CN108239067A - Quinazolinone analog derivative and its preparation method and application - Google Patents
Quinazolinone analog derivative and its preparation method and application Download PDFInfo
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- CN108239067A CN108239067A CN201611223936.6A CN201611223936A CN108239067A CN 108239067 A CN108239067 A CN 108239067A CN 201611223936 A CN201611223936 A CN 201611223936A CN 108239067 A CN108239067 A CN 108239067A
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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
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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
- C07D401/14—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
Abstract
The invention discloses quinazolinone analog derivatives and preparation method and application.The structural formula of the derivative shown in formula I, in Formulas I, R1、R2、R3, m, n be as described in claim and specification.The compound of the present invention has preferable antitumor activity, may be used as the therapeutic agent for the treatment of tumour, while is also PI3K inhibitor.
Description
Technical field
The present invention relates to pharmaceutical technology fields, particularly prepare antitumor drug technical field, and in particular to quinazolinone
Class antitumor derivative and preparation method and application.
Background technology
PI3K (phosphatidylinositol 3-kinases, phosphatidyl-inositol 3-kinase) is lipoid kinases, is passed through
Phosphatidylinositols 4 is catalyzed, 5- diphosphonic acid (PIP2) phosphoric acid turns to 3,4,5- triphosphoric acid (PIP3) of phosphatidylinositols, under then activating
Signal is passed to several stream substrates by the protein kinase B (Akt) of trip, the Akt after activation, so as to control such as transcribe, translate,
The biological effects such as cell cycle, apoptosis.PI3K is divided into I, II, III three types according to the difference of structure and phosphorylated substrate.
I types PI3K is usually called PI3K by people.I types PI3K is divided into according to the difference of their catalytic subunit etc. as PI3K α, PI3K
β, PI3K δ and tetra- kinds of hypotypes of PI3K γ.
PI3K is located at the center of several signal of interest Signal Transduction Pathways, and many members of PI3K accesses occur in tumour
Mutation shows that PI3K plays critically important effect in tumour generation, it has become current most potential cancer target
One of.It is secondary to research and develop novel poison since toxic side effect is big, causes tumor drug resistance and can't be drug for many PI3K inhibitor
Act on small, the good antitumor drug of effect is very crucial and necessary.
Invention content
The object of the present invention is to provide quinazolinone analog derivatives as well as preparation method and application thereof.Such compound has very well
Antitumor activity, can be used as new type antineoplastic medicine, for preventing or treating tumour and its tumor complication.
The present invention provides quinazolinone analog derivative and its salt, shown in general structure such as formula (I):
Wherein,
R1For H, C1-C6Alkyl, C1-C6Alkoxy, halogen;
R2For C1-C6Alkyl, C1-C6Alkoxy, substituted or unsubstituted 6-10 members aryl or 5-10 circle heterocyclic ring bases, it is described
Heterocycle contains the hetero atom of 1-3 N, O or S;The substituent group is:C1-C6Alkyl, C1-C6Alkoxy, halogen;
R3For C1-C6Alkoxy, C1-C6Alkyl amino, 5-10 circle heterocyclic ring bases, the heterocycle contain 1-3 N, O or S
Hetero atom;
M values are 3-4;
N values are 0-1.
Derivative and its salt described in preferred formula I of the present invention:
Wherein,
R1For H, C1-C4Alkyl, C1-C4Alkoxy, halogen;
R2For C1-C4Alkyl, C1-C4Alkoxy, substituted or unsubstituted phenyl;The substituent group is:C1-C4Alkyl, C1-
C4Alkoxy, halogen;
R3For C1-C4Alkoxy, C1-C4Alkyl amino, 5-6 circle heterocyclic ring bases, the heterocycle contain the miscellaneous of 1-3 N, O or S
Atom;
M values are 3-4;
N values are 0-1.
Derivative and its salt described in preferred formula I of the present invention:
Wherein,
R1For H, C1-C4Alkyl, C1-C4Alkoxy, fluorine, chlorine, bromine;
R2For C1-C4Alkyl, C1-C4Alkoxy, substituted or unsubstituted phenyl;The substituent group is:C1-C4Alkyl, C1-
C4Alkoxy, fluorine, chlorine, bromine;
R3For C1-C4Alkoxy, C1-C4Alkyl amino, 5-6 circle heterocyclic ring bases, the heterocycle contain the miscellaneous of 1-3 N, O or S
Atom;
M values are 3-4;
N values are 0-1.
Derivative and its salt described in preferred formula I of the present invention:
Wherein,
R1For H, methoxyl group, ethyoxyl, chlorine, fluorine, bromine;
R2The phenyl replaced for methyl, ethyl, butyl, unsubstituted or halogen;
R3For methoxyl group, ethyoxyl, morpholinyl, piperazinyl, imidazole radicals, pyrazolyl, 2- oxo pyridines base, dimethyl amine
Base, diethyl amido;
M values are 3-4;
N values are 0-1.
Derivative and its salt described in preferred formula I of the present invention:
Wherein,
R1For methoxyl group, chlorine;
R2For methyl, fluorine substituted-phenyl;
R3For morpholinyl, imidazole radicals, pyrazolyl, 2- oxo pyridine bases;
M values are 3-4;
N values are 0-1.
Derivative and its salt described in preferred formula I of the present invention:
Wherein,
R1For methoxyl group, chlorine;
R2For methyl, fluorine substituted-phenyl;
When it is 0 that m, which is 3, n, R3For morpholinyl, imidazole radicals, pyrazolyl, 2- oxo pyridine bases.
Derivative and its salt described in preferred formula I of the present invention:
Wherein,
R1For methoxyl group, chlorine;
R2For methyl, fluorine substituted-phenyl;
When it is 1 that m, which is 3, n, R3For morpholinyl.
Derivative and its salt described in preferred formula I of the present invention:
Wherein,
R1For methoxyl group, chlorine;
R2For methyl, fluorine substituted-phenyl;
When it is 1 that m, which is 4, n, R3For morpholinyl.
The present invention provides quinazolinone analog derivative, while the preparation method of the derivative is provided, this method synthesis
Step is easy and easily operated.Such compound has extraordinary antitumor activity, is preparing field of antineoplastic medicaments, is having
Important practical value and application prospect.
The method of compound, includes the following steps described in formula I provided by the invention:
Make Formula II compound that condensation reaction occur with formula III, obtain compound shown in formula IV.
1) compound shown in formula IV is made to be coupled with Formula V, obtains compound shown in Formulas I
R1、R2、R3, m, n as is described in the claims.
Specific embodiment
Below by specific embodiment, the present invention will be described, but the present invention is not limited thereto.
Experimental method described in following embodiments is conventional method unless otherwise specified;The reagent and biological material
Material, is commercially available unless otherwise specified.
Embodiment 1N- (5- (3- (morpholinyl propyl) -4- oxo -3,4- dihydroquinazoline -6- bases) -2- methoxyl groups-pyrrole
Pyridine -3- bases) -2,4 difluorobenzene sulfonamide (compound 1)
The synthesis of bromo- 4 (3H)-quinazolinones of step 1) 6-
In 100mL round-bottomed flasks, 2- amino -5- bromobenzoic acids 2.16g (10mmol), formamidine acetate 1.04g are added in
(10mmol), isopropanol 30ml, 100 DEG C are stirred 8 hours, and white solid is precipitated in cooling, filters, dry bromo- 4 (3H)-quinolines of 6-
Oxazoline ketone 2.1g, yield 94%.
Structural identification data is as follows:
mp 84-86℃.ESI-MS:m/z 225.0[M+H]+.
1H NMR (400MHz, DMSO) δ 12.17 (s, 1H), 8.20 (d, J=2.2Hz, 1H), 8.15 (s, 1H), 7.96
(dd, J=8.7,2.3Hz, 1H), 7.62 (d, J=8.7Hz, 1H)
The synthesis of -4 (3H)-quinazolinones of the bromo- 3- of step 2) 6- (morpholinyl propyl)
In 100mL round-bottomed flasks, 6- bromo- 4 (3H)-quinazolinone 0.45g (2mmol), 4- (3- chloropropyls) are added in
Quinoline 0.33g (2mmol), K2CO30.56g (4mmol), 20ml DMF, 60 DEG C are stirred 12 hours.DMF is concentrated later, using silicon
Rubber column gel column chromatographic isolation, mobile phase use dichloromethane and methanol system column chromatography, obtain target compound 0.64g, yield 92%.
Structural identification data is as follows:
mp 84-86℃.ESI-MS:m/z 352.2[M+H]+.
1H NMR (400MHz, DMSO) δ 8.44 (s, 1H), 8.23 (d, J=2.3Hz, 1H), 7.97 (dd, J=8.7,
2.3Hz, 1H), 7.64 (d, J=8.7Hz, 1H), 4.03 (t, J=6.8Hz, 2H), 3.45 (s, 4H), 2.32 (t, J=6.6Hz,
2H), 2.27 (s, 4H), 1.87 (p, J=6.6Hz, 2H)
Bis- fluoro- N- of step 3) 2,4- (2- methoxyl groups -5- (3- (morpholinyl propyl) -4- oxo -3,4- dihydroquinazolines -
6- yls) pyridin-3-yl) benzsulfamide
In 100mL round-bottomed flasks, 6- bromo- 3- (morpholinyl propyl) -4 (3H)-quinazolinone 0.35g is added in
(1mmol), 2,4- bis- fluoro- N- (2- methoxyl groups -5- (4,4,5,5-4 methyl-1s, 3,2- dioxy boron, penta ring -2- bases) pyridine -3-
Base) benzsulfamide 0.43g (1mmol), bi triphenyl phosphorus palladium chloride 0.035g (0.5mmol), 10ml DMF, N2Under protection,
90 DEG C are stirred 4 hours, later concentrate DMF, 100ml × 3 are extracted with ethyl acetate, detached using silica gel column chromatography, mobile phase
Using dichloromethane and methanol system column chromatography, target compound 0.44g, yield 77.8% are obtained.
Structural identification data is as follows:
mp 179-181℃.HRMS:m/z 571.1905[M]+.
1H NMR (400MHz, DMSO) δ 10.37 (s, 1H), 8.55 (s, 1H), 8.52-8.37 (m, 2H), 8.09 (d, J=
2.1Hz, 1H), 8.06 (d, J=8.7Hz, 1H), 7.83-7.68 (m, 2H), 7.64-7.50 (m, 1H), 7.20 (dd, J=
11.9,5.2Hz, 1H), 3.63 (s, 3H), 3.62-3.53 (m, 6H), 2.48-2.32 (m, 6H), 1.86 (p, J=6.8Hz,
2H).13C NMR (100MHz, DMSO) δ 165.4 (dd, J=11.8,252.2Hz), 159.9,159.8 (dd, J=13.3,
255.9Hz), 158.3,155.8,148.9,142.9,135.2,133.8,132.3 (d, J=10.1Hz), 131.1,129.4,
128.8,125.8 (dd, J=14.5,3.1Hz), 120.5 (2C), 115.7,112.4 (dd, J=22.0,3.0Hz), 106.2
(t, J=25.7Hz), 66.5,56.4,53.8,53.7,26.8,25.8.
Embodiment 2N- (5- (3- (3- pyrazolyls propyl) -4- oxo -3,4- dihydroquinazoline -6- bases) -2- methoxyl groups-pyrrole
Pyridine -3- bases) -2,4 difluorobenzene sulfonamide (compound 2)
Synthetic method is the same as compound 1
Structural identification data is as follows:
mp 182-184℃.HRMS:m/z 553.1464[M+H]+.
1H NMR (400MHz, DMSO) δ 10.37 (s, 1H), 8.43 (d, J=2.2Hz, 1H), 8.39 (s, 1H), 8.28
(d, J=2.0Hz, 1H), 8.10 (dd, J=8.5,2.1Hz, 1H), 7.97 (d, J=2.2Hz, 1H), 7.84-7.74 (m, 3H),
7.64-7.54 (m, 1H), 7.45 (d, J=1.3Hz, 1H), 7.23 (td, J=8.5,2.0Hz, 1H), 6.24 (t, J=1.9Hz,
1H), 4.22 (t, J=6.9Hz, 2H), 4.03 (t, J=6.9Hz, 2H), 3.68 (s, 3H), 2.26 (p, J=6.9Hz, 2H)13C
NMR (100MHz, DMSO) δ 165.6 (dd, J=11.1,252.3Hz), 160.7,159.8 (dd, J=13.4,256.0Hz),
158.0,148.7,147.8,142.8,139.1,135.2,134.2,132.8,132.3 (d, J=11.4Hz), 130.3,
(128.9,128.6,125.5 dd, J=14.4,3.5Hz), 123.5,122.5,120.3,112.4 (dd, J=21.9,
3.3Hz), 106.3 (d, J=26.2Hz), 105.6,54.0,49.0,44.4,30.0.
Embodiment 3N- (5- (3- (3- imidazolylpropyls) -4- oxo -3,4- dihydroquinazoline -6- bases) -2- methoxyl groups-pyrrole
Pyridine -3- bases) -2,4 difluorobenzene sulfonamide (compound 3)
Synthetic method is the same as compound 1
Structural identification data is as follows:
mp 191-193℃.HRMS:m/z 553.1474[M+H]+.1H NMR (400MHz, DMSO) δ 8.40 (d, J=
2.3Hz, 1H), 8.38 (s, 1H), 8.28 (d, J=2.1Hz, 1H), 8.10 (dd, J=8.5,2.2Hz, 1H), 7.95 (d, J=
2.3Hz, 1H), 7.83-7.71 (m, 3H), 7.61-7.52 (m, 1H), 7.26 (s, 1H), 7.22 (td, J=8.6,2.2Hz,
1H), 6.93 (s, 1H), 4.08 (t, J=7.1Hz, 2H), 4.02 (t, J=6.9Hz, 2H), 3.68 (s, 3H), 2.30-2.13
(m,2H).13C NMR (100MHz, DMSO) δ 165.4 (dd, J=10.9,251.7Hz), 160.7,159.8 (d, J=10.5,
253.5Hz), 158.0,148.5,147.8,142.3,137.6,135.4,133.6,132.8,132.3 (d, J=11.2Hz),
(128.9,128.6,128.5,125.7 dd, J=14.6,2.9Hz), 123.5,122.5,121.0,119.8,112.3 (dd, J
=21.9,3.3Hz), 106.3 (t, J=26.5Hz), 53.9,44.2,44.1,30.6.
Embodiment 4N- (5- (3- (3- (2- oxo-pyridinyls) propyl) -4- oxo -3,4- dihydroquinazoline -6- bases) -2-
Methoxv-pyridine -3- bases) -2,4 difluorobenzene sulfonamide (compound 4)
Synthetic method is the same as compound 1
Structural identification data is as follows:
mp 118-120℃.HRMS:m/z 580.1477[M+H]+.1H NMR(400MHz,DMSO)δ10.39(s,1H),
8.46 (s, 1H), 8.42 (d, J=2.2Hz, 1H), 8.28 (d, J=1.9Hz, 1H), 8.10 (dd, J=8.5,2.1Hz, 1H),
7.96 (d, J=2.2Hz, 1H), 7.83-7.75 (m, 2H), 7.73 (dd, J=6.7,1.5Hz, 1H), 7.63-7.54 (m, 1H),
7.40 (ddd, J=8.8,6.6,1.9Hz, 1H), 7.22 (td, J=8.6,1.9Hz, 1H), 6.38 (d, J=9.0Hz, 1H),
6.22 (t, J=6.2Hz, 1H), 4.06 (t, J=6.8Hz, 2H), 3.98 (t, J=7.1Hz, 2H), 3.68 (s, 3H), 2.19-
2.05(m,2H).13C NMR (100MHz, DMSO) δ 165.6 (dd, J=11.8,252.6Hz), 162.8,161.9,160.6,
159.8 (d, J=13.9,252.3Hz), 158.0,148.6,147.8,142.7,140.3,139.4,135.2,134.1,
132.7,132.3 (d, J=11.0Hz), 128.9,128.6,125.5 (dd, J=3.7,14.1Hz), 123.5,122.5,
(120.3,120.1,112.3 dd, J=3.5,22.2Hz), 106.3 (t, J=26.1Hz), 105.9,53.9,46.5,44.3,
29.1.
Embodiment 5N- (5- (3- (4- morpholinyl -4- oxos normal-butyl) -4- oxo -3,4- dihydroquinazoline -6- bases) -2-
Methoxv-pyridine -3- bases) -2,4 difluorobenzene sulfonamide (compound 5)
Synthetic method is the same as compound 1
Structural identification data is as follows:
mp 113-115℃.HRMS:m/z 600.1741[M+H]+.1H NMR(400MHz,DMSO)δ10.36(s,1H),
8.43 (d, J=2.3Hz, 1H), 8.39 (s, 1H), 8.28 (d, J=2.1Hz, 1H), 8.10 (dd, J=8.5,2.2Hz, 1H),
7.96 (d, J=2.3Hz, 1H), 7.83-7.73 (m, 2H), 7.64-7.54 (m, 1H), 7.22 (td, J=8.4,2.0Hz, 1H),
4.04 (t, J=6.8Hz, 2H), 3.68 (s, 3H), 3.60-3.53 (m, 2H), 3.53-3.48 (m, 2H), 3.41 (dd, J=
11.4,4.9Hz, 4H), 2.41 (t, J=7.2Hz, 2H), 1.98 (p, J=7.0Hz, 2H)13C NMR(100MHz,DMSO)δ
170.4,165.6 (dd, J=11.5,252.4Hz), 160.6,159.8 (dd, J=13.6,256.3Hz), 158.0,148.7,
(147.8,142.8,135.2,134.1,132.7,132.3 d, J=11.0Hz), 128.9,128.6,125.4 (dd, J=
), 14.6,3.4Hz 123.6,122.5,120.3,112.3 (dd, J=22.3,3.2Hz), 106.3 (t, J=25.8Hz),
55.4,53.9,46.3,45.8,41.9,29.5.
Embodiment 6N- (5- (3- (5- morpholinyl -5- oxos normal-butyl) -4- oxo -3,4- dihydroquinazoline -6- bases) -2-
Methoxv-pyridine -3- bases) -2,4 difluorobenzene sulfonamide (compound 6)
Synthetic method is the same as compound 1
Structural identification data is as follows:
mp 136-138℃.HRMS:m/z 614.1896[M+H]+.1H NMR(400MHz,DMSO)δ10.36(s,1H),
8.44 (s, 1H), 8.43 (d, J=2.2Hz, 1H), 8.28 (d, J=1.8Hz, 1H), 8.10 (dd, J=8.5,2.0Hz, 1H),
7.97 (d, J=2.1Hz, 1H), 7.85-7.73 (m, 2H), 7.65-7.52 (m, 1H), 7.31-7.15 (m, 1H), 4.03 (t, J
=6.8Hz, 2H), 3.68 (s, 3H), 3.52 (m, 4H), 3.42 (m, 4H), 2.36 (t, J=7.3Hz, 2H), 1.81-1.66 (m,
2H), 1.54 (dd, J=14.7,7.5Hz, 2H)13C NMR (100MHz, DMSO) δ 171.0,165.6 (dd, J=12.5,
252.6Hz), 160.5,159.8 (dd, J=14.6,255.9Hz), 158.0,148.7,147.8,142.8,135.3,134.1,
132.8,132.3 (d, J=10.6Hz), 128.9,128.6,125.4 (dd, J=14.4,3.8Hz), 123.5,122.4,
120.3,112.3 (dd, J=22.1,3.3Hz), 106.2 (t, J=26.0Hz), 53.9,46.3,45.8,41.9,31.9,
28.8,22.1.
1 anticancer experiment in vitro of active testing embodiment
It takes the logarithm the tumour cell in growth period, absorbs old culture medium, PBS washes one time and absorbs clean, 1mL pancreatin digestion 1min
Left and right (suitably being adjusted according to cell bottle size), is added in the fresh culture of ready 3-5mL in advance, and piping and druming is uniform
Afterwards, it takes on a small quantity in being counted on blood counting chamber, with 1 × 104A/mL density is inoculated in 96 orifice plates, 5%CO2, 37 DEG C were incubated
Night (12h-16h).Old culture medium is sucked, the 100 μ L of fresh culture containing each acute drug are added in per hole, make effect final concentration
For 100,50,25,10,5,2.5,1nM, each sample sets five multiple holes, while sets negative control and positive control, 5%CO2,
37 DEG C are incubated 48 hours.10 μ L MTT solution (5mg/mL, i.e. 0.5%MTT) are added in per hole, continue to cultivate 4h.Terminate culture,
2000rpm, centrifuges 5 minutes, carefully sucks culture solution in hole by 4 DEG C.100 μ L dimethyl sulfoxide (DMSO)s are added in per hole, put low speed on shaking table
10min is vibrated, crystal is made fully to dissolve.OD values are measured at 495nm with microplate reader, are calculated as follows under various concentration
Cell proliferation inhibition rate (Inhibition Rate, IR%):
IR%=(control OD- sample OD)/(control OD- blank OD) × 100%
The IC of compound is obtained by calculating50(unit μM) value
2 kinase inhibiting activity of active testing embodiment is tested
1) 1 μ L10X compounds (positive control of untested compound or various kinases) are added in per hole according to arrangement
Solution is complete that control and null suppression control wells is inhibited to add in 1 μ L reaction solutions.
2) 4 μ L2.5X kinase solutions are added in per hole according to arrangement.It is complete that control wells is inhibited to add in 4 μ L reaction solutions.
3) detection plate 1000rpm is centrifuged with mixing.
4) 4XATP solution with 4X substrate solutions is mixed in equal volume, obtains 2XATP- substrate solutions.
5) the above-mentioned 2X ATP- substrate solutions of 5 μ L are added in per hole according to arrangement.
6) detection plate 1000rpm is centrifuged with mixing.
7) detection plate is placed in 30 DEG C to react 1 hour.
8) 10 μ L Kinase glo plus or ADP-Glo reaction reagents are added in per hole, 27 DEG C are placed 20 minutes.
9) 20 μ L Kinase Detection reagents are added in per hole, 27 DEG C are placed 30 minutes.
10) Envision reads fluorescence values.
Prism5.0 analyzes initial data.
Calculate the kinase inhibition rate for surveying compound.
Kinase inhibition system leads=(- zero control wells fluorescent value of compound well fluorescent value)/(full inhibition control wells fluorescent value-zero
Control wells fluorescent value) × 100%
By the best compound 1 of cell viability, the IC of PI3K4 kind hypotypes is tested50Value, unit nM
Compound | PI3Kα | PI3Kβ | PI3Kγ | PI3Kδ |
Compound 1 | 8.5 | 237 | 82.8 | 225.9 |
Active testing embodiment 3 is to the toxicity test of normal cell
Using HUVEC (Human umbilical vein endothelial cells), the IC to the normal cell of compound 1 is tested50It is 8.91 μM,
Compared with tumour cell, 89 times are reduced to the toxicity of normal cell.
By cell and kinases test experiments, the result shows that, the compound of the present invention has good antitumor activity, special
It is not that the compound has averagely reached nanomole, and toxicity is smaller in cellular level and molecular water, before there is exploitation well
Scape.
Claims (10)
1. derivative or its pharmaceutically acceptable salt shown in logical formula (I)::
Wherein,
R1For H, C1-C6Alkyl, C1-C6Alkoxy, halogen;
R2For C1-C6Alkyl, C1-C6Alkoxy, substituted or unsubstituted 6-10 members aryl or 5-10 circle heterocyclic ring bases, the heterocycle
Base contains the hetero atom of 1-3 N, O or S;The substituent group is:C1-C6Alkyl, C1-C6Alkoxy, halogen;
R3For C1-C6Alkoxy, C1-C6Alkyl amino, 5-10 circle heterocyclic ring bases, the heterocycle contain the miscellaneous original of 1-3 N, O or S
Son;
M values are 3-4;
N values are 0-1.
2. derivative or its pharmaceutically acceptable salt shown in logical formula (I) described in claim 1:
Wherein,
R2For C1-C4Alkyl, C1-C4Alkoxy, substituted or unsubstituted phenyl;The substituent group is:C1-C4Alkyl, C1-C4Alkane
Oxygroup, the phenyl that halogen, preferably methyl, ethyl, butyl, unsubstituted or halogen replace.
3. the derivative or its pharmaceutically acceptable salt shown in logical formula (I) described in claims 1 or 2:
Wherein,
R3For C1-C4Alkoxy, C1-C4Alkyl amino, 5-6 circle heterocyclic ring bases, the heterocycle contain the miscellaneous original of 1-3 N, O or S
Son, preferably hydrogen, methyl, ethyl, morpholinyl, piperazinyl, dimethyl amido, diethyl amido.
4. the derivative or its pharmaceutically acceptable salt shown in logical formula (I) described in claim 1-3 any one:
Wherein,
R1For H, C1-C4Alkyl, C1-C4Alkoxy, halogen;Preferably H, methoxyl group, ethyoxyl, chlorine, fluorine, bromine.
5. following derivative or its pharmaceutically acceptable salt:
。
6. derivative or its pharmaceutically acceptable salt as described in claim 1-5 any one, which is characterized in that described
The salt that the derivative that salt is general formula I is formed with inorganic acid or organic acid reaction, wherein the inorganic acid is hydrochloric acid, hydrobromic acid, hydrogen
Fluoric acid, sulfuric acid, nitric acid or phosphoric acid;The organic acid for formic acid, acetic acid, propionic acid, citric acid, methanesulfonic acid, ethanesulfonic acid, oxalic acid,
Malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid or tartaric acid.
7. a kind of pharmaceutical composition includes the derivative or its pharmaceutically acceptable salt described in claim 1-6 any one
With pharmaceutically acceptable excipient.
8. the preparation method of derivative as described in claim 1, which is characterized in that
1) make Formula II compound that condensation reaction occur with formula III, obtain compound shown in formula IV;
2) compound shown in formula IV is made to be coupled with Formula V, obtains compound shown in Formulas I;
9. the medicine described in derivative or its pharmaceutically acceptable salt or claim 7 described in claim 1-6 any one
Application of the compositions in PI3K inhibitor is prepared.
10. the medicine described in derivative or its pharmaceutically acceptable salt or claim 7 described in claim 1-6 any one
Compositions application in preparation of anti-tumor drugs.
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Cited By (4)
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WO2019091476A1 (en) * | 2017-11-13 | 2019-05-16 | 罗欣生物科技(上海)有限公司 | Quinazolinone compound and application thereof |
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WO2020228729A1 (en) * | 2019-05-13 | 2020-11-19 | 罗欣药业(上海)有限公司 | Crystal form of quinazolinone compound and preparation method therefor |
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