WO2022161489A1 - Composé pentahétérocyclique, son procédé de préparation et son utilisation - Google Patents

Composé pentahétérocyclique, son procédé de préparation et son utilisation Download PDF

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Publication number
WO2022161489A1
WO2022161489A1 PCT/CN2022/074955 CN2022074955W WO2022161489A1 WO 2022161489 A1 WO2022161489 A1 WO 2022161489A1 CN 2022074955 W CN2022074955 W CN 2022074955W WO 2022161489 A1 WO2022161489 A1 WO 2022161489A1
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alkyl
membered
substituted
independently
halogen
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PCT/CN2022/074955
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English (en)
Chinese (zh)
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罗会兵
姜佳俊
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上海艾力斯医药科技股份有限公司
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Priority to CN202280011926.3A priority Critical patent/CN116829557A/zh
Publication of WO2022161489A1 publication Critical patent/WO2022161489A1/fr

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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
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • 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
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
    • C07D471/14—Ortho-condensed systems

Definitions

  • the present invention relates to a pentaheterocyclic compound, a preparation method and application thereof.
  • RAS protein is a guanine trinucleotide phosphate (GTP)-binding protein with a molecular weight of 21 kDa located on the cell membrane, consisting of 188 or 189 amino acids.
  • GTP guanine trinucleotide phosphate
  • the active state of RAS protein has effects on cell growth, differentiation, cytoskeleton, protein transport and secretion, and its activity is regulated by binding to GTP or guanine dinucleotide phosphate (GDP).
  • GTP guanine trinucleotide phosphate
  • RAS protein When RAS protein binds to GDP, it is in an "inactive" state; when stimulated by upstream specific cell growth factors, guanine nucleotide exchange factor (GEF) catalyzes the release of GDP from RAS protein, which binds to GTP and is in an "activated” state "state.
  • GEF guanine nucleotide exchange factor
  • the RAS protein bound to GTP can activate downstream proteins and activate downstream signaling pathways.
  • the RAS protein itself has weak GTPase activity and can hydrolyze GTP to GDP, thereby realizing the transformation from the activated state to the inactive state. In this hydrolysis process, GTPase activating protein (GAP) is also required, which can interact with RAS protein and greatly promote its ability to hydrolyze GTP to GDP.
  • GAP GTPase activating protein
  • RAS protein Any mutation in a RAS protein that affects its own GTPase activity or its ability to interact with GAP or its ability to hydrolyze GTP to GDP will result in the RAS protein being in a prolonged activated state, which continues to be administered Downstream protein growth signals that lead to constant cell growth and differentiation, which can eventually lead to cancer.
  • KRAS V-Ki-Ras2 Kirsten rat sarcoma virus oncogene homolog
  • NRAS neuroblastoma RAS virus oncogene homolog
  • HRAS V-Ha-Ras murine Harvey sarcoma virus oncogene homolog
  • G12C mutation is one of the most common KRAS mutations, specifically referring to the mutation of glycine at position 12 of KRAS to cysteine (cysteine), which is present in about 14% of non-small cell lung cancer (NSCLC), 4 % of colorectal cancers and 2% of pancreatic cancers.
  • Other common KRAS mutations include G12D, G12V, which are expressed at high levels in colorectal and pancreatic cancers.
  • KRAS G12C inhibitors for the treatment of diseases mediated by KRAS G12C mutations, such as cancer.
  • the technical problem to be solved by the present invention is the problem of single structure of KRAS G12C inhibitor in the prior art, and provides a pentaheterocyclic compound, its preparation method and its application.
  • the pentaheterocyclic compounds in the present application have the activity of inhibiting the proliferation of Ba/F3 KRAS-G12C cells, NCI-H358 cells and MIA PaCa-2 cells expressing the KRAS G12C mutein, and are also effective against the cell line NCI-H358 nude mice
  • the growth of subcutaneous xenografts has a good inhibitory effect.
  • the present invention solves the above-mentioned technical problems through the following technical solutions.
  • the present invention provides a compound shown in formula I, a pharmaceutically acceptable salt or a solvate thereof;
  • X is O, S, SO, SO 2 or NR 8 ;
  • Y is CH or does not exist
  • Z is O or does not exist
  • X 1 is CH, CR 7 or N;
  • Y 1 is CH, CR 7 or N;
  • A is or -SO 2 -(CH 2 ) q NR 11 R 12 ;
  • R 2 and R 3 are each independently C 1-6 alkyl, 3-6 membered cycloalkyl, 3-6 membered cycloalkenyl, H, deuterium, C 1-6 alkyl substituted with one or more deuterium , -C 1-6 alkylene-NR 11 R 12 , C 1-6 alkyl substituted with one or more hydroxy, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, or R 2.
  • R 3 and the connected atoms together form a 3-7-membered heterocycloalkyl, a 3-7-membered heterocycloalkenyl or a 5-6-membered heteroaryl; wherein the 3-12-membered heterocycloalkyl, 3- 12-membered heterocycloalkenyl, 3-7 membered heterocycloalkenyl, 3-7 membered heterocycloalkenyl, 5-6 membered heteroaryl optionally separated by 1-3 (eg 1, 2 or 3) each independently selected from halogen, C 1-6 alkyl, C 1-6 alkyl substituted with one or more deuteriums, C 1-6 alkoxy, C 1-6 alkyl substituted with one or more halogens, One or more halogen substituted C 1-6 alkoxy, -NR 11 R 12 , -OH, C 1-6 alkyl substituted with one or more hydroxy, and -C 1-6 alkylene-NH 2
  • the substituents are substituted, when the substituent
  • Each R 11 and R 12 is each independently H, C 1-6 alkyl, C 1-6 alkyl substituted with one or more deuterium, or R 11 , R 12 taken together with the attached atom to form 3-7 membered heterocycloalkyl or 3-7 membered heterocycloalkenyl;
  • R 4 is a 6-10-membered aryl group or a 5-10-membered heteroaryl group; the aryl or heteroaryl group is optionally selected from C 1 by 1-5 (eg 1, 2, 3, 4 or 5) -6 alkyl, C 1-6 alkyl substituted with one or more deuterium, C 1-6 alkoxy, C 1-6 alkyl substituted with one or more halo, substituted with one or more halo C 1-6 alkoxy, -NR 11 R 12 , -OH, halogen, -CN, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkane substituted by one or more hydroxyl groups group, -C 1-6 alkylene-NR 11 R 12 , 3-6-membered cycloalkyl, 3-6-membered cycloalkenyl, 3-7-membered heterocycloalkyl and 3-7-membered heterocycloalkenyl Substituent substitution, when there are 2-5
  • each R is independently H, deuterium , halogen, C 1-6 alkyl, or C 1-6 alkyl substituted with one or more deuterium;
  • Each R is independently H, deuterium, halogen, C 1-6 alkyl, C 1-6 alkyl substituted with one or more halo, C 1-6 alkyl substituted with one or more deuterium, -C 1-6 alkylene-NR 11 R 12 , -NR 11 R 12 , 3-7 membered heterocycloalkyl, 3-7 membered heterocycloalkenyl, 3-7 membered heterocycloalkyl substituted C 1 -6 alkyl or 3-7 membered heterocycloalkenyl substituted C 1-6 alkyl; wherein the 3-7 membered heterocycloalkyl or 3-7 membered heterocycloalkenyl is optionally substituted by halogen or C 1- 6 alkyl substitution;
  • Each R 7 is independently halogen, -CN, C 1-6 alkyl, C 1-6 alkyl substituted with one or more deuterium, C 2-6 alkenyl, C 2-6 alkynyl, or C 2-6 alkynyl or multiple halogen-substituted C 1-6 alkoxy groups;
  • R 7A is H, halogen, -CN, C 1-6 alkyl, C 1-6 alkyl substituted with one or more deuterium, C 2-6 alkenyl, C 2-6 alkynyl, or C 1-6 alkynyl substituted by one or more deuterium halogen-substituted C 1-6 alkoxy;
  • R 8 is H, C 1-6 alkyl, or C 1-6 alkyl substituted with one or more deuteriums;
  • Each R 13 is independently H, C 1-6 alkyl, C 1-6 alkyl substituted with one or more deuteriums, C 2-6 alkenyl, C 2-6 alkynyl, or C 2-6 alkynyl substituted by one or more halogen-substituted C 1-6 alkyl;
  • n 0, 1, 2, 3, 4, 5, 6 or 7;
  • q 0, 1, 2 or 3;
  • the carbon atom with "*" is a chiral carbon atom, it is in R configuration, S configuration or a mixture thereof.
  • X is O, S, SO or SO 2 , preferably O, SO or SO 2 , O is more preferred.
  • Y is CH.
  • Z is O.
  • X 1 is CR 7 or N.
  • X 1 is CH or CR 7 , preferably CR 7 ; when X 1 is CR 7 , the R 7 is preferably halogen, more preferably chlorine or fluorine, more preferably chlorine.
  • Y 1 is CR 7 or N.
  • Y 1 is CH or CR 7 , preferably CR 7 ; when Y 1 is CR 7 , the R 7 is preferably halogen, more preferably chlorine or fluorine, more preferably fluorine.
  • each R 7 is independently halogen or -CN.
  • R 7A is H.
  • the heteroatoms in the heterocycloalkyl, heterocycloalkenyl or heteroaryl are selected from one or more of N, O and S, and the number of heteroatoms is 1 or 2 , 3 or 4.
  • each R 5 is independently H, deuterium or halogen, preferably H or halogen, more preferably H or fluorine.
  • each R 6 is independently H, deuterium, halogen, C 1-6 alkyl, C 1-6 alkyl substituted by one or more halogens, or C 1-6 alkyl substituted by one or more deuteriums Substituted C 1-6 alkyl, preferably H or C 1-6 alkyl substituted with one or more halogens, more preferably H or monofluoromethyl.
  • each R 1 is independently a C 1-6 alkyl group, preferably a methyl group.
  • R 2 or R 3 are each independently H, deuterium, C 1-6 alkyl, 3-6-membered cycloalkyl, 3-6-membered cycloalkenyl, and a group consisting of one or more Deuterium substituted C 1-6 alkyl, -C 1-6 alkylene-NR 11 R 12 , C 1-6 alkyl substituted with one or more hydroxy, 3-12 membered heterocycloalkyl or 3- 12-membered heterocycloalkenyl; wherein the 3-12-membered heterocycloalkenyl, 3-12-membered heterocycloalkenyl are optionally independently selected from C 1- 6 alkyl and C 1-6 alkyl substituted by one or more deuterium-substituted substituents, when there are 2 or 3 substituents, the substituents are the same or different.
  • R 2 or R 3 are each independently H, deuterium, C 1-6 alkyl, C 1-6 alkyl substituted by one or more deuteriums, -C 1-6 alkylene Alkyl-NR 11 R 12 , 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkyl substituted with one or more (eg 2 or 3) C 1-6 alkyl or substituted by one or Multiple hydroxy substituted C 1-6 alkyl.
  • R 2 or R 3 are each independently H, C 1-6 alkyl, -C 1-6 alkylene-NR 11 R 12 , one or more (for example, 2 or 3) C 1-6 alkyl substituted 3-12 membered heterocycloalkyl or C 1-6 alkyl substituted with one or more hydroxy groups.
  • R 2 or R 3 are each independently H, C 1-6 alkyl, 3- substituted by one or more (eg 2 or 3) C 1-6 alkyl groups 12-membered heterocycloalkyl or -C 1-6 alkylene-NR 11 R 12 .
  • R 2 is H, deuterium, C 1-6 alkyl, 3-6-membered cycloalkyl, 3-6-membered cycloalkenyl, C 1- substituted by one or more deuterium 6 alkyl, -C 1-6 alkylene-NR 11 R 12 , C 1-6 alkyl substituted with one or more hydroxyl groups, 3-12-membered heterocycloalkyl or 3-12-membered heterocycloalkenyl ; wherein the 3-12-membered heterocycloalkyl, 3-12-membered heterocycloalkenyl are optionally 1-3 (eg 1, 2 or 3) independently selected from C 1-6 alkyl and by a or more substituents of the deuterium-substituted C 1-6 alkyl group are substituted, and when there are 2 or 3 substituents, the substituents are the same or different.
  • R 3 is H, deuterium, C 1-6 alkyl, -C 1-6 alkylene-NR 11 R 12 or by one or more (eg 2 or 3) C 1-6 alkyl substituted 3-12 membered heterocycloalkyl.
  • R 3 is H, deuterium or -C 1-6 alkylene-NR 11 R 12 .
  • R 3 is H or deuterium.
  • R 2 or R 3 are each independently H, C 1-6 alkyl, deuterium, C 1-6 alkyl substituted by one or more deuteriums, -C 1-6 alkyl Alkyl-NR 11 R 12 , 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkyl substituted with one or more (eg 2 or 3) C 1-6 alkyl or substituted by one or Multiple hydroxy substituted C 1-6 alkyl, preferably H, C 1-6 alkyl, -C 1-6 alkylene-NR 11 R 12 , substituted by one or more (eg 2 or 3) C 1-6 alkyl substituted 3-12 membered heterocycloalkyl or C 1-6 alkyl substituted by one or more hydroxy, more preferably H, C 1-6 alkyl, substituted by one or more (eg 2 or 3) C 1-6 alkyl substituted 3-12-membered heterocycloalkyl or -C 1-6 alkylene-
  • each R 11 and R 12 are independently H, C 1- 6 alkyl, C 1-6 alkyl substituted with one or more deuterium or R 11 , R 12 together with the attached atom to form a 3-7 membered heterocycloalkyl, preferably H, methyl, CD 3 , or R 11 , R 12 forms together with the connected atoms
  • R 4 is a 6-10-membered aryl group or a 5-10-membered heteroaryl group; the aryl or heteroaryl group is optionally replaced by 1-5 (for example, 1, 2, 3, 4 or 5) selected from C 1-6 alkyl, C 1-6 alkyl substituted with one or more deuterium, C 1-6 alkoxy, C 1-6 alkane substituted with one or more halogens base, C 1-6 alkoxy substituted by one or more halogens, -NR 11 R 12 , -OH, halogen, -CN, C 2-6 alkenyl, C 2-6 alkynyl, 3-7 membered Substituent substitution of heterocycloalkyl, 3-7-membered heterocycloalkenyl, 3-6-membered cycloalkyl and 3-6-membered cycloalkenyl, when there are 2-5 substituents, the substituents are the same or different; wherein said C 1-6 alkyl, C 1-6 alky
  • R 4 is a 6-10-membered aryl group or a 5-10-membered heteroaryl group; the aryl or heteroaryl group is optionally replaced by 1-5 (for example, 1, 2, 3, 4 or 5) selected from C 1-6 alkyl, C 1-6 alkyl substituted with one or more deuterium, C 1-6 alkoxy, C 1-6 alkane substituted with one or more halogens base, C 1-6 alkoxy substituted by one or more halogens, -NR 11 R 12 , -OH, halogen, -CN, C 2-6 alkenyl, C 2-6 alkynyl, 3-6 membered Substituent substitution of cycloalkyl and 3-6 membered cycloalkenyl, when there are 2-5 substituents, the substituents are the same or different; wherein the C 1-6 alkyl, C 1-6 alkane Oxy and C2-6alkenyl are optionally substituted with -
  • R 4 is a 6-10-membered aryl group or a 5-10-membered heteroaryl group; the aryl or heteroaryl group is optionally selected from 1-5 C 1-6 alkyl groups group, C 1-6 alkoxy, C 1-6 alkyl substituted with one or more halogens, -NR 11 R 12 , -OH, halogen, C 2-6 alkenyl, C 2-6 alkynyl and Substituent substitution of 3-7 membered heterocycloalkyl, wherein the C 1-6 alkyl, C 1-6 alkoxy and C 2-6 alkenyl are optionally substituted by -CN or C 2-6 alkynyl .
  • R 4 is a 6-10-membered aryl group or a 5-10-membered heteroaryl group; the aryl or heteroaryl group is optionally selected from 1-5 C 1-6 alkyl groups group, C 1-6 alkyl substituted with one or more halogens, amino, -OH, C 2-6 alkynyl and substituents of halogen; wherein said C 1-6 alkyl is optionally substituted with -CN or C 2-6 alkynyl substitution.
  • R 4 is a 6-10-membered aryl group or a 5-10-membered heteroaryl group, and the aryl or heteroaryl group is optionally selected from amino, -OH, Fluorine, chlorine, methyl, difluoromethyl, Ethyl, trifluoromethyl, and methoxy substituents.
  • R 4 is a 6-10-membered aryl group or a 5-10-membered heteroaryl group, and the aryl or heteroaryl group is optionally selected from amino, -OH, Substituent substitution of fluorine, chlorine, methyl, ethyl, difluoromethyl, trifluoromethyl and methoxy.
  • R 4 is a 10-membered aryl group or a 9-10-membered heteroaryl group; the aryl or heteroaryl group is optionally replaced by 1-5 (for example, 1, 2, 3, 4 or 5) one selected from the group consisting of C 1-6 alkyl, C 1-6 alkyl substituted by one or more deuteriums, C 1-6 alkoxy, C 1-6 alkyl substituted by one or more halogens, C 1-6 alkoxy, -NR 11 R 12 , -OH, halogen, -CN, C 2-6 alkenyl, C 2-6 alkynyl, 3-6 membered cycloalkane substituted with one or more halogens Substituents of 3-6 membered cycloalkenyl and 3-6 membered cycloalkenyl groups, when there are 2-5 substituents, the substituents are the same or different; wherein the C 1-6 alkyl, C 1-6 alkoxy and
  • R 4 is a 6-10-membered aryl group or a 5-10-membered heteroaryl group; the aryl or heteroaryl group is optionally selected from 1-5 C 1-6 alkyl groups group, C 1-6 alkoxy, C 1-6 alkyl substituted with one or more halogens, -NR 11 R 12 , -OH, halogen, C 2-6 alkenyl, C 2-6 alkynyl and Substituents of 3-7 membered heterocycloalkyl, preferably optionally substituted by 1-5 selected from C 1-6 alkyl, C 1-6 alkyl substituted by one or more halogens, amino, -OH and Substituent substitution of halogen, wherein said C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl are optionally substituted by -CN or C 2-6 alkynyl; preferably, the said Aryl or heteroaryl is optionally 1-5 selected from amino,
  • R 4 when R 4 is a 6-10-membered aryl group or a 5-10-membered heteroaryl group; the aryl or heteroaryl group is optionally selected from -NR 11 R by 1-5
  • the R 11 is preferably H, and the R 12 is preferably H.
  • R 4 is preferred
  • n is 0, 1 or 2, preferably 0 or 1.
  • R 1 when R 1 is a C 1-6 alkyl group, the C 1-6 alkyl group is methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl is methyl, ethyl, propyl, isopropyl, butyl, isobutyl or tert-butyl, preferably methyl.
  • R 2 or R 3 when R 2 or R 3 is independently a C 1-6 alkyl group, the C 1-6 alkyl group is methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, can be methyl, ethyl, propyl, isopropyl, butyl, isobutyl or tert-butyl.
  • R 2 or R 3 when R 2 or R 3 is independently a C 1-6 alkyl group, the C 1-6 alkyl group is a methyl group.
  • the C 1-6 alkylene is methylene, methylene Ethyl, propylene, isopropylene, n-butylene, isobutylene, sec-butylene or tert-butylene, which can be methylene, ethylene, propylene, isopropylidene , butylene, isobutylene or tert-butylene, more preferably methylene.
  • R 11 or R 12 when R 11 or R 12 is independently a C 1-6 alkyl group, the C 1-6 alkyl group is methyl, ethyl, propyl, isopropyl, n-Butyl, isobutyl, sec-butyl or tert-butyl may be methyl, ethyl, propyl, isopropyl, butyl, isobutyl or tert-butyl, preferably methyl.
  • R 2 or R 3 are each independently -C 1-6 alkylene-NR 11 R 12
  • R 11 or R 12 are each independently C 1-6 alkyl
  • the C 1-6 alkyl group is methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, and can be methyl, ethyl, propyl, isopropyl, butyl, isobutyl or tert-butyl, preferably methyl.
  • each of R 11 or R 12 is independently a C 1-6 alkyl group substituted with one or more deuteriums, the multiple is preferably two or three.
  • R 11 or R 12 are each independently a C 1-6 alkyl group substituted with one or more deuteriums
  • the C 1-6 alkyl group is preferably methyl, ethyl propyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, which can be methyl, ethyl, propyl, isopropyl, butyl, isobutyl or tert-butyl , more preferably methyl.
  • R 11 or R 12 are each independently a C 1-6 alkyl group substituted by one or more deuteriums
  • the multiple are preferably two or three
  • the C 1-6 Alkyl is preferably methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, also preferably methyl, ethyl, propyl, isopropyl, Butyl, isobutyl or tert-butyl, more preferably methyl
  • the C 1-6 alkyl group substituted with multiple deuteriums is CD 3 .
  • R 2 or R 3 are each independently -C 1-6 alkylene-NR 11 R 12 , R 11 or R 12 are each independently substituted by one or more deuteriums
  • the number of said plurality is preferably two or three.
  • R 2 or R 3 are each independently -C 1-6 alkylene-NR 11 R 12
  • R 11 or R 12 are each independently substituted by one or more deuteriums
  • the C 1-6 alkyl is preferably methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, which may be Methyl, ethyl, propyl, isopropyl, butyl, isobutyl or tert-butyl, more preferably methyl.
  • R 2 or R 3 are each independently -C 1-6 alkylene-NR 11 R 12
  • R 11 or R 12 are each independently substituted by one or more deuteriums
  • the number of said multiple is preferably two or three
  • the C 1-6 alkyl group is preferably methyl, ethyl, propyl, isopropyl, n-butyl, isopropyl Butyl, sec-butyl or tert-butyl, which can be methyl, ethyl, propyl, isopropyl, butyl, isobutyl or tert-butyl, more preferably methyl, substituted by multiple deuteriums
  • the C 1-6 alkyl group is preferably CD 3 .
  • the 3-7 membered heterocycloalkyl is monocyclic, bicyclic or tricyclic .
  • the 3-7 membered heterocycloalkyl is a spiro ring or a bridged ring.
  • the 3-7-membered heterocycloalkyl group is a tetrahydropyrrolyl group, preferably
  • R 2 or R 3 are each independently -C 1-6 alkylene-NR 11 R 12 , R 11 and R 12 together with the connected atoms form a 3-7 membered heterocycle
  • the 3-7 membered heterocycloalkyl group is monocyclic, bicyclic or tricyclic.
  • R 2 or R 3 are each independently -C 1-6 alkylene-NR 11 R 12 , R 11 and R 12 together with the connected atoms form a 3-7 membered heterocycle
  • the 3-7 membered heterocycloalkyl group is a spiro ring or a bridged ring.
  • R 2 or R 3 are each independently -C 1-6 alkylene-NR 11 R 12 , R 11 and R 12 together with the connected atoms form a 3-7 membered heterocycle
  • the 3-7 membered heterocycloalkyl group is a 4-6 membered heterocycloalkyl group.
  • R 2 or R 3 are each independently -C 1-6 alkylene-NR 11 R 12 , R 11 and R 12 together with the connected atoms form a 3-7 membered heterocycle
  • the heteroatom in the 3-7 membered heterocycloalkyl group is N.
  • R 2 or R 3 are each independently -C 1-6 alkylene-NR 11 R 12 , R 11 and R 12 together with the connected atoms form a 3-7 membered heterocycle
  • the number of heteroatoms in the 3-7 membered heterocycloalkyl group is one or two.
  • R 2 or R 3 are each independently -C 1-6 alkylene-NR 11 R 12 , R 11 and R 12 together with the connected atoms form a 3-7 membered heterocycle
  • alkyl the 3-7 membered heterocycloalkyl is tetrahydropyrrolyl, preferably
  • R 2 or R 3 is each independently -C 1-6 alkylene-NR 11 R 12
  • the C 1-6 alkylene is methylene, methylene Ethyl, propylene, isopropylidene, butylene, isobutylene or tert-butylene, preferably methylene
  • the -C 1-6 alkylene-NR 11 R 12 is preferred
  • each of R 2 or R 3 is independently a C 1-6 alkyl group substituted by one or more hydroxyl groups, the multiple is preferably two or three.
  • R 2 or R 3 are each independently a C 1-6 alkyl group substituted by one or more hydroxyl groups
  • the C 1-6 alkyl group is methyl, ethyl , propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, which can be methyl, ethyl, propyl, isopropyl, butyl, isobutyl or tert-butyl, Methyl is preferred.
  • R 2 or R 3 when R 2 or R 3 is each independently a C 1-6 alkyl group substituted by one or more hydroxyl groups, the multiple are preferably two or three, and the said multiple is preferably two or three.
  • C 1-6 alkyl is preferably methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, also preferably methyl, ethyl, propyl, isopropyl , butyl, isobutyl or tert-butyl.
  • R 2 or R 3 when R 2 or R 3 is each independently a C 1-6 alkyl group substituted by one or more hydroxyl groups, the multiple are preferably two or three, and the said multiple is preferably two or three.
  • C 1-6 alkyl is methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, which can be methyl, ethyl, propyl, isopropyl , butyl, isobutyl or tert-butyl, preferably methyl.
  • R 2 or R 3 are each independently a C 1-6 alkyl group substituted with a hydroxyl group, the C 1-6 alkyl group substituted with a hydroxyl group is
  • R 2 or R 3 when R 2 or R 3 is each independently a 3-12-membered heterocycloalkyl, the 3-12-membered heterocycloalkyl is monocyclic, bicyclic or tricyclic.
  • R 2 or R 3 are each independently a 3-12-membered heterocycloalkyl
  • the 3-12-membered heterocycloalkyl is a spiro ring or a bridged ring.
  • R 2 or R 3 is each independently a 3-12-membered heterocycloalkyl
  • the 3-12-membered heterocycloalkyl is a 3-6-membered heterocycloalkyl.
  • R 2 or R 3 is each independently a 3-12-membered heterocycloalkyl, the heteroatom in the 3-12-membered heterocycloalkyl is N.
  • R 2 or R 3 is each independently a 3-12-membered heterocycloalkyl
  • the number of heteroatoms in the 3-12-membered heterocycloalkyl is 1 or 2 indivual.
  • R 2 or R 3 are each independently a 3-12-membered heterocycloalkyl
  • the 3-12-membered heterocycloalkyl is a 3-6-membered heterocycloalkyl
  • Tetrahydropyrrolyl is preferred, more preferred (E.g ).
  • R 2 or R 3 are each independently a 3-12-membered heterocycloalkyl, and the 3-12-membered heterocycloalkyl is substituted by a C 1-6 alkyl group, C 1-6
  • the number of alkyl groups is preferably one, two or three.
  • R 2 or R 3 is each independently a 3-12-membered heterocycloalkyl, and the 3-12-membered heterocycloalkyl is substituted by C 1-6 alkyl
  • the C 1-6 Alkyl is preferably methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, also preferably methyl, ethyl, propyl, isopropyl, Butyl, isobutyl or tert-butyl, more preferably methyl.
  • R 2 or R 3 are each independently a 3-12-membered heterocycloalkyl, and the 3-12-membered heterocycloalkyl is substituted by a C 1-6 alkyl group, C 1-6
  • the number of alkyl groups is preferably one, two or three, and the C 1-6 alkyl group is preferably methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tertiary Butyl, preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl or tert-butyl, more preferably methyl
  • the 3-12 membered heterocycloalkyl is preferably 3-6 membered Heterocycloalkyl, more preferably tetrahydropyrrole, even more preferably 3-12-membered heterocycloalkyl substituted by C 1-6 alkyl is preferred
  • R 2 or R 3 are each independently hydrogen, methyl
  • R 2 is hydrogen, methyl, R 3 is hydrogen or
  • R 2 is hydrogen, methyl, R 3 is hydrogen.
  • R 4 when R 4 is a 6-10-membered aryl group, the 6-10-membered aryl group is phenyl or naphthyl, preferably phenyl, Also preferably phenyl or More preferred is phenyl.
  • R 4 when R 4 is a 6-10-membered aryl group, the 6-10-membered aryl group is not condensed with a cycloalkyl group or a heterocyclic group.
  • R 4 when R 4 is a 5-10-membered heteroaryl group, the 5-10-membered heteroaryl group is a monocyclic or bicyclic ring.
  • R 4 when R 4 is a 5-10-membered heteroaryl group, the 5-10-membered heteroaryl group is not condensed with a cycloalkyl group or a heterocyclic group.
  • R 4 when R 4 is a 5-10-membered heteroaryl group, the 5-10-membered heteroaryl group is a 9-10-membered heteroaryl group.
  • R 4 when R 4 is a 5-10-membered heteroaryl group, the heteroatom in the 5-10-membered heteroaryl group is one or more of N, O and S.
  • R 4 when R 4 is a 5-10-membered heteroaryl group, the number of heteroatoms in the 5-10-membered heteroaryl group is one or two.
  • R 4 when R 4 is a 5-10-membered heteroaryl group, the 5-10-membered heteroaryl group is pyridyl, pyrazolyl, benzothiazolyl, indazolyl, benzene oxazolyl, indolyl, benzimidazolyl, benzofuranyl or quinolinyl, and can be pyridyl, pyrazolyl, benzothiazolyl, indazolyl, benzoxazolyl, indole group, benzimidazolyl or quinolinyl, preferably
  • R 4 is a 6-10-membered aryl group or a 5-10-membered heteroaryl group, and the aryl or heteroaryl group is substituted by a substituent selected from C 1-6 alkyl
  • the The C 1-6 alkyl group mentioned is methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, which can be methyl, ethyl, propyl, isobutyl propyl, butyl, isobutyl or tert-butyl, preferably methyl or ethyl.
  • R 4 when R 4 is a 6-10-membered aryl group or a 5-10-membered heteroaryl group, and the aryl or heteroaryl group is substituted by a substituent selected from C 1-6 alkoxy,
  • the C 1-6 alkoxy is methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy, or is methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy or tert-butoxy, preferably methoxy.
  • R 4 when R 4 is a 6-10-membered aryl group or a 5-10-membered heteroaryl group, the aryl or heteroaryl group is selected from C 1-6 alkanes substituted by one or more halogens
  • the halogen is preferably fluorine, chlorine, bromine or iodine, more preferably fluorine.
  • R 4 when R 4 is a 6-10-membered aryl group or a 5-10-membered heteroaryl group, the aryl or heteroaryl group is selected from C 1-6 alkanes substituted by one or more halogens
  • the plurality of said groups are preferably two or three.
  • R 4 when R 4 is a 6-10-membered aryl group or a 5-10-membered heteroaryl group, the aryl or heteroaryl group is selected from C 1-6 alkanes substituted by one or more halogens
  • the C 1-6 alkyl group is a substituent of a group, preferably methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, and preferably methyl, Ethyl, propyl, isopropyl, butyl, isobutyl or tert-butyl, more preferably methyl.
  • R 4 when R 4 is a 6-10-membered aryl group or a 5-10-membered heteroaryl group, the aryl or heteroaryl group is selected from C 1-6 alkanes substituted by one or more halogens
  • the halogen is preferably fluorine, chlorine, bromine or iodine, more preferably fluorine
  • the multiple is preferably two or three
  • the C 1-6 alkyl is preferably methyl, ethyl , propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, also preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl or tert-butyl
  • a methyl group is more preferred, and a C 1-6 alkyl group substituted with a plurality of halogens is preferably a difluoro
  • R 4 when R 4 is a 6-10-membered aryl group or a 5-10-membered heteroaryl group, the aryl or heteroaryl group is selected from C 1-6 alkanes substituted by one or more halogens
  • the halogen is preferably fluorine, chlorine, bromine or iodine, more preferably fluorine.
  • R 4 when R 4 is a 6-10-membered aryl group or a 5-10-membered heteroaryl group, the aryl or heteroaryl group is selected from C 1-6 alkanes substituted by one or more halogens
  • the plurality of said groups are preferably two or three.
  • R 4 when R 4 is a 6-10-membered aryl group or a 5-10-membered heteroaryl group, the aryl or heteroaryl group is selected from C 1-6 alkanes substituted by one or more halogens
  • the C 1-6 alkoxy is preferably methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or Tert-butoxy, also preferably methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy or tert-butoxy, more preferably methoxy or ethoxy.
  • R 4 when R 4 is a 6-10-membered aryl group or a 5-10-membered heteroaryl group, the aryl or heteroaryl group is selected from C 1-6 alkanes substituted by one or more halogens
  • the halogen is preferably fluorine, chlorine, bromine or iodine, more preferably fluorine
  • the multiple is preferably two or three
  • the C 1-6 alkoxy is preferably methoxy , ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy, also preferably methoxy, ethoxy, propoxy, isopropoxy oxy, butoxy, isobutoxy or tert-butoxy, more preferably methoxy or ethoxy
  • C 1-6 alkoxy substituted by multiple halogens is preferably difluoromethoxy, trifluoromethyl oxy or trifluoroethoxy
  • R 4 when R 4 is a 6-10-membered aryl group or a 5-10-membered heteroaryl group, and the aryl or heteroaryl group is substituted by a substituent selected from -NR 11 R 12 , the R 11 or R 12 is preferably H.
  • R 4 when R 4 is a 6-10-membered aryl group or a 5-10-membered heteroaryl group, and the aryl or heteroaryl group is substituted by a substituent selected from halogen, the halogen is fluorine , chlorine, bromine or iodine, preferably fluorine or chlorine.
  • R 4 is a 6-10-membered aryl group or a 5-10-membered heteroaryl group, and the aryl or heteroaryl group is substituted by a substituent selected from C 2-6 alkenyl
  • the The C 2-6 alkenyl group is vinyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 1-isobutenyl or 2-isobutenyl, preferably vinyl.
  • R 4 is a 6-10-membered aryl group or a 5-10-membered heteroaryl group, and the aryl or heteroaryl group is substituted by a substituent selected from C 2-6 alkynyl
  • the Said C 2-6 alkynyl group is ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 1-isobutynyl or 2-isobutynyl.
  • R 4 is a 6-10-membered aryl group or a 5-10-membered heteroaryl group, and the aryl or heteroaryl group is substituted by a substituent selected from C 2-6 alkynyl, the Said C 2-6 alkynyl group is ethynyl group.
  • R 4 when R 4 is a 6-10-membered aryl group or a 5-10-membered heteroaryl group, the aryl or heteroaryl group is selected from C 1-6 alkanes substituted by one or more hydroxyl groups Base time, the multiple is two or three.
  • the aryl or heteroaryl group is selected from C 1-6 alkanes substituted by one or more hydroxyl groups
  • the C 1-6 alkyl group is preferably methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, and preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl or tert-butyl, more preferably methyl.
  • R 4 when R 4 is a 6-10-membered aryl group or a 5-10-membered heteroaryl group, the aryl or heteroaryl group is selected from C 1-6 alkanes substituted by one or more hydroxyl groups
  • the C 1-6 alkyl group is preferably methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl or Tert-butyl, also preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl or tert-butyl, more preferably methyl.
  • R 4 when R 4 is a 6-10-membered aryl group or a 5-10-membered heteroaryl group, the aryl or heteroaryl group is selected from C 1-6 alkanes substituted by one or more hydroxyl groups
  • the C 1-6 alkyl group substituted by one or more hydroxyl groups is a hydroxymethyl group.
  • R 4 when R 4 is a 6-10-membered aryl group or a 5-10-membered heteroaryl group, the aryl or heteroaryl group is selected from C 1-6 alkyl, C 1-6 alkoxy Substituents of C 2-6 alkenyl and C 2-6 alkenyl are substituted, when C 1-6 alkyl, C 1-6 alkoxy and C 2-6 alkenyl are substituted by -CN or C 2-6 alkynyl, the said C 2-6 alkynyl is ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 1-isobutynyl or 2-isobutynyl, preferably acetylene base.
  • R 4 when R 4 is a 6-10-membered aryl group or a 5-10-membered heteroaryl group, the aryl or heteroaryl group is selected from C 1-6 alkyl, C 1-6 alkoxy Substituents of C 2-6 alkenyl and C 2-6 alkenyl are substituted, when C 1-6 alkyl, C 1-6 alkoxy and C 2-6 alkenyl are substituted by -CN or C 2-6 alkynyl, the said C 2-6 alkynyl is ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 1-isobutynyl or 2-isobutynyl, preferably acetylene base, C 1-6 alkyl substituted by -CN is preferred C 2-6 alkenyl substituted by -CN is preferred C 1-6 alkoxy substituted by C 2-6 alkynyl is preferred C 1-6
  • R 4 is
  • the halogen is fluorine, chlorine, bromine or iodine, preferably fluorine.
  • the halogen is fluorine, chlorine, bromine or iodine, preferably fluorine.
  • R 6 when R 6 is a C 1-6 alkyl group substituted by one or more halogens, the multiple is preferably two or three.
  • the halogen is preferably fluorine, chlorine, bromine or iodine, more preferably fluorine.
  • the C 1-6 alkyl group is preferably methyl, ethyl, propyl, isopropyl , n-butyl, isobutyl, sec-butyl or tert-butyl, also preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl or tert-butyl, more preferably methyl.
  • R 6 when R 6 is a C 1-6 alkyl group substituted by one or more halogens, the multiples are preferably two or three; the halogens are preferably fluorine, chlorine, Bromine or iodine, more preferably fluorine; the C 1-6 alkyl group is preferably methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, and methyl is also preferred alkyl, ethyl, propyl, isopropyl, butyl, isobutyl or tert-butyl, more preferably methyl; C1-6 alkyl substituted with one halogen is preferably monofluoromethyl.
  • the halogen is fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine.
  • R 7 in X 1 is halogen
  • the halogen is fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine.
  • R 7 in Y 1 is halogen
  • the halogen is fluorine, chlorine, bromine or iodine, preferably fluorine.
  • the halogen is fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine, more preferably fluorine.
  • the 3 -6-membered cycloalkyl is monocyclic.
  • the 3 -6-membered cycloalkenyl is monocyclic.
  • the 3 -6-membered cycloalkenyl contains only one or two double bonds.
  • the -7-membered heterocycloalkyl is monocyclic, bicyclic or tricyclic.
  • the 3 -7-membered heterocycloalkyl is monocyclic.
  • the 3 -7-membered heterocycloalkyl is spiro or bridged.
  • the -12 membered heterocycloalkyl is monocyclic, bicyclic or tricyclic.
  • the 3 -12-membered heterocycloalkyl is monocyclic.
  • the 3 -12-membered heterocycloalkyl is spiro or bridged.
  • the -7-membered heterocycloalkenyl is monocyclic, bicyclic or tricyclic.
  • the 3 -7-membered heterocycloalkenyl is monocyclic.
  • the -7-membered heterocycloalkenyl is a spiro or bridged ring.
  • the -12-membered heterocycloalkenyl is monocyclic, bicyclic or tricyclic.
  • the 3 -12-membered heterocycloalkenyl is monocyclic.
  • the -12-membered heterocycloalkenyl is a spiro or bridged ring.
  • the -10-membered aryl group is monocyclic or bicyclic.
  • the 6 -10 membered aryl is not fused to cycloalkyl or heterocyclyl.
  • the 5 -6-membered heteroaryl is monocyclic.
  • the 5 -6-membered heteroaryl is not fused to cycloalkyl or heterocyclyl.
  • the -10-membered heteroaryl is monocyclic or bicyclic.
  • the 5 -10 membered heteroaryl is not fused to cycloalkyl or heterocyclyl.
  • all atoms are the atoms of the element in the natural abundance, that is, the mixed atoms of each isotope according to the natural abundance.
  • X is O, S, SO or SO 2 ;
  • Z is O
  • R 1 is C 1-6 alkyl
  • R 2 or R 3 are each independently H, C 1-6 alkyl, deuterium, C 1-6 alkyl substituted with one or more deuterium, -C 1-6 alkylene-NR 11 R 12 , 3 -12 membered heterocycloalkyl, 3-12 membered heterocycloalkyl substituted with one or more (eg 2 or 3) C 1-6 alkyl or C 1-6 substituted with one or more hydroxy alkyl;
  • each R 11 or R 12 is each independently H, C 1-6 alkyl, substituted by one or more Deuterium substituted C 1-6 alkyl or R 11 , R 12 together with the attached atoms form a 3-7 membered heterocycloalkyl;
  • R 4 is a 6-10-membered aryl group or a 5-10-membered heteroaryl group; the aryl or heteroaryl group may be optionally selected from 1-5 C 1-6 alkyl groups, C 1-6 alkoxy groups , C 1-6 alkyl substituted by one or more halogens, -NR 11 R 12 , -OH, halogen, C 2-6 alkenyl, C 2-6 alkynyl and 3-7 membered heterocycloalkyl Substituent substitution, wherein the C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl are optionally substituted by -CN or C 2-6 alkynyl;
  • R 5 is H, deuterium or halogen
  • R 6 is H, deuterium, halogen, C 1-6 alkyl, C 1-6 alkyl substituted with one or more halogens, or C 1-6 alkyl substituted with one or more deuteriums;
  • X 1 is CH or CR 7 , and R 7 is halogen
  • Y 1 is CH or CR 7 , and R 7 is halogen
  • R 7A is H
  • n 0 or 1
  • X is O, SO or SO 2 ;
  • Z is O
  • R 1 is C 1-6 alkyl
  • R 2 or R 3 is each independently H, C 1-6 alkyl, -C 1-6 alkylene-NR 11 R 12 , by one or more (eg 2 or 3) C 1-6 alkane 3-12-membered heterocycloalkyl substituted with one or more hydroxy groups or C 1-6 alkyl substituted with one or more hydroxyl groups;
  • each R 11 or R 12 is each independently H, C 1-6 alkyl, substituted by one or more Deuterium substituted C 1-6 alkyl or R 11 , R 12 together with the attached atoms form a 3-7 membered heterocycloalkyl;
  • R 4 is a 6-10-membered aryl group or a 5-10-membered heteroaryl group; the aryl or heteroaryl group may be optionally selected from 1-5 C 1-6 alkyl groups, C 1-6 alkoxy groups , C 1-6 alkyl substituted by one or more halogens, -NR 11 R 12 , -OH, halogen, C 2-6 alkenyl, C 2-6 alkynyl and 3-7 membered heterocycloalkyl Substituent substitution, wherein the C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl are optionally substituted by -CN or C 2-6 alkynyl;
  • R 5 is H or halogen
  • R 6 is H or C 1-6 alkyl substituted with one or more halogens
  • X 1 is CR 7 , and R 7 is halogen
  • Y 1 is CR 7 , and R 7 is halogen
  • n 0 or 1
  • X is O
  • Y is CH
  • Z is O
  • R 1 is C 1-6 alkyl
  • R 2 or R 3 are each independently H, C 1-6 alkyl, 3-12 membered heterocycloalkyl substituted with one or more (eg, 2 or 3) C 1-6 alkyl, or -C 1-6 alkylene-NR 11 R 12 ;
  • each R 11 or R 12 is each independently H, C 1-6 alkyl, substituted by one or more Deuterium substituted C 1-6 alkyl or R 11 , R 12 together with the attached atoms form a 3-7 membered heterocycloalkyl;
  • R 4 is a 6-10-membered aryl group or a 5-10-membered heteroaryl group; the aryl or heteroaryl group is optionally substituted by 1-5 alkyl groups selected from C 1-6 , and substituted by one or more halogens The C 1-6 alkyl, amino, -OH and halogen substituents are substituted; wherein the C 1-6 alkyl is optionally substituted by -CN or C 2-6 alkynyl;
  • R 5 is H or halogen
  • R 6 is H or C 1-6 alkyl substituted with one or more halogens
  • X 1 is CR 7 , and R 7 is halogen
  • Y 1 is CR 7 , and R 7 is halogen
  • n 0 or 1
  • X is O, SO or SO 2 ;
  • Z is O
  • R 1 is methyl
  • R 2 or R 3 are each independently H, methyl
  • R 4 is a 6-10-membered aryl group or a 5-10-membered heteroaryl group, and the aryl or heteroaryl group is optionally selected from amino, hydroxyl, fluorine, chlorine, methyl, difluoromethane by 1-5 base, Ethyl, trifluoromethyl, Substitute with methoxy group;
  • R 5 is H or fluorine
  • R 6 is H or monofluoromethyl
  • X 1 is CR 7 , and R 7 is chlorine
  • Y 1 is CR 7 , and R 7 is fluorine
  • n 0 or 1
  • X is O, SO or SO 2 ;
  • Z is O
  • R 1 is methyl
  • R 2 or R 3 are each independently H, methyl
  • R 5 is H or fluorine
  • R 6 is H or monofluoromethyl
  • X 1 is CR 7 , and R 7 is chlorine
  • Y 1 is CR 7 , and R 7 is fluorine
  • n 0 or 1
  • X is O
  • Y is CH
  • Z is O
  • R 1 is methyl
  • R 2 or R 3 are each independently H, methyl
  • R 5 is H or fluorine
  • R 6 is H or monofluoromethyl
  • X 1 is CR 7 , and R 7 is chlorine
  • Y 1 is CR 7 , and R 7 is fluorine
  • n 0 or 1
  • X is O, S, SO or SO 2 ;
  • Y is CH or does not exist
  • Z is O
  • X 1 is CH, CR 7 or N;
  • Y 1 is CH, CR 7 or N;
  • each R 1 is independently C 1-6 alkyl
  • R 2 and R 3 are each independently H, deuterium, C 1-6 alkyl, 3-6 membered cycloalkyl, 3-6 membered cycloalkenyl, C 1-6 alkyl substituted with one or more deuterium , -C 1-6 alkylene-NR 11 R 12 , C 1-6 alkyl substituted by one or more hydroxyl groups, 3-12-membered heterocycloalkyl or 3-12-membered heterocycloalkenyl; wherein Said 3-12-membered heterocycloalkyl, 3-12-membered heterocycloalkenyl are optionally selected from 1-3 (eg 1, 2 or 3) respectively independently selected from C 1-6 alkyl and by one or more Substituents of deuterium-substituted C 1-6 alkyl groups are substituted, and when there are 2 or 3 substituents, the substituents are the same or different;
  • R 11 and R 12 is each independently H, C 1-6 alkyl, C 1-6 alkyl substituted with one or more deuteriums, or R 11 , R 12 together with the attached atoms form 3-7 membered heterocycloalkyl or 3-7 membered heterocycloalkenyl;
  • R 4 is a 6-10-membered aryl group or a 5-10-membered heteroaryl group; the aryl or heteroaryl group is optionally selected from C 1 by 1-5 (eg 1, 2, 3, 4 or 5) -6 alkyl, C 1-6 alkyl substituted with one or more deuterium, C 1-6 alkoxy, C 1-6 alkyl substituted with one or more halo, substituted with one or more halo C 1-6 alkoxy, -NR 11 R 12 , -OH, halogen, -CN, C 2-6 alkenyl, C 2-6 alkynyl, 3-7 membered heterocycloalkyl, 3-7 membered Substituent substitution of heterocycloalkenyl, 3-6-membered cycloalkenyl and 3-6-membered cycloalkenyl, when there are 2-5 substituents, the substituents are the same or different; wherein the C 1- 6 alkyl, C 1-6 alkoxy and C 2
  • each R is independently H, deuterium , halogen, C 1-6 alkyl, or C 1-6 alkyl substituted with one or more deuteriums;
  • each R is independently H, deuterium, halogen, C 1-6 alkyl, C 1-6 alkyl substituted with one or more halogens, or C 1-6 alkyl substituted with one or more deuteriums;
  • each R is independently halogen or -CN ;
  • R 7A is H
  • n 0, 1 or 2;
  • X is O, S, SO or SO 2 ;
  • Y is CH
  • Z is O
  • X 1 is CR 7 or N
  • Y 1 is CR 7 or N
  • each R 1 is independently C 1-6 alkyl
  • R 2 is H, deuterium, 3-12-membered heterocycloalkyl or 3-12-membered heterocycloalkenyl; wherein the 3-12-membered heterocycloalkyl and 3-12-membered heterocycloalkenyl are optionally substituted by 1- 3 (eg 1, 2 or 3) substituents each independently selected from C1-6 alkyl and C1-6 alkyl substituted with one or more deuteriums, when 2 or 3 substituents , the substituents are the same or different;
  • R 3 is H, deuterium, 3-12-membered heterocycloalkyl or 3-12-membered heterocycloalkenyl; wherein the 3-12-membered heterocycloalkyl and 3-12-membered heterocycloalkenyl are optionally substituted by 1- 3 (eg 1, 2 or 3) substituents each independently selected from C1-6 alkyl and C1-6 alkyl substituted with one or more deuteriums, when 2 or 3 substituents , the substituents are the same or different;
  • R 11 and R 12 is each independently H, C 1-6 alkyl, C 1-6 alkyl substituted with one or more deuterium, or R 11 , R 12 together with the attached atoms form 3-7 membered heterocycloalkyl or 3-7 membered heterocycloalkenyl;
  • R 4 is a 10-membered aryl group or a 9-10-membered heteroaryl group; the aryl or heteroaryl group is optionally 1-5 (eg 1, 2, 3, 4 or 5) selected from C 1-6 alkyl, C 1-6 alkyl substituted with one or more deuteriums, C 1-6 alkoxy, C 1-6 alkyl substituted with one or more halogens, C 1-6 substituted with one or more halogens 1-6 alkoxy, -NR 11 R 12 , -OH, halogen, -CN, C 2-6 alkenyl, C 2-6 alkynyl, 3-6 membered cycloalkyl and 3-6 membered cycloalkenyl Substituents are substituted, when there are 2-5 substituents, the substituents are the same or different; wherein the C 1-6 alkyl, C 1-6 alkoxy and C 2-6 alkenyl are optional substituted by -CN or C 2-6 alkynyl;
  • each R is independently H, deuterium , halogen, C 1-6 alkyl, or C 1-6 alkyl substituted with one or more deuteriums;
  • each R is independently H, deuterium, halogen, C 1-6 alkyl, C 1-6 alkyl substituted with one or more halogens, or C 1-6 alkyl substituted with one or more deuteriums;
  • each R is independently halogen or -CN ;
  • R 7A is H
  • n 0, 1 or 2;
  • X is O, S, SO or SO 2 ;
  • Y is CH or does not exist
  • Z is O
  • X 1 is CR 7 or N
  • Y 1 is CR 7 or N
  • each R 1 is independently C 1-6 alkyl
  • R 2 and R 3 are each independently H, deuterium, C 1-6 alkyl, 3-6 membered cycloalkyl, 3-6 membered cycloalkenyl, C 1-6 alkyl substituted with one or more deuterium , -C 1-6 alkylene-NR 11 R 12 , C 1-6 alkyl substituted by one or more hydroxyl groups, 3-12-membered heterocycloalkyl or 3-12-membered heterocycloalkenyl; wherein Said 3-12-membered heterocycloalkyl, 3-12-membered heterocycloalkenyl are optionally selected from 1-3 (eg 1, 2 or 3) respectively independently selected from C 1-6 alkyl and by one or more Substituents of deuterium-substituted C 1-6 alkyl groups are substituted, and when there are 2 or 3 substituents, the substituents are the same or different;
  • R 11 and R 12 is each independently H, C 1-6 alkyl, C 1-6 alkyl substituted with one or more deuteriums, or R 11 , R 12 together with the attached atoms form 3-7 membered heterocycloalkyl or 3-7 membered heterocycloalkenyl;
  • R 4 is a 6-10-membered aryl group or a 5-10-membered heteroaryl group; the aryl or heteroaryl group is optionally selected from C 1 by 1-5 (eg 1, 2, 3, 4 or 5) -6 alkyl, C 1-6 alkyl substituted with one or more deuterium, C 1-6 alkoxy, C 1-6 alkyl substituted with one or more halo, substituted with one or more halo C 1-6 alkoxy, -NR 11 R 12 , -OH, halogen, -CN, C 2-6 alkenyl, C 2-6 alkynyl, 3-6 membered cycloalkyl and 3-6 membered ring Substituent substitution of alkenyl, when there are 2-5 substituents, the substituents are the same or different; wherein the C 1-6 alkyl, C 1-6 alkoxy and C 2-6 alkenyl optionally substituted with -CN or C 2-6 alkynyl;
  • each R is independently H, deuterium , halogen, C 1-6 alkyl, or C 1-6 alkyl substituted with one or more deuteriums;
  • each R is independently H, deuterium, halogen, C 1-6 alkyl, C 1-6 alkyl substituted with one or more halogens, or C 1-6 alkyl substituted with one or more deuteriums;
  • each R is independently halogen or -CN ;
  • R 7A is H
  • n 0, 1 or 2;
  • X is O, S, SO or SO 2 ;
  • Y is CH or does not exist
  • Z is O
  • X 1 is CR 7 or N
  • Y 1 is CR 7 or N
  • each R 1 is independently C 1-6 alkyl
  • R 2 is H, deuterium, C 1-6 alkyl, 3-6 membered cycloalkyl, 3-6 membered cycloalkenyl, C 1-6 alkyl substituted with one or more deuterium, -C 1-6 Alkylene-NR 11 R 12 , C 1-6 alkyl substituted with one or more hydroxyl groups, 3-12-membered heterocycloalkyl or 3-12-membered heterocycloalkenyl; wherein the 3-12-membered heterocycloalkenyl Cycloalkyl, 3-12 membered heterocycloalkenyl optionally substituted with 1-3 (eg 1, 2 or 3) each independently selected from C 1-6 alkyl and C 1- substituted with one or more deuterium 6 Substituent substitution of alkyl, when there are 2 or 3 substituents, the substituents are the same or different;
  • R 3 is H, deuterium or -C 1-6 alkylene-NR 11 R 12 ;
  • R 11 and R 12 is each independently H, C 1-6 alkyl, C 1-6 alkyl substituted with one or more deuterium, or R 11 , R 12 together with the attached atoms form 3-7 membered heterocycloalkyl or 3-7 membered heterocycloalkenyl;
  • R 4 is a 6-10-membered aryl group or a 5-10-membered heteroaryl group; the aryl or heteroaryl group is optionally selected from C 1 by 1-5 (eg 1, 2, 3, 4 or 5) -6 alkyl, C 1-6 alkyl substituted with one or more deuterium, C 1-6 alkoxy, C 1-6 alkyl substituted with one or more halo, substituted with one or more halo C 1-6 alkoxy, -NR 11 R 12 , -OH, halogen, -CN, C 2-6 alkenyl, C 2-6 alkynyl, 3-6 membered cycloalkyl and 3-6 membered ring Substituent substitution of alkenyl, when there are 2-5 substituents, the substituents are the same or different; wherein the C 1-6 alkyl, C 1-6 alkoxy and C 2-6 alkenyl optionally substituted with -CN or C 2-6 alkynyl;
  • each R is independently H, deuterium , halogen, C 1-6 alkyl, or C 1-6 alkyl substituted with one or more deuterium;
  • each R is independently H, deuterium, halogen, C 1-6 alkyl, C 1-6 alkyl substituted with one or more halogens, or C 1-6 alkyl substituted with one or more deuteriums;
  • each R is independently halogen or -CN ;
  • R 7A is H
  • n 0, 1 or 2;
  • X is O, S, SO or SO 2 ;
  • Y is CH
  • Z is O
  • X 1 is CR 7 or N
  • Y 1 is CR 7 or N
  • each R 1 is independently C 1-6 alkyl
  • R 2 is a 3-12-membered heterocycloalkyl or a 3-12-membered heterocycloalkenyl; wherein the 3-12-membered heterocycloalkyl and 3-12-membered heterocycloalkenyl are optionally surrounded by 1-3 (eg 1 , 2 or 3) substituents independently selected from C 1-6 alkyl and C 1-6 alkyl substituted by one or more deuteriums, when the substituents are 2 or 3, the The substituents are the same or different;
  • R 3 is H, deuterium or -C 1-6 alkylene-NR 11 R 12 ;
  • R 11 and R 12 is each independently H, C 1-6 alkyl, C 1-6 alkyl substituted with one or more deuteriums, or R 11 , R 12 together with the attached atoms form 3-7 membered heterocycloalkyl or 3-7 membered heterocycloalkenyl;
  • R 4 is a 10-membered aryl group or a 9-10-membered heteroaryl group; the aryl or heteroaryl group is optionally 1-5 (eg 1, 2, 3, 4 or 5) selected from C 1-6 alkyl, C 1-6 alkyl substituted with one or more deuteriums, C 1-6 alkoxy, C 1-6 alkyl substituted with one or more halogens, C 1-6 substituted with one or more halogens 1-6 alkoxy, -NR 11 R 12 , -OH, halogen, -CN, C 2-6 alkenyl, C 2-6 alkynyl, 3-6 membered cycloalkyl and 3-6 membered cycloalkenyl Substituents are substituted, when there are 2-5 substituents, the substituents are the same or different; wherein the C 1-6 alkyl, C 1-6 alkoxy and C 2-6 alkenyl are optional substituted by -CN or C 2-6 alkynyl;
  • each R is independently H, deuterium , halogen, C 1-6 alkyl, or C 1-6 alkyl substituted with one or more deuterium;
  • each R is independently H, deuterium, halogen, C 1-6 alkyl, C 1-6 alkyl substituted with one or more halogens, or C 1-6 alkyl substituted with one or more deuteriums;
  • each R is independently halogen or -CN ;
  • R 7A is H
  • n 0, 1 or 2.
  • the compound shown in the formula I is any of the following structures:
  • X, Y, Z, X 1 , Y 1 , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , A, n and R 7A are as described above, when the When the carbon atom is a chiral carbon atom, it is in the R configuration, the S configuration or a mixture thereof.
  • the compound shown in the formula I is any of the following compounds:
  • the compound shown in the formula I is any of the following compounds:
  • Retention time of 4.997min or 2.350min under the following conditions Column: DAICEL CHIRALPAK IG (250mm*30mm, 10 ⁇ m); mobile phase A: 0.1% NH 3 H 2 O, mobile phase B: ethanol; mobile phase B%: 60%-60%;
  • the pharmaceutically acceptable salt of the compound shown in formula I is any of the following structures:
  • the present invention also provides the preparation method of the compound shown in the formula (I), which comprises the following steps:
  • R 1 , R 2 , R 3 , R 4 , A, Z, X 1 , Y 1 , X, Y, R 7A and n are defined as above, when the carbon atom with "*" is a chiral carbon atom, it is in the R configuration, the S configuration, or a mixture thereof.
  • the present invention also provides the preparation method of the compound represented by the formula (II), which comprises the following steps:
  • R 1 , R 2 , R 3 , R 4 , Z, X 1 , Y 1 , X, Y, R 7A and n are defined as above, when the carbon atom with "*" is a chiral carbon atom , which is the R configuration, the S configuration, or a mixture thereof.
  • the acid can be an acid commonly used in this type of reaction in the art, preferably hydrochloric acid or trifluoroacetic acid.
  • the present invention also provides the preparation method of the compound shown in the formula (III), which comprises the following steps:
  • R 1 , R 2 , R 3 , R 4 , Z, X 1 , Y 1 , X, Y, R 7A and n are defined as above, when the carbon atom with "*" is a chiral carbon atom , which is the R configuration, the S configuration, or a mixture thereof.
  • the present invention also provides the preparation method of the compound shown in the formula (IV), which comprises the following steps:
  • R 1 , R 2 , R 3 , X 1 , Y 1 , X, Y, R 7A and n are as described above, and when the carbon atom with "*" is a chiral carbon atom, it is an R structure form, S configuration, or a mixture thereof,
  • Said ring formation reaction is preferably carried out in the presence of triphenylphosphine or tributylphosphine and diisopropyl azodicarboxylate or diethyl azodicarboxylate.
  • the present invention also provides the preparation method of the compound shown in the formula (V), which comprises the following steps:
  • R 1 , R 2 , R 3 , X 1 , Y 1 , X, Y, R 7A and n are as described above, and when the carbon atom with "*" is a chiral carbon atom, it is an R structure form, S configuration, or a mixture thereof.
  • the present invention also provides the preparation method of the compound shown in the formula (VI), which comprises the following steps:
  • R 1 , R 2 , R 3 , X 1 , Y 1 , X, Y, R 7A and n are as described above, and when the carbon atom with "*" is a chiral carbon atom, it is an R structure form, S configuration, or a mixture thereof.
  • the present invention also provides the preparation method of the compound shown in the formula (VII), which comprises the following steps:
  • R 1 , X 1 , Y 1 , R 7A and n are as described above, and when the carbon atom with "*" is a chiral carbon atom, it is R configuration, S configuration or a mixture thereof.
  • the reducing agent is preferably iron powder, zinc powder, sodium hydrosulfite or H 2 (when reducing with H 2 , it should be carried out in the presence of a catalyst, and the catalyst is selected from palladium/carbon and Pd(OH) 2 /carbon).
  • the described preparation method of the compound shown in formula (VII) may further comprise the following steps:
  • R 1 , X 1 , Y 1 , R 7A and n are as described above, and when the carbon atom with "*" is a chiral carbon atom, it is R configuration, S configuration or a mixture thereof.
  • the described preparation method of the compound shown in formula (VII) may further comprise the following steps:
  • the described preparation method of the compound shown in formula (VII) may further comprise the following steps:
  • the described preparation method of the compound shown in formula (VII) may further comprise the following steps:
  • the described preparation method of the compound shown in formula (VII) may further comprise the following steps:
  • the present invention also provides the preparation method of the compound represented by formula (I), which is route 1 or 2;
  • the described route 1 includes the following steps:
  • Z is O
  • the reaction parameters of the first step are as follows: Curtius rearrangement reaction;
  • reaction parameters of the 2nd step are as follows: deprotection reaction, acidic conditions (in the presence of the conventional acid of this type of reaction in the art, the acid is such as dilute hydrochloric acid or TFA, etc.);
  • reaction parameters of the third step are as follows: iodination reaction, acidic conditions (in the presence of an acid conventional for this type of reaction in the art, the acid is such as glacial acetic acid), iodination with N-iodosuccinimide reaction;
  • reaction parameters of the 4th step are as follows: carbonylation reaction, palladium catalysis, under basic conditions (in the presence of the conventional organic bases, inorganic bases of this type of reaction in this area), carry out carbonylation reaction with CO/ethanol;
  • reaction parameters of the 5th step are as follows: acylation reaction, carry out acylation reaction with monoethyl malonate acid chloride;
  • reaction parameters of the 6th step are as follows: ring-forming reaction, under alkaline conditions (under the presence of organic bases, inorganic bases that are conventional in this type of reaction in this area);
  • reaction parameters of the 7th step are as follows: decarboxylation reaction, acidic conditions (in the presence of conventional acids for this type of reaction in the art);
  • reaction parameters of the 8th step are as follows: nitration reaction, acidic condition (under the presence of the conventional acid of this type of reaction in this area);
  • reaction parameters of the 9th step are as follows: chlorination reaction, carry out chlorination reaction with POCl 3 , phosphorus pentachloride or thionyl chloride;
  • reaction parameters of the 10th step are as follows: substitution reaction, basic conditions (in the presence of conventional organic bases and inorganic bases for this type of reaction in this field);
  • reaction parameters of the 11th step are as follows: reductive cyclization, reducing agent (iron powder, zinc powder, hydrosulfite, H2 (in the presence of catalyst palladium/carbon, Pd(OH) 2 /carbon));
  • reaction parameters of the 12th step are as follows: esterification reaction, basic conditions (in the presence of conventional organic bases and inorganic bases for this type of reaction in this field), and esterification reaction with trifluoromethanesulfonic anhydride;
  • reaction parameters of the 13th step are as follows: substitution reaction, under acidic condition, carries out substitution reaction with bromide (sodium bromide or potassium bromide);
  • reaction parameters of the 14th step are as follows: substitution reaction, basic conditions (in the presence of conventional organic bases and inorganic bases for this type of reaction in the art);
  • reaction parameters for the 15th step are as follows: deprotection, acidic conditions (in the presence of an acid conventional in the art for this type of reaction, such as dilute hydrochloric acid) and HF, TBAF (tetrabutylammonium fluoride) or KF reaction in the presence of;
  • reaction parameters of the 16th step are as follows: ring-forming reaction, in the presence of DEAD (diethyl azodicarboxylate) or DIAD (diisopropyl azodicarboxylate) and PPh 3 or PBu 3 ;
  • reaction parameters of the 17th step are as follows: coupling reaction, Suzuki coupling reaction;
  • reaction parameters of the 18th step are as follows: deprotection, acidic conditions (in the presence of conventional acids for this type of reaction in the art, the acid is such as dilute hydrochloric acid or TFA, etc.);
  • reaction parameters of the 19th step are as follows: acylation reaction, acylation reaction with A-OH or A-Cl;
  • the route 2 described includes the following steps:
  • Z is O
  • reaction parameters of the first step are as follows: coupling reaction, palladium catalysis, under alkaline conditions, and methanol is coupled reaction;
  • reaction parameters of the second step are as follows: chlorination reaction, chlorination reaction with POCl 3 , phosphorus pentachloride or thionyl chloride;
  • reaction parameters of the 3rd step are as follows: substitution and fluorination, and substitution and fluorination are carried out under alkaline conditions;
  • reaction parameters of the 4th step are as follows: reductive cyclization, reducing agent (iron powder, zinc powder, hydrosulfite, H2 (in the presence of catalyst palladium/carbon, Pd(OH) 2 /carbon));
  • reaction parameters of the 5th step are as follows: substitution reaction, basic conditions (under the presence of organic bases, inorganic bases that are conventional in this type of reaction in this area);
  • reaction parameters in the sixth step are as follows: deprotection, acidic conditions (in the presence of an acid conventional for this type of reaction in the art, such as dilute hydrochloric acid) and HF, TBAF (tetrabutylammonium fluoride) or KF reaction in the presence of;
  • reaction parameters of the 7th step are as follows: ring-forming reaction, in the presence of DEAD (diethyl azodicarboxylate) or DIAD (diisopropyl azodicarboxylate) and PPh 3 or PBu 3 ;
  • reaction parameters of the 8th step are as follows: demethylation reaction, carrying out demethylation reaction with HI;
  • reaction parameters of the 9th step are as follows: esterification reaction, basic conditions (in the presence of the conventional organic bases and inorganic bases of this type of reaction in this area), and carry out esterification reaction with trifluoromethanesulfonic anhydride;
  • reaction parameters of the 10th step are as follows: substitution reaction, under acidic condition, carries out substitution reaction with bromide (sodium bromide, potassium bromide);
  • step 11 The reaction parameters of step 11 are as follows: coupling reaction, Suzuki coupling reaction;
  • reaction parameters of the 12th step are as follows: deprotection, acidic conditions (in the presence of conventional acids for this type of reaction in the art, the acid is such as dilute hydrochloric acid or TFA, etc.);
  • reaction parameters for step 13 are as follows: acylation reaction, acylation reaction with A-OH or A-Cl.
  • the present invention also provides the compounds shown below:
  • R 1 , R 2 , R 3 , R 4 , Z, X 1 , Y 1 , X, Y, R 7A and n are defined as above, when the carbon atom with "*" is a chiral carbon atom , which is the R configuration, the S configuration, or a mixture thereof.
  • the present invention also provides the compounds shown below:
  • the present invention also provides a pharmaceutical composition, which comprises the above-mentioned compound represented by formula I, a pharmaceutically acceptable salt or a solvate thereof, and a pharmaceutically acceptable adjuvant.
  • the present invention also provides the use of the above-mentioned "compound of formula I, a pharmaceutically acceptable salt or solvate thereof" or the above-mentioned pharmaceutical composition as a KRAS G12C mutein inhibitor.
  • the present invention also provides a use of the above-mentioned "the compound shown in formula I, a pharmaceutically acceptable salt thereof or a solvate thereof" or the above-mentioned pharmaceutical composition as a cell proliferation inhibitor.
  • the cells are preferably Ba/F3 KRAS-G12C cells expressing KRAS G12C mutein, NCI-H358 cells expressing KRAS G12C mutein or MIA PaCa-2 cells expressing KRAS G12C mutein.
  • the cancer is preferably related to KRAS G12C mutant protein, more preferably non-small cell lung cancer, pancreatic cancer, leukemia, esophageal cancer, breast cancer, melanoma, neuroblastoma, gastric cancer, liver cancer, prostate cancer, skin cancer Cancer, Sarcoma, Osteoma, Ovarian Cancer, Bladder Cancer, Kidney Cancer, Seminoma, Uterine Tumor, Thyroid Tumor, Colon Cancer, Brain Cancer, Cervical Cancer, Testicular Cancer, Head or Neck Cancer, Bone Cancer, Rectal Cancer , small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, esophageal cancer, thyroid cancer, lymphoma, glioma, glioblastoma
  • the present invention also provides a kind of above-mentioned "compound shown as formula I, its pharmaceutically acceptable salt or its solvate” or the above-mentioned pharmaceutical composition in the preparation of the medicine for treating and/or preventing cancer Application
  • the cancer is non-small cell lung cancer, pancreatic cancer, leukemia, esophageal cancer, breast cancer, melanoma, neuroblastoma, gastric cancer, liver cancer, prostate cancer, skin cancer, sarcoma, bone tumor, ovarian cancer, bladder cancer Cancer, Kidney Cancer, Seminoma, Uterine Tumor, Thyroid Tumor, Colon Cancer, Brain Cancer, Cervical Cancer, Testicular Cancer, Head or Neck Cancer, Bone Cancer, Rectal Cancer, Small Cell Lung Cancer, Lung Adenocarcinoma, Squamous Lung Cancer cancer, esophageal cancer, thyroid cancer, lymphoma, glioma, glioblastoma, gastrointestinal stromal tumor, bile duct cancer, endo
  • halogen refers to fluorine, chlorine, bromine or iodine.
  • a carbon atom with "*" is a chiral carbon atom, it is an R configuration, an S configuration or a mixture thereof.
  • plural means two, three, four or five.
  • hydroxyl refers to the -OH group.
  • amino refers to -NH2 .
  • alkyl refers to a fully saturated straight or branched hydrocarbon chain group, consists only of carbon atoms and hydrogen atoms, has, for example, 1 to 12 (preferably 1 to 8, more preferably 1 to 6, more preferably 1 to 4) carbon atoms, and is attached to the rest of the molecule by a single bond, Examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-methylbutyl, 2,2- Dimethylpropyl, n-hexyl, heptyl, 2-methylhexyl, 3-methylhexyl, octyl, nonyl, decyl and the like.
  • alkylene refers to the substitution of one hydrogen in an alkyl group, as defined above.
  • alkoxy refers to -O-alkyl, as defined above for alkyl.
  • alkenyl as part of a group or other group refers to a straight or branched hydrocarbon chain radical having at least one double bond, consisting only of carbon atoms and hydrogen atoms, having, for example, 2 to 12 (preferably 2 to 8, more preferably 2 to 6, more preferably 2 to 4) carbon atoms, and are attached to the rest of the molecule by a single bond, such as including but not limited to vinyl, n-propenyl , isopropenyl, n-butenyl, isobutenyl, sec-butenyl, tert-butenyl, n-pentenyl, 2-methylbutenyl, 2,2-dimethylpropenyl, n-hexenyl, Heptenyl, 2-methylhexenyl, 3-methylhexenyl, octenyl, nonenyl, decenyl, and the like.
  • alkynyl as part of a group or other group refers to a straight or branched hydrocarbon chain radical having at least one triple bond, consisting only of carbon atoms and hydrogen atoms, having, for example, 2 to 12 (preferably 2 to 8, more preferably 2 to 6, more preferably 2 to 4) carbon atoms, and are attached to the rest of the molecule by a single bond, for example including but not limited to ethynyl, n-propyne base, isopropynyl, n-butynyl, isobutynyl, sec-butynyl, tert-butynyl, n-pentynyl, 2-methylbutynyl, 2,2-dimethylpropynyl , n-hexynyl, heptynyl, 2-methylhexynyl, 3-methylhexynyl, octynyl, nonynyl and decy
  • cycloalkyl as a group or part of another group means a saturated monocyclic or polycyclic cyclic hydrocarbon group having 3 to 15 carbon atoms, preferably 3 to 10 carbon atoms atom, more preferably having 3 to 6 carbon atoms, for example including but not limited to cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
  • cycloalkenyl as a group or part of other groups means a monocyclic or polycyclic cyclic hydrocarbon group having at least one double bond (eg, a carbon-carbon double bond), having 3 to 15 carbon atoms, preferably 3 to 10 carbon atoms, more preferably 3 to 6 carbon atoms, such as, but not limited to, cyclopentenyl, cyclohexenyl, or cyclohexadienyl.
  • heterocycloalkyl as a group or part of another group means from 2 to 14 (preferably 2 to 6) carbon atoms and 1 to 6 carbon atoms selected from nitrogen, oxygen
  • heterocycloalkenyl means having from 2 to 14 (preferably 2 to 6) carbon atoms and 1 to 6 carbon atoms selected from nitrogen, oxygen Stable 3- to 20-membered (preferably 3- to 12-membered, more preferably 3- to 7-membered) non-aromatic monocyclic, bicyclic, tricyclic or more cyclic non-aromatic ring systems containing at least one double bond composed of heteroatoms with sulfur , for example including but not limited to pyranyl, 2,3-dihydropyrrolyl, 2,3-dihydrofuranyl, 1,2,3,4-tetrahydropyridyl or 3,4-dihydro-2H- Pyran.
  • aryl means a conjugated hydrocarbon ring system group having 6 to 18 carbon atoms, preferably 6 to 10 carbon atoms.
  • an aryl group can be a monocyclic, bicyclic, tricyclic or more ring system, and can also be fused to a cycloalkyl or heterocyclic group as defined above, provided that the aryl group is via The atoms on the aromatic ring are connected to the rest of the molecule by single bonds.
  • aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, phenanthryl, or fluorenyl.
  • heteroaryl means a ring having 1 to 15 carbon atoms (preferably 1 to 10 carbon atoms) and 1 to 6 selected from nitrogen 5- to 16-membered conjugated ring system groups of heteroatoms of , oxygen and sulfur.
  • a heteroaryl group can be a monocyclic, bicyclic, tricyclic or more cyclic ring system, and can also be fused to a cycloalkyl or heterocyclyl group as defined above, provided that the heterocyclic group The aryl group is attached to the rest of the molecule by a single bond through an atom on the aromatic ring.
  • heteroaryl groups preferably contain 1 to 5 stable 5- to 12-membered aromatic groups selected from nitrogen, oxygen and sulfur heteroatoms, more preferably 1 to 4 heteroatoms selected from nitrogen , stable 5- to 10-membered aromatic groups of heteroatoms of oxygen and sulfur, or 5- to 6-membered aromatic groups containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur (e.g., heteroaryl is a C 1 -C 5 heteroaryl group, wherein the heteroatom is selected from N, O and S, and the number of heteroatoms is 1, 2, 3 or 4).
  • heteroaryl groups include, but are not limited to, thienyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, oxadiazolyl, isoxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, Benzimidazolyl, benzopyrazolyl, indolyl, furanyl, pyrrolyl, triazolyl, tetrazolyl, triazinyl, indazinyl, isoindolyl, indazolyl, isoindazolyl , purinyl, quinolinyl, isoquinolinyl, diazanaphthyl, naphthyridinyl, quinoxalinyl, pteridyl, carbazolyl, carboline, phenanthridine, phenanthroline, acridine base, phena
  • any structural formula given herein is also intended to represent unlabeled as well as isotopically labeled forms of the compounds.
  • Isotopically-labeled compounds have the structures depicted by the formulae given herein, except that one or more atoms are replaced by atoms having the selected atomic weight or mass number.
  • isotopes that may be incorporated into the compounds of the present invention include isotopes of hydrogen , carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine, such as 2H, 3H , 11C , 13C , 14C , 15N , respectively , 18 O, 17 O, 31 P, 32 P, 35 S, 18 F, 36 Cl, 125 I, preferably 2 H.
  • the compounds of formula I of the present invention may contain one or more chiral centers and exist in various optically active forms.
  • the compound contains enantiomers.
  • the present invention includes both isomers and mixtures of isomers, such as racemic mixtures. Enantiomers can be resolved by methods known in the art, such as crystallization and chiral chromatography. When compounds of formula I contain more than one chiral center, diastereomers may exist.
  • the present invention includes resolved optically pure specific isomers as well as mixtures of diastereomers. Diastereomers can be resolved by methods known in the art, such as crystallization and preparative chromatography.
  • stereoisomer includes conformational isomers and configurational isomers, wherein configurational isomers mainly include cis-trans isomers and optical isomers.
  • the compounds described in the present invention may exist in stereoisomeric forms and therefore all possible stereoisomeric forms are encompassed, including but not limited to cis-trans isomers, tautomers, enantiomers, non-isomers Enantiomers, atropisomers, etc., the compounds of the present invention can also be in any combination or any mixture of the aforementioned stereoisomers, such as meso, racemate, atropisomer exist in the form of an equivalent mixture.
  • a single enantiomer, a single diastereomer or a mixture of the above, or a single atropisomer or a mixture thereof When the compounds of the present invention contain olefinic double bonds, unless otherwise specified, they include cis isomers and trans isomers, and any combination thereof.
  • Atropisomers of the present invention are stereoisomers based on axial or planar chirality resulting from restricted intramolecular rotation.
  • the compound of the present invention has two atropisomers derived from axial asymmetry, which are caused when the substituent R 4 is a cyclic group such as a 6-10-membered aryl group, a 5-10-membered heteroaryl group (especially When there is a substituent at the ortho positions at both ends of the connecting bond or a group with a larger steric structure at the ortho position of the connecting bond), the connecting bond between the substituted quinoline and other rings is hindered by steric hindrance and the rotation is hindered. produce.
  • the substituent R 4 is a cyclic group such as a 6-10-membered aryl group, a 5-10-membered heteroaryl group (especially When there is a substituent at the ortho positions at both ends of the connecting bond or a group with a larger steric structure at the ortho position of the connecting bond), the connecting bond between the substituted quinoline and other rings is hindered by steric hindrance and the rotation is hindered.
  • Atropisomers of the present invention wherein the compound has the structure of formula I, or the compound of formula I has isomers derived from asymmetric carbons, etc., it represents a pair of atropisomers present in each isomeric compound any of the body. And as a drug, an atropisomer having excellent activity is preferable.
  • Compounds of formula I possess optical isomers derived from asymmetric carbons, axial asymmetry, etc., if necessary, single isomers can be obtained by methods known in the art, such as crystallization or chromatography (eg, chiral chromatography) and the like obtained by splitting.
  • the present invention provides compounds represented by various structures above, or tautomers, cis-trans isomers, meso isomers, racemates, enantiomers, and diastereomers thereof.
  • pharmaceutically acceptable salt includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.
  • “Pharmaceutically acceptable acid addition salts” refers to salts with inorganic or organic acids that retain the biological effectiveness of the free base without other side effects.
  • Inorganic acid salts include but are not limited to hydrochloride, hydrobromide, sulfate, nitrate, phosphate, etc.; organic acid salts include but are not limited to formate, acetate, 2,2-dichloroacetate , trifluoroacetate, propionate, caproate, caprylate, caprate, undecylenate, glycolate, gluconate, lactate, sebacate, hexamethylene Acid, glutarate, malonate, oxalate, maleate, succinate, fumarate, tartrate, citrate, palmitate, stearate, oleate , cinnamate, laurate, malate, glutamate, pyroglutamate, aspartate, benzoate, mesylate, benzenesulfonate, p-tol
  • “Pharmaceutically acceptable base addition salts” refers to salts with inorganic or organic bases that retain the biological availability of the free acid without other adverse effects. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like. Preferred inorganic salts are ammonium, sodium, potassium, calcium and magnesium salts.
  • Salts derived from organic bases include but are not limited to the following salts: primary amine salts, secondary amine salts and tertiary amine salts, substituted amine salts, including natural substituted amine salts, cyclic amine salts and basic ion exchange resins such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, triethanolamine, dimethylethanolamine, 2-Dimethylaminoethanolate, 2-diethylaminoethanolate, dicyclohexylamine salt, lysine salt, arginine salt, histidine salt, caffeine salt, procaine salt, choline salt , betaine salt, ethylenediamine salt, glucosamine salt, methylglucamine salt, theobromine salt, purine salt, piperazine salt, piperidine salt, N-ethylpiperidine salt, polyamine resin, etc.
  • a "pharmaceutical composition” refers to a formulation of a compound of the present invention with a medium generally accepted in the art for delivering a biologically active compound to a mammal (eg, a human).
  • the medium includes a pharmaceutically acceptable carrier.
  • the purpose of the pharmaceutical composition is to facilitate the administration of the organism, facilitate the absorption of the active ingredient and then exert the biological activity.
  • pharmaceutically acceptable refers to a substance (such as a carrier or diluent) that does not affect the biological activity or properties of the compounds of the present invention, and is relatively non-toxic, ie, the substance can be administered to an individual without causing adverse effects or interacts in an undesired manner with any component contained in the composition.
  • pharmaceutically acceptable adjuvants include, but are not limited to, any adjuvant, carrier, excipient, glidant, sweetener approved by the relevant government regulatory authority as acceptable for human or livestock use , diluents, preservatives, dyes/colorants, flavoring agents, surfactants, wetting agents, dispersing agents, suspending agents, stabilizers, isotonic agents, solvents or emulsifiers.
  • solvate refers to a physical association of a compound of the present invention with one or more solvent molecules. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In certain instances, the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid.
  • Solvate includes solution phase and isolatable solvates. Non-limiting examples of solvates include ethanolates, methanolates, hydrates, and the like.
  • “Hydrate” is a solvate in which the solvent molecule is water.
  • treatment refers to therapeutic therapy or palliative measures.
  • treatment refers to: (1) ameliorating one or more biological manifestations of the disease or disorder, (2) interfering with (a) one or more points in the biological cascade leading to or causing the disorder or (b) ) one or more biological manifestations of the disorder, (3) amelioration of one or more symptoms, effects or side effects associated with the disorder, or one or more symptoms, effects or side effects associated with the disorder or its treatment, or (4) slowing the progression of the disorder or one or more biological manifestations of the disorder.
  • Treatment can also mean prolonging survival as compared to expected survival without treatment.
  • prevention refers to a reduced risk of acquiring or developing a disease or disorder.
  • any variable eg the group C 1-6 alkyl
  • their definitions are independent of each other and do not affect each other.
  • a 6-10-membered aryl group substituted by 3 C 1-6 alkyl groups means that the 6-10-membered aryl group will be substituted by 3 C 1-6 alkyl groups, the definitions of which are mutually independent and independent of each other.
  • the reagents and raw materials used in the present invention are all commercially available.
  • the positive improvement effect of the present invention is that the compounds in the present application can effectively inhibit the proliferation of Ba/F3 KRAS-G12C, NCI-H358 and MIA PaCa-2 cells containing KRAS G12C mutation, and some compounds or their salts can effectively inhibit the cell line NCI -H358 nude mice have a good inhibitory effect on the growth of subcutaneously transplanted tumors.
  • DMSO dimethyl sulfoxide
  • Boc tert-butoxycarbonyl
  • TBS tert-butyldimethylsilyl
  • CDCl 3 deuterated chloroform
  • DEA diethylamine
  • IPA isopropanol
  • ACN acetonitrile
  • PMB p-methoxybenzyl
  • THP 2-tetrahydropyranyl
  • Ms methylsulfonyl
  • FA formic acid
  • TIPS triisopropylsilyl
  • MOM methoxymethyl (CH 3 OCH 2 -)
  • Tf trifluoromethanesulfonyl.
  • LCMS monitored the completion of the reaction, poured the reaction solution into ice (1.9kg), added sodium hydroxide to adjust the pH of the reaction solution to 4, filtered, and slurried the filter cake with water, acetonitrile and ethyl acetate successively to obtain 7-bromo-6-chloro -8-Fluoroquinoline-2,4-diol (130 g, 79.31% yield), yellow solid.
  • Step 6 (3R,6R)-1-tert-Butyl-3-methyl-4-(7-bromo-2,6-dichloro-8-fluoro-3-nitroquinolin-4-yl)- 6-Methylpiperazine-1,3-dicarboxylate
  • Step 7 (2R,4aR)-tert-Butyl-10-bromo-7,11-dichloro-9-fluoro-2-methyl-5-carbonyl-4,4a,5,6-tetrahydro-1H- Pyridazo[1',2':4,5]pyrazo[2,3-c]quinoline-3(2H)-carboxylate
  • Step 2 (R)-1-Azido-3-((tert-butyldimethylsilyl)oxo)propan-2-ol
  • Step 3 (2R,4aR)-tert-Butyl-7-(((R)-1-azido-3-((tert-butyldimethylsilyl)oxo)propan-2-yl)oxy substituted)-10-bromo-11-chloro-9-fluoro-2-methyl-5-carbonyl-4,4a,5,6-tetrahydro-1H-pyranazido[1',2':4 ,5]pyranazido[2,3-c]quinoline-3(2H)-carboxylate
  • Step 4 (2R,4aR)-tert-Butyl-7-(((R)-1-azido-3-hydroxypropan-2-yl)oxo)-10-bromo-11-chloro-9-fluoro -2-Methyl-5-carbonyl-4,4a,5,6-tetrahydro-1H-pyranazino[1',2':4,5]pyranazino[2,3-c ]quinoline-3(2H)-carboxylate
  • Step 5 (2R,4aR,7S)-tert-Butyl-7-(azidomethyl)-11-bromo-12-chloro-10-fluoro-2-methyl-5-carbonyl-1,2,4a ,5,6,7-Hexahydro-8-oxa-3,5a,9,13c-tetraazanaphtho[3,2,1-de]anthracene-3(4H)-carboxylate
  • Triphenylphosphine (16.64g, 63.43mmol, 3eq) was dissolved in tetrahydrofuran (400mL), diisopropyl azodicarboxylate (12.83g, 63.43mmol, 3eq) was added at 0°C, stirred for 30 minutes, (2R) was added dropwise ,4aR)-tert-butyl-7-(((R)-1-azido-3-hydroxypropan-2-yl)oxo)-10-bromo-11-chloro-9-fluoro-2-methyl -5-Carbonyl-4,4a,5,6-tetrahydro-1H-pyranazino[1',2':4,5]pyranazino[2,3-c]quinoline-3 (2H)-carboxylate (13 g, 21.14 mmol, 1 eq), reacted at room temperature overnight.
  • Step 6 (2R,4aR,7R)-tert-Butyl-7-(aminomethyl)-11-bromo-12-chloro-10-fluoro-2-methyl-5-carbonyl-1,2,4a, 5,6,7-Hexahydro-8-oxa-3,5a,9,13c-tetraazanaphtho[3,2,1-de]anthracene-3(4H)-carboxylate
  • Step 7 (2R,4aR,7R)-tert-Butyl-11-bromo-12-chloro-7-((dimethylamino)methyl)-10-fluoro-2-methyl-5-carbonyl-1, 2,4a,5,6,7-Hexahydro-8-oxa-3,5a,9,13c-tetraazanaphtho[3,2,1-de]anthracene-3(4H)-carboxylate
  • Step 1 (R)-1-tert-Butyl-3-methyl 4-(7-bromo-2,6-dichloro-8-fluoro-3-nitroquinolin-4-yl)piperazine-1 ,3-Dicarboxylate
  • Step 2 (R)-tert-Butyl-10-bromo-7,11-dichloro-9-fluoro-5-oxo-4,4a,5,6-tetrahydro-1H-pyrazino[1' , 2':4,5]pyrazino[2,3-c]quinoline-3(2H)-carboxylate
  • Step 4 (R)-10-Bromo-7-(((R)-1-((tert-butyldimethylsilyl)oxy)-3-((4-methoxybenzyl)oxy yl)propan-2-yl)oxy)-11-chloro-9-fluoro-5-oxo-4,4a,5,6-tetrahydro-1H-pyrazino[1',2',4, 5] Pyrazino[2,3-c]quinoline-3(2H)-carboxylate tert-butyl ester
  • Step 5 (R)-10-Bromo-11-chloro-9-fluoro-7-(((S)-1-hydroxy-3-((4-methoxybenzyl)oxy)propane-2- (yl)oxy)-5-oxo-4,4a,5,6-tetrahydro-1H-pyrazino[1',2',4,5]pyrazino[2,3-c]quinoline -3(2H)-tert-butyl formate
  • Step 6 (4aR,7S)-11-Bromo-12-chloro-10-fluoro-7-(((4-methoxybenzyl)oxy)methyl)-5-oxo-1,2,4a ,5,6,7-Hexahydro-8-oxa-3,5a,9,13c-tetraazanaphtho[3,2,1-de]anthracene-3(4H)-carboxylic acid tert-butyl ester
  • Step 2 (R)-1-((tert-butyldimethylsilyl)oxo)-3-(dimethylamino)propan-2-ol
  • Step 3 (R)-2,3-bis((tert-butyldimethylsilyl)oxo)-N,N-dimethylpropan-1-amine
  • Step 4 (R)-2-((tert-Butyldimethylsilyl)oxo)-3-(dimethylamino)propan-1-ol
  • Step 2 (R)-1-((tert-butyldimethylsilyl)oxo)-3-(pyrrolidin-1-yl)propan-2-ol
  • Step 1 8-Fluoro-7-methoxy-3-nitro-1,6-naphthyridine-2,4-diol
  • reaction was complete as monitored by LCMS.
  • the reaction solution was filtered, the filtrate was adjusted to pH 2 with concentrated hydrochloric acid and then concentrated, the residue was slurried with water, filtered, and the filter cake was washed with ethyl acetate to obtain 8-fluoro-7-methoxy-3-nitro-1,6 - Naphthyridine-2,4-diol (20 g, crude).
  • Step 3 (3R,6R)-1-tert-Butyl-3-methyl 4-(2,8-difluoro-7-methoxy-3-nitro-1,6-naphthyridin-4-yl )-6-methylpiperazine-1,3-dicarboxylate
  • Step 4 (8aR,11R)-tert-Butyl-4,6-difluoro-3-methoxy-11-methyl-8-carbonyl-8a,9,11,12-tetrahydro-7H-pyran Biazo[1',2':4,5]pyranbiazo[2,3-c][1,6]naphthalene-10(8H)-carboxylate
  • Step 5 (8aR,11R)-tert-Butyl-6-((S)-2-((tert-butyldimethylsilyl)oxo)-1-((S)-1-methyl Pyrrolidin-2-yl)ethoxy)-4-fluoro-3-methoxy-11-methyl-8-carbonyl-8a,9,11,12-tetrahydro-7H-pyranazido[ 1',2':4,5]pyrazo[2,3-c][1,6]naphthalene-10(8H)-carboxylate
  • reaction solution was poured into saturated aqueous ammonium chloride solution at 0°C to quench, and extracted with ethyl acetate. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate.
  • Step 6 (8aR,11R)-tert-Butyl-4-fluoro-6-((S)-2-hydroxy-1-((S)-1-methylpyrrolidin-2-yl)ethoxy) -3-Methoxy-11-methyl-8-carbonyl-8a,9,11,12-tetrahydro-7H-pyranazino[1',2':4,5]pyranazino [2,3-c][1,6]Naphthalene-10(8H)-carboxylate
  • reaction was complete as monitored by LCMS.
  • the reaction solution was diluted with water, adjusted to pH 7-8 with sodium bicarbonate, and extracted with ethyl acetate. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate.
  • Step 7 (2R,4aR,7R)-tert-Butyl-10-fluoro-11-methoxy-2-methyl-7-((S)-1-methylpyrrolidin-2-yl)-5 - Oxyidene-1,2,4a,5,6,7-hexahydro-8-oxa-3,5a,9,12,13c-pentazanaphtho[3,2,1-de]anthracene -3(4H)-carboxylate
  • Triphenylphosphine (1.54g, 5.89mmol, 3eq) was dissolved in tetrahydrofuran (20mL), diisopropyl azodicarboxylate (1.19g, 5.89mmol, 1.14mL, 3eq) was added at 0°C, and the reaction was carried out at 0°C for 30 After min, (8aR,11R)-tert-butyl-4-fluoro-6-((S)-2-hydroxy-1-((S)-1-methylpyrrolidin-2-yl)ethoxy was added )-3-methoxy-11-methyl-8-carbonyl-8a,9,11,12-tetrahydro-7H-pyranazido[1',2':4,5]pyranazido Base [2,3-c][1,6]naphthalene-10(8H)-carboxylate (1.1 g, 1.96 mmol, 1 eq), reacted at room temperature overnight.
  • reaction was complete as monitored by LCMS.
  • the reaction solution was quenched by adding water, extracted with ethyl acetate, the organic phase was washed with saturated brine, and dried over anhydrous sodium sulfate. Filter and concentrate the filtrate.
  • Step 8 (2R,4aR,7R)-tert-Butyl-10-fluoro-11-hydroxy-2-methyl-7-((S)-1-methylpyrrolidin-2-yl)-5-carbonyl -1,2,4a,5,6,7-hexahydro-8-oxa-3,5a,9,12,13c-pentazanaphtho[3,2,1-de]anthracene-3(4H )-carboxylate
  • Mobile phase B% 0%-30%.
  • Step 9 (2R,4aR,7R)-tert-Butyl-10-fluoro-2-methyl-7-((S)-1-methylpyrrolidin-2-yl)-5-carbonyl-11-( ((trifluoromethyl)sulfonyl)oxo)-1,2,4a,5,6,7-hexahydro-8-oxa-3,5a,9,12,13c-pentazanaphtho[ 3,2,1-de]anthracene-3(4H)-carboxylate
  • Step 10 (2R,4aR,7R)-tert-Butyl-11-bromo-10-fluoro-2-methyl-7-((S)-1-methylpyrrolidin-2-yl)-5-carbonyl -1,2,4a,5,6,7-hexahydro-8-oxa-3,5a,9,12,13c-pentazanaphtho[3,2,1-de]anthracene-3(4H )-carboxylate
  • reaction was complete as monitored by LCMS.
  • the pH of the reaction solution was adjusted to 7-8 with aqueous sodium bicarbonate solution.
  • Tetrahydrofuran (5 mL), water (5 mL) and Boc acid anhydride (52.4 mg, 0.240 mmol, 2 eq) were added to the reaction solution, and the reaction was carried out at room temperature overnight.
  • the reaction was complete as monitored by LCMS.
  • the reaction solution was extracted with ethyl acetate, and the organic phase was washed with saturated brine and dried over anhydrous sodium sulfate.
  • tert-Butyl(2-chloro-3-fluoropyridin-4-yl)carbamate (124.0g, 0.504mol, 1eq) was dissolved in 1,4-dioxane/hydrochloric acid (1.3L, 4M), The mixture was stirred at room temperature for 16 hours. The reaction was completed by LCMS. The filtered solid was washed with ethyl acetate and dried under reduced pressure to obtain 2-chloro-3-fluoropyridin-4-amine hydrochloride (110.0 g, crude product) as a white solid.
  • 2-Chloro-3-fluoropyridin-4-amine hydrochloride (110.0g, 0.504mol, 1eq) was dissolved in water (2L) and sodium bicarbonate (423.4g, 5.04mol, 10eq) was added while stirring, and stirred at room temperature After two hours, TLC monitored the reaction to complete, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 2-chloro-3-fluoropyridin-4-amine (65.0 g, 88% yield) as a white solid.
  • Step 4 4-Amino-6-chloro-5-fluoronicotinic acid ethyl ester
  • Step 5 6-Chloro-4-(3-ethoxy-3-oxopropionamide)-5-fluoronicotinic acid ethyl ester
  • Step 6 Ethyl 7-chloro-8-fluoro-2,4-dihydroxy-1,6-naphthyridine-3-carboxylate
  • 6-Chloro-4-(3-ethoxy-3-oxopropionamide)-5-fluoronicotinic acid ethyl ester (17.5g, 52.59mmol, 1.0eq) was dissolved in tetrahydrofuran solution (300mL), added at 0 degrees Potassium tert-butoxide (1.8 g, 105.19 mmol, 2.0 eq) was reacted at room temperature for 1 hour. Adjust the pH to 5 with 2M hydrochloric acid, filter, and dry to obtain ethyl 7-chloro-8-fluoro-2,4-dihydroxy-1,6-naphthyridine-3-carboxylate as a white solid (14.5 g, yield 96%).
  • Ethyl 7-chloro-8-fluoro-2,4-dihydroxy-1,6-naphthyridine-3-carboxylate (14.5 g, 50.58 mmol, 1.0 eq) was dissolved in dioxane (100 mL) and concentrated Hydrochloric acid (100 mL) was reacted at 90 degrees overnight. The dioxane was spun off, filtered, and the solid was washed with a small amount of water and dried to obtain 7-chloro-8-fluoro-1,6-naphthyridine-2,4-diol (11.2 g, yield 90%) as a white solid.
  • Step 8 7-Chloro-8-fluoro-3-nitro-1,6-naphthyridine-2,4-diol
  • Example 1 Compound 1-P1 Mesylate and Compound 1-P2 Mesylate
  • Step 1 (2R,4aR)-tert-Butyl-10-bromo-7-(2-((tert-butyldimethylsilyl)oxo)ethoxy)-11-chloro-9-fluoro- 2-Methyl-5-carbonyl-4,4a,5,6-tetrahydro-1H-pyranazino[1',2':4,5]pyranazino[2,3-c] Quinoline-3(2H)-carboxylate
  • Step 2 (2R,4aR)-tert-Butyl-10-bromo-11-chloro-9-fluoro-7-(2-hydroxyethoxy)-2-methyl-5-carbonyl-4,4a,5 ,6-Tetrahydro-1H-pyridazo[1',2':4,5]pyrazo[2,3-c]quinoline-3(2H)-carboxylate
  • Step 3 (2R,4aR)-tert-Butyl-11-bromo-12-chloro-10-fluoro-2-methyl-5-carbonyl-1,2,4a,5,6,7-hexahydro-8 -oxa-3,5a,9,13c-tetraazanaphtho[3,2,1-de]anthracene-3(4H)-carboxylate
  • Step 4 (2R,4aR)-tert-Butyl-11-(2-((tert-butoxycarbonyl)amino)-5,7-difluorobenzo[d]thiazol-4-yl)-12-chloro -10-Fluoro-2-methyl-5-carbonyl-1,2,4a,5,6,7-hexahydro-8-oxa-3,5a,9,13c-tetraazanaphtho[3, 2,1-de]Anthracene-3(4H)-carboxylate
  • Step 5 (2R,4aR)-11-(2-Amino-5,7-difluorobenzo[d]thiazol-4-yl)-12-chloro-10-fluoro-2-methyl-2,3 ,4,4a,6,7-hexahydro-8-oxa-3,5a,9,13c-tetraazanaphtho[3,2,1-de]anthracene-5(1H)-one
  • Step 7 Compound 1-P1 Mesylate and Compound 1-P2 Mesylate
  • Step 1 Compound 2-1-1 and Compound 2-1-2
  • Step 2 Compound 2-2-1 and Compound 2-2-2
  • Step 3 Compound 2-3-1 and Compound 2-3-2
  • Step 4 Compound 2-P1 and Compound 2-P2
  • Example 3 Compound 3-P1 mesylate and compound 3-P2 mesylate
  • Step 1 (R)-tert-Butyl-10-bromo-7-(((R)-1-((tert-butyldimethylsilyl)oxo)-3-(dimethylamino)propane- 2-yl)oxo)-11-chloro-9-fluoro-5-carbonyl-4,4a,5,6-tetrahydro-1H-pyrandiazo[1',2':4,5]pyridine Pyridazo[2,3-c]quinoline-3(2H)-carboxylate
  • Step 2 (R)-tert-Butyl-10-bromo-11-chloro-7-(((R)-1-(dimethylamino)-3-hydroxypropan-2-yl)oxo)-9- Fluoro-5-carbonyl-4,4a,5,6-tetrahydro-1H-pyranazino[1',2':4,5]pyranazino[2,3-c]quinoline- 3(2H)-carboxylate
  • Step 3 (4aR,7R)-tert-Butyl-11-bromo-12-chloro-7-((dimethylamino)methyl)-10-fluoro-5-carbonyl-1,2,4a,5,6 ,7-Hexahydro-8-oxa-3,5a,9,13c-tetraazanaphtho[3,2,1-de]anthracene-3(4H)-carboxylate
  • Step 4 (4aR,7R)-tert-Butyl-11-(2-((tert-butoxycarbonyl)amino)-5,7-difluorobenzo[d]thiazol-4-yl)-12-chloro -7-((dimethylamino)methyl)-10-fluoro-5-carbonyl-1,2,4a,5,6,7-hexahydro-8-oxa-3,5a,9,13c-tetra Azanaphtho[3,2,1-de]anthracene-3(4H)-carboxylate
  • Step 5 (4aR,7R)-11-(2-Amino-5,7-difluorobenzo[d]thiazol-4-yl)-12-chloro-7-((dimethylamino)methyl)- 10-Fluoro-2,3,4,4a,6,7-hexahydro-8-oxa-3,5a,9,13c-tetraazanaphtho[3,2,1-de]anthracene-5( 1H)-keto
  • Step 7 Compound 3-P1 Mesylate and Compound 3-P2 Mesylate
  • Step 1 (4aR,7R)-tert-Butyl-12-chloro-7-((dimethylamino)methyl)-10-fluoro-11-(5-methyl-1H-indazol-4-yl )-5-oxo-1,2,4a,5,6,7-hexahydro-8-oxo-3,5a,9,13c-tetraazanaphthalene[3,2,1-de]anthracene-3 (4H)-carboxylate
  • Step 2 (4aR,7R)-12-chloro-7-((dimethylamino)methyl)-10-fluoro-11-(5-methyl-1H-indazol-4-yl)-2, 3,4,4a,6,7-Hexahydro-8-oxo-3,5a,9,13c-tetraazanaphthalen[3,2,1-de]anthracene-5(1H)-one

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Abstract

La présente divulgation concerne un composé pentahétérocyclique, son procédé de préparation et son utilisation. En particulier, la présente divulgation concerne un composé tel que représenté dans la formule I, un sel pharmaceutiquement acceptable ou un solvate de celui-ci, une composition comprenant le composé, et l'utilisation pharmaceutique du composé dans la préparation de médicaments pour le traitement de maladies ou de troubles liés au mécanisme d'action de la mutéine KRAS G12C. Le composé pentahétérocyclique selon la présente invention a l'activité d'inhiber la prolifération de cellules Ba/F3 KRAS-G12C, NCI-H358 et des cellules MIA PaCa-2 exprimant la mutéine KRAS G12C, et a un bon effet inhibiteur sur la croissance de tumeurs greffées sous-cutanées dans la lignée cellulaire de souris nude NCI-H358.
PCT/CN2022/074955 2021-02-01 2022-01-29 Composé pentahétérocyclique, son procédé de préparation et son utilisation WO2022161489A1 (fr)

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WO2019110751A1 (fr) * 2017-12-08 2019-06-13 Astrazeneca Ab Composés tétracycliques en tant qu'inhibiteurs de la protéine ras mutante g12c, destinés à être utilisés en tant qu'agents anticancéreux
WO2020259573A1 (fr) * 2019-06-25 2020-12-30 南京明德新药研发有限公司 Dérivé hétérocyclique à sept chaînons agissant en tant qu'inhibiteur de protéine mutante kras g12c
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CN112707905A (zh) * 2019-10-25 2021-04-27 武汉誉祥医药科技有限公司 一种三并杂环化合物及其制备方法和用途
CN113929681A (zh) * 2020-07-14 2022-01-14 浙江海正药业股份有限公司 四环类衍生物及其制备方法和用途

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WO2019110751A1 (fr) * 2017-12-08 2019-06-13 Astrazeneca Ab Composés tétracycliques en tant qu'inhibiteurs de la protéine ras mutante g12c, destinés à être utilisés en tant qu'agents anticancéreux
WO2020259573A1 (fr) * 2019-06-25 2020-12-30 南京明德新药研发有限公司 Dérivé hétérocyclique à sept chaînons agissant en tant qu'inhibiteur de protéine mutante kras g12c
CN112390818A (zh) * 2019-08-12 2021-02-23 劲方医药科技(上海)有限公司 取代的杂芳环并二氢嘧啶酮衍生物，其制法与医药上的用途
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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11845761B2 (en) 2020-12-18 2023-12-19 Erasca, Inc. Tricyclic pyridones and pyrimidones

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