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WO2024188281A1 - Composé ayant une structure de quinazoline et son utilisation - Google Patents

Composé ayant une structure de quinazoline et son utilisation Download PDF

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Publication number
WO2024188281A1
WO2024188281A1 PCT/CN2024/081502 CN2024081502W WO2024188281A1 WO 2024188281 A1 WO2024188281 A1 WO 2024188281A1 CN 2024081502 W CN2024081502 W CN 2024081502W WO 2024188281 A1 WO2024188281 A1 WO 2024188281A1
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Prior art keywords
alkyl
compound
membered
mmol
3alkyl
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Chinese (zh)
Inventor
陈曙辉
刘迎春
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Medshine Discovery Inc
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Medshine Discovery Inc
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D487/08—Bridged systems

Definitions

  • the present invention relates to a class of compounds containing quinazoline structure and applications thereof, and in particular to a compound represented by formula (VI), a stereoisomer thereof and a pharmaceutically acceptable salt thereof.
  • RAS is a functionally important guanine nucleoside binding protein, and mutated RAS proteins are considered to be important carcinogenic factors.
  • RAS mutations are found in 20% of human tumors, of which 85% are KRAS.
  • KRAS protein has 188 amino acids, and the most common mutations occur at positions 12, 13, and 61, especially at position 12, where the most common mutations are G12D, G12V, and G12C.
  • GEFs guanine nucleotide exchange factors
  • GAPs GTPase activating proteins
  • KRAS protein inhibitors with G12C mutations have made great breakthroughs.
  • Amgen's Sotorasib has achieved good results in clinical practice and has been approved by the FDA.
  • PROTACs Proteolysis-Targeting Chimeras
  • PROTACs are hybrid bifunctional small molecule compounds, one end of which is the part that binds to the target, and the other end is the E3 ligand, and the two are connected by a linker fragment.
  • PROTAC is a new class of drugs with good prospects. When one end binds to the target, the E3 ligand part at the other end induces ubiquitination, thereby degrading the target protein.
  • the biggest advantage of PROTAC technology is that it can make some targets that are considered undruggable become druggable - there is no need for particularly strong binding ability, as long as it can induce ubiquitination, the function of the target protein can be inhibited.
  • PROTAC technology to the very important but difficult-to-drug KRAS mutant protein is a very promising strategy. It is expected to overcome the drug resistance problem of KRAS mutant protein, so that these patients can have drugs available.
  • the present invention provides a compound of formula (I), a stereoisomer thereof and a pharmaceutically acceptable salt thereof,
  • Ring A is selected from 8-16 membered heterocycloalkyl, 8-16 membered heterocycloalkenyl and 8-16 membered heteroaryl, wherein the 8-16 membered heterocycloalkyl, 8-16 membered heterocycloalkenyl and 8-16 membered heteroaryl are each independently optionally substituted by 1, 2 or 3 R c ;
  • Each R c is independently selected from H, F, Cl, Br, I, CN, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl and 3-6 membered heterocycloalkyl, and the C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl and 3-6 membered heterocycloalkyl are independently optionally substituted by 1, 2 or 3 R o ;
  • G 1 is selected from phenyl and 5-6 membered heteroaryl, and the phenyl and 5-6 membered heteroaryl are each independently optionally substituted by 1, 2 or 3 R a1 ;
  • each R a1 is independently selected from H, F, Cl, Br, I, C 1-3 alkyl, C 3-6 cycloalkyl, 4-6 membered heterocycloalkyl and 5-6 membered heteroaryl, and the C 1-3 alkyl , C 3-6 cycloalkyl, 4-6 membered heterocycloalkyl and 5-6 membered heteroaryl are independently optionally substituted by 1, 2 or 3 R o ;
  • G2 is absent or selected from phenyl, naphthyl, pyridyl, benzothiazolyl and indazolyl, wherein the phenyl, naphthyl, pyridyl, benzothiazolyl and indazolyl are independently optionally substituted by 1, 2 or 3 Rb ;
  • Each R b is independently selected from D, F, Cl, Br, I, OH, NH 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy and C 1-6 alkylamino;
  • G 3 is absent or is selected from C 1-20 alkyl, C 3-20 cycloalkyl, 3-20 membered heterocycloalkyl and NR 1 R 2 , wherein the C 1-20 alkyl, C 3-20 cycloalkyl and 3-20 membered heterocycloalkyl are each independently optionally substituted by 1, 2 or 3 R 0 ;
  • R 1 is selected from C 1-6 alkyl, wherein the C 1-6 alkyl is optionally substituted by 1, 2 or 3 R 11 ;
  • R 2 is selected from 4-6 membered heterocycloalkyl, which is optionally substituted by 1, 2 or 3 R 21 ;
  • each R 11 and R 21 is independently selected from F, Cl, Br, I, CN, OH, NH 2 , CH 3 , CF 3 , CHF 2 , CH 2 F and OCH 3 ;
  • L 1 is selected from bicyclo[2.2.2]octyl, 2,3-dihydro-1H-indenyl, phenyl and pyridinyl, wherein the bicyclo[2.2.2]octyl, 2,3-dihydro-1H-indenyl, phenyl and pyridinyl are each independently optionally substituted with 1, 2 or 3 R 0 ;
  • L2 is selected from -L a -L b -L c -L d -;
  • L3 is selected from -NH- and 5-6 membered heteroaryl, wherein the -NH- and 5-6 membered heteroaryl are each independently optionally substituted by 1, 2 or 3 R0 ;
  • R 10 is selected from C 1-6 alkyl, C 3-6 cycloalkyl and 4-6 membered heterocycloalkyl, wherein the C 1-6 alkyl, C 3-6 cycloalkyl and 4-6 membered heterocycloalkyl are each independently optionally substituted by 1, 2 or 3 R 0 ;
  • R 20 is selected from H and OH
  • R 30 and R 40 are independently selected from H and C 1-6 alkyl, and the C 1-6 alkyl is optionally substituted by 1, 2 or 3 R 0 ;
  • R 30 , R 40 and the carbon atom to which they are connected together form a C 3-6 cycloalkyl group or a 4-6 membered heterocycloalkyl group, and the C 3-6 cycloalkyl group and the 4-6 membered heterocycloalkyl group are each independently optionally substituted by 1, 2 or 3 R 0 ;
  • R 5 is selected from -L 4 -R 4 ;
  • L 4 is selected from a single bond, -CH 2 -, -CD 2 -, -CH(C 1-3 alkyl)-, -O-, -S-, -NH- and -N(C 1-3 alkyl)-;
  • R4 is selected from C1-6 alkyl, 4-6 membered heterocycloalkyl, 5-6 membered heteroaryl and C1-6 alkyl-N( C1-3 alkyl)( OC1-3 alkyl), wherein the C1-3 alkyl, C1-6 alkyl, 4-6 membered heterocycloalkyl and 5-6 membered heteroaryl are each independently optionally substituted by 1, 2 or 3 R e1 ;
  • Each R 6 and R 7 is independently selected from H, F, Cl, Br, I and C 1-3 alkyl, wherein the C 1-3 alkyl is optionally substituted with 1, 2 or 3 R 0 ;
  • each R 8 and R 9 is independently selected from H, D, F, Cl, Br, I, CH 3 , CF 3 , CHF 2 and CH 2 F;
  • Each R e1 is independently selected from H, F, Cl, Br, I, CN, OH, NH 2 , CH 3 , CF 3 , CHF 2 , CH 2 F and OCH 3 ;
  • Each R 0 is independently selected from H, F, Cl, Br, I, CN, OH, NH 2 , CH 3 , CF 3 , CHF 2 , CH 2 F and OCH 3 .
  • the present invention provides a compound of formula (I), a stereoisomer thereof and a pharmaceutically acceptable salt thereof,
  • Ring A is selected from 8-16 membered heterocycloalkyl, 8-16 membered heterocycloalkenyl and 8-16 membered heteroaryl, wherein the 8-16 membered heterocycloalkyl, 8-16 membered heterocycloalkenyl and 8-16 membered heteroaryl are each independently optionally substituted by 1, 2 or 3 R c ;
  • Each R c is independently selected from H, F, Cl, Br, I, CN, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl and 3-6 membered heterocycloalkyl, and the C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl and 3-6 membered heterocycloalkyl are independently optionally substituted by 1, 2 or 3 R o ;
  • G 1 is selected from phenyl and 5-6 membered heteroaryl, and the phenyl and 5-6 membered heteroaryl are each independently optionally substituted by 1, 2 or 3 R a1 ;
  • each R a1 is independently selected from H, F, Cl, Br, I, C 1-3 alkyl, C 3-6 cycloalkyl, 4-6 membered heterocycloalkyl and 5-6 membered heteroaryl, and the C 1-3 alkyl , C 3-6 cycloalkyl, 4-6 membered heterocycloalkyl and 5-6 membered heteroaryl are independently optionally substituted by 1, 2 or 3 R o ;
  • G2 is absent or selected from phenyl, naphthyl, pyridyl, benzothiazolyl and indazolyl, wherein the phenyl, naphthyl, pyridyl, benzothiazolyl and indazolyl are independently optionally substituted by 1, 2 or 3 Rb ;
  • Each R b is independently selected from D, F, Cl, Br, I, OH, NH 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy and C 1-6 alkylamino;
  • G3 is absent or selected from C1-20 alkyl, C3-20 cycloalkyl and 3-20 membered heterocycloalkyl, wherein the C1-20 alkyl, C3-20 cycloalkyl and 3-20 membered heterocycloalkyl are each independently optionally substituted by 1, 2 or 3 R0 ;
  • L 1 is selected from bicyclo[2.2.2]octyl, 2,3-dihydro-1H-indenyl, phenyl and pyridinyl, wherein the bicyclo[2.2.2]octyl, 2,3-dihydro-1H-indenyl, phenyl and pyridinyl are each independently optionally substituted with 1, 2 or 3 R 0 ;
  • L2 is selected from -L a -L b -L c -L d -;
  • L3 is selected from -NH- and 5-6 membered heteroaryl, wherein the -NH- and 5-6 membered heteroaryl are each independently optionally substituted by 1, 2 or 3 R0 ;
  • R 10 is selected from C 1-6 alkyl, C 3-6 cycloalkyl and 4-6 membered heterocycloalkyl, wherein the C 1-6 alkyl, C 3-6 cycloalkyl and 4-6 membered heterocycloalkyl are each independently optionally substituted by 1, 2 or 3 R;
  • R 20 is selected from H and OH
  • R 30 and R 40 are independently selected from H and C 1-6 alkyl, and the C 1-6 alkyl is optionally substituted by 1, 2 or 3 R 0 ;
  • R 30 , R 40 and the carbon atom to which they are connected together form a C 3-6 cycloalkyl group or a 4-6 membered heterocycloalkyl group, and the C 3-6 cycloalkyl group and the 4-6 membered heterocycloalkyl group are each independently optionally substituted by 1, 2 or 3 R 0 ;
  • R 5 is selected from -L 4 -R 4 ;
  • L 4 is selected from a single bond, -CH 2 -, -CD 2 -, -CH(C 1-3 alkyl)-, -O-, -S-, -NH- and -N(C 1-3 alkyl)-;
  • R4 is selected from C1-6 alkyl, 4-6 membered heterocycloalkyl and 5-6 membered heteroaryl, wherein the C1-6 alkyl, 4-6 membered heterocycloalkyl and 5-6 membered heteroaryl are each independently optionally substituted by 1, 2 or 3 R e1 ;
  • Each R 6 and R 7 is independently selected from H, F, Cl, Br, I and C 1-3 alkyl, wherein the C 1-3 alkyl is optionally substituted with 1, 2 or 3 R 0 ;
  • each R 8 and R 9 is independently selected from H, D, F, Cl, Br, I, CH 3 , CF 3 , CHF 2 and CH 2 F;
  • Each R e1 is independently selected from H, F, Cl, Br, I, CN, OH, NH 2 , CH 3 , CF 3 , CHF 2 , CH 2 F and OCH 3 ;
  • Each R 0 is independently selected from H, F, Cl, Br, I, CN, OH, NH 2 , CH 3 , CF 3 , CHF 2 , CH 2 F and OCH 3 .
  • the above-mentioned compound, its stereoisomers and pharmaceutically acceptable salts thereof are selected from: Other variables are as defined in the present invention.
  • the present invention provides a compound of formula (IV), a stereoisomer thereof and a pharmaceutically acceptable salt thereof.
  • G3 is selected from 7-8 membered heterocycloalkyl and The 7-8 membered heterocycloalkyl group is optionally substituted by 1, 2 or 3 R 0 , respectively, independently;
  • R 20 is selected from H and OH
  • R 5 is selected from -O-4-6 membered heterocycloalkyl and -OC 1-3 alkyl-N(C 1-3 alkyl)(OC 1-3 alkyl), wherein the C 1-3 alkyl and the 4-6 membered heterocycloalkyl are each independently optionally substituted by 1, 2 or 3 R e1 ;
  • each R 6 and R 7 is independently selected from H, F, Cl, Br, I, CH 3 , CF 3 , CHF 2 and CH 2 F;
  • each R 8 and R 9 is independently selected from H, D, F, Cl, Br, I, CH 3 , CF 3 , CHF 2 and CH 2 F;
  • each R b is independently selected from D, F, Cl, Br, I, OH, NH 2 , CH 3 , CF 3 , CHF 2 and CH 2 F;
  • Each R e1 is independently selected from H, F, Cl, Br, I, CN, OH, NH 2 , CH 3 , CF 3 , CHF 2 , CH 2 F and OCH 3 ;
  • Each R 0 is independently selected from H, F, Cl, Br, I, CN, OH, NH 2 , CH 3 , CF 3 , CHF 2 , CH 2 F and OCH 3 .
  • the above-mentioned compound, its stereoisomers and pharmaceutically acceptable salts thereof are selected from:
  • R 5 , R 6 , R 7 and R b are as defined in the present invention.
  • the above-mentioned compound, its stereoisomers and pharmaceutically acceptable salts thereof are selected from:
  • R 5 , R 6 , R 7 and R b are as defined in the present invention.
  • the above-mentioned compound, its stereoisomers and pharmaceutically acceptable salts thereof are selected from:
  • R 5 , R 6 , R 7 and R b are as defined in the present invention.
  • the above-mentioned G2 is selected from Other variables are as defined in the present invention.
  • R b is selected from F and CH 3 , and other variables are as defined in the present invention.
  • R 5 is selected from -OR 4 , and other variables are as defined in the present invention.
  • the above R 5 is selected from -O-4-6 membered heterocycloalkyl and -OC 1-3 alkyl-N(C 1-3 alkyl)(OC 1-3 alkyl), and the C 1-3 alkyl and 4-6 membered heterocycloalkyl are each independently optionally substituted by 1, 2 or 3 R e1 , and other variables are as defined in the present invention.
  • R 5 is selected from Other variables are as defined in the present invention.
  • R 5 is selected from Other variables are as defined in the present invention.
  • the above L 4 is selected from -O-, and other variables are as defined in the present invention.
  • the above-mentioned G3 is selected from 7-8 membered heterocycloalkyl and The 7-8 membered heterocycloalkyl group is optionally substituted by 1, 2 or 3 R 0, respectively, and other variables are as defined herein.
  • the above G 3 is selected from 7-8 membered heterocycloalkyl, and the 7-8 membered heterocycloalkyl is optionally substituted by 1, 2 or 3 R, and other variables are as defined in the present invention.
  • the above-mentioned G3 is selected from Other variables are as defined in the present invention.
  • the above-mentioned G3 is selected from Other variables are as defined in the present invention.
  • the above-mentioned G3 is selected from Other variables are as defined in the present invention.
  • the above G 1 is selected from phenyl, and the phenyl is optionally substituted by 1, 2 or 3 R a1 , and other variables are as defined in the present invention.
  • the above G 1 is selected from phenyl, and other variables are as defined in the present invention.
  • the above structural unit Selected from Other variables are as defined in the present invention.
  • R 10 is selected from isopropyl, and other variables are as defined in the present invention.
  • R 20 is selected from OH, and other variables are as defined in the present invention.
  • R 30 and R 40 are independently selected from H and -CH 2 OH, and other variables are as defined in the present invention.
  • R 30 is selected from H
  • R 40 is selected from -CH 2 OH
  • other variables are as defined in the present invention.
  • R 6 is selected from CH 3 , and other variables are as defined in the present invention.
  • R 7 is selected from H, and other variables are as defined in the present invention.
  • the present invention provides a compound of formula (VI), a stereoisomer thereof or a pharmaceutically acceptable salt thereof,
  • T is selected from S and Se;
  • R 1 is selected from H, D and C 1-3 alkyl
  • R2 is selected from H, D and C1-3 alkyl
  • R 3 is selected from H, D, F, Cl, Br, CN, NH 2 , OH and C 1-3 alkyl;
  • R 5 is selected from -OR 4 ;
  • R 4 is selected from C 1-6 alkyl and 4-7 membered heterocycloalkyl, wherein the C 1-6 alkyl and 4-7 membered heterocycloalkyl are each independently optionally substituted by 1, 2 or 3 R a ;
  • each R 6 and R 7 is independently selected from H, F, Cl, Br, I, CH 3 , CF 3 , CHF 2 and CH 2 F;
  • Each R b is independently selected from D, F, Cl, Br, I, OH, NH 2 and CH 3 ;
  • n is selected from 0, 1, 2, 3 and 4;
  • the above-mentioned compound, its stereoisomers and pharmaceutically acceptable salts thereof are selected from:
  • R 1 is selected from H, D and C 1-3 alkyl
  • R2 is selected from H, D and C1-3 alkyl
  • R 3 is selected from H, D, F, Cl, Br, CN, NH 2 , OH and C 1-3 alkyl;
  • R 4 is selected from C 1-6 alkyl and 4-7 membered heterocycloalkyl, wherein the C 1-6 alkyl and 4-7 membered heterocycloalkyl are each independently optionally substituted by 1, 2 or 3 R a ;
  • R 5 is selected from -O-4-6 membered heterocycloalkyl and -OC 1-3 alkyl-N(C 1-3 alkyl)(OC 1-3 alkyl), wherein the C 1-3 alkyl is each independently optionally substituted by 1, 2 or 3 R;
  • Each R b is independently selected from D, F, Cl, Br, I, OH, NH 2 and CH 3 ;
  • n is selected from 0, 1, 2, 3 and 4;
  • the present invention provides a compound of formula (II), a stereoisomer thereof or a pharmaceutically acceptable salt thereof,
  • R 1 is selected from H, D and C 1-3 alkyl
  • R2 is selected from H, D and C1-3 alkyl
  • R 3 is selected from H, D, F, Cl, Br, CN, NH 2 , OH and C 1-3 alkyl;
  • R 4 is selected from C 1-6 alkyl and 4-7 membered heterocycloalkyl, wherein the C 1-6 alkyl and 4-7 membered heterocycloalkyl are each independently optionally substituted by 1, 2 or 3 R a ;
  • n is selected from 0, 1, 2, 3 and 4;
  • the present invention provides a compound of formula (II), a stereoisomer thereof or a pharmaceutically acceptable salt thereof,
  • R 1 is selected from H, D and C 1-3 alkyl
  • R2 is selected from H, D and C1-3 alkyl
  • R 3 is selected from H, D, F, Cl, Br, CN, NH 2 , OH and C 1-3 alkyl;
  • R 4 is selected from C 1-6 alkyl and 4-7 membered heterocycloalkyl, wherein the C 1-6 alkyl and 4-7 membered heterocycloalkyl are each independently optionally substituted by 1, 2 or 3 R a ;
  • n is selected from 0, 1, 2, 3 and 4;
  • the above-mentioned compound, its stereoisomers and pharmaceutically acceptable salts thereof are selected from:
  • R 4 is selected from C 1-6 alkyl and 4-7 membered heterocycloalkyl, wherein the C 1-6 alkyl and 4-7 membered heterocycloalkyl are optionally substituted by 1, 2 or 3 R a ;
  • R 5 is selected from -O-4-6 membered heterocycloalkyl and -OC 1-3 alkyl-N(C 1-3 alkyl)(OC 1-3 alkyl);
  • R 3 , Ra and m are as defined herein.
  • the above-mentioned compound, its stereoisomers and pharmaceutically acceptable salts thereof are selected from:
  • R 1 , R 2 , R 3 , R 4 and m are as defined in the present invention.
  • the above compound has a structure shown in formula (II-1):
  • R 4 is selected from C 1-6 alkyl and 4-7 membered heterocycloalkyl, wherein the C 1-6 alkyl and 4-7 membered heterocycloalkyl are optionally substituted by 1, 2 or 3 R a ;
  • R 3 is selected from H, D, F, Cl, Br, CN, NH 2 , OH and C 1-3 alkyl;
  • n is selected from 0, 1 and 2.
  • the above-mentioned compound, its stereoisomers and pharmaceutically acceptable salts thereof are selected from:
  • R 4 is selected from C 1-6 alkyl and 4-7 membered heterocycloalkyl, wherein the C 1-6 alkyl and 4-7 membered heterocycloalkyl are optionally substituted by 1, 2 or 3 R a ;
  • R 3 is selected from H, D, F, Cl, Br, CN, NH 2 , OH and C 1-3 alkyl;
  • n is selected from 0, 1 and 2.
  • R 1 is selected from H and D, and other variables are as defined in the present invention.
  • R 2 is selected from H, D and CH 3 , and other variables are as defined in the present invention.
  • R 3 is selected from H and Cl, and other variables are as defined in the present invention.
  • the above R 4 is selected from propyl, isopropyl, tetrahydropyranyl and pyrrolidinyl, and the propyl, isopropyl, tetrahydropyranyl and pyrrolidinyl are independently and optionally substituted by 1, 2 or 3 Ra , and other variables are as defined in the present invention.
  • R 4 is selected from Said are each independently optionally substituted by 1, 2 or 3 Ra , and other variables are as defined herein.
  • R 4 is selected from Other variables are as defined in the present invention.
  • the structural unit Selected from Other variables are as defined in the present invention.
  • the above-mentioned compound, its stereoisomers and pharmaceutically acceptable salts thereof are selected from:
  • R 3 , R 4 and m are as defined in the present invention.
  • the present invention provides the following compounds, their stereoisomers and pharmaceutically acceptable salts:
  • the above compound is selected from:
  • the above compound is selected from:
  • the present invention also provides the use of the above compound, its stereoisomer or a pharmaceutically acceptable salt thereof in the preparation of a drug for treating a disease associated with a KRAS mutant protein.
  • the above-mentioned diseases associated with KRAS mutant protein are selected from solid tumors with KRAS G12D mutation.
  • the solid tumor with the above-mentioned KRAS G12D mutation is selected from pancreatic cancer, lung cancer and colon cancer.
  • the compounds of the present invention are synthesized by the following route:
  • the present invention also refers to the following test method:
  • Test method 1 In vitro cell proliferation assay
  • RPMI-1640 medium was purchased from GIbco
  • penicillin/streptomycin antibiotics were purchased from Vicente
  • fetal bovine serum was purchased from Biosera.
  • 3D CellTiter-Glo (cell viability chemiluminescence detection reagent) reagent was purchased from Promega.
  • AsPC-1/A375 and other cell lines were purchased from ATCC, and Envision multi-label analyzer was purchased from PerkinElmer.
  • the cells were seeded in an ultra-low attachment 96-well U-shaped plate, with 80 ⁇ L of cell suspension per well, containing 1000 selected cells.
  • the cell plate was placed in a carbon dioxide incubator for overnight culture.
  • the compound to be tested was diluted 5-fold into 8 concentrations using a dispenser, i.e., from 2mM to 25.6nM, and a double-well experiment was set up. 78 ⁇ L of culture medium was added to the middle plate, and then 2 ⁇ L of the gradient diluted compound per well was transferred to the middle plate according to the corresponding position. After mixing, 20 ⁇ L of each well was transferred to the cell plate. The concentration range of the compound transferred to the cell plate was 10 ⁇ M to 0.128nM. The cell plate was placed in a carbon dioxide incubator and cultured for 6 days. Prepare another cell plate and read the signal value on the day of drug addition as the maximum value (Max value in the equation below) for data analysis.
  • the raw data were converted into inhibition rate using the equation (Sample-Min)/(Max-Min)*100%, and the IC50 value was obtained by four-parameter curve fitting (obtained using the "log(inhibitor)vs.response--Variable slope" mode in GraphPad Prism).
  • Test method 2 Cellular KRAS G12D protein degradation experiment
  • RPMI-1640 medium was purchased from GIbco
  • penicillin/streptomycin antibiotics were purchased from Vicente
  • fetal bovine serum was purchased from Biosera.
  • Protein primary and secondary antibodies were purchased from Cell Signaling Technology.
  • AsPC-1/A375 and other cell lines were purchased from ATCC, and 4% paraformaldehyde and Triton-100 were purchased from Bio-Tech. Envision multi-label analyzer (PerkinElmer).
  • the cells were seeded in ultra-low attachment 96-well black-walled plates, with 80 ⁇ L of cell suspension per well, containing 100,000 cells.
  • the cell plates were placed in a carbon dioxide incubator for overnight culture.
  • the compound to be tested was diluted 5-fold into 8 concentrations using a shotgun, i.e., from 2mM to 25.6nM, and a double-well experiment was set up. 78 ⁇ L of culture medium was added to the middle plate, and then 2 ⁇ L of the gradient diluted compound per well was transferred to the middle plate according to the corresponding position. After mixing, 20 ⁇ L of each well was transferred to the cell plate. The concentration range of the compound transferred to the cell plate was 10 ⁇ M to 0.128nM.
  • the cells were removed, the culture medium was discarded, and the cells were fixed with 4% PFA fixative for 30min, washed 3 times with PBS, permeabilized with 0.1% Triton for 20min, washed 3 times with PBS, blocked with 0.1% BSA solution at room temperature for 1h, incubated with protein primary antibody at 4°C overnight, washed 3 times with PBST, incubated with fluorescent secondary antibody at room temperature for 2h, washed 3 times with PBST,
  • FITC/Cy5 (FITCsample-FITCblank)/(FITCsample-FITCblank)
  • the inhibition % under compound treatment was calculated as [1-(FITC/Cy5comp.)/(FITC/Cy5DMSO)]*100.
  • the DC 50 value can be obtained by four-parameter curve fitting (obtained by "log(inhibitor)vs.response--Variable slope" mode in GraphPad Prism).
  • Test method 3 AsPC-1 cell p-ERK level detection
  • AsPC-1 cells were purchased from ATCC; RPMI-1640 medium was purchased from GIbco; fetal bovine serum was purchased from Hyclone; Advanced Phospho-ERK1/2 (THR202/TYR204) KIT was purchased from Bioauxilium, see Table 1 for details.
  • the raw data were converted into inhibition rate using the equation (Sample-Min)/(Max-Min)*100%, and the IC50 value was obtained by four-parameter curve fitting (log(inhibitor) vs.response--Variable slope mode in GraphPad Prism).
  • Max well The reading value of the positive control well is 1X lysate
  • Min well The reading value of the negative control well is 0.5% DMSO cell well cell lysate.
  • the compound of the present invention has good anti-cell proliferation activity and KRAS degradation activity, shows excellent in vitro activity on G12D mutated cells, and has no inhibitory activity on G12D low-expressing cell A375; shows excellent G12D degradation activity, and has good inhibitory activity on downstream pERK; has good in vivo tumor inhibition effect, specifically good efficacy and safety, and can be used for the treatment of cancer, especially pancreatic cancer.
  • the term "pharmaceutically acceptable” refers to those compounds, materials, compositions and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • the term "pharmaceutically acceptable salt” refers to salts of the compounds of the invention herein, prepared from compounds with specific substituents found in the invention herein with relatively non-toxic acids or bases.
  • base addition salts can be obtained by contacting such compounds with a sufficient amount of base in a pure solution or a suitable inert solvent.
  • acid addition salts can be obtained by contacting such compounds with a sufficient amount of acid in a pure solution or a suitable inert solvent.
  • Certain specific compounds of the invention herein contain basic and acidic functional groups and can be converted into either base or acid addition salts.
  • the pharmaceutically acceptable salts of the invention herein can be synthesized by conventional chemical methods from parent compounds containing acid radicals or bases.
  • the preparation method of such salts is: in water or an organic solvent or a mixture of the two, via the reaction of these compounds in free acid or base form with a stoichiometric amount of an appropriate base or acid to prepare.
  • the term "effective amount” or “therapeutically effective amount” refers to a non-toxic amount that can achieve the desired effect.
  • the determination of the effective amount varies from person to person, depending on the age and general condition of the recipient, and also on the specific active substance.
  • the appropriate effective amount in each case can be determined by a person skilled in the art based on routine experiments.
  • the compounds of the invention herein may exist in specific geometric or stereoisomeric forms.
  • the invention herein contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic mixtures and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of the invention herein.
  • Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All of these isomers and their mixtures are included within the scope of the invention herein.
  • the term “enantiomer” or “optical isomer” refers to stereoisomers that are mirror images of one another.
  • cis-trans isomers or “geometric isomers” result from the inability of a ring to rotate freely about double bonds or single bonds of ring carbon atoms.
  • diastereomer refers to stereoisomers that have two or more chiral centers and that are not mirror images of each other.
  • atropisomer (atropisomer) (or restricted configuration isomer (atropoisomer) is a stereoisomer with a specific spatial configuration, which is caused by the restricted rotation around a single bond due to large steric hindrance.
  • Certain compounds of the present invention may exist as atropisomers.
  • the compounds disclosed in the present invention include all atropisomers, which may be pure individual atropisomers, or enriched in one of the atropisomers, or non-specific mixtures of each. If the rotational potential around the single bond is high enough and the mutual conversion between the conformations is slow enough, separation of isomers may be allowed.
  • “(+)” means dextrorotation
  • (-) means levorotation
  • ( ⁇ )” means racemization.
  • a solid key with a wedge shape is used.
  • dotted wedge key To indicate the absolute configuration of a stereocenter, use a straight solid bond. and straight dashed key
  • a wavy line Denotes a solid wedge bond or dotted wedge key Or use a wavy line Represents a straight solid bond or straight dashed key
  • tautomer or “tautomeric form” refers to isomers of different functional groups that are in dynamic equilibrium at room temperature and can readily interconvert. If tautomerism is possible (such as in solution), chemical equilibrium of the tautomers can be achieved.
  • proton tautomers also called prototropic tautomers
  • Valence tautomers include interconversions via reorganization of some of the bonding electrons.
  • keto-enol tautomerism is the interconversion between pentane-2,4-dione and 4-hydroxypent-3-en-2-one.
  • the terms “enriched in one isomer”, “isomerically enriched”, “enriched in one enantiomer” or “enantiomerically enriched” mean that the content of one isomer or enantiomer is less than 100%, and the content of the isomer or enantiomer is greater than or equal to 60%, or greater than or equal to 70%, or greater than or equal to 80%, or greater than or equal to 90%, or greater than or equal to 95%, or greater than or equal to 96%, or greater than or equal to 97%, or greater than or equal to 98%, or greater than or equal to 99%, or greater than or equal to 99.5%, or greater than or equal to 99.6%, or greater than or equal to 99.7%, or greater than or equal to 99.8%, or greater than or equal to 99.9%.
  • the term “isomer excess” or “enantiomeric excess” refers to the difference between the relative percentages of two isomers or two enantiomers. For example, if the content of one isomer or enantiomer is 90% and the content of the other isomer or enantiomer is 10%, the isomer or enantiomeric excess (ee value) is 80%.
  • optically active (R)- and (S)-isomers and D and L isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the invention herein is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide the pure desired enantiomer.
  • a diastereomeric salt is formed with an appropriate optically active acid or base, and then the diastereoisomers are separated by conventional methods known in the art, and then the pure enantiomer is recovered.
  • the separation of enantiomers and diastereomers is usually accomplished by using chromatography, which uses a chiral stationary phase and is optionally combined with a chemical derivatization method (e.g., carbamates are generated from amines).
  • the compounds invented herein may contain unnatural proportions of atomic isotopes on one or more atoms constituting the compound.
  • compounds may be labeled with radioactive isotopes, such as tritium ( 3H ), iodine-125 ( 125I ) or C-14 ( 14C ).
  • deuterated drugs may be formed by replacing hydrogen with heavy hydrogen. The bond between deuterium and carbon is stronger than the bond between ordinary hydrogen and carbon. Compared with undeuterated drugs, deuterated drugs have the advantages of reducing toxic side effects, increasing drug stability, enhancing therapeutic effects, and extending the biological half-life of drugs. All isotopic composition changes of the compounds invented herein, whether radioactive or not, are included in the scope of the invention herein.
  • substituted means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, which may include a variant of deuterium and hydrogen, as long as the valence state of the particular atom is normal and the substituted compound is stable.
  • optionally substituted means that it may be substituted or not substituted, and unless otherwise specified, the type and number of substituents may be arbitrary on the basis of chemical achievable.
  • any variable such as R
  • its definition at each occurrence is independent.
  • the group may be optionally substituted with up to two R, and each occurrence of R has independent options.
  • substituents and/or variants thereof are permitted only if such combinations result in stable compounds.
  • linking group when the number of a linking group is 0, such as -(CRR) 0 -, it means that the linking group is a single bond.
  • substituents when the listed substituents do not indicate through which atom they are connected to the substituted group, such substituents can be bonded through any atom thereof.
  • a pyridyl group as a substituent can be connected to the substituted group through any carbon atom on the pyridine ring.
  • any one or more sites of the group can be connected to other groups through chemical bonds.
  • the chemical bond connection mode is non-positional and there are H atoms at the connectable sites, when the chemical bonds are connected, the number of H atoms at the site will decrease with the number of connected chemical bonds to become a group with a corresponding valence.
  • the chemical bond connecting the site to other groups can be a straight solid line bond.
  • the straight solid bond in -OCH 3 indicates that it is connected to other groups through the oxygen atom in the group;
  • the straight dashed bond in the group indicates that the two ends of the nitrogen atom in the group are connected to other groups;
  • the wavy line in the phenyl group indicates that it is connected to other groups through the carbon atoms at positions 1 and 2 in the phenyl group. It means that any connectable site on the piperidine group can be connected to other groups through one chemical bond, including at least These four connection methods, even if the H atom is drawn on -N-, Still includes For groups connected in this way, when one chemical bond is connected, the H at that site will be reduced by one and become a corresponding monovalent piperidine group.
  • linking direction is arbitrary, for example,
  • the connecting group L is -MW-, in which case -MW- can connect ring A and ring B in the same direction as the reading order from left to right to form You can also connect ring A and ring B in the opposite direction of the reading order from left to right to form Combinations of linkers, substituents, and/or variations thereof are permissible only if such combinations result in stable compounds.
  • ring includes a ring system containing at least one ring, each of which independently satisfies The above definition.
  • the number of atoms in a ring is generally defined as the number of members of the ring.
  • a "5-membered ring” or a “7-membered ring” refers to a “ring” with 5 or 7 atoms arranged around it.
  • C nm or C n -C m includes any specific case of n to m (m ⁇ n) carbon atoms, for example, C 1-12 includes C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , C 10 , C 11 , and C 12 , and also includes any range from n to n+m, for example, C 1-12 includes C 1-3 , C 1-6 , C 1-9 , C 3-6 , C 3-9 , C 3-12 , C 6-9 , C 6-12 , and C 13 .
  • n-membered to m-membered means that the number of atoms in the ring is n to m
  • a 3-12-membered ring includes a 3-membered ring, a 4-membered ring, a 5-membered ring, a 6-membered ring, a 7-membered ring, an 8-membered ring, a 9-membered ring, a 10-membered ring, an 11-membered ring, and a 12-membered ring, and also includes any range from n to m, for example, a 3-12-membered ring includes a 3-6-membered ring, a 3-9-membered ring, a 5-6-membered ring, a 5-7-membered ring, a 6-7-membered ring, a 6-8-membered ring, and
  • alkyl by itself or in combination with other terms is used to represent a straight or branched saturated hydrocarbon group consisting of a certain number of carbon atoms, which may be monovalent (such as methyl), divalent (such as methylene) or polyvalent (such as methine).
  • examples of alkyl include, but are not limited to: methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl, s-butyl and t-butyl), pentyl (including n-pentyl, isopentyl and neopentyl), hexyl, heptyl, octyl, etc.
  • C1-20 alkyl includes but is not limited to: C1-20 alkyl, C1-19 alkyl, C1-18 alkyl, C1-17 alkyl, C1-16 alkyl, C1-15 alkyl, C1-14 alkyl, C1-13 alkyl, C1-12 alkyl, C1-11 alkyl, C1-10 alkyl, C1-9 alkyl, C1-8 alkyl, C1-7 alkyl, C1-6 alkyl, C1-5 alkyl, C1-4 alkyl, C1-3 alkyl, C1-2 alkyl, C2-20 alkyl, C2-19 alkyl, C2-18 alkyl, C2-17 alkyl, C2-16 alkyl, C2-15 alkyl , C2-14 alkyl , C2-13 alkyl, C2-12 alkyl, C2-11 alkyl, C1-10 alkyl, C1-9 alkyl, C1-8 alkyl , C1-7 alkyl, C1-6 alkyl, C1-5 alky
  • C 1-3 alkyl is used to represent a straight or branched saturated hydrocarbon group consisting of 1 to 3 carbon atoms.
  • the C 1-3 alkyl group includes C 1-2 and C 2-3 alkyl groups, etc.; it can be monovalent (such as methyl), divalent (such as methylene) or polyvalent (such as methine).
  • Examples of C 1-3 alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), etc.
  • C 1-6 alkyl is used to represent a straight or branched chain saturated hydrocarbon group consisting of 1 to 6 carbon atoms.
  • C1-6 alkyl includes C1-2 , C1-3 , C2-3 and C1-4 alkyl, etc.; it can be monovalent (such as methyl), divalent (such as methylene) or polyvalent (such as methine).
  • Examples of C1-6 alkyl include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl, s-butyl and t-butyl), pentyl, etc.
  • C2-6 alkenyl is used to represent a straight or branched hydrocarbon group consisting of 2 to 6 carbon atoms containing at least one carbon-carbon double bond, which may be located at any position of the group.
  • the C2-6 alkenyl group includes C2-4 , C2-3 , C4 , C3 and C2 alkenyl, etc.; it may be monovalent, divalent or polyvalent.
  • Examples of C2-6 alkenyl groups include, but are not limited to, ethenyl, propenyl, butenyl, pentenyl, hexenyl, butadienyl, pentadienyl, hexadienyl, etc.
  • C 2-6 alkynyl is used to represent a straight or branched hydrocarbon group consisting of 2 to 6 carbon atoms containing at least one carbon-carbon triple bond, which may be located at any position of the group.
  • the C 2-6 alkynyl group includes C 2-4 , C 2-3 , C 4 , C 3 and C 2 alkynyl groups, etc. It may be monovalent, divalent or polyvalent. Examples of C 2-6 alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, etc.
  • C 1-6 alkoxy by itself or in combination with other terms, means an alkyl group containing 1 to 6 carbon atoms connected to the rest of the molecule through an oxygen atom.
  • the C 1-6 alkoxy includes C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-4 , C 6 , C 5 , C 4 and C 3 alkoxy, etc.
  • C 1-6 alkoxy examples include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), butoxy (including n-butoxy, isobutoxy, s-butoxy and t-butoxy), pentoxy (including n-pentoxy, isopentyl and neopentyl), hexyl and the like.
  • C 1-3 alkoxy by itself or in combination with other terms refers to those alkyl groups containing 1 to 3 carbon atoms connected to the rest of the molecule through an oxygen atom.
  • the C 1-3 alkoxy includes C 1-2 , C 2-3 , C 3 and C 2 alkoxy, etc.
  • Examples of C 1-3 alkoxy include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), etc.
  • C 1-6 alkylamino by itself or in combination with other terms refers to those alkyl groups containing 1 to 6 carbon atoms attached to the rest of the molecule through an amino group.
  • the C 1-6 alkylamino group includes C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-4 , C 6 , C 5 , C 4 , C 3 and C 2 alkylamino groups, etc.
  • C 1-6 alkylamino groups include, but are not limited to, -NHCH 3 , -N(CH 3 ) 2 , -NHCH 2 CH 3 , -N(CH 3 )CH 2 CH 3 , -N(CH 2 CH 3 )(CH 2 CH 3 ), -NHCH 2 CH 2 CH 3 , -NHCH 2 (CH 3 ) 2 , -NHCH 2 CH 2 CH 2 CH 3, and the like.
  • C 1-3 alkylamino refers to those alkyl groups containing 1 to 3 carbon atoms attached to the rest of the molecule through an amino group.
  • the C 1-3 alkylamino group includes C 1-2 , C 3 and C 2 alkylamino groups, etc.
  • Examples of C 1-3 alkylamino groups include, but are not limited to, -NHCH 3 , -N(CH 3 ) 2 , -NHCH 2 CH 3 , -N(CH 3 )CH 2 CH 3 , -NHCH 2 CH 2 CH 3 , -NHCH 2 (CH 3 ) 2 , and the like.
  • C 3-20 cycloalkyl means a saturated cyclic hydrocarbon group consisting of 3 to 20 carbon atoms, including monocyclic, bicyclic and tricyclic systems, wherein the bicyclic and tricyclic systems include spirocyclic, cyclic and bridged rings.
  • the C 3-12 cycloalkyl includes C 3-10 , C 3-8 , C 3-6 , C 3-5 , C 4-10 , C 4-8 , C 4-6 , C 4-5 , C 5-8 and C 5-6 cycloalkyl, etc.; it can be monovalent, divalent or polyvalent.
  • C 3-12 cycloalkyl examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, [2.2.2] bicyclooctane, [4.4.0] bicyclodecane, etc.
  • C 3-6 cycloalkyl means a saturated cyclic hydrocarbon group consisting of 3 to 6 carbon atoms, including monocyclic and bicyclic systems, wherein the bicyclic system includes spirocyclic, fused and bridged rings.
  • the C 3-8 cycloalkyl includes C 3-6 , C 3-5 , C 4-8 , C 4-6 , C 4-5 or C 5-6 cycloalkyl, etc.; it can be monovalent, divalent or polyvalent.
  • C 3-8 cycloalkyl examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, [2.2.2] bicyclooctane, etc.
  • heteroatoms may occupy the position at which the heterocycloalkyl is connected to the rest of the molecule.
  • the 3-6 membered heterocycloalkyl includes 3-4 membered, 3-5 membered, 4-5 membered, 4-6 membered, 5-6 membered, 3 membered, 4 membered, 5 membered, 6 membered heterocycloalkyl, etc.
  • Examples of 3-6 membered heterocycloalkyl groups include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophenyl (including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl, alkyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), dioxanyl, dithianyl, isoxazolidinyl, iso
  • 4-6 membered heterocycloalkyl by itself or in combination with other terms refers to a saturated cyclic group consisting of 4 to 6 ring atoms, 1, 2, 3 or 4 of which are heteroatoms independently selected from O, S and N, and the rest are carbon atoms, wherein the carbon atoms are optionally oxoed (i.e., C(O)), the nitrogen atoms are optionally quaternized, and the nitrogen and sulfur heteroatoms are optionally oxidized (i.e., NO and S(O) p , p is 1 or 2).
  • 4-6 membered heterocycloalkyl heteroatoms may occupy the position where the heterocycloalkyl is connected to the rest of the molecule.
  • the 4-6 membered heterocycloalkyl includes 5-6 membered, 4 membered, 5 membered and 6 membered heterocycloalkyls, etc.
  • 4-6 membered heterocycloalkyl groups include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophenyl (including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), dioxanyl, dithianyl, isoxazolidinyl, isothiazolidinyl
  • heteroatoms may occupy the position at which the heterocycloalkyl is connected to the rest of the molecule.
  • the 4-7 membered heterocycloalkyl includes 4-6 membered, 4-5 membered, 5-6 membered, 6-7 membered, 4 membered, 5 membered, 6 and 7 membered heterocycloalkyl, etc.
  • 4-7 membered heterocycloalkyl groups include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophenyl (including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), dioxanyl, dithianyl, isoxazolidinyl, isothiazolidinyl
  • 3-20 membered heterocycloalkyl includes but is not limited to 20 membered, 18 membered, 16 membered, 10 membered, 8-16 membered, 8-12 membered, 6-10 membered, 5-8 membered, 14-6 membered, 4-7 membered, 5-6 membered, 5-7 membered, 5-8 membered, 6-7 membered, 6-8 membered, 7-8 membered, 4 membered, 5 membered, 6 membered, 7 membered, and 8 membered heterocycloalkyl.
  • the 3-20 membered heterocycloalkyl group includes, but is not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophenyl (including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), dioxanyl, dithianyl, isoxazolidinyl
  • 8-16 membered heterocycloalkyl includes but is not limited to 16 membered, 10 membered, 8-16 membered, 8-15 membered, 8-14 membered, 8-13 membered, 8-12 membered, 8-11 membered, 8-10 membered, 8-9 membered, 16 membered, 15 membered, 14 membered, 13 membered, 12 membered, 11 membered, 10 membered, 9 membered, and 8 membered heterocycloalkyl.
  • examples of 4-6 membered heterocycloalkyl groups include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophenyl (including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), dioxanyl, dithianyl, isoxazolidiny
  • the 8-16 membered heterocycloalkenyl includes 8-10 membered, 8-12 membered, 8-14 membered, 8 membered, 9 membered, 10 membered, 12 membered and 16 membered heterocycloalkenyl groups.
  • Examples of 8-16 membered heterocycloalkenyl groups include, but are not limited to
  • 8-16 membered heteroaromatic ring and “8-16 membered heteroaryl” are used interchangeably in the present invention.
  • the 8-16 membered heteroaryl can be connected to the rest of the molecule through a heteroatom or a carbon atom.
  • the 8-16 membered heteroaryl includes 8-10 membered, 8-12 membered, 10 membered, 8 membered heteroaryl, etc.
  • Examples of the 8-16 membered heteroaryl include, but are not limited to, benzimidazolyl (including 2-benzimidazolyl, etc.), benzoxazolyl, indolyl (including 5-indolyl, etc.), isoquinolyl (including 1-isoquinolyl and 5-isoquinolyl, etc.), quinoxalinyl (including 2-quinoxalinyl and 5-quinoxalinyl, etc.), quinolyl (including 3-quinolyl and 6-quinolyl, etc.),
  • 5-6 membered heteroaromatic ring and “5-6 membered heteroaryl” of the present invention can be used interchangeably.
  • the 5-6 membered heteroaryl can be connected to the rest of the molecule via a heteroatom or a carbon atom.
  • the 5-6 membered heteroaryl includes 5-membered and 6-membered heteroaryl.
  • Examples of the 5-6 membered heteroaryl group include, but are not limited to, pyrrolyl (including N-pyrrolyl, 2-pyrrolyl and 3-pyrrolyl, etc.), pyrazolyl (including 2-pyrazolyl and 3-pyrazolyl, etc.), imidazolyl (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl and 5-imidazolyl, etc.), oxazolyl (including 2-oxazolyl, 4-oxazolyl and 5-oxazolyl, etc.), triazolyl (1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl) and 4H-1,2,4-triazolyl, etc
  • the compounds invented herein can be prepared by a variety of synthetic methods known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthesis methods, and equivalent substitutions known to those skilled in the art. Preferred embodiments include, but are not limited to, the embodiments invented herein.
  • the structure of the compounds invented herein can be confirmed by conventional methods known to those skilled in the art. If the invention herein involves the absolute configuration of the compound, the absolute configuration can be confirmed by conventional technical means in the art.
  • single crystal X-ray diffraction (SXRD) is used to collect diffraction intensity data of the cultivated single crystal using a Bruker D8 venture diffractometer, the light source is CuK ⁇ radiation, and the scanning mode is: / ⁇ scanning, after collecting relevant data, the direct method (Shelxs97) is further used to analyze the crystal structure to confirm the absolute configuration.
  • Boc represents tert-butyloxycarbonyl, which is an amine protecting group
  • DMF represents N,N-dimethylformamide
  • NBS represents N-bromosuccinimide
  • HATU represents O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate
  • HPLC represents high pressure liquid chromatography
  • LCMS represents liquid chromatography-mass spectrometry
  • DMSO-d 6 represents deuterated dimethyl sulfoxide
  • CD 3 OD represents deuterated methanol
  • CDCl 3 represents deuterated chloroform
  • CD 3 CN represents deuterated acetonitrile.
  • the present invention is described in detail below by way of examples, but it is not intended to impose any adverse limitations on the present invention.
  • the compounds of the present invention can be prepared by a variety of synthetic methods known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthesis methods, and equivalent substitutions known to those skilled in the art.
  • Preferred embodiments include but are not limited to the embodiments of the present invention.
  • aqueous phase was extracted with dichloromethane (2 times, 200 mL each time), and the organic phases were combined, washed with saturated brine twice, 200 mL each time, dried over anhydrous sodium sulfate, filtered and concentrated. Ethyl acetate (45 mL) was added to the obtained residue, stirred at 25 ° C for 30 min, the filter cake was collected, and dried to obtain compound B-2.
  • compound B-2 (10 g, 21.54 mmol) was added to tetrahydrofuran (100 mL), cooled to -78 °C, N, N-diisopropylamide lithium (2 mol/L, 16.16 mL) was slowly added dropwise, and the reaction was stirred at -78 °C for 0.5 h. Then iodomethane (4.59 g, 32.31 mmol, 2.01 mL) was slowly added dropwise to the reaction solution. After the addition was completed, the reaction solution was heated to 15 °C and stirred at 15 °C for 1.5 h. The reaction was completed.
  • Tetrabutylammonium fluoride (1 mol/L tetrahydrofuran solution, 10.95 mL) was added to a solution of compound 1-6 (0.75 g, 654.73 ⁇ mol) in tetrahydrofuran (10 mL), and the mixture was stirred at 25°C for 10 min. After the reaction was completed, the crude product was concentrated under reduced pressure and purified by silica gel column chromatography (eluent gradient 0-50% petroleum ether/ethyl acetate, 100 mL/min) to obtain compound 1-7. MS (ESI) m/z: 989.4 [M+H] + .
  • Tetrabutylammonium fluoride (1 mol/L tetrahydrofuran solution, 16 mL) was added to a solution of compound 2-5 (1.6 g, 1.36 mmol) in tetrahydrofuran (16 mL), and the mixture was stirred at 25°C for 0.5 h. Water (100 mL) was added to the reaction solution for dilution, and the mixture was extracted with ethyl acetate (50 mL ⁇ 2).
  • reaction solution was concentrated to obtain a crude product, which was subjected to preparative high performance liquid chromatography (chromatographic column: Phenomenex Luna C18 150*40mm*15 ⁇ m; mobile phase: [water (hydrochloric acid)-acetonitrile]; gradient: acetonitrile 15%-45%) to obtain the hydrochloride of compound 2-7A (LCMS retention time: 0.707 min), MS (ESI) m/z: 674.2 [M+H] + and the hydrochloride of compound 2-7B (LCMS retention time: 0.727 min), MS (ESI) m/z: 674.2 [M+H] + .
  • chromatographic column Phenomenex Luna C18 150*40mm*15 ⁇ m; mobile phase: [water (hydrochloric acid)-acetonitrile]; gradient: acetonitrile 15%-45%
  • lithium aluminum tetrahydride tetrahydrofuran solution (2.5 mol/L, 5.96 mL) was added to a solution of compound 3-4 (2.4 g, 14.89 mmol) in tetrahydrofuran (10 mL), and the mixture was stirred at 0°C for 1 h.
  • the reaction solution was carefully quenched with saturated ammonium chloride solution (40 mL), extracted with ethyl acetate (50 mL ⁇ 3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and dried to obtain compound 3-5.
  • Cyclopropylboric acid (580.11 mg, 6.75 mmol), [1,1-bis(diphenylphosphino)ferrocene]palladium dichloride (367.68 mg, 450.23 ⁇ mol) and potassium carbonate (1.24 g, 9.00 mmol) were added to a mixed solution of compound 3-6 (3 g, 4.50 mmol) in toluene (30 mL) and water (6 mL). The mixed system was stirred at 80 ° C for 12 h under a nitrogen atmosphere.
  • Tetrabutylammonium fluoride (2 mol/L tetrahydrofuran solution, 2 mL) was added to a solution of compound 3-9 (2 g, 1.72 mmol) in tetrahydrofuran (10 mL), and the mixture was stirred at 25°C for 10 min.
  • 1,1-bis(diphenylphosphino)ferrocenepalladium chloride (219.63 mg, 300.16 ⁇ mol) and potassium carbonate (829.66 mg, 6.00 mmol) were added to a solution of compound 4-4 (2 g, 3.00 mmol) and cyclopropylboronic acid (567.22 mg, 6.60 mmol) in toluene (40 mL) and water (8 mL), and the mixture was stirred at 80°C for 16 h under nitrogen protection.
  • reaction solution was poured into water (200 mL), then extracted with ethyl acetate (80 mL*2), and the combined organic phase was washed with water (100 mL) and saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product.
  • tetrakistriphenylphosphine palladium 516.00 mg, 446.54 ⁇ mol
  • potassium phosphate (1.42 g, 6.70 mmol) were added to a solution of compound 4-6 (1.9 g, 2.23 mmol) and intermediate B (1.39 g, 2.68 mmol) in dioxane (20 mL) and water (4 mL), and the mixture was stirred at 110°C for 16 h under nitrogen protection.
  • the reaction solution was filtered through diatomaceous earth, and the filter cake was washed with 200 mL of ethyl acetate.
  • tetrabutylammonium fluoride (1M tetrahydrofuran solution, 6.12 mL) was added to a solution of compound 4-7 (1.78 g, 1.53 mmol) in tetrahydrofuran (30 mL), and the mixture was stirred at 20°C for 0.2 h.
  • the reaction solution was diluted with 150 mL of ethyl acetate, washed with water (200 mL*3) and saturated brine (300 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 4-8.
  • sodium L-ascorbate (83.57 mg, 421.83 ⁇ mol) and copper sulfate pentahydrate (105.32 mg, 421.83 ⁇ mol) were added to a solution of the formate salt of compound 4-9B (280 mg) and intermediate D (239.21 mg, 506.19 ⁇ mol) in tert-butyl alcohol (20 mL) and water (20 mL), and the mixture was stirred at 50°C for 16 h under nitrogen protection.
  • tetrabutylammonium fluoride (2 mol/L tetrahydrofuran solution, 3 mL) was added to a solution of compound 5-3 (2.4 g, 2.15 mmol) in tetrahydrofuran (15 mL), and the resulting reaction solution was stirred at 20°C for 15 min.
  • 1,1-bis(diphenylphosphino)ferrocenepalladium chloride (1.85g, 2.53mmol) and potassium acetate (7.45g, 75.90mmol) were added to a solution of compound D-1 (8g, 25.30mmol) and bis(triphenylphosphino)ferrocenepalladium chloride (1.85g, 2.53mmol) and potassium acetate (7.45g, 75.90mmol) in dioxane (100mL), and the mixture was stirred at 100°C for 2h under nitrogen protection.
  • 1,1-bis(diphenylphosphino)ferrocenepalladium chloride (1.85g, 2.53mmol) and sodium carbonate (6.70g, 63.25mmol) were added to a solution of compound 5-6 (9.19g, 25.30mmol) and 5-12 (9.74g, 25.30mmol) in dioxane (120mL) and water (24mL), and the mixture was stirred at 100°C for 2h under nitrogen protection.
  • D-8 (1.68 g, 7.74 mmol), N,N-diisopropylethylamine (5.34 mL, 30.64 mmol) and HATU (3.50 g, 9.19 mmol) were added to a DMF (34 mL) solution of the hydrochloride salt of compound 5-17 (3.3 g), and the mixture was stirred at 20°C for 1 h under nitrogen protection.
  • compound 5-20 122.24 mg, 235.32 ⁇ mol
  • sodium ascorbate 42.38 mg, 213.92 ⁇ mol
  • copper sulfate pentahydrate 53.41 mg, 213.92 ⁇ mol
  • a mixed solution of trifluoroacetate salt of compound 5-5B 0.2 g
  • tert-butyl alcohol 20 mL
  • water 20 mL
  • 10% aqueous ammonia 50 mL
  • was added to the reaction solution at 20° C. and stirred for 10 min, and extracted with a mixed solvent of ethyl acetate/methanol 7/1 (50 mL*2).
  • RPMI-1640 medium, DMEM medium, penicillin/streptomycin antibiotics were purchased from Gibco, and fetal bovine serum was purchased from Hyclone.
  • 3DCellTiter-Glo (cell viability chemiluminescent detection reagent) reagent was purchased from Promega.
  • GP2D cell line (DMEM + 10% FBS + 1% penicillin/streptomycin) was purchased from ECACC, and PK-59 cell line (DMEM + 10% FBS + 1% penicillin/streptomycin) was purchased from Nanjing Kebai Biotechnology Co., Ltd.
  • A375 cell line (DMEM + 10% FBS + 1% penicillin/streptomycin) was purchased from ATCC, Envision multi-label analyzer (PerkinElmer).
  • the cells were seeded in an ultra-low attachment 96-well U-shaped plate, with 80 ⁇ L of cell suspension per well, containing 1000 cells.
  • the cell plate was placed in a carbon dioxide incubator for overnight culture.
  • the compound to be tested was diluted 5-fold into 8 concentrations, i.e. from 2 mM to 25.6 nM, using a pipette, and a double-well experiment was set up. Add 78 ⁇ L of culture medium, and then transfer 2 ⁇ L of the gradient dilution compound per well to the middle plate according to the corresponding position, mix well and transfer 20 ⁇ L per well to the cell plate.
  • the concentration range of the compound transferred to the cell plate is 10 ⁇ M to 0.128 nM.
  • the cell plate is placed in a carbon dioxide incubator and cultured for 5 days. Prepare another cell plate and read the signal value on the day of drug addition as the maximum value (Max value in the equation below) for data analysis.
  • the compounds of the present invention exhibit excellent in vitro activity against G12D mutated cells, but have no inhibitory activity against A375 cells with low G12D expression.
  • RPMI-1640 medium was purchased from GIbco
  • penicillin/streptomycin antibiotics were purchased from Vicente
  • fetal bovine serum was purchased from Biosera.
  • Protein primary and secondary antibodies were purchased from Cell Signaling Technology.
  • AsPC-1 cell line was purchased from ATCC, and 4% paraformaldehyde, Triton-100, etc. were purchased from Bio-Tech. Envision multi-label analyzer (PerkinElmer).
  • the cells were seeded in a 96-well black-walled plate, with 80 ⁇ L of cell suspension per well, containing 50,000 cells.
  • the cell plate was placed in a carbon dioxide incubator for overnight culture.
  • the compound to be tested was diluted 5-fold to 8 concentrations using a gun, i.e., from 2mM to 25.6nM, and a double-well experiment was set up. 78 ⁇ L of culture medium was added to the middle plate, and then 2 ⁇ L of the gradient dilution compound per well was transferred to the middle plate according to the corresponding position, and 20 ⁇ L of each well was transferred to the cell plate after mixing. The concentration range of the compound transferred to the cell plate was 10 ⁇ M to 0.128nM.
  • the cells were removed, the culture medium was discarded, and the cells were fixed with 4% PFA fixative for 30min, washed 3 times with PBS, permeabilized with 0.1% Triton for 20min, washed 3 times with PBS, blocked with 0.1% BSA solution at room temperature for 1h, incubated with protein primary antibody at 4°C overnight, washed 3 times with PBST, incubated with fluorescent secondary antibody (FITC or Cy5 labeled) at room temperature for 2h, and washed 3 times with PBST.
  • FITC or Cy5 labeled fluorescent secondary antibody
  • FITC/Cy5 (FITCsample-FITCblank)/(FITCsample-FITCblank)
  • the inhibition % under compound treatment was calculated as [1-(FITC/Cy5comp.)/(FITC/Cy5DMSO)]*100, and the DC 50 value was obtained by four-parameter curve fitting (obtained by "log(inhibitor)vs.response--Variable slope" mode in GraphPad Prism). The results are shown in Table 3.
  • AsPC-1 cells were purchased from ATCC; RPMI-1640 medium was purchased from GIbco; fetal bovine serum was purchased from Hyclone; Advanced Phospho- ERK1/2 (THR202/TYR204) KIT was purchased from Bioauxilium, see Table 3 for details.
  • the raw data were converted into inhibition rate using the equation (Sample-Min)/(Max-Min)*100%, and the IC50 value was obtained by four-parameter curve fitting (obtained by log(inhibitor) vs.response--Variable slope mode in GraphPad Prism).
  • the results of the inhibition test of the compounds of the present invention on p-ERK are shown in Table 4.
  • Max well The reading value of the positive control well is 1X lysate
  • Min well negative control well reading value is 0.5% DMSO cell well cell lysate
  • the compounds of the present invention exhibit excellent G12D degradation activity and have good inhibitory activity on downstream pERK.
  • mice Female Balb/c nude mice were inoculated subcutaneously with PK-59 human pancreatic cancer cells and randomly divided into groups (6 animals per group) according to tumor volume and body weight on day 6 after inoculation, and the drugs were administered as described below.
  • the compound of the present invention exhibits good efficacy and safety and has a good tumor inhibition effect in vivo.

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Abstract

La présente invention concerne un composé ayant une structure de quinazoline et son utilisation. Spécifiquement, la présente invention concerne un composé tel que représenté par la formule (VI), un stéréoisomère de celui-ci et un sel pharmaceutiquement acceptable de celui-ci.
PCT/CN2024/081502 2023-03-13 2024-03-13 Composé ayant une structure de quinazoline et son utilisation Pending WO2024188281A1 (fr)

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CN202310286647.4 2023-03-22
CN202310873122.0 2023-07-14
CN202310873122 2023-07-14
CN202310918759 2023-07-24
CN202310918759.7 2023-07-24
CN202311060914 2023-08-21
CN202311060914.2 2023-08-21
CN202311265591 2023-09-27
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WO2025080946A2 (fr) 2023-10-12 2025-04-17 Revolution Medicines, Inc. Inhibiteurs de ras
WO2025171296A1 (fr) 2024-02-09 2025-08-14 Revolution Medicines, Inc. Inhibiteurs de ras
US12448399B2 (en) 2023-01-26 2025-10-21 Arvinas Operations, Inc. Cereblon-based KRAS degrading PROTACs and uses related thereto
WO2025240847A1 (fr) 2024-05-17 2025-11-20 Revolution Medicines, Inc. Inhibiteurs de ras
WO2025255438A1 (fr) 2024-06-07 2025-12-11 Revolution Medicines, Inc. Procédés de traitement d'une maladie ou d'un trouble lié à la protéine ras

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WO2022173032A1 (fr) * 2021-02-15 2022-08-18 アステラス製薬株式会社 Composé quinazoline pour induire la dégradation de la protéine kras de mutation g12d
WO2022173033A1 (fr) * 2021-02-15 2022-08-18 アステラス製薬株式会社 Composés de 4-aminoquinazoline
WO2023119677A1 (fr) * 2021-12-24 2023-06-29 Astellas Pharma Inc. Composition pharmaceutique comprenant un composé quinazoline
WO2023171781A1 (fr) * 2022-03-11 2023-09-14 アステラス製薬株式会社 Composé hétérocyclique pour induire la dégradation de la protéine kras portant la mutation g12d
WO2024029613A1 (fr) * 2022-08-05 2024-02-08 アステラス製薬株式会社 Composé hétérocyclique destiné à induire la dégradation de la protéine kras portant une mutation
WO2024034123A1 (fr) * 2022-08-12 2024-02-15 アステラス製薬株式会社 Composition médicinale contenant un composé hétérocyclique
WO2024040080A1 (fr) * 2022-08-19 2024-02-22 Erasca, Inc. Conjugués inhibiteurs de kras

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CN110267957A (zh) * 2017-02-02 2019-09-20 安斯泰来制药株式会社 喹唑啉化合物
WO2022173032A1 (fr) * 2021-02-15 2022-08-18 アステラス製薬株式会社 Composé quinazoline pour induire la dégradation de la protéine kras de mutation g12d
WO2022173033A1 (fr) * 2021-02-15 2022-08-18 アステラス製薬株式会社 Composés de 4-aminoquinazoline
WO2023119677A1 (fr) * 2021-12-24 2023-06-29 Astellas Pharma Inc. Composition pharmaceutique comprenant un composé quinazoline
WO2023171781A1 (fr) * 2022-03-11 2023-09-14 アステラス製薬株式会社 Composé hétérocyclique pour induire la dégradation de la protéine kras portant la mutation g12d
WO2024029613A1 (fr) * 2022-08-05 2024-02-08 アステラス製薬株式会社 Composé hétérocyclique destiné à induire la dégradation de la protéine kras portant une mutation
WO2024034123A1 (fr) * 2022-08-12 2024-02-15 アステラス製薬株式会社 Composition médicinale contenant un composé hétérocyclique
WO2024040080A1 (fr) * 2022-08-19 2024-02-22 Erasca, Inc. Conjugués inhibiteurs de kras

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US12448399B2 (en) 2023-01-26 2025-10-21 Arvinas Operations, Inc. Cereblon-based KRAS degrading PROTACs and uses related thereto
WO2025080946A2 (fr) 2023-10-12 2025-04-17 Revolution Medicines, Inc. Inhibiteurs de ras
WO2025171296A1 (fr) 2024-02-09 2025-08-14 Revolution Medicines, Inc. Inhibiteurs de ras
WO2025240847A1 (fr) 2024-05-17 2025-11-20 Revolution Medicines, Inc. Inhibiteurs de ras
WO2025255438A1 (fr) 2024-06-07 2025-12-11 Revolution Medicines, Inc. Procédés de traitement d'une maladie ou d'un trouble lié à la protéine ras

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