WO2022242767A1 - 螺环类化合物及其用途 - Google Patents

螺环类化合物及其用途 Download PDF

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WO2022242767A1
WO2022242767A1 PCT/CN2022/094255 CN2022094255W WO2022242767A1 WO 2022242767 A1 WO2022242767 A1 WO 2022242767A1 CN 2022094255 W CN2022094255 W CN 2022094255W WO 2022242767 A1 WO2022242767 A1 WO 2022242767A1
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optionally substituted
independently selected
hydrogen
substituted
compound
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PCT/CN2022/094255
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English (en)
French (fr)
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米国瑞
赵传武
郭谦
张佳楠
李春娜
魏文利
徐艳霞
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石药集团中奇制药技术（石家庄）有限公司
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Priority to JP2023571976A priority Critical patent/JP2024519098A/ja
Priority to EP22804086.1A priority patent/EP4342891A1/en
Publication of WO2022242767A1 publication Critical patent/WO2022242767A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems
    • C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • 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
    • A61K31/4965—Non-condensed pyrazines
    • A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • the present application relates to the field of medical technology, in particular, to a class of novel compounds with SHP2 inhibitory activity and their use in the treatment and prevention of diseases, disorders and conditions mediated by SHP2 activity, such as hyperproliferative diseases.
  • SHP2 (Src homology domain, Src homology-2 domain) is encoded by protein tyrosine phosphatase non-receptor 11 (PTP nonreceptor 11, PTPN11), which catalyzes the dephosphorylation of protein tyrosine. It is generally believed that the N-terminal of SHP2 contains two SH2 domains including N-src homology 2 domain (SH2) and C-SH2, and the C-terminal contains a PTP domain with catalytic activity. In the unactivated state, SHP2 is in a state of autoinhibition, and the combination of N-SH2 and C-PTP inhibits the activity of phosphatase. In the presence of extracellular stimuli, they bind to related receptors and activate multiple downstream signaling pathways, such as Ras/MAPK, PI3K/AKT and other signaling pathways, to regulate cell proliferation, differentiation, apoptosis and survival .
  • PTP nonreceptor 11 protein tyrosine phosphatase
  • PD-1 programmed death 1
  • ITIM immunoreceptor tyrosine-based inhibition motif
  • ITMS immunoreceptor tyrosine-based switch motif
  • This application provides a class of SHP2 inhibitor compounds with a novel structure, and at the same time provides such compounds or their prodrugs, tautomers, stereoisomers, solvates, isotope derivatives or pharmaceutically acceptable salts thereof for treatment Uses for diseases, disorders and conditions mediated by SHP2 activity.
  • the application provides a compound represented by formula (I), or its prodrug, tautomer, stereoisomer, solvate, isotope derivative or pharmaceutically acceptable salt thereof, which has the following structure:
  • X is selected from O, CH2 , NH or S;
  • L is selected from N or CH
  • G is selected from a bond or S
  • A is selected from CH or N;
  • R 3 is independently selected from: optionally substituted 8-12 membered heterocyclic group, optionally substituted C 6-10 aryl, optionally substituted 5-14 membered heteroaryl, wherein the optionally substituted means
  • the hydrogen on the substituted group is unsubstituted or the hydrogen on one or more substitutable positions of the substituted group is independently selected from halogen, hydroxyl, amino, nitro, oxo, cyano, -COOH , -COCH 3 , -COOCH 3 , -CONH 2 , C 1-6 alkyl, C 1-6 alkoxy, C 3-10 cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 aromatic Substituents of bases, 5-12 membered heteroaryl groups;
  • R is independently selected from hydrogen, deuterium or amino ;
  • R 2 is independently selected from hydrogen, halogen, cyano, -CONH 2 , -COR 5 , -COOR 5 , optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, optionally substituted C 3-10 cycloalkyl, optionally substituted 3-10 membered heterocycloalkyl, wherein, R 5 is independently selected from hydrogen, optionally substituted C 1- 6 alkyl, optionally substituted C 3-6 cycloalkyl, optionally substituted 3-6 membered heterocycloalkyl, optionally substituted C 6-10 aryl, optionally substituted 5-10 membered heteroaryl
  • the optional substitution means that the hydrogen on the substituted group is not substituted or the hydrogen on one or more substitutable positions of the substituted group is independently selected from halogen, hydroxyl, amino, nitro, Substituents of oxo, cyano, C 1-6 alkyl, C 1-6
  • Y is independently selected from N or CR4 ;
  • R is independently selected from hydrogen, halogen, hydroxyl, amino, cyano, optionally substituted C 1-6 alkyl, optionally substituted C 1-6 alkoxy, wherein the optionally substituted means substituted
  • the hydrogen on the group is unsubstituted or one or more substitutable positions of the substituted group are independently selected from halogen, hydroxyl, amino, cyano, C 1-6 alkyl, C 1-6 alkoxy replaced by
  • R is independently selected from hydrogen or deuterium ;
  • the "oxo group” means that two Hs in the same substituent position are replaced by the same O to form a double bond
  • heteroatoms in the heterocycloalkyl, heteroaryl and heterocyclyl are independently selected from O, N or S, and the number of heteroatoms is 1, 2, 3 or 4.
  • X is selected from O, CH2 , NH or S;
  • L is selected from N or CH
  • G is selected from a bond or S
  • A is selected from CH or N;
  • R 3 is amino
  • R is independently selected from hydrogen, amino or deuterium ;
  • R 2 is independently selected from halogen, cyano, -CONH 2 , -COR 5 , -COOR 5 , optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, optionally substituted C 3-10 cycloalkyl, optionally substituted 3-10 membered heterocycloalkyl, wherein R is independently selected from hydrogen, optionally substituted C 1-6 alkane Base, optionally substituted C 3-6 cycloalkyl, optionally substituted 3-6 membered heterocycloalkyl, optionally substituted C 6-10 aryl, optionally substituted 5-10 membered heteroaryl,
  • the optional substitution means that the hydrogen on the substituted group is not substituted or the hydrogen on one or more substitutable positions of the substituted group is independently selected from halogen, hydroxyl, amino, nitro, oxo Substituents of group, cyano, C 1-6 alkyl, C 1-6 al
  • Y is independently selected from N or CR4 ;
  • R is independently selected from hydrogen, halogen, hydroxyl, amino, cyano, optionally substituted C 1-6 alkyl, optionally substituted C 1-6 alkoxy, the optionally substituted refers to the substituent
  • the hydrogen on the group is not substituted or one or more substitutable positions of the substituted group are independently selected from halogen, hydroxyl, amino, cyano, C 1-6 alkyl, C 1-6 alkoxy replace;
  • R is independently selected from hydrogen or deuterium ;
  • the "oxo group” means that two Hs in the same substituent position are replaced by the same O to form a double bond
  • heteroatoms in the heterocycloalkyl, heteroaryl and heterocyclyl are independently selected from O, N or S, and the number of heteroatoms is 1, 2, 3 or 4.
  • X is selected from O, CH2 , NH or S;
  • L is selected from N or CH
  • G is selected from a bond or S
  • A is selected from CH or N;
  • R is independently selected from: amino, optionally substituted 8-12 membered heterocyclic group, optionally substituted C 6-10 aryl, optionally substituted 5-14 membered heteroaryl, wherein the optionally substituted means that the hydrogen on the substituted group is unsubstituted or the hydrogen on one or more substitutable positions of the substituted group is independently selected from halogen, hydroxyl, amino, nitro, oxo, cyano, -COOH, -COCH 3 , -COOCH 3 , -CONH 2 , C 1-6 alkyl, C 1-6 alkoxy, C 3-10 cycloalkyl, 3-10 membered heterocycloalkyl, C 6- Substituents of 10 aryl and 5-12 membered heteroaryl;
  • R is independently selected from hydrogen, deuterium or amino ;
  • R 2 is independently selected from hydrogen, halogen, cyano, -CONH 2 , -COR 5 , -COOR 5 , optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, optionally substituted C 3-10 cycloalkyl, optionally substituted 3-10 membered heterocycloalkyl, wherein, R 5 is independently selected from hydrogen, optionally substituted C 1- 6 alkyl, optionally substituted C 3-6 cycloalkyl, optionally substituted 3-6 membered heterocycloalkyl, optionally substituted C 6-10 aryl, optionally substituted 5-10 membered heteroaryl
  • the optional substitution means that the hydrogen on the substituted group is not substituted or the hydrogen on one or more substitutable positions of the substituted group is independently selected from halogen, hydroxyl, amino, nitro, Substituents of oxo, cyano, C 1-6 alkyl, C 1-6
  • Y is independently selected from N or CR4 ;
  • R is independently selected from hydrogen, halogen, hydroxyl, amino, cyano, optionally substituted C 1-6 alkyl, optionally substituted C 1-6 alkoxy, the optionally substituted refers to the substituent
  • the hydrogen on the group is unsubstituted or the hydrogen on one or more substitutable positions of the substituted group is independently selected from halogen, hydroxyl, amino, cyano, C 1 ⁇ 6 alkyl, C 1-6 alkane Oxygen substituents are substituted;
  • R is independently selected from hydrogen or deuterium ;
  • the "oxo group” means that two Hs in the same substituent position are replaced by the same O to form a double bond
  • heteroatoms in the heterocycloalkyl, heteroaryl and heterocyclyl are independently selected from O, N or S, and the number of heteroatoms is 1, 2, 3 or 4.
  • R 6 is deuterium
  • X is selected from O, CH2 , NH or S;
  • L is selected from N or CH
  • G is selected from a bond or S
  • A is selected from CH or N;
  • R 3 is independently selected from optionally substituted 8-12 membered heterocyclic groups, optionally substituted C 6-10 aryls, optionally substituted 5-14 membered heteroaryls, the optional substituted means substituted
  • the hydrogen on the group is unsubstituted or the hydrogen on one or more substitutable positions of the substituted group is independently selected from halogen, hydroxyl, amino, nitro, oxo, cyano, -COOH, - COCH 3 , -COOCH 3 , -CONH 2 , C 1-6 alkyl, C 1-6 alkoxy, C 3-10 cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 aryl, Substituents of 5-12 membered heteroaryl groups;
  • R is independently selected from hydrogen, deuterium or amino ;
  • R 2 is independently selected from hydrogen, halogen, cyano, -CONH 2 , -COR 5 , -COOR 5 , optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, optionally substituted C 3-10 cycloalkyl, optionally substituted 3-10 membered heterocycloalkyl, wherein, R 5 is independently selected from hydrogen, optionally substituted C 1- 6 alkyl, optionally substituted C 3-6 cycloalkyl, optionally substituted 3-6 membered heterocycloalkyl, optionally substituted C 6-10 aryl, optionally substituted 5-10 membered heteroaryl
  • the optional substitution means that the hydrogen on the substituted group is not substituted or the hydrogen on one or more substitutable positions of the substituted group is independently selected from halogen, hydroxyl, amino, nitro, Substituents of oxo, cyano, C 1-6 alkyl, C 1-6
  • Y is independently selected from N or CR4 ;
  • R is independently selected from hydrogen, halogen, hydroxyl, amino, cyano, optionally substituted C 1-6 alkyl, optionally substituted C 1-6 alkoxy, wherein the optionally substituted means substituted
  • the hydrogen on the group is unsubstituted or the hydrogen on one or more substitutable positions of the substituted group is independently selected from halogen, hydroxyl, amino, cyano, C 1 ⁇ 6 alkyl, C 1-6 Substituents of alkoxy groups;
  • the "oxo group” means that two Hs in the same substituent position are replaced by the same O to form a double bond
  • heteroatoms in the above-mentioned heterocycloalkyl, heteroaryl and heterocyclyl are independently selected from O, N or S, and the number of heteroatoms is 1, 2, 3 or 4;
  • G, A, Y, R 1 , R 2 , R 3 , X and L are the same as those described for the compound represented by formula (I) or formula (I-1) in this application.
  • a compound of formula (I), a compound of formula (I-1), a compound of formula (I-1-1), or a prodrug or tautomer thereof as shown above is provided , stereoisomers, solvates, isotopic derivatives or pharmaceutically acceptable salts thereof, wherein the R 3 is amino.
  • a compound of formula (I), a compound of formula (I-1), a compound of formula (I-1-1), or a prodrug or tautomer thereof as shown above is provided , stereoisomers, solvates, isotopic derivatives or pharmaceutically acceptable salts thereof, wherein said R 3 is independently selected from: optionally substituted 8-12 membered heterocyclic groups, optionally substituted C 6 -10 aryl, optionally substituted 5-14 membered heteroaryl.
  • R in the compound of formula (I), compound of formula (I-1), and compound of formula (I-1-1) is independently selected from: optionally substituted 8- 12-membered bicyclic heterocyclic group, optionally substituted C 6-10 aryl, optionally substituted 5-14-membered heteroaryl, wherein the optional substitution means that the hydrogen on the substituted group is unsubstituted or replaced by
  • the hydrogen on one or more substitutable positions of the substituent group is independently selected from halogen, hydroxyl, amino, nitro, oxo, cyano, -COOH, -COCH 3 , -COOCH 3 , -CONH 2
  • R in the compound of formula (I), compound of formula (I-1), compound of formula (I-1-1) is independently selected from optionally substituted 8-10 Membered bicyclic heterocyclic group, optionally substituted C 6-8 aryl, optionally substituted 5-10 membered heteroaryl, wherein the optional substitution means that the hydrogen on the substituted group is unsubstituted or substituted
  • the hydrogen on one or more substitutable positions of the group is independently selected from halogen, hydroxyl, amino, nitro, oxo, cyano, -COOH, -COCH 3 , -COOCH 3 , -CONH 2 , Substituents of C 1-6 alkyl, C 1-6 alkoxy, C 3-10 cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 aryl, 5-12 membered heteroaryl replace.
  • R in the compound of formula (I), compound of formula (I-1), compound of formula (I-1-1) is independently selected from optionally substituted 8-10 Membered bicyclic heterocyclic group, optionally substituted C 6-8 aryl, optionally substituted 5-10 membered heteroaryl, wherein the optional substitution means that the hydrogen on the substituted group is unsubstituted or substituted Hydrogens on one or more substitutable positions of the group are independently substituted by substituents selected from halogen, hydroxyl, amino, oxo, cyano, -CONH 2 , C 1-6 alkyl.
  • R in the compound of formula (I), the compound of formula (I-1), and the compound of formula (I-1-1) is independently selected from optionally substituted 10-membered bicyclic Heterocyclyl, optionally substituted C 6-8 aryl, optionally substituted 5-10 membered heteroaryl, wherein the optional substitution means that the hydrogen on the substituted group is unsubstituted or substituted
  • the hydrogen on one or more substitutable positions of is independently selected from hydroxyl, oxo, cyano, -CONH 2 , methyl, ethyl, n-propyl, isopropyl, n-butyl substituents substituted, wherein the heteroatoms in the heterocyclic group and heteroaryl group are independently selected from O, N or S, and the number of heteroatoms is 1, 2 or 3.
  • R 3 in the compound of formula (I), compound of formula (I-1) and compound of formula (I-1-1) is independently selected from optionally substituted C 6- 8 aryl, optionally substituted 5-6 membered heteroaryl, wherein the optional substitution means that the hydrogen on the substituted group is unsubstituted or one or more substitutable positions of the substituted group Hydrogen is independently substituted by substituents selected from halogen, hydroxyl, amino, oxo, cyano, -CONH 2 , C 1-6 alkyl, wherein the heteroatoms in the heteroaryl are independently selected from O , N or S, and the number of heteroatoms is 1 or 2.
  • R in the compound of formula (I), the compound of formula (I-1), and the compound of formula (I-1-1) is independently selected from optionally substituted phenyl, Optionally substituted 5-6 membered heteroaryl, wherein the optional substitution means that the hydrogen on the substituted group is unsubstituted or the hydrogen on one or more substitutable positions of the substituted group is independently replaced by Substituents selected from cyano, -CONH 2 , methyl, wherein the heteroatoms in the heteroaryl are independently selected from O, N or S, and the number of heteroatoms is 1 or 2.
  • R 3 in the compound of formula (I), compound of formula (I-1) and compound of formula (I-1-1) is independently selected from: optionally substituted C 6 -10 aryl, optionally substituted 5-14 membered heteroaryl, wherein the optional substitution means that the hydrogen on the substituted group is unsubstituted or one or more substitutable positions of the substituted group
  • the hydrogen in is independently selected from halogen, hydroxyl, amino, nitro, oxo, cyano, -COOH, -COCH 3 , -COOCH 3 , -CONH 2 , C 1-6 alkyl, C 1-6 alkane Oxygen, C 3-10 cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 aryl, 5-12 membered heteroaryl are substituted.
  • R in the compound of formula (I), compound of formula (I-1), compound of formula (I-1-1) is independently selected from optionally substituted 5-10 Member heteroaryl, wherein the optional substitution means that the hydrogen on the substituted group is not substituted or the hydrogen on one or more substitutable positions of the substituted group is independently selected from halogen, hydroxyl, amino , Oxo, cyano, -CONH 2 , C 1-6 alkyl substituents.
  • R in the compound of formula (I), the compound of formula (I-1), and the compound of formula (I-1-1) is independently selected from optionally substituted 5-6 Member heteroaryl, wherein the optional substitution means that the hydrogen on the substituted group is not substituted or the hydrogen on one or more substitutable positions of the substituted group is independently selected from halogen, hydroxyl, amino , cyano, -CONH 2 , C 1-6 alkyl substituents, wherein the heteroatoms in the heteroaryl are independently selected from O, N or S, and the number of heteroatoms is 1 or 2.
  • R in the compound of formula (I), the compound of formula (I-1), and the compound of formula (I-1-1) is independently selected from optionally substituted 5-6 Member heteroaryl, wherein the optional substitution means that the hydrogen on the substituted group is not substituted or the hydrogen on one or more substitutable positions of the substituted group is independently selected from halogen, hydroxyl, amino , cyano, -CONH 2 , C 1-3 alkyl substituents, wherein the heteroatoms in the heteroaryl are independently selected from O, N or S, and the number of heteroatoms is 1 or 2.
  • R in the compound of formula (I), compound of formula (I-1), compound of formula (I-1-1) is independently selected from optionally substituted 5-membered hetero Aryl, wherein the optional substitution means that the hydrogen on the substituted group is unsubstituted or the hydrogen on one or more substitutable positions of the substituted group is independently selected from hydroxyl, cyano, -CONH 2. Substituted by a methyl substituent, wherein the heteroatoms in the heteroaryl group are independently selected from O, N or S, and the number of heteroatoms is 1 or 2.
  • R in the compound of formula (I), compound of formula (I-1) and compound of formula (I-1-1) is independently selected from the following structures optionally substituted :
  • R in the compound of formula (I), compound of formula (I-1) and compound of formula (I-1-1) is independently selected from the following structures optionally substituted :
  • R in the compound of formula (I), compound of formula (I-1) and compound of formula (I-1-1) is independently selected from the following structures optionally substituted :
  • R in the compound of formula (I), the compound of formula (I-1), and the compound of formula (I-1-1) is independently selected from amino, optionally substituted
  • R in the compound of formula (I), compound of formula (I-1), compound of formula (I-1-1) is independently selected from optionally substituted
  • R in the compound of formula (I), compound of formula (I-1) and compound of formula (I-1-1) is independently selected from the following structures:
  • R in the compound of formula (I), the compound of formula (I-1), and the compound of formula (I-1-1) is independently selected from the following structures:
  • the above-mentioned compound of formula (I), compound of formula (I-1), compound of formula (I-1-1)) or its prodrug and tautomer are provided , stereoisomers, solvates, isotopic derivatives or pharmaceutically acceptable salts thereof, wherein R 2 is independently selected from halogen, cyano, -CONH 2 , -COR 5 , -COOR 5 , optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, optionally substituted C 3-10 cycloalkyl, optionally substituted 3-10 membered hetero Cycloalkyl, wherein, R 5 is independently selected from hydrogen, optionally substituted C 1-6 alkyl, optionally substituted C 3-6 cycloalkyl, optionally substituted 3-6 membered heterocycloalkyl, Optionally substituted C 6-10 aryl, optionally substituted 5-10 membered heteroaryl, the optional
  • the above-mentioned compound of formula (I), compound of formula (I-1), compound of formula (I-1-1)) or its prodrug and tautomer are provided , stereoisomers, solvates, isotopic derivatives or pharmaceutically acceptable salts thereof, wherein R 2 is independently selected from hydrogen, halogen, cyano, -CONH 2 , -COR 5 , -COOR 5 , optionally Substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 3-10 cycloalkyl, optionally substituted 3-10 membered heterocycloalkyl, wherein the optionally Substitution means that the hydrogen on the substituted group is not substituted or the hydrogen on one or more substitutable positions of the substituted group is independently selected from halogen, hydroxyl, amino, nitro, oxo, cyano , C 1-6 alkyl, C 1-6 alkoxy substituents are substituted.
  • R in the compound of formula (I), the compound of formula (I-1), and the compound of formula (I-1-1) is independently selected from hydrogen, halogen, cyano, -CONH 2 , -COR 5 , -COOR 5 , optionally substituted C 1-4 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 3-6 cycloalkyl, optionally substituted 3-6 membered heterocycloalkyl, wherein the optional substitution means that the hydrogen on the substituted group is unsubstituted or the hydrogen on one or more substitutable positions of the substituted group is independently selected from halogen , Hydroxy, amino, nitro, oxo, cyano, C 1-6 alkyl, C 1-6 alkoxy substituents.
  • R 2 is independently selected from halogen, cyano, -CONH 2 , -COR 5 , -COOR 5 , C 1-4 alkyl, C 2-6 alkenyl, substituted by one or more substituents selected from hydroxyl, C 1-6 alkoxy and halogen, C 3-6 cycloalkyl or 3-6 membered heterocycloalkyl.
  • R in the compound of formula (I), the compound of formula (I-1), and the compound of formula (I-1-1) is independently selected from halogen, cyano, -CONH 2.
  • -COR 5 , -COOR 5 hydroxy-substituted C 1-4 alkyl, C 2-6 alkenyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl.
  • R 2 in the compound of formula (I), compound of formula (I-1) and compound of formula (I-1-1) is independently selected from halogen, -COR 5 , - COOR 5 , hydroxy-substituted C 1-4 alkyl, C 2-6 alkenyl or 3-6 membered heterocycloalkyl; or, R 2 is independently selected from halogen, -COR 5 , -COOR 5 , C 2- 6 alkenyl or 3-6 membered heterocycloalkyl; or, R 2 is independently selected from -COR 5 or -COOR 5 ; or, R 2 is -COR 5 or R 2 is -COOR 5 , wherein preferably, R 5 is C 3-6 cycloalkyl or C 1-6 alkyl, preferably C 3-4 cycloalkyl or C 1-3 alkyl, such as cyclopropyl, methyl; or, R 2 is independently selected from- CO(C 1-6 alkyl); alternative
  • R in the compound of formula (I), compound of formula (I-1), compound of formula (I-1-1) is independently selected from hydrogen, optionally substituted C 1-6 alkyl, optionally substituted C 3-6 cycloalkyl, optionally substituted 3-6 membered heterocycloalkyl, wherein the optional substitution means that the hydrogen on the substituted group is unsubstituted or The hydrogen on one or more substitutable positions of the substituted group is independently selected from halogen, hydroxyl, amino, nitro, oxo, cyano, C 1-6 alkyl, C 1-6 alkoxy The substituent of the group is substituted.
  • R in the compound of formula (I), compound of formula (I-1), compound of formula (I-1-1) is independently selected from hydrogen, optionally substituted C 1-6 alkyl, optionally substituted C 3-6 cycloalkyl, optionally substituted 3-6 membered heterocycloalkyl, the optional substitution means that the hydrogen on the substituted group is unsubstituted or replaced by The hydrogen on one or more substitutable positions of the substituting group is independently substituted by a substituent selected from halogen, hydroxyl, amino, C 1-6 alkyl.
  • R in the compound of formula (I), compound of formula (I-1) and compound of formula (I-1-1) is independently selected from hydrogen, C 1-6 alkane Group, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl; further, R 5 is independently selected from C 1-3 alkyl, C 3-6 cycloalkyl; or R 5 is independently selected from C 1-3 alkyl, such as methyl.
  • compounds of formula (I), compounds of formula (I-1), compounds of formula (I-1-1) or their prodrugs, tautomers, stereoisomers are provided , solvates, isotopic derivatives or pharmaceutically acceptable salts thereof, wherein R 2 is independently selected from halogen, cyano, -CONH 2 , -CO-(C 1-3 alkyl), -CO-(C 3-6 cycloalkyl), -COO-(C 1-3 alkyl), -COO-(C 3-6 cycloalkyl), -CH 2 OH, -CH 2 CH 2 OH, -CH(OH) CH 3 , C 2-6 alkenyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl.
  • R in the compound of formula (I), compound of formula (I-1), compound of formula (I-1-1) is independently selected from halogen, -CO-(C 1-3 alkyl), -CO-(C 3-6 cycloalkyl), -COO-(C 1-3 alkyl), -COO-(C 3-6 cycloalkyl), -CH 2 OH, C 2-4 alkenyl, 3-6 membered heterocycloalkyl.
  • R in the compound of formula (I), compound of formula (I-1), compound of formula (I-1-1) is independently selected from halogen, -C(O) CH3 , -C(O)-(cyclopropane), -C(O) OCH3 , -C(O)O-(cyclopropane), -CH2OH , vinyl, oxetanyl.
  • R 2 in the compound of formula (I), compound of formula (I-1) and compound of formula (I-1-1) is independently selected from -C(O)CH 3 or -C(O) OCH3 .
  • R 2 in the compound of formula (I), compound of formula (I-1) or compound of formula (I-1-1) is -C(O)CH 3 .
  • compounds of formula (I), compounds of formula (I-1), compounds of formula (I-1-1) or their prodrugs, tautomers, stereoisomers are provided Body, solvate, isotope derivative or pharmaceutically acceptable salt thereof, wherein, R 1 is independently selected from hydrogen, amino; preferably, R 1 is independently selected from amino.
  • a compound having a structure shown in formula (I-2) or its prodrug, tautomer, stereoisomer, solvate, isotope derivative or pharmaceutically acceptable accepted salt a compound having a structure shown in formula (I-2) or its prodrug, tautomer, stereoisomer, solvate, isotope derivative or pharmaceutically acceptable accepted salt
  • R 1 is independently selected from deuterium or amino, preferably amino;
  • R 2 is independently selected from cyano, -CONH 2 , -COR 5 , -COOR 5 , optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2- 6 alkynyl, optionally substituted C 3-10 cycloalkyl, optionally substituted 3-10 membered heterocycloalkyl, wherein R is independently selected from hydrogen, optionally substituted C 1-6 alkyl, Optionally substituted C 3-6 cycloalkyl, optionally substituted 3-6 membered heterocycloalkyl, optionally substituted C 6-10 aryl, optionally substituted 5-10 membered heteroaryl, the Optional substitution means that the hydrogen on the substituted group is not substituted or the hydrogen on one or more substitutable positions of the substituted group is independently selected from halogen, hydroxyl, amino, nitro, oxo, Substituents of cyano, C 1-6 alkyl, C 1-6 alkoxy;
  • R is hydrogen or deuterium, preferably deuterium ;
  • R 2 is independently selected from hydrogen, halogen, cyano, -CONH 2 , -COR 5 , -COOR 5 , optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkene group, optionally substituted C 3-10 cycloalkyl, optionally substituted 3-10 membered heterocycloalkyl, wherein the optional substitution means that the hydrogen on the substituted group is unsubstituted or substituted
  • the hydrogen on one or more substitutable positions of is independently selected from halogen, hydroxyl, amino, nitro, oxo, cyano, C 1-6 alkyl, C 1-6 alkoxy substituents replaced.
  • R 2 in the compound represented by formula (I-2) is independently selected from cyano, -CONH 2 , -COR 5 , -COOR 5 , optionally substituted C 1-4 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 3-6 cycloalkyl, optionally substituted 3-6 membered heterocycloalkyl, wherein the optional substitution refers to the substituent
  • R 2 in the compound represented by formula (I-2) is independently selected from cyano, -CONH 2 , -COR 5 , -COOR 5 , C 1-4 substituted by hydroxyl Alkyl, C 2-6 alkenyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl.
  • the compound of the structure shown in formula (I-2) or its prodrug, tautomer, stereoisomer, solvate, isotope derivative or its pharmaceutically acceptable R 2 in the salt is independently selected from cyano, -CONH 2 , -COR 5 , -COOR 5 , unsubstituted C 2-6 alkyl, substituted C 1-6 alkyl, optionally substituted C 2- 6 alkenyl, optionally substituted C 2-6 alkynyl, optionally substituted C 3-10 cycloalkyl, optionally substituted 3-10 membered heterocycloalkyl, wherein the optionally substituted means substituted
  • the hydrogen on the group is unsubstituted or the hydrogen on one or more substitutable positions of the substituted group is independently selected from halogen, hydroxyl, amino, nitro, oxo, cyano, C 1-6 Substituents of alkyl, C 1-6 alkoxy; or
  • R 2 is independently selected from cyano, -CONH 2 , -COR 5 , -COOR 5 , substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 3-6 ring Alkyl, optionally substituted 3-6 membered heterocycloalkyl, wherein the optional substitution means that the hydrogen on the substituted group is unsubstituted or the hydrogen on one or more substitutable positions of the substituted group Hydrogen is independently substituted by a substituent selected from halogen, hydroxyl, amino, nitro, oxo, cyano, C 1-6 alkyl, C 1-6 alkoxy; or
  • R 2 is independently selected from cyano, -CONH 2 , -COR 5 , -COOR 5 , C 1-6 substituted by one or more substituents selected from hydroxyl, halogen and C 1 -C 3 alkoxy Alkyl, C 2-6 alkenyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl; or
  • R 2 is selected from -CO-(C 3-6 cycloalkyl), -COOR 5 , optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, Optionally substituted C 3-10 cycloalkyl, optionally substituted 3-10 membered heterocycloalkyl, wherein the optional substitution means that the hydrogen on the substituted group is unsubstituted or one of the substituted groups or multiple hydrogens at substitutable positions are independently substituted by substituents selected from halogen, hydroxyl, amino, nitro, oxo, cyano, C 1-6 alkyl, C 1-6 alkoxy ;or
  • R 2 is selected from -CO-(C 3-6 cycloalkyl), -COOR 5 , optionally substituted C 2-6 alkenyl, optionally substituted C 3-6 cycloalkyl , an optionally substituted 3-6 membered heterocycloalkyl group, wherein the optional substitution means that the hydrogen on the substituted group is unsubstituted or the hydrogen on one or more substitutable positions of the substituted group is independently is substituted by a substituent selected from halogen, hydroxyl, amino, nitro, oxo, cyano, C 1-6 alkyl, C 1-6 alkoxy; or
  • R 2 is selected from -CO-(C 3-6 cycloalkyl), -COOR 5 , C 2-6 alkenyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkane base.
  • R 1 when R 1 is deuterium, R 2 can be halogen.
  • R 1 can be hydrogen;
  • R 2 is independently selected from halogen, -CO-(C 3 -C 6 cycloalkyl), -COOR 5 , optionally substituted C 2-6 alkenyl, optionally Substituted C 2-6 alkynyl, optionally substituted C 3-10 cycloalkyl, optionally substituted 3-10 membered heterocycloalkyl, wherein the optional substitution means that the hydrogen on the substituted group is not
  • the hydrogen on one or more substitutable positions of the substituted or substituted group is independently selected from halogen, hydroxyl, amino, nitro, oxo, cyano, C 1-6 alkyl, C 1- 6 alkoxy substituents; or
  • R 1 may be hydrogen;
  • R 2 is independently selected from halogen, -CO-(C 3 -C 6 cycloalkyl), -COOR 5 , optionally substituted C 2-6 alkenyl, optionally substituted C 3- 6 cycloalkyl groups, optionally substituted 3-6 membered heterocycloalkyl groups, wherein the optional substitution means that the hydrogen on the substituted group is unsubstituted or one or more substitutable positions of the substituted group The hydrogen on is independently replaced by a substituent selected from halogen, hydroxyl, amino, nitro, oxo, cyano, C 1-6 alkyl, C 1-6 alkoxy; or
  • R 1 can be hydrogen;
  • R 2 is independently selected from halogen, -CO-(C 3 -C 6 cycloalkyl), -COOR 5 , C 2-6 alkenyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl.
  • R in the compound represented by the above formula (I- 2 ) is independently selected from hydrogen, optionally substituted C 1-6 alkyl, optionally substituted C 3-6 ring Alkyl, optionally substituted 3-6 membered heterocycloalkyl, wherein the optional substitution means that the hydrogen on the substituted group is unsubstituted or the hydrogen on one or more substitutable positions of the substituted group Hydrogens are independently substituted by substituents selected from halogen, hydroxy, amino, nitro, oxo, cyano, C 1-6 alkyl, C 1-6 alkoxy.
  • R in the compound represented by the above formula (I- 2 ) is independently selected from hydrogen, optionally substituted C 1-6 alkyl, optionally substituted C 3-6 ring Alkyl, optionally substituted 3-6 membered heterocycloalkyl, wherein the optional substitution means that the hydrogen on the substituted group is unsubstituted or the hydrogen on one or more substitutable positions of the substituted group Hydrogens are independently substituted by substituents selected from halogen, hydroxy, amino, C 1-6 alkyl.
  • R in the compound represented by the above formula (I- 2 ) is independently selected from hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, 3-6 membered hetero Cycloalkyl.
  • R 5 in the compound represented by the above formula (I-2) is independently selected from C 1-3 alkyl, C 3-6 cycloalkyl; or R 5 is C 1- 3 alkyl; or R 5 is C 3-6 cycloalkyl.
  • R 2 is independently selected from cyano, -CONH 2 , -CO-(C 1-3 alkyl), -CO-(C 3-6 cycloalkyl), -COO-(C 1- 3 alkyl), -COO-(C 3-6 cycloalkyl), -CH 2 OH, -CH 2 CH 2 OH, -CH(OH)CH 3 , C 2-6 alkenyl, C 3-6 ring Alkyl, 3-6 membered heterocycloalkyl;
  • R 2 is independently selected from -CO-(C 1-3 alkyl), -CO-(C 3-6 cycloalkyl), -COO-(C 1-3 alkyl), -COO-( C 3-6 cycloalkyl), -CH 2 OH, C 2-4 alkenyl, 3-6 membered heterocycloalkyl;
  • R 2 is independently selected from -C(O)CH 3 , -C(O)-(cyclopropane), -C(O)OCH 3 , -C(O)O-(cyclopropane), - CH 2 OH, vinyl, oxetanyl;
  • R 2 is independently selected from -C(O)CH 3 , -C(O)OCH 3 , -CH 2 OH, -CH ⁇ CH 2 , Further preferably, R 2 is independently selected from -C(O)CH 3 , -C(O)OCH 3 , -CH ⁇ CH 2 ,
  • a compound as shown in formula (I-2) or its prodrug, tautomer, stereoisomer, solvate, isotope derivative or its pharmaceutically acceptable A salt wherein, R 2 is independently selected from -CO-(C 1-6 alkyl), -COO-(C 1-6 alkyl);
  • R 2 is independently selected from -CO-(C 1-3 alkyl), -COO-(C 1-3 alkyl);
  • R 2 is independently selected from -C(O)CH 3 , -C(O)OCH 3 ;
  • R 2 is independently selected from -C(O)CH 3 .
  • L is selected from CH
  • X is selected from O
  • G is selected from S.
  • a compound as shown in formula (I-2) or its prodrug, tautomer, stereoisomer, solvate, isotope derivative or its pharmaceutically acceptable wherein, R 1 is independently selected from amino, R 2 is independently selected from -CO-(C 1-6 alkyl), -COO-(C 1-6 alkyl), L is selected from CH, X is selected from Since O.
  • a compound as shown in formula (I-2) or its prodrug, tautomer, stereoisomer, solvate, isotope derivative or its pharmaceutically acceptable wherein, R 1 is independently selected from amino, R 2 is independently selected from -CO-(C 1-6 alkyl), -COO-(C 1-6 alkyl), L is selected from CH, R 6 independently selected from deuterium;
  • R 1 is independently selected from amino
  • R 2 is independently selected from -CO-(C 1-3 alkyl), -COO-(C 1-3 alkyl)
  • R 6 is selected from deuterium
  • L is selected from CH
  • X is selected from O
  • G is selected from S.
  • L, G, A, Y, R 1 , R 2 , R 3 , and R 6 are the same as those described above for the compound represented by formula (I), formula (I-1) or formula (I-2) in this application.
  • compound compound of formula (I), compound of formula (I-1), compound of formula (I-1-1), compound of formula (I-2)) or its prodrug is provided , tautomers, stereoisomers, solvates, isotopic derivatives or pharmaceutically acceptable salts thereof, wherein the compound has formula (I-A1), (I-1-A1) or ( The structure shown in I-2-A1):
  • G, A, Y, R 1 , R 2 , R 3 , and R 6 are the same as those described above for the compound represented by formula (I), formula (I-1) or formula (I-2) in this application.
  • the compound has a structure as shown in formula (I-A2), (I-A3), (I-2-A2) or (I-2-A3):
  • G, A, Y, R 1 , R 2 and R 3 are the same as those described for the compound represented by formula (I), formula (I-1) or formula (I-2) in this application.
  • G, A, Y, R 1 , R 2 and R 3 are the same as those described for the compound represented by formula (I), formula (I-1) or formula (I-2) in this application.
  • compound (compound of formula (I), compound of formula (I-1), compound of formula (I-1-1), compound of formula (I-2)) or its prodrug is provided , tautomers, stereoisomers, solvates, isotopic derivatives or pharmaceutically acceptable salts thereof, wherein the compound has formula (I-B1), formula (I-1-B1) or The structure shown in formula (I-2-B1):
  • G, A, Y, R 2 , R 3 and R 6 are the same as those described for the compound represented by the above formula (I), formula (I-1) or formula (I-2) in this application.
  • the compound has a structure such as formula (I-B2), (I-B3), formula (I-2-B2) or formula (I-2-B3):
  • G, A, Y, R 2 and R 3 are the same as those described for the compound represented by the above formula (I), formula (I-1) or formula (I-2) in this application.
  • compounds compounds of formula (I), compounds of formula (I-1), compounds of formula (I-1-1), compounds of formula (I-2), compounds of formula (I- A1) compound, formula (I-1-A1) compound, formula (I-2-A1) compound, formula (I-A2) compound, formula (I-A3) compound, formula (I-2-A2) compound, Formula (I-2-A3) compound, formula (I-B1) compound, formula (I-1-B1) compound, formula (I-2-B1) compound, formula (I-B2) compound, formula (I- B3) compound, formula (I-2-B2) compound, formula (I-2-B3) compound, formula (I-A) compound, formula (I-B) compound, formula (I-1-A) compound, formula (I- 1-B) compound, formula (I-2-A) compound, formula (I-2-B) compound, formula (I-Ba) compound) or its prodrug, tautomer, stereoisomer, Solvates, isotopic derivatives or pharmaceutically acceptable salts
  • compounds compounds of formula (I), compounds of formula (I-1), compounds of formula (I-1-1), compounds of formula (I-2), compounds of formula (I- A1) compound, formula (I-1-A1) compound, formula (I-2-A1) compound, formula (I-A2) compound, formula (I-A3) compound, formula (I-2-A2) compound, Formula (I-2-A3) compound, formula (I-B1) compound, formula (I-1-B1) compound, formula (I-2-B1) compound, formula (I-B2) compound, formula (I- B3) compound, formula (I-2-B2) compound, formula (I-2-B3) compound, formula (I-A) compound, formula (I-B) compound, formula (I-1-A) compound, formula (I- 1-B) compound, formula (I-2-A) compound, formula (I-2-B) compound, formula (I-Ba) compound) or its prodrug, tautomer, stereoisomer, Solvates, isotope derivatives or pharmaceutically acceptable salt
  • compounds compounds of formula (I), compounds of formula (I-1), compounds of formula (I-1-1), compounds of formula (I-2), compounds of formula (I- A1) compound, formula (I-1-A1) compound, formula (I-2-A1) compound, formula (I-A2) compound, formula (I-A3) compound, formula (I-2-A2) compound, Formula (I-2-A3) compound, formula (I-B1) compound, formula (I-1-B1) compound, formula (I-2-B1) compound, formula (I-B2) compound, formula (I- B3) compound, formula (I-2-B2) compound, formula (I-2-B3) compound, formula (I-A) compound, formula (I-B) compound, formula (I-1-A) compound, formula (I- 1-B) compound, formula (I-2-A) compound, formula (I-2-B) compound, formula (I-Ba) compound) or its prodrug, tautomer, stereoisomer, Solvates, isotope derivatives or pharmaceutically acceptable salt
  • compounds compounds of formula (I), compounds of formula (I-1), compounds of formula (I-1-1), compounds of formula (I-2), compounds of formula (I- A1) compound, formula (I-1-A1) compound, formula (I-2-A1) compound, formula (I-A2) compound, formula (I-A3) compound, formula (I-2-A2) compound, Formula (I-2-A3) compound, formula (I-B1) compound, formula (I-1-B1) compound, formula (I-2-B1) compound, formula (I-B2) compound, formula (I- B3) compound, formula (I-2-B2) compound, formula (I-2-B3) compound, formula (IA) compound, formula (IB) compound, formula (I-1-A) compound, formula (I- 1-B) compound, formula (I-2-A) compound, formula (I-2-B) compound, formula (I-Ba) compound) or its prodrug, tautomer, stereoisomer, Solvates, isotope derivatives or pharmaceutically acceptable salts thereof
  • compounds compounds of formula (I), compounds of formula (I-1), compounds of formula (I-1-1), compounds of formula (I-2), compounds of formula (I- A1) compound, formula (I-1-A1) compound, formula (I-2-A1) compound, formula (I-A2) compound, formula (I-A3) compound, formula (I-2-A2) compound, Formula (I-2-A3) compound, formula (I-B1) compound, formula (I-1-B1) compound, formula (I-2-B1) compound, formula (I-B2) compound, formula (I- B3) compound, formula (I-2-B2) compound, formula (I-2-B3) compound, formula (IA) compound, formula (IB) compound, formula (I-1-A) compound, formula (I- 1-B) compound, formula (I-2-A) compound, formula (I-2-B) compound, formula (I-Ba) compound) or its prodrug, tautomer, stereoisomer, Solvates, isotopic derivatives or pharmaceutically acceptable salts thereof,
  • R 4 is independently selected from hydrogen, halogen, amino, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino; further Preferably, wherein, R 4 is independently selected from hydrogen, fluorine, chlorine, amino, cyano, methyl, methoxy; further preferably, wherein, R 4 is selected from chlorine.
  • X in the compound of formula (I) is selected from O or CH 2 ;
  • L is CH;
  • G is S;
  • A is selected from CH or N;
  • R 3 is independently selected from: amino, optionally A substituted 8-12 membered heterocyclic group, an optionally substituted C6-10 aryl group, an optionally substituted 5-14 membered heteroaryl group, wherein the optional substitution means that the hydrogen on the substituted group is not replaced by The hydrogen on one or more substitutable positions of the substituted or substituted group is independently substituted by a substituent selected from hydroxyl, oxo, cyano, -CONH 2 or C 1-6 alkyl;
  • R 1 independently selected from hydrogen, deuterium, amino;
  • R 2 independently selected from halogen, -COR 5 , -COOR 5 , optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally Substituted 3-10 membered heterocycloalkyl; wherein, R 5
  • X is selected from O or CH 2 ;
  • L is CH;
  • G is S;
  • A is selected from CH or N;
  • R 3 is independently selected from: amino, optionally substituted 8-10 membered bicyclic heterocyclyl, optionally substituted C 6 or C 10 aryl, optionally substituted 5-6 membered heteroaryl, wherein the optional substitution means that the hydrogen on the substituted group is unsubstituted or one or more substitutable positions of the substituted group
  • the hydrogen on the point is independently substituted by a substituent selected from hydroxyl, oxo, cyano, -CONH 2 or C 1-6 alkyl;
  • R 1 is independently selected from hydrogen, deuterium, amino;
  • R 2 is independently selected from halogen, -COR 5 , -COOR 5 , optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted 3-6 membered heterocycloalkyl; wherein, R 5 are independently selected from
  • X is selected from O or CH2 ; L is CH; G is S; when A is CH, Y is CR4 ; R4 is halogen, such as Cl or F, preferably Cl; or when A is N, Y is independently selected from N or CR 4 ; R 4 is halogen, such as Cl or F, preferably Cl; R 3 is independently selected from: amino, 5-membered heteroaryl optionally substituted by C 1-2 alkyl (eg, methyl); R 1 independently selected from hydrogen, deuterium, amino; R independently selected from -COR 5 or -COOR 5 ; wherein, R independently selected from unsubstituted C 1-2 alkyl (for example, methyl) or unsubstituted C 3-4 cycloalkyl (for example, cyclopropyl); R 6 is independently selected from hydrogen or deuterium.
  • the compound of formula (I), compound of formula (I-1), compound of formula (I-1-1), compound of formula (I-2), compound of formula (I- A1) compound, formula (I-1-A1) compound, formula (I-2-A1) compound, formula (I-A2) compound, formula (I-A3) compound, formula (I-2-A2) compound, Formula (I-2-A3) compound, formula (I-B1) compound, formula (I-1-B1) compound, formula (I-2-B1) compound, formula (I-B2) compound, formula (I- B3) compound, formula (I-2-B2) compound, formula (I-2-B3) compound, formula (I-A) compound, formula (I-B) compound, formula (I-1-A) compound, formula (I- 1-B) compounds, formula (I-2-A) compounds, formula (I-2-B) compounds, formula (I-Ba) compounds do not include the following compounds:
  • the present application provides a compound represented by formula (II), or its prodrug, tautomer, stereoisomer, solvate, isotope derivative or pharmaceutically acceptable salt thereof, which has the following structure:
  • R1 rings form a C6-10 aryl group, a 5-10 membered heteroaryl group, a 3-10 membered carbocyclic group or a 3-10 membered heterocyclic group, and each group is independently optional to be replaced;
  • R a is connected together to form a 5-14 membered aromatic ring, a 5-14 membered heteroaromatic ring, a 5-14 membered heterocyclic ring or a 5-14 membered carbocyclic ring, and each ring system is independently optionally replaced;
  • Each R a is independently selected from hydrogen, deuterium, halogen, -NH 2 , -CN, -OH, -NO 2 , carboxyl, -C 1-6 alkoxy, -C 1-6 alkyl, each group groups are independently optionally replaced;
  • R 3 is deuterium
  • R 2 is selected from: hydrogen, deuterium, halogen, -NH 2 , -CN, -OH, -NO 2 , -COOH, -NH-C 1-6 alkyl, -N(C1-6 alkyl) 2 , - C 1-6 alkoxy or -C 1-6 alkyl, and each group is independently optionally substituted or unsubstituted;
  • Each R 4 and R 5 is independently selected from hydrogen, deuterium, halogen, -NH 2 , -CN, -OH, -NO 2 , -COOH, -NH-C 1-6 alkyl, -N(C 1-6 6 alkyl) 2 , -C 1-6 alkoxy or -C 1-6 alkyl, and each group is independently optionally substituted or unsubstituted; or
  • W is absent, -CH 2 -, -CH(R b )-, -C(R b ) 2 -, -C(O)-, -NH-, -NR b - or -O-;
  • Y is C, CH, -C(R b )- or N;
  • Each R b is independently selected from hydrogen, deuterium, halogen, -NH 2 , -CN, -OH, -C 1-6 alkoxy or -C 1-6 alkyl, and each group is independently optionally replaced or not replaced;
  • A is selected from: aryl, heteroaryl, cycloalkyl and heterocyclyl which are unsubstituted or optionally substituted by one or more R;
  • B is selected from: aryl, heteroaryl, cycloalkyl and heterocyclyl which are unsubstituted or optionally substituted by one or more R;
  • C is aryl, heteroaryl, cycloalkyl and heterocyclyl absent, unsubstituted or optionally substituted by one or more R;
  • Y 1 and Y 2 are each independently selected from -C(R 1 ) 2 -, -C(R d ) 2 -, -NR d -, -NR 1 - and O; when middle When representing a single bond, Y 1 is -C(R 1 ) 2 -, -C(R d ) 2 -, -NR d -, -NR 1 - or O, and Y 2 is -C(R 1 ) 2 - , -C(R d ) 2 -, -NR d -, -NR 1 - or O; or, when middle When representing a double bond, Y 1 is CR 1 , CR d or N, and Y 2 is CR 1 , CR d or N;
  • Each L1 and L2 are independently selected from: covalent bond, -S-, -S(O) - , -S(O) 2- , -O-, -C (O)-, -CO-NR d -, -NR d -, -NR d -C(O)-, -NR d -C(O)-NR d -, -C(O)O-, -NR d SO 2 -, -C(R d ) 2 -, -SO 2 NR d - and
  • Each R d is independently selected from hydrogen, deuterium, halogen, -NH 2 , -CN, -OH, -NO 2 , -COOH, -CO-C 1-6 alkyl, -COO-C 1-6 alkyl , -C 1-6 alkylene -OC 1-6 alkoxy, -C 1-6 alkoxy or -C 1-6 alkyl, and each group is independently optionally substituted or unsubstituted replace;
  • Each m, n and q are independently selected from 0, 1, 2, 3 or 4; when m is 0, W is directly connected to Y 2 ;
  • heteroatoms in the above-mentioned heterocycloalkyl, heteroaryl and heterocyclyl are independently selected from O, N or S, and the number of heteroatoms is 1, 2, 3 or 4.
  • said A is optionally substituted or unsubstituted 3-14 membered cycloalkyl, 3-14 membered heterocycloalkyl, 5- 14-membered aryl or 5-14-membered heteroaryl; preferably optionally substituted or unsubstituted 5-12-membered cycloalkyl, 5-12-membered heterocycloalkyl, 5-12-membered aryl or 5-12-membered Heteroaryl; further preferably optionally substituted or unsubstituted 6-10 membered cycloalkyl, 6-10 membered heterocycloalkyl, 6-10 membered aryl or 6-10 membered heteroaryl; further preferably any Optionally substituted or unsubstituted 6-10 membered aryl or 6-10 membered heteroaryl; further preferably optionally substituted or unsubstituted phenyl, 8-10 membered polycyclic aryl;
  • A is selected from the following groups optionally substituted or unsubstituted:
  • A is selected from the following groups optionally substituted or unsubstituted:
  • A is selected from the following groups optionally substituted or unsubstituted:
  • A is selected from the following groups optionally substituted or unsubstituted:
  • substitution is substituted by one or more R 1 ;
  • said L 2 is selected from: covalent bond, -S-, -S(O)-, -S(O) 2 -, -O-, -C(O)-, -NR d - and -C(R d ) 2 -; preferably covalent bond, -S-, -O- and -NR d -; more preferably covalent bond and -S- .
  • said B is optionally substituted or unsubstituted 3-14 membered cycloalkyl, 3-14 membered heterocycloalkyl, 5-14 membered aryl Or 5-14 membered heteroaryl; preferably optionally substituted or unsubstituted 5-12 membered cycloalkyl, 5-12 membered heterocycloalkyl, 5-12 membered aryl or 5-12 membered heteroaryl; Further preferred is optionally substituted or unsubstituted 6-10 membered cycloalkyl, 6-10 membered heterocycloalkyl, 6-10 membered aryl or 6-10 membered heteroaryl; further preferred is optionally substituted or unsubstituted Substituted 6-10 membered aryl or 6-10 membered heteroaryl; further preferably optionally substituted or unsubstituted phenyl, 8-10 membered polycyclic aryl, 5-6
  • B is selected from the following groups optionally substituted or unsubstituted:
  • each Y 3 is independently selected from C(R 1 ) 2 , CR 1 , NR 1 , N, S and O;
  • each Y 4 is independently selected from CR 1 and NR 1 ;
  • Y 3 when When representing a single bond, Y 3 is C(R 1 ) 2 , NR 1 , S and O, and Y 4 is CR 1 or N; or, when When representing a double bond, Y 3 is CR 1 or N, and Y 4 is C;
  • substitution is substituted by one or more R 1 ;
  • B is selected from substituted or unsubstituted pyridine, substituted or unsubstituted pyrazine, substituted or unsubstituted pyrimidine, substituted or unsubstituted thiazole, substituted or Unsubstituted pyridone, substituted or unsubstituted pyrimidone, substituted or unsubstituted pyridazinone and other monocyclic rings; or substituted or unsubstituted pyridine ring, pyrazine ring, pyridazine ring, pyrimidine ring, thiazole ring, pyridine Ketone ring, pyrimidinone ring, pyridazinone ring, etc.
  • B is selected from the following groups optionally substituted or unsubstituted:
  • B is selected from the following groups optionally substituted or unsubstituted:
  • substitution is substituted by one or more R 1 .
  • said L 1 is selected from: covalent bond, -S(O) 2 -, -CO-NR d -, -NR d -C(O) -, -C(O)O-, -NR d SO 2 -, -SO 2 NR d -, and Preferably it is a covalent bond, -S(O) 2 -, -CO-NR d - or -NR d -C(O)-; more preferably a covalent bond.
  • said Y is CH or N, and is a single bond; preferably N, and for a single key.
  • said W is -CH 2 -, -CH(R b )-, -C(R b ) 2 - or -O-; preferably -CH 2 - or -O-.
  • the ring C is a 5-14 - membered aryl group, a 5-14-membered Heteroaryl, 5-14 membered carbocyclyl or 5-14 membered heterocyclic group; preferably, the ring C is 5-12 membered that is absent, unsubstituted or optionally substituted by one or more R 1 Aryl, 5-12 membered heteroaryl, 5-12 membered carbocyclyl or 5-12 membered heterocyclic group; further preferably, the ring C is absent, unsubstituted or optionally replaced by one or more R 1 substituted 5-10 membered aryl, 5-10 membered heteroaryl, 5-10 membered carbocyclyl or 5-10 membered heterocyclic group; further preferably, the ring C is absent or unsubstituted Or 6-10 membered aryl, 5-10 membered heteroaryl, 5-10 membered carbocyclyl or 5
  • the ring C is absent, or selected from the following groups that are unsubstituted or optionally substituted by one or more R 1 :
  • R 1 Preferred are the following groups which are unsubstituted or optionally substituted by one or more R 1 :
  • Y 1 when middle When representing a single bond, Y 1 is -CR d - or -N-, and Y 2 is -CR d - or -N-.
  • Y 1 and Y 2 are each independently -C(R 1 ) 2 - or -C(R d ) 2 -.
  • R a is connected together to form a 5-14 membered aromatic ring, a 5-14 membered heteroaromatic ring, a 5-14 membered heterocyclic ring or a 5-14 membered carbocyclic ring, and each ring system is independently is optionally substituted; preferably, two adjacent R a are joined together to form a 6-10 membered aromatic ring, a 5-10 membered heteroaromatic ring, a 5-10 membered heterocyclic ring or a 5-10 membered carbocyclic ring, and each of said ring systems is independently optionally substituted;
  • R a and R b form a 3-14 membered aromatic ring, a 3-14 membered heteroaromatic ring, a 3-14 membered heterocyclic ring or a 3-14 membered carbocyclic ring together with their commonly connected atoms; and each ring system are independently optionally substituted; preferably, R a and R b form a 6-10 membered aromatic ring, a 5-10 membered heteroaryl ring, a 5-10 membered heterocyclic ring or a 5-10 membered Carbocycle; and each of said ring systems is independently optionally substituted;
  • Each R a is independently selected from hydrogen, deuterium, halogen, -NH 2 , -CN, -OH, -NO 2 , carboxyl, -C 1-6 alkoxy, -C 1-6 alkyl; each group groups are independently optionally substituted; preferably, each R a is independently selected from hydrogen, deuterium, halogen, -NH 2 , -CN, -OH, -C 1-6 alkoxy, -C 1-6 Alkyl; each group is independently optionally substituted.
  • R 1 on ring B is independently selected from hydrogen, deuterium, amino, halogen, cyano, -CONH 2 , -COR 6 , -COOR 6 , any Optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, optionally substituted C 3-10 cycloalkyl, optionally substituted 3- 10-membered heterocycloalkyl; preferably hydrogen, halogen, amino, cyano, -CONH 2 , -COR 6 , -COOR 6 , optionally substituted C 1-4 alkyl, optionally substituted C 2-6 alkene group, optionally substituted C 3-6 cycloalkyl, optionally substituted 3-6 membered heterocycloalkyl; more preferably halogen, cyano, -CONH 2 , -COR 6 , -COOR 6 , hydroxyl
  • the optional substitution means that the hydrogen on the substituted group is not substituted or the hydrogen on one or more substitutable positions of the substituted group is independently selected from -OH, halogen, -NH 2 , -NO 2.
  • R on the A ring is independently selected from optionally substituted 8-12 membered heterocyclic groups, optionally substituted C6-10 aryl groups, any Optionally substituted 5-14 membered heteroaryl; said optional substitution means that the hydrogen on the substituted group is unsubstituted or the hydrogen on one or more substitutable positions of the substituted group is independently selected from Halogen, hydroxyl, amino, nitro, oxo, cyano, -COOH, -COCH 3 , -COOCH 3 , -CONH 2 , C 1-6 alkyl, C 1-6 alkoxy, C 3-10 Substituents of cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 aryl, 5-12 membered heteroaryl;
  • R 2 is selected from: hydrogen, deuterium, halogen, -NH 2 , -OH, -NH-C 1-6 alkyl, -N(C 1- 6 alkyl) 2 , -C 1-6 alkoxy or -C 1-6 alkyl, and each group is independently optionally substituted or unsubstituted; preferably hydrogen, deuterium, halogen, -NH 2.
  • each group is independently optionally substituted or unsubstituted; more preferably hydrogen, -NH 2 or -OH , and each group is independently optionally substituted or unsubstituted; more preferably -NH 2 .
  • each R 4 and R 5 are independently selected from hydrogen, deuterium, halogen, -NH 2 , -CN, -OH, -C 1-6 alkoxy or -C 1-6 alkyl, and each group is independently optionally substituted or unsubstituted; preferably, each R 4 and R 5 is independently selected from hydrogen, deuterium, halogen, -NH 2 , -CN, -OH, -C 1-3 alkoxy or -C 1-3 alkyl, and each group is independently optionally substituted or unsubstituted; further preferably, each R 4 and R 5 is independently selected from hydrogen, halogen, -OH, -CH 3 or -OCH 3 ; further preferably, both R 4 and R 5 are hydrogen.
  • m is 0 or 1; q is 1; n is 1, 2 or 3; when m is 0, W is directly connected to Y 2 .
  • each R b is independently selected from hydrogen, deuterium, halogen, -NH 2 , -CN, -OH, -C 1-6 alkoxy or - C 1-6 alkyl; preferably hydrogen, deuterium, halogen, -NH 2 , -CN, -OH, -C 1-3 alkoxy or -C 1-3 alkyl.
  • each R d is independently selected from hydrogen, deuterium, halogen, -NH 2 , -CN, -OH, -NO 2 , -C(O)OH , -C(O)-C 1-6 alkyl, -C(O)-OC 1-6 alkyl, -C 1-6 alkylene-OC 1-6 alkoxy, -C 1-6 alkane Oxygen or -C 1-6 alkyl; preferably hydrogen, deuterium, halogen, -NH 2 , -CN, -OH, -NO 2 , -C(O)OH, -C(O)-C 1-3 Alkyl, -C(O)-OC 1-3 alkyl, -C 1-3 alkylene-OC 1-3 alkoxy, -C 1-3 alkoxy or -C 1-3 alkyl; More preferably hydrogen, deuterium, halogen, -NH 2 , -CN,
  • Another aspect of the present application also provides the main preparation method of the above-mentioned compound of formula (I), which can be prepared by using the methods shown in the following synthesis scheme 1 and synthesis scheme 2, for example.
  • C1 and C2 can be Cl or Br
  • compound I-3 is obtained by using compounds I-1, I-2 and Ti(OEt) 4 as basic raw materials;
  • compound I-8 is obtained by reacting compound I-7 under acidic conditions;
  • compound I-9 is obtained by using compound I-8 and (Boc) 2 O as basic raw materials;
  • compound I-11 can be obtained by using compounds I-9 and I-10 as basic raw materials under palladium catalysis and basic conditions.
  • the compound of general formula (I) can be obtained by reacting with compound I-11 etc. as basic raw materials under acidic conditions.
  • C1 and C2 can be Cl or Br
  • compound I-12 can be obtained under palladium catalysis and basic conditions;
  • compound I-13 is obtained under palladium catalysis and basic conditions;
  • compound I-13 can obtain the compound of general formula (I) under acidic conditions.
  • the present application also provides a pharmaceutical composition, which comprises (for example, a therapeutically effective amount) the compound described in the present application (compound of formula (I), compound of formula (I-1), compound of formula (I-1 -1) compound, formula (I-2) compound, formula (I-A1) compound, formula (I-1-A1) compound, formula (I-2-A1) compound, formula (I-A2) compound, formula (I-A3) compound, formula (I-2-A2) compound, formula (I-2-A3) compound, formula (I-B1) compound, formula (I-1-B1) compound, formula (I-2 -B1) compound, formula (I-B2) compound, formula (I-B3) compound, formula (I-2-B2) compound, formula (I-2-B3) compound), formula (II) compound, formula ( I-A) compound, formula (I-B) compound, formula (I-1-A) compound, formula (I-1-B) compound, formula (I-2-A) compound, formula (I-2-B) compound, Formula (I-Ba)
  • the pharmaceutical composition described in this application comprises the compound described in this application (compound of formula (I), compound of formula (I-1), compound of formula (I-1-1), compound of formula (I-2 ) compound, formula (I-A1) compound, formula (I-1-A1) compound, formula (I-2-A1) compound, formula (I-A2) compound, formula (I-A3) compound, formula (I -2-A2) compound, formula (I-2-A3) compound, formula (I-B1) compound, formula (I-1-B1) compound, formula (I-2-B1) compound, formula (I-B2 ) compound, formula (I-B3) compound, formula (I-2-B2) compound, formula (I-2-B3) compound), formula (II) compound, formula (I-A) compound, formula (I-B) compound, Formula (I-1-A) compound, formula (I-1-B) compound, formula (I-2-A) compound, formula (I-2-B) compound, formula (I-Ba) compound) or Prodrugs, tautomers, stereoiso
  • the pharmaceutical composition of the present application can be prepared by combining the compound described in the present application with suitable pharmaceutically acceptable excipients.
  • the pharmaceutical composition of the present application can be formulated into solid, semi-solid, liquid or gaseous preparations, such as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, solutions, suppositories, injections, inhalants, Gels, microspheres and aerosols, etc.
  • the above-mentioned pharmaceutical composition can be prepared by conventional preparation methods using conventional excipients in the field of formulations.
  • the application also provides the compound described in the application (compound of formula (I), compound of formula (I-1), compound of formula (I-1-1), compound of formula (I-2), compound of formula (I) -A1) compound, formula (I-1-A1) compound, formula (I-2-A1) compound, formula (I-A2) compound, formula (I-A3) compound, formula (I-2-A2) compound , formula (I-2-A3) compound, formula (I-B1) compound, formula (I-1-B1) compound, formula (I-2-B1) compound, formula (I-B2) compound, formula (I -B3) compound, formula (I-2-B2) compound, formula (I-2-B3) compound), formula (II) compound, formula (I-A) compound, formula (I-B) compound, formula (I-1- A) compound, formula (I-1-B) compound, formula (I-2-A) compound, formula (I-2-B) compound, formula (I-Ba) compound) or its prodrug, tautomorphism Conformer, stereo
  • the diseases, diseases and conditions are tumors, cancer metastasis, cardiovascular diseases, immune disorders or visual disorders.
  • the tumor includes solid tumor and hematological tumor.
  • the solid tumor includes lung cancer, and the hematological tumor includes leukemia, and the leukemia is preferably acute myeloid leukemia.
  • the cancer may also be referred to as a malignancy.
  • the application provides methods for preventing and/or treating diseases, disorders and conditions mediated by SHP2 activity, which include administering the compounds described in the application (compounds of formula (I), Formula (I-1) compound, formula (I-1-1) compound, formula (I-2) compound, formula (I-A1) compound, formula (I-1-A1) compound, formula (I-2- A1) compound, formula (I-A2) compound, formula (I-A3) compound, formula (I-2-A2) compound, formula (I-2-A3) compound, formula (I-B1) compound, formula ( I-1-B1) compound, formula (I-2-B1) compound, formula (I-B2) compound, formula (I-B3) compound, formula (I-2-B2) compound, formula (I-2- B3) compound, formula (I-A) compound, formula (I-B) compound, formula (I-1-A) compound, formula (I-1-B) compound, formula (I-2-A) compound, formula (I- 2-B) compound, formula (I-Ba) compound), formula (II)
  • the application provides the compound (compound of formula (I), compound of formula (I-1), compound of formula ( I-1-1) compound, formula (I-2) compound, formula (I-A1) compound, formula (I-1-A1) compound, formula (I-2-A1) compound, formula (I-A2) Compound, formula (I-A3) compound, formula (I-2-A2) compound, formula (I-2-A3) compound, formula (I-B1) compound, formula (I-1-B1) compound, formula ( I-2-B1) compound, formula (I-B2) compound, formula (I-B3) compound, formula (I-2-B2) compound, formula (I-2-B3) compound), formula (II) compound , formula (I-A) compound, formula (I-B) compound, formula (I-1-A) compound, formula (I-1-B) compound, formula (I-2-A) compound, formula (I-2-B ) compound, formula (I-Ba) compound) or its prodrug, tautomer, stereoisomer, solvate, iso
  • the compound described in the application (compound of formula (I), compound of formula (I-1), compound of formula (I-1-1), compound of formula (I-2) , Formula (I-A1) compound, formula (I-1-A1) compound, formula (I-2-A1) compound, formula (I-A2) compound, formula (I-A3) compound, formula (I-2 -A2) compound, formula (I-2-A3) compound, formula (I-B1) compound, formula (I-1-B1) compound, formula (I-2-B1) compound, formula (I-B2) compound , formula (I-B3) compound, formula (I-2-B2) compound, formula (I-2-B3) compound), formula (II) compound, formula (I-A) compound, formula (I-B) compound, formula ( I-1-A) compound, formula (I-1-B) compound, formula (I-2-A) compound, formula (I-2-B) compound, formula (I-Ba) compound) or its prodrug , tautomers, stereoiso
  • the application provides the compound (compound of formula (I), compound of formula (I-1), compound of formula (I-1-1), compound of formula (I-1-1), compound of formula (I-2) described in the application for inhibiting the activity of SHP2 ) compound, formula (I-A1) compound, formula (I-1-A1) compound, formula (I-2-A1) compound, formula (I-A2) compound, formula (I-A3) compound, formula (I -2-A2) compound, formula (I-2-A3) compound, formula (I-B1) compound, formula (I-1-B1) compound, formula (I-2-B1) compound, formula (I-B2 ) compound, formula (I-B3) compound, formula (I-2-B2) compound, formula (I-2-B3) compound), formula (II) compound, formula (I-A) compound, formula (I-B) compound, Formula (I-1-A) compound, formula (I-1-B) compound, formula (I-2-A) compound, formula (I-2-B) compound, formula (I-Ba) compound) or Prod
  • the "optionally substituted” or “optionally substituted” means that the group can be unsubstituted or substituted, wherein the substituents are independently selected from hydroxyl, halogen, amino, nitro, mercapto, cyano Base, azido, oxo, carboxyl, -C(O)C 1-6 alkyl, -C(O)OC 1-6 alkyl, -OC(O)-C 1-6 alkyl, - NH(C 1-6 alkyl), -N(C 1-6 alkyl)(C 1-6 alkyl), -C(O)NH-C 1-6 alkyl, -NHC(O)-C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkyl, C 1-6 alkoxy, C 3-10 cycloalkyl, C 3-10 cycloalkyl
  • One or more of sulfonyl, 3-10 membered heterocycloalkyl one or
  • alkyl refers to a monovalent saturated aliphatic hydrocarbon group, a straight-chain or branched group containing 1-20 carbon atoms, preferably containing 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms (i.e. C 1-10 alkyl), further preferably comprising 1-8 carbon atoms (C 1-8 alkyl), more preferably comprising 1-6 carbon atoms (i.e. C 1-6 alkyl), for example "C 1-6 alkyl” means that the group is an alkyl, and the number of carbon atoms in the carbon chain is between 1-6 (specifically 1, 2, 3, 4, 5 or 6).
  • Examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, neopentyl, 1,1-dimethyl Propyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, n-heptyl , N-octyl, etc.
  • alkenyl refers to a straight or branched unsaturated aliphatic hydrocarbon group composed of carbon atoms and hydrogen atoms and having at least one double bond. Alkenyl may contain 2-20 carbon atoms, preferably 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms (i.e.
  • C 2-10 alkenyl more preferably 2-8 Carbon atom (C 2-8 alkenyl), more preferably contains 2-6 carbon atoms (ie C 2-6 alkenyl), 2-5 carbon atoms (ie C 2-5 alkenyl), 2-4 Carbon atom (ie C 2-4 alkenyl), 2-3 carbon atoms (ie C 2-3 alkenyl), 2 carbon atoms (ie C 2 alkenyl), for example "C 2-6 alkenyl” means What is required is that the group is an alkenyl group, and the number of carbon atoms in the carbon chain is between 2-6 (specifically 2, 3, 4, 5 or 6).
  • alkenyl include, but are not limited to, vinyl, 1-propenyl, 2-propenyl, 1-butenyl, isobutenyl, 1,3-butadienyl, and the like.
  • alkynyl refers to a straight or branched unsaturated aliphatic hydrocarbon group consisting of carbon atoms and hydrogen atoms and having at least one triple bond.
  • the alkynyl group may contain 2-20 carbon atoms, preferably 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms (i.e. C2-10 alkynyl), more preferably 2-8 Carbon atom (C 2-8 alkynyl), more preferably contains 2-6 carbon atoms (ie C 2-6 alkynyl), 2-5 carbon atoms (ie C 2-5 alkynyl), 2-4 Carbon atom (i.e. C 2-4 alkynyl), 2-3 carbon atoms (i.e.
  • C 2-3 alkynyl 2 carbon atoms (i.e. C 2 alkynyl), for example "C 2-6 alkynyl” means What is required is that the group is an alkynyl group, and the number of carbon atoms in the carbon chain is between 2-6 (specifically 2, 3, 4, 5 or 6).
  • alkynyl include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, and the like.
  • cycloalkyl refers to a monocyclic saturated aliphatic hydrocarbon group with a specific number of carbon atoms, including 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 carbon atoms (i.e. C 3-14 cycloalkyl), preferably comprising 3-12 carbon atoms (i.e. C 3-12 cycloalkyl), more preferably comprising 3- 10 carbon atoms (C 3-10 cycloalkyl), further preferably 3-7 carbon atoms (C 3-7 cycloalkyl), 4-6 carbon atoms (C 4-6 cycloalkyl), 5- 6 carbon atoms (C 5-6 cycloalkyl).
  • cycloalkyl refers to a monocyclic saturated aliphatic hydrocarbon group with a specific number of carbon atoms consisting of carbon atoms and hydrogen atoms.
  • cycloalkyl also preferably contains 3-4 carbon atoms (C 3-4 cycloalkyl), 3-5 carbon atoms (C 3-5 cycloalkyl) or 4- 5 carbon atoms (C 4-5 cycloalkyl).
  • alkoxy refers to -O-alkyl, the definition of which is the same as above, that is, containing 1-20 carbon atoms, preferably containing 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, preferably 1-8 carbon atoms, more preferably 1-6 carbon atoms (specifically 1, 2, 3, 4, 5 or 6).
  • Representative examples include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, 1-methylpropoxy, 2-methylpropoxy, tert-butoxy, pentyloxy, Oxygen, 1-methylbutoxy, 2-methylbutoxy, 3-methylbutoxy, 1,1-dimethylpropoxy, 1,2-dimethylpropoxy, 2 , 2-dimethylpropoxy, 1-ethylpropoxy, etc.
  • haloalkyl refers to an alkyl group as defined above in which one, two or more hydrogen atoms or all hydrogen atoms are replaced by halogen.
  • Representative examples of haloalkyl include CCl3 , CF3 , CHCl2 , CH2Cl , CH2Br , CH2I , CH2CF3 , CF2CF3 , and the like.
  • heterocyclyl or “heterocycle” refers to a saturated or partially unsaturated monocyclic, bicyclic or polycyclic ring non-aromatic substituted ring carbon atoms and 1 to 4 ring heteroatoms A group comprising 3-20 ring atoms, wherein 1, 2, 3 or more ring atoms are selected from N, O or S, and the remaining ring atoms are C.
  • ring atoms Preferably comprising 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 ring atoms (ie 3-14 membered heterocyclyl), preferably comprising 3 to 12 ring atoms (3- 12-membered heterocyclic group), further preferably containing 3-10 ring atoms (3-10-membered heterocyclic group), or 3-8 ring atoms (3-8-membered heterocyclic group), or 3-6 ring atoms (3-6 membered heterocyclic group), or 4 to 6 ring atoms (4-6 membered heterocyclic group), or 5 to 6 ring atoms (5-6 membered heterocyclic group).
  • the number of heteroatoms is preferably 1-4, more preferably 1-3 (ie 1, 2 or 3).
  • Examples of monocyclic heterocyclyl groups include oxiranyl, pyrrolidinyl, N-methylpyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrofuranyl, dihydropyrrolyl, piperidinyl, piperazinyl , pyranyl, morpholinyl, thiomorpholinyl and tetrahydrothiophenyl, etc.
  • Polycyclic heterocyclyls include spiro, fused and bridged heterocyclyls.
  • Heterocyclyl can be monocyclic (“monocyclic heterocyclyl") or a fused (“fused heterocyclyl” or “heterofused cycloyl”), bridged (“heterobridged cycloyl” or “bridged heterocyclyl”) or spiro-fused (“heterospirocyclyl” or “spiroheterocyclyl") ring system, such as a bicyclic ring system (“bicyclic heterocyclyl”), and can be saturated or may be partially unsaturated.
  • Heterocyclyl bicyclic ring systems can include one or more heteroatoms in one or both rings.
  • Heterocyclyl also includes ring systems in which the heterocyclyl ring as defined above is fused by one or more carbocyclyl groups, wherein the point of attachment is on the carbocyclyl or heterocyclyl ring, or "Heterocyclyl” also includes ring systems wherein the heterocyclyl ring as defined above is fused by one or more aryl or heteroaryl groups, or a cycloalkyl ring as defined above is fused by one or more A ring system fused to a heteroaryl group, wherein the point of attachment is on the heterocyclyl ring or cycloalkyl ring, and in such cases, the number of members of the heterocyclyl ring system is the post-fused ring system atomic number.
  • each instance of heterocyclyl is independently optionally substituted, e.g., unsubstituted (an "unsubstituted heterocyclyl") or substituted with one or more substituents (a "substituted heterocyclyl").
  • exemplary 3-membered heterocyclyl groups containing 1 heteroatom include, but are not limited to, aziridinyl, oxiranyl, and thiorenyl.
  • Exemplary 4-membered heterocyclyl groups containing 1 heteroatom include, but are not limited to, azetidinyl, oxetanyl, and thietanyl.
  • Exemplary 5-membered heterocyclyl groups containing 1 heteroatom include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrophenylthio, dihydrophenylthio, pyrrolidinyl, dihydropyrrolyl, and pyrrole Base-2,5-dione.
  • Exemplary 5-membered heterocyclyl groups containing 2 heteroatoms include, but are not limited to, dioxolanyl, oxathiolanyl, dithiolanyl, and oxazolidin-2-one .
  • Exemplary 5-membered heterocyclyl groups containing 3 heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl.
  • Exemplary 6-membered heterocyclyl groups containing 1 heteroatom include, but are not limited to, piperidinyl, tetrahydropyranyl, dihydropyridyl, and thianyl.
  • Exemplary 6-membered heterocyclyl groups containing 2 heteroatoms include, but are not limited to, piperazinyl, morpholinyl, dithianyl, and dioxanyl.
  • Exemplary 6-membered heterocyclyl groups containing 3 heteroatoms include, but are not limited to, triazacyclohexyl, oxadiazinyl, thiadiazinyl, oxathiazinyl, and dioxo Dioxazinanyl.
  • Exemplary 7-membered heterocyclyl groups containing 1 heteroatom include, but are not limited to, azepanyl, oxepanyl, and thiepanyl.
  • Exemplary 8-membered heterocyclyl groups containing 1 heteroatom include, but are not limited to, azacanyl, oxocanyl, and thiecanyl.
  • Exemplary 5-membered heterocyclyl groups (also referred to herein as a 5,6-bicyclic heterocycle) fused to a C6 aryl ring include, but are not limited to, indolinyl, isodihydro Indolyl, dihydrobenzofuryl, dihydrobenzothienyl, benzoxazolinonyl, and the like.
  • Exemplary 6-membered heterocyclyl groups (also referred to herein as a 6,6-bicyclic heterocycle) fused to an aryl ring include, but are not limited to, tetrahydroquinolinyl, tetrahydroisoquinolinyl Base etc.
  • heterocycloalkyl refers to a monocyclic, saturated “heterocyclyl” or “heterocycle” as defined above, and the definition of ring atoms is the same as above, that is, it contains 3 to 20 ring atoms ("3 -20-membered heterocycloalkyl"), the number of heteroatoms is 1 to 4 (1, 2, 3 or 4), preferably 1 to 3 (1, 2 or 3), wherein The atoms are each independently selected from N, O or S.
  • ring atoms 3-12 membered heterocycloalkyl
  • 3-12 membered heterocycloalkyl 3-12 membered heterocycloalkyl
  • 10-membered heterocycloalkyl 3 to 10 ring atoms
  • 3-12 membered heterocycloalkyl 10-membered heterocycloalkyl
  • 3-12 membered heterocycloalkyl 3-12 membered heterocycloalkyl
  • 3-8 membered heterocycloalkyl 3-8 membered heterocycloalkyl
  • 4-7 membered heterocycloalkyl 4 to 7 ring atoms
  • Alkyl more preferably containing 5-10 ring atoms ("5-10 membered heterocycloalkyl"), still more preferably containing 5-6 ring atoms ("5-6 membered heterocycloalkyl” ).
  • each instance of heterocycloalkyl is independently optionally substituted, for example, unsubstituted (an "unsubstituted heterocycloalkyl") or substituted by one or more Substituted (a "substituted heterocycloalkyl").
  • heterocyclyl or “heterocycle” part has given some exemplary “heterocycloalkyl”, including, but not limited to, aziridine, oxirane, thiiridine Azetidinyl, oxetanyl, thietanyl, tetrahydrofuranyl, oxanyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl , oxathianyl, oxazolidinyl, dioxanyl, dithianyl, thiazolidinyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, etc.
  • aryl or “aromatic ring group” means a group containing 6-16 carbon atoms, or 6-14 carbon atoms, or 6-12 carbon atoms, or 6-10 carbon atoms Monocyclic, bicyclic and tricyclic aromatic carbocyclic ring systems, preferably 6-10 carbon atoms, the term “aryl” may be used interchangeably with the term “aromatic ring”. Examples of aryl groups may include, but are not limited to, phenyl, naphthyl, anthracenyl, phenanthrenyl, or pyrenyl, and the like. Polycyclic aryl groups include fused and bridged aryl groups, and the explanations for fused and bridged rings are similar to polycyclic heterocyclic groups.
  • heteroaryl or “heteroaryl ring group” means a structure containing 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 members, or preferably a 5-10 member structure , or preferably a 5-8 membered structure, more preferably a 5-6 membered aromatic monocyclic or polycyclic ring system, wherein 1, 2, 3 or more ring atoms are heteroatoms and the remaining atoms are carbon , the heteroatoms are independently selected from O, N or S, and the number of heteroatoms is preferably 1, 2 or 3.
  • heteroaryl examples include, but are not limited to, furyl, thienyl, oxazolyl, thiazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl , tetrazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, thiodiazolyl, triazinyl, phthalazinyl, quinolinyl, isoquinolinyl, pteridyl, purinyl, indyl Indolyl, Isoindolyl, Indazolyl, Benzofuryl, Benzothienyl, Benzopyridyl, Benzopyrimidinyl, Benzopyrazinyl, Benzimidazolyl, Benzophthalazinyl, Pyrrole A[2,3
  • a substituent can be bonded to more than one atom on a ring
  • the substituent can be bonded to any atom on the ring (including heteroatoms such as NH), e.g. Indicates that the connection site can be at any position on the benzene ring or pyridine ring, or can be at any position on the benzene ring or tetrahydrofuran ring.
  • the term "pharmaceutically acceptable salt” or “pharmaceutically acceptable salt” refers to any salt suitable for use in contact with mammalian, especially human, tissues without undue toxicity, irritation, or allergic reaction within the scope of sound medical judgment. Salts commensurate with a reasonable benefit/risk ratio, such as the pharmaceutically acceptable salts of amines, carboxylic acids, and other types of compounds are well known in the art. The salts can be prepared in situ during the final isolation and purification of the compounds of the present application, or alone by reacting the free base or acid with a suitable reagent.
  • the pharmaceutically acceptable salts of the present application include acid addition salts or base addition salts of the compounds described in the present application, which are composed of the compounds described in the present application and inorganic acids or organic acids and inorganic bases or organic acids well known to those skilled in the art. Obtained by organic base reaction.
  • isotopic derivatives means that the compounds of the present application may exist in isotopically labeled or enriched forms, containing one or more atoms whose atomic mass or mass number is different from that found in nature The atomic mass or mass number of the most abundant atom. Isotopes can be radioactive or non-radioactive isotopes.
  • Isotopes commonly used for isotope labeling are: Hydrogen isotopes, 2 H and 3 H; Carbon isotopes: 13 C and 14 C; Chlorine isotopes: 35 Cl and 37 Cl; Fluorine isotopes: 18 F; Iodine isotopes: 123 I and 125 I ; Nitrogen isotopes: 13 N and 15 N; Oxygen isotopes: 15 O, 17 O and 18 O and sulfur isotope 35 S. These isotope-labeled compounds can be used to study the distribution of pharmaceutical molecules in tissues. Especially 2 H and 13 C are more widely used because of their easy labeling and convenient detection.
  • Isotopically labeled compounds are generally synthesized starting from labeled starting materials and carried out in the same way as non-isotopically labeled compounds using known synthetic techniques.
  • solvate and “solvate” mean a physical association of a compound of the present application with one or more solvent molecules (whether organic or inorganic). This physical association includes hydrogen bonding.
  • solvent molecules in solvates may exist in regular and/or disordered arrangements.
  • Solvates may contain stoichiometric or non-stoichiometric amounts of solvent molecules.
  • Solvate encompasses both solution-phase and isolatable solvates.
  • Exemplary solvates include, but are not limited to, hydrates, ethanolates, methanolates, and isopropanolates. Solvation methods are well known in the art.
  • stereoisomer refers to compounds that have the same chemical structure but differ in the way the atoms or groups are arranged in space.
  • Stereoisomers include enantiomers, diastereomers, conformational isomers (rotamers), geometric isomers (cis/trans) isomers, atropisomers, and the like.
  • the resulting mixture of any stereoisomers can be separated into pure or substantially pure geometric isomers, enantiomers, diastereoisomers on the basis of differences in the physicochemical properties of the components, for example, by chromatography method and/or fractional crystallization.
  • tautomer refers to structural isomers with different energies that are interconvertible through a low energy barrier. If tautomerism is possible (eg, in solution), then a chemical equilibrium of the tautomers can be achieved.
  • proton tautomers also known as prototropic tautomers
  • Bonded tautomers include interconversions by recombination of some of the bonding electrons.
  • the structural formulas described in this application include all isomeric forms (such as enantiomers, diastereoisomers, and geometric isomerism (or conformational isomerism)): for example, containing asymmetric centers The R, S configuration of the double bond, (Z), (E) isomers, and (Z), (E) conformational isomers. Accordingly, individual stereochemical isomers of the compounds of the present application or mixtures thereof as enantiomers, diastereomers, or geometric isomers (or conformational isomers) are within the scope of the present application.
  • prodrug refers to a drug that is converted into the parent drug in vivo.
  • Prodrugs are often useful to ameliorate some identified, undesirable physical or biological property. Physical properties are usually related to solubility (too high or insufficient lipid or water solubility) or stability, while problematic biological properties include too fast metabolism or poor bioavailability, which may themselves be related to physicochemical properties. For example, they are bioavailable orally, whereas the parent is not. Prodrugs also have improved solubility in pharmaceutical compositions compared to the parent drug.
  • prodrug may be any of the compounds of the application administered as an ester ("prodrug") to facilitate delivery across cell membranes where water solubility is detrimental to mobility but once entered Intracellular water solubility is beneficial, which is then metabolically hydrolyzed to carboxylic acids, the active entities.
  • prodrug could be a short peptide (polyamino acid) bound to an acid group, where the peptide is metabolized to reveal the active moiety.
  • treatment encompasses any treatment of a disease, disorder, or condition in a patient, including: (a) inhibiting the symptoms, i.e., arresting the progression, of a disease, disorder, or condition; or (b) ameliorating a disease, disorder, or condition and symptoms of the condition, ie, causing regression of the disease or symptoms; or (c) ameliorating or eliminating the disease, disorder and condition, or one or more symptoms associated with the disease.
  • the term "therapeutically effective amount” means (i) treating a particular disease, disorder or condition, (ii) alleviating, ameliorating or eliminating one or more symptoms of a particular disease, disorder or condition, or (iii) ) an amount of a compound of the present application that delays the onset of one or more symptoms of a particular disease, disorder or condition described herein.
  • the amount of a compound of the present application that constitutes a “therapeutically effective amount” will vary depending on the compound, the disease state and its severity, the mode of administration, and the age of the mammal to be treated, but can be routinely determined by a person skilled in the art according to its own knowledge and this disclosure.
  • the term "pharmaceutically acceptable excipients” refers to those excipients that have no obvious irritating effect on organisms (such as humans) and will not impair the biological activity and performance of active compounds. Suitable excipients are well known to those skilled in the art, such as carbohydrates, waxes, water-soluble and/or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water and the like.
  • “Pharmaceutically acceptable excipients” can also refer to the inert substances that are administered together with the active ingredient to facilitate the administration of the active ingredient, including but not limited to those approved by the US Food and Drug Administration as acceptable for human or animal ( any glidants, sweeteners, diluents, preservatives, dyes/colorants, flavoring agents, surfactants, wetting agents, dispersants, disintegrants, suspending agents, stabilizers, Excipients such as isotonic agents, solvents or emulsifiers.
  • This application designs a class of compounds with novel structures, which provides a new direction for the treatment of tumors, cancers, cancer metastasis, cardiovascular diseases, immune disorders or visual disorders.
  • the compound of the present application has one or more of the following advantages: (1) strong SHP2 kinase inhibitory effect; (2) higher exposure and good absorption; (3) no obvious inhibitory effect on hERG channel, can have a lower (4) good tolerance and high drug safety; and (5) high tumor inhibition rate in vivo.
  • this application studies a specific synthesis method, which is simple in process, convenient in operation, and conducive to large-scale industrial production and application.
  • Step b Cool the solution of 3-(tert-butylsulfanyl)-2-chloroaniline (7.0g, 32.55mmol, 1eqv) in concentrated hydrochloric acid (15ml) to -10 ⁇ -5°C, add dropwise sodium nitrite ( 3.369g, 48.83mmol, 1.5eqv) in water (105ml) solution, keep warm for 30min after dripping; at the same temperature, add potassium iodide (6.484g, 39.06mmol, 1.2eqv) in water (65ml) Insulated reaction for 20min; Add ethyl acetate (100ml) and saturated sodium thiosulfate solution (100ml) to the reaction solution, stir for 10min, separate liquids, extract the aqueous phase with EA (2 ⁇ 50ml), and combine the organic phases; Washed with brine (100 mL), concentrated under reduced pressure, and the residue was purified by column chromatography (n-hexane) to obtain ter
  • Step b Under nitrogen protection, 2-ethyl-hexyl 3-(2-(2,3-dichloropyridin-4-yl)sulfanyl)propanoate (666mg, 1.834mmol, 1.0eqv), pyr 1,4-dioxane of oxazine-2-boronic acid (250mg, 2.02mmol, 1.1eqv), Pd(dppf)Cl2 ( 134mg , 0.183mmol, 0.1eqv) and potassium carbonate (760mg, 5.503mmol, 3eqv) (60mL) and water (10ml) solution reacted overnight at 96°C; lowered the temperature, concentrated under reduced pressure, added water (200ml) and EA (100ml) to the residue, separated the layers, extracted the aqueous phase with EA (2 ⁇ 50ml), and combined organic phase; the organic phase was washed with brine (100ml), concentrated under reduced pressure, and the residue was purified by column
  • Step c Under nitrogen protection, 2-ethyl-hexyl 3-((3-chloro-2-(pyrazin-2-yl)pyridin-4-yl)sulfanyl)propionate (637mg, 1.565mmol , 1.0eqv), NaOH (66mg, 1.643mmol, 1.05eqv) in methanol (60ml) was reacted at 50°C for 3h; the temperature was lowered to about 0°C, and 4M HCl/MeOH solution was added dropwise to adjust the pH to 3-4.
  • Steps a ⁇ b according to the method of preparing Compound 8 from Compound 7 according to WO2021061706A1.
  • Step b Add (R)-N-((R)-1'-(3-acetyl-6-aminopyrazin-2-yl)-3H-spiro[benzofuran-2,4'- Piperidin]-3-yl)-2-methylpropane-2-sulfinamide (321mg, 0.724mmol, 1.0eqv) was added into the reaction flask of HCl/CH 3 OH solution (10mL), stirred at room temperature for 4h, The reaction solution was spin-dried to obtain the crude product ((R)-1-(5-amino-3-(3-amino-3H-spiro[benzofuran-2,4'-piperidin]-1'-yl)pyridine Azin-2-yl)ethanone. (ES, m/z): 340.10[M+H] + .
  • Step c Add TEA (220mg, 2.175mmol, 3.0eqv) to (R)-1-(5-amino-3-(3-amino-3H-spiro[benzofuran-2,4'-Piperidin]-1'-yl)pyrazin-2-yl)ethanone (246mg, 0.724mmol, 1.0eqv) in DCM (50ml) was then added (Boc)2O ( 316mg , 1.448mmol, 2.0 eqv), overnight reaction at room temperature.
  • Step d Add NBS (94mg, 0.528mmol, 1.05eqv) into (R)-(1'-(3-acetyl-6-aminopyrazin-2-yl)-3H-spiro [Benzofuran-2,4'-piperidin]-3-yl) tert-butyl carbamate (221 mg, 0.503 mmol, 1.0 eqv) in DCM (20 ml) was stirred at constant temperature for 10 min.
  • Step a Methyl 3-chloro-5-((2,4-dimethoxybenzyl)amino)pyrazine-2-carboxylate (200 mg, 0.593 mmol, 1.0 eqv), (R)-2- Methyl-N-((R)-3H-spiro[benzofuran-2,4'-piperidin]-3-yl)propane-2-sulfinamide (201 mg, 0.653 mmol, 1.1 eqv) and DIPEA ( 230mg, 1.779mmol, 3.0eqv) in DMSO (10ml) solution, reacted at 110°C for 10h; cooled to room temperature, added water (60ml) and EA (60ml) to the reaction solution, separated, and used EA (3 ⁇ 20ml) for the aqueous phase ) extraction, combined the organic phase; the organic phase was washed with H 2 O (100ml), brine (50ml), concentrated under reduced pressure, and
  • Step b To 5-((2,4-dimethoxybenzyl)amino)-3-((R)-3-((R)-1,1-dimethylethylsulfonamido) CF 3 COOH (6ml) was added to -3H-spiro[benzofuran-2,4'-piperidin]-1'-yl)pyrazine-2-carboxylic acid methyl ester (305mg, 0.501mmol, 1.0eqv), After stirring and reacting at room temperature for 3 h, the reaction solution was spin-dried to obtain the crude product 5-amino-3-((R)-3-((R)-1,1-dimethylethylsulfonamido)-3H-spiro Methyl [benzofuran-2,4'-piperidin]-1'-yl)pyrazine-2-carboxylate (230 mg). (ES, m/z): 460.15[M+H] + .
  • Step c To 5-amino-3-((R)-3-((R)-1,1-dimethylethylsulfonamido)-3H-spiro[benzofuran-2,4'- Add HCl/CH 3 OH solution (10mL) to the crude product of piperidin]-1'-yl)pyrazine-2-carboxylate (230mg), stir the reaction at room temperature for 2h, spin the reaction solution to dryness, and obtain the crude product (R )-methyl 5-amino-3-(3-amino-3H-spiro[benzofuran-2,4'-piperidin]-1'-yl)pyrazine-2-carboxylate (178 mg). (ES, m/z): 356.11[M+H] + .
  • Step d Add TEA (253.3mg, 2.505mmol, 5.0eqv) to (R)-5-amino-3-(3-amino-3H-spiro[benzofuran-2,4'-piperidine at room temperature ]-1'-yl)pyrazine-2-carboxylic acid methyl ester (178mg, 0.501mmol, 1.0eqv) in DCM (20ml) was then added (Boc)2O (142mg, 0.651mmol , 1.3eqv), React overnight at room temperature.
  • TEA 253.3mg, 2.505mmol, 5.0eqv
  • Step e Add NBS (57mg, 0.321mmol, 1.1eqv) to (R)-5-amino-3-(3-((tert-butoxycarbonyl)amino)-3H-spiro[
  • NBS 57mg, 0.321mmol, 1.1eqv
  • methyl benzofuran-2,4'-piperidin]-1'-yl)pyrazine-2-carboxylate 133 mg, 0.292 mmol, 1.0 eqv
  • Step b To 6-bromo-3-((R)-3-((R)-1,1-dimethylethylsulfinamido)-3H-spiro[benzofuran-2,4'- Add HCl/CH 3 OH solution (10ml) to methyl piperidine]-1'-yl)pyrazine-2-carboxylate (375mg, 0.718mmol, 1.0eqv), stir and react at room temperature for 4h, then spin the reaction solution to dryness , to obtain crude (R)-3-(3-amino-3H-spiro[benzofuran-2,4'-piperidin]-1'-yl)-6-bromopyrazine-2-carboxylic acid methyl ester. (ES, m/z): 419.02[M+H] + .
  • Step c Add TEA (218mg, 2.155mmol, 3.0eqv) to (R)-3-(3-amino-3H-spiro[benzofuran-2,4'-piperidine]-1' at room temperature -yl)-6-bromopyrazine-2-carboxylic acid methyl ester (300mg, 0.718mmol, 1.0eqv) in DCM (50ml) was then added (Boc)2O ( 299mg , 1.437mmol, 2.0eqv), React overnight at room temperature.
  • Step a Adding (R)-6-bromo-3-(3-((tert-butoxycarbonyl)amino)-3H-spiro[benzofuran-2,4'-piperidin]-1'-yl)
  • a solution of methyl pyrazine-2-carboxylate (500mg, 0.965mmol, 1eqv), LiOH ⁇ H 2 O (81mg, 1.93mmol, 2eqv) in THF (10ml) and water (10ml) was reacted overnight at room temperature; Adjust the pH of the solution to 3-4, concentrate under reduced pressure, add water (60ml) and EA (60ml) to the residue, separate the layers, extract the aqueous phase with EA (3 ⁇ 20ml), combine the organic phases; use H2O for the organic phases (100ml), brine (50ml), washed under reduced pressure, eluted and purified by silica gel column chromatography (eluent is DCM:MeOH 80:1 ⁇
  • Step b Under nitrogen protection, at 0°C, to (R)-6-bromo-3-(3-((tert-butoxycarbonyl)amino)-3H-spiro[benzofuran-2,4'-piper Pyridine]-1'-yl)pyrazine-2-carboxylic acid (400mg, 0.793mmol, 1eqv) in anhydrous DMF (10ml) solution, add methoxymethylamine (58mg, 0.952mmol, 1.2eqv), EDCI (182.4mg, 0.952mmol, 1.2eqv), HOBt (128.6mg, 0.952mmol, 1.2eqv) and Et 3 N (160mg, 1.586mmol, 2eqv), then reacted at room temperature for 6h; added water (60ml) and EA (60ml), separated, the aqueous phase was extracted with EA (3 ⁇ 20ml), and the organic phases were combined; the organic phase was washed with H
  • Step c Under nitrogen protection, at -78 ° C, to (R)-(1'-(5-bromo-3-(methoxy(methyl)carbamoyl)pyrazin-2-yl)-3H -Spiro[benzofuran-2,4'-piperidin]-3-yl)carbamate tert-butyl ester (227mg, 0.415mmol, 1eqv) in anhydrous THF (10ml) was added dropwise methylmagnesium bromide ( 3.0M, 0.276ml, 2eqv), naturally heated to 0°C for 2h; quenched the reaction with saturated NH 4 Cl solution; added water (60ml) and EA (60ml) to the reaction, separated the liquid, and used EA (3 ⁇ 20ml), combined the organic phases; the organic phases were washed with H 2 O (100ml), brine (50ml), concentrated under reduced pressure, and eluted and purified by silica gel column chromatography
  • Step b Under nitrogen protection, 6-chloro-3-((2-chloro-3-(oxazol-2-yl)phenyl)sulfanyl]pyrazin-2-amine (5.50 g, 26.085mmol, 1.00eqv), K 2 CO 3 (7.20g, 52.17mmol, 2.00eqv) in MeOH (160ml) solution, add dropwise ICl (6.35g, 39.128mmol, 1.50eqv) in DCM (160ml) solution , temperature controlled reaction for 2h, then overnight reaction at room temperature; 500ml of 10% Na 2 SO 3 was added to the reaction solution to quench, liquid separation, the aqueous phase was extracted with DCM (3 ⁇ 250ml), and the organic phase was combined; the organic phase was saturated with NaCl 250ml was washed, dried over anhydrous sodium sulfate and concentrated under reduced pressure; 6-chloro-3-((2-chloro-3-(oxazol-2-yl)phenyl)s
  • Step c Replace nitrogen with dtbpy (551mg, 1.832mmol, 0.10eqv) and DMA (200ml), add NiBr 2 .DME (724mg, 1.832mmol, 0.10eqv), stir at room temperature for 0.5h; then add 6-chloro-3- ((2-Chloro-3-(oxazol-2-yl)phenyl)sulfanyl)-5-iodopyrazin-2-amine (8.5g, 18.324mmol, 1.00eqv), 3-bromooxyheterocycle Butane (5.624g, 36.647mmol, 2.00eqv), TBAI (758.2mg, 1.832mmol, 0.10eqv), Zn (2.686g, 36.647mmol, 2.00eqv), stirred overnight at 75°C under nitrogen protection; After soil filtration, the filtrate was poured into water (1000ml), extracted with EA (2 ⁇ 500ml), and the organic phases were combined; the organic
  • Step b Under nitrogen protection, methyl 3-((4-iodopyrimidin-2-yl)sulfanyl)propanoate (595mg, 1.834mmol, 1.0eqv), oxazol-2-ylboronic acid (228mg, 2.02 mmol, 1.1eqv), Pd(dppf)Cl2 ( 134mg , 0.183mmol, 0.1eqv) and potassium carbonate (760mg, 5.503mmol, 3eqv) in 1,4-dioxane (50mL) and water (10ml) solution React overnight at 96°C; cool down, concentrate under reduced pressure, add water (200ml) and EA (100ml) to the residue, separate the layers, extract the aqueous phase with EA (2 ⁇ 50ml), combine the organic phases; use brine (100ml) for the organic phase Washing, concentration under reduced pressure, and the residue was purified by column chromatography (n-hexane: EA
  • Steps a ⁇ b Under nitrogen protection, add tert-butyl 3-oxospiro[1-benzofuran-2,4'-piperidine]-1'-carboxylate (10.00g, 32.965mmol, 1.00eqv) and (R)-(+)-tert-butylsulfinamide (7.99g, 65.93mmol, 2eqv) in 2-MeTHF (40ml) solution, add Ti(OEt) 4 (100ml), react at 80°C for 48h; then Cool down to -5°C, add NaBD 4 (1.66g, 39.55mmol, 1.2eqv), react at room temperature overnight; cool down to 0°C, add methanol (30ml) dropwise to the reaction solution, add water (1000ml) and EA (1000ml) , stirred for 30min, filtered, and the filtrate was separated; the organic phase was washed with brine (1000ml), dried over anhydrous sodium sulfate, and concentrated
  • Step c Dissolve M23-2 (10.5g) in DCM (20ml), add trifluoroacetic acid (20ml) dropwise at 0°C, react at room temperature for 6h, concentrate under reduced pressure, add water (50ml) to the residue, and use Adjust the pH to 10 with 25% ammonia water, extract the aqueous phase with EA (50ml ⁇ 3), combine the organic phases, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain (R)-2-methyl-N-((R)-
  • the crude product (7.84 g) of 3-deuterium-spiro[benzofuran-2,4'-piperidin]-3-yl)propane-2-sulfinamide (M-23) was directly used in the next reaction without purification.
  • Step ab nitrogen protection, 2-amino-5-bromo-6-chloropyrazine (20.0g, 96.67mmol, 1.0eqv), tributyl (1-ethoxyvinyl) tin (52.36g, 144.98mmol , 1.5eqv), CuI (1.84g, 9.667mmol, 0.1eqv), Pd(Ph 3 P) 2 Cl 2 (6.78g, 9.667mmol, 0.1eqv) in 1,4-dioxane (240ml), Reaction overnight at 100°C, TLC detected that the reaction was complete, and (R)-2-methyl-N-((R)-3-deuterium-spiro[benzofuran-2,4'-piperidin]-3-yl) Propane-2-sulfinamide (M-23) crude product (35.86g, 115.987mmol, 1.2eqv) in 1,4-dioxane (200ml) was added to the reaction solution
  • Step c Add NBS (11.563g, 64.97mmol, 1.2eqv) to a solution of M25-1 (24.05g, 54.14mmol, 1.0eqv) in DCM (250ml) at 0°C, react overnight at room temperature, and then add 4M HCl/CH 3 OH solution (10ml) was stirred for 1h; saturated aqueous sodium bicarbonate solution (100ml) was added to the reaction solution, separated, the aqueous phase was extracted with DCM (50ml ⁇ 2), and the organic phase was combined; the organic phase was washed with H 2 O (200ml), brine (200ml), dried over anhydrous sodium sulfate, and filtered to obtain a crude DCM solution of M25-2, which was directly used in the next step without treatment. (ES, m/z): 419.00[M+H] + .
  • Step a under nitrogen protection, M-25 (3.00g, 5.78mmol, 1.0eqv), methyl 3-mercaptopropionate (1.04g, 8.67mmol, 1.5eqv), Pd(OAc) 2 (250mg, 1.16mmol, 0.2eqv), Xantphos (1.34g, 2.31mmol, 0.4eqv), DIPEA (2.25g, 7.34mmol, 3eqv) in 1,4-dioxane (60ml) reaction solution, react overnight at 97°C.
  • Step b Add NaOH (242mg, 5.907mmol, 1.1eqv) to a solution of M27-1 (3.00g, 5.37mmol, 1.0eqv) in MeOH (30ml), stir at 55°C for 2h; Add water (100ml) to the mixture, adjust the pH to 3 ⁇ 4 with 1N HCl, extract with EA (100ml ⁇ 2), and combine the organic phases; the organic phases are washed with H 2 O (20ml), brine (20ml), anhydrous Dry over sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain M-27 (1.33 g, yield 78.4%) (ES, m/z): 473.10[M+H] + .
  • Step a Under nitrogen protection, (R)-(1'-(3-acetyl-6-amino-5-bromopyrazin-2-yl)-3H-spiro[benzofuran-2,4'- Piperidin]-3-yl) tert-butyl carbamate (140mg, 0.27mmol, 1.0eqv), 2-chloro-3-(oxazol-2-yl) benzenethiol (69mg, 0.325mmol, 1.2eqv), DIPEA (123mg, 0.954mmol, 3.5eqv), Pd2(dba )3 ( 50mg, 0.054mmol, 0.2eqv) and Xantphos (63mg, 0.109mmol, 0.4eqv) in 1,4-dioxane (10mL) , react at 96°C for 6h; cool down to room temperature, add silica gel to the reaction solution, and purify by silica gel column chromatography
  • Step b To (R)-(1'-(3-acetyl-6-amino-5-((2-chloro-3-(oxazol-2-yl)phenyl)sulfanyl)pyrazine- 2-yl)-3H-spiro[benzofuran-2,4'-piperidin]-3-yl)carbamate tert-butyl ester (152mg) in dichloromethane (10ml) solution, add trifluoroacetic acid (5ml ), stirred at room temperature for 3h; the reaction solution was concentrated under reduced pressure, EA (50ml) and water (50ml) were added to the residue, and the pH was adjusted to 10 with 25% ammonia water, and the liquids were separated; the aqueous phase was extracted with EA (20ml), and the organic phase; the organic phase was washed with water (50ml), brine (50ml), and concentrated under reduced pressure; the residue was purified by column chromatography (CH 2 Cl 2 : CH
  • Step a Under nitrogen protection, (R)-5-amino-6-bromo-3-(3-((tert-butoxycarbonyl)amino)-3H-spiro[benzofuran-2,4'-piper Pyridine]-1'-yl)pyrazine-2-carboxylic acid methyl ester (144mg, 0.27mmol, 1.0eqv), 2-chloro-3-(oxazol-2-yl)benzenethiol (69mg, 0.324mmol, 1.2eqv), DIPEA (123mg, 0.954mmol, 3.5eqv), Pd 2 (dba) 3 (50mg, 0.054mmol, 0.2eqv) and Xantphos (63mg, 0.109mmol, 0.4eqv) of 1,4-dioxane (20ml) solution was reacted at 96°C for 6h; cooled to room temperature, silica gel was added to the reaction solution, and purified
  • Step b To (R)-5-amino-3-(3-((tert-butoxycarbonyl)amino)-3H-spiro[benzofuran-2,4'-piperidin]-1'-yl) -6-(2-Chloro-3-(oxazol-2-yl)phenyl)sulfanyl)pyrazine-2-carboxylic acid methyl ester (152mg) in dichloromethane (20ml) solution, add trifluoro Acetic acid (5ml), stirred at room temperature for 3h; the reaction solution was concentrated under reduced pressure, EA (100ml) and water (50ml) were added to the residue, the pH was adjusted to 10 with 25% ammonia water, and the liquid was separated; the aqueous phase was extracted with EA (20ml) , combined the organic phase; the organic phase was washed with water (50ml), brine (50ml), dried over anhydrous sodium sulfate, concentrated; the residue was purified by column
  • Step a 6-chloro-3-((2-chloro-3-(oxazol-2-yl)phenyl)sulfanyl)-5-(oxetan-3-yl)pyrazine-2 -Amine (613 mg, 1.556 mmol, 1.0 eqv), (R)-2-methyl-N-((R)-3H-spiro[benzofuran-2,4'-piperidin]-3-yl)propane -2-sulfenamide (575mg, 1.867mmol, 1.2eqv), DIPEA (603mg, 4.665mmol, 3.0eqv) in DMSO (10ml) solution, reacted at 110°C for 6h; cooled to room temperature, added water (100ml), and used EA (3 ⁇ 50ml) was extracted, and the organic phases were combined; the organic phase was washed with H2O (50ml), brine (50ml), concentrated under reduced pressure, and purified by silica gel column
  • Step b To (R)-N-((R)-1'-(6-amino-5-((2-chloro-3-(oxazol-2-yl)phenyl)sulfanyl)-3 -(oxetan-3-yl)pyrazin-2-yl)-3H-spiro[benzofuran-2,4'-piperidin]-3-yl)-2-methylpropane-2-ylidene
  • Add HCl/CH 3 OH solution (60mL) to sulfonamide (677mg) react overnight at room temperature, concentrate the reaction solution under reduced pressure, add EA (50ml) and water (50ml) to the residue, adjust the pH to 9 with 25% ammonia water ⁇ 10, separation; the aqueous phase was extracted with EA (20ml), and the organic phase was combined; the organic phase was washed with water (50ml), brine (50ml), concentrated; the residue was purified by column chromatography (CH 2 Cl 2 : CH
  • Step a Under nitrogen protection, (R)-(1'-(3-acetyl-6-amino-5-bromopyrazin-2-yl)-3H-spiro[benzofuran-2,4'- Piperidin]-3-yl) tert-butyl carbamate (140mg, 0.27mmol, 1.0eqv), 2-(oxazol-2-yl)pyrimidine-4-thiol (58mg, 0.325mmol, 1.2eqv), DIPEA (123mg, 0.954mmol, 3.5eqv), Pd 2 (dba) 3 (50mg, 0.054mmol, 0.2eqv) and Xantphos (63mg, 0.109mmol, 0.4eqv) in 1,4-dioxane (10mL) solution in React at 96°C for 6h; cool down to room temperature, add silica gel to the reaction solution, and purify by silica gel column chromatography (elu
  • Step b To (R)-(1'-(3-acetyl-6-amino-5-((2-(oxazol-2-yl)pyrimidin-4-yl)sulfanyl)pyrazine-2 -yl)-3H-spiro[benzofuran-2,4'-piperidin]-3-yl)carbamate tert-butyl ester (126mg) in dichloromethane (5ml) was added trifluoroacetic acid (5ml), Stir at room temperature for 3 hours; the reaction solution was concentrated under reduced pressure, EA (50ml) and water (50ml) were added to the residue, the pH was adjusted to 10 with 25% ammonia water, and the liquids were separated; the aqueous phase was extracted with EA (20ml), and the organic phases were combined; The organic phase was washed with water (50ml), brine (50ml), and concentrated under reduced pressure; the residue was purified by column chromatography (CH 2 Cl 2 :
  • Step a under nitrogen protection, M-27 (256mg, 0.542mmol, 1.0eqv), 2-amino-3-chloro-4-iodopyridine (207mg, 0.813mmol, 1.5eqv), Pd 2 (dba) 3 ( 99mg, 0.108mmol, 0.2eqv), Xantphos (125mg, 0.217mmol, 0.4eqv), DIPEA (245mg, 1.897mmol, 3.5eqv) in 1,4-dioxane (20ml) reaction solution, react overnight at 97°C; Cool down, concentrate the reaction solution to dryness, add water (30ml) to the concentrate, extract with EA (20ml ⁇ 2), and combine the organic phases; the organic phases are washed with H 2 O (20ml), brine (20ml), anhydrous Dry over sodium sulfate, filter, concentrate the filtrate under reduced pressure, and purify by silica gel column chromatography (eluent is n-he
  • Compound TW-45 (structure as follows) was prepared according to the preparation method of compound 45 in TW201840553A.
  • Test Example 1 Test of Inhibitory Effect on SHP2 Enzyme
  • a substrate solution of DiFMUP (#D6567, Invitrogen TM ) was prepared with 1x kinase buffer, and its concentration should be 2 times the final concentration of the experiment (final concentration of DiFMUP: 10 ⁇ M).
  • Use an electric pipette to transfer 5 ⁇ l of the prepared substrate solution to each well of the enzyme-linked plate to initiate the reaction. Centrifuge at 1000 rpm for 30 seconds. Seal the plate and incubate the plate in a constant temperature incubator at 25°C for 60 minutes. Place the enzyme-linked plate on the Spark machine, and read the data at excitation/emission wavelengths of 358/455nm.
  • Test Example 2 In vitro Inhibitory Effect on Human Acute Myeloid Leukemia MV-4-11 Cell Proliferation
  • Human acute myeloid leukemia MV-4-11 cells used in the experiment were purchased from Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences. The complete medium required for cell culture was IMDM (GIBCO), supplemented with 10% fetal bovine serum (GIBCO). Cells were cultured at 37°C in a 5% CO 2 incubator.
  • the reagents used in the experiment include dimethyl sulfoxide (purchased from Tianjin Kemiou Chemical Reagent Co., Ltd.), MTT (Shanghai Tebo Chemical Technology Co., Ltd., CAS.NO.298-93-1). The test substance was sealed and stored at 4°C.
  • test substance Using dimethyl sulfoxide as a solvent, fully dissolve the test substance, prepare a stock solution with a concentration of 5 ⁇ 10 -2 mol/L, and store the stock solution at -20°C.
  • the complete medium was used as the diluent, and the test substances were diluted in different concentrations for later use.
  • a 96-well culture plate add 100 ⁇ L/well (2 ⁇ 10 4 cells/well) MV-4-11 cell complete culture medium suspension, respectively add 100 ⁇ L/well of corresponding test substances of different concentrations, each test Set 8 concentrations of the test substance, and set 3 duplicate wells for each concentration, and cultivate them in a 5% CO 2 incubator at 37°C.
  • Inhibition rate (control well OD-test well OD)/(control well OD-blank well OD)*100%. According to the inhibition rate of each concentration, SPSS software was used to calculate the IC50 value of the half inhibitory concentration. The results are shown in Table 2.
  • Test Example 3 In vitro Inhibitory Effect on the Proliferation of Human Lung Adenocarcinoma NCI-H441 Cells
  • the human lung adenocarcinoma cell NCI-H441 used in the experiment was purchased from ATCC, and the complete medium required for cell culture was RPMI1640 Medium (GIBCO Company), supplemented with 10% fetal bovine serum (GIBCO Company). Cells were cultured at 37°C in a 5% CO 2 incubator.
  • the reagents used in the experiment include dimethyl sulfoxide (purchased from Sigma), 3D Cell Viability assay kit (purchased from Promega), and the control substance TW-45 used in the experiment was obtained by self-made. The test substance was sealed and stored at 4°C.
  • test substance Using dimethyl sulfoxide as a solvent, fully dissolve the test substance, prepare a stock solution with a concentration of 1 ⁇ 10 -2 mol/L, and store the stock solution at -20°C.
  • the complete medium was used as the diluent, and the test substances were diluted in different concentrations for use (final test concentrations were 10000, 3333, 1111, 370, 123, 41, 13.7, 4.5, 1.5, 0.5nM).
  • Cells were cultured for 5 days at 37°C in a 5% CO2 incubator. For detection on day 5, 30 ⁇ L of reagent (Celltiter Glo Assay Kit-3D) was added to each well and the plate was shaken on a plate shaker (protected from light) for 30 minutes. Plates were incubated at room temperature (protected from light) for 120 minutes.
  • the Multiplate reader records the chemiluminescence values.
  • Percent Inhibition 100 - (Signal cmpd - Signal Ave - PC )/(Signal Ave - VC - Signal Ave - PC ) x 100.
  • LUM chemiluminescence signal per well
  • VC average chemiluminescence signal of high quality control (wells containing 0.1% DMSO)
  • PC average chemiluminescence signal of low quality control (blank medium only).
  • ICR mice were intragastrically administered the compound at 10 mg/kg or 20 mg/kg, and at different time points (0.25h, 0.5h, 1h, 2h, 4h, 8h, 24h) after administration, blood was collected from the mouse orbit, and the collected Whole blood was anticoagulated with heparin sodium, and centrifuged at 3000g to obtain mouse plasma samples. Methanol protein precipitation was used to determine the drug concentration in mouse plasma after administration by HPLC-MS/MS, and the drug-time curve was drawn and the pharmacokinetics were calculated. Kinetic parameters, through non-compartmental model statistical moment parameters to describe the pharmacokinetic behavior of the compound in mice after administration.
  • Test example 5 hERG test
  • This test includes the following aspects:
  • the hERG current was recorded on the CHO-K1 cell line stably expressing hERG channel by manual patch clamp technique;
  • the inhibition rate of each concentration was calculated according to the hERG tail current
  • hERG currents were recorded using the whole-cell patch clamp technique. Take the cell suspension and add it to the cell tank, and place it on the stage of the upright microscope. After the cells adhered to the wall, they were perfused with extracellular fluid at a flow rate of 1–2 mL/min. The glass microelectrode is drawn in two steps by a microelectrode pulling instrument, and its water resistance value is 2-5M ⁇ . After establishing whole-cell recordings, the clamping potential was maintained at -80mV. Depolarization to +60mV and repolarization to -50mV elicited hERG tail currents when voltage stimulation was given. All recordings were performed after the current was stabilized.
  • the administration of extracellular perfusion starts at a low concentration, and each concentration lasts for 5-10 minutes until the current is stable, and then the next concentration is given.
  • the half maximal inhibitory concentration (IC50 ) of the test compound was obtained by the best fit of the Logistic equation.
  • test results show that compound No. 1 and compound No. 56 of the application have no obvious inhibitory effect on the hERG channel within the detection concentration range of this test, which can reflect to a certain extent that the compound of the application has low cardiotoxicity and has a positive effect on drug safety evaluation. significance.
  • Test method Female ICR mice were divided into 4 groups according to body weight balance, 5 mice in each group, and the administration doses were 50 mg/kg and 200 mg/kg respectively.
  • the method of administration is intragastric administration, once a day, for 7 consecutive days, and the dosage and results are shown in the table below.

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Abstract

提供一类式(I)所示的化合物、或其前药、互变异构体、立体异构体、溶剂化物、同位素衍生物或其药学上可接受的盐。所述化合物具有SHP2激酶抑制作用，可用于治疗和/或预防通过SHP2活性介导的疾病、病症和病况，例如肿瘤、癌症、癌转移、心血管疾病、免疫紊乱或视觉紊乱等。

Description

螺环类化合物及其用途
相关申请的交叉引用
本申请要求分别于2021年05月21日和2021年08月27日向中华人民共和国国家知识产权局提交的第202110557549.0号和第202111000088.3号中国发明专利申请的权益和优先权，在此将它们的全部内容以援引的方式整体并入本申请中。
技术领域
本申请涉及医药技术领域，具体而言，涉及一类具有SHP2抑制剂活性的新颖化合物及其在治疗和预防通过SHP2活性介导的疾病、病症和病况，如过度增殖性疾病中的用途。
背景技术
SHP2(Src同源性结构域，Src homology-2 domain)由蛋白酪氨酸磷酸酶非受体型11(PTP nonreceptor 11，PTPN11)编码，催化蛋白质酪氨酸去磷酸化反应。通常认为，SHP2的N端包含N-src同源2域(SH2)和C-SH2在内的2个SH2结构域，C端包含1个具有催化活性的PTP结构域。在未激活状态下，SHP2处于自抑制状态，N-SH2与C-PTP相互结合抑制了磷酸酶活性。而在存在细胞外刺激的情况下，它们与相关受体结合，激活下游多种信号通路，如包括Ras/MAPK、PI3K/AKT等多种信号传导通路，调节细胞增殖、分化、凋亡和存活。
文献披露(Eur J Med Genet.2015.58:509；WO2018013597)PTPN11以及SHP2的种系突变已经确定与多种人类疾病相关，如Noonan综合征(NS)、豹皮症侯群(Leopard Syndrome)以及多种恶性肿瘤(白血病等)。Revolution Medicines的研究也表明，SHP2在一些常见癌症的致癌生长和生存信号中起重要作用。
此外，研究表明(Sci Adv.2020,6(5):eaay4458)，程序性死亡1(PD-1)也参与介导和激活SHP2。在癌症中，PD-1抑制T细胞刺激并介导免疫逃逸。刺激后，PD-1在其基于免疫受体酪氨酸的抑制基序(ITIM)和基于免疫受体酪氨酸的开关基序(ITSM)处被磷酸化，然后结合SHP2，启动T细胞失活。因此，SHP2抑制剂可以刺激肿瘤微环境中的适应性免疫和先天免疫活性，具有恢复已被癌细胞沉默的抗肿瘤免疫应答的潜力。
有鉴于此，亟需用作SHP2抑制剂的化合物以治疗和预防通过SHP2活性介导的疾病、病症和病况。
发明内容
本申请提供了一类新型结构的SHP2抑制剂化合物，同时提供该类化合物或其前药、互变异构体、立体异构体、溶剂化物、同位素衍生物或其药学上可接受的盐治疗SHP2活性介导的疾病、病症和病况的应用。
一方面，本申请提供了一种式(I)所示的化合物，或其前药、互变异构体、立体异构体、溶剂化物、同位素衍生物或其药学上可接受的盐，其具有如下结构：
Figure PCTCN2022094255-appb-000001
其中，
X选自O、CH 2、NH或S；
L选自N或CH；
G选自键或S；
A选自CH或N；
R 3独立地选自：任选取代的8-12元杂环基、任选取代的C 6-10芳基、任选取代的5-14元杂芳基，其中所述任选取代是指被取代基团上的氢未被取代或被取代基团的一个或多个可取代位点上的氢独立地被选自卤素、羟基、氨基、硝基、氧代基、氰基、-COOH、-COCH 3、-COOCH 3、-CONH 2、C 1-6烷基、C 1-6烷氧基、C 3-10环烷基、3-10元杂环烷基、C 6-10芳基、5-12元杂芳基的取代基所取代；
R 1独立地选自氢、氘或氨基；
R 2独立地选自氢、卤素、氰基、-CONH 2、-COR 5、-COOR 5、任选取代的C 1-6烷基、任选取代的C 2-6烯基、任选取代的C 2-6炔基、任选取代的C 3-10环烷基、任选取代的3-10元杂环烷基，其中，R 5独立地选自氢、任选取代的C 1-6烷基、任选取代的C 3-6环烷基、任选取代的3-6元杂环烷基、任选取代的C 6-10芳基、任选取代的5-10元杂芳基，所述任选取代是指被取代基团上的氢未被取代或被取代基团的一个或多个可取代位点上的氢独立地被选自卤素、羟基、氨基、硝基、氧代基、氰基、C 1-6烷基、C 1-6烷氧基的取代基所取代；
Y独立地选自N或CR 4；
R 4独立地选自氢、卤素、羟基、氨基、氰基、任选取代的C 1-6烷基、任选取代的C 1-6烷氧基，其中所述任选取代是指被取代基团上的氢未被取代或被取代基团的一个或多个可取代位点独立地被选自卤素、羟基、氨基、氰基、C 1～6烷基、C 1-6烷氧基所取代；
R 6独立地选自氢或氘；
所述“氧代基”是指相同取代位的两个H被同一个O替代形成双键；
所述杂环烷基、杂芳基、杂环基中的杂原子独立地选自O、N或S，杂原子数量为1个、2个、3个或4个。
在本申请的一个实施方案中，提供了一种式(I)所示的化合物，或其前药、互变异构体、立体异构体、溶剂化物、同位素衍生物或其药学上可接受的盐，其具有如下结构：
Figure PCTCN2022094255-appb-000002
其中，
X选自O、CH 2、NH或S；
L选自N或CH；
G选自键或S；
A选自CH或N；
R 3为氨基；
R 1独立地选自氢、氨基或氘；
R 2独立地选自卤素、氰基、-CONH 2、-COR 5、-COOR 5、任选取代的C 1-6烷基、任选取代的C 2-6烯基、任选取代的C 2-6炔基、任选取代的C 3-10环烷基、任选取代的3-10元杂环烷基，其中，R 5独立地选自氢、任选取代的C 1-6烷基、任选取代的C 3-6环烷基、任选取代的3-6元杂环烷基、任选取代的C 6-10芳基、任选取代的5-10元杂芳基，所述任选取代 是指被取代基团上的氢未被取代或被取代基团的一个或多个可取代位点上的氢独立地被选自卤素、羟基、氨基、硝基、氧代基、氰基、C 1-6烷基、C 1-6烷氧基的取代基所取代；
Y独立地选自N或CR 4；
R 4独立地选自氢、卤素、羟基、氨基、氰基、任选取代的C 1-6烷基、任选取代的C 1-6烷氧基，所述任选取代是指被取代基团上的氢未被取代或被取代基团的一个或多个可取代位点独立地被选自卤素、羟基、氨基、氰基、C 1～6烷基、C 1-6烷氧基所取代；
R 6独立地选自氢或氘；
所述“氧代基”是指相同取代位的两个H被同一个O替代形成双键；
所述杂环烷基、杂芳基、杂环基中的杂原子独立地选自O、N或S，杂原子数量为1个、2个、3个或4个。
在本申请的又一个实施方案中，提供了一种式(I)所示的化合物，或其前药、互变异构体、立体异构体、溶剂化物、同位素衍生物或其药学上可接受的盐，其具有如下结构：
Figure PCTCN2022094255-appb-000003
其中，
X选自O、CH 2、NH或S；
L选自N或CH；
G选自键或S；
A选自CH或N；
R 3独立地选自：氨基、任选取代的8-12元杂环基、任选取代的C 6-10芳基、任选取代的5-14元杂芳基，其中所述任选取代是指被取代基团上的氢未被取代或被取代基团的一个或多个可取代位点上的氢独立地被选自卤素、羟基、氨基、硝基、氧代基、氰基、-COOH、-COCH 3、-COOCH 3、-CONH 2、C 1-6烷基、C 1-6烷氧基、C 3-10环烷基、3-10元杂环烷基、C 6-10芳基、5-12元杂芳基的取代基所取代；
R 1独立地选自氢、氘或氨基；
R 2独立地选自氢、卤素、氰基、-CONH 2、-COR 5、-COOR 5、任选取代的C 1-6烷基、任选取代的C 2-6烯基、任选取代的C 2-6炔基、任选取代的C 3-10环烷基、任选取代的3-10元杂环烷基，其中，R 5独立地选自氢、任选取代的C 1-6烷基、任选取代的C 3-6环烷基、任选取代的3-6元杂环烷基、任选取代的C 6-10芳基、任选取代的5-10元杂芳基，所述任选取代是指被取代基团上的氢未被取代或被取代基团的一个或多个可取代位点上的氢独立地被选自卤素、羟基、氨基、硝基、氧代基、氰基、C 1-6烷基、C 1-6烷氧基的取代基所取代；
Y独立地选自N或CR 4；
R 4独立地选自氢、卤素、羟基、氨基、氰基、任选取代的C 1-6烷基、任选取代的C 1-6烷氧基，所述任选取代是指被取代基团上的氢未被取代或被取代基团的一个或多个可取代位点上的氢独立地被选自卤素、羟基、氨基、氰基、C 1～6烷基、C 1-6烷氧基的取代基所取代；
R 6独立地选自氢或氘；
所述“氧代基”是指相同取代位的两个H被同一个O替代形成双键；
所述杂环烷基、杂芳基、杂环基中的杂原子独立地选自O、N或S，杂原子数量为1个、2个、3个或4个。
在本申请的又一个实施方案中，R 6为氘。
在本申请的另一个实施方案中，提供一种式(I-1)所示的化合物，或其前药、互变异构体、立体异构体、溶剂化物、同位素衍生物或其药学上可接受的盐，其具有如下结构：
Figure PCTCN2022094255-appb-000004
其中，
X选自O、CH 2、NH或S；
L选自N或CH；
G选自键或S；
A选自CH或N；
R 3独立地选自任选取代的8-12元杂环基、任选取代的C 6-10芳基、任选取代的5-14元杂芳基，所述任选取代是指被取代基团上的氢未被取代或被取代基团的一个或多个可取代位点上的氢独立地被选自卤素、羟基、氨基、硝基、氧代基、氰基、-COOH、-COCH 3、-COOCH 3、-CONH 2、C 1-6烷基、C 1-6烷氧基、C 3-10环烷基、3-10元杂环烷基、C 6-10芳基、5-12元杂芳基的取代基所取代；
R 1独立地选自氢、氘或氨基；
R 2独立地选自氢、卤素、氰基、-CONH 2、-COR 5、-COOR 5、任选取代的C 1-6烷基、任选取代的C 2-6烯基、任选取代的C 2-6炔基、任选取代的C 3-10环烷基、任选取代的3-10元杂环烷基，其中，R 5独立地选自氢、任选取代的C 1-6烷基、任选取代的C 3-6环烷基、任选取代的3-6元杂环烷基、任选取代的C 6-10芳基、任选取代的5-10元杂芳基，所述任选取代是指被取代基团上的氢未被取代或被取代基团的一个或多个可取代位点上的氢独立地被选自卤素、羟基、氨基、硝基、氧代基、氰基、C 1-6烷基、C 1-6烷氧基的取代基所取代；
Y独立地选自N或CR 4；
R 4独立地选自氢、卤素、羟基、氨基、氰基、任选取代的C 1-6烷基、任选取代的C 1-6烷氧基，其中所述任选取代是指被取代基团上的氢未被取代或被取代基团的一个或多个可取代位点上的氢独立地被选自卤素、羟基、氨基、氰基、C 1～6烷基、C 1-6烷氧基的取代基所取代；
所述“氧代基”是指相同取代位的两个H被同一个O替代形成双键；
上述杂环烷基、杂芳基、杂环基中的杂原子独立地选自O、N或S，杂原子数量为1个、2个、3个或4个；
其中该化合物不是：
Figure PCTCN2022094255-appb-000005
在本申请的另一个实施方案中，提供具有如式(I-1-1)所示结构的化合物，或其前药、互变异构体、立体异构体、溶剂化物、同位素衍生物或其药学上可接受的盐，
Figure PCTCN2022094255-appb-000006
其中，G、A、Y、R 1、R 2、R 3、X和L的定义同本申请上述式(I)或式(I-1)所示化合物所述。
在本申请的某些实施方案中，提供了如上述所示式(I)化合物、式(I-1)化合物、式(I-1-1)化合物、或其前药、互变异构体、立体异构体、溶剂化物、同位素衍生物或其药学上可接受的盐，其中，所述R 3为氨基。
在本申请的某些实施方案中，提供了如上述所示式(I)化合物、式(I-1)化合物、式(I-1-1)化合物、或其前药、互变异构体、立体异构体、溶剂化物、同位素衍生物或其药学上可接受的盐，其中，所述R 3独立地选自：任选取代的8-12元杂环基、任选取代的C 6-10芳基、任选取代的5-14元杂芳基。
在本申请的某些实施方案中，所述式(I)化合物、式(I-1)化合物、式(I-1-1)化合物中的R 3独立地选自：任选取代的8-12元双环杂环基、任选取代的C 6-10芳基、任选取代的5-14元杂芳基，其中所述任选取代是指被取代基团上的氢未被取代或被取代基团的一个或多个可取代位点上的氢独立地被选自卤素、羟基、氨基、硝基、氧代基、氰基、-COOH、-COCH 3、-COOCH 3、-CONH 2、C 1-6烷基、C 1-6烷氧基、C 3-10环烷基、3-10元杂环烷基、C 6-10芳基、5-12元杂芳基的取代基所取代。
在本申请的某些实施方案中，所述式(I)化合物、式(I-1)化合物、式(I-1-1)化合物中的R 3独立地选自任选取代的8-10元双环杂环基、任选取代的C 6-8芳基、任选取代的5-10元杂芳基，其中所述任选取代是指被取代基团上的氢未被取代或被取代基团的一个或多个可取代位点上的氢独立地被选自卤素、羟基、氨基、硝基、氧代基、氰基、-COOH、-COCH 3、-COOCH 3、-CONH 2、C 1-6烷基、C 1-6烷氧基、C 3-10环烷基、3-10元杂环烷基、C 6-10芳基、5-12元杂芳基的取代基所取代。
在本申请的某些实施方案中，所述式(I)化合物、式(I-1)化合物、式(I-1-1)化合物中的R 3独立地选自任选取代的8-10元双环杂环基、任选取代的C 6-8芳基、任选取代的5-10元杂芳基，其中所述任选取代是指被取代基团上的氢未被取代或被取代基团的一个或多个可取代位点上的氢独立地被选自卤素、羟基、氨基、氧代基、氰基、-CONH 2、C 1-6烷基的取代基所取代。
在本申请的某些实施方案中，所述式(I)化合物、式(I-1)化合物、式(I-1-1)化合物中的R 3独立地选自任选取代的10元双环杂环基、任选取代的C 6-8芳基、任选取代的5-10元杂芳基，其中所述任选取代是指被取代基团上的氢未被取代或被取代基团的一个或多个可取代位点上的氢独立地被选自羟基、氧代基、氰基、-CONH 2、甲基、乙基、正丙基、异丙基、正丁基的取代基所取代，其中所述杂环基、杂芳基中的杂原子独立地选自O、N或S，杂原子数量为1个、2个或3个。
在本申请的某些实施方案中，所述式(I)化合物、式(I-1)化合物、式(I-1-1)化合物中的R 3独立地选自任选取代的C 6-8芳基、任选取代的5-6元杂芳基，其中所述任选取代是指被取代基团上的氢未被取代或被取代基团的一个或多个可取代位点上的氢独立地被选自卤素、羟基、氨基、氧代基、氰基、-CONH 2、C 1-6烷基的取代基所取代，其中所述杂芳基中的杂原子独立地选自O、N或S，杂原子数量为1个或2个。
在本申请的某些实施方案中，所述式(I)化合物、式(I-1)化合物、式(I-1-1)化合物中的R 3独立地选自任选取代的苯基、任选取代的5-6元杂芳基，其中所述任选取代是指被取代基团上的氢未被取代或被取代基团的一个或多个可取代位点上的氢独立地被选自氰基、-CONH 2、甲基的取代基所取代，其中所述杂芳基中的杂原子独立地选自O、N或S，杂原子数量为1个或2个。
在本申请的某些实施方案中，所述式(I)化合物、式(I-1)化合物、式(I-1-1)化合物中的R 3独立地选自：任选取代的C 6-10芳基、任选取代的5-14元杂芳基，其中所述任选取 代是指被取代基团上的氢未被取代或被取代基团的一个或多个可取代位点上的氢独立地被选自卤素、羟基、氨基、硝基、氧代基、氰基、-COOH、-COCH 3、-COOCH 3、-CONH 2、C 1-6烷基、C 1-6烷氧基、C 3-10环烷基、3-10元杂环烷基、C 6-10芳基、5-12元杂芳基的取代基所取代。
在本申请的某些实施方案中，所述式(I)化合物、式(I-1)化合物、式(I-1-1)化合物中的R 3独立地选自任选取代的5-10元杂芳基，其中所述任选取代是指被取代基团上的氢未被取代或被取代基团的一个或多个可取代位点上的氢独立地被选自卤素、羟基、氨基、氧代基、氰基、-CONH 2、C 1-6烷基的取代基所取代。
在本申请的某些实施方案中，所述式(I)化合物、式(I-1)化合物、式(I-1-1)化合物中的R 3独立地选自任选取代的5-6元杂芳基，其中所述任选取代是指被取代基团上的氢未被取代或被取代基团的一个或多个可取代位点上的氢独立地被选自卤素、羟基、氨基、氰基、-CONH 2、C 1-6烷基的取代基所取代，其中所述杂芳基中的杂原子独立地选自O、N或S，杂原子数量为1个或2个。
在本申请的某些实施方案中，所述式(I)化合物、式(I-1)化合物、式(I-1-1)化合物中的R 3独立地选自任选取代的5-6元杂芳基，其中所述任选取代是指被取代基团上的氢未被取代或被取代基团的一个或多个可取代位点上的氢独立地被选自卤素、羟基、氨基、氰基、-CONH 2、C 1-3烷基的取代基所取代，其中所述杂芳基中的杂原子独立地选自O、N或S，杂原子数量为1个或2个。
在本申请的某些实施方案中，所述式(I)化合物、式(I-1)化合物、式(I-1-1)化合物中的R 3独立地选自任选取代的5元杂芳基，其中所述任选取代是指被取代基团上的氢未被取代或被取代基团的一个或多个可取代位点上的氢独立地被选自羟基、氰基、-CONH 2、甲基的取代基所取代，其中所述杂芳基中的杂原子独立地选自O、N或S，杂原子数量为1个或2个。
在本申请的某些实施方案中，所述式(I)化合物、式(I-1)化合物、式(I-1-1)化合物中的R 3独立地选自任选取代的下述结构：
Figure PCTCN2022094255-appb-000007
在本申请的某些实施方案中，所述式(I)化合物、式(I-1)化合物、式(I-1-1)化合物中的R 3独立地选自任选取代的下述结构：
Figure PCTCN2022094255-appb-000008
在本申请的某些实施方案中，所述式(I)化合物、式(I-1)化合物、式(I-1-1)化合物中的R 3独立地选自任选取代的下述结构：
Figure PCTCN2022094255-appb-000009
在本申请的某些实施方案中，所述式(I)化合物、式(I-1)化合物、式(I-1-1)化合物中的R 3独立地选自氨基、任选取代的
Figure PCTCN2022094255-appb-000010
在本申请的某些实施方案中，所述式(I)化合物、式(I-1)化合物、式(I-1-1)化合物中的R 3独立地选自任选取代的
Figure PCTCN2022094255-appb-000011
在本申请的某些实施方案中，在所述式(I)化合物、式(I-1)化合物、式(I-1-1)化合物中的R 3独立地选自下述结构：
Figure PCTCN2022094255-appb-000012
在本申请的某些实施方案中，所述式(I)化合物、式(I-1)化合物、式(I-1-1)化合物中的R 3独立地选自下述结构：
Figure PCTCN2022094255-appb-000013
在本申请的某些实施方案中，提供了上述所示的式(I)化合物、式(I-1)化合物、式(I-1-1)化合物)或其前药、互变异构体、立体异构体、溶剂化物、同位素衍生物或其药学上可接受的盐，其中，R 2独立地选自卤素、氰基、-CONH 2、-COR 5、-COOR 5、任选取代的C 1-6烷基、任选取代的C 2-6烯基、任选取代的C 2-6炔基、任选取代的C 3-10环烷基、任选取代的3-10元杂环烷基，其中，R 5独立地选自氢、任选取代的C 1-6烷基、任选取代的C 3-6环烷基、任选取代的3-6元杂环烷基、任选取代的C 6-10芳基、任选取代的5-10元杂芳基，所述任选取代是指被取代基团上的氢未被取代或被取代基团的一个或多个可取代位点上的氢独立地被选自卤素、羟基、氨基、硝基、氧代基、氰基、C 1-6烷基、C 1-6烷氧基的取代基所取代。
在本申请的某些实施方案中，提供了上述所示的式(I)化合物、式(I-1)化合物、式 (I-1-1)化合物)或其前药、互变异构体、立体异构体、溶剂化物、同位素衍生物或其药学上可接受的盐，其中，R 2独立地选自氢、卤素、氰基、-CONH 2、-COR 5、-COOR 5、任选取代的C 1-6烷基、任选取代的C 2-6烯基、任选取代的C 3-10环烷基、任选取代的3-10元杂环烷基，其中所述任选取代是指被取代基团上的氢未被取代或被取代基团的一个或多个可取代位点上的氢独立地被选自卤素、羟基、氨基、硝基、氧代基、氰基、C 1-6烷基、C 1-6烷氧基的取代基所取代。
在本申请的某些实施方案中，所述式(I)化合物、式(I-1)化合物、式(I-1-1)化合物中的R 2独立地选自氢、卤素、氰基、-CONH 2、-COR 5、-COOR 5、任选取代的C 1-4烷基、任选取代的C 2-6烯基、任选取代的C 3-6环烷基、任选取代的3-6元杂环烷基，其中所述任选取代是指被取代基团上的氢未被取代或被取代基团的一个或多个可取代位点上的氢独立地被选自卤素、羟基、氨基、硝基、氧代基、氰基、C 1-6烷基、C 1-6烷氧基的取代基所取代。
在本申请某些特定的实施方案中，在所述式(I)化合物、式(I-1)化合物、式(I-1-1)化合物中，R 2独立地选自卤素、氰基、-CONH 2、-COR 5、-COOR 5、被选自羟基、C 1-6烷氧基和卤素中的一个或多个取代基取代的C 1-4烷基、C 2-6烯基、C 3-6环烷基或3-6元杂环烷基。
在本申请的某些实施方案中，所述式(I)化合物、式(I-1)化合物、式(I-1-1)化合物中的R 2独立地选自卤素、氰基、-CONH 2、-COR 5、-COOR 5、羟基取代的C 1-4烷基、C 2-6烯基、C 3-6环烷基、3-6元杂环烷基。在本申请的某些实施方案中，所述式(I)化合物、式(I-1)化合物、式(I-1-1)化合物中的R 2独立地选自卤素、-COR 5、-COOR 5、羟基取代的C 1-4烷基、C 2-6烯基或3-6元杂环烷基；或者，R 2独立地选自卤素、-COR 5、-COOR 5、C 2-6烯基或3-6元杂环烷基；或者，R 2独立地选自-COR 5或-COOR 5；或者，R 2为-COR 5或R 2为-COOR 5，其中优选地，R 5为C 3-6环烷基或C 1-6烷基，优选C 3-4环烷基或C 1-3烷基，例如环丙基、甲基；或者，R 2独立地选自-CO(C 1-6烷基)；或者，R 2独立地选自-CO(C 1-3烷基)。
在本申请的某些实施方案中，所述式(I)化合物、式(I-1)化合物、式(I-1-1)化合物中的R 5独立地选自氢、任选取代的C 1-6烷基、任选取代的C 3-6环烷基、任选取代的3-6元杂环烷基，其中所述任选取代是指被取代基团上的氢未被取代或被取代基团的一个或多个可取代位点上的氢独立地被选自卤素、羟基、氨基、硝基、氧代基、氰基、C 1-6烷基、C 1-6烷氧基的取代基所取代。
在本申请的某些实施方案中，所述式(I)化合物、式(I-1)化合物、式(I-1-1)化合物中的R 5独立地选自氢、任选取代的C 1-6烷基、任选取代的C 3-6环烷基、任选取代的3-6元杂环烷基，所述任选取代是指被取代基团上的氢未被取代或被取代基团的一个或多个可取代位点上的氢独立地被选自卤素、羟基、氨基、C 1-6烷基的取代基所取代。
在本申请的某些实施方案中，所述式(I)化合物、式(I-1)化合物、式(I-1-1)化合物中的R 5独立地选自氢、C 1-6烷基、C 3-6环烷基、3-6元杂环烷基；进一步地，R 5独立地选自C 1-3烷基、C 3-6环烷基；或者R 5独立地选自C 1-3烷基，例如甲基。
在本申请的某些实施方案中，提供了式(I)化合物、式(I-1)化合物、式(I-1-1)化合物或其前药、互变异构体、立体异构体、溶剂化物、同位素衍生物或其药学上可接受的盐，其中，R 2独立地选自卤素、氰基、-CONH 2、-CO-(C 1-3烷基)、-CO-(C 3-6环烷基)、-COO-(C 1-3烷基)、-COO-(C 3-6环烷基)、-CH 2OH、-CH 2CH 2OH、-CH(OH)CH 3、C 2-6烯基、C 3-6环烷基、3-6元杂环烷基。
在本申请的某些实施方案中，所述式(I)化合物、式(I-1)化合物、式(I-1-1)化合物中的R 2独立地选自卤素、-CO-(C 1-3烷基)、-CO-(C 3-6环烷基)、-COO-(C 1-3烷基)、-COO-(C 3-6环烷基)、-CH 2OH、C 2-4烯基、3-6元杂环烷基。
在本申请的某些实施方案中，所述式(I)化合物、式(I-1)化合物、式(I-1-1)化合物中的R 2独立地选自卤素、-C(O)CH 3、-C(O)-(环丙烷)、-C(O)OCH 3、-C(O)O-(环丙烷)、-CH 2OH、乙烯基、氧杂环丁烷基。
在本申请的某些实施方案中，所述式(I)化合物、式(I-1)化合物、式(I-1-1)化合物中的R 2独立地选自氢、氟、-C(O)CH 3、-C(O)OCH 3、-CH 2OH、-CH＝CH 2、
Figure PCTCN2022094255-appb-000014
在本申请的某些实施方案中，所述式(I)化合物、式(I-1)化合物、式(I-1-1)化合物中的R 2独立地选自氟、-C(O)CH 3、-C(O)OCH 3、-CH＝CH 2、
Figure PCTCN2022094255-appb-000015
在本申请的某些实施方案中，所述式(I)化合物、式(I-1)化合物、式(I-1-1)化合物中的R 2独立地选自-C(O)CH 3或-C(O)OCH 3。
在本申请的某些实施方案中，所述式(I)化合物、式(I-1)化合物、式(I-1-1)化合物中的R 2为-C(O)CH 3。
在本申请的某些优选实施方案中，提供了式(I)化合物、式(I-1)化合物、式(I-1-1)化合物或其前药、互变异构体、立体异构体、溶剂化物、同位素衍生物或其药学上可接受的盐，其中，R 1独立地选自氢、氨基；优选地，R 1独立地选自氨基。
在本申请的一个实施方案中，提供了具有式(I-2)所示结构的化合物或其前药、互变异构体、立体异构体、溶剂化物、同位素衍生物或其药学上可接受的盐，
Figure PCTCN2022094255-appb-000016
其中，R 1独立地选自氘或氨基，优选为氨基；
R 2独立地选自氰基、-CONH 2、-COR 5、-COOR 5、任选取代的C 1-6烷基、任选取代的C 2-6烯基、任选取代的C 2-6炔基、任选取代的C 3-10环烷基、任选取代的3-10元杂环烷基，其中，R 5独立地选自氢、任选取代的C 1-6烷基、任选取代的C 3-6环烷基、任选取代的3-6元杂环烷基、任选取代的C 6-10芳基、任选取代的5-10元杂芳基，所述任选取代是指被取代基团上的氢未被取代或被取代基团的一个或多个可取代位点上的氢独立地被选自卤素、羟基、氨基、硝基、氧代基、氰基、C 1-6烷基、C 1-6烷氧基的取代基所取代；
R 6为氢或氘，优选为氘；
X、L、G、A、Y定义同本申请上述式(I)或式(I-1)化合物所述。
在本申请的一个实施方案中，提供了如式(I-2)所示的化合物或其前药、互变异构体、立体异构体、溶剂化物、同位素衍生物或其药学上可接受的盐，其中，R 2独立地选自氢、卤素、氰基、-CONH 2、-COR 5、-COOR 5、任选取代的C 1-6烷基、任选取代的C 2-6烯基、任选取代的C 3-10环烷基、任选取代的3-10元杂环烷基，其中所述任选取代是指被取代基团上的氢未被取代或被取代基团的一个或多个可取代位点上的氢独立地被选自卤素、羟基、氨基、硝基、氧代基、氰基、C 1-6烷基、C 1-6烷氧基的取代基所取代。
在本申请的一个实施方案中，式(I-2)所示的化合物中的R 2独立地选自氰基、-CONH 2、-COR 5、-COOR 5、任选取代的C 1-4烷基、任选取代的C 2-6烯基、任选取代的C 3-6环烷基、任选取代的3-6元杂环烷基，其中所述任选取代是指被取代基团上的氢未被取 代或被取代基团的一个或多个可取代位点上的氢独立地被选自卤素、羟基、氨基、硝基、氧代基、氰基、C 1-6烷基、C 1-6烷氧基的取代基所取代。
在本申请的又一个实施方案中，式(I-2)所示的化合物中的R 2独立地选自氰基、-CONH 2、-COR 5、-COOR 5、羟基取代的C 1-4烷基、C 2-6烯基、C 3-6环烷基、3-6元杂环烷基。
在本申请的另一个实施方案中，式(I-2)所示结构的化合物或其前药、互变异构体、立体异构体、溶剂化物、同位素衍生物或其药学上可接受的盐中的R 2独立地选自氰基、-CONH 2、-COR 5、-COOR 5、未取代的C 2-6烷基、取代的C 1-6烷基、任选取代的C 2-6烯基、任选取代的C 2-6炔基、任选取代的C 3-10环烷基、任选取代的3-10元杂环烷基，其中所述任选取代是指被取代基团上的氢未被取代或被取代基团的一个或多个可取代位点上的氢独立地被选自卤素、羟基、氨基、硝基、氧代基、氰基、C 1-6烷基、C 1-6烷氧基的取代基所取代；或者
R 2独立地选自氰基、-CONH 2、-COR 5、-COOR 5、取代的C 1-6烷基、任选取代的C 2-6烯基、任选取代的C 3-6环烷基、任选取代的3-6元杂环烷基，其中所述任选取代是指被取代基团上的氢未被取代或被取代基团的一个或多个可取代位点上的氢独立地被选自卤素、羟基、氨基、硝基、氧代基、氰基、C 1-6烷基、C 1-6烷氧基的取代基所取代；或者
R 2独立地选自氰基、-CONH 2、-COR 5、-COOR 5、被选自羟基、卤素和C 1-C 3烷氧基中的一个或多个取代基取代的C 1-6烷基、C 2-6烯基、C 3-6环烷基、3-6元杂环烷基；或者
当R 1为氘时，R 2选自-CO-(C 3-6环烷基)、-COOR 5、任选取代的C 2-6烯基、任选取代的C 2-6炔基、任选取代的C 3-10环烷基、任选取代的3-10元杂环烷基，其中所述任选取代是指被取代基团上的氢未被取代或被取代基团的一个或多个可取代位点上的氢独立地被选自卤素、羟基、氨基、硝基、氧代基、氰基、C 1-6烷基、C 1-6烷氧基的取代基所取代；或者
当R 1为氘时，R 2选自-CO-(C 3-6环烷基)、-COOR 5、任选取代的C 2-6烯基、任选取代的C 3-6环烷基、任选取代的3-6元杂环烷基，其中所述任选取代是指被取代基团上的氢未被取代或被取代基团的一个或多个可取代位点上的氢独立地被选自卤素、羟基、氨基、硝基、氧代基、氰基、C 1-6烷基、C 1-6烷氧基的取代基所取代；或者
当R 1为氘时，R 2选自-CO-(C 3-6环烷基)、-COOR 5、C 2-6烯基、C 3-6环烷基、3-6元杂环烷基。
在本申请式(I-2)所示结构化合物的一个实施方案中，当R 1为氘时，R 2可以为卤素。
在本申请的某些实施方案中，在具有式(I-2)所示结构的化合物或其前药、互变异构体、立体异构体、溶剂化物、同位素衍生物或其药学上可接受的盐中，R 1可以为氢；R 2独立地选自卤素、-CO-(C 3-C 6环烷基)、-COOR 5、任选取代的C 2-6烯基、任选取代的C 2-6炔基、任选取代的C 3-10环烷基、任选取代的3-10元杂环烷基，其中所述任选取代是指被取代基团上的氢未被取代或被取代基团的一个或多个可取代位点上的氢独立地被选自卤素、羟基、氨基、硝基、氧代基、氰基、C 1-6烷基、C 1-6烷氧基的取代基所取代；或者
R 1可以为氢；R 2独立地选自卤素、-CO-(C 3-C 6环烷基)、-COOR 5、任选取代的C 2-6烯基、任选取代的C 3-6环烷基、任选取代的3-6元杂环烷基，其中所述任选取代是指被取代基团上的氢未被取代或被取代基团的一个或多个可取代位点上的氢独立地被选自卤素、羟基、氨基、硝基、氧代基、氰基、C 1-6烷基、C 1-6烷氧基的取代基所取代；或者
R 1可以为氢；R 2独立地选自卤素、-CO-(C 3-C 6环烷基)、-COOR 5、C 2-6烯基、C 3-6环 烷基、3-6元杂环烷基。
在本申请的一个实施方案中，上述式(I-2)所示的化合物中的R 5独立地选自氢、任选取代的C 1-6烷基、任选取代的C 3-6环烷基、任选取代的3-6元杂环烷基，其中所述任选取代是指被取代基团上的氢未被取代或被取代基团的一个或多个可取代位点上的氢独立地被选自卤素、羟基、氨基、硝基、氧代基、氰基、C 1-6烷基、C 1-6烷氧基的取代基所取代。
在本申请的一个实施方案中，上述式(I-2)所示的化合物中的R 5独立地选自氢、任选取代的C 1-6烷基、任选取代的C 3-6环烷基、任选取代的3-6元杂环烷基，其中所述任选取代是指被取代基团上的氢未被取代或被取代基团的一个或多个可取代位点上的氢独立地被选自卤素、羟基、氨基、C 1-6烷基的取代基所取代。
在本申请的一个实施方案中，上述式(I-2)所示的化合物中的R 5独立地选自氢、C 1-6烷基、C 3-6环烷基、3-6元杂环烷基。
在本申请的一个实施方案中，上述式(I-2)所示的化合物中的R 5独立地选自C 1-3烷基、C 3-6环烷基；或者R 5为C 1-3烷基；或者R 5为C 3-6环烷基。
在本申请的一个实施方案中，提供了如式(I-2)所示的化合物或其前药、互变异构体、立体异构体、溶剂化物、同位素衍生物或其药学上可接受的盐，其中，R 2独立地选自氰基、-CONH 2、-CO-(C 1-3烷基)、-CO-(C 3-6环烷基)、-COO-(C 1-3烷基)、-COO-(C 3-6环烷基)、-CH 2OH、-CH 2CH 2OH、-CH(OH)CH 3、C 2-6烯基、C 3-6环烷基、3-6元杂环烷基；
优选地，R 2独立地选自-CO-(C 1-3烷基)、-CO-(C 3-6环烷基)、-COO-(C 1-3烷基)、-COO-(C 3-6环烷基)、-CH 2OH、C 2-4烯基、3-6元杂环烷基；
进一步优选地，R 2独立地选自-C(O)CH 3、-C(O)-(环丙烷)、-C(O)OCH 3、-C(O)O-(环丙烷)、-CH 2OH、乙烯基、氧杂环丁烷基；
进一步优选地，R 2独立地选自-C(O)CH 3、-C(O)OCH 3、-CH 2OH、-CH＝CH 2、
Figure PCTCN2022094255-appb-000017
进一步优选地，R 2独立地选自-C(O)CH 3、-C(O)OCH 3、-CH＝CH 2、
Figure PCTCN2022094255-appb-000018
在本申请的一个实施方案中，提供了如式(I-2)所示的化合物或其前药、互变异构体、立体异构体、溶剂化物、同位素衍生物或其药学上可接受的盐，其中，R 2独立地选自-CO-(C 1-6烷基)、-COO-(C 1-6烷基)；
优选地，R 2独立地选自-CO-(C 1-3烷基)、-COO-(C 1-3烷基)；
进一步优选地，R 2独立地选自-C(O)CH 3、-C(O)OCH 3；
进一步优选地，R 2独立地选自-C(O)CH 3。
在本申请的一个实施方案中，提供了如式(I-2)所示的化合物或其前药、互变异构体、立体异构体、溶剂化物、同位素衍生物或其药学上可接受的盐，其中，L选自CH，X选自O；
优选地，L选自CH，X选自O，G选自S。
在本申请的一个实施方案中，提供了如式(I-2)所示的化合物或其前药、互变异构体、立体异构体、溶剂化物、同位素衍生物或其药学上可接受的盐，其中，R 1独立地选自氨基，R 2独立地选自-CO-(C 1-6烷基)、-COO-(C 1-6烷基)，L选自CH，X选自O。
在本申请的一个实施方案中，提供了如式(I-2)所示的化合物或其前药、互变异构体、立体异构体、溶剂化物、同位素衍生物或其药学上可接受的盐，其中，R 1独立地选自氨基，R 2独立地选自-CO-(C 1-6烷基)、-COO-(C 1-6烷基)，L选自CH，R 6独立地选自氘；
优选地，R 1独立地选自氨基，R 2独立地选自-CO-(C 1-3烷基)、-COO-(C 1-3烷基)，R 6选自氘，L选自CH，X选自O，G选自S。
在本申请的某些实施方案中，提供了式(I)化合物、式(I-1)化合物、式(I-1-1)化合物、式(I-2)化合物或其前药、互变异构体、立体异构体、溶剂化物、同位素衍生物或其药学上可接受的盐，其中，X选自O或CH 2；优选地，X选自O。
在本申请的某些实施方案中，提供了式(I)化合物、式(I-1)化合物、式(I-1-1)化合物、式(I-2)化合物或其前药、互变异构体、立体异构体、溶剂化物、同位素衍生物或其药学上可接受的盐，其中，所述化合物具有如式(I-A)、(I-B)、(I-1-A)、(I-1-B)、(I-2-A)或(I-2-B)所示的结构：
Figure PCTCN2022094255-appb-000019
其中，L、G、A、Y、R 1、R 2、R 3、R 6定义同本申请上述式(I)、式(I-1)或式(I-2)所示化合物所述。
在本申请的某些实施方案中，提供了式(I)化合物、式(I-1)化合物、式(I-1-1)化合物、式(I-2)化合物或其前药、互变异构体、立体异构体、溶剂化物、同位素衍生物或其药学上可接受的盐，其中，L选自CH。
在本申请的某些实施方案中，提供了化合物(式(I)化合物、式(I-1)化合物、式(I-1-1)化合物、式(I-2)化合物)或其前药、互变异构体、立体异构体、溶剂化物、同位素衍生物或其药学上可接受的盐，其中，所述化合物具有如式(I-A1)、(I-1-A1)或(I-2-A1)所示的结构：
Figure PCTCN2022094255-appb-000020
Figure PCTCN2022094255-appb-000021
其中，G、A、Y、R 1、R 2、R 3、R 6定义同本申请上述式(I)、式(I-1)或式(I-2)所示化合物所述。
在本申请某些的实施方案中，所述化合物具有如式(I-A2)、(I-A3)、(I-2-A2)或(I-2-A3)所示的结构：
Figure PCTCN2022094255-appb-000022
其中，G、A、Y、R 1、R 2、R 3定义同本申请上述式(I)、式(I-1)或式(I-2)所示化合物所述。
在本申请的某些实施方案中，提供了式(I)化合物、式(I-1)化合物、式(I-1-1)化合物、式(I-2)化合物或其前药、互变异构体、立体异构体、溶剂化物、同位素衍生物或其药学上可接受的盐，其中，所述化合物具有如式(I-Ba)所示的结构：
Figure PCTCN2022094255-appb-000023
其中，G、A、Y、R 1、R 2、R 3定义同本申请上述式(I)、式(I-1)或式(I-2)所示化合物所述。
在本申请的某些实施方案中，提供了化合物(式(I)化合物、式(I-1)化合物、式(I-1-1)化合物、式(I-2)化合物)或其前药、互变异构体、立体异构体、溶剂化物、同位素衍生物或其药学上可接受的盐，其中，所述化合物具有如式(I-B1)、式(I-1-B1)或式(I-2-B1)所示的结构：
Figure PCTCN2022094255-appb-000024
其中，G、A、Y、R 2、R 3、R 6定义同本申请上述式(I)、式(I-1)或式(I-2)所示化合物所述。
在本申请的某些实施方案中，所述化合物具有如式(I-B2)、(I-B3)、式(I-2-B2)或式(I-2-B3)所示的结构：
Figure PCTCN2022094255-appb-000025
其中，G、A、Y、R 2、R 3定义同本申请上述式(I)、式(I-1)或式(I-2)所示化合物所述。
在本申请的某些实施方案中，提供了化合物(式(I)化合物、式(I-1)化合物、式(I-1-1)化合物、式(I-2)化合物、式(I-A1)化合物、式(I-1-A1)化合物、式(I-2-A1)化合物、式(I-A2)化合物、式(I-A3)化合物、式(I-2-A2)化合物、式(I-2-A3)化合物、式(I-B1)化合物、式(I-1-B1)化合物、式(I-2-B1)化合物、式(I-B2)化合物、式(I-B3)化合物、式(I-2-B2)化合物、式(I-2-B3)化合物、式(I-A)化合物、式(I-B)化合物、式(I-1-A)化合物、式(I-1-B)化合物、式(I-2-A)化合物、式(I-2-B)化合物、式(I-Ba)化合物)或其前药、互变异构体、立体异构体、溶剂化物、同位素衍生物或其药学上可接受的盐，其中，G选自S。
在本申请的某些实施方案中，提供了化合物(式(I)化合物、式(I-1)化合物、式(I-1-1)化合物、式(I-2)化合物、式(I-A1)化合物、式(I-1-A1)化合物、式(I-2-A1)化合物、式(I-A2)化合物、式(I-A3)化合物、式(I-2-A2)化合物、式(I-2-A3)化合物、式(I-B1)化合物、式(I-1-B1)化合物、式(I-2-B1)化合物、式(I-B2)化合物、式(I-B3)化合物、式(I-2-B2)化合物、式(I-2-B3)化合物、式(I-A)化合物、式(I-B)化合物、式(I-1-A)化合物、式(I-1-B)化合物、式(I-2-A)化合物、式(I-2-B)化合物、式(I-Ba)化合物)或其前药、互变异构体、立体异构体、溶剂化物、同位素衍生物或其药学上可接受的盐，其中，A选自CH。
在本申请的某些实施方案中，提供了化合物(式(I)化合物、式(I-1)化合物、式(I-1-1)化合物、式(I-2)化合物、式(I-A1)化合物、式(I-1-A1)化合物、式(I-2-A1)化合物、式(I-A2) 化合物、式(I-A3)化合物、式(I-2-A2)化合物、式(I-2-A3)化合物、式(I-B1)化合物、式(I-1-B1)化合物、式(I-2-B1)化合物、式(I-B2)化合物、式(I-B3)化合物、式(I-2-B2)化合物、式(I-2-B3)化合物、式(I-A)化合物、式(I-B)化合物、式(I-1-A)化合物、式(I-1-B)化合物、式(I-2-A)化合物、式(I-2-B)化合物、式(I-Ba)化合物)或其前药、互变异构体、立体异构体、溶剂化物、同位素衍生物或其药学上可接受的盐，其中，A选自N。
在本申请的某些实施方案中，提供了化合物(式(I)化合物、式(I-1)化合物、式(I-1-1)化合物、式(I-2)化合物、式(I-A1)化合物、式(I-1-A1)化合物、式(I-2-A1)化合物、式(I-A2)化合物、式(I-A3)化合物、式(I-2-A2)化合物、式(I-2-A3)化合物、式(I-B1)化合物、式(I-1-B1)化合物、式(I-2-B1)化合物、式(I-B2)化合物、式(I-B3)化合物、式(I-2-B2)化合物、式(I-2-B3)化合物、式(I-A)化合物、式(I-B)化合物、式(I-1-A)化合物、式(I-1-B)化合物、式(I-2-A)化合物、式(I-2-B)化合物、式(I-Ba)化合物)或其前药、互变异构体、立体异构体、溶剂化物、同位素衍生物或其药学上可接受的盐，其中，Y选自CR 4；或者A为CH且Y为CR 4；或者A为N且Y为CR 4；或者A为N且Y为N。
在本申请的某些实施方案中，提供了化合物(式(I)化合物、式(I-1)化合物、式(I-1-1)化合物、式(I-2)化合物、式(I-A1)化合物、式(I-1-A1)化合物、式(I-2-A1)化合物、式(I-A2)化合物、式(I-A3)化合物、式(I-2-A2)化合物、式(I-2-A3)化合物、式(I-B1)化合物、式(I-1-B1)化合物、式(I-2-B1)化合物、式(I-B2)化合物、式(I-B3)化合物、式(I-2-B2)化合物、式(I-2-B3)化合物、式(I-A)化合物、式(I-B)化合物、式(I-1-A)化合物、式(I-1-B)化合物、式(I-2-A)化合物、式(I-2-B)化合物、式(I-Ba)化合物)或其前药、互变异构体、立体异构体、溶剂化物、同位素衍生物或其药学上可接受的盐，其中，R 4独立地选自氢、卤素、羟基、氨基、氰基、任选取代的C 1-6烷基、任选取代的C 1-6烷氧基，其中所述任选取代是指被取代基团上的氢未被取代或被取代基团的一个或多个可取代位点上的氢独立地被选自卤素、羟基、氨基的取代基所取代。
在本申请的一个实施方案中，其中，R 4独立地选自氢、卤素、氨基、氰基、C 1-6烷基、C 1-6烷氧基、C 1-6烷基氨基；进一步优选地，其中，R 4独立地选自氢、氟、氯、氨基、氰基、甲基、甲氧基；进一步优选地，其中，R 4选自氯。
在本申请的一个实施方案中，式(I)化合物中的X选自O或CH 2；L为CH；G为S；A选自CH或N；R 3独立地选自：氨基、任选取代的8-12元杂环基、任选取代的C 6-10芳基、任选取代的5-14元杂芳基，其中所述任选取代是指被取代基团上的氢未被取代或被取代基团的一个或多个可取代位点上的氢独立地被选自羟基、氧代基、氰基、-CONH 2或C 1-6烷基的取代基所取代；R 1独立地选自氢、氘、氨基；R 2独立地选自卤素、-COR 5、-COOR 5、任选取代的C 1-6烷基、任选取代的C 2-6烯基、任选取代的3-10元杂环烷基；其中，R 5独立地选自未取代的C 1-6烷基或未取代的C 3-6环烷基，其中所述任选取代是指被取代基团上的氢未被取代或被取代基团的一个或多个可取代位点上的氢独立地被选自卤素、羟基、C 1-6烷氧基的取代基所取代；Y独立地选自N或CR 4；R 4为卤素；R 6独立地选自氢、氘；或者
X选自O或CH 2；L为CH；G为S；A选自CH或N；R 3独立地选自：氨基、任选取代的8-10元双环杂环基、任选取代的C 6或C 10芳基、任选取代的5-6元杂芳基，其中所述任选取代是指被取代基团上的氢未被取代或被取代基团的一个或多个可取代位点上的氢独立地被选自羟基、氧代基、氰基、-CONH 2或C 1-6烷基的取代基所取代；R 1独立地选自氢、氘、氨基；R 2独立地选自卤素、-COR 5、-COOR 5、任选取代的C 1-6烷基、任选取代的C 2-6烯基、任选取代的3-6元杂环烷基；其中，R 5独立地选自未取代的C 1-6烷基或未取代的C 3-6环烷基，其中所述任选取代是指被取代基团上的氢未被取代或被取代基团的一个或多个可取代位点上的氢独立地被选自卤素、羟基、C 1-6烷氧基的 取代基所取代；Y独立地选自N或CR 4；R 4为卤素；R 6独立地选自氢或氘；或者
X选自O或CH 2；L为CH；G为S；A选自CH或N；R 3独立地选自：氨基、被C 1-6烷基任选取代的5-6元杂芳基；R 1独立地选自氢、氘、氨基；R 2独立地选自卤素、-COR 5、-COOR 5、任选取代的C 2-6烯基、任选取代的3-6元杂环烷基；其中，R 5独立地选自未取代的C 1-6烷基或未取代的C 3-6环烷基，其中所述任选取代是指被取代基团上的氢未被取代或被取代基团的一个或多个可取代位点上的氢独立地被选自卤素、羟基、C 1-6烷氧基的取代基所取代；Y独立地选自N或CR 4；R 4为卤素；R 6独立地选自氢、氘；或者
X选自O或CH 2；L为CH；G为S；A选自CH或N；R 3独立地选自：氨基、被C 1-6烷基任选取代的5-6元杂芳基；R 1独立地选自氢、氘、氨基；R 2独立地选自卤素、-COR 5、-COOR 5、未取代的C 2-6烯基、未取代的3-6元杂环烷基；其中，R 5独立地选自未取代的C 1-6烷基或未取代的C 3-6环烷基；Y独立地选自N或CR 4；R 4为卤素；R 6独立地选自氢、氘；或者
X选自O或CH 2；L为CH；G为S；A选自CH或N；R 3独立地选自：氨基、被C 1-4烷基任选取代的5元杂芳基；R 1独立地选自氢、氘、氨基；R 2独立地选自-COR 5或-COOR 5；其中，R 5独立地选自未取代的C 1-4烷基或未取代的C 3-6环烷基；Y独立地选自N或CR 4；R 4为卤素，例如Cl或F，优选Cl；R 6独立地选自氢、氘；或者
X选自O或CH 2；L为CH；G为S；A为CH时Y为CR 4；R 4为卤素，例如Cl或F，优选Cl；或A为N时Y独立地选自N或CR 4；R 4为卤素，例如Cl或F，优选Cl；R 3独立地选自：氨基、被C 1-2烷基(例如，甲基)任选取代的5元杂芳基；R 1独立地选自氢、氘、氨基；R 2独立地选自-COR 5或-COOR 5；其中，R 5独立地选自未取代的C 1-2烷基(例如，甲基)或未取代的C 3-4环烷基(例如，环丙基)；R 6独立地选自氢或氘。
在本申请的某些实施方案中，如上所述的式(I)化合物、式(I-1)化合物、式(I-1-1)化合物、式(I-2)化合物、式(I-A1)化合物、式(I-1-A1)化合物、式(I-2-A1)化合物、式(I-A2)化合物、式(I-A3)化合物、式(I-2-A2)化合物、式(I-2-A3)化合物、式(I-B1)化合物、式(I-1-B1)化合物、式(I-2-B1)化合物、式(I-B2)化合物、式(I-B3)化合物、式(I-2-B2)化合物、式(I-2-B3)化合物、式(I-A)化合物、式(I-B)化合物、式(I-1-A)化合物、式(I-1-B)化合物、式(I-2-A)化合物、式(I-2-B)化合物、式(I-Ba)化合物均不包括如下化合物：
Figure PCTCN2022094255-appb-000026
Figure PCTCN2022094255-appb-000027
Figure PCTCN2022094255-appb-000028
Figure PCTCN2022094255-appb-000029
Figure PCTCN2022094255-appb-000030
Figure PCTCN2022094255-appb-000031
Figure PCTCN2022094255-appb-000032
另一方面，本申请提供一种式(II)所示的化合物，或其前药、互变异构体、立体异构体、溶剂化物、同位素衍生物或其药学上可接受的盐，其具有如下结构：
Figure PCTCN2022094255-appb-000033
其中，
每个R 1独立地选自氢、氘、卤素、-NH 2、-NHR a、-N(R a) 2、-CN、-OH、-NO 2、氧代、＝O、羧基、-C(O)-NH 2、-C(O)-NHR a、-C(O)R a、-C(O)OR a、C 2-6烯基、C 2-6炔基、-C(O)-C(O)OR a-C 1-6烷氧基、-C 1-6烷基、-C 1-6卤代烷基、-C 3-10环烷基、-C 1-6亚烷 基-N(R a)2、-C 1-6亚烷基-O-C 1-6烷基、-C 1-6亚烷基-C(O)-OR a、-C 1-6亚烷基-(3-10元杂环基)、-C 1-6亚烷基-(5-10元杂芳基)、-C 1-6亚烷基-C(O)-N(R a) 2、-C 1-6亚烷基-NR a-C(O)-N(R a) 2、-C 1-6亚烷基-NR a-C(O)-C 1-6烷基、-C(O)-N(R a) 2、-C(O)-C(O)-N(R a)2、-C 3-10碳环基、-5-10元杂芳基、-3-10元杂环基、-C(O)-C 1-6烷基、-C(O)-C 3-6环烷基、-C(O)-C 6-14芳基、-C(O)-C 5-10杂芳基、-C(O)O-C 1-6烷基、-C(O)-C 1-6亚烷基-N(R a)2、-C(O)-NR a-(3-10元杂环基)、-C(O)-NR a-(3-10元杂环基)、-C(O)-(3-10元杂环基)、-O-C 1-6亚烷基-C(O)-OR a、-O-C 1-6亚烷基-C(O)-N(R a) 2、-O-C 1-6亚烷基-N(R a) 2、-O-C 3-10碳环基、-O-(3-10元杂环基)、-NR a-C(O)-C 1-6烷基、-NR a-C(O)-N(R a) 2、-NR a-C(O)-(5-10元杂芳基)、-NR a-C(O)-(5-10元杂环基)、-NR a-C(O)-C 3-8环烷基、-NR a-C 1-6亚烷基-N(R a) 2、-NR a-C 1-6亚烷基-(3-10元杂环基)、-NR a-C 1-6亚烷基-(5-10元杂芳基)、-NR a-SO 2C 1-6烷基、-S-C 1-6烷基、-SON(R a) 2、-SO 2N(R a) 2、-SO-C 1-6烷基、-SO 2-C 1-6烷基、-PO(C 1-6烷基) 2、-PO(C 1-6烷氧基) 2、-3-10元杂环基、-5-14元芳基或-5-14元杂芳基，每个基团独立地任选地被取代；
或者相邻的两个R 1环合形成C 6-10芳基、5-10元杂芳基、3-10元碳环基或3-10元杂环基，每个基团独立地任选地被取代；
或两个相邻的R a连接在一起形成5-14元芳环、5-14元杂芳环、5-14元杂环或5-14元碳环，且所述每个环系独立地任选地被取代；
每个R a独立地选自氢、氘、卤素、-NH 2、-CN、-OH、-NO 2、羧基、-C 1-6烷氧基、-C 1-6烷基，每个基团独立地任选地被取代；
R 3为氘；
R 2选自：氢、氘、卤素、-NH 2、-CN、-OH、-NO 2、-COOH、-NH-C 1-6烷基、-N(C1-6烷基) 2、-C 1-6烷氧基或-C 1-6烷基，且每个基团独立地任选地被取代或未被取代；
每个R 4和R 5独立地选自氢、氘、卤素、-NH 2、-CN、-OH、-NO 2、-COOH、-NH-C 1-6烷基、-N(C 1-6烷基) 2、-C 1-6烷氧基或-C 1-6烷基，且每个基团独立地任选地被取代或未被取代；或者
R 4和R 5与它们共同连接的碳原子一起形成3-14元碳环、3-14元杂环、5-14元芳环、5-14元杂芳环或C＝NRb，且所述每个环系独立地任选地被取代或未被取代；
W为不存在、-CH 2-、-CH(R b)-、-C(R b) 2-、-C(O)-、-NH-、-NR b-或-O-；
Y为C、CH、-C(R b)-或N；
当Y为CH、-C(R b)-或N时，其相邻的
Figure PCTCN2022094255-appb-000034
为单键；或当Y为C时，其相邻的
Figure PCTCN2022094255-appb-000035
为双键；
每个R b独立地选自氢、氘、卤素、-NH 2、-CN、-OH、-C 1-6烷氧基或-C 1-6烷基，且每个基团独立地任选地被取代或未被取代；
A选自：未被取代或任选被一个或多个R 1取代的芳基、杂芳基、环烷基和杂环基；
B选自：未被取代或任选被一个或多个R 1取代的芳基、杂芳基、环烷基和杂环基；
C为不存在、未被取代或任选被一个或多个R 1取代的芳基、杂芳基、环烷基和杂环基；
当C不存在时，Y 1和Y 2各自独立地选自-C(R 1) 2-、-C(R d) 2-、-NR d-、-NR 1-和O；当
Figure PCTCN2022094255-appb-000036
中的
Figure PCTCN2022094255-appb-000037
表示单键时，Y 1是-C(R 1) 2-、-C(R d) 2-、-NR d-、-NR 1-或O，且Y 2是-C(R 1) 2-、-C(R d) 2-、-NR d-、-NR 1-或O；或者，当
Figure PCTCN2022094255-appb-000038
中的
Figure PCTCN2022094255-appb-000039
表示双键时，Y 1是CR 1、CR d或N，且Y 2是CR 1、CR d或N；
当C是芳环、杂芳环、环烷基或杂环烷基时；当
Figure PCTCN2022094255-appb-000040
中的
Figure PCTCN2022094255-appb-000041
表示单键时，Y 1是CR d、C-R 1或N，且Y 2是CR d或N；或者，当
Figure PCTCN2022094255-appb-000042
中的
Figure PCTCN2022094255-appb-000043
表示双键时， Y 1是C，且Y 2是C；
每个L 1和L 2独立地选自：共价键、-S-、-S(O)-、-S(O) 2-、-O-、-C(O)-、-CO-NR d-、-NR d-、-NR d-C(O)-、-NR d-C(O)-NR d-、-C(O)O-、-NR dSO 2-、-C(R d) 2-、-SO 2NR d-和
Figure PCTCN2022094255-appb-000044
每个R d独立地选自氢、氘、卤素、-NH 2、-CN、-OH、-NO 2、-COOH、-CO-C 1-6烷基、-COO-C 1-6烷基、-C 1-6亚烷基-O-C 1-6烷氧基、-C 1-6烷氧基或-C 1-6烷基，且每个基团独立地任选地被取代或未被取代；
---表示键存在或不存在；且
i)---表示键不存在时，X也不存在；
ii)---表示键存在时，X为CH 2；
每个m、n和q独立地选自0、1、2、3或4；当m为0时，W直接与Y 2相连；
上述取代独立地选自-OH、卤素、未取代的C 1-6烷基、-NH 2、-NO 2、未取代的-COC 1-6烷基、-CN、＝O、-COOH、-COCH 3-、-COOCH 3-、-CONH 2、未取代的C 3-10环烷基、未取代的-NH-C 1-6烷基、未取代的-N(C 1-6烷基)(C 1-6烷基)、未取代的-NH-C 3-6环烷基、未取代的-N(C 3-6环烷基)(C 3-6环烷基)、未取代的3-10元杂环烷基、未取代的C 6-14芳基或未取代的5-12元杂芳基基团中的一个或多个取代基；
取代基“氧代”或“＝O”是指同一取代位置的两个氢原子被氧原子所取代；
上述杂环烷基、杂芳基、杂环基中的杂原子独立地选自O、N或S，杂原子数量为1个、2个、3个或4个。
在本申请的一个实施方案中，在式(II)所示的化合物中，所述A为任选取代或未取代的3-14元环烷基、3-14元杂环烷基、5-14元芳基或5-14元杂芳基；优选为任选取代或未取代的5-12元环烷基、5-12元杂环烷基、5-12元芳基或5-12元杂芳基；进一步优选为任选取代或未取代的6-10元环烷基、6-10元杂环烷基、6-10元芳基或6-10元杂芳基；进一步优选为任选取代或未取代的6-10元芳基或6-10元杂芳基；进一步优选为任选取代或未取代的苯基、8-10元多环芳基、5-6元单环杂芳基或8-10元多环杂芳基；进一步优选为任选取代或未取代的苯基、8-10元稠环芳基、8-10元桥环芳基、8-10元螺环芳基、5-6元单环杂芳基、8-10元稠环杂芳基、8-10元桥环杂芳基或8-10元螺环杂芳基；进一步优选为任选取代或未取代的苯基、8-10元稠环芳基、5-6元单环杂芳基或8-10元稠环杂芳基；其中，上述每个杂芳基或杂环含有1、2或3个独立选自N、O或S的杂原子；
进一步优选地，A选自任选取代或未取代的以下基团：
Figure PCTCN2022094255-appb-000045
进一步优选地，A选自任选取代或未取代的以下基团：
Figure PCTCN2022094255-appb-000046
进一步优选地，A选自任选取代或未取代的以下基团：
Figure PCTCN2022094255-appb-000047
进一步优选地，A选自任选取代或未取代的以下基团：
Figure PCTCN2022094255-appb-000048
其中，所述取代为被一个或多个R 1取代；
Figure PCTCN2022094255-appb-000049
表示与L 2相连接。
在本申请式(II)所示化合物的一个实施方案中，所述L 2选自：共价键、-S-、-S(O)-、-S(O) 2-、-O-、-C(O)-、-NR d-和-C(R d) 2-；优选为共价键、-S-、-O-和-NR d-；进一步优选为共价键和-S-。
在本申请式(II)所示化合物的一个实施方案中，所述B为任选取代或未取代的3-14元环烷基、3-14元杂环烷基、5-14元芳基或5-14元杂芳基；优选为任选取代或未取代的5-12元环烷基、5-12元杂环烷基、5-12元芳基或5-12元杂芳基；进一步优选为任选取代或未取代的6-10元环烷基、6-10元杂环烷基、6-10元芳基或6-10元杂芳基；进一步优选为任选取代或未取代的6-10元芳基或6-10元杂芳基；进一步优选为任选取代或未取代的苯基、8-10元多环芳基、5-6元单环杂芳基或8-10元多环杂芳基；进一步优选为任选取代或未取代的苯基、8-10元稠环芳基、8-10元桥环芳基、8-10元螺环芳基、5-6元单环杂芳基、8-10元稠环杂芳基、8-10元桥环杂芳基或8-10元螺环杂芳基；进一步优选为任选取代或未取代的苯基、8-10元稠环芳基、5-6元单环杂芳基或8-10元稠环杂芳基；其中，上述每个杂芳基或杂环含有1、2或3个独立选自N、O或S的杂原子；
进一步优选地，B选自任选取代或未取代的以下基团：
Figure PCTCN2022094255-appb-000050
其中，
每个Y 3各自独立地选自C(R 1) 2、CR 1、NR 1、N、S和O；
每个Y 4各自独立地选自CR 1和NR 1；
当
Figure PCTCN2022094255-appb-000051
表示单键时，Y 3是C(R 1) 2、NR 1、S和O，且Y 4是CR 1或N；或者，当
Figure PCTCN2022094255-appb-000052
表示双键时，Y 3是CR 1或N，且Y 4是C；
其中，所述取代为被一个或多个R 1取代；
Figure PCTCN2022094255-appb-000053
表示分别与L 1和L 2相连接。
在本申请式(II)所示化合物的一个实施方案中，B选自取代或未取代的吡啶、取代或未取代的吡嗪、取代或未取代的嘧啶、取代或未取代的噻唑、取代或未取代的吡啶酮、取代或未取代的嘧啶酮、取代或未取代的哒嗪酮等单环；或者取代或未取代的吡啶环、吡嗪环、哒嗪环、嘧啶环、噻唑环、吡啶酮环、嘧啶酮环、哒嗪酮环等与取代或未 取代的咪唑、取代或未取代的三氮唑、取代或未取代的吡唑、取代或未取代的吲唑、取代或未取代的噁唑等形成的二元或者三元并环或稠环体系；
优选地，B选自任选取代或未取代的以下基团：
Figure PCTCN2022094255-appb-000054
进一步优选地，B选自任选取代或未取代的以下基团：
Figure PCTCN2022094255-appb-000055
更进一步优选为
Figure PCTCN2022094255-appb-000056
其中，所述取代为被一个或多个R 1取代。
在本申请式(II)所示化合物的一个实施方案中，所述L 1选自：共价键、-S(O) 2-、-CO-NR d-、-NR d-C(O)-、-C(O)O-、-NR dSO 2-、-SO 2NR d-和
Figure PCTCN2022094255-appb-000057
优选为共价键、-S(O) 2-、-CO-NR d-或-NR d-C(O)-；进一步优选为共价键。
在本申请式(II)所示化合物的一个实施方案中，所述Y为CH或N，且
Figure PCTCN2022094255-appb-000058
为单键；优选为N，且
Figure PCTCN2022094255-appb-000059
为单键。
在本申请式(II)所示化合物的一个实施方案中，所述W为-CH 2-、-CH(R b)-、-C(R b) 2-或-O-；优选为-CH 2-或-O-。
在本申请式(II)所示化合物的一个实施方案中，所述环C为不存在、未被取代或任选被一个或多个R 1取代的5-14元芳基、5-14元杂芳基、5-14元碳环基或5-14元杂环基；优选地，所述环C为不存在、未被取代或任选被一个或多个R 1取代的5-12元芳基、5-12元杂芳基、5-12元碳环基或5-12元杂环基；进一步优选地，所述环C为不存在、未被取代或任选被一个或多个R 1取代的5-10元芳基、5-10元杂芳基、5-10元碳环基或5-10元杂环基；进一步优选地，所述环C为不存在、未被取代或任选被一个或多个R 1取代的6-10元芳基、5-10元杂芳基、5-10元碳环基或5-10元杂环基；进一步优选地，所述环C为不存在、未被取代或任选被一个或多个R 1取代的6-10元单环芳基、6-10元稠环芳基、5-10元单环杂芳基、5-10元稠环杂芳基、5-7元单环碳环基、7-10元稠环碳环基、5-7元单环杂环基或7-10元稠环杂环基；进一步优选地，所述环C为不存在、未被取代或任选被一个或多个R 1取代的苯基、萘基、5元单环杂芳基、6元单环杂芳基、7元单环杂芳基、8元稠环杂芳基、9元稠环杂芳基、10元稠环杂芳基、5元碳环基、6元碳环基、7元碳环基、8元稠环碳环基、9元稠环碳环基、10元稠环碳环基、5元杂环基、6元杂环基、7元杂环基、8元稠环杂环基、9元稠环杂环基或10元稠环杂环基；其中，上述每个杂芳基或杂环含有1、2或3个独立选自N、O或S的杂原子；
进一步优选地，所述环C为不存在，或选自未被取代或任选被一个或多个R 1取代的下列基团：
Figure PCTCN2022094255-appb-000060
优选为未被取代或任选被一个或多个R 1取代的下列基团：
Figure PCTCN2022094255-appb-000061
进一步优选为未被取代或任选被一个或多个R 1取代的下列基团：
Figure PCTCN2022094255-appb-000062
进一步优选为未被取代或任选被一个或多个R 1取代的下列基团：
Figure PCTCN2022094255-appb-000063
其中，
Figure PCTCN2022094255-appb-000064
表示单键或双键。
在本申请式(II)所示化合物的一个实施方案中，当
Figure PCTCN2022094255-appb-000065
中的
Figure PCTCN2022094255-appb-000066
表示单键时，Y 1是-CR d-或-N-，且Y 2是-CR d-或-N-。
在本申请式(II)所示化合物的一个实施方案中，当环C不存在时，Y 1和Y 2各自独立地为-C(R 1) 2-或-C(R d) 2-。
在本申请式(II)所示化合物的一个实施方案中，每个R 1独立地选自氢、氘、卤素、-N(R a) 2、-CN、-OH、-NO 2、氧代、＝O、羧基、-C 1-6烷氧基、-C 1-6烷基、-C 1-6卤代烷基、-C 3-8环烷基、-C 1-6亚烷基-N(R a) 2、-C 1-6亚烷基-O-C 1-6烷基、-C 1-6亚烷基-C(O)-OR a、-C 1-6亚烷基-(3-10元杂环基)、-C 1-6亚烷基-(5-10元杂芳基)、-C 1-6亚烷基-C(O)-N(R a) 2、-C 1-6亚烷基-NR a-C(O)-C 1-6烷基、-C(O)-N(R a) 2、-C(O)-C(O)-N(R a) 2、-C 3-10碳环基、-5-10元杂芳基、-3-10元杂环基、-C(O)-C 1-6烷基、-C(O)O-C 1-6烷基、-C(O)-C 1-6亚烷基-N(R a) 2、-C(O)-NR a-(3-10元杂环基)、-C(O)-NR a-(3-10元杂环基)、-C(O)-(3-10元杂环基)、-O-C 1-6亚烷基-C(O)-OR a、-O-C 3-10碳环基、-O-(3-10元杂环基)、-NR a-C(O)-C 1-6烷基、-NR a-C(O)-(5-10元杂芳基)、-NR a-C(O)-C 3-8环烷基、-NR a-C 1-6亚烷基-N(R a) 2、-NR a-C 1-6亚烷基-(3-10元杂环基)、-NR a-C 1-6亚烷基-(5-10元杂芳基)、-NR a-S(O) 2C 1-6烷基、-S(O)-N(R a) 2、-S(O) 2-N(R a) 2、-3-10元杂环基或-5-10元杂芳基；优选地，每个R 1独立地选自-H、-F、-Cl、-Br、-NH 2、-N(CH 3) 2、-CN、-OH、氧代基、＝O、羧基、甲氧基、乙氧基、甲基、乙基、异丙基、叔丁基、-CH 2NH 2、-CH 2CH 2OCH 3、-CH 2-C(O)OH、-CH 2NH-C(O)-NHCH 3、-C(O)-NH 2、-C(O)-N(CH 3) 2、-C(O)-NHOH、-C(O)-NHCH 2CH 2OH、-C(O)-CH 3、-C(O)O-CH 3、-S(O) 2-NH 2、-NHS(O) 2CH 3、-NH-C(O)-CH 3、-NH-C(O)-NHCH 3、
Figure PCTCN2022094255-appb-000067
其中，上述每个R 1独立地任选地被1、2或3个-F、-Cl、-NH 2、-OH、氧代基、＝O、甲基、乙基或丙基取代；
或两个相邻的R a连接在一起形成5-14元芳环、5-14元杂芳环、5-14元杂环或5-14元碳环，且所述每个环系独立地任选地被取代；优选地，两个相邻的R a连接在一起形成6-10元芳环、5-10元杂芳环、5-10元杂环或5-10元碳环，且所述每个环系独立地任选地被取代；
或R a和R b与它们共同连接的原子一起形成3-14元芳环、3-14元杂芳环、3-14元杂环或3-14元碳环；且所述每个环系独立地任选地被取代；优选地，R a和R b与它们共同连接的原子一起形成6-10元芳环、5-10元杂芳环、5-10元杂环或5-10元碳环；且所述每个环系独立地任选地被取代；
每个R a独立地选自氢、氘、卤素、-NH 2、-CN、-OH、-NO 2、羧基、-C 1-6烷氧基、-C 1-6烷基；每个基团独立地任选地被取代；优选地，每个R a独立地选自氢、氘、卤素、-NH 2、-CN、-OH、-C 1-6烷氧基、-C 1-6烷基；每个基团独立地任选地被取代。
在本申请式(II)所示化合物的一个实施方案中，B环上的R 1独立地选自氢、氘、氨基、卤素、氰基、-CONH 2、-COR 6、-COOR 6、任选取代的C 1-6烷基、任选取代的C 2-6烯基、任选取代的C 2-6炔基、任选取代的C 3-10环烷基、任选取代的3-10元杂环烷基；优选为氢、卤素、氨基、氰基、-CONH 2、-COR 6、-COOR 6、任选取代的C 1-4烷基、任选取代的C 2-6烯基、任选取代的C 3-6环烷基、任选取代的3-6元杂环烷基；进一步优选为卤素、氰基、-CONH 2、-COR 6、-COOR 6、羟基取代的C 1-4烷基、C 2-6烯基、C 3-6环烷基、3-6元杂环烷基；其中，R 6独立地选自氢、任选取代的C 1-6烷基、任选取代的C 3-6环烷基、任选取代的3-6元杂环烷基、任选取代的C 6-10芳基、任选取代的5-10元杂芳基；优选地，R 6独立地选自氢、任选取代的C 1-6烷基、任选取代的C 3-6环烷基、任选取代的3-6元杂环烷基；进一步优选地，R 5独立地选自氢、C 1-6烷基、C 3-6环烷基、3-6元杂环烷基；
所述任选取代是指被取代基团上的氢未被取代或被取代基团的一个或多个可取代位点上的氢独立地被选自-OH、卤素、-NH 2、-NO 2、C 1-6烷基、C 1-6烷氧基、C 3-6环烷基、-NH-C 1-6烷基、-N(C 1-6烷基)-C 1-6烷基、-NH-C 3-6环烷基、-N(C 3～6环烷基)-C 3～6环烷基、3～6元杂环烷基、C 6～14芳基或5～10元杂芳环基的取代基所取代；优选为被选自卤素、羟基、氨基、硝基、氧代基、氰基、C 1-6烷基、C 1-6烷氧基的取代基所取代。
在本申请式(II)所示化合物的一个实施方案中，A环上的R 1独立地选自任选取代的8-12元杂环基、任选取代的C 6-10芳基、任选取代的5-14元杂芳基；所述任选取代是指被取代基团上的氢未被取代或被取代基团的一个或多个可取代位点上的氢独立地被选 自卤素、羟基、氨基、硝基、氧代基、氰基、-COOH、-COCH 3、-COOCH 3、-CONH 2、C 1-6烷基、C 1-6烷氧基、C 3-10环烷基、3-10元杂环烷基、C 6-10芳基、5-12元杂芳基的取代基所取代；
在本申请式(II)所示化合物的一个实施方案中，C环上的R 1独立地选自选自氢、卤素、-NH 2、-NHR 7、-N(R 7) 2、-CN、-NO 2、＝O、-C(O)-OR 7、-C(O)-NH 2、-CO-NHR 7、-CO-N(R 7) 2、-C(O)R 7、-COOH、-OH、-SC 1-6烷基、-SOC 1-6烷基、-S(O) 2C 1-6烷基、取代或未取代的C 1-6烷基、取代或未取代的C 1～6烷氧基；其中，R 7各自独立地为C 1～6烷基；所述“取代”是指取代基独立地选自一个或多个-OH、卤素、C 1-6烷基、-NH 2、-NO 2、-COCH 3和、-CN和＝O的基团，取代基为“＝O”的情况是指同一取代位置的两个氢原子被氧原子所取代。
在本申请式(II)所示化合物的一个实施方案中，R 2选自：氢、氘、卤素、-NH 2、-OH、-NH-C 1-6烷基、-N(C 1-6烷基) 2、-C 1-6烷氧基或-C 1-6烷基，且每个基团独立地任选地被取代或未被取代；优选为氢、氘、卤素、-NH 2、-OH、-C 1-3烷氧基或-C 1-3烷基，且每个基团独立地任选地被取代或未被取代；进一步优选为氢、-NH 2或-OH，且每个基团独立地任选地被取代或未被取代；进一步优选为-NH 2。
在本申请式(II)所示化合物的一个实施方案中，每个R 4和R 5独立地选自氢、氘、卤素、-NH 2、-CN、-OH、-C 1-6烷氧基或-C 1-6烷基，且每个基团独立地任选地被取代或未被取代；优选地，每个R 4和R 5独立地选自氢、氘、卤素、-NH 2、-CN、-OH、-C 1-3烷氧基或-C 1-3烷基，且每个基团独立地任选地被取代或未被取代；进一步优选地，每个R 4和R 5独立地选自氢、卤素、-OH、-CH 3或-OCH 3；进一步优选地，R 4和R 5均为氢。
在本申请式(II)所示化合物的一个实施方案中，m为0或1；q为1；n为1、2或3；当m为0时，W直接与Y 2相连。
在本申请式(II)所示化合物的一个实施方案中，---表示键不存在。
在本申请式(II)所示化合物的一个实施方案中，上述取代独立地选自-OH、卤素、未取代的C1-6烷基、-NH 2、-NO 2、未取代的-COC 1-6烷基、-CN、＝O、-C(O)OH、-C(O)-CH 3-、-C(O)OCH 3-、-C(O)-NH 2、未取代的C 3～10环烷基、未取代的-NH-C 1～6烷基、未取代的-N(C 1～6烷基)(C 1～6烷基)、未取代的-NH-C 3～6环烷基、未取代的-N(C 3～6环烷基)(C 3～6环烷基)、未取代的3～10元杂环烷基、未取代的C 6～14芳基或未取代的5～12元杂芳基基团中的一个或多个取代基；优选为-OH、卤素、未取代的C 1-6烷基、-NH 2、-NO 2、未取代的-COC 1-6烷基、-CN、＝O、-C(O)OH、-C(O)-CH 3-、-C(O)OCH 3-、-C(O)-NH 2、未取代的-NH-C 1～6烷基或未取代的-N(C 1～6烷基)(C 1～6烷基)。
在本申请式(II)所示化合物的一个实施方案中，每个R b独立地选自氢、氘、卤素、-NH 2、-CN、-OH、-C 1-6烷氧基或-C 1-6烷基；优选为氢、氘、卤素、-NH 2、-CN、-OH、-C 1-3烷氧基或-C 1-3烷基。
在本申请式(II)所示化合物的一个实施方案中，每个R d独立地选自氢、氘、卤素、-NH 2、-CN、-OH、-NO 2、-C(O)OH、-C(O)-C 1-6烷基、-C(O)-O-C 1-6烷基、-C 1-6亚烷基-O-C 1-6烷氧基、-C 1-6烷氧基或-C 1-6烷基；优选为氢、氘、卤素、-NH 2、-CN、-OH、-NO 2、-C(O)OH、-C(O)-C 1-3烷基、-C(O)-O-C 1-3烷基、-C 1-3亚烷基-O-C 1-3烷氧基、-C 1-3烷氧基或-C 1-3烷基；进一步优选为氢、氘、卤素、-NH 2、-CN、-OH、-NO 2、-C(O)OH、-C(O)-C 1-3烷基、-C 1-3亚烷基-O-C 1-3烷氧基。
在本申请某些实施方案中，提供了下列化合物或其前药、互变异构体、立体异构体、溶剂化物、同位素衍生物或其药学上可接受的盐：
Figure PCTCN2022094255-appb-000068
Figure PCTCN2022094255-appb-000069
Figure PCTCN2022094255-appb-000070
Figure PCTCN2022094255-appb-000071
Figure PCTCN2022094255-appb-000072
Figure PCTCN2022094255-appb-000073
在本申请某些优选方案中，提供了下列化合物或其前药、互变异构体、立体异构体、溶剂化物、同位素衍生物或其药学上可接受的盐：
Figure PCTCN2022094255-appb-000074
Figure PCTCN2022094255-appb-000075
在本申请某些优选方案中，提供了下列化合物或其前药、互变异构体、立体异构体、溶剂化物、同位素衍生物或其药学上可接受的盐：
Figure PCTCN2022094255-appb-000076
Figure PCTCN2022094255-appb-000077
在本申请某些优选方案中，提供了下列化合物或其前药、互变异构体、立体异构体、溶剂化物、同位素衍生物或其药学上可接受的盐：
Figure PCTCN2022094255-appb-000078
本申请另一方面还提供了上述式(I)化合物主要的制备方法，所述方法例如可以使用下述合成方案一和合成方案二所示的方法来制备。
合成方案一
Figure PCTCN2022094255-appb-000079
C1和C2可以为Cl或Br
其中A、Y、G、X、L、R 1、R 2、R 3和R 6如式(I)化合物中所定义，
I)化合物I-1和I-2发生化学转化得到化合物I-3；
如以化合物I-1、I-2和Ti(OEt) 4等为基本原料，得到化合物I-3；
II)化合物I-3发生化学转化得到化合物I-4；
如以化合物I-3为基本原料在还原剂存在下，反应得到化合物I-4；
III)化合物I-4发生化学转化得到化合物I-5；
如化合物I-4在酸性条件得到化合物I-5；
IV)化合物I-5发生化学转化得到化合物I-7；
如以化合物I-5和I-6等为基本原料，碱性条件下反应得到化合物I-7；
V)化合物I-7发生化学转化得到化合物I-8；
如以化合物I-7在酸性条件下反应得到化合物I-8；
VI)化合物I-8发生化学转化得到化合物I-9；
如以化合物I-8和(Boc) 2O等为基本原料，得到化合物I-9；
VII)化合物I-9发生化学转化得到化合物I-11；
如以化合物I-9和I-10等为基本原料在钯催化、碱性条件下发生得到化合物I-11。
VIII)化合物I-11发生化学转化得到通式(I)化合物；
如以化合物I-11等为基本原料在酸性条件下发生反应得到通式(I)化合物。
合成方案二
Figure PCTCN2022094255-appb-000080
C1和C2可以为Cl或Br
其中A、Y、G、X、L、R 1、R 2、R 3和R 6如式(I)化合物中所定义，
2-I)化合物I-10和I-6发生化学转化得到化合物I-12；
如以化合物I-10和I-6等为基本原料，在钯催化、碱性条件下得到化合物I-12；
2-II)化合物I-12和I-5发生化学转化得到化合物I-13；
如以化合物I-12和I-5为基本原料，在钯催化、碱性条件下得到化合物I-13；
2-III)化合物I-13发生化学转化得到通式(I)化合物；
如化合物I-13在酸性条件得到通式(I)化合物。
本申请另一方面还提供了一种药物组合物，其包含(例如，治疗有效量的)本申请所述的化合物(式(I)化合物、式(I-1)化合物、式(I-1-1)化合物、式(I-2)化合物、式(I-A1)化合物、式(I-1-A1)化合物、式(I-2-A1)化合物、式(I-A2)化合物、式(I-A3)化合物、式(I-2-A2) 化合物、式(I-2-A3)化合物、式(I-B1)化合物、式(I-1-B1)化合物、式(I-2-B1)化合物、式(I-B2)化合物、式(I-B3)化合物、式(I-2-B2)化合物、式(I-2-B3)化合物)、式(II)化合物、式(I-A)化合物、式(I-B)化合物、式(I-1-A)化合物、式(I-1-B)化合物、式(I-2-A)化合物、式(I-2-B)化合物、式(I-Ba)化合物)或其前药、互变异构体、立体异构体、溶剂化物、同位素衍生物或其药学上可接受的盐。
进一步地，本申请所述的药物组合物，其包含本申请所述的化合物(式(I)化合物、式(I-1)化合物、式(I-1-1)化合物、式(I-2)化合物、式(I-A1)化合物、式(I-1-A1)化合物、式(I-2-A1)化合物、式(I-A2)化合物、式(I-A3)化合物、式(I-2-A2)化合物、式(I-2-A3)化合物、式(I-B1)化合物、式(I-1-B1)化合物、式(I-2-B1)化合物、式(I-B2)化合物、式(I-B3)化合物、式(I-2-B2)化合物、式(I-2-B3)化合物)、式(II)化合物、式(I-A)化合物、式(I-B)化合物、式(I-1-A)化合物、式(I-1-B)化合物、式(I-2-A)化合物、式(I-2-B)化合物、式(I-Ba)化合物)或其前药、互变异构体、立体异构体、溶剂化物、同位素衍生物或其药学上可接受的盐，以及药学上可接受的辅料。
本申请化合物(式(I)化合物、式(I-1)化合物、式(I-1-1)化合物、式(I-2)化合物、式(I-A1)化合物、式(I-1-A1)化合物、式(I-2-A1)化合物、式(I-A2)化合物、式(I-A3)化合物、式(I-2-A2)化合物、式(I-2-A3)化合物、式(I-B1)化合物、式(I-1-B1)化合物、式(I-2-B1)化合物、式(I-B2)化合物、式(I-B3)化合物、式(I-2-B2)化合物、式(I-2-B3)化合物)、式(II)化合物、式(I-A)化合物、式(I-B)化合物、式(I-1-A)化合物、式(I-1-B)化合物、式(I-2-A)化合物、式(I-2-B)化合物、式(I-Ba)化合物)或其前药、互变异构体、立体异构体、溶剂化物、同位素衍生物或其药学上可接受的盐的给药可以以纯的形式或适宜的药物组合物的形式通过提供类似用途的药物的任何可接受的给药方式来进行。本申请的药物组合物可通过将本申请所述的化合物与适宜的药学上可接受的辅料相组合而制备。本申请的药物组合物可配制成固态、半固态、液态或气态制剂，如片剂、丸剂、胶囊剂、粉剂、颗粒剂、膏剂、乳剂、悬浮剂、溶液剂、栓剂、注射剂、吸入剂、凝胶剂、微球及气溶胶等等。一般地，上述药物组合物可以采用制剂领域中常规的辅料通过常规的制备方法制备。
本申请另一方面还提供了本申请所述的化合物(式(I)化合物、式(I-1)化合物、式(I-1-1)化合物、式(I-2)化合物、式(I-A1)化合物、式(I-1-A1)化合物、式(I-2-A1)化合物、式(I-A2)化合物、式(I-A3)化合物、式(I-2-A2)化合物、式(I-2-A3)化合物、式(I-B1)化合物、式(I-1-B1)化合物、式(I-2-B1)化合物、式(I-B2)化合物、式(I-B3)化合物、式(I-2-B2)化合物、式(I-2-B3)化合物)、式(II)化合物、式(I-A)化合物、式(I-B)化合物、式(I-1-A)化合物、式(I-1-B)化合物、式(I-2-A)化合物、式(I-2-B)化合物、式(I-Ba)化合物)或其前药、互变异构体、立体异构体、溶剂化物、同位素衍生物或其药学上可接受的盐或本申请药物组合物在制备用于预防和/或治疗通过SHP2活性介导的疾病、病症和病况的药物中的用途。
进一步地，本申请提供的用途中，所述的疾病、病症和病况为肿瘤、癌转移、心血管疾病、免疫紊乱或视觉紊乱。
进一步地，本申请提供的用途中，所述肿瘤包括实体瘤和血液瘤。
进一步地，本申请提供的用途中，所述实体瘤包括肺癌，所述血液瘤包括白血病，所述白血病优选急性髓性白血病。在本领域某些语境下，所述癌症也可称为恶性肿瘤。
又一方面，本申请提供了用于预防和/或治疗通过SHP2活性介导的疾病、病症和病况的方法，其包括向有需要的个体施用本申请所述的化合物(式(I)化合物、式(I-1)化合物、式(I-1-1)化合物、式(I-2)化合物、式(I-A1)化合物、式(I-1-A1)化合物、式(I-2-A1)化合物、式(I-A2)化合物、式(I-A3)化合物、式(I-2-A2)化合物、式(I-2-A3)化合物、式(I-B1)化合物、式(I-1-B1)化合物、式(I-2-B1)化合物、式(I-B2)化合物、式(I-B3)化合物、式(I-2-B2)化合物、式(I-2-B3)化合物、式(I-A)化合物、式(I-B)化合物、式(I-1-A)化合物、式(I-1-B) 化合物、式(I-2-A)化合物、式(I-2-B)化合物、式(I-Ba)化合物)、式(II)化合物)或其前药、互变异构体、立体异构体、溶剂化物、同位素衍生物或其药学上可接受的盐或本申请药物组合物；优选地，所述疾病、病症和病况为肿瘤、癌转移、心血管疾病、免疫紊乱或视觉紊乱；更优选地，所述肿瘤包括实体瘤和血液瘤；更优选地，所述实体瘤包括肺癌，所述血液瘤包括白血病，所述白血病优选急性髓性白血病。
另一方面，本申请提供了用于预防和/或治疗通过SHP2活性介导的疾病、病症和病况的本申请所述的化合物(式(I)化合物、式(I-1)化合物、式(I-1-1)化合物、式(I-2)化合物、式(I-A1)化合物、式(I-1-A1)化合物、式(I-2-A1)化合物、式(I-A2)化合物、式(I-A3)化合物、式(I-2-A2)化合物、式(I-2-A3)化合物、式(I-B1)化合物、式(I-1-B1)化合物、式(I-2-B1)化合物、式(I-B2)化合物、式(I-B3)化合物、式(I-2-B2)化合物、式(I-2-B3)化合物)、式(II)化合物、式(I-A)化合物、式(I-B)化合物、式(I-1-A)化合物、式(I-1-B)化合物、式(I-2-A)化合物、式(I-2-B)化合物、式(I-Ba)化合物)或其前药、互变异构体、立体异构体、溶剂化物、同位素衍生物或其药学上可接受的盐或本申请药物组合物；优选地，所述疾病、病症和病况为肿瘤、癌转移、心血管疾病、免疫紊乱或视觉紊乱；更优选地，所述肿瘤包括实体瘤和血液瘤；更优选地，所述实体瘤包括肺癌，所述血液瘤包括白血病，所述白血病优选急性髓性白血病。
进一步地，本申请提供的用途或方法中，本申请所述的化合物(式(I)化合物、式(I-1)化合物、式(I-1-1)化合物、式(I-2)化合物、式(I-A1)化合物、式(I-1-A1)化合物、式(I-2-A1)化合物、式(I-A2)化合物、式(I-A3)化合物、式(I-2-A2)化合物、式(I-2-A3)化合物、式(I-B1)化合物、式(I-1-B1)化合物、式(I-2-B1)化合物、式(I-B2)化合物、式(I-B3)化合物、式(I-2-B2)化合物、式(I-2-B3)化合物)、式(II)化合物、式(I-A)化合物、式(I-B)化合物、式(I-1-A)化合物、式(I-1-B)化合物、式(I-2-A)化合物、式(I-2-B)化合物、式(I-Ba)化合物)或其前药、互变异构体、立体异构体、溶剂化物、同位素衍生物或其药学上可接受的盐或本申请药物组合物与另一种、两种或更多种具有抑制肿瘤活性的化合物组合使用。
再一方面，本申请提供了用于抑制SHP2活性的本申请所述的化合物(式(I)化合物、式(I-1)化合物、式(I-1-1)化合物、式(I-2)化合物、式(I-A1)化合物、式(I-1-A1)化合物、式(I-2-A1)化合物、式(I-A2)化合物、式(I-A3)化合物、式(I-2-A2)化合物、式(I-2-A3)化合物、式(I-B1)化合物、式(I-1-B1)化合物、式(I-2-B1)化合物、式(I-B2)化合物、式(I-B3)化合物、式(I-2-B2)化合物、式(I-2-B3)化合物)、式(II)化合物、式(I-A)化合物、式(I-B)化合物、式(I-1-A)化合物、式(I-1-B)化合物、式(I-2-A)化合物、式(I-2-B)化合物、式(I-Ba)化合物)或其前药、互变异构体、立体异构体、溶剂化物、同位素衍生物或其药学上可接受的盐或本申请药物组合物。
定义
术语“任选”、“任意”、“任选地”或“任意地”指的是随后描述的事件或状况可能但不是必需出现的，并且该描述包括其中所述事件或状况发生的情况以及所述事件或状况不发生的情况。
除另有特别限定，所述“任选取代”或“任意取代”是指基团可以为未取代的或取代的，其中取代基独立地选自羟基、卤素、氨基、硝基、巯基、氰基、叠氮基、氧代基、羧基、-C(O)C 1-6烷基、-C(O)O-C 1-6烷基、-OC(O)-C 1-6烷基、-NH(C 1-6烷基)、-N(C 1-6烷基)(C 1-6烷基)、-C(O)NH-C 1-6烷基、-NHC(O)-C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷基、C 1-6烷氧基、C 3-10环烷基、C 3-10环烷基磺酰基、3-10元杂环烷基、C 6-14芳基、5-12元杂芳基基团中的一个或多个；其中，所述C 2-6烯基、C 2-6炔基、C 1-6烷基、C 1-6烷氧基、C 3-10环烷基、C 3-10环烷基磺酰基、3-10元杂环烷基、C 6-14芳基或5-12元杂芳环基可任选地被选自卤素、羟基、氨基、氰基、C 1-6烷基或C 1-6烷氧基中的一个或多个所取代。
术语“氧代基”是指相同取代位的两个氢原子被同一个氧原子替代形成双键，即＝O。
除另有特别限定，术语“烷基”指一价饱和脂肪族烃基团，包含1-20个碳原子的直链或支链基团，优选包含1、2、3、4、5、6、7、8、9或10个碳原子(即C 1-10烷基)，进一步优选包含1-8个碳原子(C 1-8烷基)，更优选包含1-6个碳原子(即C 1-6烷基)，例如“C 1-6烷基”指的是该基团为烷基，且碳链上的碳原子数量在1-6之间(具体地为1个、2个、3个、4个、5个或6个)。实例包括但不限于甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、新戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、正庚基、正辛基等。
除另特别限定，术语“烯基”是指由碳原子和氢原子组成的直链或支链的具有至少一个双键的不饱和脂肪族烃基。烯基可以包含2-20个碳原子，优选包含2、3、4、5、6、7、8、9或10个碳原子(即C 2-10烯基)，进一步优选包含2-8个碳原子(C 2-8烯基)，更优选包含2-6个碳原子(即C 2-6烯基)、2-5个碳原子(即C 2-5烯基)、2-4个碳原子(即C 2-4烯基)、2-3个碳原子(即C 2-3烯基)、2个碳原子(即C 2烯基)，例如“C 2-6烯基”指的是该基团为烯基，且碳链上的碳原子数量在2-6之间(具体地为2个、3个、4个、5个或6个)。烯基的非限制性实例包括但不限于乙烯基、1-丙烯基、2-丙烯基、1-丁烯基、异丁烯基和1,3-丁二烯基等。
除另有特别限定，术语“炔基”是指由碳原子和氢原子组成的直链或支链的具有至少一个叁键的不饱和脂肪族烃基。炔基可以包含2-20个碳原子，优选包含2、3、4、5、6、7、8、9或10个碳原子(即C 2-10炔基)，进一步优选包含2-8个碳原子(C 2-8炔基)，更优选包含2-6个碳原子(即C 2-6炔基)、2-5个碳原子(即C 2-5炔基)、2-4个碳原子(即C 2-4炔基)、2-3个碳原子(即C 2-3炔基)、2个碳原子(即C 2炔基)，例如“C 2-6炔基”指的是该基团为炔基，且碳链上的碳原子数量在2-6之间(具体地为2个、3个、4个、5个或6个)。炔基的非限制性实例包括但不限于乙炔基、1-丙炔基、2-丙炔基和1-丁炔基等。
除另有特别限定，术语“环烷基”“碳环基”或“碳环”指的是具有特定碳原子数的单环饱和脂烃基，包含3、4、5、6、7、8、9、10、11、12、13或14个碳原子(即C 3-14环烷基)，优选地包含3-12个碳原子(即C 3-12环烷基)，更优选包含3-10个碳原子(C 3-10环烷基)，进一步优选3-7个碳原子(C 3-7环烷基)、4-6个碳原子(C 4-6环烷基)、5-6个碳原子(C 5-6环烷基)。实例包括但不限于环丙基、环丁基、环戊基、环己基、甲基环丙基、2-乙基-环戊基、二甲基环丁基等。在本申请的一些实施方案中，“环烷基”指的是由碳原子和氢原子组成的具有特定碳原子数的单环饱和脂肪族烃基。在本申请的一些实施方案中，环烷基还优选地包含3-4个碳原子(C 3-4环烷基)、3-5个碳原子(C 3-5环烷基)或4-5个碳原子(C 4-5环烷基)。
除另有特别限定，术语“烷氧基”指-O-烷基，所述烷基的定义同上，即包含1-20个碳原子，优选地，包含1、2、3、4、5、6、7、8、9或10个碳原子，较佳地1-8个碳原子，更佳地1～6个碳原子(具体地为1个、2个、3个、4个、5个或6个)。代表的例子包括但不限于甲氧基、乙氧基、丙氧基、异丙氧基、丁氧基、1-甲基丙氧基、2-甲基丙氧基、叔丁氧基、戊氧基、1-甲基丁氧基、2-甲基丁氧基、3-甲基丁氧基、1,1-二甲基丙氧基、1,2-二甲基丙氧基、2,2-二甲基丙氧基、1-乙基丙氧基等。
除另有特别限定，术语“羧基”指-COOH基团。术语“卤素”或“卤代”是指F、Cl、Br、I。术语“卤代烷基”是指如上所定义的烷基中一个、两个或多个氢原子或全部氢原子被卤素取代。卤代烷基的代表性例子包括CCl 3、CF 3、CHCl 2、CH 2Cl、CH 2Br、CH 2I、CH 2CF 3、CF 2CF 3等。
除另有特别限定，术语“杂环基”或“杂环”指具有环碳原子和1到4个环杂原子的饱和或部分不饱和的单环、双环或多环环状非芳香族取代基，包含3-20个环原子，其中1 个、2个、3个或更多个环原子选自N、O或S，其余环原子为C。优选包含3、4、5、6、7、8、9、10、11、12、13或14个环原子(即3-14元杂环基)，优选包含3～12个环原子(3-12元杂环基)，进一步优选包含3-10个环原子(3-10元杂环基)，或3～8个环原子(3-8元杂环基)，或3～6个环原子(3-6元杂环基)，或4～6个环原子(4-6元杂环基)，或5～6个环原子(5-6元杂环基)。杂原子优选1-4个，更优选1～3个(即1个、2个或3个)。单环杂环基的实例包括环氧乙烷基、吡咯烷基、N-甲基吡咯烷基、吡唑烷基、咪唑烷基、四氢呋喃基、二氢吡咯基、哌啶基、哌嗪基、吡喃基、吗啉基、硫代吗啉基和四氢噻吩基等。多环杂环基包括螺环、稠环和桥环的杂环基。“杂环基”可以是单环的(“单环杂环基”)或一种稠合的(“稠杂环基”或“杂稠环基”)、桥接的(“杂桥环基”或“桥环杂环基”)或螺接-稠合(“杂螺环基”或“螺环杂环基”)的环系统，如一个双环系统(“双环杂环基”)，并且可以是饱和的或可以是部分不饱和的。杂环基双环系统可以在一个或两个环中包括一个或多个杂原子。“杂环基”还包括其中如上所定义的该杂环基环被一个或多个碳环基基团稠合的环系统，其中附接点是在该碳环基或杂环基环上，或者“杂环基”还包括其中如上所定义的该杂环基环被一个或多个芳基或杂芳基基团稠合的环系统，或如上所定义的环烷基环被一个或多个杂芳基基团稠合的环系统，其中附接点是在该杂环基环或环烷基环上，并且在此类情况下，该杂环基环系统的元数为稠合后环系统原子数。在某些实施方案中，杂环基的每个例子独立地是可任选取代的，例如，未取代的(一种“未取代的杂环基”)或被一个或多个取代基取代的(一种“取代的杂环基”)。含有1个杂原子的示例性3元杂环基基团包括，但不限于氮杂环丙烷基、氧杂环丙烷基(oxiranyl)和硫杂环丙烷基(thiorenyl)。含有1个杂原子的示例性4元杂环基基团包括，但不限于氮杂环丁烷基、氧杂环丁烷基和硫杂环丁烷基。含有1个杂原子的示例性5元杂环基基团包括，但不限于四氢呋喃基、二氢呋喃基、四氢苯硫基、二氢苯硫基、吡咯烷基、二氢吡咯基以及吡咯基-2,5-二酮。含有2个杂原子的示例性5元杂环基基团包括，但不限于二氧戊环基、氧杂硫杂环戊烷基、二硫杂环戊烷基以及噁唑烷-2-酮。含有3个杂原子的示例性5元杂环基基团包括，但不限于三唑啉基、噁二唑啉基和噻二唑啉基。含有1个杂原子的示例性6元杂环基基团包括，但不限于哌啶基、四氢吡喃基、二氢吡啶基以及硫杂环己烷基(thianyl)。含有2个杂原子的示例性6元杂环基基团包括，但不限于哌嗪基、吗啉基、二硫杂环己烷基以及二氧杂环己烷基。含有3个杂原子的示例性6元杂环基基团包括，但不限于三氮杂环己烷基、氧杂二嗪烷基、噻二嗪烷基、氧杂噻嗪烷基以及二氧杂氮杂环己烷基(dioxazinanyl)。含有1个杂原子的示例性7元杂环基基团包括，但不限于氮杂环庚烷基、氧杂环庚烷基和硫杂环庚烷基。含有1个杂原子的示例性8元杂环基基团包括，但不限于氮杂环辛烷基、氧杂环辛烷基和硫杂环辛烷基。稠合到一个C 6芳基环上的示例性5元杂环基基团(在此又称为一种5,6-双环杂环)包括，但不限于二氢吲哚基、异二氢吲哚基、二氢苯并呋喃基、二氢苯并噻吩基、苯并噁唑啉酮基等。稠合到一个芳基环上的示例性6元杂环基基团(在此又称为一种6,6-双环杂环)包括，但不限于四氢喹啉基、四氢异喹啉基等。
除另有特别限定，“杂环烷基”是指单环、饱和的如上文定义的“杂环基”或“杂环”，环原子定义同上，即包含3～20个环原子(“3-20元杂环烷基”)，杂原子数量为1～4个(1个、2个、3个或4个)，优选1～3个(1个、2个或3个)，其中杂原子各自独立地选自N、O或S。优选包含3、4、5、6、7、8、9、10、11或12个环原子(“3-12元杂环烷基”)，进一步优选包含3～10个环原子(“3-10元杂环烷基”)，更进一步优选包含3～8个环原子(“3-8元杂环烷基”)，更进一步优选包含4～7个环原子(“4-7元杂环烷基”)，更进一步优选地包含5-10个环原子(“5-10元杂环烷基”)，更进一步优选包含5-6个环原子(“5-6元杂环烷基”)。在某些实施方案中，杂环烷基的每个例子独立地是可任选取代的，例如， 未取代的(一种“未取代的杂环烷基”)或被一个或多个取代基取代的(一种“取代的杂环烷基”)。上文“杂环基”或“杂环”部分已给出了部分示例性的“杂环烷基”，还包括，但不限于氮杂环丙烷基、氧杂环丙烷基、硫杂环丙烷基、氮杂环丁烷基、氧杂环丁烷基、硫杂环丁烷基、四氢呋喃基、氧杂环己烷基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、氧杂硫杂环己基、噁唑烷基、二噁烷基、二硫杂环己基、噻唑烷基、吡咯烷基、吡唑烷基、咪唑啉啶等。
除另有特别限定，术语“芳基”或“芳环基”表示含有6-16个碳原子，或6-14个碳原子，或6-12个碳原子，或6-10个碳原子的单环、双环和三环的芳香碳环体系，优选6-10个碳原子，术语“芳基”可以和术语“芳香环”交换使用。芳基基团的实例可以包括但不限于苯基、萘基、蒽基、菲基或芘基等。多环芳基包括稠环和桥环的芳基，关于稠环和桥环的解释与多环杂环基类似。
除另有特别限定，术语“杂芳基”或“杂芳环基”表示含有5、6、7、8、9、10、11、12、13或14元结构，或优选5-10元结构，或优选5-8元结构，更优选5-6元结构的芳香单环或者多环环状系统，其中1个、2个、3个或更多个环原子为杂原子且其余原子为碳，杂原子独立地选自O、N或S，杂原子数量优选为1个、2个或3个。杂芳基的实例包括但不限于呋喃基、噻吩基、噁唑基、噻唑基、异噁唑基、噁二唑基、噻二唑基、吡咯基、吡唑基、咪唑基、三唑基、四唑基、吡啶基、嘧啶基、吡嗪基、哒嗪基、硫代二唑基、三嗪基、酞嗪基、喹啉基、异喹啉基、喋啶基、嘌呤基、吲哚基、异吲哚基、吲唑基、苯并呋喃基、苯并噻吩基、苯并吡啶基、苯并嘧啶基、苯并吡嗪基、苯并咪唑基、苯并酞嗪基、吡咯并[2,3-b]吡啶基、咪唑并[1,2-a]吡啶基、吡唑并[1,5-a]吡啶基、吡唑并[1,5-a]嘧啶基、咪唑并[1,2-b]哒嗪基、[1,2,4]三唑并[4,3-b]哒嗪基、[1,2,4]三唑并[1,5-a]嘧啶基、[1,2,4]三唑并[1,5-a]吡啶基等。多环杂芳基包括稠环和桥环的杂芳基，关于稠环和桥环的解释与多环杂环基类似。
当一个取代基可以连接到一个环上的一个以上原子时，这种取代基可以与这个环上的任意原子(包括杂原子，例如NH)相键合，例如
Figure PCTCN2022094255-appb-000081
表示连接位点可以在苯环或吡啶环上的任意一个位置，或者可以在苯环或四氢呋喃环上的任意一个位置。
除另有特别限定，术语“药物上可接受的盐”或“可药用盐”是指在合理医学判断范围内适用于与哺乳动物特别是人的组织接触而无过度毒性、刺激、过敏反应等并与合理的效益/风险比相称的盐，比如胺、羧酸和其他类型化合物的医学上可接受的盐在所属领域中是被熟知的。可以在本申请化合物的最终分离和纯化期间原位制备所述盐，或单独通过将游离碱或游离酸与合适的试剂反应制备所述盐。本申请的药物上可接受的盐包括本申请所述化合物的酸加成盐或碱加成盐，其分别由本申请所述化合物与本领域技术人员所熟知的无机酸或有机酸以及无机碱或有机碱反应而获得。
除另有特别限定，术语“同位素衍生物”是指本申请的化合物可以以同位素示踪的或富集形式存在，含有一个或多个原子，这些原子的原子量或质量数不同于自然界中发现的最大量的原子的原子量或质量数。同位素可以是放射性或非放射性的同位素。通常用作同位素标记的同位素是：氢同位素， 2H和 3H；碳同位素： 13C和 14C；氯同位素： 35Cl和 37Cl；氟同位素： 18F；碘同位素： 123I和 125I；氮同位素： 13N和 15N；氧同位素： 15O、 17O和 18O和硫同位素 35S。这些同位素标记化合物可以用来研究药用分子在组织中的分布情况。尤其是 2H和 13C，由于它们容易标记且方便检测，运用更为广泛。某些重 同位素，比如重氢( 2H)的取代能增强代谢的稳定性，延长半衰期从而达到减少剂量的目的而提供疗效优势。同位素标记的化合物一般从已被标记的起始物开始，用已知的合成技术如同合成非同位素标记的化合物一样来完成其合成。
除另有特别限定，术语“溶剂合物”、“溶剂化物”意指本申请化合物与一个或多个溶剂分子(无论有机的还是无机的)的物理缔合。该物理缔合包括氢键。在某些情形中，例如当一个或多个溶剂分子纳入结晶固体的晶格中时，溶剂化物将能够被分离。溶剂化物中的溶剂分子可按规则排列和/或无序排列存在。溶剂合物可包含化学计量或非化学计量的溶剂分子。“溶剂合物”涵盖溶液相和可分离的溶剂合物。示例性溶剂合物包括但不限于水合物、乙醇合物、甲醇合物和异丙醇合物。溶剂化方法是本领域公知的。
除另有特别限定，术语“立体异构体”是指具有相同化学构造，但原子或基团在空间上排列方式不同的化合物。立体异构体包括对映异构体、非对映异构体、构象异构体(旋转异构体)、几何异构体(顺/反)异构体、阻转异构体等。所得的任何立体异构体的混合物可以依据组分物理化学性质上的差异被分离成纯的或基本纯的几何异构体，对映异构体，非对映异构体，例如，通过色谱法和/或分步结晶法。
除另有特别限定，术语“互变异构体”是指具有不同能量的可通过低能垒互相转化的结构异构体。若互变异构是可能的(如在溶液中)，则可以达到互变异构体的化学平衡。例如，质子互变异构体(也称为质子转移互变异构体)包括通过质子迁移来进行的互相转化，如酮-烯醇异构化和亚胺-烯胺异构化。价键互变异构体包括通过一些成键电子的重组来进行的互相转化。
除有其他特别说明，本申请所描述的结构式包括所有的同分异构形式(如对映异构，非对映异构，和几何异构(或构象异构))：例如含有不对称中心的R、S构型，双键的(Z)、(E)异构体，和(Z)、(E)的构象异构体。因此，本申请的化合物的单个立体化学异构体或其对映异构体，非对映异构体，或几何异构体(或构象异构体)的混合物都属于本申请的范围。
除另有特别限定，术语“前药”是指在体内转化为母体药物的药物。前药通常是有用的，其可以改善一些确定的、不合需要的物理或生物学性质。物理性能通常是相关的溶解度(过高或不足的脂质或水溶性)或稳定性，而有问题的生物学特性包括代谢太快或生物利用率差，这本身可能与物理化学性质相关。例如，它们可以通过口服而被生物利用，而母体则不能。与母体药物相比，前药在药物组合物中的溶解度也有所提高。前药的一个例子，但不限于此，可以是任何本申请的化合物，其作为酯(“前药”)给药，以促进穿过细胞膜的传递，其中水溶性对迁移性有害，但一旦进入细胞内水溶性是有益的，其随后被代谢水解成羧酸，即活性实体。前药的另一个例子可以是与酸基团结合的短肽(聚氨基酸)，其中肽被代谢以显示活性部分。
除另有特别限定，术语“治疗”涵盖了对患者疾病、病症和病况的任何治疗，包括：(a)抑制疾病、病症和病况的症状，即阻止其发展；或(b)缓解疾病、病症和病况的症状，即，导致疾病或症状消退；或(c)改善或消除疾病、病症和病况或与所述疾病相关的一个或多个症状。
除另有特别限定，术语“治疗有效量”意指(i)治疗特定疾病、病症或病况，(ii)减轻、改善或消除特定疾病、病症或病况的一种或多种症状，或(iii)延迟本文中所述的特定疾病、病症或病况的一种或多种症状发作的本申请化合物的用量。构成“治疗有效量”的本申请化合物的量取决于该化合物、疾病状态及其严重性、给药方式以及待被治疗的哺乳动物的年龄而改变，但可例行性地由本领域技术人员根据其自身的知识及本公开内容而确定。
除另有特别限定，术语“药学上可接受的辅料”是指对有机体(例如人)无明显刺激作 用，而且不会损害活性化合物的生物活性及性能的那些辅料。合适的辅料是本领域技术人员熟知的，例如碳水化合物、蜡、水溶性和/或水可膨胀的聚合物、亲水性或疏水性材料、明胶、油、溶剂、水等。“药学上可接受的辅料”还可指与活性成分一同给药的、有利于活性成分给药的惰性物质，包括但不限于被美国食品药品管理局许可为可接受的用于人或动物(例如家畜)的任何助流剂、增甜剂、稀释剂、防腐剂、染料/着色剂、矫味剂、表面活性剂、润湿剂、分散剂、崩解剂、助悬剂、稳定剂、等渗剂、溶剂或乳化剂等辅料。
本申请的有益效果为：
本申请设计了一类结构新颖的化合物，为治疗肿瘤、癌症、癌转移、心血管疾病、免疫紊乱或视觉紊乱提供一个新的方向。本申请化合物具有一个或多个以下优点：(1)较强的SHP2激酶抑制作用；(2)较高的暴露量并且吸收好；(3)对hERG通道没有明显的抑制作用，可具有较低的心脏毒性；(4)耐受性好，药物安全性高；和(5)体内抑瘤率高。此外，本申请研究了特定的合成方法，该合成方法工艺简单，操作便捷，利于规模化工业生产和应用。
具体实施方式
下面结合具体实施例，进一步阐述本申请的各个方面。应理解，这些实施例仅用于示例性说明本申请而不用于限制本申请描述的各方面的范围。如果实施例中未注明具体条件的实验方法，通常按照常规条件或者按照制造厂商所建议的条件进行实施的。除非另行定义，本申请中所使用的所有专业与科学用语与本领域专业人员所熟悉的意义相同。此外，任何与所记载内容相似或均等的方法及材料皆可应用于本申请方法之中。本申请所示的较佳实施方法与材料仅做示范之用。
制备实施例、实施例及本文其他地方使用的缩写词是：
DCM          二氯甲烷
TEA          三乙胺
EA           乙酸乙酯
DMSO         二甲基亚砜
DMF          N,N-二甲基甲酰胺
TFA          三氟乙酸
DIPEA        N,N-二异丙基乙胺
Pd(dppf)Cl 2  1,1'-双二苯基膦二茂铁二氯化钯
Pd 2(dba) 3    三(二亚苄基丙酮)二钯
Pd(PPh 3) 4    四(三苯基膦)钯(0)
XantPhos     4,5-双二苯基膦-9,9-二甲基氧杂蒽
(Boc) 2O      二碳酸二叔丁酯
NBS          N-溴代琥珀酰亚胺
Dtbpy        4,4'-二叔丁基联吡啶
DMA          N,N-二甲基乙酰胺
TBAI         四丁基碘化铵
EDCI         1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐。
中间体制备例1：1-(5-氨基-3-氯吡嗪-2-基)乙酮(中间体1)
Figure PCTCN2022094255-appb-000082
向2-氨基-5-溴-6-氯吡嗪(20.0g，96.67mmol，1.0eqv)的1,4-二氧六环(240ml)溶液中加入三丁基(1-乙氧基乙烯基)锡(52.36g，144.98mmol，1.5eqv)、CuI(1.84g，9.667mmol，0.1eqv)和Pd(Ph 3P) 2Cl 2(6.78g，9.667mmol，0.1eqv)，氮气保护，100℃过夜反应。降温至室温，向反应液中加入硅胶，减压浓缩至干，进行柱层析纯化(正己烷：EA＝10:1～5:1)，得到1-(5-氨基-3-氯吡嗪-2-基)乙酮(5.1g，收率31％)。(ES,m/z):171.97[M+H] +。
中间体制备例2：3-氯-5-((2,4-二甲氧基苄基)氨基)吡嗪-2-羧酸甲酯(中间体2)
Figure PCTCN2022094255-appb-000083
氮气保护下，向3,5-二氯吡嗪-2-羧酸甲酯(3.8g,18.36mmol,1eqv)、2,4-二甲氧基苯甲胺(3.07g,18.36mmol,1eqv)的DMSO(40mL)中加入CsF(8.36g,55.07mmol,3eqv)，然后升温至75℃，反应3h；降温至室温，将反应液倾入水(200ml)和EA(100ml)中，分液，水相用EA(2×50ml)萃取，合并有机相。有机相用盐水(100ml)洗涤，减压浓缩，残留物经柱层析纯化(正己烷：EA＝10:1～1:1)，得3-氯-5-((2,4-二甲氧基苄基)氨基)吡嗪-2-羧酸甲酯(4g，收率54.06％)。(ES,m/z):338.1[M+H] +； 1H NMR(400MHz,CDCl 3)：δppm 7.82(s,1H)7.23(d,J＝8.4Hz,1H)6.41-6.51(m,2H)5.66(br s,1H)4.55(d,J＝5.6Hz,2H)3.94(s,3H)3.85(s,3H)3.81(s,3H)。
中间体制备例3：2-氯-3-(噁唑-2-基)苯硫醇(中间体3)
Figure PCTCN2022094255-appb-000084
步骤a：将2-氯-3-氟苯胺(5.00g,33.663mmol,1eqv)、叔丁基硫醇(3.64g,40.396mmol,1.2eqv)、Cs 2CO 3(32.90g,100.989mmol,3eqv)的DMF(50ml)溶液在130℃反应24h；降温至室温，将反应液倾入水(300ml)，用EA(2×300ml)萃取，合并有机相，有机相用盐水(2×500ml)洗涤，减压浓缩，残留物经柱层析纯化(正己烷：EA＝100:1～20:1)，得3-(叔丁基硫烷基)-2-氯苯胺(7.0g，收率94.46％)。(ES,m/z):216[M+H] +。
步骤b：将3-(叔丁基硫烷基)-2-氯苯胺(7.0g,32.55mmol,1eqv)的浓盐酸(15ml)液降温至-10～-5℃，滴加亚硝酸钠(3.369g，48.83mmol,1.5eqv)的水(105ml)溶液，滴毕后保温反应30min；同温下，滴加碘化钾(6.484g，39.06mmol,1.2eqv)的水(65ml)溶液，滴毕后保温反应20min；向反应液中加入乙酸乙酯(100ml)和饱和硫代硫酸钠溶液(100ml)，搅拌10min，分液，水相用EA(2×50ml)萃取，合并有机相；有机相用盐水(100mL)洗涤， 减压浓缩，残留物经柱层析纯化(正己烷)，得叔丁基(2-氯-3-碘苯基)硫烷(6.52g，收率61.45％)。 1H-NMR(400MHz,DMSO-d6)δ7.99(dd,J＝7.9,1.5Hz,1H),7.68(dd,J＝7.7,1.5Hz,1H),7.10(t,J＝7.8Hz,1H),1.29(s,9H)。
步骤c：将叔丁基(2-氯-3-碘苯基)硫烷(6.5g，19.94mmol,1eqv)、噁唑(2.75g，39.88mmol,2eqv)、叔丁醇锂(1.92g，23.93mmol，1.2eqv)、CuI(380mg，1.994mmol，0.1eqv)的DMF(50ml)溶液在氮气保护下140℃反应2h，TLC检测反应完全；降温至室温，将反应液倾入水(300ml)，用EA(2×150ml)萃取，合并有机相，有机相用盐水(2×100ml)洗涤，减压浓缩，残留物经柱层析纯化(正己烷：EA＝25:1～10:1)，得2-(3-(叔丁硫烷基)-2-氯苯基)噁唑(3.12g，收率58.58％)。(ES,m/z):267.93[M+H] +。 1H-NMR(400MHz,CDCl 3)δ7.91(dd,J＝7.8,1.7Hz,1H),7.80(d,J＝0.7Hz,1H),7.78(dd,J＝7.7,1.7Hz,1H),7.36-7.31(m,2H),1.37(s,9H)。
步骤d:0℃下，向2-(3-(叔丁硫烷基)-2-氯苯基)噁唑(3.12g,11.68mmol,1eqv)的甲苯(60ml)溶液中加入三氯化铝(6.23g，46.72mmol，4eqv)，室温过夜反应；降温至0℃，滴加水(60ml)，搅拌30min，分液；水相用甲苯(30ml)萃取，合并有机相；减压浓缩，残留物经柱层析纯化(正己烷：EA＝20:1～5:1)，得2-氯-3-(噁唑-2-基)苯硫醇(1.726g，收率70％)。(ES,m/z):211.89[M+H] +。
中间体制备例4～5：
采用中间体制备例3的步骤及以下相应的起始原料合成中间体4～5：
Figure PCTCN2022094255-appb-000085
中间体制备例6：2-氯-3-(吡嗪-2-基)苯硫醇(中间体6)
Figure PCTCN2022094255-appb-000086
步骤a：氮气保护下，将叔丁基(2-氯-3-碘苯基)硫烷(3.26g,10mmol,1eqv)、吡嗪-2-硼酸(1.49g,12mmol,1.2eqv)、K 2CO 3(4.14g,30mmol,3eqv)和Pd(dppf)Cl 2(731.7mg,1mmol,0.1eqv)的1,4-二氧六环(80ml)和水(20ml)溶液在100℃过夜反应；反应液减压浓缩，残留物经柱层析纯化(正己烷：EA＝50:1～25:1)，得2-(3-(叔丁硫烷基)-2-氯苯基)吡嗪(1.21g，收率43.5％)。(ES,m/z):279.00[M+H] +。
步骤b：0℃下，向2-(3-(叔丁硫烷基)-2-氯苯基)吡嗪(1.21g,4.35mmol,1eqv)的甲苯(60ml)溶液中，分批加入三氯化铝(2.32g，17.4mmol，4eqv)，室温过夜反应；降温至0℃，滴加水(60ml)，搅拌30min，分液；水相用甲苯(30ml)萃取，合并有机相；减压浓缩，残留物经柱层析纯化(正己烷：EA＝20:1～5:1)，得2-氯-3-(吡嗪-2-基)苯硫醇(726mg，收率75.2％)。(ES,m/z):222.89[M+H] +。
中间体制备例7～9
采用中间体制备例6的步骤及以下相应的起始原料合成中间体7～9：
Figure PCTCN2022094255-appb-000087
中间体制备例10：3-氯-2-(吡嗪-2-基)吡啶-4-硫醇(中间体10)
Figure PCTCN2022094255-appb-000088
步骤a：氮气保护下，将2,3-二氯-4-碘吡啶(2.00g,7.33mmol,1.00eqv)、3-巯基丙酸-2-乙基-己酯(2.07g,9.51mmol,1.3eqv)、DIPEA(2.862g,21.99mmol,3.00eqv)、Pd 2(dba) 3(1.342g,1.466mmol,0.2eqv)和XantPhos(1.696g,2.932mmol,0.4eqv)的1,4-二氧六环(50ml)溶液在96℃搅拌8h；降温至室温，反应液通过硅藻土抽滤，滤液减压浓缩；残留物经柱层析纯化(正己烷：EA＝20:1)，得3-(2-(2,3-二氯吡啶-4-基)硫烷基)丙酸2-乙基-己酯(2.076g，收率78％)。(ES,m/z):364.06[M+H] +。
步骤b：氮气保护下，将3-(2-(2,3-二氯吡啶-4-基)硫烷基)丙酸2-乙基-己酯(666mg,1.834mmol,1.0eqv)、吡嗪-2-硼酸(250mg,2.02mmol,1.1eqv)、Pd(dppf)Cl 2(134mg,0.183mmol,0.1eqv)和碳酸钾(760mg,5.503mmol,3eqv)的1,4-二氧六环(60mL)和水(10ml)溶液96℃过夜反应；降温，减压浓缩，残留物中加入水(200ml)和EA(100ml)，分液，水相用EA(2×50ml)萃取，合并有机相；有机相用盐水(100ml)洗涤，减压浓缩，残留物经柱层析纯化(正己烷：EA＝30:1～10:1)，得3-((3-氯-2-(吡嗪-2-基)吡啶-4-基)硫烷基)丙酸2-乙基-己酯(637mg，收率85.3％)。(ES,m/z):408.15[M+H] +。
步骤c：氮气保护下，将3-((3-氯-2-(吡嗪-2-基)吡啶-4-基)硫烷基)丙酸2-乙基-己酯(637mg,1.565mmol,1.0eqv)，NaOH(66mg,1.643mmol,1.05eqv)的甲醇(60ml)溶液在50℃下反应3h；降温至0℃左右，滴加4M HCl/MeOH液，调节pH至3～4，减压浓缩，进行柱层析纯化(正己烷：EA＝10:1～5:1)，得3-氯-2-(吡嗪-2-基)吡啶-4-硫醇(320mg，收率91.7％)。(ES,m/z):223.92[M+H] +。
中间体制备例11：(R)-2-甲基-N-((R)-3H-螺[苯并呋喃-2,4'-哌啶]-3-基)丙烷-2-亚磺酰胺 (中间体11)
Figure PCTCN2022094255-appb-000089
步骤a～b:按照WO2021061706A1由Compound 7制备Compound 8方法进行。
步骤c：将产物M11-2(5.0g，12.238mmol)溶于DCM(90ml)，0℃条件下滴加三氟乙酸(30ml)，室温反应3h，减压浓缩，向残留物中加入水(50ml)，用25％氨水调节pH至10，水相用EA:THF＝1:1的混合溶液萃取(60ml×4)，合并有机相，无水硫酸钠干燥，减压浓缩，得到(R)-2-甲基-N-((R)-3H-螺[苯并呋喃-2,4'-哌啶]-3-基)丙烷-2-亚磺酰胺(3.2g)。(ES,m/z):309.10[M+H] +。
中间体制备例11A：(R)-N-((S)-1,3-二氢螺[茚-2,4'-哌啶]-1-基)-2-甲基丙烷-2-亚磺酰胺(中间体11A)
Figure PCTCN2022094255-appb-000090
将(S)-叔丁基1-((R)-1,1-二甲基乙基亚磺酰氨基)-1,3-二氢螺[茚-2,4'-哌啶]-1'-羧酸酯(48.00g)、TFA(40ml)的DCM(160ml)溶液室温过夜反应；反应液减压浓缩，向残留物中加入EA(200ml)和水(200ml)，用25％氨水调节pH至10，分液；水相用EA(100ml×2)萃取，合并有机相；有机相用水(100ml)，盐水(100ml)洗涤，无水硫酸钠干燥，浓缩，得(R)-N-((S)-1,3-二氢螺[茚-2,4'-哌啶]-1-基)-2-甲基丙烷-2-亚磺酰胺粗品(中间体11A)(32g)。(ES,m/z):307.09[M+H] +。
中间体制备例12：(R)-(1'-(3-乙酰基-6-氨基-5-溴吡嗪-2-基)-3H-螺[苯并呋喃-2,4'-哌啶]-3-基)氨基甲酸叔丁酯(中间体12)
Figure PCTCN2022094255-appb-000091
步骤a：将1-(5-氨基-3-氯吡嗪-2-基)乙酮(266mg，1.555mmol，1.0eqv)、(R)-2-甲基-N-((R)-3H-螺[苯并呋喃-2,4'-哌啶]-3-基)丙烷-2-亚磺酰胺(575mg，1.866mmol，1.2eqv)、DIPEA(603mg，4.6655mmol，3.0eqv)的DMSO(10ml)溶液在110℃反应8h；降至室温， 加入水(50ml)，用EA(3×30ml)萃取，合并有机相；有机相用H 2O(100ml)、盐水(100ml)洗涤，减压浓缩，用硅胶柱层析进行纯化(洗脱剂为DCM:MeOH＝80:1～50:1)，得到(R)-N-((R)-1'-(3-乙酰基-6-氨基吡嗪-2-基)-3H-螺[苯并呋喃-2,4'-哌啶]-3-基)-2-甲基丙烷-2-亚磺酰胺(321mg，收率46％)。(ES,m/z):444.16[M+H] +。
步骤b：向装有(R)-N-((R)-1'-(3-乙酰基-6-氨基吡嗪-2-基)-3H-螺[苯并呋喃-2,4'-哌啶]-3-基)-2-甲基丙烷-2-亚磺酰胺(321mg，0.724mmol，1.0eqv)的反应瓶中加入HCl/CH 3OH溶液(10mL)，室温搅拌反应4h后，将反应液旋干，得到粗品((R)-1-(5-氨基-3-(3-氨基-3H-螺[苯并呋喃-2,4'-哌啶]-1'-基)吡嗪-2-基)乙酮。(ES,m/z):340.10[M+H] +。
步骤c：室温条件下，将TEA(220mg，2.175mmol，3.0eqv)加入到(R)-1-(5-氨基-3-(3-氨基-3H-螺[苯并呋喃-2,4'-哌啶]-1'-基)吡嗪-2-基)乙酮(246mg，0.724mmol，1.0eqv)的DCM(50ml)溶液中，然后加入(Boc) 2O(316mg，1.448mmol，2.0eqv)，室温过夜反应。向反应液加入水(50ml)，分液，水相用DCM(20ml×2)萃取，合并有机相；并用H 2O(20mL)、盐水(20mL)洗涤合并的有机相，减压浓缩，用硅胶柱层析进行纯化(正己烷:EA＝5:1～1:5)，得到(R)-(1'-(3-乙酰基-6-氨基吡嗪-2-基)-3H-螺[苯并呋喃-2,4'-哌啶]-3-基)氨基甲酸叔丁酯(221mg，收率69.5％)。(ES,m/z):440.15[M+H] +。
步骤d：-15℃条件下，将NBS(94mg，0.528mmol，1.05eqv)加入含(R)-(1'-(3-乙酰基-6-氨基吡嗪-2-基)-3H-螺[苯并呋喃-2,4'-哌啶]-3-基)氨基甲酸叔丁酯(221mg，0.503mmol，1.0eqv)的DCM(20ml)溶液中，恒温搅拌反应10min。反应液加入饱和碳酸氢钠水溶液(10ml)淬灭，分液，水相用DCM(10ml×2)萃取，合并有机相；有机相用H 2O(20ml)、盐水(20ml)洗涤，减压浓缩，用硅胶柱层析进行纯化(正己烷:EA＝5:1～1:1)，得到(R)-(1'-(3-乙酰基-6-氨基-5-溴吡嗪-2-基)-3H-螺[苯并呋喃-2,4'-哌啶]-3-基)氨基甲酸叔丁酯(132mg，收率50.75％)。(ES,m/z):518.09[M+H] +。
中间体制备例13：(R)-5-氨基-6-溴-3-(3-((叔丁氧基羰基)氨基)-3H-螺[苯并呋喃-2,4'-哌啶]-1'-基)吡嗪-2-羧酸甲酯(中间体13)
Figure PCTCN2022094255-appb-000092
步骤a：将3-氯-5-((2,4-二甲氧基苄基)氨基)吡嗪-2-羧酸甲酯(200mg，0.593mmol，1.0eqv)、(R)-2-甲基-N-((R)-3H-螺[苯并呋喃-2,4'-哌啶]-3-基)丙烷-2-亚磺酰胺(201mg，0.653mmol，1.1eqv)和DIPEA(230mg，1.779mmol，3.0eqv)的DMSO(10ml)溶液中110℃反应10h；降至室温，向反应液中加入水(60ml)和EA(60ml)，分液，水相用EA(3×20ml) 萃取，合并有机相；有机相用H 2O(100ml)、盐水(50ml)洗涤，减压浓缩，用硅胶柱层析进行洗脱纯化(洗脱剂为EA:MeOH＝80:1～20:1)，得到5-((2,4-二甲氧基苄基)氨基)-3-((R)-3-((R)-1,1-二甲基乙基亚磺酰氨基)-3H-螺[苯并呋喃-2,4'-哌啶]-1'-基)吡嗪-2-羧酸甲酯(305mg，收率84.42％)。(ES,m/z):610.20[M+H] +。
步骤b：向5-((2,4-二甲氧基苄基)氨基)-3-((R)-3-((R)-1,1-二甲基乙基亚磺酰氨基)-3H-螺[苯并呋喃-2,4'-哌啶]-1'-基)吡嗪-2-羧酸甲酯(305mg，0.501mmol，1.0eqv)中加入CF 3COOH(6ml)，室温搅拌反应3h后，将反应液旋干，得到粗品5-氨基-3-((R)-3-((R)-1,1-二甲基乙基亚磺酰氨基)-3H-螺[苯并呋喃-2,4'-哌啶]-1'-基)吡嗪-2-羧酸甲酯(230mg)。(ES,m/z):460.15[M+H] +。
步骤c：向5-氨基-3-((R)-3-((R)-1,1-二甲基乙基亚磺酰氨基)-3H-螺[苯并呋喃-2,4'-哌啶]-1'-基)吡嗪-2-羧酸甲酯粗品(230mg)中加入HCl/CH 3OH溶液(10mL)，室温搅拌反应2h后，将反应液旋干，得到粗品(R)-5-氨基-3-(3-氨基-3H-螺[苯并呋喃-2,4'-哌啶]-1'-基)吡嗪-2-羧酸甲酯(178mg)。(ES,m/z):356.11[M+H] +。
步骤d：室温条件下，将TEA(253.3mg，2.505mmol，5.0eqv)加入(R)-5-氨基-3-(3-氨基-3H-螺[苯并呋喃-2,4'-哌啶]-1'-基)吡嗪-2-羧酸甲酯(178mg，0.501mmol，1.0eqv)的DCM(20ml)溶液中，然后加入(Boc) 2O(142mg，0.651mmol，1.3eqv)，室温过夜反应。向反应液加入水(25ml)，分液，水相用DCM(10mL×2)萃取，合并有机相；有机相用H 2O(20ml)、盐水(20ml)洗涤，减压浓缩，用硅胶柱层析进行纯化，洗脱剂为DCM:MeOH＝100:1～20:1，得到(R)-5-氨基-3-(3-((叔丁氧基羰基)氨基)-3H-螺[苯并呋喃-2,4'-哌啶]-1'-基)吡嗪-2-羧酸甲酯(133mg，收率58.3％)。(ES,m/z):456.16[M+H] +。
步骤e：-15℃条件下，将NBS(57mg，0.321mmol，1.1eqv)加入到(R)-5-氨基-3-(3-((叔丁氧基羰基)氨基)-3H-螺[苯并呋喃-2,4'-哌啶]-1'-基)吡嗪-2-羧酸甲酯(133mg，0.292mmol，1.0eqv)的DCM(30ml)溶液中，保温反应10min。反应液加入饱和碳酸氢钠水溶液(20ml)，分液，水相用DCM(10ml×2)萃取，合并有机相；有机相用H 2O(20ml)、盐水(20ml)洗涤，减压浓缩，用硅胶柱层析进行纯化，洗脱剂为正己烷:EA＝5:1～1:2，得到(R)-5-氨基-6-溴-3-(3-((叔丁氧基羰基)氨基)-3H-螺[苯并呋喃-2,4'-哌啶]-1'-基)吡嗪-2-羧酸甲酯(100mg，收率64.3％)。(ES,m/z):534.09[M+H] +。
中间体制备例14：(R)-6-溴-3-(3-((叔丁氧基羰基)氨基)-3H-螺[苯并呋喃-2,4'-哌啶]-1'-基)吡嗪-2-羧酸甲酯(中间体14)
Figure PCTCN2022094255-appb-000093
步骤a：将3,6-二溴吡嗪-2-羧酸甲酯(460mg，1.555mmol，1.0eqv)、(R)-2-甲基-N-((R)-3H-螺[苯并呋喃-2,4'-哌啶]-3-基)丙烷-2-亚磺酰胺(575mg，1.866mmol，1.2eqv)、DIPEA(603mg，4.6655mmol，3.0eqv)的DMSO(10ml)溶液在110℃反应6h；降至室温，加入水(50ml)，用EA(3×30ml)萃取，合并有机相；有机相用H 2O(100ml)、盐水(100ml) 洗涤，减压浓缩，用硅胶柱层析进行纯化(洗脱剂为DCM:MeOH＝100:1～40:1)，得到6-溴-3-((R)-3-((R)-1,1-二甲基乙基亚磺酰氨基)-3H-螺[苯并呋喃-2,4'-哌啶]-1'-基)吡嗪-2-羧酸甲酯(375mg，收率46.2％)。(ES,m/z):523.01[M+H] +。
步骤b：向6-溴-3-((R)-3-((R)-1,1-二甲基乙基亚磺酰氨基)-3H-螺[苯并呋喃-2,4'-哌啶]-1'-基)吡嗪-2-羧酸甲酯(375mg，0.718mmol，1.0eqv)中加入HCl/CH 3OH溶液(10ml)，室温搅拌反应4h后，将反应液旋干，得到粗品(R)-3-(3-氨基-3H-螺[苯并呋喃-2,4'-哌啶]-1'-基)-6-溴吡嗪-2-羧酸甲酯。(ES,m/z):419.02[M+H] +。
步骤c：室温条件下，将TEA(218mg，2.155mmol，3.0eqv)加入到(R)-3-(3-氨基-3H-螺[苯并呋喃-2,4'-哌啶]-1'-基)-6-溴吡嗪-2-羧酸甲酯(300mg，0.718mmol，1.0eqv)的DCM(50ml)溶液中，然后加入(Boc) 2O(299mg，1.437mmol，2.0eqv)，室温过夜反应。向反应液加入水(50ml)，分液，水相用DCM(20ml×2)萃取，合并有机相；用H 2O(20mL)、盐水(20mL)洗涤合并的有机相，减压浓缩，用硅胶柱层析进行纯化(正己烷:EA＝5:1～1:5)，得到(R)-6-溴-3-(3-((叔丁氧基羰基)氨基)-3H-螺[苯并呋喃-2,4'-哌啶]-1'-基)吡嗪-2-羧酸甲酯(279mg，收率75％)。(ES,m/z):519.09[M+H] +。
中间体制备例14A：
采用中间体制备例14的步骤及以下相应的起始原料合成中间体14A：
Figure PCTCN2022094255-appb-000094
中间体制备例15：(R)-(1'-(3-乙酰基-5-溴吡嗪-2-基)-3H-螺[苯并呋喃-2,4'-哌啶]-3-基)氨基甲酸叔丁酯(中间体15)
Figure PCTCN2022094255-appb-000095
步骤a：将(R)-6-溴-3-(3-((叔丁氧基羰基)氨基)-3H-螺[苯并呋喃-2,4'-哌啶]-1'-基)吡嗪-2-羧酸甲酯(500mg,0.965mmol,1eqv)、LiOH·H 2O(81mg,1.93mmol,2eqv)的THF(10ml)和水(10ml)的溶液室温过夜反应；用1N HCl溶液调节pH至3～4，减压浓缩，残留物中加入水(60ml)和EA(60ml)，分液，水相用EA(3×20ml)萃取，合并有机相；有机相用H 2O(100ml)、盐水(50ml)洗涤，减压浓缩，用硅胶柱层析进行洗脱纯化(洗脱剂为DCM:MeOH＝80:1～20:1)，得到(R)-6-溴-3-(3-((叔丁氧基羰基)氨基)-3H-螺[苯并呋喃-2,4'-哌啶]-1'-基)吡嗪-2-羧酸(440mg，收率90.45％)。(ES,m/z):505.02[M+H] +。
步骤b：氮气保护下，0℃下，向(R)-6-溴-3-(3-((叔丁氧基羰基)氨基)-3H-螺[苯并呋喃-2,4'-哌啶]-1'-基)吡嗪-2-羧酸(400mg,0.793mmol,1eqv)的无水DMF(10ml)溶液中，加入甲氧基甲基胺(58mg,0.952mmol,1.2eqv)、EDCI(182.4mg,0.952mmol,1.2eqv)、HOBt(128.6mg，0.952mmol,1.2eqv)和Et 3N(160mg,1.586mmol,2eqv)，然后室温反应6h；向反应中加入水(60ml)和EA(60ml)，分液，水相用EA(3×20ml)萃取，合并有机相；有机相用H 2O(100ml)、盐水(50ml)洗涤，减压浓缩，用硅胶柱层析进行洗脱纯化(洗脱剂为DCM:MeOH＝100:1～25:1)，得到(R)-(1'-(5-溴-3-(甲氧基(甲基)氨基甲酰基)吡嗪-2-基)-3H-螺[苯并呋喃-2,4'-哌啶]-3-基)氨基甲酸叔丁酯(227mg，收率52.32％)。(ES,m/z):548.10[M+H] +。
步骤c：氮气保护下，在-78℃下，向(R)-(1'-(5-溴-3-(甲氧基(甲基)氨基甲酰基)吡嗪-2-基)-3H-螺[苯并呋喃-2,4'-哌啶]-3-基)氨基甲酸叔丁酯(227mg,0.415mmol,1eqv)的无水THF(10ml)溶液中滴加甲基溴化镁(3.0M,0.276ml,2eqv)，自然升温至0℃反应2h；用饱和NH 4Cl溶液淬灭反应；向反应中加入水(60ml)和EA(60ml)，分液，水相用EA(3×20ml)萃取，合并有机相；有机相用H 2O(100ml)、盐水(50ml)洗涤，减压浓缩，用硅胶柱层析进行洗脱纯化(洗脱剂为DCM:MeOH＝50:1～20:1)，得到(R)-(1'-(3-乙酰基-5-溴吡嗪-2-基)-3H-螺[苯并呋喃-2,4'-哌啶]-3-基)氨基甲酸叔丁酯(100mg，收率48％)。(ES,m/z):503.07[M+H] +。
中间体制备例15A～15C：
采用中间体制备例15的步骤及以下相应的起始原料合成中间体15A～15C：
Figure PCTCN2022094255-appb-000096
中间体制备例16：6-氯-3-((2-氯-3-(噁唑-2-基)苯基)硫烷基)-5-(氧杂环丁-3-基)吡嗪-2-胺(中间体16)
Figure PCTCN2022094255-appb-000097
步骤a：氮气保护下，将3-溴-6-氯-吡嗪-2-胺(5.00g,23.988mmol,1.00equiv)、2-氯-3-(噁唑-2-基)苯硫醇(6.70g,28.786mmol,1.2eqv)、DIPEA(9.30g,71.963mmol,3.0eqv)、Pd 2(dba) 3.CHCl 3(0.62g,0.600mmol,0.025eqv)和XantPhos(0.69g,1.199mmol,0.05eqv)的1,4-二氧六环(100mL)溶液在95℃过夜反应，降温至室温，反应液通过硅藻土抽滤，滤液减压浓缩；残留物经柱层析纯化(正己烷：EA＝2:1)，得6-氯-3-((2-氯-3-(噁唑-2-基)苯基)硫烷基]吡嗪-2-胺(中间体M16-1)(5.86g，收率72.3％)。(ES,m/z):338.90[M+H] +。
步骤b：氮气保护下，0℃条件下，向6-氯-3-((2-氯-3-(噁唑-2-基)苯基)硫烷基]吡嗪-2-胺(5.50g,26.085mmol,1.00eqv),K 2CO 3(7.20g,52.17mmol,2.00eqv)的MeOH(160ml)溶液中，滴加ICl(6.35g,39.128mmol,1.50eqv)的DCM(160ml)溶液，控温反应2h，然后室温过夜反应；向反应液中加入500ml的10％Na 2SO 3淬灭，分液，水相用DCM(3×250ml)萃取，合并有机相；有机相用饱和NaCl 250ml洗涤，无水硫酸钠干燥并减压浓缩；得6-氯-3-((2-氯-3-(噁唑-2-基)苯基)硫烷基)-5-碘吡嗪-2-胺(中间体M16-2)(8.71g，收率72％)。(ES,m/z):464.80[M+H] +。
步骤c：将dtbpy(551mg,1.832mmol,0.10eqv)和DMA(200ml)置换氮气，加入NiBr 2.DME(724mg,1.832mmol,0.10eqv)，室温搅拌0.5h；然后加入6-氯-3-((2-氯-3-(噁唑-2-基)苯基)硫烷基)-5-碘吡嗪-2-胺(8.5g,18.324mmol,1.00eqv)、3-溴氧杂环丁烷(5.624g,36.647mmol,2.00eqv)、TBAI(758.2mg,1.832mmol,0.10eqv)、Zn(2.686g,36.647mmol,2.00eqv)，氮气保护下，75℃过夜搅拌反应；经硅藻土过滤，滤液倾入水(1000ml)中，用EA(2×500ml)萃取，合并有机相；有机相用盐水洗涤，无水硫酸钠干燥，减压浓缩，残留物用Prep-HPLC纯化(20-50％的乙腈水溶液梯度洗脱，用0.1％NH 4HCO 3改性)，得6-氯-3-((2-氯-3-(噁唑-2-基)苯基)硫烷基)-5-(氧杂环丁-3-基)吡嗪-2-胺(810mg，收率11.22％)。(ES,m/z):394.92[M+H] +。
中间体制备例17：6-氯-3-((2-氯-3-(噁唑-2-基)苯基)硫烷基)-5-乙烯基吡嗪-2-胺(中间体17)
Figure PCTCN2022094255-appb-000098
氮气保护下，将6-氯-3-((2-氯-3-(噁唑-2-基)苯基)硫烷基)-5-碘吡嗪-2-胺(197mg,0.425mmol,1eqv)、乙烯基三氟硼酸钾(116mg,0.85mmol,2eqv)、Pd(PPh 3) 4(50mg,0.0425mmol,0.1eqv)、碳酸钾(176mg,1.275mmol,3eqv)加入到甲苯(60ml)、乙醇(30ml)和水(15ml)中，在80℃反应5h；将反应液减压浓缩，向残留物中加入水(100ml)，用 EA(2×50ml)萃取，合并有机相；有机相用盐水(50ml)洗涤，减压浓缩，残留物经柱层析纯化(CH 2Cl 2:CH 3OH＝100:1)，得到6-氯-3-((2-氯-3-(噁唑-2-基)苯基)硫烷基)-5-乙烯基吡嗪-2-胺(101mg，收率65.3％)。(ES,m/z):364.93[M+H] +。
中间体制备例18：4-(噁唑-2-基)嘧啶-2-硫醇(中间体18)
Figure PCTCN2022094255-appb-000099
步骤a：氮气保护下，将2,4-二碘嘧啶(7.96g,23.99mmol,1eqv)、3-巯基丙酸甲酯(3.02g,25.19mmol,1.05eqv)、DIPEA(6.20g,47.97mmol,2eqv)、Pd(OAc) 2(538.53mg,2.40mmol,0.1eqv)和Xantphos(2.08g,3.60mmol,0.15eqv)的1,4-二氧六环(160ml)溶液在95℃过夜反应；降温至室温，反应液通过硅藻土抽滤，滤液减压浓缩；残留物经柱层析纯化(正己烷：EA＝100:1～20:1)，得3-((4-碘嘧啶-2-基)硫烷基)丙酸甲酯(5g,收率64.34％)。(ES,m/z):324.90[M+H] +。
步骤b：氮气保护下，将3-((4-碘嘧啶-2-基)硫烷基)丙酸甲酯(595mg,1.834mmol,1.0eqv)、噁唑-2-基硼酸(228mg,2.02mmol,1.1eqv)、Pd(dppf)Cl 2(134mg,0.183mmol,0.1eqv)和碳酸钾(760mg,5.503mmol,3eqv)的1,4-二氧六环(50mL)和水(10ml)溶液96℃过夜反应；降温，减压浓缩，残留物中加入水(200ml)和EA(100ml)，分液，水相用EA(2×50ml)萃取，合并有机相；有机相用盐水(100ml)洗涤，减压浓缩，残留物经柱层析纯化(正己烷：EA＝30:1～10:1)，得3-((4-(噁唑-2-基)嘧啶-2-基)硫烷基)丙酸甲酯(256mg，收率52.65％)。(ES,m/z):266[M+H] +。
步骤c：氮气保护下，将3-((4-(噁唑-2-基)嘧啶-2-基)硫烷基)丙酸甲酯(256mg,0.966mmol,1.0eqv)，NaOH(40.6mg,1.014mmol,1.05eqv)的甲醇(10ml)溶液在50℃下反应4h；降温至0℃左右，滴加4M HCl/MeOH溶液，调节pH至3～4；加入硅胶，进行柱层析纯化(正己烷：EA＝10:1～5:1)，得4-(噁唑-2-基)嘧啶-2-硫醇(130mg，收率75.2％)。(ES,m/z):179.92[M+H] +。
中间体制备例19～22
采用中间体制备例18的步骤及以下相应的起始原料合成中间体19～22：
Figure PCTCN2022094255-appb-000100
Figure PCTCN2022094255-appb-000101
中间体制备例23：(R)-2-甲基-N-((R)-3-氘-螺[苯并呋喃-2,4'-哌啶]-3-基)丙烷-2-亚磺酰胺(M-23)
Figure PCTCN2022094255-appb-000102
步骤a～b:氮气保护下，向3-氧代螺[1-苯并呋喃-2,4'-哌啶]-1'-羧酸叔丁酯(10.00g,32.965mmol,1.00eqv)和(R)-(+)-叔丁基亚磺酰胺(7.99g,65.93mmol,2eqv)的2-MeTHF(40ml)溶液中，加入Ti(OEt) 4(100ml)，在80℃反应48h；然后降温至-5℃，加入NaBD 4(1.66g，39.55mmol,1.2eqv)，室温过夜反应；降温至0℃，将甲醇(30ml)滴加入反应液中，加入水(1000ml)和EA(1000ml)，搅拌30min，过滤，滤液分液；有机相用盐水(1000ml)洗涤，无水硫酸钠干燥，减压浓缩；残留物经柱层析纯化(正己烷：EA＝6:1～2:1)，得M23-2(10.5g，收率77.78％)，(ES,m/z):410.13[M+H] +。
1H-NMR(600MHz,CDCl 3)δ7.285-7.273(m,1H),7.250-7.224(m,1H),6.929-6.904(m,1H),6.817(d,J＝7.8Hz,1H),4.086(br s,2H),3.673(s,1H),3.178(s,2H),2.011(s,1H),1.856(s,1H),1.770-1.748(m,1H),1.716-1.690(m,1H),1.465(s,9H),1.255(s,9H)。
步骤c：将M23-2(10.5g)溶于DCM(20ml)，0℃条件下滴加三氟乙酸(20ml)，室温反应6h，减压浓缩，向残留物中加入水(50ml)，用25％氨水调节pH至10，水相用EA萃取(50ml×3)，合并有机相，无水硫酸钠干燥，减压浓缩，得到(R)-2-甲基-N-((R)-3-氘-螺[苯并呋喃-2,4'-哌啶]-3-基)丙烷-2-亚磺酰胺(M-23)粗品(7.84g)，未纯化直接用于下步反应。(ES,m/z):310.07[M+H] +。
中间体制备例24：
采用中间体制备例23的步骤及以下相应的起始原料合成中间体24：
Figure PCTCN2022094255-appb-000103
中间体制备例25：(R)-(1'-(3-乙酰基-6-氨基-5-溴吡嗪-2-基)-3-氘-螺[苯并呋喃-2,4'-哌啶]-3-基)氨基甲酸叔丁酯(M-25)
Figure PCTCN2022094255-appb-000104
步骤a-b:氮气保护，将2-氨基-5-溴-6-氯吡嗪(20.0g，96.67mmol，1.0eqv)、三丁基(1-乙氧基乙烯基)锡(52.36g，144.98mmol，1.5eqv)、CuI(1.84g，9.667mmol，0.1eqv)、Pd(Ph 3P) 2Cl 2(6.78g，9.667mmol，0.1eqv)的1,4-二氧六环(240ml)溶液，100℃过夜反应，TLC检测反应完全，将(R)-2-甲基-N-((R)-3-氘-螺[苯并呋喃-2,4'-哌啶]-3-基)丙烷-2-亚磺酰胺(M-23)粗品(35.86g，115.987mmol，1.2eqv)的1,4-二氧六环(200ml)溶液加入反应液中，然后加入DIPEA(37.48g,289.97mmol，3.0eqv)，100℃过夜反应；降至室温，减压浓缩至干，用硅胶柱层析进行纯化(洗脱剂为EA:正己烷＝1:1～2:1)，得到M25-1(24.05g，收率56.01％)。(ES,m/z):445.07[M+H] +。
步骤c：0℃条件下，向M25-1(24.05g，54.14mmol，1.0eqv)的DCM(250ml)溶液中，加入NBS(11.563g，64.97mmol，1.2eqv)，室温过夜反应，然后加入4M HCl/CH 3OH溶液(10ml)搅拌1h；向反应液中加入饱和碳酸氢钠水溶液(100ml)，分液，水相用DCM(50ml×2)萃取，合并有机相；有机相用H 2O(200ml)、盐水(200ml)洗涤，无水硫酸钠干燥，过滤，得到M25-2粗品DCM溶液，未处理直接用于下步反应。(ES,m/z):419.00[M+H] +。
步骤d:0℃下，向步骤c的M25-2的DCM溶液中加入(Boc) 2O(14.2g)，滴加Et 3N(10.96g)，滴毕后，室温过夜反应；加入水(200ml)，分液，水相用DCM(100ml×2)萃取，合并有机相；有机相用H 2O(200ml)、盐水(200ml)洗涤，减压浓缩至干，用硅胶柱层析进行纯化(洗脱剂为EA:正己烷＝1:3～2:1)，得到M-25(16.43g)。(ES,m/z):519.09[M+H] +。
中间体制备例25A：M-25A的制备
采用中间体制备例25的步骤及以下相应的起始原料合成中间体M-25A：
Figure PCTCN2022094255-appb-000105
中间体制备例26：
采用中间体制备例13的步骤及以下相应的起始原料合成中间体26：
Figure PCTCN2022094255-appb-000106
中间体制备例27：M-27的制备
Figure PCTCN2022094255-appb-000107
步骤a：氮气保护，将M-25(3.00g，5.78mmol，1.0eqv)、3-巯基丙酸甲酯(1.04g，8.67mmol，1.5eqv)、Pd(OAc) 2(250mg，1.16mmol，0.2eqv)、Xantphos(1.34g，2.31mmol，0.4eqv)、DIPEA(2.25g，7.34mmol，3eqv)的1,4-二氧六环(60ml)反应液，97℃过夜反应。降温，减压浓缩，用硅胶柱层析进行纯化(洗脱剂为EA:正己烷＝1:3～2:1)，得到M27-1(3.00g，收率93％)，(ES,m/z):559.17[M+H] +。
步骤b：向M27-1(3.00g，5.37mmol，1.0eqv)的MeOH(30ml)溶液中，加入NaOH(242mg，5.907mmol，1.1eqv)，55℃搅拌反应2h；减压浓缩，向浓缩物中加入水(100ml)混合，用1N HCl调至pH至3～4，用EA(100ml×2)萃取，合并有机相；有机相用H 2O(20ml)、盐水洗涤(20ml)，无水硫酸钠干燥，过滤，滤液减压浓缩，得到M-27(1.33g，收率78.4％)(ES,m/z):473.10[M+H] +。
中间体制备例28～30：
采用中间体制备例27的步骤及以下相应的起始原料合成中间体28～30：
Figure PCTCN2022094255-appb-000108
Figure PCTCN2022094255-appb-000109
以下为本申请示例性化合物的制备实施例。
制备例1：(R)-1-(5-氨基-3-(3-氨基-3H-螺[苯并呋喃-2,4'-哌啶]-1'-基)-6-((2-氯-3-(噁唑-2-基)苯基)硫烷基)吡嗪-2-基)乙酮(化合物1)
Figure PCTCN2022094255-appb-000110
步骤a：氮气保护下，将(R)-(1'-(3-乙酰基-6-氨基-5-溴吡嗪-2-基)-3H-螺[苯并呋喃-2,4'-哌啶]-3-基)氨基甲酸叔丁酯(140mg,0.27mmol,1.0eqv)、2-氯-3-(噁唑-2-基)苯硫醇(69mg,0.325mmol,1.2eqv)、DIPEA(123mg,0.954mmol,3.5eqv)、Pd 2(dba) 3(50mg,0.054mmol,0.2eqv)和Xantphos(63mg,0.109mmol,0.4eqv)的1,4-二氧六环(10mL)溶液，在96℃反应6h；降温至室温，向反应液中加入硅胶，用硅胶柱层析进行纯化(洗脱剂为正己烷:EA＝10:1～1:2)，得(R)-(1'-(3-乙酰基-6-氨基-5-((2-氯-3-(噁唑-2-基)苯基)硫烷基)吡嗪-2-基)-3H-螺[苯并呋喃-2,4'-哌啶]-3-基)氨基甲酸叔丁酯(152mg，收率86.85％)。(ES,m/z):649.14[M+H] +。
步骤b：向(R)-(1'-(3-乙酰基-6-氨基-5-((2-氯-3-(噁唑-2-基)苯基)硫烷基)吡嗪-2-基)-3H-螺[苯并呋喃-2,4'-哌啶]-3-基)氨基甲酸叔丁酯(152mg)的二氯甲烷(10ml)溶液中，加入三氟乙酸(5ml)，室温搅拌3h；反应液减压浓缩，向残留物中加入EA(50ml)和水(50ml)，用25％氨水调节pH至10，分液；水相用EA(20ml)萃取，合并有机相；有机相用水(50ml)、盐水(50ml)洗涤，减压浓缩；残留物经柱层析纯化(CH 2Cl 2：CH 3OH＝20:1～15:1)，得(R)-1-(5-氨基-3-(3-氨基-3H-螺[苯并呋喃-2,4'-哌啶]-1'-基)-6-((2-氯-3-(噁唑-2-基)苯基)硫烷基)吡嗪-2-基)乙酮(120mg，收率93.4％)。(ES,m/z):549.10[M+H] +。 1H-NMR(400MHz,DMSO-d6)δ8.33.(s,1H),7.750(d,J＝6.6Hz,1H),7.476(s,1H),7.416(t,J＝7.8Hz,1H),7.321(d,J＝7.2Hz,1H),7.148-7.060(m,4H),6.859(t,J＝7.2Hz,1H),6.772(d,J＝7.2Hz,1H),4.105(s,1H),3.876-3.854(m,1H),3.762-3.740(m,1H),3.309-3.290(m,1H),2.320(s,3H),2.033-1.985(m,3H),1.867-1.705(m,4H)。
制备例2～15和11A：
参照制备例1的合成路线及操作，采用对应的中间体作为起始物，制备化合物2～15和11A。
Figure PCTCN2022094255-appb-000111
Figure PCTCN2022094255-appb-000112
Figure PCTCN2022094255-appb-000113
制备例16：(R)-5-氨基-3-(3-氨基-3H-螺[苯并呋喃-2,4'-哌啶]-1'-基)-6-((2-氯-3-(噁唑-2-基)苯基)硫烷基)吡嗪-2-羧酸甲酯(化合物16)
Figure PCTCN2022094255-appb-000114
步骤a：氮气保护下，将(R)-5-氨基-6-溴-3-(3-((叔丁氧基羰基)氨基)-3H-螺[苯并呋喃-2,4'-哌啶]-1'-基)吡嗪-2-羧酸甲酯(144mg,0.27mmol,1.0eqv)、2-氯-3-(噁唑-2-基)苯硫醇(69mg,0.324mmol,1.2eqv)、DIPEA(123mg,0.954mmol,3.5eqv)、Pd 2(dba) 3(50mg,0.054mmol,0.2eqv)和Xantphos(63mg,0.109mmol,0.4eqv)的1,4-二氧六环(20ml)溶液在96℃反应6h；降温至室温，向反应液中加入硅胶，用硅胶柱层析进行纯化(洗脱剂为正己烷:EA＝20:1～1:1)，得(R)-5-氨基-3-(3-((叔丁氧基羰基)氨基)-3H-螺[苯并呋喃-2,4'-哌啶]-1'-基)-6-(2-氯-3-(噁唑-2-基)苯基)硫烷基)吡嗪-2-羧酸甲酯(152mg，收率84.75％)。(ES,m/z):665.14[M+H] +。
步骤b：向(R)-5-氨基-3-(3-((叔丁氧基羰基)氨基)-3H-螺[苯并呋喃-2,4'-哌啶]-1'-基)-6-(2-氯-3-(噁唑-2-基)苯基)硫烷基)吡嗪-2-羧酸甲酯(152mg)的二氯甲烷(20ml)溶液中，加入三氟乙酸(5ml)，室温搅拌3h；反应液减压浓缩，向残留物中加入EA(100ml)和水(50ml)，用25％氨水调节pH至10，分液；水相用EA(20ml)萃取，合并有机相；有机相用水(50ml)、盐水(50ml)洗涤，无水硫酸钠干燥，浓缩；残留物经柱层析纯化(CH 2Cl 2:CH 3OH＝50:1～15:1)，得(R)-5-氨基-3-(3-氨基-3H-螺[苯并呋喃-2,4'-哌啶]-1'-基)-6-((2-氯-3-(噁唑-2-基)苯基)硫烷基)吡嗪-2-羧酸甲酯(118mg，收率91.4％)。(ES,m/z):565.10[M+H] +。
制备例17～20：
参照制备例16的合成路线及操作，采用对应的中间体作为起始物，制备化合物17～20。
Figure PCTCN2022094255-appb-000115
Figure PCTCN2022094255-appb-000116
制备例21：(R)-1'-(6-氨基-5-((2-氯-3-(噁唑-2-基)苯基)硫烷基)-3-(氧杂环丁-3-基)吡嗪-2-基)-3H-螺[苯并呋喃-2,4'-哌啶]-3-胺(化合物21)
Figure PCTCN2022094255-appb-000117
步骤a：将6-氯-3-((2-氯-3-(噁唑-2-基)苯基)硫烷基)-5-(氧杂环丁-3-基)吡嗪-2-胺(613mg，1.556mmol，1.0eqv)、(R)-2-甲基-N-((R)-3H-螺[苯并呋喃-2,4'-哌啶]-3-基)丙烷-2-亚磺酰胺(575mg，1.867mmol，1.2eqv)、DIPEA(603mg，4.665mmol，3.0eqv)的DMSO(10ml)溶液，在110℃反应6h；降至室温，加入水(100ml)，用EA(3×50ml)萃取，合并有机相；有机相用H 2O(50ml)、盐水(50ml)洗涤，减压浓缩，用硅胶柱层析进行纯化(洗脱剂为DCM:MeOH＝100:1～25:1)，得到(R)-N-((R)-1'-(6-氨基-5-((2-氯-3-(噁唑-2-基)苯基)硫烷基)-3-(氧杂环丁-3-基)吡嗪-2-基)-3H-螺[苯并呋喃-2,4'-哌啶]-3-基)-2-甲基丙烷-2-亚磺酰胺(677mg，收率65.31％)。(ES,m/z):667.11[M+H] +。
步骤b：向(R)-N-((R)-1'-(6-氨基-5-((2-氯-3-(噁唑-2-基)苯基)硫烷基)-3-(氧杂环丁-3-基)吡嗪-2-基)-3H-螺[苯并呋喃-2,4'-哌啶]-3-基)-2-甲基丙烷-2-亚磺酰胺(677mg)中加入HCl/CH 3OH溶液(60mL)，室温过夜反应，反应液减压浓缩，向残留物中加入EA(50ml)和水(50ml)，用25％氨水调节pH至9～10，分液；水相用EA(20ml)萃取，合并有机相；有机相用水(50ml)、盐水(50ml)洗涤，浓缩；残留物经柱层析纯化(CH 2Cl 2：CH 3OH＝20:1)，得(R)-1'-(6-氨基-5-((2-氯-3-(噁唑-2-基)苯基)硫烷基)-3-(氧杂环丁-3-基)吡嗪-2-基)-3H-螺[苯并呋喃-2,4'-哌啶]-3-胺(487mg，收率85.2％)。(ES,m/z):563.10[M+H] +。
制备例22:
参照制备例21的合成路线及操作，采用对应的中间体作为起始物，制备化合物22。
Figure PCTCN2022094255-appb-000118
Figure PCTCN2022094255-appb-000119
制备例23：(R)-1'-(6-氨基-5-((2-氯-3-(噁唑-2-基)苯基)硫烷基)-3-氟吡嗪-2-基)-3H-螺[苯并呋喃-2,4'-哌啶]-3-胺(化合物23)
Figure PCTCN2022094255-appb-000120
步骤a：将6-氯-3-((2-氯-3-(噁唑-2-基)苯基)硫烷基)()吡嗪-2-胺(526mg，1.556mmol，1.0eqv)、(R)-2-甲基-N-((R)-3H-螺[苯并呋喃-2,4'-哌啶]-3-基)丙烷-2-亚磺酰胺(575mg，1.867mmol，1.2eqv)、DIPEA(603mg，4.665mmol，3.0eqv)的DMSO(10ml)溶液，100℃过夜反应；降至室温，加入水(100ml)，用EA(3×50ml)萃取，合并有机相；有机相用H 2O(50ml)、盐水(50ml)洗涤，减压浓缩，用硅胶柱层析进行纯化(洗脱剂为DCM:MeOH＝80:1～25:1)，得到(R)-N-((R)-1'-(6-氨基-5-((2-氯-3-(噁唑-2-基)苯基)硫烷基)吡嗪-2-基)-3H-螺[苯并呋喃-2,4'-哌啶]-3-基)-2-甲基丙烷-2-亚磺酰胺(724mg，收率76.26％)。(ES,m/z):611.09[M+H] +。
步骤b：向(R)-N-((R)-1'-(6-氨基-5-((2-氯-3-(噁唑-2-基)苯基)硫烷基)吡嗪-2-基)-3H-螺[苯并呋喃-2,4'-哌啶]-3-基)-2-甲基丙烷-2-亚磺酰胺(724mg)中加入HCl/CH 3OH溶液(50mL)，室温过夜反应，反应液减压浓缩，向残留物中加入EA(50ml)和水(50ml)，用25％氨水调节pH至9～10，分液；水相用EA(20ml)萃取，合并有机相；有机相用水(50ml)，盐水(50ml)洗涤，浓缩；残留物经柱层析纯化(CH 2Cl 2：CH 3OH＝30:1～15:1)，得(R)-1'-(6-氨基-5-((2-氯-3-(噁唑-2-基)苯基)硫烷基)吡嗪-2-基)-3H-螺[苯并呋喃-2,4'-哌啶]-3-胺(557mg，收率92.75％)。(ES,m/z):507.03[M+H] +。
步骤c：氮气保护下，-15℃下向(R)-1'-(6-氨基-5-((2-氯-3-(噁唑-2-基)苯基)硫烷基)吡嗪-2-基)-3H-螺[苯并呋喃-2,4'-哌啶]-3-胺(557mg,1.1mmol,1eqv)的乙腈(100ml)溶液中，加入N-氟代双苯磺酰胺(380mg,1.21eqv,1.1eqv)，加完缓慢升温至室温，过夜反应；减压浓缩，经两次Pre-TLC(DCM:MeOH＝15:1)纯化，得(R)-1'-(6-氨基-5-((2-氯-3-(噁唑-2-基)苯基)硫烷基)-3-氟吡嗪-2-基)-3H-螺[苯并呋喃-2,4'-哌啶]-3-胺(109mg，收率18.9％)。(ES,m/z):525.09[M+H] +。
制备例24：(R)-1-(5-氨基-3-(3-氨基-3H-螺[苯并呋喃-2,4'-哌啶]-1'-基)-6-((2-(噁唑-2-基)嘧啶-4-基)硫烷基)吡嗪-2-基)乙酮(化合物24)
Figure PCTCN2022094255-appb-000121
步骤a：氮气保护下，将(R)-(1'-(3-乙酰基-6-氨基-5-溴吡嗪-2-基)-3H-螺[苯并呋喃-2,4'-哌啶]-3-基)氨基甲酸叔丁酯(140mg,0.27mmol,1.0eqv)、2-(噁唑-2-基)嘧啶-4-硫醇(58mg,0.325mmol,1.2eqv)、DIPEA(123mg,0.954mmol,3.5eqv)、Pd 2(dba) 3(50mg,0.054mmol,0.2eqv)和Xantphos(63mg,0.109mmol,0.4eqv)的1,4-二氧六环(10mL)溶液在96℃反应6h；降温至室温，向反应液中加入硅胶，用硅胶柱层析进行纯化(洗脱剂为正己烷:EA＝10:1～1:2)，得(R)-(1'-(3-乙酰基-6-氨基-5-((2-(噁唑-2-基)嘧啶-4-基)硫烷基)吡嗪-2-基)-3H-螺[苯并呋喃-2,4'-哌啶]-3-基)氨基甲酸叔丁酯(126mg，收率75.74％)。(ES,m/z):617.14[M+H] +。
步骤b：向(R)-(1'-(3-乙酰基-6-氨基-5-((2-(噁唑-2-基)嘧啶-4-基)硫烷基)吡嗪-2-基)-3H-螺[苯并呋喃-2,4'-哌啶]-3-基)氨基甲酸叔丁酯(126mg)的二氯甲烷(5ml)溶液中加入三氟乙酸(5ml)，室温搅拌3h；反应液减压浓缩，向残留物中加入EA(50ml)和水(50ml)，用25％氨水调节pH至10，分液；水相用EA(20ml)萃取，合并有机相；有机相用水(50ml)、盐水(50ml)洗涤，减压浓缩；残留物经柱层析纯化(CH 2Cl 2：
CH 3OH＝20:1～15:1)，得(R)-1-(5-氨基-3-(3-氨基-3H-螺[苯并呋喃-2,4'-哌啶]-1'-基)-6-((2-(噁唑-2-基)嘧啶-4-基)硫烷基)吡嗪-2-基)乙酮(97mg，收率91.9％)。(ES,m/z):517.10[M+H] +。
参照中间体制备例1～22及制备例1～24的制备工艺路线、操作，采用2,4-二碘嘧啶和相应中间体，制备化合物25～55。
Figure PCTCN2022094255-appb-000122
Figure PCTCN2022094255-appb-000123
Figure PCTCN2022094255-appb-000124
制备例56：(R)-1-(5-氨基-6-((2-氨基-3-氯吡啶-4-基)硫烷基)-3-(3-氨基-3-氘-螺[苯并呋喃-2,4'-哌啶]-1'-基)吡嗪-2-基)乙酮(化合物56)
Figure PCTCN2022094255-appb-000125
步骤a：氮气保护下，将M-27(256mg，0.542mmol，1.0eqv)、2-氨基-3-氯-4-碘吡啶(207mg，0.813mmol，1.5eqv)、Pd 2(dba) 3(99mg，0.108mmol，0.2eqv)、Xantphos(125mg，0.217mmol，0.4eqv)、DIPEA(245mg，1.897mmol，3.5eqv)的1,4-二氧六环(20ml)反应液，97℃过夜反应；降温，将反应液浓缩至干，向浓缩物中加入水(30ml)，用EA(20ml×2)萃取，合并有机相；有机相用H 2O(20ml)、盐水(20ml)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱层析进行纯化(洗脱剂为正己烷:EA＝5:1～1:3)，得到M56-1(300mg，收率92％)，(ES,m/z):599.17[M+H] +。
步骤b：向M56-1(300mg，0.501mmol，1.0eqv)的DCM(5ml)溶液中加入CF 3COOH(5ml)，室温搅拌反应2h后，将反应液旋干，向残留物中加入水(30ml)和EA(30ml)，用25％氨水调pH至9～10，分液，水相用EA(20ml×2)萃取，合并有机相；有机相用H 2O(20ml)、盐水(20ml)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱层析进行纯化(洗脱剂为CH 2Cl 2:CH 3OH＝20:1～15:1)，得(R)-1-(5-氨基-6-((2-氨基-3-氯吡啶-4-基)硫烷基)-3-(3-氨基-3-氘-螺[苯并呋喃-2,4'-哌啶]-1'-基)吡嗪-2-基)乙酮(200mg，收率80％)(ES,m/z):499.10[M+H] +。 1H-NMR(600MHz,DMSO-d6)δ7.686(d,J＝5.4Hz,1H),7.321(d,J＝7.2Hz,1H),7.141(t,J＝7.2Hz,1H),7.081(s,2H),6.862(t,J＝7.2Hz,1H),6.773(d,J＝7.2Hz,1H),6.315(s,2H),5.887(d,J＝5.4Hz,1H),3.882-3.860(m,1H),3.768-3.747(m,1H),3.372-3.330(m,1H),3.293-3.286(m,1H),2.381(s,3H),2.029-1.980(m,2H),1.861-1.773(m,2H),1.727-1.704(m,1H)。
制备例56A、57～59:
参照制备例56的合成路线及操作，采用对应的中间体作为起始物，制备化合物56A、57～59。
Figure PCTCN2022094255-appb-000126
Figure PCTCN2022094255-appb-000127
制备例60：化合物60的制备
Figure PCTCN2022094255-appb-000128
步骤a：氮气保护下，将M-25(840mg,2.004mmol,1.0eqv)、2-氯-3-(噁唑-2-基)苯硫醇(634mg,3.006mmol,1.5eqv)、DIPEA(906mg,7.014mmol,3.5eqv)、Pd 2(dba) 3(367mg,0.401mmol,0.2eqv)和Xantphos(464mg,0.802mmol,0.4eqv)的1,4-二氧六环(10mL)溶液在96℃过夜反应；降温至室温，向反应液中加入硅胶，用硅胶柱层析进行纯化(洗脱剂为正己烷:EA＝5:1～3:1)，得M60-1(600mg，收率46％)。(ES,m/z):650.12[M+H] +。
步骤b：向M60-1(600mg,0.924mmol)的二氯甲烷(15ml)溶液中加入三氟乙酸(5ml)，室温搅拌3h；反应液减压浓缩，向残留物中加入EA(50ml)和水(50ml)，用25％氨水调节pH至10，分液；水相用EA(20ml)萃取，合并有机相；有机相用水(50ml)、盐水(50ml)洗涤，减压浓缩；残留物经柱层析纯化(CH 2Cl 2：CH 3OH＝40:1～15:1)，得化合物60(350mg，收率69％)。(ES,m/z):550.12[M+H] +。
制备例61:
参照制备例60的合成路线及操作，采用对应的中间体作为起始物，制备化合物61。
Figure PCTCN2022094255-appb-000129
Figure PCTCN2022094255-appb-000130
制备例62：
参照制备例60的合成路线及操作，采用对应的中间体作为起始物，制备化合物62。
Figure PCTCN2022094255-appb-000131
备注：阳性药制备：按照TW201840553A中化合物45制备方法制备化合物TW-45(结构如下)。
Figure PCTCN2022094255-appb-000132
以下描述本申请化合物的生物试验。
试验例1：对SHP2酶的抑制效果试验
1.配制工作缓冲液及化合物准备
配制工作缓冲液1x激酶缓冲液。将待测化合物用DMSO溶剂稀释成10mM的储存浓度。首先将待测化合物稀释成1000μM的中间浓度，然后用DMSO再将其3倍作梯度稀释。故待测化合物的中间梯度稀释浓度为：1000μM,3倍稀释,11个梯度。利用Echo550仪器，将384 LDV echo板里的各个浓度的化合物各转移100nl到一块新的384酶联板(assay plate)(corning,Cat#4514)，确保加入10μl的反应试剂后待测化合物的最终浓度都是10μM,3倍稀释,11个梯度,2个复孔。最终的DMSO浓度为1％。对于阴性对照孔和阳性对照孔，都将被转移100nl DMSO。
2.SHP2酶学反应步骤
用1X酶缓冲液配制：2X工作SHP2试剂(0.4nM)以及0.5μM SHP-2激活肽(BPS bioscience#79319-2)的混合液。上述的混合液在25℃下孵育60分钟后，用移液器转移5μl活化的SHP2激酶溶液至化合物板的化合物孔以及Max对照孔(Corning，#4514)中。然后再转移5μl 1x激酶缓冲液至Min control对照孔中。以1000rpm离心30秒。封板，并将板子放在25℃的恒温培养箱中孵育30分钟。用1x激酶缓冲液制备DiFMUP(#D6567，Invitrogen TM)的底物溶液，其浓度应为实验终浓度的2倍(DiFMUP终浓度：10μM)。利用电动移液枪转移5μl配制好的底物溶液到酶联板的每个孔中起始反应。以1000rpm离心30秒。封板，并将板子放在25℃的恒温培养箱中孵育60分钟。将酶联板放置在Spark机器上，读取激发/发射波长为358/455nm的数据。
3.计算方法及检测结果：
从Spark复制RLU的值，用RLU值计算抑制率，抑制率＝(最大值-样品RLU)/(最大值-最小值)*100，“最小值”是指无酶对照的RLU，“最大值”是指DMSO对照的RLU。在XLFit excel插件版本5.4.0.8中拟合数据以获得IC 50值，结果见表1。
表1本申请化合物对SHP2的酶学效果试验
制备例编号 酶学 制备例编号 酶学 制备例编号 酶学
1 A 22 A 58 A
8 A 23 A 59 A
16 A 24 A 60 A
19 A 56 A 61 A
21 A 57 A 62 A
备注：表示为“A”的化合物具有小于或等于20nM的IC 50值。
以上数据表明：本申请化合物对SHP2激酶具有较强的抑制作用。
试验例2：对人急性髓性白血病MV-4-11细胞增殖的体外抑制作用
1.试验材料：
实验用人急性髓性白血病MV-4-11细胞购自于中国科学院上海生命科学研究院，细胞培养所需完全培养基为IMDM(GIBCO公司)，补加10％胎牛血清(GIBCO公司)。细胞于37℃，5％CO 2培养箱中培养。实验所用试剂包括二甲亚砜(购自天津市科密欧化学试剂有限公司)，MTT(上海特伯化学科技有限公司，CAS.NO.298-93-1)。受试物密封于4℃储存。
2.试验方法及结果：
以二甲亚砜为溶媒，充分溶解受试物，配制成浓度为5×10 -2mol/L储存液，将储存液置于-20℃存放。以完全培养基作为稀释液，梯度稀释受试物为不同浓度备用。在96孔培养板中，加入100μL/孔(2×10 4细胞数/孔)MV-4-11细胞完全培养基悬液，分别加入相应的不同浓度的受试物100μL/孔，每个受试物设置8个浓度，每个浓度设置3个复孔，于37℃，5％CO 2培养箱中培养。受试物作用72h后，加入MTT 20μL/孔，于37℃，5％CO 2培养箱中培养4小时，弃掉上清液，加入二甲亚砜150μL/孔，震荡混匀，使用酶标仪在550nm波长下检测OD值。只加细胞悬液不含受试物的孔为对照孔，只加完全培养基的孔为空白孔。下列公式计算细胞生长的抑制率：
抑制率＝(对照孔OD-受试孔OD)/(对照孔OD-空白孔OD)*100％，根据各浓度抑制率，采用SPSS软件计算半数抑制浓度IC 50值，结果见表2。
表2本申请化合物细胞增殖抑制效果试验
Figure PCTCN2022094255-appb-000133
备注：表示为“A”的化合物具有小于或等于20nM的IC 50值。
以上数据表明，本申请化合物在人急性髓性白血病细胞增殖抑制试验中均显示出良好的抑制活性。
试验例3：对人肺腺癌NCI-H441细胞增殖的体外抑制作用
1.试验材料：
实验用人肺腺癌细胞NCI-H441购自于ATCC，细胞培养所需完全培养基为RPMI1640Medium(GIBCO公司)，补加10％胎牛血清(GIBCO公司)。细胞于37℃，5％CO 2培养箱中培养。实验所用试剂包括二甲亚砜(购自Sigma)，3D Cell Viability assay kit(购自Promega)，试验用对照物TW-45通过自制获得。受试物密封于4℃储存。
2.试验方法及结果：
以二甲亚砜为溶媒，充分溶解受试物，配制成浓度为1×10 -2mol/L储存液，将储存液置于-20℃存放。以完全培养基作为稀释液，梯度稀释受试物为不同浓度备用(最终测试浓度为10000、3333、1111、370、123、41、13.7、4.5、1.5、0.5nM)。细胞于37℃，5％CO 2培养箱中培养5天。第5天检测，每孔加入30μL试剂(Celltiter Glo检测试剂盒-3D)并在板振荡器上摇动板(避光)30分钟。将板在室温下孵育(避光)120分钟。Multiplate reader记录化学发光值。
数据分析，使用VC和PC数据进行稳定性检查。抑制百分比＝100-(Signal cmpd-Signal Ave-PC)/(Signal Ave-VC-Signal Ave-PC)×100。LUM：每个孔的化学发光信号，VC：高质控的平均化学发光信号(含0.1％DMSO的孔)，PC：低质控平均化学发光信号(仅空白培养基)。
使用GraphPad Prism 8软件计算化合物的IC50并绘制效果-剂量曲线：Y＝Bottom+(Top-Bottom)/(1+10^((LogIC 50-X)*HillSlope))。X：cpd浓度的对数Y：抑制百分比：
结果见表3。
表3本申请化合物NCI-H441细胞增殖抑制效果试验
Figure PCTCN2022094255-appb-000134
备注：表示为“A”的化合物具有小于或等于20nM的IC 50值，表示为“B”的化合物具有大于20nM且小于50nM的IC 50值。
以上数据表明，本申请化合物在人肺腺癌细胞增殖抑制试验中均显示出良好的抑制活性。
试验例4：小鼠药代动力学试验
1.试验方法：
ICR小鼠以10mg/kg或20mg/kg灌胃给予化合物，于给药后的不同时间点(0.25h、0.5h、1h、2h、4h、8h、24h)，由小鼠眼眶采血，所采集全血经肝素钠抗凝，3000g离心分离得到小鼠血浆样品，采用甲醇蛋白沉淀，用HPLC-MS/MS法测定给药后小鼠血浆中的药物浓度，绘制药-时曲线并计算药代动力学参数，通过非房室模型统计矩参数描述化合物给药后小鼠体内的药代动力学行为。
2、试验结果：
对本申请制备例1化合物和制备例56化合物进行了上述药代动力学试验，试验结果表明，本申请的化合物在小鼠体内具有较高的暴露量，吸收均较好。
表4本申请化合物小鼠药代动力学实验结果
Figure PCTCN2022094255-appb-000135
试验例5：hERG试验
1、试验方法：
此试验包括以下几个方面：
利用手动膜片钳技术在稳定表达hERG通道的CHO-K1细胞株上记录hERG电流；
根据hERG尾电流计算每个浓度的抑制率；
每个化合物测试5个浓度，推算IC 50值；
每个浓度测试3个细胞；
一个阳性对照药物。
采用全细胞膜片钳技术记录hERG电流。取细胞悬液加于细胞槽中，置于正置显微镜载物台上。待细胞贴壁后，用细胞外液灌流，流速为1–2mL/min。玻璃微电极由微电极拉制仪两步拉制，其入水电阻值为2-5MΩ。建立全细胞记录后，保持钳制电位为-80mV。给予电压刺激时去极化至+60mV，然后复极化至-50mV引出hERG尾电流。所有记录均在电流稳定后进行。胞外灌流给药从低浓度开始，每个浓度5-10min至电流稳定，再给下一个浓度。测试化合物的半数抑制浓度(IC 50)由Logistic方程最佳拟合得出。
2、试验结果：
表5在CHO-K1稳定细胞株上所记录到的化合物的hERG IC 50值
制备例编号 IC 50(μM)
1 A
56 A
备注：表示为“A”的化合物具有大于10μM的IC 50值。
试验结果表明，本申请1号化合物和56号化合物在本试验的检测浓度范围内对hERG通道没有明显的抑制作用，可一定程度反映本申请化合物具有较低心脏毒性，对药物安全性评估具有积极意义。
试验例7：小鼠耐受性试验
试验方法：
试验用动物：ICR小鼠，雌性，5周龄
溶剂：2％DMSO+98％(0.5％MC)，充分涡旋，超声得到均一混悬溶液
试验方法：将雌性ICR小鼠按照体重均衡分组，共4组，每组5只，给药剂量分别为50mg/kg和200mg/kg。给药方式为灌胃，每天一次，连续给药7天，给药剂量及结果见下表。
试验结果：
表6本申请化合物小鼠耐受试验结果(7天)
Figure PCTCN2022094255-appb-000136
试验结果表明，本申请56号化合物在50mg/kg和200mg/kg给药7天后均没有出现死亡；阳性对照化合物TW-45在200mg/kg给药4天后出现死亡，至第7天全部死亡。56号小鼠最大耐受剂量MTD>200mg/kg，TW-45<200mg/kg。可见，本申请56号化合物在小鼠中的耐受性明显优于阳性对照化合物TW-45。

Claims (27)

  1. 一种如式(I)所示化合物或其前药、互变异构体、立体异构体、溶剂化物、同位素衍生物或其药学上可接受的盐，其具有如下结构：
    Figure PCTCN2022094255-appb-100001
    其中，
    X选自O、CH 2、NH或S；
    L选自N或CH；
    G选自键或S；
    A选自CH或N；
    R 3独立地选自：任选取代的8-12元杂环基、任选取代的C 6-10芳基、任选取代的5-14元杂芳基，其中所述任选取代是指被取代基团上的氢未被取代或被取代基团的一个或多个可取代位点上的氢独立地被选自卤素、羟基、氨基、硝基、氧代基、氰基、-COOH、-COCH 3、-COOCH 3、-CONH 2、C 1-6烷基、C 1-6烷氧基、C 3-10环烷基、3-10元杂环烷基、C 6-10芳基、5-12元杂芳基的取代基所取代；
    R 1独立地选自氢、氘或氨基；
    R 2独立地选自氢、卤素、氰基、-CONH 2、-COR 5、-COOR 5、任选取代的C 1-6烷基、任选取代的C 2-6烯基、任选取代的C 2-6炔基、任选取代的C 3-10环烷基、任选取代的3-10元杂环烷基，其中，R 5独立地选自氢、任选取代的C 1-6烷基、任选取代的C 3-6环烷基、任选取代的3-6元杂环烷基、任选取代的C 6-10芳基、任选取代的5-10元杂芳基，所述任选取代是指被取代基团上的氢未被取代或被取代基团的一个或多个可取代位点上的氢独立地被选自卤素、羟基、氨基、硝基、氧代基、氰基、C 1-6烷基、C 1-6烷氧基的取代基所取代；
    Y独立地选自N或CR 4；
    R 4独立地选自氢、卤素、羟基、氨基、氰基、任选取代的C 1-6烷基、任选取代的C 1-6烷氧基；所述任选取代是指被取代基团上的氢未被取代或被取代基团的一个或多个可取代位点独立地被选自卤素、羟基、氨基、氰基、C 1～6烷基、C 1-6烷氧基所取代；
    R 6独立地选自氢或氘；
    所述“氧代基”是指相同取代位的两个H被同一个O替代形成双键；
    所述杂环烷基、杂芳基、杂环基中的杂原子独立地选自O、N或S，杂原子数量为1个、2个、3个或4个；
    其中所述式(I)化合物不包括以下化合物：
    Figure PCTCN2022094255-appb-100002
  2. 一种如式(I)所示化合物或其前药、互变异构体、立体异构体、溶剂化物、同位素衍生物或其药学上可接受的盐，其具有如下结构：
    Figure PCTCN2022094255-appb-100003
    其中，
    X选自O、CH 2、NH或S；
    L选自N或CH；
    G选自键或S；
    A选自CH或N；
    R 3为氨基；
    R 1独立地选自氢、氨基或氘；
    R 2独立地选自卤素、氰基、-CONH 2、-COR 5、-COOR 5、任选取代的C 1-6烷基、任选取代的C 2-6烯基、任选取代的C 2-6炔基、任选取代的C 3-10环烷基、任选取代的3-10元杂环烷基，其中，R 5独立地选自氢、任选取代的C 1-6烷基、任选取代的C 3-6环烷基、任选取代的3-6元杂环烷基、任选取代的C 6-10芳基、任选取代的5-10元杂芳基，所述任选取代是指被取代基团上的氢未被取代或被取代基团的一个或多个可取代位点上的氢独立地被选自卤素、羟基、氨基、硝基、氧代基、氰基、C 1-6烷基、C 1-6烷氧基的取代基所取代；
    Y独立地选自N或CR 4；
    R 4独立地选自氢、卤素、羟基、氨基、氰基、任选取代的C 1-6烷基、任选取代的C 1-6烷氧基，其中所述任选取代是指被取代基团上的氢未被取代或被取代基团的一个或多个可取代位点独立地被选自卤素、羟基、氨基、氰基、C 1～6烷基、C 1-6烷氧基所取代；
    R 6独立地选自氢或氘；
    所述“氧代基”是指相同取代位的两个H被同一个O替代形成双键；
    所述杂环烷基、杂芳基、杂环基中的杂原子独立地选自O、N或S，杂原子数量为1个、2个、3个或4个；
    其中所述式(I)化合物不包括以下化合物：
    Figure PCTCN2022094255-appb-100004
    Figure PCTCN2022094255-appb-100005
    Figure PCTCN2022094255-appb-100006
    Figure PCTCN2022094255-appb-100007
    Figure PCTCN2022094255-appb-100008
    Figure PCTCN2022094255-appb-100009
  3. 一种式(I)所示的化合物，或其前药、互变异构体、立体异构体、溶剂化物、同位素衍生物或其药学上可接受的盐，其具有如下结构：
    Figure PCTCN2022094255-appb-100010
    其中，
    X选自O、CH 2、NH或S；
    L选自N或CH；
    G选自键或S；
    A选自CH或N；
    R 3独立地选自：氨基、任选取代的8-12元杂环基、任选取代的C 6-10芳基、任选取代的5-14元杂芳基，其中所述任选取代是指被取代基团上的氢未被取代或被取代基团的一个或多个可取代位点上的氢独立地被选自卤素、羟基、氨基、硝基、氧代基、氰基、-COOH、-COCH 3、-COOCH 3、-CONH 2、C 1-6烷基、C 1-6烷氧基、C 3-10环烷基、3-10元杂环烷基、C 6-10芳基、5-12元杂芳基的取代基所取代；
    R 1独立地选自氢、氘或氨基；
    R 2独立地选自氢、卤素、氰基、-CONH 2、-COR 5、-COOR 5、任选取代的C 1-6烷基、任选取代的C 2-6烯基、任选取代的C 2-6炔基、任选取代的C 3-10环烷基、任选取代的3-10元杂环烷基，其中，R 5独立地选自氢、任选取代的C 1-6烷基、任选取代的C 3-6环烷基、任选取代的3-6元杂环烷基、任选取代的C 6-10芳基、任选取代的5-10元杂芳基，所述任选取代是指被取代基团上的氢未被取代或被取代基团的一个或多个可取代位点上的氢独立地被选自卤素、羟基、氨基、硝基、氧代基、氰基、C 1-6烷基、C 1-6烷氧基的取代基所取代；
    Y独立地选自N或CR 4；
    R 4独立地选自氢、卤素、羟基、氨基、氰基、任选取代的C 1-6烷基、任选取代的C 1-6烷氧基，所述任选取代是指被取代基团上的氢未被取代或被取代基团的一个或多个可取代位点上的氢独立地被选自卤素、羟基、氨基、氰基、C 1～6烷基、C 1-6烷氧基的取代基所取代；
    R 6独立地选自氢或氘；
    所述“氧代基”是指相同取代位的两个H被同一个O替代形成双键；
    所述杂环烷基、杂芳基、杂环基中的杂原子独立地选自O、N或S，杂原子数量为1个、2个、3个或4个；
    其中，所述式(I)所示的化合物不包括以下化合物：
    Figure PCTCN2022094255-appb-100011
    Figure PCTCN2022094255-appb-100012
    Figure PCTCN2022094255-appb-100013
    Figure PCTCN2022094255-appb-100014
    Figure PCTCN2022094255-appb-100015
    Figure PCTCN2022094255-appb-100016
    Figure PCTCN2022094255-appb-100017
  4. 根据权利要求1或3所述的化合物或其前药、互变异构体、立体异构体、溶剂化物、同位素衍生物或其药学上可接受的盐，其中所述化合物具有如式(I-1)所示的结构：
    Figure PCTCN2022094255-appb-100018
    其中，
    X、L、G、A、R 3、R 1、R 2、Y、R 4如权利要求1或3中所定义。
  5. 根据权利要求1或3所述的化合物或其前药、互变异构体、立体异构体、溶剂化物、同位素衍生物或其药学上可接受的盐，其中R 6为氘。
  6. 根据权利要求1和3-5中任一项所述的化合物或其前药、互变异构体、立体异构体、溶剂化物、同位素衍生物或其药学上可接受的盐，其中R 3独立地选自：任选取代的8-12元双环杂环基、任选取代的C 6-10芳基、任选取代的5-14元杂芳基；或者
    R 3独立地选自任选取代的8-10元双环杂环基、任选取代的C 6-8芳基、任选取代的5-10元杂芳基；或者
    R 3独立地选自任选取代的8-10元双环杂环基、任选取代的C 6-8芳基、任选取代的5-10元杂芳基，其中所述任选取代是指被取代基团上的氢未被取代或被取代基团的一个或多个可取代位点上的氢独立地被选自卤素、羟基、氨基、氧代基、氰基、-CONH 2、C 1-6烷基的取代基所取代；或者
    R 3独立地选自任选取代的C 6-8芳基、任选取代的5-6元杂芳基，其中所述任选取代是指被取代基团上的氢未被取代或被取代基团的一个或多个可取代位点上的氢独立地被选自卤素、羟基、氨基、氧代基、氰基、-CONH 2、C 1-6烷基的取代基所取代；或者
    R 3独立地选自任选取代的C 6芳基、任选取代的5-6元杂芳基，其中所述任选取代是指被取代基团上的氢未被取代或被取代基团的一个或多个可取代位点上的氢独立地被选自羟基、氧代基、氰基、-CONH 2、C 1-6烷基(例如，甲基)的取代基所取代；或者
    R 3独立地选自任选取代的5-6元杂芳基，其中所述任选取代是指被取代基团上的氢未被取代或被取代基团的一个或多个可取代位点上的氢独立地被选自卤素、羟基、氨基、氰基、-CONH 2、C 1-3烷基(例如，甲基)的取代基所取代，其中所述杂芳基中的杂原子独立地选自O、N或S，杂原子数量为1个或2个。
  7. 根据权利要求1和3-6中任一项所述的化合物或其前药、互变异构体、立体异构体、溶剂化物、同位素衍生物或其药学上可接受的盐，其中R 2独立地选自氢、卤素、氰基、-CONH 2、-COR 5、-COOR 5、任选取代的C 1-6烷基、任选取代的C 2-6烯基、任选取代的C 3-10环烷基、任选取代的3-10元杂环烷基，其中所述任选取代是指被取代基团上的氢未被取代或被取代基团的一个或多个可取代位点独立地被选自卤素、羟基、氨基、硝基、氧代基、氰基、C 1-6烷基、C 1-6烷氧基所取代；或者
    R 2独立地选自卤素、氰基、-CONH 2、-COR 5、-COOR 5、羟基取代的C 1-4烷基、C 2-6烯基、C 3-6环烷基、3-6元杂环烷基；或者
    R 2独立地选自卤素、氰基、-CONH 2、-COR 5、-COOR 5、被选自羟基、C 1-6烷氧基和卤素中的一个或多个取代基取代的C 1-4烷基、C 2-6烯基、C 3-6环烷基或3-6元杂环烷基；或者
    R 2独立地选自卤素、-COR 5、-COOR 5、羟基取代的C 1-4烷基、C 2-6烯基或3-6元杂环烷基；或者
    R 2独立地选自-COR 5或-COOR 5；或者
    R 2独立地选自-COR 5。
  8. 根据权利要求1～7中任一项所述的化合物或其前药、互变异构体、立体异构体、溶剂化物、同位素衍生物或其药学上可接受的盐，其中R 1独立地选自氢或氨基；优选地，R 1为氨基。
  9. 根据权利要求2或3所述的化合物或其前药、互变异构体、立体异构体、溶剂化物、同位素衍生物或其药学上可接受的盐，其中，
    当R 1为氨基时，
    R 2独立地选自氰基、-CONH 2、-COR 5、-COOR 5、未取代的C 2-6烷基、取代的C 1-6烷基、任选取代的C 2-6烯基、任选取代的C 2-6炔基、任选取代的C 3-10环烷基、任选取代的3-10元杂环烷基，其中所述任选取代是指被取代基团上的氢未被取代或被取代基团的一个或多个可取代位点独立地被选自卤素、羟基、氨基、硝基、氧代基、氰基、C 1-6烷基、C 1-6烷氧基所取代；或者
    R 2独立地选自氰基、-CONH 2、-COR 5、-COOR 5、取代的C 1-6烷基、任选取代的C 2-6烯基、任选取代的C 3-6环烷基、任选取代的3-6元杂环烷基，其中所述任选取代是指被取代基团上的氢未被取代或被取代基团的一个或多个可取代位点上的氢独立地被选自卤素、羟基、氨基、硝基、氧代基、氰基、C 1-6烷基、C 1-6烷氧基的取代基所取代；或者
    R 2独立地选自氰基、-CONH 2、-COR 5、-COOR 5、被选自羟基、卤素和C 1-C 3烷氧基中的一个或多个取代基取代的C 1-6烷基、C 2-6烯基、C 3-6环烷基、3-6元杂环烷基；或者
    R 2独立地选自-COR 5；以及
    当R 1为氘时，
    R 2独立地选自卤素、氰基、-CONH 2、-COR 5、-COOR 5、未取代的C 2-6烷基、取代的C 1-6烷基、任选取代的C 2-6烯基、任选取代的C 2-6炔基、任选取代的C 3-10环烷基、任选取代的3-10元杂环烷基，其中所述任选取代是指被取代基团上的氢未被取代或被取代基团的一个或多个可取代位点独立地被选自卤素、羟基、氨基、硝基、氧代基、氰基、C 1-6烷基、C 1-6烷氧基所取代；或者
    R 2独立地选自卤素、氰基、-CONH 2、-COR 5、-COOR 5、取代的C 1-6烷基、C 2-6烯基、C 3-6环烷基、3-6元杂环烷基；或者
    R 2选自-CO-(C 3-6环烷基)、-COOR 5、任选取代的C 2-6烯基、任选取代的C 3-6环烷基、任选取代的3-6元杂环烷基，其中所述任选取代是指被取代基团上的氢未被取代或被取代基团的一个或多个可取代位点上的氢独立地被选自卤素、羟基、氨基、硝基、氧代基、氰基、C 1-6烷基、C 1-6烷氧基的取代基所取代；以及
    当R 1为氢时，
    R 2独立地选自卤素、-CO-(C 3-C 6环烷基)、-COOR 5、任选取代的C 2-6烯基、任选取代的C 2-6炔基、任选取代的C 3-10环烷基、任选取代的3-10元杂环烷基，其中所述任选取代是指被取代基团上的氢未被取代或被取代基团的一个或多个可取代位点上的氢独立地被选自卤素、羟基、氨基、硝基、氧代基、氰基、C 1-6烷基、C 1-6烷氧基的取代基所取代；或者
    R 2独立地选自卤素、-CO-(C 3-C 6环烷基)、-COOR 5、C 2-6烯基、C 3-6环烷基、3-6元杂环烷基；
    优选地，R 6为氘。
  10. 根据权利要求2所述的化合物或其前药、互变异构体、立体异构体、溶剂化物、同位素衍生物或其药学上可接受的盐，其中所述化合物具有如式(I-2)所示的结构：
    Figure PCTCN2022094255-appb-100019
    其中，R 1独立地选自氘或氨基，优选为氨基；
    R 2独立地选自氰基、-CONH 2、-COR 5、-COOR 5、任选取代的C 1-6烷基、任选取代的C 2-6烯基、任选取代的C 2-6炔基、任选取代的C 3-10环烷基、任选取代的3-10元杂环烷基，其中，R 5独立地选自氢、任选取代的C 1-6烷基、任选取代的C 3-6环烷基、任选取代的3-6元杂环烷基、任选取代的C 6-10芳基、任选取代的5-10元杂芳基，所述任选取代是指被取代基团上的氢未被取代或被取代基团的一个或多个可取代位点上的氢独立地被选自卤素、羟基、氨基、硝基、氧代基、氰基、C 1-6烷基、C 1-6烷氧基的取代基所取代；
    R 6为氢或氘，优选为氘；
    X选自O、CH 2、NH或S，优选为O；
    L、G、A和Y如权利要求2中所定义。
  11. 根据权利要求1-10中任一项所述的化合物或其前药、互变异构体、立体异构体、溶剂化物、同位素衍生物或其药学上可接受的盐，其中，R 5独立地选自氢、任选取代的C 1-6烷基、任选取代的C 3-6环烷基、任选取代的3-6元杂环烷基，其中所述任选取代是指被取代基团上的氢未被取代或被取代基团的一个或多个可取代位点上的氢独立地被选自卤素、羟基、氨基、硝基、氧代基、氰基、C 1-6烷基、C 1-6烷氧基的取代基所取代；或者
    R 5独立地选自氢、C 1-6烷基、C 3-6环烷基、3-6元杂环烷基；或者
    R 5独立地选自C 1-3烷基或C 3-6环烷基；或者
    R 5为C 1-3烷基；或者
    R 5为甲基。
  12. 根据权利要求1-11中任一项所述的化合物或其前药、互变异构体、立体异构体、溶剂化物、同位素衍生物或其药学上可接受的盐，其中X选自O或CH 2；或者X为O。
  13. 根据权利要求1-12中任一项所述的化合物或其前药、互变异构体、立体异构体、溶剂化物、同位素衍生物或其药学上可接受的盐，其中所述化合物具有如式(I-A)、(I-B)、(I-1-A)、(I-1-B)、(I-2-A)或(I-2-B)所示的结构：
    Figure PCTCN2022094255-appb-100020
    Figure PCTCN2022094255-appb-100021
    其中L、G、A、Y、R 1、R 2、R 3和R 6如同权利要求1-9中任一项所定义。
  14. 根据权利要求1-13中任一项所述的化合物或其前药、互变异构体、立体异构体、溶剂化物、同位素衍生物或其药学上可接受的盐，其中L为CH。
  15. 根据权利要求1-14中任一项所述的化合物或其前药、互变异构体、立体异构体、溶剂化物、同位素衍生物或其药学上可接受的盐，其中G为S。
  16. 根据权利要求1～15中任一项所述的化合物或其前药、互变异构体、立体异构体、溶剂化物、同位素衍生物或其药学上可接受的盐，其中A为CH；或者A为N且Y为N；或者A选自CH或N且Y为CR 4。
  17. 根据权利要求1～16中任一项所述的化合物或其前药、互变异构体、立体异构体、溶剂化物、同位素衍生物或其药学上可接受的盐，其中R 4独立地选自氢、卤素、羟基、氨基、氰基、任选取代的C 1-6烷基、任选取代的C 1-6烷氧基；所述任选取代是指被取代基团上的氢未被取代或被取代基团的一个或多个可取代位点上的氢独立地被选自卤素、羟基、氨基的取代基所取代；或者
    R 4独立地选自氢、卤素、氨基、氰基、C 1-6烷基、C 1-6烷氧基、C 1-6烷基氨基；或者
    R 4独立地选自氢、氟、氯、氨基、氰基、甲基、甲氧基；或者
    R 4为氯。
  18. 根据权利要求1或3所述的化合物或其前药、互变异构体、立体异构体、溶剂化物、同位素衍生物或其药学上可接受的盐，其中X选自O或CH 2；L为CH；G为S；A选自CH或N；R 3独立地选自任选取代的8-12元杂环基、任选取代的C 6-10芳基、任选取代的5-14元杂芳基，其中所述任选取代是指被取代基团上的氢未被取代或被取代基团的一个或多个可取代位点上的氢独立地被选自羟基、氧代基、氰基、-CONH 2或C 1-6烷基的取代基所取代；R 1独立地选自氢、氘或氨基；R 2独立地选自卤素、-COR 5、-COOR 5、任选取代的C 1-6烷基、任选取代的C 2-6烯基、任选取代的3-10元杂环烷基，其中，R 5独立地选自未取代的C 1-6烷基或未取代的C 3-6环烷基，其中所述任选取代是指被取代基团上的氢未被取代或被取代基团的一个或多个可取代位点上的氢独立地被选自卤素、羟基、C 1-6烷氧基的取代基所取代；Y独立地选自N或CR 4；R 4为卤素；R 6独立地选自氢、氘；或者
    X选自O或CH 2；L为CH；G为S；A选自CH或N；R 3独立地选自：任选取代的8-10元双环杂环基、任选取代的C 6或C 10芳基、任选取代的5-6元杂芳基，其中所述任选取代是指被取代基团上的氢未被取代或被取代基团的一个或多个可取代位点上的氢独立地被选自羟基、氧代基、氰基、-CONH 2或C 1-6烷基的取代基所取代；R 1独立地选自氢、氘、氨基；R 2独立地选自 卤素、-COR 5、-COOR 5、任选取代的C 1-6烷基、任选取代的C 2-6烯基、任选取代的3-6元杂环烷基，其中，R 5独立地选自未取代的C 1-6烷基或未取代的C 3-6环烷基，所述任选取代是指被取代基团上的氢未被取代或被取代基团的一个或多个可取代位点上的氢独立地被选自卤素、羟基、C 1-6烷氧基的取代基所取代；Y独立地选自N或CR 4；R 4为卤素；R 6独立地选自氢、氘；或者
    X选自O或CH 2；L为CH；G为S；A选自CH或N；R 3独立地选自：被C 1-6烷基任选取代的5-6元杂芳基；R 1独立地选自氢、氘、氨基；R 2独立地选自 卤素、-COR 5、-COOR 5、任选取代的C 2-6烯基、任选取代的3-6元杂环烷基，其中，R 5独立地选自未取代的C 1-6烷基或未取代的C 3-6环烷基，所述任选取代是指被取代基团上的氢未被取代或被取代基团的一个或多个可取代位点上的氢独立地被选自卤素、羟基、C 1-6烷氧基的取代基所取代；Y独立地选自N或CR 4；R 4为卤素；R 6独立地选自氢、氘；或者
    X选自O或CH 2；L为CH；G为S；A选自CH或N；R 3独立地选自：被C 1-6烷基任选取代的5-6元杂芳基；R 1独立地选自氢、氘、氨基；R 2独立地选自 卤素、-COR 5、-COOR 5、未取代的C 2-6烯基、未取代的3-6元杂环烷基，其中，R 5独立地选自未取代的C 1-6烷基或未取代的C 3-6环烷基；Y独立地选自N或CR 4；R 4为卤素；R 6独立地选自氢、氘；或者
    X选自O或CH 2；L为CH；G为S；A选自CH或N；R 3独立地选自：被C 1-4烷基任选取代的5元杂芳基；R 1独立地选自氢、氘、氨基；R 2独立地选自-COR 5或-COOR 5，其中，R 5独立地选自未取代的C 1-4烷基或未取代的C 3-6环烷基；Y独立地选自N或CR 4；R 4为卤素，例如Cl或F，优选Cl；R 6独立地选自氢、氘；或者
    X选自O或CH 2；L为CH；G为S；A为CH时Y为CR 4；R 4为卤素，例如Cl或F，优选Cl；或A为N时Y独立地选自N或CR 4；R 4为卤素，例如Cl或F，优选Cl；R 3独立地选自：被C 1-2烷基(例如，甲基)任选取代的5元杂芳基；R 1独立地选自氢、氘、氨基；R 2独立地选自-COR 5或-COOR 5，其中，R 5独立地选自未取代的C 1-2烷基(例如，甲基)或未取代的C 3-4环烷基(例如，环丙基)；R 6独立地选自氢、氘。
  19. 根据权利要求2所述的化合物或其前药、互变异构体、立体异构体、溶剂化物、同位素衍生物或其药学上可接受的盐，其中X选自O或CH 2；L为CH；G为S；A选自CH或N；R 3为氨基；R 2独立地选自卤素、-COR 5、-COOR 5、任选取代的C 1-6烷基、任选取代的C 2-6烯基、任选取代的3-10元杂环烷基，其中，R 5独立地选自未取代的C 1-6烷基或未取代的C 3-6环烷基，所述任选取代是指被取代基团上的氢未被取代或被取代基团的一个或多个可取代位点上的氢独立地被选自卤素、羟基、C 1-6烷氧基的取代基所取代；Y独立地选自N或CR 4；R 4为卤素；R 6独立地选自氢、氘；或者
    X选自O或CH 2；L为CH；G为S；A选自CH或N；R 3为氨基；R 1独立地选自氢、氘、氨基；R 2独立地选自 卤素、-COR 5、-COOR 5、任选取代的C 1-6烷基、任选取代的C 2-6烯基、任选取代的3-6元杂环烷基，其中，R 5独立地选自未取代的C 1-6烷基或未取代的C 3-6环烷基，所述任选取代是指被取代基团上的氢未被取代或被取代基团的一个或多个可取代位点上的氢独立地被选自卤素、羟基、C 1-6烷氧基的取代基所取代；Y独立地选自N或CR 4；R 4为卤素；R 6独立地选自氢或氘；或者
    X选自O；L为CH；G为S；A为N；R 3为氨基；R 1为氨基；R 2独立地选自-COR 5或-COOR 5，其中，R 5独立地选自未取代的C 1-6烷基或未取代的C 3-6环烷基；Y独立地选自N或CR 4；R 4为卤素；R 6独立地选自氢或氘；或者
    X选自O；L为CH；G为S；A为N；R 3为氨基；R 1为氨基；R 2独立地选自-COR 5或-COOR 5，其中，R 5独立地选自未取代的C 1-2烷基(例如甲基)或未取代的C 3-4环烷基(例如环丙基)；Y独立地选自N或CR 4；R 4为卤素(例如Cl)；R 6独立地选自氢或氘。
  20. 根据权利要求3所述的化合物或其前药、互变异构体、立体异构体、溶剂化物、同位素衍生物或其药学上可接受的盐，其特征在于：所述化合物选自：
    Figure PCTCN2022094255-appb-100022
    Figure PCTCN2022094255-appb-100023
    Figure PCTCN2022094255-appb-100024
    Figure PCTCN2022094255-appb-100025
    Figure PCTCN2022094255-appb-100026
    Figure PCTCN2022094255-appb-100027
  21. 根据权利要求3所述的化合物或其前药、互变异构体、立体异构体、溶剂化物、同位素衍生物或其药学上可接受的盐，其中所述化合物选自：
    Figure PCTCN2022094255-appb-100028
    Figure PCTCN2022094255-appb-100029
  22. 根据权利要求3所述的化合物或其前药、互变异构体、立体异构体、溶剂化物、同位素衍生物或其药学上可接受的盐，其中所述化合物选自：
    Figure PCTCN2022094255-appb-100030
    Figure PCTCN2022094255-appb-100031
  23. 根据权利要求3所述的化合物或其前药、互变异构体、立体异构体、溶剂化物、同位素衍生物或其药学上可接受的盐，其中所述化合物选自：
    Figure PCTCN2022094255-appb-100032
  24. 一种药物组合物，其包含权利要求1～23中任一项所述的化合物或其前药、互变异构体、立体异构体、溶剂化物、同位素衍生物或其药学上可接受的盐。
  25. 根据权利要求1～23中任一项所述的化合物或其前药、互变异构体、立体异构体、溶剂化物、同位素衍生物或其药学上可接受的盐或权利要求24所述的药物组合物在制备用于预防和/或治疗通过SHP2活性介导的疾病、病症和病况的药物中的用途。
  26. 根据权利要求25所述的用途，其中所述的疾病、病症和病况为肿瘤、癌转移、心血管疾病、免疫紊乱或视觉紊乱；优选地，所述肿瘤包括实体瘤和血液瘤；进一步优选地，所述实体瘤包括肺癌，所述血液瘤包括白血病，所述白血病优选为急性髓性白血病。
  27. 根据权利要求25或26所述的用途，其中权利要求1～23中任一项所述的化合 物或其前药、互变异构体、立体异构体、溶剂化物、同位素衍生物或其药学上可接受的盐或权利要求24所述的药物组合物与另一种、两种或更多种具有抑制肿瘤活性的化合物组合使用。
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