Oxaazaquinazolin-7 (8H) -ones, their preparation and pharmaceutical use
阅读说明：本技术 氧杂氮杂喹唑啉-7(8h)-酮类化合物,其制法与医药上的用途 (Oxaazaquinazolin-7 (8H) -ones, their preparation and pharmaceutical use ) 是由 周福生 蔡礼健 蒋涛 赵吉辰 刘颖涛 赵金柱 张磊涛 刘柱博 彭灵 何宛 杨华彬 于 2020-04-28 设计创作，主要内容包括：一种对KRAS基因突变具有选择抑制作用的氧杂氮杂喹唑啉-7(8H)-酮类化合物及其药学上可接受的盐、立体异构体、溶剂化合物或前药,如式I或式II所示,式中各基团的定义详见说明书。此外,本发明还公开了包含该化合物的药物组合物,及其在制备癌症药物中的应用。(An oxazaquinazoline-7 (8H) -ketone compound with selective inhibition effect on KRAS gene mutation and pharmaceutically acceptable salts, stereoisomers, solvent compounds or prodrugs thereof are shown as a formula I or a formula II, and the definitions of all groups in the formula are shown in the specification. In addition, the invention also discloses a pharmaceutical composition containing the compound and application thereof in preparing cancer drugs.)
A compound represented by formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof,
in the formula (I), the compound is shown in the specification,
R 1、R 2each independently of the other is hydrogen, cyano, C1-3Alkyl or-C1-3alkyl-NRaR b；
R 01、R 02、R 03、R 04、R 05、R 06Each independently is hydrogen, C1-6Alkyl, -C1-4Alkyl-hydroxy, -C1-4Alkyl-cyano, -C1-4alkyl-C1-6Alkoxy, -C1-4Alkyl-halo C1-6Alkyl or-C1-4Alkyl-halo C1-6An alkoxy group;
or R01、R 02Together with the carbon atom to which they are attached form C 3-6A monocyclic cycloalkyl group;
or R03、R 04Together with the carbon atom to which they are attached form C3-6A monocyclic cycloalkyl group;
or R05、R 06Together with the carbon atom to which they are attached form C3-6A monocyclic cycloalkyl group;
l is a bond, (CR)L1R L2) n、C(O)、C(O)C(R L1R L2) Or C (R)L1R L2) C (O); wherein R isL1、R L2Each independently is hydrogen, halogen or C1-6An alkyl group;
n is 1 or 2;
X 1is NRx1O or CRx2R x3(ii) a Wherein R isx1Is hydrogen or C1-6An alkyl group; rx2、R x3Each independently of the others is hydrogen, halogen, cyano, C1-6Alkyl radical, C1-6Alkoxy, halo C1-6Alkyl, halo C1-6Alkoxy radical, C3-6Monocyclic cycloalkyl, NRgR h、-C 1-4Alkyl-hydroxy, -C1-4Alkyl-cyano, -C1-4alkyl-C1-6Alkoxy, -C1-4Alkyl-halo C1-6Alkyl or-C1-4Alkyl-halo C1-6An alkoxy group;
X 2is N or CRx4(ii) a Wherein R isx4Is hydrogen, halogen, cyano, C1-6Alkyl radical, C1-6Alkoxy, halo C1-6Alkyl, halo C1-6Alkoxy radical, C3-6Monocyclic cycloalkyl, NRgR h、-C 1-4Alkyl-hydroxy, -C1-4Alkyl-cyano, -C1-4alkyl-C1-6Alkoxy, -C1-4Alkyl-halo C1-6Alkyl or-C1-4Alkyl-halo C1-6An alkoxy group;
R ais hydrogen, halogen, cyano, C1-6Alkyl radical, C1-6Alkoxy, halo C1-6Alkyl, halo C1-6Alkoxy radical, C3-6Monocyclic cycloalkyl, NRcR d、C 2-4Alkenyl radical, C2-4Alkynyl, -C1-4Alkyl-hydroxy, -C1-4Alkyl-cyano, -C1-4alkyl-C 1-6Alkoxy, -C1-4Alkyl-halo C1-6Alkyl or-C1-4Alkyl-halo C 1-6An alkoxy group;
R bis C6-10Aryl or C5-10A heteroaryl group; said C is6-10Aryl radical, C5-10Heteroaryl is unsubstituted or substituted with 1,2,3 or 4 substituents independently selected from group S1, said group S1 substituents being halogen, cyano, nitro, hydroxy, C1-6Alkyl radical, C1-6Alkoxy, halo C1-6Alkyl, halo C1-6Alkoxy radical, C3-6Monocyclic cycloalkyl, NRiR j、C(O)NR eR f、-SO 2C 1-3Alkyl, -SO2Halogen substituted C1-3Alkyl, -SO2NR eR f、-C 1-4Alkyl-hydroxy, -C1-4Alkyl-cyano, -C1-4alkyl-C1-6Alkoxy, -C1-4Alkyl-halo C1-6Alkyl, -C1-4Alkyl-halo C1-6Alkoxy, -C1-4alkyl-C3-6Monocyclic heterocyclyl, -C1-4alkyl-NReR f、-C 1-4alkyl-C (O) NReR f、-C 1-4alkyl-SO2C 1-3Alkyl or C2-4An alkynyl group;
R cis C1-6Alkyl radical, C6-10Aryl radical, C5-10Heteroaryl group, C3-6Monocyclic cycloalkyl, C3-6Monocyclic heterocyclyl, 7-to 11-membered spirocycloalkyl, -C1-4alkyl-C6-10Aryl radical, -C1-4alkyl-C5-10Heteroaryl, -NRe-C 6-10Aryl, -O-C6-10Aryl radical, -C1-4alkyl-C3-6Monocyclic heterocyclyl, -C1-4alkyl-C3-6A monocyclic cycloalkyl group; wherein
Said C3-6Monocyclic cycloalkyl is selected from: cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cyclobutanone, cyclobutane-1, 2-dione, cyclopentanone, cyclopentane-1, 3-dione, cyclohexanone, cyclohexane-1, 3-dione;
said C3-6The monocyclic heterocyclic group is selected from: aziridine, ethylene oxide, azetidine, azetidin-2-one, oxetane, oxetan-2-one, oxazolidine, pyrrolidin-2-one, pyrrolidine-2, 5-dione, 1, 3-dioxolane, dihydrofuran-2 (3H) -one, dihydrofuran-2, 5-dione, piperidin-2-one, piperidine-2, 6-dione, tetrahydro-2H-pyran-2-one, imidazolidine, tetrahydrofuran, tetrahydrothiophene, tetrahydropyrrole, 1, 3-dioxolan-2-one, oxazolidin-2-one, imidazolidin-2-one, piperidine, piperazine, piperazin-2-one, morpholine, morpholin-3-one, morpholine-3-one, and mixtures thereof, Morpholin-2-one, thiomorpholin-3-one 1, 1-dioxide, thiomorpholine-1, 1-dioxide, tetrahydropyran, 1, 2-dihydroazetidine, 1, 2-dihydrooxetane, 2, 5-dihydro-1H-pyrrole, 2, 5-dihydrofuran, 2, 3-dihydro-1H-pyrrole, 3, 4-dihydro-2H-pyran, 1,2,3, 4-tetrahydropyridine, 3, 6-dihydro-2H-pyran, 1,2,3, 6-tetrahydropyridine, 1, 3-oxazinane, hexahydropyrimidine, 1, 4-dioxane, tetrahydropyrimidin-2 (1H) -one, thiomorpholine-1, 1-dioxide, tetrahydropyran, 1, 3-dihydrooxacyclobutane, 1, 4-dioxan, tetrahydropyrimidin-2 (1H) -one, 2, 3-dihydrofuran, 2, 3-tetrahydropyran, 3-one, piperidine, 2-one, 2-oxadiazine, 2-one, 2-one, and optionally, 1, 4-dioxan-2-one, 5, 6-dihydro-2H-pyran-2-one, 5, 6-dihydropyrimidin-4 (3H) -one, 3, 4-dihydropyridin-2 (1H) -one, 5, 6-dihydropyridin-2 (1H) -one;
said-C1-4Alkyl-is unsubstituted or substituted by 1, 2, 3 or 4 groups independently selected from C1-3Alkyl substitution;
said C1-6Alkyl radical, C6-10Aryl radical, C5-10Heteroaryl, 7-to 11-membered spirocycloalkyl, C3-6Monocyclic cycloalkyl, C3-6Monocyclic hetero ringThe cyclic group is unsubstituted or substituted by 1, 2, 3 or 4 substituents independently selected from group S2, the substituents of group S2 are halogen, cyano, hydroxy, C1-6Alkyl radical, C1-6Alkoxy, halo C1-6Alkyl, halo C1-6Alkoxy radical, C3-6Monocyclic cycloalkyl, C3-6Monocyclic heterocyclic group, NRiR j、C(O)NR eR f、-SO 2C 1-3Alkyl, -SO2Halogen substituted C1-3Alkyl, -SO2NR eR f、-C 1-4Alkyl-hydroxy, -C1-4alkyl-C2-4Alkynyl, -C1-4Alkyl-cyano, -C1-4alkyl-C1-6Alkoxy, -C1-4Alkyl-halo C1-6Alkyl, -C1-4Alkyl-halo C1-6Alkoxy, -C1-4alkyl-C3-6Monocyclic heterocyclyl, -C1-4alkyl-C3-6Monocyclic cycloalkyl, -C1-4alkyl-NReR f、-C 1-4alkyl-C (O) NReR f、-C 1-4alkyl-SO2C 1-3Alkyl or C2-4An alkynyl group; wherein C is as described for substituent of group S23-6Monocyclic cycloalkyl is selected from: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl; said C3-6The monocyclic heterocyclic group is selected from: aziridine, ethylene oxide, azetidine, oxetane, tetrahydrofuran, tetrahydrothiophene, tetrahydropyrrole, piperidine, piperazine, morpholine, thiomorpholine-1, 1-dioxide, tetrahydropyran; and C in the substituent of group S2 1-6Alkyl radical, C1-6Alkoxy, -C1-4Alkyl-, C3-6Monocyclic cycloalkyl, C3-6Monocyclic heterocyclyl is optionally substituted with 1, 2 or 3 substituents independently selected from halogen, methylEthyl, propyl, isopropyl, trifluoromethyl, amino, N (CH)3) 2Hydroxyl and carboxyl; wherein said C3-6Monocyclic cycloalkyl is selected from: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl; said C3-6The monocyclic heterocyclic group is selected from: aziridine, ethylene oxide, azetidine, oxetane, tetrahydrofuran, tetrahydrothiophene, tetrahydropyrrole, piperidine, piperazine, morpholine, thiomorpholine-1, 1-dioxide, tetrahydropyran;
R a、R b、R c、R d、R e、R f、R g、R heach independently is hydrogen or C1-3An alkyl group;
R i、R jeach independently is hydrogen, C1-3Alkyl, -C (O) C1-3Alkyl, -CO2C 1-3An alkyl group.
The compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, solvate, or prodrug thereof, wherein R is1、R 2Each independently of the other is hydrogen, cyano, C1-3Alkyl, -CH2NH 2、-CH 2NHCH 3or-CH2N(CH 3) 2。
The compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, solvate, or prodrug thereof, wherein R is01、R 02、R 03、R 04、R 05、R 06Each independently is hydrogen, C1-3Alkyl, -C1-2Alkyl-hydroxy, -C 1-2Alkyl-cyano, -C1-2alkyl-C1-3Alkoxy, -C1-2Alkyl-halo C1-3Alkyl, -C1-2Alkyl-halo C1-3An alkoxy group;
or R01、R 02Together with the carbon atom to which they are attached form C3-6A monocyclic cycloalkyl group;
or R03、R 04Together with the carbon atom to which they are attached form C3-6A monocyclic cycloalkyl group;
or R05、R 06Together with the carbon atom to which they are attached form C3-6A monocyclic cycloalkyl group.
The compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, solvate, or prodrug thereof, wherein R is02、R 04Each independently is hydrogen, CH3、-CH 2-hydroxy or-CH2-a cyano group; r01、R 03、R 05、R 06Is hydrogen.
The compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, solvate, or prodrug thereof, wherein L is a bond or (CR)L1R L2) n(ii) a Wherein R isL1、R L2Each independently is hydrogen, halogen or C1-6An alkyl group; n is 1 or 2.
The compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, solvate, or prodrug thereof, wherein X is1Is NRx1Or O; wherein R isx1Is hydrogen or C1-6An alkyl group.
The compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, solvate, or prodrug thereof, wherein X is2Is N or CR x4(ii) a Wherein R isx4Is hydrogen, halogen, C1-6Alkyl radical, C1-6Alkoxy or halo C1-6An alkyl group.
The compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, solvate, or prodrug thereof, wherein R isaIs hydrogen, halogen, cyano, C1-4Alkyl radical, C1-4Alkoxy, halo C1-3Alkyl, halo C1-3Alkoxy radical, C3-6Monocyclic cycloalkyl, NRcR d、C 2-4Alkenyl radical, C2-4Alkynyl, -C1-2Alkyl-hydroxy, -C1-2Alkyl-cyano, -C1-2alkyl-C1-3Alkoxy, -C1-2Alkyl-halo C1-3Alkyl or-C1-2Alkyl-halo C1-3An alkoxy group; wherein R isc、R dEach independently is hydrogen or C1-3An alkyl group.
The compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, solvate, or prodrug thereof, wherein R iscThe 7-to 11-membered spirocycloalkyl group described in (1) is a monocyclic spirocycloalkyl group containing one spiro atom formed from any two monocyclic cycloalkyl rings selected from among cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl rings.
The compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, solvate, or prodrug thereof, wherein R isb、R cC as described in (1)6-10Aryl is each independently phenyl, naphthyl, phenyl and a C 5-6A 9-or 10-membered aromatic fused bicyclic ring formed by fusing a monocyclic heterocyclic group, or phenyl with a C5-6Monocyclic cycloalkyl groups are fused to form 9 or 10 membered aromatic fused bicyclic rings.
The compound of claim 10, or a pharmaceutically acceptable salt, stereoisomer, solvate, or prodrug thereof, wherein phenyl is substituted with a C5-6C in 9-or 10-membered aromatic condensed bicyclic ring formed by fusing monocyclic heterocyclic group5-6The monocyclic heterocyclic group is selected from: oxazolidines, pyrrolidin-2-ones, pyrrolidine-2, 5-diones, 1, 3-dioxolanes, dihydrofuran-2 (3H) -one, dihydrofuran-2, 5-dione, piperidin-2-one, piperidine-2, 6-dione, tetrahydro-2H-pyran-2-one, imidazolidine, tetrahydrofuran, tetrahydrothiophene, tetrahydropyrrole, 1, 3-dioxolan-2-one, oxazolidin-2-one, imidazolidin-2-one, piperidine, piperazine, piperazin-2-one, morpholine, morpholin-3-one, morpholin-2-one, thiomorpholin-3-one 1, 1-dioxide, thiomorpholine-1, 1-dioxide, tetrahydropyran, 2, 5-dihydro-1H-pyrrole, 2, 5-dihydrofuran, 2, 3-dihydro-1H-pyrrole, 3, 4-dihydro-2H-pyran, 1,2,3, 4-tetrahydropyridine, 3, 6-dihydro-2H-pyran, 1,2,3, 6-tetrahydropyridine, 1, 3-oxazinane, hexahydropyrimidine, 1, 4-dioxane, tetrahydropyrimidin-2 (1H) -one, 1, 4-dioxan-2-one, 5, 6-dihydro-2H-pyran-2-one, 5, 6-dihydropyrimidin-4 (3H) -one, 3, 4-dihydropyridin-2 (1H) -one, dihydropyran-2-one, 2, 3-dihydropyran-1H-one, 2, 3-dihydropyran-2-one, 2, 3-dihydropyran-2-one, 2-H-one, 2-dihydropyran-2-one, 2-dihydropyran-one, 2-one, and a method for producing a compound, 5, 6-dihydropyridin-2 (1H) -one.
The compound of claim 10, or a pharmaceutically acceptable salt, stereoisomer, solvate, or prodrug thereof, wherein phenyl is substituted with a C5-6C in 9-or 10-membered aromatic condensed bicyclic ring formed by fusing monocyclic cycloalkyl5-6Monocyclic cycloalkyl is selected from: cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cyclopentanone, cyclopentane-1, 3-dione, cyclohexanone, cyclohexane-1, 3-dione.
The compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, solvate, or prodrug thereof, wherein R isb、R cC as described in (1)5-10Heteroaryl is independently of each other 5-or 6-membered monoheteroaryl, 9-or 10-membered bisheteroaryl formed by phenyl fused with 5-or 6-membered monoheteroaryl, 8-to 10-membered bisheteroaryl formed by 5-or 6-membered monoheteroaryl fused with 5-or 6-membered monoheteroaryl, 5-or 6-membered monoheteroaryl with one C5-6A monocyclic heterocyclic group fused to form an 8-to 10-membered bis-heteroaryl group, or a 5-or 6-membered mono-heteroaryl group with one C5-6Monocyclic cycloalkyl groups are fused to form 8-to 10-membered bis-heteroaryl groups.
The compound of claim 13, or a pharmaceutically acceptable salt, stereoisomer, solvate, or prodrug thereof, wherein R is b、R cC as described in (1)5-10When heteroaryl is a 5 or 6 membered single heteroaryl, each of said 5 or 6 membered single heteroaryl is independently selected from: thiophene, N-alkylcyclopyrrole, furan, thiazole, isothiazole, imidazole, oxazole, pyrrole, pyrazole, triazole, 1,2, 3-triazole, 1,2, 4-triazole, 1,2, 5-triazole, 1,3, 4-triazole, tetrazole, isoxazole, oxadiazole, 1,2, 3-oxadiazole, 1,2, 4-oxadiazole, 1,2, 5-oxadiazole, 1,3, 4-oxadiazole, thiadiazole, pyridine, pyridazine, pyrimidine or pyrazine.
The compound of claim 13, or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, wherein the 5 or 6 membered monoheteroaryl in the 9 or 10 membered diheteroaryl fused to a 5 or 6 membered monoheteroaryl is selected from: thiophene, N-alkylcyclopyrrole, furan, thiazole, isothiazole, imidazole, oxazole, pyrrole, pyrazole, triazole, 1,2, 3-triazole, 1,2, 4-triazole, 1,2, 5-triazole, 1,3, 4-triazole, tetrazole, isoxazole, oxadiazole, 1,2, 3-oxadiazole, 1,2, 4-oxadiazole, 1,2, 5-oxadiazole, 1,3, 4-oxadiazole, thiadiazole, pyridine, pyridazine, pyrimidine or pyrazine.
The compound of claim 13, or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, wherein the 5 or 6 membered monoheteroaryl in an 8 to 10 membered diheteroaryl group formed by fusing a 5 or 6 membered monoheteroaryl with a 5 or 6 membered monoheteroaryl is selected from the group consisting of: thiophene, N-alkylcyclopyrrole, furan, thiazole, isothiazole, imidazole, oxazole, pyrrole, pyrazole, triazole, 1,2, 3-triazole, 1,2, 4-triazole, 1,2, 5-triazole, 1,3, 4-triazole, tetrazole, isoxazole, oxadiazole, 1,2, 3-oxadiazole, 1,2, 4-oxadiazole, 1,2, 5-oxadiazole, 1,3, 4-oxadiazole, thiadiazole, pyridine, pyridazine, pyrimidine or pyrazine.
The compound of claim 13, or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, wherein the 5 or 6 membered monoheteroaryl is substituted with one C5-6The 5-or 6-membered monoheteroaryl group in the 8-to 10-membered diheteroaryl group formed by fusing monocyclic heterocyclic groups is selected from: thiophene, N-alkylcyclopyrrole, furan, thiazole, isothiazole, imidazole, oxazole, pyrrole, pyrazole, triazole, 1,2, 3-triazole, 1,2, 4-triazole, 1,2, 5-triazole, 1,3, 4-triazole, tetrazole, isoxazole, oxadiazole, 1,2, 3-oxadiazole, 1,2, 4-oxadiazole, 1,2, 5-oxadiazole, 1,3, 4-oxadiazole, thiadiazole, pyridine, pyridazine, pyrimidine or pyrazine;
said C5-6The monocyclic heterocyclic group is selected from: oxazolidines, pyrrolidin-2-ones, pyrrolidine-2, 5-diones, 1, 3-dioxolanes, dihydrofuran-2 (3H) -one, dihydrofuran-2, 5-dione, piperidin-2-one, piperidine-2, 6-dione, tetrahydro-2H-pyran-2-one, imidazolidine, tetrahydrofuran, tetrahydrothiophene, tetrahydropyrrole, 1, 3-dioxolan-2-one, oxazolidin-2-one, imidazolidin-2-one, piperidine, piperazine, piperazin-2-one, morpholine, morpholin-3-one, morpholin-2-one, thiomorpholin-3-one 1, 1-dioxide, thiomorpholine-1, 1-dioxide, tetrahydropyran, 2, 5-dihydro-1H-pyrrole, 2, 5-dihydrofuran, 2, 3-dihydro-1H-pyrrole, 3, 4-dihydro-2H-pyran, 1,2,3, 4-tetrahydropyridine, 3, 6-dihydro-2 H-pyran, 1,2,3, 6-tetrahydropyridine, 1, 3-oxazinane, hexahydropyrimidine, 1, 4-dioxane, tetrahydropyrimidin-2 (1H) -one, 1, 4-dioxan-2-one, 5, 6-dihydro-2H-pyran-2-one, 5, 6-dihydropyrimidin-4 (3H) -one, 3, 4-dihydropyridin-2 (1H) -one, 5, 6-dihydropyridin-2 (1H) -one.
The compound of claim 13, or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, wherein the 5 or 6 membered monoheteroaryl is substituted with one C5-6The 5-or 6-membered monoheteroaryl group in the 8-to 10-membered diheteroaryl group formed by fusing monocyclic cycloalkyl groups is selected from: thiophene, N-alkylcyclopyrrole, furan, thiazole, isothiazole, imidazole, oxazole, pyrrole, pyrazole, triazole, 1,2, 3-triazole, 1,2, 4-triazole, 1,2, 5-triazole, 1,3, 4-triazole, tetrazole, isoxazole, oxadiazole, 1,2, 3-oxadiazole, 1,2, 4-oxadiazole, 1,2, 5-oxadiazole, 1,3, 4-oxadiazole, thiadiazole, pyridine, pyridazine, pyrimidine or pyrazine;
said C5-6Monocyclic cycloalkyl is selected from: cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cyclopentanone, cyclopentane-1, 3-dione, cyclohexanone, cyclohexane-1, 3-dione.
The compound of claim 10, or a pharmaceutically acceptable salt, stereoisomer, solvate, or prodrug thereof, wherein phenyl is substituted with a C 5-6The 9 or 10 membered aromatic fused bicyclic ring formed by fusing the monocyclic heterocyclic group is selected from the following structures:
the compound of claim 13, or a pharmaceutically acceptable salt, stereoisomer, solvate, or prodrug thereof, wherein the 9-or 10-membered bis-heteroaryl formed by the fusion of a phenyl group with a 5-or 6-membered mono-heteroaryl is selected from the following structures:
the compound of claim 13, or a pharmaceutically acceptable salt, stereoisomer, solvate, or prodrug thereof, wherein the 8-to 10-membered bis-heteroaryl formed by the fusion of a 5-or 6-membered single heteroaryl with a 5-or 6-membered single heteroaryl is selected from the structures:
the compound of claim 13, or a pharmaceutically acceptable salt, stereoisomer, solvate, or prodrug thereof, wherein the 9-or 10-membered bis-heteroaryl formed by the fusion of a phenyl group with a 5-or 6-membered mono-heteroaryl is selected from the following structures:
the compound of claim 13, or a pharmaceutically acceptable salt, stereoisomer, solvate, or prodrug thereof, wherein the 8-to 10-membered bis-heteroaryl formed by the fusion of a 5-or 6-membered single heteroaryl with a 5-or 6-membered single heteroaryl is selected from the structures:
the compound of claim 13, or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, wherein the 9-or 10-membered bis-heteroaryl formed by the fusion of a phenyl group with a 5-or 6-membered single heteroaryl group, or the 8-to 10-membered bis-heteroaryl formed by the fusion of a 5-or 6-membered single heteroaryl group with a 5-or 6-membered single heteroaryl group, is selected from the structures:
The compound of claim 10, or a pharmaceutically acceptable salt, stereoisomer, solvate, or prodrug thereof, wherein phenyl is substituted with a C5-6The 9 or 10 membered aromatic fused bicyclic ring formed by fusing the monocyclic heterocyclic group is selected from the following structures:
the compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, solvate, or prodrug thereof, wherein R isbSelected from the following structures:
the compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, solvate, or prodrug thereof, wherein R iscSelected from the following structures:
the compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, wherein the compound of formula (I) is selected from the specific compounds noted in the examples.
The compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, solvate, or prodrug thereof, wherein the compound of formula (I) has the structure of formula (IA) or formula (IB):
wherein each group is as defined in claim 1.
A pharmaceutical composition comprising a compound of any one of claims 1 to 28 and 29, or a pharmaceutically acceptable salt, stereoisomer, solvate, or prodrug thereof; and a pharmaceutically acceptable carrier.
Use of a compound of any one of claims 1 to 28 and 29, or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, or a pharmaceutical composition of claim 30, in the manufacture of a medicament for the prevention and/or treatment of cancer.
Use of a compound of any one of claims 1 to 28 and 29, or a pharmaceutically acceptable salt, stereoisomer, solvate, or prodrug thereof, or a pharmaceutical composition of claim 30, for the preparation of a KRAS mutation inhibitor, (preferably, the KRAS mutation is KRAS G12C mutation).
An oxaazaquinazolin-7 (8H) -one compound represented by formula (II), or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof:
wherein
R 1、R 2Each independently of the other is hydrogen, cyano, C1-3Alkyl or-C1-3alkyl-NRaR b；
R 01、R 02、R 03、R 04、R 05、R 06Each independently isHydrogen, C1-6Alkyl, -C1-4Alkyl-hydroxy, -C1-4Alkyl-cyano, -C1-4alkyl-C1-6Alkoxy, -C1-4Alkyl-halo C1-6Alkyl or-C1-4Alkyl-halo C1-6An alkoxy group;
or R01、R 02Together with the carbon atom to which they are attached form C3-6A monocyclic cycloalkyl group;
or R03、R 04Together with the carbon atom to which they are attached form C3-6A monocyclic cycloalkyl group;
or R05、R 06Together with the carbon atom to which they are attached form C 3-6A monocyclic cycloalkyl group;
l is a bond, (CR)L1R L2) n、C(O)、C(O)C(R L1R L2) Or C (R)L1R L2) C (O); wherein R isL1、R L2Each independently is hydrogen, halogen or C1-6An alkyl group;
n is 1 or 2;
X 1is NRx1O or CRx2R x3(ii) a Wherein R isx1Is hydrogen or C1-6An alkyl group; rx2、R x3Each independently of the others is hydrogen, halogen, cyano, C1-6Alkyl radical, C1-6Alkoxy, halo C1-6Alkyl, halo C1-6Alkoxy radical, C3-6Monocyclic cycloalkyl, NRgR h、-C 1-4Alkyl-hydroxy, -C1-4Alkyl-cyano, -C1-4alkyl-C1-6Alkoxy, -C1-4Alkyl-halo C1-6Alkyl or-C1-4Alkyl-halo C1-6Alkoxy radical；
X 2Is N or CRx4(ii) a Wherein R isx4Is hydrogen, halogen, cyano, C1-6Alkyl radical, C1-6Alkoxy, halo C1-6Alkyl, halo C1-6Alkoxy radical, C3-6Monocyclic cycloalkyl, NRgR h、-C 1-4Alkyl-hydroxy, -C1-4Alkyl-cyano, -C1-4alkyl-C1-6Alkoxy, -C1-4Alkyl-halo C1-6Alkyl or-C1-4Alkyl-halo C1-6An alkoxy group;
R ais hydrogen, halogen, cyano, C1-6Alkyl radical, C1-6Alkoxy, halo C1-6Alkyl, halo C1-6Alkoxy radical, C3-6Monocyclic cycloalkyl, NRcR d、C 2-4Alkenyl radical, C2-4Alkynyl, -C1-4Alkyl-hydroxy, -C1-4Alkyl-cyano, -C1-4alkyl-C1-6Alkoxy, -C1-4Alkyl-halo C1-6Alkyl or-C1-4Alkyl-halo C1-6An alkoxy group;
R b' is C6-10Aryl radical, C5-10Heteroaryl group, C3-6A monocyclic heterocyclic group, a pyrimidinone group or a pyridonyl group; said C is6-10Aryl radical, C5-10Heteroaryl group, C 3-6The monocyclic heterocyclyl, pyrimidinone and pyridonyl groups are unsubstituted or substituted with 1,2, 3 or 4 substituents independently selected from group S1, or with 1,2, 3 or 4 substituents independently selected from deuterated C1-6Alkyl and deuterated C1-6Substituent substitution of alkoxy; the substituent of the S1 group is halogen, cyano, nitro, hydroxyl and C1-6Alkyl radical, C1-6Alkoxy, halo C1-6Alkyl, halo C1-6Alkoxy radical, C3-6Monocyclic cycloalkyl, NRiR j、C(O)NR eR f、-SO 2C 1-3Alkyl, -SO2Halogen substituted C1-3Alkyl, -SO2NR eR f、-C 1-4Alkyl-hydroxy, -C1-4Alkyl-cyano, -C1-4alkyl-C1-6Alkoxy, -C1-4Alkyl-halo C1-6Alkyl, -C1-4Alkyl-halo C1-6Alkoxy, -C1-4alkyl-C3-6Monocyclic heterocyclyl, -C1-4alkyl-NReR f、-C 1-4alkyl-C (O) NReR f、-C 1-4alkyl-SO2C 1-3Alkyl or C2-4An alkynyl group;
R c' is C1-6Alkyl radical, C6-10Aryl radical, C5-10Heteroaryl group, C3-6Monocyclic cycloalkyl, C3-6Monocyclic heterocyclyl, 7-to 11-membered spirocycloalkyl, -C1-4alkyl-C6-10Aryl radical, -C1-4alkyl-C5-10Heteroaryl, -NRe-C 6-10Aryl, -O-C6-10Aryl radical, -C1-4alkyl-C3-6Monocyclic heterocyclyl, -C1-4alkyl-C3-6Monocyclic cycloalkyl, pyrimidinonyl, or pyridonyl;
wherein
Said C3-6Monocyclic cycloalkyl is selected from: cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cyclobutanone, cyclobutane-1, 2-dione, cyclopentanone, cyclopentane-1, 3-dione, cyclohexanone, cyclohexane-1, 3-dione;
Said C3-6The monocyclic heterocyclic group is selected from: aziridine, ethylene oxide, azetidine, azetidin-2-one, oxetane, oxetan-2-one, oxazolidine, pyrrolidin-2-one, pyrrolidine-2, 5-dione, 1, 3-dioxolane, dihydrofuran-2 (3H) -one, dihydrofuran-2, 5-dione, piperidin-2-one, piperidine-2, 6-dione, tetrahydro-2H-pyran-2-one, imidazolidine, tetrahydrofuran, tetrahydrothiophene, tetrahydropyrrole, 1, 3-dioxolan-2-one, oxazolidin-2-one, imidazolidin-2-one, piperidine, piperazine, piperazin-2-one, morpholine, morpholin-3-one, morpholine-3-one, and mixtures thereof, Morpholin-2-one, thiomorpholin-3-one 1, 1-dioxide, thiomorpholine-1, 1-dioxide, tetrahydropyran, 1, 2-dihydroazetidine, 1, 2-dihydrooxetane, 2, 5-dihydro-1H-pyrrole, 2, 5-dihydrofuran, 2, 3-dihydro-1H-pyrrole, 3, 4-dihydro-2H-pyran, 1,2,3, 4-tetrahydropyridine, 3, 6-dihydro-2H-pyran, 1,2,3, 6-tetrahydropyridine, 1, 3-oxazinane, hexahydropyrimidine, 1, 4-dioxane, tetrahydropyrimidin-2 (1H) -one, thiomorpholine-1, 1-dioxide, tetrahydropyran, 1, 3-dihydrooxacyclobutane, 1, 4-dioxan, tetrahydropyrimidin-2 (1H) -one, 2, 3-dihydrofuran, 2, 3-tetrahydropyran, 3-one, piperidine, 2-one, 2-oxadiazine, 2-one, 2-one, and optionally, 1, 4-dioxan-2-one, 5, 6-dihydro-2H-pyran-2-one, 5, 6-dihydropyrimidin-4 (3H) -one, 3, 4-dihydropyridin-2 (1H) -one, 5, 6-dihydropyridin-2 (1H) -one;
said-C1-4Alkyl-is unsubstituted or substituted by 1, 2, 3 or 4 groups independently selected from C1-3Alkyl substitution;
said C1-6Alkyl radical, C6-10Aryl radical, C5-10Heteroaryl, 7-to 11-membered spirocycloalkyl, C3-6Monocyclic cycloalkyl, C3-6The monocyclic heterocyclyl, pyrimidinone and pyridonyl groups are unsubstituted or substituted with 1, 2, 3 or 4 substituents independently selected from group S2, or with 1, 2, 3 or 4 substituents independently selected from deuterated C1-6Alkyl and deuterated C1-6Substituent substitution of alkoxy; the substituent of the S2 group is halogen, cyano, hydroxyl, C1-6Alkyl radical, C1-6Alkoxy, halo C1-6Alkyl, halo C1-6Alkoxy radical, C3-6Monocyclic cycloalkyl, C3-6Monocyclic heterocyclic group, NRiR j、C(O)NR eR f、-SO 2C 1-3Alkyl, -SO2Halogen substituted C1-3Alkyl, -SO2NR eR f、-C 1-4Alkyl-hydroxy, -C1-4alkyl-C2-4Alkynyl, -C1-4Alkyl-cyano, -C1-4alkyl-C1-6Alkoxy, -C1-4Alkyl-halo C1-6Alkyl, -C1-4Alkyl-halo C1-6Alkoxy, -C1-4alkyl-C3-6Monocyclic heterocyclyl, -C1-4alkyl-C3-6Monocyclic cycloalkyl, -C1-4alkyl-NReR f、-C 1-4alkyl-C (O) NReR f、-C 1-4alkyl-SO2C 1-3Alkyl or C2-4An alkynyl group; wherein C is as described for substituent of group S23-6Monocyclic cycloalkyl is selected from: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl; said C3-6The monocyclic heterocyclic group is selected from: aziridine, ethylene oxide, azetidine, oxetane, tetrahydrofuran, tetrahydrothiophene, tetrahydropyrrole, piperidine, piperazine, morpholine, thiomorpholine-1, 1-dioxide, tetrahydropyran; and C in the substituent of group S2 1-6Alkyl radical, C1-6Alkoxy, -C1-4Alkyl-, C3-6Monocyclic cycloalkyl, C3-6Monocyclic heterocyclyl is optionally substituted with 1, 2 or 3 substituents independently selected from halogen, methyl, ethyl, propyl, isopropyl, trifluoromethyl, amino, N (CH)3) 2Hydroxyl and carboxyl; wherein said C3-6Monocyclic cycloalkyl is selected from: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl; said C3-6The monocyclic heterocyclic group is selected from: aziridine, oxirane, azetidine, oxetane, tetrazineHydrogen furan, tetrahydrothiophene, tetrahydropyrrole, piperidine, piperazine, morpholine, thiomorpholine-1, 1-dioxide, tetrahydropyran;
R a、R b、R c、R d、R e、R f、R g、R heach independently is hydrogen or C1-3An alkyl group;
R i、R jeach independently is hydrogen, C1-3Alkyl, -C (O) C1-3Alkyl, -CO2C 1-3An alkyl group.
The compound of claim 33, or a pharmaceutically acceptable salt, stereoisomer, solvate, or prodrug thereof, wherein the compound of formula (II) has the structure of formula (IIA) or formula (IIB):
wherein each group is as defined in claim 33.
The compound of claim 33, or a pharmaceutically acceptable salt, stereoisomer, solvate, or prodrug thereof, wherein the compound of formula (II) is selected from table a-1.
The compound of claim 33, or a pharmaceutically acceptable salt, stereoisomer, solvate, or prodrug thereof, wherein the compound of formula (II) is selected from table a-2.
A pharmaceutical composition comprising a compound of any one of claims 33 to 36, or a pharmaceutically acceptable salt, stereoisomer, solvate, or prodrug thereof; and a pharmaceutically acceptable carrier.
Use of a compound of any one of claims 33 to 36, or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, or a pharmaceutical composition of claim 37, in the manufacture of a medicament for the prevention and/or treatment of cancer.
Use of a compound of any one of claims 33 to 36, or a pharmaceutically acceptable salt, stereoisomer, solvate, or prodrug thereof, or a pharmaceutical composition of claim 37, in the preparation of a KRAS mutation inhibitor, (preferably, the KRAS mutation is KRAS G12C mutation).
- 上一篇：一种医用注射器针头装配设备
- 下一篇：制备铼螯合MAG3寡核苷酸的新方法