CN116693501A - Quinazolinone derivative and application thereof in medicine - Google Patents

Quinazolinone derivative and application thereof in medicine Download PDF

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Publication number
CN116693501A
CN116693501A CN202310037716.8A CN202310037716A CN116693501A CN 116693501 A CN116693501 A CN 116693501A CN 202310037716 A CN202310037716 A CN 202310037716A CN 116693501 A CN116693501 A CN 116693501A
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alkyl
heterocycloalkyl
cycloalkyl
quinazolinone derivative
group
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周锡兵
张靖
魏用刚
孙毅
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Chengdu Baiyu Pharmaceutical Co Ltd
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Chengdu Baiyu Pharmaceutical Co Ltd
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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
    • C07D401/12—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 linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Abstract

The invention relates to a quinazolinone derivative shown in a general formula (I) and application thereof in medicines, in particular to a quinazolinone derivative shown in the general formula (I) or a stereoisomer thereof, a pharmaceutical composition containing the quinazolinone derivative, and application of the quinazolinone derivative or the pharmaceutical composition in preparation of antitumor drugs.

Description

Quinazolinone derivative and application thereof in medicine
Technical Field
The invention relates to a quinazolinone derivative or a stereoisomer thereof and application thereof in medicine.
Background
PARPs (ploy (ADP-ribose) polymerase is a type of Poly ADP-ribose polymerase that catalyzes the ribosylation of multiple proteins, poly-ADP-ribosylation, which plays an important role in many cellular processes such as DNA damage repair, transcriptional regulation, chromatin recombination and remodeling. At present, although a plurality of PARP1/2 inhibitors are successfully marketed, no matter the PARP1/2 inhibitors are used singly or in combination, side effects such as blood, gastrointestinal tract and the like still commonly exist clinically, so that the clinical application is limited. Therefore, the development of safer and more effective PARP inhibitors remains a problem to be solved clinically. A series of researches show that compared with the PARP1/2 inhibitor, the high-selectivity PARP1 inhibitor has better curative effect and lower toxicity, is hopeful to reduce the potential risk of the PARP medicament in clinic at present, widens the clinical application range and improves the life quality of patients.
Disclosure of Invention
The invention aims to provide a quinazolinone derivative or a stereoisomer thereof, a pharmaceutical composition thereof and a medical application thereof.
One or more embodiments of the present invention provide compounds of formula (I), or stereoisomers thereof:
wherein:
R 1 selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl or C 3-8 Heterocycloalkyl, said C 3-8 Heterocycloalkyl may contain 1 to 4 heteroatoms selected from N, O or S;
x is selected from N or C (R) x )；
Y is selected from C (R) y ) Or N;
z is selected from C (R) z ) Or N;
R x 、R y 、R z each independently selected from H, halogen, hydroxy, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl or C 3-8 Heterocycloalkyl, said C 3-8 Heterocycloalkyl may contain 1 to 4 heteroatoms selected from N, O or S;
R 2 selected from cyano, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl or C 3-8 Heterocycloalkyl or C (=o) NH (R 3 ) The C is 3-8 Heterocycloalkyl may contain 1 to 4 heteroatoms selected from N, O or S;
R 3 selected from C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl or C 3-8 A heterocycloalkyl group; the C is 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl or C 3-8 The heterocycloalkyl group optionally being further substituted by 1 or more groups selected from halogen, hydroxy, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl or C 3-8 Substituted with a substituent of heterocycloalkyl, said C 3-8 Heterocycloalkyl may contain 1 to 4 heteroatoms selected from N, O or S;
one or more embodiments of the present invention provide compounds of formula (I), or stereoisomers thereof:
x is selected from N or C (R) x )；R x Selected from C 1-6 Alkyl or halogen;
and X is selected from N, R 3 Cannot be C 1-6 An alkyl group.
One or more embodiments of the present invention provide compounds of formula (I), or stereoisomers thereof:
R 2 selected from cyano or C (=O) NH (R) 3 )；
R 3 Selected from C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl or C 3-8 A heterocycloalkyl group; the C is 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl or C 3-8 The heterocycloalkyl group optionally being further substituted by 1 or more groups selected from halogen, hydroxy, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl or C 3-8 Substituents of heterocycloalkyl groups; the C is 3-8 The heterocycloalkyl group may contain 1 to 4 heteroatoms selected from N, O or S.
One or more embodiments of the present invention provide compounds of formula (I), or stereoisomers thereof, wherein:
y is selected from C (R) y ) Or N; r is R y Selected from H or C 1-6 Alkyl or halogen.
One or more embodiments of the present invention provide compounds of formula (I), or stereoisomers thereof, wherein:
z is selected from C (H) or N.
One or more embodiments of the present invention provide compounds of formula (I), or stereoisomers thereof, wherein:
R 1 selected from C 1-4 An alkyl group.
One or more embodiments of the present invention provide compounds of formula (I), or stereoisomers thereof, wherein:
R 4 selected from halogen or C 1-6 An alkyl group.
In one or more embodiments of the invention, the compounds of the invention are selected from:
one or more embodiments of the present invention provide a pharmaceutical composition comprising:
(1) A compound of the invention or a stereoisomer thereof;
(2) Optionally one or more other active ingredients; and
(3) Pharmaceutically acceptable carriers and/or excipients.
One or more embodiments of the present invention provide the use of a compound of the present invention or a stereoisomer thereof or a pharmaceutical composition of the present invention in the manufacture of a medicament for the treatment of cancer.
Unless stated to the contrary, the terms used in the specification and claims have the following meanings.
The carbon, hydrogen, oxygen, sulfur, nitrogen or F, cl, br, I referred to in the groups and compounds of the invention each include their isotopic condition, and the carbon, hydrogen, oxygen, sulfur or nitrogen referred to in the groups and compounds of the invention are optionally further replaced by one or more of their corresponding isotopes, where the isotopes of carbon include 12 C、 13 C and C 14 Isotopes of C, hydrogen include protium (H), deuterium (D, also known as heavy hydrogen), tritium (T, also known as super heavy hydrogen), isotopes of oxygen include 16 O、 17 O and 18 isotopes of O, sulfur include 32 S、 33 S、 34 S and 36 isotopes of S, nitrogen include 14 N and 15 isotopes of N, fluorine include 17 F and F 19 Isotopes of F, chlorine include 35 Cl and Cl 37 Isotopes of Cl, bromine include 79 Br and 81 Br。
"alkyl" refers to a straight or branched chain saturated aliphatic hydrocarbon group of 1 to 20 carbon atoms, preferably an alkyl group of 1 to 8 carbon atoms, more preferably an alkyl group of 1 to 6 carbon atoms, and even more preferably an alkyl group of 1 to 4 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, neobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl and various branched isomers thereof; when the alkyl group is substituted, it may optionally be further substituted with 1 or more substituents.
"alkoxy" refers to a group formed by substitution of at least 1 carbon atom in an alkyl group with an oxygen atom. Non-limiting examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, n-hexoxy, cyclopropoxy and cyclobutoxy. The alkyl group is as defined above for the "alkyl" group.
"cycloalkyl" refers to a saturated cyclic hydrocarbon group, the ring of which may be a 3 to 10 membered monocyclic, 4 to 12 membered bicyclic or 10 to 20 membered polycyclic ring system, the ring carbon atoms preferably being 3 to 10 carbon atoms, more preferably 3 to 8 carbon atoms. Non-limiting examples of "cycloalkyl" include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, 1, 5-cyclooctadienyl, 1, 4-cyclohexanedienyl, cycloheptatrienyl, and the like. When substituted, may optionally be further substituted with 0 or more substituents.
"heterocycloalkyl" means a substituted or unsubstituted saturated non-aromatic ring radical which may be a 3 to 8 membered monocyclic, 4 to 12 membered bicyclic or 10 to 15 membered tricyclic ring system and contains 1 to 3 heteroatoms selected from N, O or S, preferably 3 to 8 membered heterocyclic groups. Optionally substituted N, S in the ring of the "heterocycloalkyl" group can be oxidized to various oxidation states; "heterocycloalkyl" may be attached to a heteroatom or carbon atom; "heterocycloalkyl" may be a bridged or spiro ring. Non-limiting examples of "heterocycloalkyl" include epoxy ethyl, aziridinyl, oxetanyl, azetidinyl, 1, 3-dioxolanyl, 1, 4-dioxolanyl, 1, 3-dioxanyl, azepanyl, piperidinyl, piperdinyl, morpholinyl, thiomorpholinyl, 1, 3-dithianyl, tetrahydrofuranyl, tetrahydropyrrolyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydropyranyl, azabicyclo [3.2.1] octanyl, azabicyclo [5.2.0] nonanyl, oxatricyclo [5.3.1.1] dodecyl, azaadamantyl, and oxaspiro [3.3] heptanyl.
"alkenyl" means an alkenyl group containing 1 to 10 (e.g., 1,2, 3,4, 5, 6, 7, 8, 9, 10) carbon-carbon double bonds, a straight or branched chain unsaturated aliphatic hydrocarbon group consisting of 2 to 20 carbon atoms, preferably 2 to 12 (e.g., 2, 3,4, 5, 6, 7, 8, 9, 10, 11, 12) carbon atoms, more preferably 2 to 8 carbon atoms, even more preferably 2 to 6 carbon atoms. Non-limiting examples include vinyl, propen-2-yl, buten-2-yl, penten-4-yl, hexen-2-yl, hexen-3-yl, hepten-2-yl, hepten-3-yl, hepten-4-yl, octen-3-yl, nonen-3-yl, decen-4-yl and undecen-3-yl. The alkenyl group may optionally be further substituted with 1 or more substituents.
"alkynyl" refers to an alkynyl group containing 1 to 3 carbon-carbon triple bonds, a straight or branched chain unsaturated aliphatic hydrocarbon group consisting of 2 to 20 carbon atoms, preferably 2 to 12 carbon atoms, more preferably 2 to 8 carbon atoms, still more preferably 2 to 6 carbon atoms. Non-limiting examples include ethynyl, propyn-1-yl, propyn-2-yl, butyn-1-yl, butyn-2-yl, butyn-3-yl, 3-dimethylbutyyn-2-yl, pentyn-1-yl, pentyn-2-yl, hexyn-1-yl, 1-heptyn-1-yl, heptyn-3-yl, heptyn-4-yl, octyn-3-yl, nonyn-3-yl, decyn-4-yl, undecyn-3-yl, dodyn-4-yl. The alkynyl group may be optionally further substituted with 0 to 4 substituents selected from F, cl, br, I, alkyl, alkoxy, straight-chain alkenyl, straight-chain alkynyl, amino, nitro, cyano, mercapto, amido, carbocyclyl or heterocyclyl.
"heterocycle" or "heterocyclyl" refers to a saturated or unsaturated aromatic or non-aromatic heterocycle, which, when aromatic, is as defined above for "heteroaryl"; when a non-aromatic heterocycle, it may be a 3 to 10 membered (e.g. 3,4, 5, 6, 7, 8, 9, 10 membered) monocyclic, 4 to 12 membered (e.g. 4, 5, 6, 7, 8, 9, 10, 11, 12 membered) bicyclic or 10 to 15 membered (e.g. 10, 11, 12, 13, 14, 15 membered) tricyclic ring system and contains 1 to 4 (e.g. 1,2, 3, 4) heteroatoms selected from N, O or S, preferably 3 to 8 membered heterocyclyl. 1 to 4 (e.g., 1,2, 3, 4) N, S optionally substituted by "heterocyclyl" or a ring of "heterocycle" can be oxidized to various oxidation states; "heterocyclyl" or "heterocycle" may be attached to a heteroatom or carbon atom; "heterocyclyl" or "heterocycle" may be a fused, bridged or spiro ring. The "heterocyclyl" or "heterocycle" may be optionally further substituted with 1 or more substituents.
When "alkyl", "alkoxy", "alkenyl", "alkynyl", "heterocyclyl", "heterocycle", "cycloalkane" are described aboveWhen the group "or" heterocycloalkyl "is substituted, it may optionally be further substituted with 0, 1,2, 3,4, 5, 6, 7, 8, 9 or 10 groups selected from F, cl, br, I, hydroxy, mercapto, nitro, cyano, amino, C 1-6 Alkylamino, = O, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, -NR q4 R q5 、＝NR q6 、-C(＝O)OC 1-6 Alkyl, -OC (=o) C 1-6 Alkyl, -C (=o) NR q4 R q5 、C 3-8 Cycloalkyl, C 3-8 Heterocycloalkyl, C 6-10 Aryl, C 5-10 Heteroaryl, -C (=o) OC 6-10 Aryl, -OC (=o) C 6-10 Aryl, -OC (=o) C 5-10 Heteroaryl, -C (=o) OC 5-10 Heteroaryl, -OC (=o) C 3-8 Heterocycloalkyl, -C (=o) OC 3-8 Heterocycloalkyl, -OC (=o) C 3-8 Cycloalkyl, -C (=o) OC 3-8 Cycloalkyl, -NHC (=o) C 3-8 Heterocycloalkyl, -NHC (=o) C 6-10 Aryl, -NHC (=o) C 5-10 Heteroaryl, -NHC (=o) C 3-8 Cycloalkyl, -NHC (=o) C 3-8 Heterocycloalkyl, -NHC (=o) C 2-6 Alkenyl or-NHC (=o) C 2-6 Substituted by alkynyl groups, and wherein said substituents C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, C 3-8 Heterocycloalkyl, C 6-10 Aryl, C 5-10 Heteroaryl, -NHC (=o) C 6-10 Aryl, -NHC (=o) C 5-10 Heteroaryl, -NHC (=o) C 3-8 Heterocycloalkyl or-NHC (=o) C 3-8 Cycloalkyl is optionally further substituted with 1 to 3 substituents selected from OH, F, cl, br, I, C 1-6 Alkyl, C 1-6 Alkoxy, -NR q4 R q5 Or = O; r is R q1 Selected from C 1-6 Alkyl, C 1-6 Alkoxy or C 6-10 An aryl group; r is R q2 、R q3 Selected from H or C 1-6 An alkyl group; r is R q4 、R q5 Selected from H, C 1-6 Alkyl, -NH (c=nr q1 )NR q2 R q3 、-S(＝O) 2 NR q2 R q3 、-C(＝O)R q1 or-C (=O) NR q2 R q3 Wherein said C 1-6 The alkyl group optionally being further substituted by 1 or more groups selected from OH, F, cl, br, I, C 1-6 Alkyl, C 1-6 Alkoxy, C 6-10 Aryl, C 5-10 Heteroaryl, C 3-8 Cycloalkyl or C 3-8 Substituted by a substituent of heterocycloalkyl; or R is q4 And R is R q5 And the N atom forms a 3 to 8 membered heterocyclic ring, which may contain 1 or more heteroatoms selected from N, O or S.
"pharmaceutical composition" refers to a mixture of one or more compounds of the present invention, pharmaceutically acceptable salts or prodrugs thereof, and other chemical components, wherein "other chemical components" refers to pharmaceutically acceptable carriers, excipients, and/or one or more other therapeutic agents.
By "carrier" is meant a material that does not cause significant irritation to the organism and does not abrogate the biological activity and properties of the administered compound.
"excipient" refers to an inert substance that is added to a pharmaceutical composition to facilitate administration of a compound. Non-limiting examples include calcium carbonate, calcium phosphate, sugars, starches, cellulose derivatives (including microcrystalline cellulose), gelatin, vegetable oils, polyethylene glycols, diluents, granulating agents, lubricants, binders, and disintegrating agents.
"stereoisomers" refers to isomers arising from the spatial arrangement of atoms in a molecule, and include cis-trans isomers, enantiomers and conformational isomers.
"optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. For example, "a heterocyclic group optionally substituted with an alkyl group" means that the alkyl group may be, but is not necessarily, present, and the description includes cases where the heterocyclic group is substituted with an alkyl group, and cases where the heterocyclic group is not substituted with an alkyl group.
Detailed Description
The following examples illustrate the technical aspects of the present invention in detail, but the scope of the present invention is not limited thereto.
The structure of the compounds is determined by Nuclear Magnetic Resonance (NMR) or (sum) Mass Spectrometry (MS). NMR shift (. Delta.) of 10 -6 Units of (ppm) are given. NMR was performed using a Bruker Avance III and Bruker Avance300 magnetonucleate, with deuterated dimethyl sulfoxide (DMSO-d) 6 ) Deuterated chloroform (CDCl) 3 ) Deuterated methanol (CD) 3 OD), internal standard Tetramethylsilane (TMS);
agilent 6120B (ESI) and Agilent 6120B (APCI) for MS measurement;
the thin layer chromatography silica gel plate uses a smoke table yellow sea HSGF254 or Qingdao GF254 silica gel plate, the specification of the silica gel plate used by Thin Layer Chromatography (TLC) is 0.15mm-0.20mm, and the specification of the thin layer chromatography separation and purification product is 0.4mm-0.5mm;
column chromatography generally uses tobacco stage yellow sea silica gel 200-300 mesh silica gel as carrier.
Example 1
5- (4- ((2-ethyl-8-methyl-3-oxo-3, 4-dihydroquinolin-6-yl) methyl) piperazin-1-yl) -N-methylpyridine amide compound 1
5-(4-((2-ethyl-8-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl)-N-methylpicolinamide
First step
5-bromo-3-toluene-1, 2-diamine 1b
5-bromo-3-methylbenzene-1,2-diamine
4-bromo-2-methyl-6-nitroaniline compound 1a (5 g,21.6 mmol) was dissolved in 200mL of 1, 4-dioxane solution, sodium bicarbonate (8.3 g,99.4 mmol) and sodium dithionite (26 g,149 mmol) dissolved in 100mL of water were added, reacted at room temperature for 2 hours with stirring, 200mL of ethyl acetate and 100mL of aqueous sodium bicarbonate solution were added to extract, the organic phase was collected, dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation to give compound 1b (yellow solid, 4.2g, yield 96.7%).
LCMS m/s＝202.07[M+1].
And a second step of:
7-bromo-3-ethyl-5-methylquinolin-2 (1H) -one 1c
7-bromo-3-ethyl-5-methylquinoxalin-2(1H)-one
5-bromo-3-toluene-1, 2-diamine compound 1b (2 g,10.0 mmol) was dissolved in 100mL of toluene, methyl 2-oxobutyrate compound (1.4 g,11.2 mmol) was added, the reaction was heated at 100℃for 2 hours, the filter cake was filtered, and the filter cake was collected and washed three times with petroleum ether (50 mL) to give compound 1c (white solid, 910mg, yield 34.1%).
LCMS m/s＝268.1[M+1].
And a third step of:
3-ethyl-7- (hydroxymethyl) -5-methylquinolin-2 (1H) -one 1d
3-ethyl-7-(hydroxymethyl)-5-methylquinoxalin-2(1H)-one
Compound 1c (500 mg,1.87 mmol) was dissolved in 10mL of 1, 4-dioxane solution, and tetrakis triphenylphosphine palladium (280 mg,0.24 mmol) and (tributyltin) methanol (1.2 g,3.74 mmol) were added and reacted under nitrogen at 100℃for 8h, the solvent was removed by rotary evaporation, and isolated by medium pressure preparation to give compound 1d (white solid, 207mg, 40% yield).
1 H NMR(400MHz,DMSO-d 6 )δ12.22(s,1H),7.10(d,1H),7.05(s,1H),5.35(s,1H),4.53(s,2H),2.79(q,2H),2.55(s,3H),1.23(t,3H).
LCMS m/s＝219.26[M+1].
Fourth step:
7- (bromomethyl) -3-ethyl-5-methylquinolin-2 (1H) -one 1e
7-(bromomethyl)-3-ethyl-5-methylquinoxalin-2(1H)-one
Compound 1d (100 mg,0.35 mmol) was dissolved in 2mL of 33% hydrogen bromide acetic acid solution, and reacted at 80℃for 1h with heating, and the solvent was removed by rotary evaporation to give crude compound 1e (yellow solid, 100 mg).
LCMS m/s＝282.15[M+1].
Fifth step:
5- (4- ((2-ethyl-8-methyl-3-oxo-3, 4-dihydroquinolin-6-yl) methyl) piperazin-1-yl) -N-methylpyridine amide compound 1
5-(4-((2-ethyl-8-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl)-N-methylpicolinamide
Compound 1e (100 mg,0.35 mmol) was dissolved in 3mL of N-methylpyrrolidone, compound 1f (92 mg,0.42 mmol) and N, N-diisopropylethylamine (226 mg,1.75 mmol) were added, and the reaction mixture was dried by heating at 80℃for 4 hours to prepare and isolate compound 1 (white solid, 42mg, yield 28%).
1 H NMR(400MHz,DMSO-d 6 )δ12.14(s,1H),8.41(d,1H),8.27(d,1H),7.83(d,1H),7.39(dd,1H),7.11(s,2H),3.55(s,2H),3.27(s,4H),2.81(t,2H),2.78(d,3H),2.57(s,3H),2.54(t,4H),1.23(t,3H).
LCMS m/s＝421.52[M+1].
Example 2
5- (4- ((2-ethyl-8-methyl-3-oxo-3, 4-dihydroquinolin-6-yl) methyl) piperazin-1-yl) pyridine carbonitrile compound 2
5-(4-((2-ethyl-8-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl)picolinonitrile
Compound 2 (white solid, 14mg, 32% yield) was prepared according to the procedure of compound 1.
1 H NMR(400MHz,DMSO-d 6 )δ11.89(s,1H),8.45(d,1H),7.84(d,1H),7.33-7.21(m,2H),7.13(d,1H),3.56(s,2H),3.23(s,4H),2.85(t,2H),2.71(t,2H),2.61(s,3H),2.51(dd,2H),1.24(t,3H).
LCMS m/s＝389.48[M+1].
Example 3
5- (4- ((8-chloro-2-ethyl-3-oxo-3, 4-dihydroquinoxalin-6-yl) methyl) piperazin-1-yl) -N-methylpyridine amide compound 3
5-(4-((8-chloro-2-ethyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl)-N-methylpicolinamide
Compound 3 (white solid, 29mg, 46% yield) was prepared according to the procedure of compound 1.
1 H NMR(400MHz,DMSO-d 6 )δ11.83(s,1H),8.42(d,1H),7.81(d,1H),7.43-7.25(m,3H),7.18(q,1H),3.56(s,2H),3.41(t,4H),2.82(t,2H),2.69(t,2H),2.58(s,3H),2.51(dd,2H),1.24(t,3H).
LCMS m/s＝441.2[M+1].
Example 4
(R) -5- (4- ((8-chloro-2-ethyl-3-oxo-3, 4-dihydroquinoxalin-6-yl) methyl) piperazin-1-yl) -6-methyl-N- (tetrahydrofuran-3-yl) picolinamide Compound 4
(R)-5-(4-((8-chloro-2-ethyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl)-6-methyl-N-(tetrahydrofuran-3-yl)picolinamide
Compound 4 (white solid, 20mg, 37% yield) was prepared according to the procedure of compound 1.
1 H NMR(400MHz,DMSO-d 6 )δ11.82(s,1H),8.39(d,,1H),7.61(s,1H),7.45(t,1H),6.81-6.78(m,2H),4.40(d,1H),3.81(td,2H),3.73-3.66(m,1H),3.64(s,2H),3.53(dd,1H),3.28(s,4H),2.71-2.54(m,6H),2.47(s,3H),2.17-2.06(m,1H),1.87(dd,1H),1.18(t,3H).
LCMS m/s＝511.1[M+1].
Example 5
(R) -4- (4- ((2-ethyl-8-methyl-3-oxo-3, 4-dihydroquinoxalin-6-yl) methyl) piperazin-1-yl) -3-fluoro-N- (tetrahydrofuran-3-yl) benzamide compound 5
(R)-4-(4-((2-ethyl-8-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl)-3-fluoro-N-(tetrahydrofuran-3-yl)benzamide
Compound 5 (white solid, 22mg, 37% yield) was prepared following the procedure of compound 1.
1 H NMR(400MHz,DMSO-d 6 )δ11.75(s,1H),8.41(d,,1H),7.63(s,1H),7.38(t,1H),6.85(d,2H),4.32(d,1H),3.80(td,2H),3.74(t,1H),3.61(s,2H),3.50(dd,1H),3.21(s,4H),2.72-2.59(m,6H),2.46(s,3H),2.17-2.12(m,1H),1.82(dd,1H),1.18(t,3H).
LCMS m/s＝494.2[M+1].
Example 6
(R) -5- (4- ((2-ethyl-8-methyl-3-oxo-3, 4-dihydroquinoxalin-6-yl) methyl) piperazin-1-yl) -6-methyl-N- (tetrahydrofuran-3-yl) picolinamide Compound 6
(R)-5-(4-((2-ethyl-8-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl)-6-methyl-N-(tetrahydrofuran-3-yl)picolinamide
Compound 6 (white solid, 21mg, 39% yield) was prepared according to the procedure of compound 1.
1 H NMR(400MHz,DMSO-d 6 )δ11.73(s,1H),8.42(d,,1H),7.60(s,1H),7.42(t,1H),6.88-6.82(m,2H),4.38(d,1H),3.80(td,2H),3.76(t,1H),3.64(s,2H),3.51(dd,1H),3.23(s,4H),2.71-2.58(m,6H),2.46(s,3H),2.31(s,3H),2.16-2.11(m,1H),1.85(dd,1H),1.18(t,3H).
LCMS m/s＝491.2[M+1].
Biological assay
PARP1, PARP2 Activity inhibition assay
The inhibitory activity of the compounds on PARP1 and PARP2 was measured by PARP1 Chemiluminescent assay (purchased from BPS Bioscience, cat# 80551) and PARP2 Chemiluminescent assay (purchased from BPS Bioscience, cat# 80552), respectively. The results were quantified using chemiluminescence, and the specific experimental protocol was as follows:
(1) The 96-well plate was coated overnight with 1×history mix (50 μl/well);
(2) Discarding the coating liquid; blocking buffer 3 (200. Mu.L) was added to each well and incubated for 90 minutes at room temperature;
(3) Discarding the sealing liquid, and washing with PBST for 2 times; add 25. Mu.L of master mix (containing 2.5. Mu.L of 10 XPAR buffer, 2.5. Mu.L of 10X PARP Assay mixture, 5. Mu.L of activated DNA, 15. Mu.L of ddH 2O), 5. Mu.L of inhibitor (initial concentration of inhibitor 10. Mu.M, 8 diluted 1:5 fold), 20. Mu.L of enzyme (2 ng/. Mu.L); incubating for 1 hour at room temperature;
(4) Discarding liquid and washing with PBST for 2 times; 50. Mu.L of strepavidin-HRP (50-fold dilution with Blocking buffer 3) was added; incubating for 30 minutes at room temperature;
(5) Discarding liquid and washing with PBST for 3 times; 100 μ L ELISA ECL Substrate A/B mix (50 μL each) was added;
(6) The result of the detection by the microplate reader was used to calculate the IC50 using GraphPad Prism 8.
Numbering of compounds PARP1 IC50(μM) PARP2 IC50(μM)
Compound 1 <1 <10
Compound 2 <1 <10
The results show that the compound provided by the invention has remarkable inhibitory activity on PARP1 and good selectivity relative to PARP 2.
MDA-MB-436 cell proliferation inhibition assay
DMEM medium (10% FBS,1% PS) was used to culture MDA-MB-436 cells (supplier ATCC) at 37℃with 5% CO 2 . When the cells grew to the logarithmic growth phase, the cells were resuspended and diluted to 1500 cells/ml with DMEM medium. The compound to be tested was added at 40. Mu.L per well in 384 well plates (final concentrations 10000nM, 2000nM, 400nM, 80nM, 16nM, 3.2nM, 0.64nM, 0.128nM, 0.0256nM, 0.00512nM, respectively); control 1 (0.1% dmso added) and control 2 (blank medium) were set up in 2 replicates per concentration gradient. Subsequently 40. Mu.L of cell suspension was added to 384 well plates (control group 2 was without cells).
The 384-well plate was placed in an incubator (37 ℃,5% co 2) and cultured for 7 days, and then the 384-well plate was taken out and left at room temperature for 30 minutes. 30 mu L Celltiter Glo assay kit detection liquid is added into each hole, the vibration plate machine is vibrated for 3 minutes, and the mixture is placed at room temperature for 30 minutes. The chemiluminescent value was measured by a microplate reader (Perkinelmer; enVision).
The detection results were curve fitted with GraphPad Prism 8 and IC50 calculated.
Numbering of compounds MDA-MB-436 cell IC50 (mu M)
Compound 1 <1
The results show that the compound has obvious inhibition effect on MDA-MB-436 cell proliferation.
While the specification describes in detail specific embodiments of the present invention, those skilled in the art will recognize that the foregoing embodiments are illustrative and not to be construed as limiting the invention, and that many variations and modifications of the invention may be made without departing from the spirit of the invention, which is intended to fall within the scope of the appended claims.

Claims (9)

1. A quinazolinone derivative represented by the general formula (I) and its stereoisomers,
wherein:
R 1 selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl or C 3-8 Heterocycloalkyl, said C 3-8 Heterocycloalkyl may contain 1 to 4 heteroatoms selected from N, O or S;
x is selected from N or C (R) x )；
Y is selected from C (R) y ) Or N;
z is selected from C (R) z ) Or N;
R x 、R y 、R z each independently selected from H, halogen, hydroxy, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl or C 3-8 Heterocycloalkyl, said C 3-8 Heterocycloalkyl may contain 1 to 4 heteroatoms selected from N, O or S;
R 2 selected from cyano, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl or C 3-8 Heterocycloalkyl or C (=o) NH (R 3 ) The C is 3-8 The heterocycloalkyl group may contain 1 to 4 members selected from N, OOr a heteroatom of S;
R 3 selected from C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl or C 3-8 A heterocycloalkyl group; the C is 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl or C 3-8 The heterocycloalkyl group optionally being further substituted by 1 or more groups selected from halogen, hydroxy, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl or C 3-8 Substituted with a substituent of heterocycloalkyl, said C 3-8 The heterocycloalkyl group may contain 1 to 4 heteroatoms selected from N, O or S.
2. A quinazolinone derivative according to claim 1, and stereoisomers thereof, wherein:
x is selected from N or C (R) x )；R x Selected from C 1-6 Alkyl or halogen;
and X is selected from N, R 3 Cannot be C 1-6 An alkyl group.
3. A quinazolinone derivative according to claim 2, and stereoisomers thereof, wherein:
R 2 selected from cyano or C (=O) NH (R) 3 )。
4. A quinazolinone derivative according to claim 2, and stereoisomers thereof, wherein:
y is selected from C (R) y ) Or N; r is R y Selected from H or C 1-6 Alkyl or halogen.
5. A quinazolinone derivative according to claim 2, and stereoisomers thereof, wherein:
z is selected from C (H) or N.
6. A quinazolinone derivative according to claim 2, and stereoisomers thereof, wherein:
R 1 selected from C 1-4 An alkyl group.
7. A quinazolinone derivative according to claims 1 to 6, or a stereoisomer thereof, selected from the group consisting of:
8. a pharmaceutical composition, the pharmaceutical composition comprising:
(1) A quinazolinone derivative of claims 1 to 7 or a stereoisomer thereof;
(2) Optionally one or more other active ingredients; and
(3) Pharmaceutically acceptable carriers and/or excipients.
9. Use of a pharmaceutical composition according to claim 8 or a quinazolinone derivative according to any one of claims 1 to 8 or a stereoisomer thereof in the manufacture of an anti-tumour medicament.
CN202310037716.8A 2022-02-10 2023-01-09 Quinazolinone derivative and application thereof in medicine Pending CN116693501A (en)

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