15mmol), glycol dibromide (0.18mmol) and potassium bicarbonate (0.18mmol)
It is added sequentially in DMF (5mL), in 60 DEG C of reactions overnight.In reactant liquor, add 10mL water, repeatedly extract 3 with dichloromethane
Secondary, merge organic facies, wash 3 times with saturated common salt and dried with anhydrous sodium sulfate, separate (methanol/bis-through silica gel column chromatography
Chloromethanes: 0～50%), obtain yellow solid title compound (I)-5 (0.06mmol, yield is 40%).
ESI (+) m/z:512.
Embodiment 6:2,4-bis-fluoro-N-{2-methoxyl group-5-[4-(2-aminopyrimidine-4-base)-3,4-dihydro-2H-1,4-
Benzo [b] [Isosorbide-5-Nitrae]
Piperazine-6-base] pyridin-3-yl } synthesis of benzsulfamide
By the compound Ie-3 (0.71mmol) prepared in embodiment 3 and the chloro-pyrimidine of 2-amino-4-(Ia-6,
0.71mmol) reflux overnight in appropriate isopropanol, obtain compound If-6 (0.48mmol).Compound If-6
(0.48mmol), glycol dibromide (0.56mmol) and potassium carbonate (0.5mmol) are added sequentially in DMF (8mL), in 60
DEG C reaction overnight.In reactant liquor, add 15mL water, repeatedly extract with dichloromethane 3 times, merge organic facies, use saturated aqueous common salt
Wash 3 times and dried with anhydrous sodium sulfate, separate (ethanol/methylene: 0～50%) through silica gel column chromatography, obtain white solid
Body shape title compound (I)-6 (0.06mmol, yield is 40%).
ESI (+) m/z:527.
Embodiment 7:2,4-bis-fluoro-N-{2-methoxyl group-5-[4-(6-(mesyl) thieno [3,2-d] pyrimidine-4-
Base)-3,4-dihydro-2H-1,4-benzo [b] [Isosorbide-5-Nitrae]
Piperazine-6-base] pyridin-3-yl } synthesis of benzsulfamide
By the compound Ie-3 (0.71mmol) prepared in embodiment 3 and 4-chloro-6-methylsulfonyl thieno [3,2-d]
Pyrimidine (Ia-7,0.71mmol) refluxes overnight in appropriate isopropanol, obtains compound If-7 (0.57mmol).Compound
If-7 (0.57mmol), glycol dibromide (0.68mmol) and potassium bicarbonate (0.6mmol) are added sequentially to acetone
(20mL), in, overnight, enriched mixture is to remove acetone afterwards, is added thereto to 5mL water, repeatedly extracts with dichloromethane in backflow
3 times, merge organic facies, wash 3 times with saturated common salt and dried with anhydrous sodium sulfate, through silica gel column chromatography (methanol/dichloromethane
Alkane: 0～50%), obtain yellow solid title compound (I)-7 (0.26mmol, yield is 45%).
ESI (+) m/z:646.
Embodiment 8:2,4-bis-fluoro-N-{2-methoxyl group-5-[4-(2-ring propyl formamide yl pyrimidines-4-base)-3,4-dihydro-
2H-1,4-benzo [b] [Isosorbide-5-Nitrae]
Piperazine-6-base] pyridin-3-yl } synthesis of benzsulfamide
Iso-cytosine (18mmol) is dissolved in 50mL pyridine, adds ring the third formyl chloride (19.8mmol) in 0 DEG C, stir 2
Intermediate compound I a-8 (15mmol) is obtained after hour.The chemical combination that will prepare in intermediate compound I a-8 (0.71mmol) and embodiment 3
Thing Ie-3 (0.71mmol) refluxes 48 hours in appropriate isopropanol, obtains compound If-8 (0.11mmol).Compound If-
8 (0.11mmol), glycol dibromide (0.12mmol) and potassium carbonate (0.12mmol) are added sequentially in DMF (10mL),
In 60 DEG C of reactions overnight.In reactant liquor, add 15mL water, repeatedly extract with dichloromethane 3 times, merge organic facies, use saturated food
Salt is washed 3 times and dried with anhydrous sodium sulfate, separates (ethanol/methylene: 0～50%) through silica gel column chromatography, obtains white
Color solid, shaped title compound (I)-8 (0.025mmol), yield is 23%.
ESI (+) m/z:595.
ESI (-) m/z:593
Embodiment 9:2,4-bis-fluoro-N-{2-methoxyl group-5-[4-(2-acetamido pyrimidine-4-yl)-3,4-dihydro-2H-
Isosorbide-5-Nitrae-benzo [b] [Isosorbide-5-Nitrae]
Piperazine-6-base] pyridin-3-yl } synthesis of benzsulfamide
The chloro-pyrimidine of 2-amino-4-(4mmol) is joined in 6mL acetic anhydride, refluxes and obtain Ia-9 in 45 minutes
(2.5mmol).The compound Ie-3 (0.71mmol) prepared in intermediate compound I a-9 (0.71mmol) and embodiment 3 is being fitted
Amount isopropanol refluxes 48 hours, obtains compound If-9 (0.31mmol).By compound If-9 (0.31mmol), 1,2-dibromo
Ethane (0.34mmol) and potassium carbonate (0.34mmol) are added sequentially in DMF (15mL), in 60 DEG C of reactions overnight.To reaction
Liquid adds 15mL water, repeatedly extracts with dichloromethane 3 times, merge organic facies, wash 3 times with saturated common salt and use anhydrous slufuric acid
Sodium is dried, separates (ethanol/methylene: 0～50%) through silica gel column chromatography, obtain white solid title compound (I)-
9 (0.18mmol, yield is 53%).
ESI (+) m/z:569.
ESI (-) m/z:567.
Embodiment 10:2,4-tri-fluoro-N-{2-methoxyl group-5-[4-(nicotinoyl)-3,4-dihydro-2H-1,4-benzo [b]
[Isosorbide-5-Nitrae]
Piperazine-6-base] pyridin-3-yl } synthesis of benzsulfamide
By bromo-for 6-3,4-dihydro-2H-benzo [b] [Isosorbide-5-Nitrae]Piperazine (18.0mmol), connection boric acid pinacol ester
(21.6mmol), [1,1 '-bis-(diphenylphosphino) ferrocene] palladium chloride (1.5mmol) and potassium acetate (54mmol) are successively
Joining in Isosorbide-5-Nitrae-dioxane (100mL), backflow overnight, obtains Compound Ig per (17.5mmol).Compound Ig per
(17.5mmol), N-[5-bromo-2-methoxypyridine-3-base]-2,4 difluorobenzene sulfonamide (17.5mmol), 2M potassium carbonate are water-soluble
Liquid (26mL) and double (triphenylphosphine) palladium chloride (1.7mmol) are added sequentially in Isosorbide-5-Nitrae-dioxane (250mL), in
100 DEG C of reactions overnight, obtain compound Ih (10mmol).By compound Ih (0.3mmol), DIPEA
(DIPEA, 0.9mmol) and nicotinoyl chloride hydrochloride (0.6mmol) are added sequentially in dichloromethane (15mL), are stirred at room temperature 30 points
Clock, obtains Ii-10 compound (0.25mmol).Compound Ii-10 (0.25mmol) is dissolved in 3mL dichloromethane and 3mL methanol
In mixed solvent, add 4.0N sodium hydrate aqueous solution (0.4mL), be stirred at room temperature 30 minutes, obtain title compound (I)-10
(0.19mmol, yield is 76%).
H1-NMR(CDCl3): δ 8.78 (s, 2H), δ 7.93-6.94 (m, 11H), δ 4.47 (s, 2H), δ 4.10 (s, 2H), δ
3.89 (s, 3H).
ESI (+) m/z:539.
ESI (+) m/z:537.
Embodiment 11:2,4-bis-fluoro-N-{2-methoxyl group-5-[4-(6-isopropoxy nicotinoyl)-3,4-dihydro-2H-1,
4-benzo [b] [Isosorbide-5-Nitrae]
Piperazine-6-base] pyridin-3-yl } synthesis of benzsulfamide
By in embodiment 10 preparation compound Ih (0.3mmol), DIPEA (DIPEA, 0.9mmol) with
And 6-isopropoxy nicotinoyl chlorine (0.6mmol) is added sequentially in dichloromethane (15mL), it is stirred at room temperature 30 minutes, obtains Ii-
11 compounds (0.23mmol).Compound Ii-11 (0.23mmol) is dissolved in 3mL dichloromethane and 3mL methanol mixed solvent,
Adding 4.0N sodium hydrate aqueous solution (0.4mL), be stirred at room temperature 30 minutes, (0.20mmol receives to obtain title compound (I)-11
Rate is 87%).
ESI (+) m/z:597.
ESI (+) m/z:595.
Embodiment 12:2,4-bis-fluoro-N-{2-methoxyl group-5-[4-(the different nicotinoyl of 2-isopropoxy)-3,4-dihydro-2H-
Isosorbide-5-Nitrae-benzo [b] [Isosorbide-5-Nitrae]
Piperazine-6-base] pyridin-3-yl } synthesis of benzsulfamide
By compound Ih (0.3mmol), DIPEA (DIPEA, 0.9mmol) and the different nicotinoyl of 2-isopropoxy
Chlorine (0.6mmol) is added sequentially in dichloromethane (15mL), is stirred at room temperature 30 minutes, obtains compound Ii-12
(0.24mmol).Compound Ii-12 (0.24mmol) is dissolved in 3mL dichloromethane and 3mL methanol mixed solvent, adds 4.0N
Sodium hydrate aqueous solution (0.4mL), is stirred at room temperature 30 minutes, and (0.22mmol, yield is to obtain title compound (I)-12
92%).
ESI (+) m/z:597.
ESI (+) m/z:595.
Embodiment 13:2,4-bis-fluoro-N-{2-methoxyl group-5-[4-(2-amino-6-methylpyrimidine-4-base)-3,4-dihydro-
2H-1,4-benzo [b] [Isosorbide-5-Nitrae]
Piperazine-6-base] pyridin-3-yl } synthesis of benzsulfamide
The compound Ie-3 that will prepare in 2-amino-4-chloro-6-methylpyrimidine (0.52mmol) and embodiment 3
(0.52mmol) reflux 48 hours in appropriate isopropanol, obtain compound If-13 (0.21mmol).By compound If-13
(0.21mmol), glycol dibromide (0.22mmol) and potassium carbonate (0.25mmol) be added sequentially in DMF (10mL), in
60 DEG C of reactions are overnight.In reactant liquor, add 15mL water, repeatedly extract with dichloromethane 3 times, merge organic facies, use saturated common salt
Wash 3 times and dried with anhydrous sodium sulfate, separate (ethanol/methylene: 0～50%) through silica gel column chromatography, obtain white
Solid, shaped title compound (I)-13 (0.046mmol, yield is 21.9%).
ESI (+) m/z:541.
ESI (-) m/z:539.
Embodiment 14:2,4-bis-fluoro-N-{2-methoxyl group-5-[4-(pyridin-4-yl)-3,4-dihydro-2H-1,4-benzo
[b] [Isosorbide-5-Nitrae]
Piperazine-6-base] pyridin-3-yl } synthesis of benzsulfamide
The compound Ie-3 (0.32mmol) prepared in 4-chloropyridine hydrochloric acid salt (0.32mmol) and embodiment 3 is existed
Isopropanol refluxes 24 hours, obtains compound If-14 (0.13mmol).By compound If-14 (0.13mmol), 1,2-dibromo
Ethane (0.15mmol) and potassium carbonate (0.20mmol) are added sequentially in DMF (10mL), in 60 DEG C of reactions overnight.To reaction
Liquid adds 15mL water, repeatedly extracts with dichloromethane 3 times, merge organic facies, wash 3 times with saturated common salt and use anhydrous slufuric acid
Sodium is dried, separates (ethanol/methylene: 0～50%) through silica gel column chromatography, obtains white solid (I)-14
(0.036mmol, yield is 27.2%).
ESI (+) m/z:511.
II. embodiment prepared by the preparation of the compounds of this invention
Embodiment 15: the preparation of capsule
Formula:
Embodiment 2 compound 20g
Starch 140g
Microcrystalline Cellulose 68g
According to a conventional method, after above-mentioned substance mix homogeneously, load common gelatine capsule, obtain 1000 capsules.
By similar approach, prepare the capsule containing other embodiments compound respectively.
III. the compounds of this invention active testing embodiment
Testing example 1: the compounds of this invention is to Human Prostate Cancer Cells (PC-3) inhibited proliferation
The Human Prostate Cancer Cells being in exponential phase is inoculated in 96 well culture plates with the density in about 5500/hole,
180 μ l/ holes.Each concentration sets three wells.And set the Vehicle controls of respective concentration and acellular zeroing hole.Adherent growth 24hr is again
Add embodiment compound or positive control drug (LY294002) 20 μ l/ hole, cell 10%Hyclone hyclone, 37 DEG C and
5%CO2Under the conditions of cultivate 72 hours.Add cold trichloroacetic acid (TCA) the 50 μ L of 50%, place 1 hour for 4 DEG C, fixing cell.Incline
Remove liquid, with the light and slow washing of distilled water 5 times, natural drying in air.Add by the SRB 4mg/mL solution of 1% glacial acetic acid preparation
100 μ L/ holes, dye 15 minutes in room temperature.Abandon supernatant, wash 5 times with 1% acetic acid, air drying.Every hole adds 150 μ L
The Tris solution (pH=10.5) of 10mM, dissolve the SRB combined.Measure OD value under microplate reader 510nm wavelength, obtained by calculating
Obtain the embodiment compound IC for PC-3 cell50Value:
| Compound | IC50(μM) |
| LY294002 | 5.47 |
| Embodiment compound 3 | 13.40 |
| Embodiment compound 5 | 0.17 |
| Embodiment compound 6 | 0.20 |
| Embodiment compound 7 | 4.61 |
| Embodiment compound 10 | 2.26 |
| Embodiment compound 11 | 16.63 |
| Embodiment compound 12 | 2.55 |
Test result shows: the compounds of this invention has good inhibited proliferation to Human Prostate Cancer Cells (PC-3).
Testing example 2: the compounds of this invention is to human breast cancer cell (MDA-MB-231) inhibited proliferation
It is measured with reference to testing example 1 experimental technique, obtains embodiment compound for MDA-MB-by calculating
The IC of 231 cells50Value:
| Compound | IC50(μM) |
| Embodiment compound 11 | 19.27 |
| Embodiment compound 12 | 1.74 |
Test result shows: human breast cancer cell (MDA-MB-231) is had good Proliferation Ability to make by the compounds of this invention
With.
Testing example 3: the compounds of this invention is to Non-small cell lung carcinoma cell (A549) inhibited proliferation
It is measured with reference to testing example 1 experimental technique, obtains embodiment compound for A549 cell by calculating
IC50Value:
| Compound | IC50(μM) |
| LY294002 | 16.10 |
| Embodiment compound 3 | 8.81 |
| Embodiment compound 5 | 0.26 |
| Embodiment compound 7 | 14.77 |
| Embodiment compound 10 | 3.64 |
| Embodiment compound 11 | 13.64 |
| Embodiment compound 12 | 6.32 |
Test result shows: Non-small cell lung carcinoma cell (A549) is had good Proliferation Ability to make by the compounds of this invention
With.
Testing example 4: the compounds of this invention is to Proliferation of Human Ovarian Cell (SK-OV-3) inhibited proliferation
It is measured with reference to testing example 1 experimental technique, thin for SK-OV-3 by calculating acquisition embodiment compound
The IC of born of the same parents50Value:
| Compound | IC50(μM) |
| LY294002 | 6.05 |
| Embodiment compound 3 | 116.5 |
| Embodiment compound 5 | 0.49 |
| Embodiment compound 6 | 0.25 |
| Embodiment compound 10 | 2.10 |
| Embodiment compound 11 | 5.20 |
| Embodiment compound 12 | 2.28 |
Test result shows: the compounds of this invention has good inhibited proliferation to Proliferation of Human Ovarian Cell (SK-OV-3).
Testing example 5: the compounds of this invention non-small cell lung cancer cell H1975 to sudden change(L858R/T790M- EGFR) inhibited proliferation
It is measured with reference to testing example 1 experimental technique, obtains embodiment compound for H1975 cell by calculating
IC50Value:
| Compound | IC50(μM) |
| Embodiment compound 5 | 12.78 |
| Embodiment compound 7 | 20.70 |
| Embodiment compound 10 | 63.07 |
| Embodiment compound 11 | 13.61 |
| Embodiment compound 12 | 12.84 |
Test result shows: non-small cell lung cancer cell H1975 (L858R/T790M-EGFR) is had by the compounds of this invention
Good inhibited proliferation.
The present invention has been made complete detailed description by applicant.Obviously, after the foregoing having read the present invention,
The present invention can be made various modification under the principle without prejudice to spirit of the present invention, change or revise by those skilled in the art,
These equivalent form of values fall within the application appended claims limited range equally.
Claims (10)
1. lead to benzo morpholinium compound or its pharmaceutically acceptable salt that formula (I) represents,
Wherein:
R1Selected from following one group of group: hydrogen, hydroxyl, C1～C6Alkoxyl and C1～C6Alkyl；
R2Selected from following one group of group: halogen substiuted or unsubstituted phenyl；
R3It is selected from the pyridine radicals of substituent group of A group group, pyrimidine radicals or Thienopyrimidine base, or R selected from 0～53For-
CO-R4, wherein R4For with 0～5 pyridine radicals selected from the substituent group of A group group or pyrimidine radicals；And
A group group is selected from following one group: hydroxyl, C1～C6Alkoxyl, C1～C6Alkyl ,-NRR ' ,-SO2R, R and R ' point therein
Not independently be hydrogen or C1～C6Alkyl.
2. logical formula (I) compound as claimed in claim 1 or its pharmaceutically acceptable salt, wherein R1For C1～C4Alkyl or C1
～C4Alkoxyl.
3. logical formula (I) compound as claimed in claim 1 or its pharmaceutically acceptable salt, wherein R2Benzene for halogen substiuted
Base.
4. logical formula (I) compound as claimed in claim 1 or its pharmaceutically acceptable salt, wherein said A group substituent group
Selected from C1～C4Alkoxyl ,-NRR ' and-SO2R, R and R ' therein are separately hydrogen or C1～C4Alkyl.
5. logical formula (I) compound as claimed in claim 1 or its pharmaceutically acceptable salt, wherein R3For with 0～2-
The pyrimidine radicals of NRR ' or pyridine radicals, R and R ' therein is separately hydrogen.
6. logical formula (I) compound as claimed in claim 1 or its pharmaceutically acceptable salt, wherein R3For-CO-R4, therein
R4For with 0～2 C1～C4The pyridine radicals of alkoxyl or pyrimidine radicals.
7. logical formula (I) compound as claimed in claim 1, selected from following compounds or its pharmaceutically acceptable salt:
2,4-bis-fluoro-N-{2-methoxyl group-5-[4-(thieno [3,2-d] pyrimidine-4-yl)-3,4-dihydro-2H-1,4-benzo
[b] [Isosorbide-5-Nitrae]Piperazine-6-base] pyridin-3-yl } benzsulfamide；
2,4-bis-fluoro-N-{2-methoxyl group-5-[4-(pyrimidine-4-yl)-3,4-dihydro-2H-1,4-benzo [b] [Isosorbide-5-Nitrae]Piperazine-6-
Base] pyridin-3-yl } benzsulfamide；
2,4-bis-fluoro-N-{2-methoxyl group-5-[4-(2-aminopyrimidine-4-base)-3,4-dihydro-2H-1,4-benzo [b] [Isosorbide-5-Nitrae]Piperazine-6-base] pyridin-3-yl } benzsulfamide；
2,4-bis-fluoro-N-{2-methoxyl group-5-[4-(6-(mesyl) thieno [3,2-d] pyrimidine-4-yl)-3,4-dihydro-
2H-1,4-benzo [b] [Isosorbide-5-Nitrae]Piperazine-6-base] pyridin-3-yl } benzsulfamide；
2,4-bis-fluoro-N-{2-methoxyl group-5-[4-(nicotinoyl)-3,4-dihydro-2H-1,4-benzo [b] [Isosorbide-5-Nitrae]Piperazine-6-base]
Pyridin-3-yl } benzsulfamide；
2,4-bis-fluoro-N-{2-methoxyl group-5-[4-(6-isopropoxy nicotinoyl)-3,4-dihydro-2H-1,4-benzo [b] [Isosorbide-5-Nitrae]Piperazine-6-base] pyridin-3-yl } benzsulfamide；
2,4-bis-fluoro-N-{2-methoxyl group-5-[4-(the different nicotinoyl of 2-isopropoxy)-3,4-dihydro-2H-1,4-benzo [b] [1,
4]Piperazine-6-base] pyridin-3-yl } benzsulfamide；
2,4-bis-fluoro-N-{2-methoxyl group-5-[4-(2-amino-6-methylpyrimidine-4-base)-3,4-dihydro-2H-1,4-benzo
[b] [Isosorbide-5-Nitrae]Piperazine-6-base] pyridin-3-yl } benzsulfamide；And
2,4-bis-fluoro-N-{2-methoxyl group-5-[4-(pyridin-4-yl)-3,4-dihydro-2H-1,4-benzo [b] [Isosorbide-5-Nitrae]Piperazine-6-
Base] pyridin-3-yl } benzsulfamide.
8. pharmaceutical composition, it comprises the logical formula (I) compound described in any one of claim 1-7 or it is pharmaceutically acceptable
Salt and pharmaceutically acceptable carrier.
9. formula (I) compound or its pharmaceutically acceptable salt of any one of claim 1-7 is used for treating tumor in preparation
Medicine in terms of application.
10. the method for preparation formula (I) compound described in claim 1, it comprises the following steps: to work as R3For pyridine radicals, pyrimidine radicals
Or during Thienopyrimidine base,
Method one:
With 2-amino-4-bromophenol as initiation material, with Formulas I a compound generation nucleophilic substitution, obtain Formulas I b compound,
Formulas I b compound and glycol dibromide generation ring-closure reaction, obtain Formulas I c compound, exists at conventional transition metal catalyst
Under conditions of, Formulas I c compound and connection boric acid pinacol ester generation coupling reaction, production Id compound, Formulas I d compound and N-
[5-X-2-R1Pyridin-3-yl]-R2There is coupling reaction in-sulfonamide under conventional transition metal catalyst, obtains formula
(I) compound；Or
Method two:
With 2-amino-4-bromophenol as initiation material, send out with connection boric acid pinacol ester in the presence of conventional transition metal catalyst
Raw coupling reaction, obtains 3-amino-4-hydroxylphenyl boric acid pinacol ester, then makes it exist at conventional transition metal catalyst
Under conditions of with N-[5-X-2-R1Pyridin-3-yl]-R2-sulfonamide generation coupling reaction, obtain compound Ie, compound Ie with
Ia compound generation nucleophilic substitution, obtains Formulas I f compound, Formulas I f compound and glycol dibromide generation ring-closure reaction,
Obtain logical formula (I) compound；
Work as R3For-CO-R4Time,
With 6-bromo-3,4-dihydro-2H-benzo [b] [Isosorbide-5-Nitrae]Piperazine is initiation material, in the presence of conventional transition metal catalyst
With connection boric acid pinacol ester generation coupling reaction, obtain Compound Ig per, under conditions of conventional transition metal catalyst exists, change
Compound Ig Yu N-[5-X-2-R1Pyridin-3-yl]-R2-sulfonamide generation coupling reaction, obtains compound Ih, compound Ih and acyl
Chlorine X-CO-R4Acylation reaction occurring, obtains Formulas I i compound, Formulas I i compound reacts in the basic conditions, obtains logical formula (I)
Compound；
In above-mentioned reaction process, R1、R2、R3And R4Definition identical with claim 1；Ia is the R of halo3；And X represents
Halogen.
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| PCT/CN2012/000462 WO2012136080A1 (en) | 2011-04-08 | 2012-04-09 | Benzomorpholine derivatives, preparation method and use thereof |
| CN201280012517.1A CN103534252B (en) | 2011-04-08 | 2012-04-09 | Benzomorpholine derivatives and its preparation method and application |
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|---|---|---|---|---|
| CN1249748A (en) * | 1997-03-03 | 2000-04-05 | 贝林格尔·英格海姆药物公司 | Small molecules useful in treatment of inflamatory disease |
| WO2001081346A2 (en) * | 2000-04-25 | 2001-11-01 | Icos Corporation | Inhibitors of human phosphatidyl-inositol 3-kinase delta |
| WO2001083456A1 (en) * | 2000-04-27 | 2001-11-08 | Yamanouchi Pharmaceutical Co., Ltd. | Condensed heteroaryl derivatives |
| US6559139B1 (en) * | 1997-08-29 | 2003-05-06 | University Of Pittsburgh Of The Commonwealth System Of Higher Education | Combination chemotherapy |
| WO2004056820A1 (en) * | 2002-12-20 | 2004-07-08 | Warner-Lambert Company Llc | Benzoxazines and derivatives thereof as inhibitors of pi3ks |
| WO2007067875A2 (en) * | 2005-12-05 | 2007-06-14 | Glaxo Group Limted | Pyridinyl sulfonamide modulators of chemokine receptors |
| WO2009055418A1 (en) * | 2007-10-22 | 2009-04-30 | Smithkline Beecham Corporation | Pyridosulfonamide derivatives as pi3 kinase inhibitors |
| WO2009155121A2 (en) * | 2008-05-30 | 2009-12-23 | Amgen Inc. | Inhibitors of pi3 kinase |
-
2011
- 2011-04-08 CN CN2011100872815A patent/CN102731525A/en active Pending
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1249748A (en) * | 1997-03-03 | 2000-04-05 | 贝林格尔·英格海姆药物公司 | Small molecules useful in treatment of inflamatory disease |
| US6559139B1 (en) * | 1997-08-29 | 2003-05-06 | University Of Pittsburgh Of The Commonwealth System Of Higher Education | Combination chemotherapy |
| WO2001081346A2 (en) * | 2000-04-25 | 2001-11-01 | Icos Corporation | Inhibitors of human phosphatidyl-inositol 3-kinase delta |
| WO2001083456A1 (en) * | 2000-04-27 | 2001-11-08 | Yamanouchi Pharmaceutical Co., Ltd. | Condensed heteroaryl derivatives |
| WO2004056820A1 (en) * | 2002-12-20 | 2004-07-08 | Warner-Lambert Company Llc | Benzoxazines and derivatives thereof as inhibitors of pi3ks |
| WO2007067875A2 (en) * | 2005-12-05 | 2007-06-14 | Glaxo Group Limted | Pyridinyl sulfonamide modulators of chemokine receptors |
| WO2009055418A1 (en) * | 2007-10-22 | 2009-04-30 | Smithkline Beecham Corporation | Pyridosulfonamide derivatives as pi3 kinase inhibitors |
| WO2009155121A2 (en) * | 2008-05-30 | 2009-12-23 | Amgen Inc. | Inhibitors of pi3 kinase |
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| WO2012136080A1 (en) | 2012-10-11 |
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|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| CP01 | Change in the name or title of a patent holder | ||
| CP01 | Change in the name or title of a patent holder |
Address after: 201203, Zhangjiang hi tech park, Shanghai, Harley Road, No. 5, building 1118 Patentee after: Shanghai ALLIST medicine Polytron Technologies Inc. Address before: 201203, Zhangjiang hi tech park, Shanghai, Harley Road, No. 5, building 1118 Patentee before: SHANGHAI ALLIST PHARMACEUTICALS, Inc. |
|
| CP02 | Change in the address of a patent holder | ||
| CP02 | Change in the address of a patent holder |
Address after: 201203 floor 5, building 1, No. 1227, zhangheng Road, free trade zone, Pudong New Area, Shanghai Patentee after: Shanghai ALLIST medicine Polytron Technologies Inc. Address before: 201203, Zhangjiang hi tech park, Shanghai, Harley Road, No. 5, building 1118 Patentee before: Shanghai ALLIST medicine Polytron Technologies Inc. |
|
| CP02 | Change in the address of a patent holder | ||
| CP02 | Change in the address of a patent holder |
Address after: No. 268 Lingxiaohua Road, Zhoupu Town, Pudong New Area, Shanghai, 201318 Patentee after: Shanghai ALLIST medicine Polytron Technologies Inc. Address before: 201203 5th floor, building 1, 1227 zhangheng road and 1118 HaLei Road, Pudong New Area Free Trade Zone, Shanghai Patentee before: Shanghai ALLIST medicine Polytron Technologies Inc. |