CN112047948B - Kras mutant inhibitors - Google Patents
Kras mutant inhibitors Download PDFInfo
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- CN112047948B CN112047948B CN201910808883.1A CN201910808883A CN112047948B CN 112047948 B CN112047948 B CN 112047948B CN 201910808883 A CN201910808883 A CN 201910808883A CN 112047948 B CN112047948 B CN 112047948B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- C—CHEMISTRY; METALLURGY
- 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
- C07D495/02—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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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
- C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
- C07D513/04—Ortho-condensed systems
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
The invention belongs to the technical field of medicines, and particularly relates to a Kras mutant inhibitor compound, pharmaceutically acceptable salts and isomers thereof, a pharmaceutical composition containing the compound, the pharmaceutically acceptable salts and the isomers thereof, a method for preparing the compound, the pharmaceutically acceptable salts and the stereoisomers thereof, and application of the compound, the pharmaceutically acceptable salts and the isomers thereof.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a Kras mutant inhibitor compound, a pharmaceutically acceptable salt and an isomer thereof, a pharmaceutical composition containing the compound, the pharmaceutically acceptable salt and the isomer thereof, and application of the compound, the pharmaceutically acceptable salt and the isomer thereof.
Background
Ras belongs to a monomeric GTP binding protein, and Ras subfamily members mainly comprise Hras, Kras and Nras, and any one of the Hras, the Kras and the Nras is mutated and can cause cancer. In the discovered tumors, about 30% of people have Ras gene carrying mutations. Of note, Kras mutations were detected in 25-30% of tumors. In contrast, the Nras and Hras are relatively low in mutations, 8% and 3%, respectively.
Kras is a protooncogene, normally wild-type, which becomes a cancer driver gene after mutation. Kras, a 21kD protein consisting of 190 amino acids, has weak gtpase activity, and has effects on growth, differentiation, cytoskeleton, protein transport and secretion of cells. Under normal physiological conditions, when cells activate signal channels such as EGFR after being stimulated by the outside, wild-type Kras is activated transiently after being phosphorylated by tyrosine kinase such as active EGFR, the activated Kras can activate downstream signal proteins in the signal channels, and then the Kras is inactivated rapidly. The Kras activation/inactivation effect is controlled, with its activity being regulated by binding to GTP or GDP. Normally, Kras is bound to GDP in an "inactivated state", and when Kras is mutated, it is more likely to bind to GTP, i.e., in an "activated" state, causing an abnormality.
The activity of Kras is controlled by two proteins, one being a Guanosine Exchange Factor (GEF), which acts to facilitate the release of GDP from the Ras protein and, instead, GTP, thereby activating Ras. Another controlling Ras protein activity is GTPase Activating Protein (GAP), which is present in normal cells and mainly functions to activate the GTPase of Ras protein, hydrolyze GTP bound to Ras protein into GDP, and make it an inactive Ras protein-GDP.
After Kras mutation, it can be activated continuously independent of the activation of upstream signals, thereby causing the cells to proliferate continuously. The Kras mutation accounts for 30% of all tumors (30% non-small cell lung cancer, 40-50% colon cancer, > 80% pancreatic cancer present Kras mutation), with 96% of Kras gene mutations occurring at codons 12, 13 of exon 2, the most common being the G12C mutation. The G12C mutation accounted for 14% of NSCLC and 5% of colorectal cancers. When Kras is mutated by G12C, GAP cannot bind to Kras, so GTP cannot be hydrolyzed into GDP, and the signaling pathway is continuously activated.
Aiming at Kras mutation, research is slow in progress for many years, and due to the fact that no proper medicine action site exists on Kras, the affinity of Kras after mutation and GTP is extremely strong, the concentration of GTP in cells is high, and no small molecule can be competitively combined with GTP. With the intensive research on Kras, it is found that after mutation of G12C, Kras protein can form a site capable of acting with drugs, and after binding with small molecule drugs, Kras can be locked in the state of inactive Kras protein-GDP, thereby inhibiting Kras pathway activation, and initiating an anti-tumor effect. Therefore, finding and discovering highly effective Kras mutation inhibitors is of great clinical significance.
Disclosure of Invention
The invention aims to provide a compound which has a novel structure and a good inhibitory effect on Kras mutants. Furthermore, the compounds can be used for preparing medicines for treating and/or preventing related diseases mediated by Kras mutants.
The technical scheme of the invention is as follows:
in one aspect, the present invention provides a compound represented by the following general formula (I), a pharmaceutically acceptable salt thereof, or an isomer thereof,
X 1 、X 2 、X 4 、X 5 each independently is selected from CH or N;
X 3 selected from C, CH or N;
L 1 is selected from CH 2 NH, O, S or absent;
X 6 each L 2 Independently selected from-CHR 3 -、-NR 4 -, -O-or-S-;
ring A is selected from 6-10 membered aryl or 5-10 membered heteroaryl optionally substituted with 1-3 of Q1;
each Q1 is independently selected from halogen, hydroxy, mercapto, amino, nitro, cyano, C 1-6 Alkyl radical, C 1-6 Alkylamino radical, di (C) 1-6 Alkyl) amino, halo C 1-6 Alkyl, hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl radical, C 1-6 Alkoxy radical, C 1-6 Alkylthio, halo C 1-6 Alkoxy, halo C 1-6 Alkylthio, hydroxy C 1-6 Alkoxy, hydroxy C 1-6 Alkylthio, amino C 1-6 Alkoxy or amino C 1-6 An alkylthio group;
ring B is selected from 3-10 membered cycloalkyl or 3-10 membered heterocyclyl optionally substituted with 1-3 of Q2;
each Q2 is independently selected from halogen, hydroxy, mercapto, amino, nitro, cyano, C 1-6 Alkyl radical, C 1-6 Alkyl radicalAmino, di (C) 1-6 Alkyl) amino, halo C 1-6 Alkyl, hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl radical, C 1-6 Alkoxy radical, C 1-6 Alkylthio, halogeno C 1-6 Alkoxy, halo C 1-6 Alkylthio, hydroxy C 1-6 Alkoxy, hydroxy C 1-6 Alkylthio, amino C 1-6 Alkoxy or amino C 1-6 An alkylthio group;
ring C is selected from the following structures:
R 1 selected from-CO-CH ═ CHR 5 or-CO-CH 2 CH 2 R 5 ，R 5 Selected from hydrogen, amino, cyano, -CO-NH-C 1-6 Alkyl, -CO-N (C) 1-6 Alkyl radical) 2 、C 1-6 Alkyl radical, C 1-6 Alkylamino radical, di (C) 1-6 Alkyl) amino, halo C 1-6 Alkyl, hydroxy C 1-6 Alkyl or amino C 1-6 An alkyl group;
each R 2 Independently selected from halogen, hydroxyl, sulfydryl, amino, nitro, cyano and C 1-6 Alkyl radical, C 1-6 Alkylamino radical, di (C) 1-6 Alkyl) amino, halo C 1-6 Alkyl, hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl, cyano C 1-6 Alkyl, mercapto C 1-6 Alkyl radical, C 1-6 Alkoxy radical C 1-6 Alkyl or halo C 1-6 Alkoxy radical C 1-6 An alkyl group;
R 3 、R 4 each independently selected from hydrogen, halogen, hydroxyl, sulfhydryl, amino, nitro, cyano and C 1-6 Alkyl, halo C 1-6 Alkyl radical, C 1-6 Alkoxy or halo C 1-6 An alkoxy group;
m and n are independently selected from 0, 1,2 or 3;
dotted- - -means a chemical bond or absent.
In certain embodiments, the ring A is selected from 8-1 optionally substituted with 1-2Q 1A 0-membered fused aryl or 8-10 membered fused heteroaryl; each Q1 is independently selected from halogen, hydroxy, mercapto, amino, nitro, cyano, C 1-6 Alkyl, halo C 1-6 Alkyl radical, C 1-6 Alkoxy radical, C 1-6 Alkylthio, halo C 1-6 Alkoxy or halo C 1-6 An alkylthio group.
In certain embodiments, the ring a is selected from the following optionally substituted with 1-2Q 1:
each Q1 is independently selected from fluoro, chloro, bromo, iodo, hydroxy, amino, nitro, cyano, methyl, ethyl, propyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, 1,1, 1-trifluoroethyl, 1,1, 1-trifluoroisopropyl, methoxy, ethoxy, propoxy, isopropoxy, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, 1,1, 1-trifluoroethoxy, or 1,1, 1-trifluoroisopropoxy.
In certain preferred embodiments, ring a is selected from the following optionally substituted with 1-2Q 1:
each Q1 is independently selected from fluoro, chloro, bromo, iodo, hydroxy, amino, nitro, cyano, methyl, ethyl, trifluoromethyl, methoxy, ethoxy, difluoromethoxy, or trifluoromethoxy.
In certain preferred embodiments, ring a is selected from the following groups optionally substituted with 1-2Q 1:
each Q1 is independently selected from fluoro, chloro, bromo, iodo, hydroxy, amino, nitro, cyano, methyl, ethyl, trifluoromethyl, methoxy, ethoxy, difluoromethoxy, or trifluoromethoxy.
In certain embodiments, ring a is selected from 6-8 membered monocyclic aryl or 5-8 membered monocyclic heteroaryl optionally substituted with 1-2Q 1; each Q1 is independently selected from halogen, hydroxy, mercapto, amino, nitro, cyano, C 1-6 Alkyl, halo C 1-6 Alkyl radical, C 1-6 Alkoxy radical, C 1-6 Alkylthio, halo C 1-6 Alkoxy or halo C 1-6 An alkylthio group.
In certain embodiments, ring a is selected from phenyl or 5-6 membered monocyclic heteroaryl optionally substituted with 1-2Q 1;
each Q1 is independently selected from halogen, hydroxy, mercapto, amino, nitro, cyano, C 1-6 Alkyl, halo C 1-6 Alkyl radical, C 1-6 Alkoxy radical, C 1-6 Alkylthio, halo C 1-6 Alkoxy or halo C 1-6 An alkylthio group.
In certain preferred embodiments, ring a is selected from phenyl or 5-6 membered nitrogen containing monocyclic heteroaryl optionally substituted with 1-2Q 1; each Q1 is independently selected from halogen, hydroxy, mercapto, amino, nitro, cyano, C 1-6 Alkyl, halo C 1-6 Alkyl radical, C 1-6 Alkoxy radical, C 1-6 Alkylthio, halo C 1-6 Alkoxy or halo C 1-6 An alkylthio group.
In certain embodiments, ring a is selected from phenyl, pyrrolyl, thienyl, furyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, optionally substituted with 1-2Q 1;
each Q1 is independently selected from fluoro, chloro, bromo, iodo, hydroxy, amino, nitro, cyano, methyl, ethyl, propyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, 1,1, 1-trifluoroethyl, 1,1, 1-trifluoroisopropyl, methoxy, ethoxy, propoxy, isopropoxy, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, 1,1, 1-trifluoroethoxy, or 1,1, 1-trifluoroisopropoxy.
In certain embodiments, ring a is selected from phenyl, pyridinyl, pyrimidinyl, pyridazinyl, or pyrazinyl optionally substituted with 1-2Q 1;
each Q1 is independently selected from fluoro, chloro, bromo, iodo, hydroxy, amino, nitro, cyano, methyl, ethyl, propyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, 1,1, 1-trifluoroethyl, 1,1, 1-trifluoroisopropyl, methoxy, ethoxy, propoxy, isopropoxy, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, 1,1, 1-trifluoroethoxy, or 1,1, 1-trifluoroisopropoxy.
In certain embodiments, ring B is selected from 3-7 membered monocyclic cycloalkyl or 3-7 membered monocyclic heterocyclyl optionally substituted with 1-2Q 2;
each Q2 is independently selected from halogen, hydroxy, mercapto, amino, nitro, cyano, C 1-6 Alkyl, halo C 1-6 Alkyl radical, C 1-6 Alkoxy radical, C 1-6 Alkylthio, halo C 1-6 Alkoxy or halo C 1-6 An alkylthio group.
In certain embodiments, ring B is selected from 3-7 membered monocyclic saturated cycloalkyl or 3-7 membered monocyclic saturated heterocyclyl optionally substituted with 1-2Q 2.
In certain embodiments, ring B is selected from 5-6 membered monocyclic saturated cycloalkyl or 5-6 membered monocyclic saturated heterocyclyl optionally substituted with 1-2Q 2;
each Q2 is independently selected from halogen, hydroxy, mercapto, amino, nitro, cyano, C 1-6 Alkyl, halo C 1-6 Alkyl radical, C 1-6 Alkoxy radical, C 1-6 Alkylthio, halo C 1-6 Alkoxy or halo C 1-6 An alkylthio group.
In certain preferred embodiments, ring B is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropyloxy, oxetanyl, azetidinyl, tetrahydrofuryl, tetrahydrothienyl, tetrahydropyrrolyl, tetrahydroimidazolyl, tetrahydropyrazolyl, tetrahydrothiazolyl, tetrahydrooxazolyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, or hexahydropyrimidinyl, optionally substituted with 1-2Q 2;
each Q2 is independently selected from fluoro, chloro, bromo, iodo, hydroxy, amino, nitro, cyano, methyl, ethyl, propyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, 1,1, 1-trifluoroethyl, 1,1, 1-trifluoroisopropyl, methoxy, ethoxy, propoxy, isopropoxy, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, 1,1, 1-trifluoroethoxy, or 1,1, 1-trifluoroisopropoxy.
In certain preferred embodiments, ring B is selected from tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyrrolyl, tetrahydroimidazolyl, tetrahydropyrazolyl, tetrahydrothiazolyl, tetrahydrooxazolyl, optionally substituted with 1-2Q 2;
each Q2 is independently selected from fluoro, chloro, bromo, iodo, hydroxy, amino, nitro, cyano, methyl, ethyl, trifluoromethyl, methoxy, ethoxy, monofluoromethoxy, difluoromethoxy, or trifluoromethoxy.
In certain preferred embodiments, ring B is selected from tetrahydropyrrolyl, tetrahydropyrimidinyl, tetrahydropyrazolyl, tetrahydrothiazolyl, tetrahydrooxazolyl, piperidinyl, piperazinyl, morpholinyl, or hexahydropyrimidyl, optionally substituted with 1-2Q 2;
each Q2 is independently selected from fluoro, chloro, bromo, iodo, hydroxy, amino, nitro, cyano, methyl, ethyl, trifluoromethyl, methoxy, ethoxy, monofluoromethoxy, difluoromethoxy, or trifluoromethoxy.
In certain preferred embodiments, ring B is selected from tetrahydropyrrolyl, tetrahydroimidazolyl, tetrahydropyrazolyl, tetrahydrothiazolyl, tetrahydrooxazolyl, optionally substituted with 1-2Q 2;
each Q2 is independently selected from fluoro, chloro, bromo, iodo, hydroxy, amino, nitro, cyano, methyl, ethyl, trifluoromethyl, methoxy, ethoxy, monofluoromethoxy, difluoromethoxy, or trifluoromethoxy.
In certain preferred embodiments, ring C is selected from the following structures:
in certain preferred embodiments, ring C is selected from the following structures:
in certain preferred embodiments, R 1 is-CO-CH ═ CHR 5 ，R 5 Selected from hydrogen, amino, cyano, -CO-NH-CH 3 、-CO-NH-CH 2 -CH 3 、-CO-N(CH 3 ) 2 、-CO-N(CH 2 CH 3 ) 2 Methyl, ethyl, isopropyl, methylamino, dimethylamino, monofluoromethyl, difluoromethyl, trifluoromethyl or aminomethyl.
In certain preferred embodiments, R 1 is-CO-CH ═ CHR 5 ，R 5 Selected from hydrogen, amino, cyano, -CO-NH-CH 3 、-CO-NH-CH 2 -CH 3 、-CO-N(CH 3 ) 2 、-CO-N(CH 2 CH 3 ) 2 Methyl, ethyl, trifluoromethyl or aminomethyl.
In certain preferred embodiments, each R is 2 Independently selected from fluoro, chloro, bromo, iodo, hydroxy, amino, cyano, methyl, ethyl, propyl, isopropyl, trifluoromethyl, trifluoroethyl, hydroxymethyl, 1-hydroxyethyl, 1-hydroxypropyl, aminomethyl, 1-aminoethyl, 1-aminopropyl, cyanomethyl, 1-cyanoethyl, 1-cyanopropyl, 1-cyanoisopropyl, methoxymethyl, methoxyethyl, difluoromethoxymethyl, trifluoromethoxy methyl, difluoromethoxy ethyl or trifluoromethoxyethyl.
In certain preferred embodiments, each R is 2 Independently selected from fluoro, chloro, bromo, iodo, amino, cyano, methyl, ethyl, propyl, isopropyl, trifluoromethyl, trifluoroethyl, aminomethyl, 1-aminoethyl, 1-aminopropyl, cyanomethyl, 1-cyanoethyl, 1-cyanopropyl or 1-cyanoisopropyl.
In certain embodiments, the compound, a pharmaceutically acceptable salt thereof, or an isomer thereof, wherein,
X 1 、X 2 、X 4 、X 5 each independently is selected from CH or N;
X 3 selected from C, CH or N;
L 1 selected from absent;
X 6 is selected from-CH 2 -, -NH-, -O-or-S-;
L 2 is-CH 2 -；
Ring a is selected from the following optionally substituted with 1-2Q 1:
each Q1 is independently selected from fluoro, chloro, bromo, iodo, hydroxy, amino, nitro, cyano, methyl, ethyl, propyl, isopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1,1, 1-trifluoroethyl, 1,1, 1-trifluoroisopropyl, methoxy, ethoxy, propoxy, isopropoxy, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, 1,1, 1-trifluoroethoxy, or 1,1, 1-trifluoroisopropoxy;
ring B is selected from cyclopentyl, cyclohexyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyrrolyl, tetrahydroimidazolyl, tetrahydropyrazolyl, tetrahydrothiazolyl, tetrahydrooxazolyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, or hexahydropyrimidinyl, optionally substituted with 1-2Q 2;
each Q2 is independently selected from fluoro, chloro, bromo, iodo, hydroxy, amino, nitro, cyano, methyl, ethyl, propyl, isopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1,1, 1-trifluoroethyl, 1,1, 1-trifluoroisopropyl, methoxy, ethoxy, propoxy, isopropoxy, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, 1,1, 1-trifluoroethoxy, or 1,1, 1-trifluoroisopropoxy;
ring C is selected from the following structures:
R 1 selected from-CO-CH ═ CHR 5 ，R 5 Selected from hydrogen, amino, cyano、-CO-NH-CH 3 、-CO-NH-CH 2 -CH 3 、 -CO-N(CH 3 ) 2 、-CO-N(CH 2 CH 3 ) 2 Methyl, ethyl, isopropyl, methylamino, dimethylamino, monofluoromethyl, difluoromethyl, trifluoromethyl, or aminomethyl;
each R 2 Independently selected from the group consisting of halogen, hydroxy, mercapto, amino, nitro, cyano, methyl, ethyl, propyl, isopropyl, methylamino, dimethylamino, trifluoromethyl, trifluoroethyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1-hydroxypropyl, 2-hydroxypropyl, 3-hydroxypropyl, 1-hydroxyisopropyl, aminomethyl, 1-aminoethyl, 2-aminoethyl, 1-aminopropyl, 2-aminopropyl, 3-aminopropyl, 1-aminoisopropyl, cyanomethyl, 1-cyanoethyl, 1-cyanopropyl, 1-cyanoisopropyl, methoxymethyl, methoxyethyl, monofluoromethoxymethyl, difluoromethoxymethyl, trifluoromethoxymethyl, monofluoromethoxyethyl, difluoromethoxyethyl or trifluoromethoxyethyl;
m and n are independently selected from 1 or 2;
dotted- - -means a chemical bond or absence.
In certain embodiments, the compound, a pharmaceutically acceptable salt thereof, or an isomer thereof, wherein,
ring a is selected from the following optionally substituted with 1-2Q 1:
each Q1 is independently selected from fluoro, chloro, bromo, iodo, hydroxy, amino, nitro, cyano, methyl, ethyl, propyl, isopropyl, trifluoromethyl, methoxy, ethoxy, propoxy, isopropoxy, monofluoromethoxy, difluoromethoxy, or trifluoromethoxy;
ring B is selected from tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyrrolyl, tetrahydroimidazolyl, tetrahydropyrazolyl, tetrahydrothiazolyl, tetrahydrooxazolyl, tetrahydropyranyl, piperidinyl, piperazinyl, or morpholinyl, optionally substituted with 1-2Q 2;
each Q2 is independently selected from fluoro, chloro, bromo, iodo, hydroxy, amino, nitro, cyano, methyl, ethyl, propyl, isopropyl, trifluoromethyl, methoxy, ethoxy, propoxy, isopropoxy, monofluoromethoxy, difluoromethoxy, or trifluoromethoxy;
ring C is selected from the following structures:
R 1 selected from-CO-CH ═ CHR 5 ，R 5 Selected from hydrogen, amino, cyano, -CO-NH-CH 3 、-CO-NH-CH 2 -CH 3 、 -CO-N(CH 3 ) 2 、-CO-N(CH 2 CH 3 ) 2 Methyl, ethyl, isopropyl, methylamino, dimethylamino, monofluoromethyl, difluoromethyl, trifluoromethyl, or aminomethyl;
each R 2 Independently selected from fluoro, chloro, bromo, iodo, hydroxy, amino, cyano, methyl, ethyl, propyl, isopropyl, trifluoromethyl, trifluoroethyl, hydroxymethyl, 1-hydroxyethyl, 1-hydroxypropyl, aminomethyl, 1-aminoethyl, 1-aminopropyl, cyanomethyl, 1-cyanoethyl, 1-cyanopropyl, 1-cyanoisopropyl, methoxymethyl, methoxyethyl, difluoromethoxymethyl, trifluoromethoxy methyl, difluoromethoxyethyl, or trifluoromethoxy ethyl.
In certain embodiments, the compound, a pharmaceutically acceptable salt thereof, or an isomer thereof, wherein,
X 1 、X 2 、X 4 、X 5 each independently is selected from CH or N;
X 3 selected from C, CH or N; l is 1 Selected from absent;
X 6 is selected from-CH 2 -, -NH-, -O-or-S-; l is 2 is-CH 2 -；
Ring a is selected from phenyl, pyrrolyl, thienyl, furyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, optionally substituted with 1-2Q 1;
each Q1 is independently selected from fluoro, chloro, bromo, iodo, hydroxy, amino, nitro, cyano, methyl, ethyl, propyl, isopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1,1, 1-trifluoroethyl, 1,1, 1-trifluoroisopropyl, methoxy, ethoxy, propoxy, isopropoxy, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, 1,1, 1-trifluoroethoxy, or 1,1, 1-trifluoroisopropoxy;
ring B is selected from cyclopentyl, cyclohexyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyrrolyl, tetrahydroimidazolyl, tetrahydropyrazolyl, tetrahydrothiazolyl, tetrahydrooxazolyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, or hexahydropyrimidinyl, optionally substituted with 1-2Q 2;
each Q2 is independently selected from fluoro, chloro, bromo, iodo, hydroxy, amino, nitro, cyano, methyl, ethyl, propyl, isopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1,1, 1-trifluoroethyl, 1,1, 1-trifluoroisopropyl, methoxy, ethoxy, propoxy, isopropoxy, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, 1,1, 1-trifluoroethoxy, or 1,1, 1-trifluoroisopropoxy;
ring C is selected from the following structures:
R 1 selected from-CO-CH ═ CHR 5 ，R 5 Selected from hydrogen, amino, cyano, -CO-NH-CH 3 、-CO-NH-CH 2 -CH 3 、 -CO-N(CH 3 ) 2 、-CO-N(CH 2 CH 3 ) 2 Methyl, ethyl, isopropyl, methylamino, dimethylamino, monofluoromethyl, difluoromethyl, trifluoromethyl, or aminomethyl;
each R 2 Independently selected from halogen, hydroxy, mercapto, amino, nitro, cyano, methyl, ethyl, propyl, isopropyl, methylamino, dimethylAlkylamino, trifluoromethyl, trifluoroethyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1-hydroxypropyl, 2-hydroxypropyl, 3-hydroxypropyl, 1-hydroxyisopropyl, aminomethyl, 1-aminoethyl, 2-aminoethyl, 1-aminopropyl, 2-aminopropyl, 3-aminopropyl, 1-aminoisopropyl, cyanomethyl, 1-cyanoethyl, 1-cyanopropyl, 1-cyanoisopropyl, methoxymethyl, methoxyethyl, monofluoromethoxymethyl, difluoromethoxymethyl, trifluoromethoxy methyl, fluoromethoxyethyl, difluoromethoxyethyl or trifluoromethoxyethyl;
m and n are independently selected from 1 or 2;
dotted- - -means a chemical bond or absence.
In certain preferred embodiments, ring a is selected from phenyl, pyridyl, pyrimidinyl, pyridazinyl, or pyrazinyl, optionally substituted with 1-2Q 1;
each Q1 is independently selected from fluoro, chloro, bromo, iodo, hydroxy, amino, nitro, cyano, methyl, ethyl, propyl, isopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1,1, 1-trifluoroethyl, 1,1, 1-trifluoroisopropyl, methoxy, ethoxy, propoxy, isopropoxy, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, 1,1, 1-trifluoroethoxy, or 1,1, 1-trifluoroisopropoxy;
ring B is selected from cyclopentyl, cyclohexyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyrrolyl, tetrahydroimidazolyl, tetrahydropyrazolyl, tetrahydrothiazolyl, tetrahydrooxazolyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, or hexahydropyrimidinyl, optionally substituted with 1-2Q 2;
each Q2 is independently selected from fluoro, chloro, bromo, iodo, hydroxy, amino, nitro, cyano, methyl, ethyl, propyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, propoxy, isopropoxy, monofluoromethoxy, difluoromethoxy, or trifluoromethoxy;
ring C is selected from the following structures:
R 1 selected from-CO-CH ═ CH 2 ；
Each R 2 Independently selected from halogen, hydroxy, mercapto, amino, nitro, cyano, methyl, ethyl, propyl, isopropyl, methylamino, dimethylamino, trifluoromethyl, trifluoroethyl, hydroxymethyl, aminomethyl, cyanomethyl, 1-cyanoethyl, methoxymethyl, methoxyethyl, monofluoromethoxymethyl, difluoromethoxymethyl or trifluoromethoxy methyl;
m and n are independently selected from 1 or 2;
dotted- - -means a chemical bond or absence.
The technical solutions of the present invention can be combined with each other to form a new technical solution, and the formed new technical solution is also included in the scope of the present invention.
In certain embodiments, the compound of formula (I), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, is selected from the group consisting of:
in another aspect, the present invention also provides a pharmaceutical composition, which contains the compound described in the aforementioned general formula (I), its pharmaceutically acceptable salt or its isomer, and one or more pharmaceutically acceptable excipients, and the pharmaceutical composition can be in any pharmaceutically acceptable dosage form. Pharmaceutically acceptable excipients are substances which are non-toxic, compatible with the active ingredient and otherwise biologically suitable for use in the organism. The choice of a particular excipient will depend on the mode of administration or disease type and state used to treat a particular patient.
In certain embodiments, the pharmaceutical compositions described above may be administered to a patient or subject in need of such treatment by oral, parenteral, rectal, or pulmonary administration, among others. For oral administration, the pharmaceutical composition can be prepared into oral preparations, for example, conventional oral solid preparations such as tablets, capsules, pills, granules and the like; can also be made into oral liquid preparation, such as oral solution, oral suspension, syrup, etc. When the composition is formulated into oral preparations, appropriate filler, binder, disintegrating agent, lubricant, etc. can be added. For parenteral administration, the pharmaceutical preparations can also be prepared into injections, including injections, sterile powders for injection, and concentrated solutions for injection. The injection can be prepared by conventional method in the existing pharmaceutical field, and can be prepared without adding additives or adding suitable additives according to the properties of the medicine. For rectal administration, the pharmaceutical composition may be formulated as a suppository or the like. For pulmonary administration, the pharmaceutical composition may be formulated as an inhalation formulation, aerosol, powder spray, or the like.
In one aspect, the invention provides a compound shown as a general formula (I), a pharmaceutically acceptable salt thereof or an isomer thereof, and application of the pharmaceutical composition in preparation of a medicament for treating and/or preventing cancer.
In certain embodiments, the cancer is mediated by Kras mutation.
In certain preferred embodiments, the Kras mutation is selected from one or more of Kras G12D, Kras G12S, Kras G12V and Kras G12C.
In certain preferred embodiments, the Kras mutation is Kras G12C.
In certain embodiments, the cancer is selected from lung cancer, colorectal cancer, or pancreatic cancer.
In certain preferred embodiments, the lung cancer is selected from non-small cell lung cancer.
In another aspect, the present invention also provides a method for treating cancer, which comprises administering to a patient in need thereof an effective amount of a compound represented by the aforementioned general formula (I), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, the aforementioned pharmaceutical composition; the cancer is mediated by Kras mutations.
In another aspect, the present invention also provides a method for modulating the activity of Kras mutein comprising reacting Kras mutein with a compound of the general formula (I) as defined above, a pharmaceutically acceptable salt thereof or a stereoisomer thereof, the aforementioned pharmaceutical composition.
In another aspect, the present invention also provides a method of inhibiting proliferation of a cell population, the method comprising contacting a Kras mutein with a compound of formula (I) as set forth above, a pharmaceutically acceptable salt thereof or a stereoisomer thereof, or a pharmaceutical composition as set forth above; inhibition of proliferation of the cell population is measured as a decrease in cell viability of the cell population.
By "effective amount" is meant a dosage of a drug that prevents, alleviates, retards, inhibits or cures a condition in a subject. The size of the administered dose is determined by the drug administration mode, the pharmacokinetics of the agent, the severity of the disease, the individual signs of the subject (sex, weight, height, age), and the like.
In the present invention, unless otherwise defined, scientific and technical terms used herein have meanings commonly understood by those skilled in the art, however, in order to better understand the present invention, definitions of some terms are provided below. To the extent that the definitions and explanations of terms provided herein do not conform to the meanings commonly understood by those skilled in the art, the definitions and explanations of terms provided herein shall control.
The "halogen" as referred to herein means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
"C" according to the invention 1-6 Alkyl "denotes straight or branched alkyl having 1 to 6 carbon atoms, including for example" C 1-4 Alkyl group "," C 1-3 Alkyl group "," C 1-2 Alkyl group "," C 2-6 Alkyl group "," C 2-5 Alkyl group "," C 2-4 Alkyl group "," C 2-3 Alkyl radical”、“C 3-6 Alkyl group "," C 3-5 Alkyl group "," C 3-4 Alkyl "and the like, specific examples include, but are not limited to: methyl, ethyl, n-propyl (propyl), isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, n-hexyl, isohexyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3-dimethylbutyl, 2-dimethylbutyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 1, 2-dimethylpropyl, and the like. "C" according to the invention 1-4 Alkyl "means C 1-6 Specific examples of the alkyl group having 1 to 4 carbon atoms.
"C" according to the invention 1-6 Alkoxy "means" C 1-6 alkyl-O- ", said" C 1-6 Alkyl "is as defined above. "C" according to the invention 1-4 Alkoxy "means" C 1-4 alkyl-O- ", said" C 1-4 Alkyl "is as defined above.
"C" according to the invention 1-6 Alkylthio "means" C 1-6 alkyl-S- ", said" C 1-6 Alkyl "is as defined above. "C" according to the invention 1-4 Alkylthio "means" C 1-4 alkyl-S- ", said" C 1-4 Alkyl "is as defined above.
The "hydroxy group C" of the present invention 1-6 Alkyl, amino C 1-6 Alkyl, halo C 1-6 Alkyl "means C 1-6 One or more hydrogens of the alkyl group are each replaced by one or more hydroxyl groups, amino groups or halogens. C 1-6 Alkyl is as previously defined
The "hydroxy group C" of the present invention 1-6 Alkoxy, amino C 1-6 Alkoxy, halo C 1-6 Alkoxy "means" C 1-6 One or more hydrogens of "alkoxy" are replaced with one or more hydroxy, amino, or halogen.
The "hydroxyl group C" of the present invention 1-6 Alkylthio, amino C 1-6 Alkylthio, halo C 1-6 Alkylthio "means" C 1-6 Alkylthio "is one in which one or more hydrogens are replaced with one or more hydroxy, amino, or halogen.
"C" according to the invention 1-6 Alkylamino radical, di (C) 1-6 Alkyl) amino "means independently C 1-6 alkyl-NH-),
"C" according to the invention 1-6 Alkoxy radical C 1-6 Alkyl "means" C 1-6 alkyl-O-C 1-6 Alkyl radical', said "C 1-6 Alkyl "is as defined above.
The "halo C" of the present invention 1-6 Alkoxy radical C 1-6 Alkyl "means" halo C 1-6 alkyl-O-C 1-6 Alkyl group ", said" halogeno C 1-6 Alkyl group "," C 1-6 Alkyl "is as defined above.
The "6-to 10-membered aryl" as referred to in the present invention includes "6-to 8-membered monocyclic aryl" and "8-to 10-membered fused ring aryl".
The "6-to 8-membered monocyclic aryl" as referred to herein means a monocyclic aryl group containing 6 to 8 ring carbon atoms, examples of which include, but are not limited to: phenyl, cyclooctatetraenyl, and the like; phenyl is preferred.
The "8-to 10-membered fused ring aryl" as referred to herein means an unsaturated aromatic cyclic group having 8 to 10 ring carbon atoms, formed by two or more cyclic structures sharing two adjacent atoms with each other, and is preferably a "9-to 10-membered fused ring aryl", and specific examples thereof are naphthyl and the like.
The "5-to 10-membered heteroaryl" as used herein includes "5-to 8-membered monocyclic heteroaryl" and "8-to 10-membered fused heteroaryl".
The "5-to 8-membered monocyclic heteroaryl group" according to the present invention means a monocyclic cyclic group having aromaticity, which contains 5 to 8 ring atoms, at least one of which is a heteroatom such as nitrogen atom, oxygen atom or sulfur atom. Optionally, a ring atom (e.g., a carbon atom, a nitrogen atom, or a sulfur atom) in the cyclic structure may be oxo. "5-to 8-membered monocyclic heteroaryl" includes, for example, "5-to 7-membered monocyclic heteroaryl", "5-to 6-membered nitrogen-containing monocyclic heteroaryl", "6-membered nitrogen-containing monocyclic heteroaryl", and the like, in which the heteroatom contains at least one nitrogen atom, for example, contains only 1 or 2 nitrogen atoms, or contains one nitrogen atom and 1 or 2 other heteroatoms (for example, oxygen atom and/or sulfur atom), or contains 2 nitrogen atoms and 1 or 2 other heteroatoms (for example, oxygen atom and/or sulfur atom). Specific examples of "5-to 8-membered monocyclic heteroaryl" include, but are not limited to, furyl, thienyl, pyrrolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, imidazolyl, pyrazolyl, 1,2, 3-triazolyl, 1,2, 4-triazolyl, 1,2, 3-oxadiazolyl, 1,2, 4-oxadiazolyl, 1,2, 5-oxadiazolyl, 1,3, 4-oxadiazolyl, pyridyl, 2-pyridonyl, 4-pyridonyl, pyrimidinyl, pyridazinyl, pyrazinyl, 1,2, 3-triazinyl, 1,3, 5-triazinyl, 1,2,4, 5-tetrazinyl, azepinyl, 1, 3-diazacycloheptenyl, azacyclooctatetraenyl, and the like. The "5-6 membered monocyclic heteroaryl" refers to a specific example containing 5 to 6 ring atoms in a 5-8 membered heteroaryl.
The "8-to 10-membered fused heteroaryl group" as used herein refers to an unsaturated aromatic cyclic structure having 8 to 10 ring atoms (at least one of which is a heteroatom such as nitrogen atom, oxygen atom or sulfur atom) formed by two or more cyclic structures sharing two adjacent atoms with each other. Optionally, a ring atom (e.g., a carbon atom, a nitrogen atom, or a sulfur atom) in the cyclic structure may be oxo. Including "9-to 10-membered thick heteroaryl", "8-to 9-membered thick heteroaryl", "9-to 10-membered thick heteroaryl containing 1 to 2 heteroatoms selected from nitrogen, oxygen or sulfur", etc., which may be fused in a benzo-5-to 6-membered heteroaryl, 5-to 6-membered heteroaryl and 5-to 6-membered heteroaryl, etc.; specific examples include, but are not limited to: pyrrolopyrrole, pyrrolofuran, pyrazolopyrrole, pyrazolothiophene, furothiophene, pyrazoloxazole, benzofuranyl, benzisofuranyl, benzothiophenyl, indolyl, isoindolyl, benzoxazolyl, benzimidazolyl, indazolyl, benzotriazolyl, quinolinyl, 2-quinolinonyl, 4-quinolinonyl, 1-isoquinolinyl, acridinyl, phenanthridinyl, pyridazinyl, phthalazinyl, quinazolinyl, quinoxalinyl, purinyl, naphthyridinyl, and the like.
The "3-to 10-membered cycloalkyl" described herein includes "3-to 7-membered monocyclic cycloalkyl" and "8-to 10-membered fused ring cycloalkyl".
The "3-7 membered monocyclic cycloalkyl group" as referred to herein means a saturated or partially saturated monocyclic cyclic group having 3 to 7 ring atoms and having no aromaticity, and examples thereof include, but are not limited to: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cyclohexene, etc.
The "8-to 10-membered fused ring cycloalkyl" as referred to herein means a saturated or partially saturated, nonaromatic cyclic group containing 8 to 10 ring atoms formed by two or more cyclic structures sharing two adjacent atoms with each other, and examples thereof include, but are not limited to:
and the like.
The "3-to 10-membered heterocyclic group" described in the present invention includes "3-to 7-membered heteromonocyclic group" and "8-to 10-membered fused heterocyclic group".
The "3-to 7-membered heterocyclic group" as used herein means a saturated or partially saturated and non-aromatic monocyclic cyclic group containing at least one hetero atom (e.g., 1,2,3, 4 or 5) which is a nitrogen atom, an oxygen atom and/or a sulfur atom, and having 3 to 7 ring atoms, and optionally, a ring atom (e.g., a carbon atom, a nitrogen atom or a sulfur atom) in the cyclic structure may be oxo. The "3-7 membered heteromonocyclic group" described herein includes "3-7 membered saturated heteromonocyclic group" and "3-7 membered partially saturated heteromonocyclic group". Preferably, the "3-7 membered heteromonocyclic group" described herein contains 1-3 heteroatoms; preferably, the "3-7 membered heteromonocyclic group" of the present invention contains 1 to 2 heteroatoms selected from nitrogen atom and/or oxygen atom; preferably, the "3-7 membered heteromonocyclic group" described herein contains 1 nitrogen atom. The "3-to 7-membered heteromonocyclic group" is preferably "3-to 6-membered heteromonocyclic group", "4-to 7-membered heteromonocyclic group", "4-to 6-membered heteromonocyclic group", "6-to 8-membered heteromonocyclic group", "5-to 7-membered heteromonocyclic group", "5-to 6-membered heteromonocyclic group", "3-to 6-membered saturated heteromonocyclic group", "3-to 6-membered nitrogen-containing heteromonocyclic group", "3-to 6-membered saturated nitrogen-containing heteromonocyclic group", "5-to 6-membered saturated nitrogen-containing heteromonocyclic group", etc. For example, containing only 1 or 2 nitrogen atoms, or, alternatively, containing one nitrogen atom and 1 or 2 other heteroatoms (e.g., oxygen and/or sulfur atoms). Specific examples of "3-7 membered heteromonocyclic group" include, but are not limited to: aziridinyl, 2H-aziridinyl, diazacyclopropenyl, 3H-diazacyclopropenyl, azetidinyl, 1, 4-dioxanyl, 1, 3-dioxolanyl, 1, 4-dioxadienyl, tetrahydrofuryl, dihydropyrrolyl, pyrrolidinyl, imidazolidinyl, 4, 5-dihydroimidazolyl, pyrazolidinyl, 4, 5-dihydropyrazolyl, 2, 5-dihydrothienyl, tetrahydrothienyl, 4, 5-dihydrothiazolyl, thiazolidinyl, piperidinyl, tetrahydropyridinyl, piperidonyl, piperazinyl, morpholinyl, 4, 5-dihydrooxazolyl, 4, 5-dihydroisoxazolyl, 2, 3-dihydroisoxazolyl, 3H-diazacyclopropenyl, imidazolidinyl, 4, 5-dihydroimidazolyl, pyrazolidinyl, 4, 5-dihydrothiazolyl, thiazolidinyl, piperidyl, piperidonyl, tetrahydropyridinyl, piperidyl, piperazinyl, morpholinyl, 4, 5-dihydroisoxazolyl, 2, 3-dihydroisoxazolyl, and the like, Oxazolidinyl, 2H-1, 2-oxazinyl, 4H-1, 2-oxazinyl, 6H-1, 2-oxazinyl, 4H-1, 3-oxazinyl, 6H-1, 3-oxazinyl, 4H-1, 4-oxazinyl, 4H-1, 3-thiazinyl, 6H-1, 3-thiazinyl, 2H-pyranyl, 2H-pyran-2-onyl, 3, 4-dihydro-2H-pyranyl and the like.
The "8-to 10-membered fused heterocyclic group" of the present invention refers to a saturated or partially saturated, nonaromatic cyclic group containing 8 to 10 ring atoms, wherein at least one ring atom is a heteroatom, which may be an aromatic ring, but the fused ring as a whole does not have aromaticity, formed by two or more cyclic structures sharing two adjacent atoms with each other, and the heteroatom is a nitrogen atom, an oxygen atom and/or a sulfur atom, optionally, a ring atom (e.g., a carbon atom, a nitrogen atom or a sulfur atom) in the cyclic structure may be oxo, and includes, but is not limited to, "8-to 9-membered fused heterocyclic group", "9-to 10-membered fused heterocyclic group", and the like; specific examples of the "8-to 10-membered fused heterocyclic group" include, but are not limited to: pyrrolidinyl-cyclopropyl, cyclopenta-cyclopropyl, pyrrolidinyl-cyclobutyl, pyrrolidinyl-piperidinyl, pyrrolidinyl-piperazinyl, pyrrolidinyl-morpholinyl, piperidinyl-morpholinyl, benzopyrrolidinyl, benzocyclopentyl, benzocyclohexyl, benzotetrahydrofuranyl, benzopyrrolidinyl, pyrimido-tetrahydropyranyl; tetrahydroimidazo [4,5-c ] pyridyl, 3, 4-dihydroquinazolinyl, 1, 2-dihydroquinoxalinyl, benzo [ d ] [1,3] dioxolyl, 2H-chromenyl, 2H-chromen-2-one, 4H-chromenyl, 4H-chromen-4-one, 4H-1, 3-benzoxazinyl, 4, 6-dihydro-1H-furo [3,4-d ] imidazolyl, 3a,4,6,6 a-tetrahydro-1H-furo [3,4-d ] imidazolyl, 4, 6-dihydro-1H-thieno [3,4-d ] imidazolyl, 4, 6-dihydro-1H-pyrrolo [3,4-d ] imidazolyl, octahydro-benzo [ d ] imidazolyl, decahydroquinolinyl, hexahydrothienoimidazolyl, hexahydrofuroimidazolyl, 4,5,6, 7-tetrahydro-1H-benzo [ d ] imidazolyl, octahydro cyclopenta [ c ] pyrrolyl, 4H-1, 3-benzoxazinyl and the like.
The expression "carbon atom, nitrogen atom or sulfur atom is oxo" as used herein means that C-O, N-O, S-O or SO is formed 2 The structure of (1).
The term "optionally substituted" as used herein means both the case where one or more hydrogen atoms on a substituent may be "substituted" or "unsubstituted" by one or more substituents.
In the chemical structure, when the bond to the chiral carbon atom is
Or "-" means that the compound is a mixture containing all possible isomers, the different isomers of which may be present in any ratio.
"pharmaceutically acceptable salt" as used herein refers to an acidic functional group (e.g., -COOH, -OH, -SO) present in a compound 3 H, etc.) with a suitable inorganic or organic cation (base), including salts with alkali or alkaline earth metals, ammonium salts, and salts with nitrogen-containing organic bases; and basic functional groups present in the compound (e.g. -NH) 2 Etc.) with suitable inorganic materialsOr salts with organic anions (acids), including salts with inorganic or organic acids (e.g., carboxylic acids, etc.).
"isomers" as used herein refers to compounds of the present invention when they contain one or more asymmetric centers and thus may be present as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. The compounds of the present invention may have asymmetric centers that each independently produce two optical isomers. The scope of the present invention includes all possible optical isomers and mixtures thereof. The compounds of the present invention, if they contain an olefinic double bond, include cis-isomers and trans-isomers, unless otherwise specified. The compounds of the invention may exist in tautomeric (one of the functional group isomers) forms having different points of attachment of hydrogen through one or more double bond shifts, e.g., a ketone and its enol form are keto-enol tautomers. The compounds of the present invention contain a spiro ring structure, and substituents on the ring may be present on both sides of the ring to form the opposite cis (cis) and trans (trans) isomers, depending on the steric structure of the ring. Each tautomer and mixtures thereof are included within the scope of the present invention. All enantiomers, diastereomers, racemates, meso, cis-trans isomers, tautomers, geometric isomers, epimers, mixtures thereof and the like of the compounds are included within the scope of the present invention.
The compounds of the invention may be prepared by enantiospecific synthesis or by resolution from a mixture of enantiomers in such a way as to give the individual enantiomers. Conventional resolution techniques include resolving mixtures of enantiomers of the starting material or the final product using various well-known chromatographic methods.
When the stereochemistry of the disclosed compounds is named or depicted by structure, the named or depicted stereoisomer is at least 60%, 70%, 80%, 90%, 99% or 99.9% pure by weight relative to the other stereoisomers. When a single isomer is named or depicted by structure, the depicted or named enantiomer is at least 60%, 70%, 80%, 90%, 99%, or 99.9% pure by weight. The optical purity wt% is the ratio of the weight of an enantiomer to the weight of the enantiomer plus the weight of its optical isomer.
In another aspect, the present invention also provides a process for the preparation of a compound of the invention:
a process for the preparation of a compound of formula (I):
wherein X, X 'and X' are independently selected from F, Cl, Br and I; y is selected from boric acid, borate ester, -NH 2 OH or SH; corresponding to X 1 -X 6 、R 1 -R 2 Ring A, ring B, ring C, L 1 、L 2 M, n are as defined above.
Reacting the intermediate 1 and the intermediate 2 under alkaline conditions to generate an intermediate 3;
the intermediate 3 and the intermediate 4 react under the action of an alkaline condition and a palladium catalyst to generate an intermediate 5; or the intermediate 3 and the intermediate 4 react under the alkaline condition and the action of a palladium catalyst and a ligand to generate an intermediate 5;
removing a protecting group of the intermediate 5 under an acidic condition to generate an intermediate 6;
and reacting the intermediate 6 with the intermediate 7 under basic conditions to generate the compound shown in the formula (I).
In the above preparation method, all reactions can be performed in a conventional solvent, including but not limited to DMSO, DMF, acetonitrile, methanol, tetrahydrofuran, toluene, dimethyl ether, dichloromethane, chloroform, 1, 4-dioxane, trifluoroacetic acid, water, etc., and a single organic solvent or a mixed solvent of two or more solvents can be used in the reaction process. Alternatively, if a certain reactant is a liquid, the reaction may be carried out in the absence of another solvent.
The alkaline condition refers to the condition containing organic base or inorganic base, the organic base includes but is not limited to pyridine, triethylamine, N-dimethylaniline, sodium methoxide, potassium ethoxide, potassium tert-butoxide, sodium tert-butoxide, potassium acetate, N-diisopropylethylamine and the like; preferred inorganic bases include, but are not limited to, potassium carbonate, sodium carbonate, cesium carbonate, sodium hydride, potassium hydroxide, sodium hydroxide, lithium hydroxide, potassium acetate, sodium acetate, potassium phosphate, sodium phosphate, and the like.
The acidic condition refers to a condition containing organic acid or inorganic acid, and the organic acid includes but is not limited to formic acid, acetic acid, trifluoroacetic acid, propionic acid, benzoic acid, methanesulfonic acid, p-toluenesulfonic acid, tartaric acid and the like; inorganic acids include, but are not limited to, hydrochloric acid, concentrated sulfuric acid, hydrobromic acid, hydrofluoric acid, nitric acid, nitrous acid, boric acid, and the like.
Such palladium catalysts include, but are not limited to: pd (PPh) 3 ) 4 、PdCl 2 (PPh 3 ) 2 、PdCl 2 (MeCN) 2 、Pd(dppf) Cl 2 、Pd 2 (dba) 3 Palladium chloride, palladium acetate, palladium triphenylphosphine, and the like.
Such ligands include, but are not limited to: ph 2 P(CH 2 ) 2 PPh 2 (dppe)、Ph 2 P(CH 2 ) 3 PPh 2 (dppp), 2-dicyclohexylphosphine-2 ',6' -dimethoxybiphenyl, and the like.
In the present invention, the compounds and intermediates of the present invention can be isolated and purified using methods well known to those skilled in the art of organic synthesis. Examples of conventional methods for isolating and purifying compounds may include, but are not limited to: chromatography on a solid support (e.g., silica gel, alumina or silica derivatized with alkylsilanes), thin layer chromatography, distillation at various pressures, vacuum sublimation, trituration, for example, as described below: "Vogel's Textbook of Practical Organic Chemistry",5th edition (1989), Furniss et al, pub. Longman Scientific & Technical, Essex CM 202 JE, England.
It is understood that the chemical reaction, if involving reactive groups such as-NH-which need not participate in the reaction 2 The reactive groups-OH, -COOH, etc., can be protected by methods known to those skilled in the art, including but not limited to ester, amide, etc., followed by further reaction,Alkylamines, ethers, and the like. Common methods of carboxyl protection include, but are not limited to, ester formation with aliphatic or aromatic alcohols, amide or hydrazide formation with amines or hydrazines. Common amino protecting groups include, but are not limited to: (1) an alkoxycarbonyl amino-protecting group such as benzyloxycarbonyl (Cbz), tert-butoxycarbonyl (Boc), fluorenyl methoxycarbonyl (Fmoc), allyloxycarbonyl (Alloc), trimethylsilethoxycarbonyl (Teoc), etc.; (2) acyl amino groups such as phthaloyl (Pht), p-toluenesulfonyl (Tos), trifluoroacetyl (Tfa), o- (p) nitrobenzenesulfonyl (Ns), pivaloyl and the like; (3) alkyl amino-protecting groups, trityl (Trt), 2, 4-dimethoxybenzyl (Dmb), p-methoxybenzyl (PMB), benzyl (Bn), and the like. Common hydroxyl protecting groups include, but are not limited to, silyl ether protecting groups, benzyl ether protecting groups, alkoxymethyl ethers or alkoxy-substituted methyl ethers, acetyl, benzoyl, pivaloyl and the like. After the reaction, the protecting group can be deprotected by a method known to those skilled in the art, and the deprotection conditions include, but are not limited to, deprotection under acidic conditions, deprotection under basic conditions, hydrogenation deprotection, and the like.
The raw materials and/or intermediates directly used in the preparation method of the present invention can be commercially or self-prepared, and the intermediate can be obtained by a person skilled in the art according to a known conventional chemical reaction preparation method, and the preparation method thereof is also within the protection scope of the present invention.
Advantageous effects of the invention
1. The compound, the pharmaceutically acceptable salt or the isomer thereof has excellent Kras mutant inhibition effect, good pharmacokinetic property in organisms, lasting effect and high bioavailability.
2. The compound, the pharmaceutically acceptable salt thereof or the isomer thereof has better therapeutic effect on benign tumors and cancers.
3. The compound of the invention has simple preparation process, high medicine purity, stable quality and easy large-scale industrial production.
Detailed description of the preferred embodiments
The present invention will be described in further detail with reference to the following embodiments, but it should not be construed that the scope of the above subject matter is limited to the following. All the technologies realized based on the above contents of the present invention belong to the scope of the present invention.
Abbreviations:
DIEA is N, N-diisopropylethylamine; pd 2 (dba) 3 Tris (dibenzylideneacetone) dipalladium (0); TFA is trifluoroacetic acid; boc 2 O: di-tert-butyl dicarbonate; tf 2 O is trifluoromethanesulfonic anhydride; pd (dppf) Cl 2 :1, 1' -bis (diphenylphosphino) ferrocene]Palladium dichloride
The first embodiment is as follows: preparation of 2- (1-acryloyl-4- (6- (8-methylnaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) thieno [3,2-d ] pyrimidin-4-yl) piperazin-2-yl) acetonitrile (Compound 3)
Preparation of 4,4,5, 5-tetramethyl-2- (8-methylnaphthalen-1-yl) -1,3, 2-dioxaborane
1-bromo-8-methylnaphthalene (660.0mg,3.0mmol) was dissolved in dioxane (20.0mL), and pinacol diboron (914.4g,3.6mmol), Pd (PPh) were added 3 ) 2 Cl 2 (63.0mg, 0.09mmol) and potassium acetate (882.0mg,9.0mmol), the system was reacted at 90 ℃ for 3 hours under nitrogen, after completion of the reaction, concentrated, and purified by column chromatography (petroleum ether: ethyl acetate 50:1) to obtain a product (420.0mg, yield: 52.2%).
Preparation of 2- (4- (2, 6-dichlorothieno [3,2-d ] pyrimidin-4-yl) piperazin-2-yl) acetonitrile
2,4, 6-Trichlorothieno [3,2-d ] pyrimidine (2.3g,9.6mmol), 2- (piperazin-2-yl) acetonitrile (1.9g,9.6mmol) and DIEA (5.0g,38.7mmol) were dissolved in dioxane (100.0mL) and reacted at 50 ℃ for 5 hours, after which the reaction was completed, and the next reaction was carried out directly.
3. Preparation of tert-butyl 2- (cyanomethyl) -4- (2, 6-dichlorothieno [3,2-d ] pyrimidin-4-yl) piperazine-1-carboxylate
Adding Boc into the reaction liquid obtained in the last step 2 O (4.2g,19.2mmol), reacted at 50 ℃ for 2 hours, after completion of the reaction, concentrated and purified by column chromatography (petroleum ether: ethyl acetate ═ 3:1) to give a compound (2.0g, two-step yield: 48.6%).
4. Preparation of tert-butyl 4- (6-chloro-2- (((S) -1-methylpyrrolidin-2-yl) methoxy) thieno [3,2-d ] pyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate
(S) - (1-Methylpyrrolidin-2-yl) methanol (1.6g,13.9mmol) was dissolved in THF (50.0mL), NaH (60%, 752.0mg,18.8mmol) was added at 0 deg.C, and after the addition was completed, the reaction was carried out at 20 deg.C for 10 hours, followed by addition of tert-butyl 2- (cyanomethyl) -4- (2, 6-dichlorothieno [3,2-d ] pyrimidin-4-yl) piperazine-1-carboxylate (2.0g,4.7mmol) and reaction at 60 deg.C for 10 hours. After the reaction was completed, the pH was adjusted to 7 to 8, followed by spin-drying and column chromatography (dichloromethane: methanol 15:1) to obtain the product (720.0mg, yield: 30.2%).
5. Preparation of tert-butyl 2- (cyanomethyl) -4- (6- (8-methylnaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) thieno [3,2-d ] pyrimidin-4-yl) piperazine-1-carboxylate
Tert-butyl 4- (6-chloro-2- (((S) -1-methylpyrrolidin-2-yl) methoxy) thieno [3,2-d]Pyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate (550.0mg,1.08mmol) was dissolved in dioxane (50.0mL) and water (5.0mL), and 4,4,5, 5-tetramethyl-2- (8-methylnaphthalen-1-yl) -1,3, 2-dioxaborane (290.0mg,1.08mmol), 2-dicyclohexylphosphine-2-carboxylate (',6' -Dimethoxybiphenyl (4.5mg,0.011mmol), Pd (OAc) 2 (1.5mg,0.011mmol) and K 3 PO 4 (1.5g, 4.0mmol)。N 2 The reaction was carried out at 110 ℃ for 15 hours under protection, filtered, spin-dried, and purified by column chromatography (dichloromethane: methanol: triethylamine: 20:1: 1%) to obtain a product (230.0mg, yield: 34.7%).
Preparation of 2- (4- (6- (8-methylnaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) thieno [3,2-d ] pyrimidin-4-yl) piperazin-2-yl) acetonitrile
Tert-butyl 2- (cyanomethyl) -4- (6- (8-methylnaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) thieno [3,2-d ] pyrimidin-4-yl) piperazine-1-carboxylate (177.0mg,0.29mmol) was dissolved in dichloromethane (20.0mL), trifluoroacetic acid (7.0mL) was added, reacted at 18 ℃ for 3 hours, spun dry, and the residue was used directly in the next step.
Preparation of 2- (1-acryloyl-4- (6- (8-methylnaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) thieno [3,2-d ] pyrimidin-4-yl) piperazin-2-yl) acetonitrile
The crude product (0.29mmol) obtained above was dissolved in dichloromethane (3mL), triethylamine (50.6mg) and acryloyl chloride (5.4 mg,0.06mmol) were added, reacted at 20 ℃ for 30 minutes, spin-dried, purified by column chromatography (dichloromethane: methanol ═ 20:1) to give a crude product (220.0mg), and purified by high pressure reverse phase preparation (water: acetonitrile ═ 1:1) to give a pure product (6.5mg, yield: 3.9%).
Molecular formula C 32 H 34 N 6 O 2 Molecular weight of S566.7 LC-MS (M/e):567.0(M + H) + )
1 H-NMR(400MHz,MeOD)δ:8.03-8.00(m,J＝9.6Hz,1H),7.85(d,J＝8.0Hz,1H), 7.56-7.46(m,2H),7.46-4.42(m,1H)7.36(d,J＝5.6Hz,1H),7.17(s,1H),6.31(d,J＝4.0Hz, 1H),5.85(d,J＝16Hz,1H),5.02(d,J＝64Hz,2H),4.85(s,2H),4.62-2.72(m,2H),3.91(s, 1H),3.75(s,3H),3.31(s,1H),3.15(s,3H),2.90(d,J＝80Hz,2H),2.45-2.39(m,1H),2.32 (s,3H),2.30-2.20(m,1H),2.20-2.01(m,2H)。
Example two: preparation of 2- (1-acryloyl-4- (6- (2-fluoro-6-isopropylphenyl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) thieno [3,2-d ] pyrimidin-4-yl) piperazin-2-yl) acetonitrile (Compound 7)
1. Preparation of tert-butyl 2- (cyanomethyl) -4- (6- (2-fluoro-6-hydroxyphenyl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) thieno [3,2-d ] pyrimidin-4-yl) piperazine-1-carboxylate
Tert-butyl 4- (6-bromo-2- (((S) -1-methylpyrrolidin-2-yl) methoxy) thieno [3,2-d]Pyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate (230mg,0.42mmol), 2-fluoro-6-hydroxyphenylboronic acid (97.8mg,0.63mmol), Pd (dppf) Cl 2 (30.7mg, 42. mu. mol), potassium acetate (82.3mg,0.84mmol) dissolved in 1, 4-dioxane (10mL) and water (1mL), after addition, N 2 And reacting for 3h at the temperature of 95 ℃ under protection. The solvent was concentrated, and the mixture was purified with a silica gel column (dichloromethane: methanol ═ 10:1) to obtain the objective compound (120mg, yield: 49.3%).
2. Preparation of tert-butyl 2- (cyanomethyl) -4- (6- (2-fluoro-6- (((trifluoromethyl) sulfonyl) oxy) phenyl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) thieno [3,2-d ] pyrimidin-4-yl) piperazine-1-carboxylate
Reacting tert-butyl 2- (cyanomethyl) -4- (6- (2-fluoro-6-hydroxyphenyl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) thieno [3,2-d]Pyrimidin-4-yl) piperazine-1-carboxylate (120mg,0.21mmol) in dichloromethane (10mL) was added pyridine (49.8mg,0.63mmol) and Tf was added at 20 ℃ 2 O (116.3mg,0.42mmol), after addition, the reaction was carried out at-20 ℃ for 2 h. Quenching with water, extracting with DCM, and dissolving the organic phase with citric acidThe solution was washed, dried and concentrated to give the title compound (140mg, yield: 95.1%).
3. Preparation of tert-butyl 2- (cyanomethyl) -4- (6- (2-fluoro-6- (prop-1-en-2-yl) phenyl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) thieno [3,2-d ] pyrimidin-4-yl) piperazine-1-carboxylate
Reacting tert-butyl 2- (cyanomethyl) -4- (6- (2-fluoro-6- (((trifluoromethyl) sulfonyl) oxy) phenyl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) thieno [3,2-d]Pyrimidin-4-yl) piperazine-1-carboxylate (130mg,0.18mmol), isopropenylboronic acid pinacol ester (45.9mg,0.27mmol), Pd (dppf) Cl 2 (13.2mg,18.0μmol)，Na 2 CO 3 (38.2mg, 0.36mmol) was dissolved in water (1mL) and 1, 4-dioxane (10mL), N 2 And reacting for 2 hours at the temperature of 100 ℃ under protection. Quenched with water, extracted with ethyl acetate, and purified on a large plate (dichloromethane: methanol 10:1) to give the title compound (60mg, yield: 54.5%).
4. Preparation of tert-butyl 2- (cyanomethyl) -4- (6- (2-fluoro-6-isopropylphenyl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) thieno [3,2-d ] pyrimidin-4-yl) piperazine-1-carboxylate
Tert-butyl 2- (cyanomethyl) -4- (6- (2-fluoro-6- (prop-1-en-2-yl) phenyl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) thieno [3,2-d ] pyrimidin-4-yl) piperazine-1-carboxylate (60mg,0.1mmol) was dissolved in methanol (15mL), Pd/C (30mg) was added, and hydrogenation was completed at 25 ℃ for 12 h. Filtration through celite, and concentration of the solvent gave the title compound (60mg, yield: 99.7%).
Preparation of 2- (4- (6- (2-fluoro-6-isopropylphenyl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) thieno [3,2-d ] pyrimidin-4-yl) piperazin-2-yl) acetonitrile
Tert-butyl 2- (cyanomethyl) -4- (6- (2-fluoro-6-isopropylphenyl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) thieno [3,2-d ] pyrimidin-4-yl) piperazine-1-carboxylate (60mg,0.1mmol) was dissolved in dichloromethane (10mL) and added TFA (4mL) to react at 25 ℃ for 1 h. The concentrated solvent was used directly in the next step.
Preparation of 2- (1-acryloyl-4- (6- (2-fluoro-6-isopropylphenyl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) thieno [3,2-d ] pyrimidin-4-yl) piperazin-2-yl) acetonitrile
2- (4- (6- (2-fluoro-6-isopropylphenyl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) thieno [3,2-d ] pyrimidin-4-yl) piperazin-2-yl) acetonitrile (crude from the previous step, 0.1mmol) was dissolved in dichloromethane (5mL), DIEA (25.8mg, 0.2mmol) and acryloyl chloride (14.3mg,0.15mmol) were added and the reaction was carried out at 25 ℃ for 2 h. The solvent was concentrated and preparative-HPLC purification (acetonitrile ═ 0% to 40%) gave the title compound (9mg, two-step yield: 16.2%).
Molecular formula C 30 H 35 FN 6 O 2 Molecular weight of S562.7 LC-MS (M/e):563.3(M + H) + )
1 H-NMR(400MHz,CDCl 3 )δ:7.41-7.46(m,1H),7.21-7.24(m,2H),7.02(t,J＝8.0 Hz,1H),7.00-7.04(m,1H),6.42(d,J＝16.8Hz,1H),5.86(d,J＝10.0Hz,1H),4.2-5.2(m,4H), 3.51-3.77(m,4H),3.03-3.06(m,1H),2.74-2.95(m,4H),1.91-2.45(m,2H),1.60(s,3H),1.31- 1.38(m,4H),1.21(d,J＝6.8Hz 6H)
Example three: preparation of 2- (1-acryloyl-4- (6- (2-fluoro-6-hydroxyphenyl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) thieno [3,2-d ] pyrimidin-4-yl) piperazin-2-yl) acetonitrile (Compound 8)
1. Preparation of tert-butyl 2- (cyanomethyl) -4- (6- (2-fluoro-6-methoxyphenyl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) thieno [3,2-d ] pyrimidin-4-yl) piperazine-1-carboxylate
Reacting tert-butyl 4- (6-chloro-2- (((S) -1-methylpyrrolidin-2-yl) methoxy) thieno [3,2-d]Pyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate (300mg,0.59mmol), (2-fluoro-6-methoxyphenyl) boronic acid (401mg, 2.36mmol) was dissolved in 1.4-dioxane (30mL) and Pd (dppf) Cl was added 2 (87.8mg,0.12mmol), potassium acetate (232mg,2.36mmol), H 2 O(3mL)，N 2 Stirring was carried out at 95 ℃ for 18 hours under protection, and the mixture was filtered through celite, and purified by silica gel column chromatography (dichloromethane/methanol: 10/1) to obtain the product (130mg, yield: 36.8%).
Preparation of 2- (4- (6- (2-fluoro-6-hydroxyphenyl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) thieno [3,2-d ] pyrimidin-4-yl) piperazin-2-yl) acetonitrile
Reacting tert-butyl 2- (cyanomethyl) -4- (6- (2-fluoro-6-methoxyphenyl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) thieno [3,2-d]tert-Butylpyrimidin-4-yl) piperazine-1-carboxylate (130mg,0.22mmol) was dissolved in dichloroethane (10mL) and BBr was added 3 (225mg,0.9mmol), reacted at 85 ℃ for 1 hour, quenched by addition of methanol (1mL), adjusted to pH 8 with saturated sodium bicarbonate solution, extracted with water (10mL) and dichloromethane (20 mL), and purified by C18 column chromatography (water/methanol 1/9) to give the product (30mg, yield: 28.5%).
Preparation of 2- (4- (4-acryloyl-3- (cyanomethyl) piperazin-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) thieno [3,2-d ] pyrimidin-6-yl) -3-fluorophenyl acrylate
2- (4- (6- (2-fluoro-6-hydroxyphenyl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) thieno [3,2-d ] pyrimidin-4-yl) piperazin-2-yl) acetonitrile (30mg,0.06mmol) was dissolved in dichloromethane (10mL), DIEA (38.8mg,0.3mmol) was added, stirring was performed at 0 ℃, acryloyl chloride (5.6mg,0.06mmol) was added dropwise, the reaction was warmed to 30 ℃ for 30 minutes, the reaction was complete, the system was directly spin-dried and purified by silica gel column chromatography (dichloromethane/methanol ═ 10/1) to give a product (16mg, yield: 43.6%).
Preparation of 2- (1-acryloyl-4- (6- (2-fluoro-6-hydroxyphenyl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) thieno [3,2-d ] pyrimidin-4-yl) piperazin-2-yl) acetonitrile
2- (4- (4-acryloyl-3- (cyanomethyl) piperazin-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) thieno [3,2-d ] pyrimidin-6-yl) -3-fluorophenylacrylate (16.0mg,0.027mmol) tetrahydrofuran (5mL) was added, an aqueous solution of lithium hydroxide monohydrate (1.3mg,0.054mmol) was then added, the reaction was carried out at 0 ℃ for 10 minutes, and the solvent was purified by silica gel column chromatography (dichloromethane/methanol ═ 10/1) to give the product (2mg, yield: 13.8%).
Molecular formula C 27 H 29 FN 6 O 3 S molecular weight 536.2LC-MS (M/e) 536.9(M + H) + )
1 H-NMR(400MHz,CDCl 3 )δ:10.20(s,1H),8.40-8.30(m,1H),7.29-7.25(m,1H), 7.19-7.18(m,1H),6.90-6.84(m,1H),6.75-6.69(m,1H),6.23-6.19(m,1H),5.81-5.76(m, 1H),4.95(m,1H),3.67-3.50(m,2H),3.07-2.94(m,2H),2.72-2.68(m,1H),2.03-1.98(m, 3H),1.91(s,3H),1.46(m,1H),1.36-1.30(m,2H),1.13-0.84(m,6H).
Experimental protocol
An exemplary experimental scheme of a portion of the compounds of the invention is provided below to show the advantageous activity and advantageous technical effects of the compounds of the invention. It should be understood, however, that the following experimental protocols are only illustrative of the present disclosure and are not intended to limit the scope of the present disclosure.
Experiment ofEXAMPLE 1 in vitro cytological Activity of Compounds of the invention
Test article: the compound, the structural formula and the preparation method are shown in the preparation examples disclosed in the disclosure.
The cell lines used in the following experiments represent the following:
calu-1: human lung cancer cell (containing Kras G12C mutation)
NCI-H2030: human lung cancer cell (containing Kras G12C mutation)
MIAPaCa-2: human pancreatic cancer cells (containing Kras G12C mutation)
H358: human lung cancer cell (containing Kras G12C mutation)
A549: human lung cancer cell (containing Kras G12S mutation)
Experimental methods
1. Cell culture
Cell culture conditions are as follows:
| cell lines | Cell type | Growth characteristics | Cell number/well | Culture medium |
| Calu-1 | Lung cancer | Wall-attached type | 1500 | McCoy＇s 5A+10％FBS |
| H2030 | Lung cancer | Wall-attached type | 1500 | RPMI1640+10％FBS |
| MIA PaCa-2 | Pancreatic cancer | Wall-attached type | 1500 | DMEM + 10% FBS + 2.5% horse serum |
| H358 | Lung cancer | Wall-attached type | 4000 | RPMI1640+10％FBS |
| A549 | Lung cancer | Wall-attached type | 2000 | F-12K+10％FBS |
The information on the complete medium of Calu-1, NCI-H2030, MIAPaCa-2, H358, A549 is shown in the above table at 37 ℃ with 5% CO 2 And culturing in a cell culture box. The degree of cell fusion reached 80% for the experiments.
1) Cells in the logarithmic growth phase were harvested and counted using a platelet counter. Detecting the cell activity by trypan blue exclusion method, ensuring the cell activity to be more than 90%, counting twice, and taking the average value.
2) Adjusting the cell concentration, and respectively adding 90 mu L of cell suspension into a 96-well plate to serve as a drug hole to be detected and a cell control hole; culture medium control wells were supplemented with 90 μ L of complete medium.
3) Cells in 96-well plates were incubated at 37 ℃ with 5% CO 2 And cultured overnight under 95% humidity conditions.
2. Preparation of Compound solutions
Preparing a drug solution with a final concentration of 1000 times: a proper amount of the compound of the invention is dissolved in a certain amount of DMSO to prepare a drug stock solution of 10mM, and the stock solution is diluted by 3-fold gradient with the DMSO, wherein the concentrations of 9 diluted drugs are 10mM, 3.33mM, 1.11mM, 0.37mM, 123. mu.M, 41.1. mu.M, 13.7. mu.M, 4.57. mu.M and 1.52. mu.M respectively.
Preparing a drug solution with a final concentration of 10 times: compound DMSO solutions were diluted in gradient, each concentration 100-fold with complete medium, and the drug concentrations after dilution were: 100. mu.M, 33.3. mu.M, 11.1. mu.M, 3.7. mu.M, 1.23. mu.M, 411nM, 137nM, 45.7nM, 15.2 nM.
3. After 24 hours of cell culture, 10 μ L of compound solution at 10-fold final concentration (total volume 100 μ L) was added to each well, 10uL of complete medium containing 1% DMSO (final concentration 0.1%) was added to the cell control wells, and 10uL of complete medium was added to the medium control wells.
After addition of the compound, 5% CO at 37 deg.C 2 Under the conditions of (1), culturing for 72 hours.
4. Terminal reading board
The 96-well plate was removed from the incubator and allowed to equilibrate to room temperature for 30 minutes. Add 60. mu.L of CellTiter-Glo reagent to each well. Cells were lysed by shaking for 2 min. The plates were incubated at room temperature for 20 minutes to generate a stable light signal. The Victor X4 multifunctional microplate reader reads the light signal value.
5. Data processing
Data were analyzed using GraphPad Prism 5.0 software, fitted to the data using non-linear sigmoidal regression to derive a dose-effect curve, and IC was calculated therefrom 50 The value is obtained.
The inhibition rate (%) × 100% (Lum cell control-Lum test drug)/(Lum cell control-Lum culture solution control).
Results of the experiment
TABLE 1 in vitro cytostatic Activity of Compounds of the invention
Conclusion of the experiment
The compound has good Kras mutant inhibition activity and tumor inhibition effect.
Experimental example 2 in vitro cytological Activity of Compounds of the invention
Test article: the compound, the structural formula and the preparation method are shown in the preparation examples disclosed in the disclosure.
The cell lines used in the following experiments represent the following:
MIAPaCa-2: human pancreatic cancer cell (containing Kras G12C mutation)
H358: human lung cancer cell (containing Kras G12C mutation)
Experimental methods
1. Cell culture
Cell culture conditions are as follows:
| cell lines | Cell type | Growth characteristics | Cell number/well | Culture medium |
| MIAPaCa-2 | Pancreatic cancer | Wall-attached type | 1200 | DMEM + 10% FBS + 2.5% horse serum |
| H358 | Lung cancer | Wall-attached type | 4000 | RPMI1640+10％FBS |
The information for the MIAPaCa-2, H358 complete medium is shown above, at 37 ℃ and 5% CO 2 And culturing in a cell culture box. The degree of cell fusion reached 80% for the experiments.
1) Cells in the logarithmic growth phase were harvested and counted using a platelet counter. Detecting the cell activity by trypan blue exclusion method, ensuring the cell activity to be more than 90%, counting twice, and taking the average value.
2) Adjusting the cell concentration, and respectively adding 90 mu L of cell suspension into a 96-well plate or an ultralow-adhesion 96-well plate to serve as a drug well to be detected and a cell control well; culture medium control wells were supplemented with 90 μ L of complete medium. The common 96-well plate is 2D cultured, and the ultra-low adhesion 96-well plate is 3D cultured.
3) Cells in 96-well plates were incubated at 37 ℃ with 5% CO 2 And cultured overnight under 95% humidity conditions.
2. Preparation of Compound solutions
Preparing a drug solution with a final concentration of 1000 times: a proper amount of the compound of the invention is dissolved in a certain amount of DMSO to prepare a drug stock solution of 10mM, and the stock solution is diluted by 3-fold gradient with the DMSO, wherein the concentrations of 9 diluted drugs are 10mM, 3.33mM, 1.11mM, 0.37mM, 123. mu.M, 41.1. mu.M, 13.7. mu.M, 4.57. mu.M and 1.52. mu.M respectively.
Preparing a drug solution with a final concentration of 10 times: compound DMSO solutions were diluted in gradient, each concentration 100-fold with complete medium, and the drug concentrations after dilution were: 100. mu.M, 33.3. mu.M, 11.1. mu.M, 3.7. mu.M, 1.23. mu.M, 411nM, 137nM, 45.7nM, 15.2 nM.
3. After 24 hours of cell culture, 10 μ L of compound solution at 10-fold final concentration (total volume 100 μ L) was added to each well, 10uL of complete medium containing 1% DMSO (final concentration 0.1%) was added to the cell control wells, and 10uL of complete medium was added to the medium control wells.
After addition of the compound, 5% CO at 37 deg.C 2 Under the conditions of (3), culture was carried out for 72 hours (2D culture) or 5 days (3D culture).
4. Terminal reading board
After adding the medicines for 72 hours, taking the 96-hole culture plate out of the incubator, and balancing to room temperature for 30 minutes. Add 60. mu.L of CellTiter-Glo reagent to each well. Cells were lysed by shaking for 2 min. The plates were incubated at room temperature for 20 minutes to generate a stable light signal. The Victor X4 multifunctional microplate reader reads the light signal value.
After 5 days of dosing, the ultra low adhesion 96 well plates were removed from the incubator and allowed to equilibrate to room temperature for 30 minutes. 50 μ L of CellTiter-Glo reagent was added to each well. Cells were lysed by shaking for 10 min. Plates were incubated at room temperature for a total of 20 minutes to generate a steady light signal and the liquid in wells was transferred in parallel to a white 96-well plate for detection. The Victor X4 multifunctional microplate reader reads the light signal value.
5. Data processing
Data were analyzed using GraphPad Prism 5.0 software, fitted to the data using non-linear sigmoidal regression to derive a dose-effect curve, and IC was calculated therefrom 50 The value is obtained.
The inhibition rate (%) × 100% (Lum cell control-Lum test drug)/(Lum cell control-Lum culture solution control).
Results of the experiment
TABLE 2 in vitro cell inhibitory Activity of Compounds of the invention
Conclusion of the experiment
The compound of the invention has good inhibition effect on Kras mutant tumor cells.
Claims (10)
1. A compound, or a pharmaceutically acceptable salt thereof, selected from the following structures:
2. a compound, or a pharmaceutically acceptable salt thereof, selected from the following structures:
3. a pharmaceutical composition comprising a compound according to any one of claims 1-2, or a pharmaceutically acceptable salt thereof, in a pharmaceutically acceptable dosage form, wherein the pharmaceutical composition comprises one or more pharmaceutically acceptable excipients.
4. Use of a compound of any one of claims 1-2, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 3, for the manufacture of a medicament for the treatment and/or prevention of cancer.
5. The use of claim 4, wherein the cancer is mediated by a KRAS mutation.
6. The use of claim 5, wherein the KRAS mutation is selected from one or more of KRAS G12D, KRAS G12S, KRAS G12V and KRAS G12C.
7. The use according to any one of claims 4 to 6, wherein the cancer is selected from lung cancer, colorectal cancer or pancreatic cancer.
8. The use according to claim 7, wherein the lung cancer is selected from non-small cell lung cancer.
9. A process for the preparation of a compound of formula (I) comprising the steps of:
wherein X, X 'and X' are independently selected from F, Cl, Br and I; y is selected from boric acid, borate ester, -NH 2 OH or SH; corresponding to X 1 -X 6 、R 1 -R 2 Ring A, ring B, ring C, L 1 、L 2 M, n are as defined in any one of claims 1-2;
1) reacting the intermediate 1 and the intermediate 2 under alkaline conditions to generate an intermediate 3;
2) the intermediate 3 and the intermediate 4 react under the action of an alkaline condition and a palladium catalyst to generate an intermediate 5; or the intermediate 3 and the intermediate 4 react under the alkaline condition and the action of a palladium catalyst and a ligand to generate an intermediate 5;
3) removing a protecting group of the intermediate 5 under an acidic condition to generate an intermediate 6;
and 4) reacting the intermediate 6 with the intermediate 7 under alkaline conditions to generate a compound of formula (I);
the reaction processes involved in the above preparation methods can be carried out in conventional solvents.
10. The production method according to claim 9, wherein,
the solvent is selected from one or more of DMSO, DMF, acetonitrile, methanol, tetrahydrofuran, dichloromethane, 1, 4-dioxane, trifluoroacetic acid or water;
the palladium catalyst is selected from Pd (PPh) 3 ) 4 、PdCl 2 (PPh 3 ) 2 、PdCl 2 (MeCN) 2 、Pd(dppf)Cl 2 、Pd 2 (dba) 3 Palladium chloride, palladium acetate or palladium triphenylphosphine;
the ligand is selected from Ph 2 P(CH 2 ) 2 PPh 2 (dppe)、Ph 2 P(CH 2 ) 3 PPh 2 (dppp) or 2-dicyclohexylphosphine-2 ',6' -dimethoxybiphenyl.
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| WO2022028492A1 (en) * | 2020-08-05 | 2022-02-10 | Beigene, Ltd. | Imidazotriazine and pyrrolopyrimidine derivatives as kras g12c inhibitors |
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