WO2023061294A1 - 含氮杂环类衍生物调节剂、其制备方法及应用 - Google Patents

含氮杂环类衍生物调节剂、其制备方法及应用 Download PDF

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WO2023061294A1
WO2023061294A1 PCT/CN2022/124111 CN2022124111W WO2023061294A1 WO 2023061294 A1 WO2023061294 A1 WO 2023061294A1 CN 2022124111 W CN2022124111 W CN 2022124111W WO 2023061294 A1 WO2023061294 A1 WO 2023061294A1
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substituted
compound
pharmaceutically acceptable
acceptable salt
unsubstituted
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PCT/CN2022/124111
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French (fr)
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何勇
贾兰齐
顾禹归
陆军
吴文挺
李尚丰
陆晓杰
李静
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再鼎医药(上海)有限公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems
    • 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 invention belongs to the field of drug synthesis, and specifically relates to a nitrogen-containing heterocyclic derivative inhibitor such as a compound represented by formula (I), its preparation method and application.
  • Rat sarcoma (rat sarcoma, RAS), encoded by the proto-oncogenes HRAS, NRAS and KRAS, is a GTP-binding protein that is activated when it binds to GTP and inactive when it binds to GDP.
  • RAS is distributed on the inner surface of the cell membrane and is activated when bound to GTP, and inactive when bound to GDP.
  • the upstream of RAS is receptor tyrosine kinase (RTK), which after activation regulates downstream signaling pathways such as PI3K and RAF, thereby regulating cell growth, survival, migration and differentiation.
  • RAS proteins are central to the axes of many important cellular signaling networks, and these signals are associated with multiple tumor markers, hyperactivated RAS signaling may ultimately contribute to tumorigenesis.
  • KRAS oncogenic mutations are most common in KRAS (85%), and the abnormal expression of KRAS accounts for up to 20% of all cancers, of which G12D mutations account for 25% of pancreatic cancer (PDAC), 13.3% of colon cancer (CRC), Rectal cancer (RC) 10.1%, non-small cell lung cancer (NSCLC) 4.1%.
  • PDAC pancreatic cancer
  • CRC colon cancer
  • RC Rectal cancer
  • NSCLC non-small cell lung cancer
  • the present invention provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof,
  • R 1 is selected from H, -L-substituted or unsubstituted aryl, -L-substituted or unsubstituted heteroaryl, -L-substituted or unsubstituted heterocycloalkyl and -L-substituted or unsubstituted Cycloalkyl;
  • Q 1 is selected from CR and N, and the R is selected from H, CN, CF 3 , OH, halogen, substituted or unsubstituted C 1-3 alkyl and substituted or unsubstituted C 1-3 alkoxy;
  • Y is selected from a bond, -O-, -S- and -NH-;
  • Z is selected from -NR 5 R 6 and substituted or unsubstituted heterocycloalkyl
  • R 5 is H
  • R 6 is selected from substituted or unsubstituted heterocycloalkyl and substituted or unsubstituted C 3-6 alkyl;
  • X 1 is selected from -OH and C 1-3 alkoxy
  • X 2 is vinyl
  • the substituent of said vinyl is selected from substituted or unsubstituted aryl, substituted or unsubstituted heterocycloalkyl and substituted or Unsubstituted heteroaryl;
  • X1 and X2 form 5-membered heteroaryl, 5-membered or 6-membered heterocycloalkyl together with the carbon atom to which they are jointly attached, or
  • the 5-membered heteroaryl group and the 5-membered or 6-membered heterocycloalkyl group (1) are substituted by a group selected from substituted or unsubstituted aryl, substituted or unsubstituted heterocycloalkyl and substituted or unsubstituted heteroaryl, and (2) may be substituted by a group selected from C 1-3 alkyl, CF 3 , CN and halogen;
  • R is selected from substituted or unsubstituted aryl (for example, substituted or unsubstituted phenyl, anthracenyl and naphthyl), substituted or unsubstituted heterocycloalkyl and substituted or unsubstituted heteroaryl;
  • R 4 is selected from H, C 1-3 alkyl, C 3-8 cycloalkyl, C 1-3 alkoxy, -OCF 3 , -OCHF 2 , -SCF 3 , halo, -NH 2 , OH and CF 3 ;
  • Q 2 is selected from C-R' and N, and the R' is selected from H, CN, CF 3 , OH, halogen, substituted or unsubstituted -SC 1-3 alkyl, substituted or unsubstituted C 1-3 alkyl And substituted or unsubstituted C 1-3 alkoxy;
  • R' and R together with their joint carbon atoms form a substituted or unsubstituted 5-membered or 6-membered heteroaryl group or a substituted or unsubstituted 5-membered or 6-membered heterocycloalkyl group;
  • Q 3 is selected from CR 2 and N, and the R 2 is selected from H, halogen, OH, CN, substituted or unsubstituted C 1-3 alkyl and substituted or unsubstituted C 1-3 alkoxy;
  • the substituents in the substituted C 1-3 alkoxy group are selected from oxy, C 2-8 alkynyl, C 2-8 alkenyl, aryl, heteroaryl, heterocycloalkyl, cycloalkyl, C 1- 8Alkoxy , -O-Phenyl, -COOR 7 , -NR 7 R 8 , -OCONR 7 R 8 , -CONR 7 R 8 , -COR 7 , -SR 7 , -CN, -NO 2 , -OH ,-OCF 3, halogen and C 1-8 alkyl, the aryl, heteroaryl, heterocycloalky
  • R 7 and R 8 are each independently selected from H, C 1-4 alkyl and benzyl, or R 7 and R 8 form a 5-membered or 6-membered heterocycloalkyl group together with the N atom they are connected to;
  • R3 is aryl or heteroaryl which is at least substituted by aryl or
  • R 5 is H
  • R 6 is selected from substituted or unsubstituted heterocycloalkyl
  • Q 1 is N
  • X1 and X2 together with the carbon atom to which they are jointly attached form
  • at least one of Q 2 and Q 3 is N.
  • R 5 is H
  • R 6 is selected from substituted or unsubstituted Substituted heterocycloalkyl
  • Q 1 is N
  • X 1 and X 2 together form the carbon atom to which they are jointly attached
  • at least one of Q 2 and Q 3 is N and R 4 is not H.
  • Z is not a bridged heterocycloalkyl group.
  • R 4 is selected from C 1-3 alkyl, C 3-8 cycloalkyl, C 1-3 alkoxy, -OCF 3 , -OCHF 2 , -SCF 3 , halo, -NH 2 ,OH and CF 3..
  • Q 2 is selected from C-R', and the R' is selected from H, CN, CF 3 , OH, halogen, substituted or unsubstituted-SC 1-3 alkyl, substituted or unsubstituted C 1-3 alkyl and substituted or unsubstituted C 1-3 alkoxy.
  • Q 3 is selected from CR 2
  • the R 2 is selected from H, halogen, OH, CN, substituted or unsubstituted C 1-3 alkyl and substituted or unsubstituted C 1-3 alkoxy .
  • Q 2 is selected from C-R', and the R' is selected from H, CN, CF 3 , OH, halogen, substituted or unsubstituted-SC 1-3 alkyl, substituted or unsubstituted C 1-3 alkyl and substituted or unsubstituted C 1-3 alkoxy, and Q 3 is selected from CR 2 , said R 2 is selected from H, halogen, OH, CN, substituted or unsubstituted C 1-3 alkyl and substituted or unsubstituted C 1-3 alkoxy.
  • X1 is -OH
  • X2 is vinyl
  • the substituents of said vinyl are selected from substituted or unsubstituted aryl, substituted or unsubstituted heterocycloalkyl and substituted or unsubstituted the heteroaryl.
  • X 1 is C 1-3 alkoxy
  • X 2 is vinyl
  • the substituents of the vinyl are selected from substituted or unsubstituted aryl, substituted or unsubstituted heterocycloalkyl And substituted or unsubstituted heteroaryl.
  • X 1 is -OCH 3 .
  • X 2 is vinyl, and the vinyl is substituted by substituted or unsubstituted phenyl or naphthyl.
  • phenyl or naphthyl can be substituted by OH, phenyl, C 1-3 alkyl , ethynyl or vinyl substitution.
  • X 2 is selected from
  • X 1 and X 2 form a 5-membered heteroaryl group together with their joint carbon atoms
  • the 5-membered heteroaryl group (1) is substituted by a group selected from Substituted or unsubstituted aryl, substituted or unsubstituted heterocycloalkyl and substituted or unsubstituted heteroaryl (2) may be further substituted by 1 group selected from C 1-3 alkyl , CF 3 , CN and halogen.
  • the 5-membered heteroaryl is selected from pyrazolyl, furyl, oxazolyl, pyrrolyl and thienyl
  • the pyrazolyl, furyl, oxazolyl Azolyl, pyrrolyl and thienyl (1) are substituted by a group selected from substituted or unsubstituted aryl, substituted or unsubstituted heterocycloalkyl and substituted or unsubstituted heteroaryl (2) It can be substituted by another group selected from C 1-3 alkyl, CF 3 , CN and halogen.
  • X 1 and X 2 form a 6-membered heterocycloalkyl group together with their joint carbon atoms
  • the 6-membered heterocycloalkyl group (1) is substituted by a group, and the group selected from substituted or unsubstituted aryl, substituted or unsubstituted heterocycloalkyl and substituted or unsubstituted heteroaryl (2) may be further substituted by a group selected from C 1-3 Alkyl, CF 3 , CN and halogen.
  • the 6-membered heterocycloalkyl group is selected from said Substituted by 1 group selected from substituted or unsubstituted aryl, substituted or unsubstituted heterocycloalkyl and substituted or unsubstituted heteroaryl (2) may be substituted by 1 more group , the group is selected from C 1-3 alkyl, CF 3 , CN and halogen.
  • X 1 and X 2 form a 5-membered heteroaryl group together with their joint carbon atoms, and the 5-membered or 6-membered heterocycloalkyl group is substituted by a group selected from
  • X 1 and X 2 together form the carbon atom that they are connected together
  • Q 2 is N.
  • Q 2 is CR', and the R' is selected from H, Cl, F, CN, -OCH 3 and -OH.
  • R is selected from H and F.
  • Q 2 is CR', and R' and R 4 form a substituted or unsubstituted 5-membered or 6-membered heteroaryl group or a substituted or unsubstituted 5-membered or 6-membered heteroaryl group together with their joint carbon atoms. Heterocycloalkyl. In some schemes of the present invention, Q 2 is CR', and R' and R 4 together form the carbon atom to which they are jointly attached
  • Q 3 is N. In some schemes of the present invention, Q 3 is CR 2 , and the R 2 is selected from H, -OH and F.
  • Q 2 is CR', and the R' is selected from H, -CH 3 , -CH 2 CH 3 , -CH(CH 3 ) 2 , -SCF 3 , Cl, F, CN, - OCH3 and -OH.
  • Q 2 is CR', and the R' is selected from H, -CH 3 , -CH 2 CH 3 , -CH(CH 3 ) 2 , -SCF 3 , Cl, F, CN, - OCH 3 and -OH, and Q 3 is CR 2 , and the R 2 is selected from H, -OH and F.
  • the compound represented by formula (I) or a pharmaceutically acceptable salt thereof is selected from the compound represented by formula (II) or a pharmaceutically acceptable salt thereof,
  • Q 2' is consistent with the definition of formula (I) Q 2
  • R 4' is consistent with the definition of formula (I) R 4
  • Z' is consistent with the definition of formula (I) Z, Y, R 1 ,
  • R 2 , R 3 have the same definition as formula (I).
  • Q 2' is N. In some schemes of the present invention, Q 2' is CH, C-CH 3 , C-CH 2 CH 3 , -C-CH(CH 3 ) 2 , -S -CF 3 ,CF or C-Cl.
  • R 4' is selected from H. In some schemes of the present invention, R 4' is selected from C 1-3 alkyl, C 3-8 cycloalkyl, C 1-3 alkoxy,- OCF 3 , -OCHF 2 , -SCF 3 , halo, -NH 2 , OH and CF 3 .
  • R 4' is selected from -CH 3 , -OCH 3 , -OCH 2 CH 3 , -OCH (CH 3 ) 2 , -SCF 3 , -CH(CH 3 ) 2 , -OCF 3 , OH, -CF 3 , -OCHF 2 , cyclopropyl, Cl, F, and -NH 2 .
  • Z' or Z is a heterocycloalkyl group with only one heteroatom selected from N, O and S on the substituted or unsubstituted ring. In some schemes of the present invention, Z' or Z is selected from A heterocycloalkyl group with only one N heteroatom on the substituted or unsubstituted ring.
  • Z' or Z is selected from substituted or unsubstituted azetidinyl, tetrahydropyrrolyl, piperidine group, cycloheximide group
  • these substituents are one or more selected from hydroxyl, oxy, C 1-8 alkyl, fluorine, chlorine, C 1-8 alkyl substituted with 1-5 halogen, one or more C 1-8 alkyl substituted by hydroxy, C 1-8 alkyl substituted by one or more CN, C 1-8 alkyl substituted by C 1-8 alkoxy, -NHCOC 1-8 alkyl substituted C 1-8 alkyl, C 1-8 alkoxy, C 1-8 alkoxy substituted with 1-5 halogen, C 1-8 alkoxy substituted with one or more hydroxy groups, -CN, amino, mono Or double C 1-8 alkyl substituted amino.
  • these substituents contain one or two hydroxyl groups.
  • R 3 is selected from unsubstituted or substituted pyridyl, phenyl and naphthyl, and these substituents are one or more, selected from hydroxyl, -NH 2 , fluorine, chlorine, C 1-8 Alkyl, 1-5 halogen substituted C 1-8 alkyl, C 3-6 cycloalkyl, C 2-8 alkenyl, and C 2-8 alkynyl.
  • R 3 is selected from
  • Q 1 is CR
  • R is selected from H, CN, CF 3 , OH, halogen, substituted or unsubstituted C 1-3 alkyl and substituted or unsubstituted C 1-3 alkoxy .
  • Q 1 is CR
  • R is selected from H and CN.
  • Y is O.
  • R 1 is selected from L-substituted or unsubstituted 9- or 10-membered fused bicyclic aryl, L-substituted or unsubstituted 8-10-membered fused bicyclic heteroaryl, L- Substituted or unsubstituted 7-10 membered fused bicyclic heterocycloalkyl containing at least one N atom, L-substituted or unsubstituted 3-8 membered monocyclic cycloalkyl, and L-substituted or unsubstituted A 5-7 membered monocyclic heterocycloalkyl group containing at least one N atom.
  • the 9- or 10-membered fused bicyclic aryl group, the 8-10-membered fused bicyclic heteroaryl group, A 7-10 membered fused bicyclic heterocycloalkyl group containing at least one N atom, and a 5-7 membered monocyclic heterocycloalkyl group containing at least one N atom may be substituted by one or more members selected from F and Unsubstituted C 1-3 alkyl group substitution.
  • R 1 is selected from Wherein, R 7 and R 8 are each independently selected from H, C 1-4 alkyl and benzyl, or R 7 and R 8 form a 5-membered or 6-membered heterocycloalkyl together with the N atom they are jointly connected to.
  • L is selected from a bond and CH 2 .
  • Z or Z' is -NR 5 R 6 , said R 5 is H, and R 6 is selected from substituted or unsubstituted heterocycloalkyl and substituted or unsubstituted C 3-6 alkyl .
  • Z or Z' is In some solutions of the present invention, Z or Z' is selected from
  • Z or Z' is a substituted or unsubstituted heterocycloalkyl.
  • Z or Z' is a heterocycloalkyl group with only one heteroatom selected from N, O and S on the substituted or unsubstituted ring.
  • Z and Z' are substituted or unsubstituted 5-7 membered monocyclic heterocycloalkyl groups. In some schemes of the present invention, Z is selected from
  • Z and Z' are not bridged heterocycloalkyl.
  • Z and Z' are selected from substituted or unsubstituted
  • Z and Z' are selected from
  • Z and Z' are substituted or unsubstituted 6-10 membered fused bicyclic heterocycloalkyl groups. In some schemes of the present invention, Z and Z' are substituted or unsubstituted In some solutions of the present invention, Z and Z' are selected from
  • Z and Z' are substituted or unsubstituted 6-12 membered spiroheterocycloalkyl groups. In some schemes of the present invention, Z and Z' are substituted or unsubstituted In some solutions of the present invention, Z and Z' are
  • Z and Z' are substituted or unsubstituted 7-12 membered bridged heterocycloalkyl groups. In some schemes of the present invention, Z and Z' are substituted or unsubstituted 7-membered bridged heterocycloalkyl groups. Cycloalkyl. In some schemes of the present invention, Z and Z' are substituted or unsubstituted 7-membered bridge heterocycloalkyls containing at least one N atom. In some schemes of the present invention, Z is substituted or unsubstituted of
  • Z and Z' are substituted or unsubstituted or In some solutions of the present invention, Z and Z' are selected from
  • Z and Z' are selected from
  • the compound represented by formula (I) or its pharmaceutically acceptable salt is selected from
  • the compound represented by formula (I) or its pharmaceutically acceptable salt is selected from
  • the compound represented by formula (II) or a pharmaceutically acceptable salt thereof is selected from
  • the compound shown in formula (I) or its pharmaceutically acceptable salt is selected from the compound shown in formula (III) or its pharmaceutically acceptable salt:
  • R 1' is selected from -CH 2 -5-12 membered heterocycloalkyl, and the 3-12 membered heterocycloalkyl can be replaced by -CH 3 , F, Cl, -CH 2 N(CH 3 ) 2 , -CH 2 OC(O)N(CH 3 ) 2 , -CH 2 -morpholinyl, -CH 2 OC(O)-morpholinyl, and -CF 3 substituted,
  • Y' is O or key
  • Q 1' is selected from N, CH, C-CF 3 , C-OH, C-Cl, CF, C-CH 3 , C-OCH 3 and C-CN,
  • Z" is Z in formula (I), including Z in each scheme described above,
  • R 4' is selected from H, -CF 3 , -OH, -OMe, -OEt, -CH 3 , -SCF 3 , -OCH(CH 3 ) 2 , -CH(CH 3 ) 2 , -OCF 3 , -OCHF 2 , cyclopropyl, -NH 2 , F and Cl,
  • Q 2' is selected from C-R' and N, the R' is selected from H, CN, CF 3 , OH, halogen, substituted or unsubstituted -SC 1-3 alkyl, substituted or unsubstituted C 1-3 alkane and substituted or unsubstituted C 1-3 alkoxy, substituted or unsubstituted C 3-8 cycloalkyl,
  • R 3' is R 3 in formula (I), including R 3 in each of the schemes described above, such as selected from substituted or unsubstituted aryl (for example, substituted or unsubstituted phenyl, anthracenyl and naphthalene group), substituted or unsubstituted heterocycloalkyl and substituted or unsubstituted heteroaryl,
  • Q 3' is selected from N, CH, CF, C-Cl, C-OH, C-CN, C-CF 3 , C-CH 3 and C-OCH 3 .
  • Q 1' in formula (III) when Q 1' in formula (III) is N, Z" is a substituted or unsubstituted heterocycloalkyl or -NR 5 R 6 , R 5 is H, and R 6 is selected from substituted or Unsubstituted heterocycloalkyl, then at least one of Q 2' and Q 3' is N.
  • Q 2' is selected from CH, CF, C-OH, C-CH 3 , C-CF 3 , C-Cl, C-CN, C-CH 2 CH 3 , -C-CH( CH 3 ) 2 , -S-CF 3 , and C-OCH 3 .
  • Q 2' is N.
  • R 4' is selected from -CF 3 , -OH, OMe , OEt, -CH 3 , -SCF 3 , -OCH(CH 3 ) 2 , -CH(CH 3 ) 2 , -OCF 3 , -OCHF 2 , cyclopropyl, -NH 2 , F and Cl.
  • Q 1' is N.
  • Q 1' is selected from CH, C-CF 3 , C-OH, C-Cl, CF, C-CH 3 , C-OCH 3 and C -CN.
  • Q 3' is N.
  • Q 3' is selected from CH, CF, C-Cl, C-OH, C-CN, C-CF 3 , C- CH 3 and C-OCH 3 .
  • R 1 ' in formula (III) is selected from
  • R 3' is selected from
  • the compound represented by formula (I) or a pharmaceutically acceptable salt thereof is selected from the compounds represented by formula (IV) and formula (V) or a pharmaceutically acceptable salt thereof:
  • Ring A is selected from 4-10 members, and there is only one heteroatom in the ring, and the heteroatom is N,
  • R a is selected from oxy, hydroxyl, C 1-8 alkyl, C 3-8 cycloalkyl, fluorine, chlorine, 1-5 halogen substituted C 1-8 alkyl, one or more hydroxy substituted C 1 -8 alkyl, C 1-8 alkyl substituted by C 1-8 alkoxy, C 1-8 alkyl substituted by CN, C 1-8 alkyl substituted by -NHCOC 1-8 alkyl, C 1- 8 alkoxy, 1-5 halogen substituted C 1-8 alkoxy, one or more hydroxy substituted C 1-8 alkoxy, CN, amino, mono or double C 1-8 alkyl substituted amino ,
  • n 0, 1, 2 or 3
  • R 7 and R 8 are each independently selected from H, C1-4 alkyl and benzyl, or R 7 and R 8 form a 5-membered or 6-membered heterocycloalkyl group together with the N atom they are jointly connected to,
  • Y a is O or a bond
  • Q 1' is selected from N, CH, C-CF 3 , C-OH, C-Cl, CF, C-CH 3 , C-OCH 3 and C-CN,
  • Q 2' is selected from C-R' and N, the R' is selected from H, CN, CF 3 , OH, halogen, substituted or unsubstituted -SC 1-3 alkyl, substituted or unsubstituted C 1-3 alkane and substituted or unsubstituted C 1-3 alkoxy, substituted or unsubstituted C 3-8 cycloalkyl,
  • R 2' is selected from H, F, OH, CH 3 , CN, CF 3 , Cl, and OCH 3 ,
  • R 3" is selected from unsubstituted or substituted pyridyl, phenyl, benzo[b]thiophene and naphthyl, and these substituents are one or more selected from hydroxyl, fluorine, chlorine, C 1-8 alkyl, C 1-8 alkoxy, -NH 2 , C 1-8 alkyl substituted with 1-5 halogen, C 3-6 cycloalkyl, C 2-8 alkenyl, and C 2-8 alkynyl,
  • R 4' is selected from H, -CF 3 , -OH, -OMe, -OEt, -CH 3 , -SCF 3 , -OCH(CH 3 ) 2 , -CH(CH 3 ) 2 , -OCF 3 , -OCHF 2 , cyclopropyl, -NH 2 , F and Cl.
  • Q 1' and Q 2' in formula (IV) are not N at the same time. In some schemes of the present invention, neither Q 1' nor Q 2' in formula (IV) is N.
  • Q 1' in formula (IV) and formula (V) is selected from CH, C-CF 3 , C-OH, C-Cl, CF, C-CH 3 , C-OCH 3 and C-CN.
  • Q 2' in formula (IV) is selected from CH, C-CH 2 CH 3 , -C-CH(CH 3 ) 2 , -S-CF 3 , CF, C-OH, C -CH 3 , C-CF 3 , C-Cl, C-CN, and C-OCH 3 .
  • Q 1' in formula (IV) and formula (V) is selected from CH, C-CF 3 , C-OH, C-Cl, CF, C-CH 3 , C-OCH 3 and C-CN
  • Q 2' is selected from CH, C-CH 2 CH 3 , -C-CH(CH 3 ) 2 , -S-CF 3 , CF, C-OH, C-CH 3 , C-CF 3 , C-Cl, C-CN, and C-OCH 3.
  • R 4' in formula (IV) and formula (V) is selected from -CF 3 , -OH, -OMe, -OEt, -CH 3 , -SCF 3 , -OCH(CH 3 ) 2 , -CH(CH 3 ) 2 , -OCF 3 , -OCHF 2 , Cyclopropyl, -NH 2 , F and Cl.
  • R a is selected from oxygen, OH, NH 2 , -CH 2 OH, CH 3 , F, Cl, -CH 2 CH 3 , -CH(CH 3 ) 2 , cyclopropyl, CN, CF 3 , -CH 2 OCH 3 , -CH 2 CN, -CH 2 OH, -CH 2 NHCOCH 3 and OCH 3.
  • Q 1' in formula (IV) and formula (V) is N.
  • Q2 " in formula (IV) is N.
  • formula R 4' in (IV) is H.
  • ring A is not a bridged heterocycloalkyl group.
  • ring A is selected from
  • R 3 " is selected from
  • the compound shown in formula (I) or its pharmaceutically acceptable salt is selected from the compound shown in formula (VI) and formula (VII) or its pharmaceutically acceptable salt:
  • Ring A is selected from 4-10 members, and there is only one heteroatom in the ring, and the heteroatom is N,
  • R a is selected from oxy, hydroxyl, C 1-8 alkyl, C 3-8 cycloalkyl, fluorine, chlorine, 1-5 halogen substituted C 1-8 alkyl, one or more hydroxy substituted C 1 -8 alkyl, C 1-8 alkyl substituted by C 1-8 alkoxy, C 1-8 alkyl substituted by CN, C 1-8 alkyl substituted by -NHCOC 1-8 alkyl, C 1- 8 alkoxy, 1-5 halogen substituted C 1-8 alkoxy, one or more hydroxy substituted C 1-8 alkoxy, CN, amino, mono or double C 1-8 alkyl substituted amino ,
  • n 0, 1, 2 or 3
  • R 7 and R 8 are each independently selected from H, C1-4 alkyl and benzyl, or R 7 and R 8 form a 5-membered or 6-membered heterocycloalkyl group together with the N atom they are jointly connected to,
  • Y a is O or a bond
  • Q 1' is selected from N, CH, C-CF 3 , C-OH, C-Cl, CF, C-CH 3 , C-OCH 3 and C-CN,
  • R 3" is selected from unsubstituted or substituted pyridyl, phenyl and naphthyl, and these substituents are one or more selected from hydroxyl, fluorine, chlorine, C 1-8 alkyl, C 1-8 alkoxy ,-NH 2 , 1-5 halogen substituted C 1-8 alkyl, C 3-6 cycloalkyl, C 2-8 alkenyl, and C 2-8 alkynyl,
  • R 4' is selected from H, -CF 3 , -OH, -OMe, -OEt, -CH 3 , -SCF 3 , -OCH(CH 3 ) 2 , -CH(CH 3 ) 2 , -OCF 3 , -OCHF 2 , cyclopropyl, -NH 2 , F and Cl.
  • R 4' in formula (IV) and formula (V) is selected from -CF 3 , -OH, -OMe, -OEt, -CH 3 , -SCF 3 , -OCH(CH 3 ) 2 , -CH(CH 3 ) 2 , -OCF 3 , -OCHF 2 , Cyclopropyl, -NH 2 , F and Cl.
  • R a is selected from oxygen, OH, NH 2 , -CH 2 OH, CH 3 , F, Cl, -CH 2 CH 3 , -CH(CH 3 ) 2 , cyclopropyl, CN, CF 3 , -CH 2 OCH 3 , -CH 2 CN, -CH 2 OH, -CH 2 NHCOCH 3 and OCH 3.
  • Q 1' in formula (IV) and formula (V) is N.
  • Q2 " in formula (IV) is N.
  • formula R 4' in (IV) is H.
  • ring A is selected from
  • R 3 " is selected from
  • the compound represented by formula (II) or a pharmaceutically acceptable salt thereof is selected from:
  • the compound represented by formula (I) or a pharmaceutically acceptable salt thereof is selected from:
  • Additional embodiments 1-113 of the invention include:
  • R 1 is selected from H, -L-substituted or unsubstituted aryl, -L-substituted or unsubstituted heteroaryl, -L-substituted or unsubstituted heterocycloalkyl and -L-substituted or unsubstituted Cycloalkyl;
  • Q 1 is selected from CR and N, said R is selected from H, CN, CF 3 , OH, halogen, substituted or unsubstituted C 1-3 alkyl and substituted or unsubstituted C 1-3 alkoxy;
  • Y is selected from a bond, -O-, -S- and -NH-;
  • Z is selected from -NR 5 R 6 and substituted or unsubstituted heterocycloalkyl
  • R 5 is H
  • R 6 is selected from substituted or unsubstituted heterocycloalkyl and substituted or unsubstituted C 3-6 alkyl;
  • X 1 is selected from -OH and C 1-3 alkoxy
  • X 2 is vinyl
  • the substituent of said vinyl is selected from substituted or unsubstituted aryl, substituted or unsubstituted heterocycloalkyl and substituted or Unsubstituted heteroaryl;
  • X1 and X2 form 5-membered heteroaryl, 5-membered or 6-membered heterocycloalkyl together with the carbon atom to which they are jointly attached, or
  • the 5-membered heteroaryl group and the 5-membered or 6-membered heterocycloalkyl group (1) are substituted by a group selected from substituted or unsubstituted aryl, substituted or unsubstituted heterocycloalkyl and substituted or unsubstituted heteroaryl, (2) may be substituted by a group selected from C 1-3 alkyl, CF 3 , CN and halogen;
  • R is selected from substituted or unsubstituted aryl, substituted or unsubstituted heterocycloalkyl and substituted or unsubstituted heteroaryl;
  • R 4 is selected from H, C 1-3 alkyl, C 3-8 cycloalkyl, C 1-3 alkoxy, -OCF 3 , -OCHF 2 , -SCF 3 , halo, -NH 2 , OH and CF 3 ;
  • Q 2 is selected from C-R' and N, and the R' is selected from H, CN, CF 3 , OH, halogen, substituted or unsubstituted -SC 1-3 alkyl, substituted or unsubstituted C 1-3 alkyl And substituted or unsubstituted C 1-3 alkoxy, substituted or unsubstituted C 3-8 cycloalkyl;
  • R' and R together with their joint carbon atoms form a substituted or unsubstituted 5-membered or 6-membered heteroaryl group or a substituted or unsubstituted 5-membered or 6-membered heterocycloalkyl group;
  • Q 3 is selected from CR 2 and N, and the R 2 is selected from H, halogen, OH, CN, substituted or unsubstituted C 1-3 alkyl and substituted or unsubstituted C 1-3 alkoxy;
  • R3 is aryl or heteroaryl which is at least substituted by aryl or
  • X 1 and X 2 form a 5-membered heteroaryl group together with their joint carbon atoms
  • the 5-membered heteroaryl group (1) is Substituted by 1 group selected from substituted or unsubstituted aryl, substituted or unsubstituted heterocycloalkyl and substituted or unsubstituted heteroaryl (2) may be substituted by another group, The group is selected from C 1-3 alkyl, CF 3 , CN and halogen.
  • the substituted heteroaryl (2) can be substituted by another group selected from C 1-3 alkyl, CF 3 , CN and halogen.
  • R 4 is selected from C 1-3 alkyl, C 3-8 cycloalkyl, C 1-3 alkoxy radical, -OCF 3 , -OCHF 2 , -SCF 3 , halo, -NH 2 , OH and CF 3 .
  • the compound shown in formula (I) or its pharmaceutically acceptable salt is selected from the compound shown in formula (II) or its pharmaceutically acceptable salt Salt,
  • Q 2' is consistent with the definition of formula (I) Q 2
  • R 4' is consistent with the definition of formula (I) R 4
  • Z' is as described in Z of scheme 1
  • Y, R 1 , R 2 , R 3 are as in scheme 1 described.
  • Q 2' is CH, C-CH 3 , C-CH 2 CH 3 , -C-CH(CH 3 ) 2 , -S-CF 3 ,CF or C-Cl.
  • R 4' is selected from C 1-3 alkyl, C 3-8 cycloalkyl, C 1-3 alkoxy ,-OCF 3 ,-OCHF 2 ,-SCF 3 ,halo,-NH 2 ,OH and CF 3.
  • R 4' is selected from -CH 3 , -OCH 3 , -OCH 2 CH 3 , -OCH(CH 3 ) 2 , -SCF 3 , -CH (CH 3 ) 2 , -OCF 3 ,OH, -CF 3 , -OCHF 2 , cyclopropyl, Cl, F, and -NH 2 .
  • R is selected from H, -OH and F.
  • R is selected from L-substituted or unsubstituted 9- or 10-membered fused bicyclic aryl groups, L-substituted Or unsubstituted 8-10-membered fused bicyclic heteroaryl, L-substituted or unsubstituted 3-8-membered monocyclic cycloalkyl, L-substituted or unsubstituted 7-10-membered containing at least one N atom fused bicyclic heterocycloalkyl, and L-substituted or unsubstituted 5-7 membered monocyclic heterocycloalkyl containing at least one N atom.
  • R 7 and R 8 are each independently selected from H, C1-4 alkyl and benzyl, or R 7 and R 8 form a 5-membered or 6-membered heterocycloalkyl together with the N atom they are jointly connected to.
  • Ring A is selected from 4-10 members, heterocycloalkyl group with only one heteroatom on the ring, said heteroatom is N, R a is selected from oxy group, hydroxyl, C 1-8 alkyl, C 3-8 cycloalkane group, fluorine, chlorine, C 1-8 alkyl substituted by 1-5 halogen, C 1-8 alkyl substituted by one or more hydroxy groups, C 1-8 alkyl substituted by C 1-8 alkoxy, CN Substituted C 1-8 alkyl, -NHCOC 1-8 alkyl substituted C 1-8 alkyl, C 1-8 alkoxy, 1-5 halogen substituted C 1-8 alkoxy, one or more C 1-8 alkoxy substituted by hydroxyl, CN, amino, mono or double C 1-8 alkyl substituted amino,
  • n 0, 1, 2 or 3
  • R 7 and R 8 are each independently selected from H, C1-4 alkyl and benzyl, or R 7 and R 8 form a 5-membered or 6-membered heterocycloalkyl group together with the N atom they are connected to;
  • Y a is O or a bond
  • Q 1' is selected from N, CH, C-CF 3 , C-OH, C-Cl, CF, C-CH 3 , C-OCH 3 and C-CN,
  • Q 2' is selected from C-R' and N, the R' is selected from H, CN, CF 3 , OH, halogen, substituted or unsubstituted -SC 1-3 alkyl, substituted or unsubstituted C 1-3 alkane and substituted or unsubstituted C 1-3 alkoxy, substituted or unsubstituted C 3-8 cycloalkyl,
  • R 2' is selected from H, F, OH, CH 3 , CF 3 , Cl, CN, and OCH 3 ,
  • R 3" is selected from unsubstituted or substituted pyridyl, phenyl, benzo[b]thiophene and naphthyl, and these substituents are one or more selected from hydroxyl, fluorine, chlorine, C 1-8 alkyl, 1-5 halogen substituted C 1-8 alkyl, C 1-8 alkoxy, -NH 2 , C 3-6 cycloalkyl, C 2-8 alkenyl, and C 2-8 alkynyl,
  • R 4' is selected from H, -CF 3 , -OH, -OMe, OEt, -CH 3 , -SCF 3 , -OCH(CH 3 ) 2 , -CH(CH 3 ) 2 , -OCF 3 , -OCHF 2 , cyclopropyl, -NH 2 , F and Cl.
  • R a is selected from oxygen, OH, NH 2 , -CH 2 OH, CH 3 , F, Cl, -CH 2 CH 3 , -CH (CH 3 ) 2 , CN, CF 3 , Cyclopropyl, -CH 2 OCH 3 , -CH 2 CN, -CH 2 OH, -CH 2 NHCOCH 3 and OCH 3.
  • R 4' in formula (IV) and formula (V) is selected from -CF 3 , -OH, -OMe, -OEt, -CH 3 , -SCF 3 , -OCH(CH 3 ) 2 , -CH(CH 3 ) 2 , -OCF 3 , -OCHF 2 , Cyclopropyl, -NH 2 , F and Cl
  • R 1' is selected from -CH 2 -3-12 membered heterocycloalkyl, and the 3-12 membered heterocycloalkyl can be replaced by -CH 3 , F, Cl, -CH 2 N(CH 3 ) 2 , -CH 2 OC(O)N(CH 3 ) 2 , -CH 2 -morpholinyl, -CH 2 OC(O)-morpholinyl, and -CF 3 substituted,
  • Y' is O or key
  • Q 1' is selected from N, CH, C-CF 3 , C-OH, C-Cl, CF, C-CH 3 , C-OCH 3 and C-CN,
  • R 4' is selected from H, -CF 3 , -OH, OMe, OEt, -CH 3 , -SCF 3 , -OCH(CH 3 ) 2 , -CH(CH 3 ) 2 , -OCF 3 , -OCHF 2 , Cyclopropyl, -NH 2 , F and Cl,
  • Q 2' is selected from C-R' and N, the R' is selected from H, CN, CF 3 , OH, halogen, substituted or unsubstituted -SC 1-3 alkyl, substituted or unsubstituted C 1-3 alkane and substituted or unsubstituted C 1-3 alkoxy, substituted or unsubstituted C 3-8 cycloalkyl,
  • R 3' is selected from substituted or unsubstituted aryl (for example, substituted or unsubstituted phenyl, benzo[b]thiophene, anthracenyl and naphthyl), substituted or unsubstituted heterocycloalkyl and substituted or unsubstituted Substituted Heteroaryl,
  • Q 3' is selected from N, CH, CF, C-Cl, C-OH, C-CN, C-CF 3 , C-CH 3 and C-OCH 3 .
  • a pharmaceutical composition comprising a compound according to any one of Schemes 1-106, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • the disease or condition associated with the KRAS G12D mutation is cancer.
  • the cancer being selected from the group consisting of malignant tumors (carcinoma) affecting epithelial tissue or the lining of abdominal organs, squamous cell carcinoma, pancreatic cancer, prostate cancer, rectal cancer, colon cancer, colorectal cancer, non- Small cell lung cancer, prostate cancer, small bowel cancer, sarcoma, leukemia, melanoma, and lymphoma.
  • malignant tumors cancerma
  • the cancer being selected from the group consisting of malignant tumors (carcinoma) affecting epithelial tissue or the lining of abdominal organs, squamous cell carcinoma, pancreatic cancer, prostate cancer, rectal cancer, colon cancer, colorectal cancer, non- Small cell lung cancer, prostate cancer, small bowel cancer, sarcoma, leukemia, melanoma, and lymphoma.
  • said other anticancer agents are selected from paclitaxel, cisplatin, carboplatin and oxaliplatin, PARP inhibitors (such as niraparib, olaparib), anti-PD- 1 Antibodies, anti-PD-L1 antibodies, anti-CTLA-4 antibodies, mTOR inhibitors, IGF1R inhibitors, HADC inhibitors, EGFR inhibitors, such as anti-EGFR antibodies (such as panitumumab), HIF-1 inhibitors, and VEGF /VEGFR inhibitors (such as sorafenib, bevacizumab).
  • PARP inhibitors such as niraparib, olaparib
  • anti-PD- 1 Antibodies anti-PD-L1 antibodies, anti-CTLA-4 antibodies
  • mTOR inhibitors IGF1R inhibitors
  • HADC inhibitors mTOR inhibitors
  • IGF1R inhibitors such as panitumumab
  • HIF-1 inhibitors such as sorafeni
  • KRAS such as KRAS-G12D
  • the disclosed compounds are useful in methods of treating or preventing diseases or conditions in which inhibition of KRAS would provide benefit.
  • the most important of these diseases and conditions are cancer and proliferative diseases. Such as pancreatic cancer, colorectal cancer, non-small cell lung cancer, etc.
  • the disclosed compounds may be used in combination with other anti-cancer agents, such as immunosuppressants such as PD-1 or other drugs.
  • a dash ("-") to the left of a substituent is used to indicate a point of attachment for a substituent.
  • -CONH 2 is attached through a carbon atom.
  • wavy line Indicates the chemical bond at which the site is attached to another group.
  • the wavy line in indicates that the 1-position carbon atom in the phenyl group is connected to other groups.
  • alkyl herein refers to a straight or branched hydrocarbon chain containing 1 to 14 carbon atoms.
  • the C symbol preceded by the term “alkyl” with a numerical range subscript represents the number of carbon atoms in the alkyl group.
  • C 1-5 alkyl represents an alkyl group containing 1, 2, 3, 4 or 5 carbon atoms.
  • Examples of C 1-5 alkyl include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, tert-butyl, and pentyl.
  • alkenyl herein refers to an unsaturated branched or straight hydrocarbon chain containing at least one carbon-carbon double bond.
  • the group can be in the cis or trans configuration of the double bond.
  • the C symbol preceded by the term “alkenyl” with a numerical range subscript represents the number of carbon atoms in the alkenyl group.
  • C 2-8 alkenyl means an alkenyl group containing 2, 3, 4, 5, 6, 7 or 8 carbon atoms.
  • alkenyl groups include, but are not limited to, vinyl; propenyl such as prop-1-en-1-yl, prop-1-en-2-yl, prop-2-en-1-yl (allyl ), prop-2-en-2-yl, cycloprop-1-en-1-yl; cycloprop-2-en-1-yl; butenyl, such as but-en-1-yl, but-1 -en-2-yl, 2-methyl-prop-1-en-1-yl, but-2-en-1-yl, but-2-en-1-yl, but-2-en-2- Base, but-1,3-dien-1-yl, but-1,3-dien-2-yl, cyclobut-1-en-1-yl, cyclobut-1-en-3-yl, Cyclobut-1,3-dien-1-yl, etc.
  • alkenyl groups have 2 to 10 carbon atoms, and in other embodiments, 2 to 6 carbon atoms and contain a carbon-carbon double bond
  • alkynyl herein refers to an unsaturated branched or straight hydrocarbon chain containing at least one carbon-carbon triple bond.
  • the C symbol preceded by the term “alkynyl” with a numerical range subscript represents the number of carbon atoms in the alkynyl group.
  • C 2-8 alkynyl represents an alkynyl group containing 2, 3, 4, 5, 6, 7 or 8 carbon atoms.
  • alkynyl groups include, but are not limited to, ethynyl; propynyl, such as prop-1-yn-2-yl, prop-2-yn-2-yl; butynyl, such as but-1-yn-2- group, but-1-yn-3-yl, but-3-yn-2-yl, etc.
  • alkynyl groups have 2 to 10 carbon atoms, and in other embodiments, 2 to 6 carbon atoms and contain a carbon-carbon triple bond.
  • alkoxy herein refers to -O-alkyl.
  • the C symbol preceded by the term “alkoxy” with a numerical range subscript represents the number of carbon atoms in the alkoxy group.
  • C 1-5 alkoxy denotes an alkoxy group containing 1, 2, 3, 4 or 5 carbon atoms.
  • Examples of C 1-5 alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, and pentoxy.
  • aryl refers to a 6-10 membered monocyclic aromatic hydrocarbon ring, such as phenyl.
  • Aryl also means a spiro, fused or bridged bicyclic or polycyclic ring system in which at least one ring is aromatic and contains no heteroatoms selected from O, S and N as ring atoms, the remaining rings may be saturated partially saturated or aromatic, provided that (1) when the remaining ring is aromatic, it contains no heteroatoms selected from O, S and N as ring atoms, and (2) when the remaining ring is not When aromatic, it may or may not contain heteroatoms selected from O, S and N as ring atoms.
  • the point of attachment can be any ring atom.
  • Examples of aryl groups include naphthyl and anthracenyl.
  • cycloalkyl herein refers to a saturated or partially unsaturated 3-14 membered monocyclic hydrocarbon group or a spiro, fused or bridged bicyclic or polycyclic hydrocarbon group having only carbon atoms as ring atoms.
  • the C symbol preceded by the term “cycloalkyl” with a numerical range subscript represents the number of carbon ring atoms in the cycloalkyl.
  • C 3-5 cycloalkyl represents a cycloalkyl group containing 3, 4 or 5 carbon ring atoms, ie cyclopropyl, cyclobutyl or cyclopentyl.
  • the ring may be saturated or have one or more double bonds (ie, partially unsaturated), but not fully conjugated.
  • the cycloalkyl is a spiro, fused or bridged bicyclic or polycyclic ring, none of the rings is aromatic.
  • heteroaryl refers to a 5-14 membered monoaromatic ring, such as a 5 or 6 membered monoaromatic ring, which contains one or more heteroatoms selected from N, O and S, for example, 1 to 4, Or in some embodiments, 1 to 3, with the remaining ring atoms being carbon atoms.
  • Heteroaryl also refers to a 7- to 14-membered spiro, fused or bridged bicyclic or polycyclic ring system in which at least one ring is aromatic and contains one or more heteroatoms selected from N, O and S As ring atoms, for example, 1 to 4, or in some embodiments, 1 to 3, the remaining ring (1) may or may not contain heteroatoms selected from N, O and S as ring atoms, and ( 2) Can be saturated, partially saturated or aromatic. The point of attachment can be any ring atom. For example, is heteroaryl.
  • heteroaryl groups include, but are not limited to, pyridyl, pyrazinyl, pyrimidinyl, pyrazolyl, imidazolinyl, isoxazolyl, oxazolyl, thiazolyl, thiadiazolyl, tetrazolyl , thienyl, benzothienyl, furyl, benzofuryl, benzimidazolyl, indolyl, pyridyl, triazolyl, quinolinyl and 5,6,7,8-tetrahydroisoquinyl Linyl
  • heterocycloalkyl refers to a saturated or partially unsaturated 5-14 membered monocyclic ring, or a fused, spiro or bridged bicyclic or polycyclic ring, which contains one or more selected from N , O, and S heteroatoms, eg, 1 to 4, or in some embodiments, 1 to 3, with the remaining ring atoms being carbon atoms.
  • the point of attachment can be any ring atom.
  • the heterocycloalkyl is a spiro, fused or bridged bicyclic or polycyclic ring, none of the rings is aromatic.
  • heterocycloalkyl groups include, but are not limited to, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, tetrahydrofuranyl, 5,6,7,8-tetrahydroimidazo[1,2-a]pyrrolidinyl Azinyl, tetrahydro-2H-pyranyl, 8-oxa-3-azabicyclo[3.2.1]octyl, 3-oxa-9-azaspiro[5.5]undecyl, 7- Oxa-2-azaspiro[3.5]nonyl and 2-oxa-7-azaspiro[3.5]nonyl, azepanyl, 1,2,5-triazepanyl ,6,7,8,9-Tetrahydro-1H,5H-[1,2,4]triazolo[1,2-a][1,2,5]triazepanyl, diazepam Heptyl, 3,6-diazabicyclo[3.
  • Halogen means F, Cl, Br or I.
  • substituted or unsubstituted means that the group defined by the term can be substituted by a substituent.
  • the substituent can be selected from oxy, C 2-8 alkynyl, C 2-8 alkenyl, aryl, hetero Aryl, heterocycloalkyl, cycloalkyl, C 1-8 alkoxy, -O-phenyl, -COOR 7 , -NR 7 R 8 , -OCONR 7 R 8 , -CONR 7 R 8 , -COR 7 , -SR 7 , -CN, -NO 2 , -OH, -OCF 3 , halogen and C 1-8 alkyl, the aryl, heteroaryl, heterocycloalkyl, cycloalkyl, C 1- 8 alkoxy and C 1-8 alkyl can be replaced by 1-5 halogen, -CN, -OH, -OCONR 7 R 8 , -NR 7 R 8 , -NHCOC 1
  • “Pharmaceutically acceptable salt” refers to a salt form of a compound (eg, a drug) having at least one group capable of forming a salt, which salt form does not cause significant adverse toxicological effects in a subject.
  • Pharmaceutically acceptable salts include, for example, salts prepared by reacting with inorganic acids, organic acids or bases, depending on the nature of the compound (eg, drug).
  • Inorganic acid can be hydrochloric acid, hydrobromic acid, carbonic acid, sulfuric acid, phosphoric acid, etc.
  • organic acid can be fumaric acid, maleic acid, succinic acid, acetic acid, citric acid, tartaric acid, methanesulfonic acid, etc.
  • the base capable of forming a salt with an acidic drug may be an amine-containing compound or an inorganic base such as sodium hydroxide, sodium carbonate, and the like.
  • Suitable pharmaceutically acceptable salt forms can be found, for example, in: Handbook of Pharmaceutical Salts: Properties, Selection and Use, edited by P.H. Stahl and C.G. Wermuth, Weinheim/Zürich: Wiley - VCH Press/VHCA, 2002.
  • treating a disease means slowing or arresting the progression of a disease, alleviating symptoms or side effects of a disease, and/or causing regression of a disease.
  • the term also refers to a reduction in morbidity in a subject compared to a subject who has not received treatment.
  • “Pharmaceutically acceptable excipients” refer to excipients that are generally safe, non-toxic and have no adverse effects on biology or other aspects and can be used for the preparation of pharmaceutical compositions, including veterinary acceptable and human pharmaceutical excipients. acceptable excipients.
  • a "pharmaceutically acceptable excipient” as used in the specification and claims includes both one and more than one such excipient.
  • subject refers to an animal (eg mammal) or a human.
  • compounds of formula (I) or pharmaceutically acceptable salts thereof as described herein also include compounds of formula (I) in which certain atoms in formula (I) are replaced by their corresponding isotopes or pharmaceutically acceptable salts thereof Accepted salts, eg, wherein some of the H's are replaced by D (deuterium).
  • the compounds disclosed herein (the term "compound disclosed herein” includes pharmaceutically acceptable salts thereof) will be administered in a therapeutically effective amount by any acceptable mode of administration of an agent having similar utility in the form of a pharmaceutical composition.
  • a therapeutically effective amount of a compound disclosed herein may range from 0.01 to 500 mg/kg body weight of a subject, which may be administered in single or multiple doses per day.
  • the pharmaceutical composition may contain from 1.0 to 1000 mg of a compound disclosed herein, for example 1.0, 5.0, 10, 15, 20, 25, 50, 75, 100, 150, 200, 250, 300, 350, 400,
  • the compounds disclosed herein are provided in the form of 450, 500, 550, 600, 650, 700, 750, 800, 850, 900 and 1000 mg tablets or capsules.
  • the compounds disclosed herein can also be administered as pharmaceutical compositions by, for example, transdermal, intranasal, suppository, intramuscular, intravenous or subcutaneous administration.
  • compositions comprising a compound disclosed herein and a pharmaceutically acceptable excipient.
  • the pharmaceutical compositions can contain from 1 mg to 1000 mg of a compound disclosed herein.
  • Exemplary solid pharmaceutical excipients include starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, flour, calcium carbonate, silica gel, magnesium stearate, sodium stearate, monostearate Glycerides, Sodium Chloride, Skimmed Milk Powder, etc.
  • Liquid and semisolid excipients can be selected from glycerol, propylene glycol, water, ethanol and various oils, including those of petroleum, animal, vegetable or synthetic origin, for example, peanut oil, soybean oil, mineral oil, sesame oil and the like.
  • Preferred liquid excipients, especially for injection solutions include water, physiological saline, aqueous dextrose and glycols.
  • methods of inhibiting KRAS G12D activity in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound described herein.
  • a method of treating a disease or condition associated with a KRAS G12D mutation in a subject in need thereof comprising administering to the patient a therapeutically effective amount of a compound described herein.
  • the disease or condition associated with a KRAS G12D mutation can be cancer.
  • Cancers include, but are not limited to, carcinoma, squamous cell carcinoma, pancreatic cancer, prostate cancer, rectal cancer, colon cancer, colorectal cancer, non-small cell lung cancer, prostate cancer, small bowel cancer, sarcoma, leukemia, melanoma, and lymphoma.
  • anticancer agents can be paclitaxel, cisplatin, carboplatin and oxaliplatin, PARP inhibitors (such as niraparib, olaparib), anti-PD-1 antibodies, anti-PD-L1 antibodies, anti-CTLA- 4 Antibodies, mTOR inhibitors, IGF1R inhibitors, HADC inhibitors, EGFR inhibitors, such as anti-EGFR antibodies (such as panitumumab), HIF-1 inhibitors, VEGF/VEGFR inhibitors (such as sorafenib, valizumab)
  • the following first step N-alkylation reaction with primary or secondary amines, or Buchwald reaction, or Ullmann reaction
  • second step O-alkylation with various alcohols reaction, or Buchwald reaction, or Ullmann reaction
  • third step carry out Suzuki coupling with various aryl boronic acids (esters), or carry out Negishi coupling with zinc reagent, or carry out Stille coupling with tin reagent, follow-up or have Other reaction operations, such as the protection and deprotection of amino groups or/and phenol groups.
  • Its general formula is as follows:
  • Q1, Q2 are selected from, for example, CH, N, C-CN, C-hydroxyl, C-halogen, C-alkyl, C-alkoxy;
  • X is selected from, for example, fluorine, chlorine, bromine, iodine , triflate, p-toluenesulfonate, sulfonyl, etc.;
  • R1 is selected from, for example, hydrogen, halogen or C1-C3 alkyl;
  • R2 is selected from, for example, hydrogen, -L-heteroaryl ring or -L-heterocyclic compound; wherein L is, for example, an independent C1-C4 carbon chain, containing perhydrogen, and substituents such as hydroxyl, hydroxyalkyl, methoxy, and amino;
  • R3 is selected from, for example, an aromatic ring , heteroaryl ring or heterocycloalkane.
  • Step 1 4-Bromophthalate-2-ol (9.5 g, 42.8 mmol) and N,N-diisopropylethylamine (11.0 g, 85.6 mmol) were dissolved in 95 mL of dichloromethane. Bromo(methoxy)methane (5.8 g, 47.1 mmol) was added under ice-cooling, and the reaction was stirred at room temperature for 4 hours. Add water (100 mL), and extract with dichloromethane (100 mL ⁇ 3).
  • Step 2 Mix 1-bromo-3-(methoxymethoxy)naphthalene (8.0g, 30.0mmol), potassium acetate (7.4g, 75mmol), 1,1'-bisdiphenylphosphinoferrocene Palladium chloride (1.1 g, 1.5 mmol), bis(pinacolate) diboron (10.7 g, 42.0 mmol) were dissolved in 80 mL of dioxane. Under the protection of nitrogen, the reaction was stirred at 90° C. for 4 hours. Add water (200 mL), and extract with ethyl acetate (200 mL ⁇ 3).
  • Step 1 Triisopropyl ((6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) Naphthalen-1-yl)ethynyl)silane (1.0g, 2.02mmol) was dissolved in DMF (10mL), cesium fluoride (619mg, 4.07mmol) was added, and reacted at room temperature for 2 hours. TLC reaction was complete.
  • Step 2 Add 2-(8-ethynyl-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxa Borane (611 mg, 1.81 mmol) was dissolved in methanol (10 mL), and Lindella catalyst (catalytic amount) and quinoline (catalytic amount) were added. The hydrogen was replaced 3 times, and the reaction was carried out at room temperature for 1 hour. TLC starting material reacted completely.
  • Step 1 Dissolve 4-aminophenol (10.0g, 91.7mmol) in dichloromethane (100mL), add imidazole (9.3g, 137.6mmol), cool down to 0°C, and drop triisopropylchlorosilane (30mL , 137.6mmol), after dropping, rise to room temperature and react for 5 hours. TLC detection showed that the reaction was complete.
  • the reaction solution was filtered with celite, the filter cake was washed with dichloromethane (20 mL), and the filtrate was concentrated. The residue was purified by silica gel column chromatography to obtain 4-((triisopropylsilyl)oxy)aniline (23.0 g, brown oil) with a yield of 95.8%.
  • LC-MS: m/z 266.2 [M+H] + .
  • Step 2 Dissolve 04-((triisopropylsilyl)oxy)aniline (1.0g, 3.8mmol) in dichloromethane (10mL), drop the temperature to 0°C and add Br 2 /DCM (1.5g, 9.4 mmol/5mL), after dropping, keep the reaction at low temperature for 2 hours. TLC detection showed that the reaction of raw materials was complete.
  • reaction solution was eluted with saturated sodium sulfite solution (20mL), extracted with ethyl acetate (25mL x3), washed with saturated brine (10mL), dried over anhydrous sodium sulfate, concentrated, and the residue was purified by silica gel column chromatography to obtain 2,6 -Dibromo-4-((triisopropylsilyloxy)aniline (340 mg, yellow solid), yield 22%.
  • Step 3 Dissolve 2,6-dibromo-4-((triisopropylsilyloxy)aniline (340mg, 0.8mmol) in acetic acid (5mL), add acetic anhydride (520mg, 4.0mmol), and heat to Reaction at 90°C for 1 hour. TLC detection showed that the reaction was complete.
  • reaction solution was cooled to room temperature, added saturated sodium carbonate solution to adjust the pH value to neutral, extracted with ethyl acetate (25mL x3), washed with saturated brine (10mL), anhydrous sulfuric acid Drying over sodium and concentration gave N-(2,6-dibromo-4-((triisopropylsilyloxy)phenyl)acetamide (350 mg, yellow solid, crude).
  • Step 4 Dissolve N-(2,6-dibromo-4-((triisopropylsilyloxy)phenyl)acetamide (350 mg, crude product) in toluene (5 mL), add Lawson’s reagent (152 mg , 0.37mmol), heated to 110 ° C for 2 hours. TLC detection showed that the reaction was complete.
  • reaction solution was cooled to room temperature, added water, extracted with ethyl acetate (15mL x3), washed with saturated brine (10mL), dried over anhydrous sodium sulfate, Concentration, the residue was purified by silica gel column chromatography to obtain N-(2,6-dibromo-4-((triisopropylsilyloxy)phenyl)ethanesulfonamide (200mg, yellow oil), two-step yield 52%.
  • Step 5 Dissolve N-(2,6-dibromo-4-((triisopropylsilyloxy)phenyl)ethanesulfonamide (200 mg, 0.41 mmol) in ethylene glycol dimethyl ether (4 mL) , add cuprous iodide (10mg, 0.04mmol) and 1,10-phenanthroline (10mg, 0.06mmol), nitrogen pumping three times, heated to 80 ° C for 1.5 hours. TLC detection shows that the reaction is complete.
  • Step 6 Dissolve 4-bromo-2-methylbenzo[d]thiazole-6-ol (47mg, 0.1mmol) in toluene (3mL), add biboronic acid pinacol ester (119mg, 0.47mmol) and potassium acetate (46mg, 0.47mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (15mg, 0.01mmol), pump three times with nitrogen, and heat to 130°C React for 2 hours. TLC detection showed that the reaction was complete.
  • reaction solution was cooled to room temperature, and the reaction solution was filtered with diatomaceous earth, the filter cake was washed three times with ethyl acetate, the filtrate was concentrated, and the residue was purified by Prep-TLC to obtain 2-methyl-4-(4,4,5,5-tetra Methyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazol-6-ol (28 mg, yellow solid), yield 50%.
  • Step 1 Dissolve m-bromoanisole (3.0g, 16.1mmol) in chloroform (15mL), at room temperature, add silver trifluoroacetate (4.0g, 18.2mmol), iodine (4.5g, 17.6mmol), under nitrogen protection , react at room temperature for 12 hours, filter the reaction solution, add water (30mL) to the filtrate, extract with dichloromethane (30mL x3), and concentrate after drying the combined organic phase to obtain 2-bromo-1-iodo-4-anisole (4.7 g, yellow oil), crude product.
  • Step 2 2-Bromo-1-iodo-4-anisole (2.5g, 7.9mmol) was dissolved in ethylene glycol dimethyl ether/water (15mL/5mL), phenylboronic acid (1.0g, 8.2mmol) was added, Bis(triphenylphosphine)palladium dichloride (400mg, 0.57mmol), potassium carbonate (2.2g, 15.9mmol), under nitrogen protection, reacted at 100°C for 12 hours and cooled to room temperature, added water, ethyl acetate (30mL x3 ) extraction, the combined organic phase was dried and concentrated, and the resulting residue was purified by silica gel column chromatography with eluent (petroleum ether) to obtain 2-bromo-4'-methoxybiphenyl (1.6g, yellow oil) Yield: 76%.
  • Step 1 Dissolve m-naphthalenediol (16.5g, 103.02mmol) in 1,4-dioxane (250mL), and add (2-bromoethynyl)triisopropylsilane (32.26g, 123.57mmol), potassium acetate (20.24g, 206.03mmol) and dichlorobis(4-methylisopropylphenyl) ruthenium (II) (6.30g, 10.29mmol), under nitrogen protection, the temperature was raised to 110°C for reaction 16 Hours, TLC detection raw material reaction is complete.
  • Step 2 Dissolve 8-((triisopropylsilyl)ethynyl)naphthalene-1,3-diol (22.0g, 64.6mmol) in dichloromethane (500mL), add N,N- Diisopropylethylamine (25.0g, 193.8mmol), cooled to 0°C, slowly added chloromethyl methyl ether (7.8g, 96.9mmol) dropwise, kept at 0°C, continued to stir for 1 hour, TLC detected that the reaction of raw materials was complete .
  • Step 3 3-(Methoxymethoxy)-8-(triisopropylsilyl)ethynyl)naphthalen-1-ol (18.0 g, 46.8 mmol) was dissolved in dichloromethane (500 mL), Add N,N-diisopropylethylamine (18.1g, 140.4mmol) at room temperature, cool down to -40°C, slowly add trifluoromethanesulfonic anhydride (26.4g, 93.6mmol) dropwise, keep at -40°C, and continue stirring After 0.5 hour, TLC detected that the reaction of the raw material was complete.
  • Step 4 Add 3-(methoxymethoxy)-8-(triisopropylsilyl)ethynyl)naphthalene-1-trifluoromethanesulfonate (15.0 g, 29.02 mmol), diboronic acid pina Dispersion of alcohol ester (29.5g, 116.08mmol), potassium acetate (11.4g, 116.08mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (2.12g, 2.90mmol) In toluene (180 mL), nitrogen was replaced three times, and the temperature was raised to 130° C. for 16 hours. TLC detected that the reaction of the raw materials was complete.
  • reaction solution was lowered to room temperature, filtered with a pad of diatomaceous earth, the filter cake was washed with ethyl acetate (300 mL), the filtrate was washed with water (400 mL x2), and saturated brine (100 mL x1), the organic phase was dried over anhydrous sodium sulfate and concentrated.
  • Step 1 Boc-L-proline methyl ester (53.0g, 231.1mmol) was dissolved in tetrahydrofuran (400mL), under the protection of nitrogen, the temperature was lowered to -60°C, and 1M bistrimethylsilylamine was slowly added dropwise Lithium (347mL, 347mmol), reacted at -60°C for 1 hour, then slowly added 1-bromo-3-chloropropane (181.0g, 1.1mol) dropwise, raised to room temperature and reacted for 2 hours, quenched the reaction liquid with ethyl acetate Ester extraction.
  • Step 2 Add trifluoroacetic acid (100 mL) to 1-(tert-butyl) 2-methyl 2-(3-chloropropyl) pyrrolidine-1,2-dicarboxylic acid (59.1 g, 193.2 mmol) and react at room temperature After 2 hours, the reaction solution was concentrated to obtain a crude product, which was dissolved in dichloromethane and concentrated to obtain methyl 2-(3-chloropropyl)pyrrolidine-2-carboxylate (102 g, colorless oil). Crude.
  • Step 3 Methyl 2-(3-chloropropyl)pyrrolidine-2-carboxylate (102g, crude product) was dissolved in methanol (100mL), potassium iodide (3.7g, 16.4mmol), potassium carbonate (79.2g, 38.6mmol), reacted at room temperature for 2 hours, the system became turbid, the reaction solution was concentrated to obtain a white solid, dissolved in ethyl acetate (1000mL), filtered with suction, the filtrate was concentrated to obtain a crude product, the crude product was dissolved in ethyl acetate, washed with saturated saline, washed with ethyl acetate The ester was extracted twice, the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to give methyl tetrahydro-1H-pyrrolazine-7a(5H)-carboxylate (25 g, colorless oil).
  • Step 4 Tetrahydro-1H-pyrrolazine-7a(5H)-methyl carboxylate (25g, 148mmol) was dissolved in tetrahydrofuran (300mL), and lithium aluminum tetrahydrogen (16.1g, 424.8mmol) was slowly added at 0°C, The reaction was carried out at room temperature for 2 hours, and TLC showed that the reaction was complete.
  • Step 1 Dissolve 1-(tert-butyl) 2-methylpiperidine-1,2-dicarboxylate (28.5g, 0.117mol) in tetrahydrofuran (200mL), cool to -60°C with dry ice under nitrogen protection After °C, LiHMDS solution (176mL, 0.176mol) was added dropwise, kept stirring for 1 hour, 1-bromo-3-chloropropane (100g, 0.583mol) was added dropwise, the reaction solution was naturally raised to room temperature and stirred for 2 hours, and TLC detected that the reaction was complete.
  • LiHMDS solution 176mL, 0.176mol
  • Step 2 The mixture 1-(tert-butyl)2-methyl 2-(4-chlorobutyl)piperidine-1,2-dicarboxylate (56.8 g, 0.117 mol) was dissolved in dichloromethane (20 mL ), TFA (50 mL) was added dropwise in an ice bath, and the reaction solution was stirred at room temperature for 1 hour, and TLC detected that the reaction was complete. The reaction solution was concentrated to obtain methyl 2-(4-chlorobutyl)piperidine-2-carboxylate (27.3 g, crude product).
  • Step 3 Crude methyl 2-(4-chlorobutyl)piperidine-2-carboxylate (27.3g, 0.117mol) was dissolved in methanol (100mL), potassium carbonate (48.5g, 0.351mol) and potassium iodide were added (1.94g, 11.7mmol), the reaction solution was stirred at room temperature for 3 hours, and TLC detected that the reaction was complete. The reaction solution was filtered, and the filtrate was concentrated and purified by column chromatography to obtain methyl octahydro-9aH-quinoline-9a-carboxylate (9.1 g, three-step yield 39.4%).
  • Step 4 Lithium aluminum hydride (5.3g, 138mmol) was dissolved in tetrahydrofuran (60mL), and tetrahydrofuran solution (9.1g, 46.13mmol) of octahydro-9aH-quinoline-9a-methyl carboxylate was added dropwise under ice-cooling , the reaction solution was stirred at room temperature for 2 hours, and TLC detected that the reaction was complete.
  • Step 1 Ethyl (S)-5-oxopyrrolidine-2-carboxylate (300.0g, 1.91mol) and 3-chloro-2-chloromethylpropene (716.0g, 5.73mol) were added to tetrahydrofuran (2.0 In L), lower the temperature to -40°C, under the protection of nitrogen, slowly add lithium bistrimethylsilylamide (3.82L, 3.82mol, 1N) dropwise, after the addition is complete, stir at -40°C for 1.0 hour, add saturated Quenched with ammonium chloride aqueous solution, added ethyl acetate (1.5L), separated layers, extracted the aqueous phase with ethyl acetate (1.5L), combined the organic phases, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the residue was washed with silica gel Purified by column chromatography to obtain ethyl 2-(2-(chloromethyl)allyl)-5-oxopyrrolidine-2
  • Step 2 Under nitrogen protection, add sodium hydride (74.0g, 1.85mol, 60%) in portions to tetrahydrofuran (18L) cooled to 0°C, and then add 2-(2-(chloromethyl)allyl) dropwise )-5-oxopyrrolidine-2-carboxylic acid ethyl ester (303.0 g, 1.23 mol) in tetrahydrofuran (3 L), after the dropwise addition, the temperature was raised to reflux for 6.0 hours, and the reaction was complete as monitored by LCMS.
  • Step 4 Dissolve ethyl 2,5-dioxotetrahydro-1H-pyrrolazine-7a(5H)-carboxylate (68.6g, 0.32mol) in methanol (1.0L), cool in an ice-water bath, and add in batches at 0°C Sodium borohydride (3.08g, 81.19mmol) was added, and reacted at 0°C for 1.0h. TLC showed that the starting material was reacted to completion.
  • Step 5 Dissolve ethyl (2R,7aR)-2-hydroxy-5-oxotetrahydro-1H-pyrrolazine-7a(5H)-carboxylate (32.8g, 0.15mol) in dichloromethane (800mL) , -60°C, under the protection of nitrogen, slowly add a solution of diethylaminosulfur trifluoride (37.2g, 0.23mmol) in DCM (200mL) dropwise.
  • Step 6 Under nitrogen, add lithium aluminum hydride (9.95g, 0.26mol) into THF (200ml), cool in an ice-water bath to 0°C, add dropwise (trans)-2-fluoro-5-oxotetrahydro-1H -Pyrrolazine-7A(5H)-THF (30mL) solution of ethyl formate (18.8g, 87.35mmol), dropwise finished, warming up to reflux reaction for 4.5 hours, LCMS monitors that the reaction is complete, cools to zero degrees, and slowly adds water ( 10mL), NaOH (15%; 10mL), water (30mL), stirred for 30 minutes, the reaction solution was filtered with celite, the filtrate was concentrated, and the residue was purified by silica gel column chromatography to obtain ((trans)-2-fluorotetra Hydrogen-1H-pyrrolizine 7A(5H)-yl)methanol (6.8 g, pale yellow oil), yield 49%.
  • Step 3 2-Chloro-3-fluoro-4-aminopyridine (20.3g, 138.5mmol) was dissolved in acetonitrile (100mL), N-iodosuccinimide (37.3g, 165.8mmol) and p-toluene were added Sulfonic acid (1.2g, 6.9mmol), the temperature of the reaction solution was raised to 70°C and stirred for 12 hours.
  • Step 5 4-amino-6-chloro-5-fluoronicotinic acid ethyl ester (22.7g, 103.8mmol) was dissolved in tetrahydrofuran (120mL), trichloroacetyl isocyanate (25.4g, 134.8mmol) was added at room temperature, and the reaction solution After stirring at room temperature for 1 hour, the reaction solution was concentrated, and the residue was slurry-filtered with methyl tert-butyl ether (200 mL) to obtain 6-chloro-5-fluoro-4-(3-(2,2,2-trichloroacetyl ) ureido) nicotinic acid ethyl ester (38.4g, white solid), yield: 90%.
  • Step 6 Ethyl 6-chloro-5-fluoro-4-(3-(2,2,2-trichloroacetyl)ureido)nicotinate (38.4 g, 94.35 mmol) was dissolved in methanol (200 mL), 7M ammonia-methanol solution (40 mL) was added dropwise at room temperature, the reaction solution changed from cloudy to clear and solids precipitated out, and the reaction solution was stirred at room temperature for 1 hour. The reaction solution was concentrated, and the residue was beaten with MTBE to obtain 7-chloro-8-fluoropyridin[4,3-d]pyrimidine-2,4-diol (20.3 g, off-white solid), yield: 100%.
  • Step 7 7-chloro-8-fluoropyridino[4,3-d]pyrimidine-2,4-diol (10.0g, 39.7mmol) was dissolved in phosphorus oxychloride (120mL), and N was added at 0°C, N-Diisopropylethylamine (24mL, 144.8mmol), the system was insoluble, raised to 130°C and refluxed for 5 hours, the system was dissolved, cooled down to room temperature, concentrated to remove most of phosphorus oxychloride, diluted with ethyl acetate Finally, add it dropwise into water at 20°C to quench phosphorus oxychloride, release heat, and stir for 30 minutes to confirm that phosphorus oxychloride has been completely quenched.
  • Step 1 3-bromo-2,4-difluoroaniline (10.0 g, 48.3 mmol) was dissolved in 50 mL of acetic acid, and N-iodosuccinimide (11.4 g, 50.7 mmol) was added. The reaction was stirred at room temperature for 3 hours. Add water (200 mL), and extract with ethyl acetate (200 mL ⁇ 3).
  • Step 2 Add 3-bromo-2,4-difluoro-6-iodoaniline (4.0g, 12mmol), 1,1'-bisdiphenylphosphinoferrocenepalladium dichloride (440mg, 0.6mmol), Triethylamine (3.3 mL, 24 mmol) was dissolved in 20 mL of ethanol. Under the protection of carbon monoxide, the reaction was stirred at 70°C for 3 hours.
  • Step 3 Ethyl 2-amino-4-bromo-3,5-difluorobenzoate (2.6 g, 9.3 mmol) was dissolved in methanol/tetrahydrofuran/water (26 mL/10 mL/5 mL). Lithium hydroxide monohydrate (1.2 g, 28.0 mmol) was added. The reaction was stirred at room temperature for 2 hours. Concentrate under reduced pressure to remove the organic solvent, add water (50mL), adjust pH ⁇ 6 with 1M hydrochloric acid, filter to obtain 2-amino-4-bromo-3,5-difluorobenzoic acid (2.2g, white solid), yield: 96 %. 1 H NMR(400MHz,DMSO-d 6 ) ⁇ 7.47-7.44(m,1H).
  • Step 4 Heat urea (12g, 200mmol) to 150°C until it melts, add 2-amino-4-bromo-3,5-difluorobenzoic acid (2.5g, 10mmol), and stir at 190°C for 2 hours. Turn off the heating, add water (100mL) and stir for five minutes, cool to room temperature, and filter to obtain 7-bromo-6,8-difluoroquinazoline-2,4-diol (1.9g, yellow solid), yield: 70% .
  • 1 H NMR 400MHz, DMSO_d 6 ) ⁇ 11.21 (brs, 2H), 7.64-7.61 (m, 1H).
  • Step 2 Add zinc powder (9.15g, 140.8mmol) and ammonium chloride (9.5g, 176.0mmol) to 2-bromo-3-fluoro-1-methoxy-4-nitrobenzene (4.4 g, 17.6mmol) in methanol (80mL) and tetrahydrofuran (80mL) solution. After stirring at room temperature for half an hour, acetic acid (3.5 mL) was added to the reaction solution. After continuing to stir at room temperature for 4 hours, the reaction solution was poured into water and extracted with ethyl acetate.
  • Step 3 Add chloral hydrate (4.87g, 29.5mmol), 3N hydrochloric acid (6mL) and aqueous solution (7.7mL) of hydroxylamine hydrochloride (2.96g) to 3-bromo-2-fluoro-4-methanone in sequence at 55°C In a mixture of oxyaniline (2.95g, 13.4mmol), sodium sulfate (15.23g, 107.28mmol) and water (38mL). After stirring at 95°C for 1.5 hours, it was cooled to room temperature and extracted with ethyl acetate.
  • Step 5 Add hydrogen peroxide (30%, 1.2 mL) to 6-bromo-7-fluoro-5-methoxyindazoline-2,3-dione (690 mg, 2.52 mmol) and 2N hydroxide at 0 °C Sodium (12mL). After stirring at room temperature for 2 hours, the pH was adjusted to 2 with 2N hydrochloric acid. Extracted with ethyl acetate, the combined organic phases were washed with saturated brine, dried and concentrated, the resulting residue was 2-amino-4-bromo-3-fluoro-5-methoxybenzoic acid (600 mg, yellow solid), yielding Rate: 90%.
  • Step 6 Under nitrogen protection, 2-amino-4-bromo-3-fluoro-5-methoxybenzoic acid (445mg, 1.69mmol) and urea (3.0g, 50.6mmol) were stirred at 180°C for 1.5 hours. Distilled water was slowly added to the reaction system, and then the temperature was gradually cooled to room temperature. After suction filtration, the filter cake was dried under reduced pressure to obtain 7-bromo-8-fluoro-6-methoxyquinazoline-2,4-diol (460 mg, yellow solid), yield: 94%.
  • 1 H NMR 400MHz, DMSO-d6) ⁇ 11.33 (brs, 2H), 7.29 (s, 1H), 3.92 (s, 3H).
  • Step 7 To a mixture of 7-bromo-8-fluoro-6-methoxyquinazoline-2,4-diol (460mg, 1.59mmol) and toluene (12mL) was added sequentially diisopropylethyl at room temperature Amine (0.81 mL, 4.77 mmol) and phosphorus oxychloride (1.2 mL, 12.73 mmol).
  • Step 1 Dissolve 2-chloro-3-fluoroisonicotinic acid (60.0g, 0.34mol) and triethylamine (41.5g, 0.41mol) in toluene (200mL) and tert-butanol (300mL), at 0°C Diphenylphosphoryl azide (103.5 g, 0.38 mol) was added dropwise, raised to room temperature and stirred for 0.5 hours after addition, then raised to 100° C. and stirred for 2 hours.
  • Step 2 Dissolve tert-butyl 2-chloro-3-fluoropyridine-4-carbamate (40.7g, 164.9mmol) in acetonitrile (50mL), add hydrochloric acid/1,4-dioxane solution (163mL, 4M), stirred overnight at room temperature.
  • Step 3 Dissolve 2-chloro-3-fluoro-4-aminopyridine (20.3g, 138.5mmol) in acetonitrile (100mL), add N-iodosuccinimide (37.3g, 165.8mmol) at room temperature and p-toluenesulfonic acid (1.2g, 6.9mmol), heated to 70°C and stirred for 12 hours.
  • Step 4 Dissolve 2-chloro-3-fluoro-4-amino-5-iodopyridine (44.0g, 161.5mmol) and triethylamine (58.8g, 581.1mmol) in ethanol (300mL), add bis Triphenylphosphinepalladium dichloride (11.4g, 16.24mmol) was heated to 80°C under a carbon monoxide gas atmosphere and stirred for 40 hours.
  • Step 5 Dissolve ethyl 4-amino-6-chloro-5-fluoronicotinate (10.0 g, 48.89 mmol), cyanoacetic acid (8.3 g, 97.75 mmol) and pyridine (23.2 g, 293.34 mmol) in ethyl acetate (200 mL), 1-propylphosphoric anhydride T 3 P (43.8 g, 0.14 mol, 50% ethyl acetate solution) was added and reacted at room temperature for 1 hour. TLC showed that about 60% of the starting material remained.
  • reaction solution was quenched with water (30mL), extracted with ethyl acetate (30mL x3), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and the residue was purified by silica gel chromatography to obtain 6-chloro-4-(2-cyano Acetamide)-ethyl 5-fluoronicotinate (7.2 g, yield: 55%) and ethyl 4-amino-6-chloro-5-fluoronicotinate (2.0 g, 9.8 mmol) were recovered.
  • Step 6 Dissolve ethyl 6-chloro-4-(2-cyanoacetamide)-5-fluoronicotinate (7.2g, 26.51mmol) in tetrahydrofuran (100mL), cool to 0°C, add sodium hydride ( 1.6g, 39.77mmol, 60%), maintained at 0°C for 30 minutes, TLC showed that the reaction was complete. The reaction solution was quenched by adding a small amount of dilute hydrochloric acid (1N), and concentrated to give the crude product 7-chloro-8-fluoro-2,4-dihydroxy-1,6-naphthalene-3-carbonitrile (7.2 g, crude product). used directly in the next reaction.
  • Step 7 Disperse crude 7-chloro-8-fluoro-2,4-dihydroxy-1,6-naphthyridine-3-carbonitrile (3.5 g, 14.61 mmol) in phosphorus oxychloride (40 mL) , N,N-diisopropylethylamine (7.4g, 73.03mmol) and N,N-dimethylformamide (0.2g, 2.53mmol) were added at room temperature and reacted at room temperature for 1 hour, TLC showed that the reaction was complete.
  • reaction solution was slowly added to ice water (30mL), extracted with ethyl acetate (30mL x3), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to give 4,7-dichloro-8-fluoro-2-hydroxyl-1, 6-Naphthalene-3-carbonitrile (2.1 g, crude product) was directly used in the next reaction.
  • Step 1 At 55°C, chloral hydrate (4.87g, 29.5mmol), 3N hydrochloric acid (12mL) and aqueous solution (20mL) of hydroxylamine hydrochloride (20.8g, 315.8mmol) were added to 3-bromo-2-fluoro Aniline (10.0g, 52.6mmol), sodium sulfate (149.5g, 1.05mol) and water (80mL) mixture, then stirred at 90°C for 3 hours. Add water (100 mL), and extract with dichloromethane (100 mL ⁇ 3).
  • Step 2 (E)-N-(3-bromo-2-fluorophenyl)-2-(hydroxyimino)acetamide (11.0 g, 42.5 mmol) was slowly added to 300 mL of concentrated sulfuric acid. Under the protection of nitrogen, the reaction was stirred at 90° C. for 3 hours.
  • Step 3 6-Bromo-7-fluoroindoline-2,3-dione (8.5 g, 35.1 mmol) was dissolved in 2N aqueous sodium hydroxide solution (100 mL). Hydrogen peroxide (20 mL) was added at 0°C. The reaction was stirred at 0°C for 2 hours. After the reaction was completed, 1N hydrochloric acid was added to adjust the pH to 2, the solid precipitated out, and 2-amino-4-bromo-3-fluorobenzoic acid (4.6 g, white solid) was obtained by filtration, yield: 57%.
  • Step 4 Dissolve 2-amino-4-bromo-3-fluorobenzoic acid (4.5g, 19.4mmol), N-iodosuccinimide (4.5g, 29.1mmol) in N,N-dimethyl formamide (150 mL). The reaction was stirred at 75°C for 3 hours.
  • Step 5 Heat urea (12g, 26.3mmol) to 150°C until it melts, add 2-amino-4-bromo-3-fluoro-5-iodobenzoic acid (4.7g, 13.1mmol), and stir at 190°C for 2 hours . Turn off the heating, add water (100mL) and stir for five minutes, cool to room temperature, and filter to obtain 7-bromo-8-fluoro-6-iodoquinazoline-2,4-diol (1.9g, yellow solid), yield: 70 %. MS m/z(ESI):382.9,384.8[MH] + .
  • Step 1 Dissolve 2-chloro-3-fluorobenzoic acid (30.0g, 172.0mmol) and palladium acetate (2.0g, 8.6mmol) in 150mL N,N-dimethylformamide, add N-iodobutyl Diimide (42.6 g, 189.2 mmol). Under the protection of nitrogen, the reaction was stirred at 100° C. for 24 hours. Add water (500 mL), and extract with ethyl acetate (300 mL ⁇ 3).
  • Step 2 2-chloro-3-fluoro-6-iodobenzoic acid (19.0 g, 63.0 mmol) was dissolved in 95 mL tetrahydrofuran. Under nitrogen protection, borane tetrahydrofuran (1M/tetrahydrofuran, 315mL, 315mmol) was slowly added dropwise at 0°C, heated to 70°C and stirred for 20 hours.
  • Step 3 Mix (2-chloro-3-fluoro-6-iodophenyl)methanol (5.0g, 17.5mmol), bis(triphenylphosphine)palladium(II) chloride (614mg, 0.88mmol) and triethyl
  • the amine 7. mL, 52.5 mmol
  • the reaction was stirred at 90°C for 3 hours. Concentrate under reduced pressure to remove most of the organic solvent, add water (100 mL), and extract with ethyl acetate (100 mL ⁇ 3).
  • Step 4 Dissolve 4-chloro-5-fluoroisobenzofuran-1(3H)-one (7.2g, 38.7mmol) in 30mL of concentrated sulfuric acid, slowly add concentrated nitric acid (8mL) at 0°C, and stir at room temperature for reaction 16 Hour.
  • Step 5 4-Chloro-5-fluoro-6-nitroisobenzofuran-1(3H)-one (8.1 g, 35.0 mmol) was dissolved in 120 mL of dry toluene. Diisobutylaluminum hydride (35 mL, 1.5M/toluene, 52.6 mmol) was added dropwise under nitrogen protection at -78°C, and the reaction was stirred at -78°C for 2 hours.
  • Step 6 4-Chloro-5-fluoro-6-nitro-1,3-dihydroisobenzofuran-1-ol (4.7 g, 20.0 mmol) was dissolved in 60 mL of dry dichloromethane. Boron trifluoride diethyl ether (2 mL) and triethylsilane (10 mL) were added successively under nitrogen protection at 0°C. The reaction was stirred at room temperature for 2 hours. Quenched with saturated aqueous sodium bicarbonate (100 mL), extracted with dichloromethane (100 mL ⁇ 3).
  • Step 7 4-Chloro-5-fluoro-6-nitro-1,3-dihydroisobenzofuran (3.5 g, 16.1 mmol) was dissolved in acetic acid/ethanol (10 mL/40 mL). Iron powder (2.7 g, 48.3 mmol) was added, and under nitrogen protection, the reaction was stirred at 70° C. for 1 hour.
  • Step 8 7-Chloro-6-fluoro-1,3-dihydroisobenzofuran-5-amine (2.4 g, 12.8 mmol) was dissolved in 24 mL of acetic acid. N-iodosuccinimide (3.0 g, 13.4 mmol) was added, and the reaction was stirred at room temperature for 1 hour. The reaction solution was poured into water (200 mL), filtered, washed with water (100 mL), and the filter cake was dried to obtain 7-chloro-6-fluoro-4-iodo-1,3-dihydroisobenzofuran-5-amine (3.5 g, yellow solid), yield: 88%.
  • 1 H NMR 400MHz, CDCl 3 ) ⁇ 5.21(s,2H),4.99(s,2H),4.21(brs,2H).
  • Step 9 Mix 7-chloro-6-fluoro-4-iodo-1,3-dihydroisobenzofuran-5-amine (3.5g, 11.2mmol), 1,1'-bisdiphenylphosphine Iron palladium dichloride (820 mg, 1.12 mmol) and triethylamine (3.1 mL, 22.4 mmol) were dissolved in 70 mL of methanol. Under the protection of carbon monoxide, the reaction was stirred at 70°C for 16 hours.
  • Step 10 Dissolve methyl 5-amino-7-chloro-6-fluoro-1,3-dihydroisobenzofuran-4-carboxylate (1.7 g, 6.9 mmol) in methanol/tetrahydrofuran/water (20 mL/ 20mL/10mL). Lithium hydroxide monohydrate (1.2 g, 27.6 mmol) was added, and the reaction was stirred at room temperature for 1 hour.
  • reaction solution was concentrated to remove most of the organic solvent, added water (100mL), 1M dilute hydrochloric acid to adjust the pH ⁇ 5, filtered, washed with water (100mL), and the filter cake was dried to obtain 5-amino-7-chloro-6-fluoro-1,3- Dihydroisobenzofuran-4-carboxylic acid (1.5 g, white solid), yield: 94%.
  • 1 H NMR 400MHz,DMSO-d 6 ) ⁇ 7.01(brs,1H),5.19(s,2H),4.94(s,2H).
  • Step 11 Put urea (10.1 g, 169 mmol) in a reaction flask and heat to 150° C. until all urea is dissolved.
  • 5-Amino-7-chloro-6-fluoro-1,3-dihydroisobenzofuran-4-carboxylic acid (1.3g, 5.6mmol) was added into the reaction flask, heated to 190°C, and stirred for 2 hours. Stop heating, add water (50 mL), stir for 10 minutes, filter, wash with water (100 mL), and dry the filter cake to obtain 6-chloro-5-fluoro-7,9-dihydrofuro[3,4-f]quinazoline -1,3-diol (1.4 g, yellow solid), yield: 100%.
  • 1 H NMR 400MHz,DMSO-d 6 ) ⁇ 11.32(brs,2H),5.32(s,2H),5.02(s,2H).
  • Step 12 Combine 6-chloro-5-fluoro-7,9-dihydrofuro[3,4-f]quinazoline-1,3-diol (1.4g, 5.5mmol) and phosphorus oxychloride (6.7 g, 44mmol) was dissolved in 30mL dry toluene. N,N-Diisopropylethylamine (3.5 g, 27.5 mmol) was slowly added at 0°C, heated to 110°C, and stirred for 4 hours.
  • Step 1 Dissolve 2-chloro-1,3-difluoro-4-nitrobenzene (20.0g, 100.0mmol) and triethylamine (12.1g, 120.0mmol) in 200mL tetrahydrofuran, at 0°C, add p Methoxybenzylamine (15.1 g, 110.0 mmol). The reaction was stirred overnight at room temperature. Add water (100 mL), and extract with ethyl acetate (100 mL ⁇ 3).
  • Step 2 2-Chloro-3-fluoro-N-(4-methoxybenzyl)-6-nitroaniline (29.0 g, 93.33 mmol) was dissolved in 20 mL of dichloromethane. Trifluoroacetic acid (40 mL) was added at room temperature, and the reaction was stirred at room temperature for 2 hours.
  • Step 5 Dissolve 5-bromo-3-chloro-4-fluorobenzene-1,2-diamine (16.7g, 69.73mmol) in 60mL acetic acid and 10mL water, add sodium nitrite (5.8g, 83.67mmol) in water (10mL). The reaction was stirred at room temperature for 2 hours. Suction filtration, rinse the solid with water, and dry to obtain 5-bromo-7-chloro-6-fluoro-1H-benzo[d][1,2,3]triazole (13.3g, off-white solid), yield: 76%.
  • LC-MS: m/z 249.9[M+H] + .
  • Step 6 Dissolve 5-bromo-7-chloro-6-fluoro-1H-benzo[d][1,2,3]triazole (13.3g, 53.10mmol) in 100mL N,N-dimethylformaldehyde amides. Sodium hydride (2.5g, 63.72mmol) was added at 0°C, and the reaction was stirred at 0°C for 15 minutes, then (trimethylsilyl)ethoxymethyl (10.6g, 63.72mmol) was added, warmed to room temperature, and the reaction was stirred 2 Hour.
  • Step 7 Adding 5-bromo-7-chloro-6-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d][1,2,3 ] Triazole (19.0g, 49.90mmol), benzhydrylamine (10.8g, 59.88mmol), tridibenzylideneacetone dipalladium (2.3g, 2.49mmol), 4,5-bisdiphenylphosphine-9 , 9-Dimethylxanthene (2.8 g, 4.99 mmol) and cesium carbonate (48.6 g, 149.7 mmol) were dissolved in 1,4-dioxane (200 mL).
  • Step 8 Diphenylmethylaniline 7-chloro-N-(diphenylmethylene)-6-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)- 1H benzo[d][1,2,3]triazol-5-amine (18.2g, 37.90mmol), potassium acetate (7.4g, 75.80mmol) and hydroxylamine hydrochloride (5.3g, 75.80mmol) were dissolved in 180mL methanol .
  • Step 9 Adding 7-chloro-6-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d][1,2,3]triazole- 5-Amine (2.5g, 7.39mmol) was dissolved in 20mL N,N-dimethylformamide. N-iodosuccinimide (1.9 g, 8.87 mmol) was added at room temperature, and the reaction was stirred at room temperature for 3 hours.
  • Step 10 Adding 7-chloro-6-fluoro-4-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d][1,2,3 ]triazol-5-amine (1.7g, 3.34mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (268mg, 0.33mmol), triethylamine (1.0g , 10.02mmol) was dissolved in 20mL methanol.
  • Step 11 Adding 5-amino-7-chloro-6-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d][1,2,3 ]Triazole-4-carboxylic acid methyl ester (1.5g, 4.00mmol) was dissolved in 20mL acetonitrile, and trichloro(isocyanate)methane (829mg, 4.40mmol) was added at room temperature, reacted at room temperature for 1 hour, filtered to obtain a white solid, and decompressed dry. Dissolve the white solid in 20 mL of ammonia-methanol solution, stir and react at 70°C for 2 hours.
  • Step 12 Adding trichloro(isocyanate)methane 4-chloro-5-fluoro-3-((2-(trimethylsilyl)ethoxy)methyl)-3H-[1,2,3]triazole Diol [4,5-f]quinazoline-7,9-diol (800mg, 2.07mmol) was dissolved in 4mL of dichloromethane. Added trifluoroacetic acid (4mL) at 0°C and stirred at room temperature for 1 hour.
  • Step 13 Dissolve 4-chloro-5-fluoro-3H-[1,2,3]triazolo[4,5-f]quinazoline-7,9-diol (410 mg, 1.6 mmol) in 10 mL Phosphorus oxychloride. Add N,N-diisopropylethylamine (619mg, 4.8mmol) at 0°C, heat to 100°C and stir the reaction overnight.
  • Step 14 Mix 4,7,9-trichloro-5-fluoro-3H-[1,2,3]triazolo[4,5-f]quinazoline (260mg, 0.89mmol), tert-butyl 3 , 8-diazacyclo[3.2.1]octane-8-carboxylate (227mg, 1.07mmol) and N,N-diisopropylethylamine (230mg, 1.78mmol) were dissolved in 4mL N,N- Dimethylethylamine. The reaction was stirred at 0°C for 1 hour.
  • Step 15 (Hexahydro-1H-pyrrolizin-7a-yl)methanol (59 mg, 0.42 mmol) was dissolved in 4 mL of N,N-dimethylformamide. Add sodium hydride (17mg, 0.42mmol) at 0°C and stir for 15 minutes. Then add tert-butyl 3-(4,7-dichloro-5-fluoro-1H-[1,2,3]triazolo[4,5-f]quinazolin-9-yl)-3,8 - Diazabicyclo[3.2.1]octane-8-carboxylate 100mg, 0.21mmol), the temperature was raised to 50°C, and the reaction was stirred for 7 hours.
  • Step 16 Tris Azolyl[4,5-f]quinazolin-9-yl)-3,8-diazacyclo[3.2.1]octane-8-carboxylate (50mg, 0.087mmol) was dissolved in 2mL N, N-Dimethylformamide. Sodium hydride (5mg, 0.13mmol) was added at 0°C and stirred for 15 minutes. Then (trimethylsilyl)ethoxymethyl (22 mg, 0.13 mmol) was added, and the reaction was stirred at room temperature for 1 hour.
  • Step 5 tert-butyl 2,3-trans-3,4-cis-3,4-dihydroxy-2-methylpyrrolidine-1-carboxylate
  • Step 1 Benzyl 8-oxa-4-azabicyclo[5.1.0]octane-4-carboxylate
  • Step 1 4-en-2-pentyl methanesulfonate:
  • Step 3 tert-butyl allyl(4-pent-en-2-yl)carbamate:
  • reaction solution was quenched by adding saturated aqueous sodium sulfite solution (20 mL), extracted with ethyl acetate (50 mL x2), combined the organic phases, washed with water, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product (210 mg), which was dissolved in 4M hydrochloric acid/1,4- Dioxane solution (4 mL) was reacted at room temperature for 1 hour. TLC detected that the reaction was complete. The reaction solution was concentrated to obtain the title compound I52 (120 mg, yield 21.8%) as a colorless liquid.
  • Step 1 tert-butyl 2-methyl-6-oxo-3-azabicyclo[3.1.0]hexane-3-carboxylate
  • Step 2 tert-butyl (3R,4R)-3,4-dihydroxy-2-methylpyrrolidine-1-carboxylate
  • Step 1 (3aR,6aS)-5-Hydroxy-5-methylhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylic acid tert-butyl ester
  • reaction solution was diluted with water (20mL), extracted with ethyl acetate (20mL x3), the organic phases were combined, washed with brine (20mL), dried over anhydrous sodium sulfate, and concentrated to give the title compound I54-1 (500mg, yield 46.7 %).
  • Step 1 tert-butyl 3-(cyanomethyl)-3-hydroxypiperidine-1-carboxylate
  • Diisopropylamine (1.01g, 10mmol) was dissolved in tetrahydrofuran (20mL), and n-butyl lithium (625mg, 9.75mmol) was added at -60°C. The temperature of the solution was cooled to -60°C, and N-tert-butoxycarbonyl-3-piperidone (1.0g, 5.0mmol) was added. After the addition was complete, the temperature of the reaction solution was raised to 25°C for 12 hours, and the reaction of the raw materials was basically complete as detected by TLC.
  • reaction solution was diluted with water (60mL), extracted with ethyl acetate (3x 30mL), the organic phases were combined, washed with saturated aqueous ammonium chloride (60mL), dried over anhydrous sodium sulfate, and concentrated to give the title compound I55-1 (830 mg , crude product) was directly used in the next reaction.
  • Step 3 tert-butyl allyl(4-pent-en-2-yl)carbamate
  • Step 4 tert-butyl 2-methyl-3,6-dihydropyridine-1(2H)-carboxylate
  • Step 5 tert-butyl 4-methyl-7-oxa-3-azabicyclo[4.1.0]heptane-3-carboxylate
  • Step 1 Benzyl 3-Hydroxy-3,4-dihydropyridine-1(2H)-carboxylate
  • Step 2 Benzyl cis-cis-4-hydroxy-2-azabicyclo[4.1.0]heptane-2-carboxylate
  • Step 1 (R)-3-Methyl-5-oxopiperidine-1-carboxylic acid tert-butyl ester
  • Step 1 2-(8-ethynyl-7-fluoronaphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborinane
  • Step 1 8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetra Hydrogen-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-ol
  • Step 2 7-(8-Ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a(5H) -yl)methoxy)pyrido[4,3-d]pyrimidin-4-ol
  • Step 1 (S)-4-(Benzyloxy)-7-chloro-8-fluoro-2-(1-methylpyrrolidin-2-yl)methoxy)pyrido[4,3-d] pyrimidine
  • Step 2 (S)-4-(Benzyloxy)-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2- (1-Methylpyrrolidin-2-yl)methoxy)pyrido[4,3-d]pyrimidine
  • Step 3 (S)-7-(8-Ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(1-methylpyrrolidine- 2-yl)methoxy)pyrido[4,3-d]pyrimidin-4-ol
  • Step 1 (S)-8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-((1-methylpyrrolidine- 2-yl)methoxy)pyrido[4,3-d]pyrimidin-4-ol
  • Step 2 (S)-7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(1-methylpyrrolidin-2-yl)methoxy)pyrido[ 4,3-d]pyrimidin-4-ol
  • reaction solution was cooled to room temperature, concentrated to remove most of the solvent, the crude product was diluted with water (40mL), extracted with ethyl acetate (50mL x2), the organic phases were combined, washed with water (50mL), dried over anhydrous sodium sulfate, and concentrated to give the title compound I64 as a white solid -1 (1.1 g, crude product), used directly in the next step.
  • Step 3 1-(7-Bromo-6-chloro-8-fluoro-2-fluorotetrahydro-1H-pyrrolazin-7a-yl)methoxyquinazolin-4-ylpiperidine
  • LC-MS: m/z 517.1[M+H] +
  • Step 5 4-(Benzyloxy)-7-(7,8-difluoronaphthalen-1-yl)-8-fluoro-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrole Phylin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine
  • Step 6 7-(7,8-Difluoronaphthalen-1-yl)-8-fluoro-2-(2R,7aS)-2-fluorotetrahydro-1H-pyrroline-7a(5H)-yl)methanol Oxy)pyrido[4,3-d]pyrimidin-4-ol
  • Step 1 4-(benzyloxy)-7-(3-chloro-2-cyclopropyl-5-(methoxymethoxy)phenyl)-8-fluoro-2-(((2R,7aS )-2-fluorotetrahydro-1H-pyrrolazin-7a(5H))-yl)methoxy)pyrido[4,3-d]pyrimidine
  • Step 2 7-(3-chloro-2-cyclopropyl-5-(methoxymethoxy)phenyl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-Pyrroline-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-ol
  • Step 1 (4-(4-(Benzyloxy)-8-fluoro-2-((2R,7aS)-2-fluorohexahydro-1H-pyrroline-7a-yl)methoxy)pyrido [4,3-d]pyrimidin-7-yl)-3-cyano-7-fluorobenzo[b]thiophen-2-yl)carbamate tert-butyl
  • Step 2 (3-cyano-7-fluoro-4-(8-fluoro-2-((2R,7aS)-2-fluorohexahydro-1H-pyrroline-7a-yl)methoxy)-4 -Hydroxypyrido[4,3-d]pyrimidin-7-yl)benzo[b]thiophen-2-yl)carbamate tert-butyl
  • Step 1 4-(Benzyloxy)-7-(8-ethylnaphthalen-1-yl)-8-fluoro-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrroline- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine
  • Step 2 7-(8-Ethylnaphthalen-1-yl)-8-fluoro-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrroline-7a(5H)-yl)methoxy base) pyrido[4,3-d]pyrimidin-4-ol
  • Step 2 5-Methyl-1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxobenzofuran -2-yl)-1H indazole
  • Step 3 4-(Benzyloxy)-8-fluoro-2-((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)-7-(5- Methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)pyrido[4,3-d]pyrimidine
  • Step 4 8-fluoro-2-((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)-7-(5-methyl-1-(tetrahydro -2H-pyran-2-yl)-1H-indazol-4-yl)pyrido[4,3-d]pyrimidin-4-ol
  • Step 1 8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(( 2R,7aS)-2-fluorotetrahydro-1H-pyrrolin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-ol
  • Step 2 7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-((2R,7aS)-2-fluorotetrahydro -1H-pyrroline-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-ol
  • reaction solution was quenched with water (100mL), extracted with ethyl acetate (100mL x2), combined the organic phases, washed with saturated brine (100mL), dried over anhydrous sodium sulfate, concentrated, the crude product was slurried with ethyl acetate (30mL), and suction filtered , and the filter cake was dried to obtain the title compound I77 (1.35 g, yield: 79%) as an off-white solid.
  • Step 2 4-(Benzyloxy)-7-bromo-6,8-difluoro-2-((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy ) quinazoline
  • Step 3 4-(Benzyloxy)-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-6,8-difluoro-2-( (2R,7aS)-2-Fluorohexahydro-1H-pyrroline-7a-yl)methoxy)quinazoline
  • Step 4 7-(8-Ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-6,8-difluoro-2-((2R,7aS)-2- Fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)quinazolin-4-ol
  • Step 2 (R)-1-(7-bromo-6-chloro-8-fluoro-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-ylmethyl Oxy)quinazolin-4-yl)-3-methylpiperidin-3-ol
  • Step 3 (4-(6-Chloro-8-fluoro-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4- ((R)-3-Hydroxy-3-methylpiperidin-1-yl)quinazolin-7-yl)-3-cyano-7-fluorobenzo[b]thiophen-2-yl)carbamate tert-butyl ester
  • Step 2 1-(7-Bromo-6,8-difluoro-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrroline-7a(5H)-yl)methoxy)quinazole (Piperin-4-yl)piperidin-4-ol
  • Step 3 (3-cyano-4-(6,8-difluoro-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrroline-7a(5H)-yl)methoxy) -4-(4-Hydroxypiperidin-1-yl)quinazolin-7-yl)-7-fluorobenzothiophen-2-yl)carbamate tert-butyl ester
  • Step 1 Disperse 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (400 mg, 1.5 mmol) in dichloromethane (10 mL), add N,N-diisopropyl 2,6-diazaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (316mg, 1.6mmol) was added, and the reaction was stirred for 50 minutes. TLC detection showed that the reaction was complete.
  • Step 2 Add 6-(2,7-dichloro-8-fluoropyridin[4,3-d]pyrimidin-4-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylic acid Tert-butyl ester (250 mg, 0.60 mmol) and (tetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (127 mg, 0.90 mmol) were dispersed in ultra-dry 1,4-dioxane (3 mL) , cesium carbonate (590mg, 1.80mmol) was added, replaced with nitrogen three times, and heated to 90°C for 12 hours. TLC detection showed that the reaction of raw materials was complete.
  • Step 3 Add tert-butyl 6-(7-chloro-8-fluoro-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d] Pyrimidin-4-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (174 mg, mmol) and 2-(3-methoxynaphthalen-1-yl)-4,4 ,5,5-Tetramethyl-1,3,2-dioxaborane (190mg, 0.67mmol) was dispersed in 1,4-dioxane and water (8mL/1mL), cesium carbonate (234mg, 0.99mmol) and methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl) (2-amino-1,1'-biphenyl- 2-yl)
  • Step 4 tert-butyl 6-(8-fluoro-7-(3-methoxynaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy yl)pyrido[4,3-d]pyrimidine-4-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (123 mg) was dissolved in dichloromethane (2 mL), Boron tribromide (0.5 mL) was added dropwise at low temperature. After the drop was completed, the reaction was slowly raised to room temperature for 1.5 hours. TLC detection showed that the reaction was complete.
  • Compound 16 4-(4-(3,8-diazabicyclo[3.2.1]octane-3-yl)-6,8-difluoro-2-((hexahydro-1H-pyrrole Lizin-7a-yl)methoxy)quinazolin-7-yl)naphthalene-2-ol dihydrochloride
  • Compound 17 4-(4-((3-Azabicyclo[3.1.0]hex-6-yl)amino)-8-fluoro-2-((tetrahydro-1H-pyrrolizine-7a(5H)- Base)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalene-2-ol
  • Compound 20 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-((tetrahydro-1H-pyrrolazine 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-vinylnaphthalen-2-ol
  • Compound 24 4-(4-(3,6-diazabicyclo[3.1.1]heptane-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyridine Alloxazin-7a(5H-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynylnaphthalen-2-ol
  • Compound 27 4-(8-fluoro-4-(1,2,5-oxadiazepin-5-yl)-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy base) Pyrido[4,3-d]pyrimidin-7-yl)naphth-2-ol
  • Compound 39 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-7-(8-ethynyl-3-hydroxynaphthalene-1- Base)-8-fluoro-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-1,6-naphthyridine-3-carbonitrile bistrifluoroacetate
  • Compound 41 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-7-(3-hydroxynaphthalene-1- Base)-2-((tetrahydro-1H-pyrrolizine7a(5H)-yl)methoxy)-1,6-naphthyridine-3-carbonitrile bistrifluoroacetic acid
  • Compound 45 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-7-(3-hydroxynaphthalene-1- Base)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-1,6-naphthyridine-3-carbonitrile trifluoroacetate
  • Step 2 Ethyl 2-cyano-2-(3-methoxybenzamido)acetate (2.69 g, 10.26 mmol) was dissolved in 4M hydrochloric acid ethyl acetate solution (30 mL), and reacted at 80° C. for 2 hours.
  • LC-MS monitored the completion of the reaction. Add saturated sodium bicarbonate solution to adjust alkalinity, wash the organic phase with water, wash with saturated brine, dry over anhydrous sodium sulfate, and concentrate the organic phase to obtain 5-amino-2-(3-methoxyphenyl)oxazole-4-carboxylic acid Ethyl ester (2.4 g, white solid). Yield 89.2%.
  • LC-MS: m/z 263.1[M+H] + .
  • Step 3 Ethyl 5-amino-2-(3-methoxyphenyl)oxazole-4-carboxylate (1.7g, 6.49mmol) was dissolved in THF (20mL), and trichloroacetylisocyanate ( 1.35g, 7.14mmol), stirred at room temperature for 10 minutes, TLC showed that the reaction of the raw materials was complete, and the reaction solution was concentrated to dryness to obtain 2-(3-methoxyphenyl)-5-(3-(2,2,2-tri Ethyl chloroacetyl)ureido)oxazole-4-carboxylate (2.53 g, white solid), yield 86.6%.
  • Step 4 Ethyl 2-(3-methoxyphenyl)-5-(3-(2,2,2-trichloroacetyl)ureido)oxazole-4-carboxylate (2.53g, crude ) was suspended in methanol (30mL), the system was turbid, ammonia methanol (5mL) was added, the system was clarified, solids were precipitated immediately, stirred at room temperature for 2 hours, TLC showed that the raw materials disappeared, the reaction solution was suction filtered, and the filter cake was washed twice with ethanol, The filter cake was dried to give ethyl 2-(3-methoxyphenyl)-5-ureidooxazole-4-carboxylate (1.4 g, white solid). Yield 82.4%.
  • LC-MS: m/z 306.1[M+H] + .
  • Step 5 Ethyl 2-(3-methoxyphenyl)-5-ureidoxazole-4-carboxylate 5 (1.4 g, 4.59 mmol) was dispersed in 6% sodium hydroxide solution (20 ml), Reflux reaction for 3 hours, TLC reaction was complete. 1N dilute hydrochloric acid was added to adjust the acidity, and a solid was precipitated. Filtration and drying gave 2-(3-methoxyphenyl)oxazolo[5,4-d]pyrimidine-5,7-diol (1.2 g, white solid). Yield 100%.
  • Step 6 2-(3-methoxyphenyl)oxazolo[5,4-d]pyrimidine-5,7-diol (100mg, 0.42mmol) was dissolved in phosphorus oxychloride (6ml) and added DIPEA (163 mg, 1.26 mmol). React at 105°C for 48 hours. TLC reaction was complete.
  • Step 7 Dissolve 5,7-dichloro-2-(3-methoxyphenyl)oxazolo[5,4-d]pyrimidine (143mg, crude product) in dichloromethane (10mL), under nitrogen protection, Cool down to -40°C, add (1R,5S)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (103mg, 0.48mmol), drop into DIPEA (186mg, 1.44 mmol), stirred at -40°C for 30 minutes, a small amount of TLC material remained.
  • Step 8 Add tert-butyl(1R,5S)-3-(5-chloro-2-(3-methoxyphenyl)oxazolo[5,4-d]pyrimidin-7-yl)-3, 8-Diazabicyclo[3.2.1]octane-8-carboxylate (362 mg, 0.042 mmol) was dissolved in dry 1,4-dioxane (10 mL) and potassium tert-butoxide (172 mg, 1.54 mmol) was added ), (hexahydro-1H-pyrroline-7a-yl)methanol (163mg, 1.15mmol), react overnight at 110°C, and the TLC reaction is complete.
  • Step 9 Add tert-butyl(1R,5S)-3-(2-(3-methoxyphenyl)-5-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy )oxazolo[5,4-d]pyrimidine-7-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (70mg, 0.12mmol) was dissolved in dichloromethane (6 mL), was added boron tribromide (1 mL). Stir at room temperature for 1 hour. The reaction solution was diluted with dichloromethane and quenched with methanol.

Abstract

公开了一种含氮杂环类衍生物调节剂、其制备方法及应用。特别地，公开了通式(I)所示的化合物、其制备方法及含有该化合物的药物组合物，及其作为KRAS G12D突变调节剂，在治疗肿瘤等疾病或病症的用途，其中通式(I)中的各个取代基与说明书中的定义相同。

Description

含氮杂环类衍生物调节剂、其制备方法及应用 发明领域
本发明属于药物合成领域，具体涉及一种含氮杂环类衍生物抑制剂如式(I)所示化合物及其制备方法和应用。
背景技术
大鼠肉瘤(rat sarcoma,RAS)，由原癌基因HRAS，NRAS以及KRAS编码，是一种GTP结合蛋白，其结合GTP时为活化状态，而结合GDP时为失活状态。RAS分布于细胞膜内表面，结合GTP时为活化状态，而结合GDP时为失活状态。RAS上游为受体酪氨酸激酶(RTK)，激活后调控下游的PI3K，RAF等信号通路，从而调控细胞的生长、存活、迁移和分化等功能。由于RAS蛋白在许多重要细胞信号网络的轴上处于中心位置，且这些信号与多种肿瘤标志物相关联，因此过度活化的RAS信号转导可能最终导致肿瘤发生。
在RAS家族成员中，致癌突变最常见于KRAS(85％)，KRAS的异常表达占所有癌症的比例高达20％，其中G12D突变占胰腺癌(PDAC)25％，结肠癌(CRC)13.3％，直肠癌(RC)10.1％，非小细胞肺癌(NSCLC)4.1％。
虽然存在极大的临床需求，但至今没有一个直接靶向KRAS G12D突变的药物上市。KRAS G12D抑制剂的研发困难主要有两方面，一方面是RAS蛋白结构平滑，表面没有明显的小分子可以结合的口袋；另一方面是KRAS蛋白对GTP的亲和力高达皮摩尔级别，再加上本身内源性GTP水平高，小分子药物难以阻断两者的结合。目前针对G12D突变还没有靶向药进入临床研究阶段，存在较大的临床需求。
发明内容
本发明提供了式(I)所示化合物或其药学上可接受的盐,
Figure PCTCN2022124111-appb-000001
其中,
R 1选自H,-L-取代或未取代的芳基,-L-取代或未取代的杂芳基,-L-取代或未取代的杂环烷基 和-L-取代或未取代的环烷基；
L选自-CH 2-,-C(CH 3)H-,CH 2-CH 2-,-CHF-,-CH 2-CH 2-CH 2-,-CH 2-CH(F)-CH 2-,-CH 2-CF 2-CH 2-,-CH 2-CH(CH 3)-CH 2-,-CH 2-C(CH 3) 2-CH 2-,
Figure PCTCN2022124111-appb-000002
-C＝O-,-C＝-和键；
Q 1选自C-R和N,所述R选自H,CN,CF 3,OH,卤素,取代或未取代的C 1-3烷基和取代或未取代的C 1-3烷氧基；
Y选自键,-O-,-S-和-NH-；
Z选自-NR 5R 6和取代或未取代的杂环烷基；
R 5为H,R 6选自取代或未取代的杂环烷基和取代或未取代C 3-6烷基；
X 1选自-OH和C 1-3烷氧基,X 2为乙烯基,所述乙烯基的取代基选自取代或未取代的芳基,取代或未取代的杂环烷基和取代或未取代的杂芳基；
或者X 1和X 2与它们共同连接的碳原子一起形成5元杂芳基,5元或6元杂环烷基,或
Figure PCTCN2022124111-appb-000003
所述5元杂芳基和5元或6元杂环烷基(1)被1个基团取代,所述基团选自取代或未取代的芳基,取代或未取代的杂环烷基和取代或未取代的杂芳基,和(2)可以被1个基团取代,所述基团选自C 1-3烷基,CF 3,CN和卤素；
R 3选自取代或未取代的芳基(例如,取代或未取代的苯基,蒽基和萘基),取代或未取代的杂环烷基和取代或未取代的杂芳基；
R 4选自H,C 1-3烷基,C 3-8环烷基,C 1-3烷氧基,-OCF 3,-OCHF 2,-SCF 3,halo,-NH 2,OH和CF 3；
Q 2选自C-R’和N,所述R’选自H,CN,CF 3,OH,卤素,取代或未取代-S-C 1-3烷基,取代或未取代C 1-3烷基和取代或未取代C 1-3烷氧基；
或者R’和R 4与它们共同连接的碳原子一起形成取代或未取代的5元或6元杂芳基或取代或未取代5元或6元杂环烷基；
Q 3选自CR 2和N,所述R 2选自H,卤素,OH,CN,取代或未取代C 1-3烷基和取代或未取代C 1-3烷氧基；
取代或未取代的芳基,取代或未取代的杂环烷基,取代或未取代的杂芳基,取代或未取代的环烷基,取代或未取代C 1-3烷基和取代或未取代C 1-3烷氧基里面的取代基选自氧基,C 2-8炔基,C 2-8烯基,芳基,杂芳基,杂环烷基,环烷基,C 1-8烷氧基,-O-苯基,-COOR 7,-NR 7R 8,-OCONR 7R 8,-CONR 7R 8,-COR 7,-SR 7,-CN,-NO 2,-OH,-OCF 3,卤素和C 1-8烷基,所述芳基, 杂芳基,杂环烷基,环烷基,C 1-8烷氧基和C 1-8烷基可以被1-5卤素,-CN,-OH,-OCONR 7R 8,-NR 7R 8,芳基,杂芳基,杂环烷基,C 1-8烷氧基,C 1-8烷基或环烷基取代；
R 7和R 8各自独立地选自H,C 1-4烷基和苯甲基,或者R 7和R 8与它们共同连接的N原子一起形成5元或6元杂环烷基；
前提条件是(1)当Q 1和Q 2为N,R 4为H,Q 3为CR 2,那么(a)Z不是取代或未取代的
Figure PCTCN2022124111-appb-000004
或者(b)如果Z是取代或未取代的
Figure PCTCN2022124111-appb-000005
那么(i)R 3为芳基或杂芳基,所述芳基或杂芳基至少被芳基取代或者(ii)R 1选自-L-取代或未取代的芳基,-L-取代或未取代的杂芳基和-L-取代或未取代的环烷基,所述L选自-C＝O-,-C＝-和键,(2)当Q 1为N,X 1和X 2与它们共同连接的碳原子一起形成5元杂芳基,5元或6元杂环烷基,或
Figure PCTCN2022124111-appb-000006
那么Z不是以N为连接点的取代或未取代的,环上至少有另一个选自N,O,和S的杂原子的8-10元桥连杂环烷基,或者R 1不是取代或未取代的3-6元环烷基,,5元或6元饱和杂环烷基和8-10元部分非饱和杂环烷基.
本发明的一些方案中,当Z为取代或未取代的杂环烷基或-NR 5R 6,R 5为H,R 6选自取代或未取代的杂环烷基,Q 1为N,X 1和X 2与它们共同连接的碳原子一起形成
Figure PCTCN2022124111-appb-000007
那么Q 2和Q 3至少有一个是N.本发明的一些方案中,当Z为取代或未取代的杂环烷基或-NR 5R 6,R 5为H,R 6选自取代或未取代的杂环烷基,Q 1为N,X 1和X 2与它们共同连接的碳原子一起形成
Figure PCTCN2022124111-appb-000008
那么Q 2和Q 3至少有一个是N而且R 4不是H.
本发明的一些方案中,Z不是桥连杂环烷基.
本发明的一些方案中,R 4选自C 1-3烷基,C 3-8环烷基,C 1-3烷氧基,-OCF 3,-OCHF 2,-SCF 3,halo,-NH 2,OH和CF 3..
本发明的一些方案中,Q 2选自C-R’,所述R’选自H,CN,CF 3,OH,卤素,取代或未取代-S-C 1-3烷基,取代或未取代C 1-3烷基和取代或未取代C 1-3烷氧基.
本发明的一些方案中,Q 3选自CR 2,所述R 2选自H,卤素,OH,CN,取代或未取代C 1-3烷基和取代或未取代C 1-3烷氧基.
本发明的一些方案中,Q 2选自C-R’,所述R’选自H,CN,CF 3,OH,卤素,取代或未取代-S-C 1-3烷基,取代或未取代C 1-3烷基和取代或未取代C 1-3烷氧基,并且Q 3选自CR 2,所述R 2选自H,卤素,OH,CN,取代或未取代C 1-3烷基和取代或未取代C 1-3烷氧基.
本发明的一些方案中,X 1为-OH,X 2为乙烯基,所述乙烯基的取代基选自取代或未取代的芳基,取代或未取代的杂环烷基和取代或未取代的杂芳基.
本发明的一些方案中,X 1为C 1-3烷氧基,X 2为乙烯基,所述乙烯基的取代基选自取代或未取代的芳基,取代或未取代的杂环烷基和取代或未取代的杂芳基.例如,X 1为-OCH 3.
本发明的一些方案中,X 2为乙烯基,所述乙烯基被取代或未取代的苯基或萘基取代.例如,苯基或萘基可以被OH,苯基,C 1-3烷基,乙炔基或乙烯基取代.
本发明的一些方案中,X 2选自
Figure PCTCN2022124111-appb-000009
Figure PCTCN2022124111-appb-000010
Figure PCTCN2022124111-appb-000011
本发明的一些方案中,X 1和X 2与它们共同连接的碳原子一起形成5元杂芳基,所述5元杂芳基(1)被1个基团取代,所述基团选自取代或未取代的芳基,取代或未取代的杂环烷基和取代或未取代的杂芳基(2)可以再被1个基团取代,所述基团选自C 1-3烷基,CF 3,CN和卤素.本发明的一些方案中,该5元杂芳基选自吡唑基、呋喃基、恶唑基、吡咯基和噻吩基,所述吡唑基、呋喃基、恶唑基、吡咯基和噻吩基(1)被1个基团取代,所述基团选自取代或未取代的芳基,取代或未取代的杂环烷基和取代或未取代的杂芳基(2)可以再被1个基团取代,所述基团选自C 1-3烷基,CF 3,CN和卤素.
本发明的一些方案中,X 1和X 2与它们共同连接的碳原子一起形成6元杂环烷基,所述6元杂环烷基(1)被1个基团取代,所述基团选自取代或未取代的芳基,取代或未取代的杂环烷基和取代或未取代的杂芳基(2)可以再被1个基团取代,所述基团选自C 1-3烷基,CF 3,CN和卤素.本发明的一些方案中,该6元杂环烷基选自
Figure PCTCN2022124111-appb-000012
Figure PCTCN2022124111-appb-000013
所述
Figure PCTCN2022124111-appb-000014
被1个基团取代,所述基团选自取代或未取代的芳基,取代或未取代的杂环烷基和取代或未取代的杂芳基(2)可以再被1个基团取代,所述基团选自C 1-3烷基,CF 3,CN和卤素.
本发明的一些方案中,X 1和X 2与它们共同连接的碳原子一起形成的5元杂芳基,5 元或6元杂环烷基被1个基团取代,所述基团选自
Figure PCTCN2022124111-appb-000015
Figure PCTCN2022124111-appb-000016
Figure PCTCN2022124111-appb-000017
本发明的一些方案中,X 1和X 2与它们共同连接的碳原子一起形成
Figure PCTCN2022124111-appb-000018
本发明的一些方案中,Q 2为N.本发明的一些方案中,Q 2为CR’,所述R’选自H,Cl,F,CN,-OCH 3和-OH.
本发明的一些方案中,R 4选自H和F.
本发明的一些方案中,Q 2为CR’,R’和R 4与它们共同连接的碳原子一起形成取代或未取代的5元或6元杂芳基或取代或未取代5元或6元杂环烷基.本发明的一些方案中,Q 2为CR’,R’和R 4与它们共同连接的碳原子一起形成
Figure PCTCN2022124111-appb-000019
本发明的一些方案中,Q 3为N.本发明的一些方案中,Q 3为CR 2,所述R 2选自H,-OH和F.
本发明的一些方案中,Q 2为CR’,所述R’选自H,-CH 3,-CH 2CH 3,-CH(CH 3) 2,-SCF 3,Cl,F,CN,-OCH 3和-OH.
本发明的一些方案中,Q 2为CR’,所述R’选自H,-CH 3,-CH 2CH 3,-CH(CH 3) 2,-SCF 3,Cl,F,CN,-OCH 3和-OH,并且Q 3为CR 2,所述R 2选自H,-OH和F.
本发明的一些方案中,式(I)所示化合物或其药学上可接受的盐选自式(II)所示化合物或其药学上可接受的盐,
Figure PCTCN2022124111-appb-000020
其中,Q 2’和式(I)Q 2定义一致,R 4’和式(I)R 4定义一致,Z’和式(I)Z定义一致,Y,R 1,
R 2,R 3和式(I)定义一致.
本发明的一些方案中,Q 2’为N.本发明的一些方案中,Q 2’为C-H,C-CH 3,C-CH 2CH 3,-C-CH(CH 3) 2,-S-CF 3,C-F or C-Cl.
本发明的一些方案中,R 4’选自H.本发明的一些方案中,R 4’选自C 1-3烷基,C 3-8环烷基,C 1-3烷氧基,-OCF 3,-OCHF 2,-SCF 3,halo,-NH 2,OH和CF 3.本发明的一些方案中,R 4’选自-CH 3,-OCH 3,-OCH 2CH 3,-OCH(CH 3) 2,-SCF 3,-CH(CH 3) 2,-OCF 3,OH,-CF 3,-OCHF 2,环丙基,Cl,F,和-NH 2.
本发明的一些方案中,Z’或Z为取代或未取代的环上只有一个选自N,O和S的杂原子的杂环烷基.本发明的一些方案中,Z’或Z选自取代或未取代的环上只有一个N杂原子的杂环烷基.本发明的一些方案中,Z’或Z选自取代或未取代的氮杂环丁烷基,四氢吡咯基,哌啶基,环己亚胺基,
Figure PCTCN2022124111-appb-000021
Figure PCTCN2022124111-appb-000022
Figure PCTCN2022124111-appb-000023
本发明的一些方案中,这些取代基为一个或多个,选自羟基,氧基,C 1-8烷基,氟、氯,1-5卤素取代的C 1-8烷基,一个或多个羟基取代的C 1-8烷基,一个或多个CN取代的C 1-8烷基,C 1-8烷氧基取代的C 1-8烷基,-NHCOC 1-8烷基取代的C 1-8烷基,C 1-8 烷氧基,1-5卤素取代的C 1-8烷氧基,一个或多个羟基取代的C 1-8烷氧基,-CN,氨基,单或双C 1-8烷基取代的氨基.本发明的一些方案中,这些取代基包含一个或两个羟基.
本发明的一些方案中,R 3选自未取代或取代的吡啶基,苯基和萘基,这些取代基为一个或多个,选自羟基,-NH 2,氟、氯,C 1-8烷基,1-5卤素取代的C 1-8烷基,C 3-6环烷基,C 2-8烯基,和C 2-8炔基.
本发明的一些方案中,R 3选自
Figure PCTCN2022124111-appb-000024
Figure PCTCN2022124111-appb-000025
Figure PCTCN2022124111-appb-000026
本发明的一些方案中,Q 1为CR,R选自H,CN,CF 3,OH,卤素,取代或未取代的C 1-3烷基和取代或未取代的C 1-3烷氧基.本发明的一些方案中,Q 1为CR,R选自H和CN.
本发明的一些方案中,Y为O.
本发明的一些方案中,R 1选自L-取代或未取代的9或10元的稠合双环芳基,L-取代或未取代的8-10元的稠合双环杂芳基,L-取代或未取代的7-10元的包含至少一个N原子的稠合双环杂环烷基,L-取代或未取代的3-8元的单环环烷基,和L-取代或未取代的5-7元的包含至少一个N原子的单环杂环烷基.本发明的一些方案中,所述9或10元的稠合双环芳基,8-10元的稠合双环杂芳基,7-10元的包含至少一个N原子的稠合双环杂环烷基,和5-7 元的包含至少一个N原子的单环杂环烷基可以被1个或多个选自F和取代或未取代的C 1-3烷基的基团取代.本发明的一些方案中,R 1选自
Figure PCTCN2022124111-appb-000027
Figure PCTCN2022124111-appb-000028
Figure PCTCN2022124111-appb-000029
其中,R 7和R 8各自独立地选自H,C 1-4烷基和苯甲基,或者R 7和R 8与它们共同连接的N原子一起形成5元或6元杂环烷基.
本发明的一些方案中,L选自键和CH 2.
本发明的一些方案中,Z或Z’为-NR 5R 6,所述R 5为H,R 6选自取代或未取代的杂环烷基和取代或未取代的C 3-6烷基.
本发明的一些方案中,Z或Z’为
Figure PCTCN2022124111-appb-000030
本发明的一些方案中,Z或Z’选自
Figure PCTCN2022124111-appb-000031
本发明的一些方案中,Z或Z’为取代或未取代的杂环烷基.
本发明的一些方案中,Z或Z’为取代或未取代的环上只有一个选自N,O和S的杂原子的杂环烷基.
本发明的一些方案中,Z和Z’为取代或未取代的5-7元单环杂环烷基.本发明的一 些方案中,Z选自
Figure PCTCN2022124111-appb-000032
本发明的一些方案中,Z和Z’不是桥连杂环烷基.
本发明的一些方案中,Z和Z’选自取代或未取代的
Figure PCTCN2022124111-appb-000033
Figure PCTCN2022124111-appb-000034
本发明的一些方案中,Z和Z’选自
Figure PCTCN2022124111-appb-000035
Figure PCTCN2022124111-appb-000036
Figure PCTCN2022124111-appb-000037
本发明的一些方案中,Z和Z’为取代或未取代的6-10元稠合双环杂环烷基.本发明的一些方案中,Z和Z’为取代或未取代的
Figure PCTCN2022124111-appb-000038
本发明的一些方案中,Z和Z’选自
Figure PCTCN2022124111-appb-000039
Figure PCTCN2022124111-appb-000040
本发明的一些方案中,Z和Z’为取代或未取代的6-12元螺合杂环烷基.本发明的一 些方案中,Z和Z’为取代或未取代的
Figure PCTCN2022124111-appb-000041
本发明的一些方案中,Z和Z’为
Figure PCTCN2022124111-appb-000042
Figure PCTCN2022124111-appb-000043
本发明的一些方案中,Z和Z’为取代或未取代的7-12元桥连杂环烷基.本发明的一些方案中,Z和Z’为取代或未取代的7元桥连杂环烷基.本发明的一些方案中,Z和Z’为取代或未取代的7元的桥连包含至少一个N原子的杂环烷基.本发明的一些方案中,Z为取代或未取代的
Figure PCTCN2022124111-appb-000044
本发明的一些方案中,Z和Z’为取代或未取代的
Figure PCTCN2022124111-appb-000045
Figure PCTCN2022124111-appb-000046
或者
Figure PCTCN2022124111-appb-000047
本发明的一些方案中,Z和Z’选自
Figure PCTCN2022124111-appb-000048
Figure PCTCN2022124111-appb-000049
Figure PCTCN2022124111-appb-000050
本发明的一些方案中,Z和Z’选自
Figure PCTCN2022124111-appb-000051
Figure PCTCN2022124111-appb-000052
本发明的一些方案中,式(I)所示化合物或其药学上可接受的盐选自
Figure PCTCN2022124111-appb-000053
Figure PCTCN2022124111-appb-000054
Figure PCTCN2022124111-appb-000055
Figure PCTCN2022124111-appb-000056
Figure PCTCN2022124111-appb-000057
或其药学上可接受的盐.
本发明的一些方案中,式(I)所示化合物或其药学上可接受的盐选自
Figure PCTCN2022124111-appb-000058
Figure PCTCN2022124111-appb-000059
或其药学上可接受的盐.
本发明的一些方案中,式(II)所示化合物或其药学上可接受的盐选自
Figure PCTCN2022124111-appb-000060
Figure PCTCN2022124111-appb-000061
Figure PCTCN2022124111-appb-000062
Figure PCTCN2022124111-appb-000063
,或其药学上可接受的盐.
本发明的一些方案中,式(I)所示化合物或其药学上可接受的盐选自式(III)所示化合物或其药学上可接受的盐:
Figure PCTCN2022124111-appb-000064
Figure PCTCN2022124111-appb-000065
其中,
R 1’选自-CH 2-5-12元杂环烷基,所述3-12元杂环烷基可以被-CH 3,F,Cl,-CH 2N(CH 3) 2,-CH 2OC(O)N(CH 3) 2,-CH 2-morpholinyl,-CH 2OC(O)-morpholinyl,和-CF 3取代,
Y’是O或键,
Q 1’选自N,CH,C-CF 3,C-OH,C-Cl,C-F,C-CH 3,C-OCH 3和C-CN,
Z”是式(I)中的Z,包含前面描述的每一个方案中的Z,
R 4’选自H,-CF 3,-OH,-OMe,-OEt,-CH 3,-SCF 3,-OCH(CH 3) 2,-CH(CH 3) 2,-OCF 3,-OCHF 2,环丙基,-NH 2,F和Cl,
Q 2’选自C-R’和N,所述R’选自H,CN,CF 3,OH,卤素,取代或未取代-S-C 1-3烷基,取代或未取代C 1-3烷基和取代或未取代C 1-3烷氧基,取代或未取代C 3-8环烷基,
R 3’是式(I)中的R 3,包含前面描述的每一个方案中的R 3,比如选自取代或未取代的芳基(例如,取代或未取代的苯基,蒽基和萘基),取代或未取代的杂环烷基和取代或未取代的杂芳基,
Q 3’选自N,C-H,C-F,C-Cl,C-OH,C-CN,C-CF 3,C-CH 3和C-OCH 3.
本发明的一些方案中,当式(III)中的Q 1’为N,Z”为取代或未取代的杂环烷基或-NR 5R 6,R 5为H,R 6选自取代或未取代的杂环烷基,那么Q 2’和Q 3’至少有一个是N.
本发明的一些方案中,Q 2’选自C-H,C-F,C-OH,C-CH 3,C-CF 3,C-Cl,C-CN,C-CH 2CH 3,-C-CH(CH 3) 2,-S-CF 3,和C-OCH 3.本发明的一些方案中,Q 2’是N.本发明的一些方案中,R 4’选自-CF 3,-OH,OMe,OEt,-CH 3,-SCF 3,-OCH(CH 3) 2,-CH(CH 3) 2,-OCF 3,-OCHF 2,环丙基,-NH 2,F和Cl.本发明的一些方案中,Q 1’是N.本发明的一些方案中,Q 1’选自CH,C-CF 3,C-OH,C-Cl,C-F,C-CH 3,C-OCH 3和C-CN.本发明的一些方案中,Q 3’是N.本发明的一些方案中Q 3’选自C-H,C-F,C-Cl,C-OH,C-CN,C-CF 3,C-CH 3和C-OCH 3.
本发明的一些方案中,式(III)中的R 1’选自
Figure PCTCN2022124111-appb-000066
Figure PCTCN2022124111-appb-000067
本发明的一些方案中,R 3’选自
Figure PCTCN2022124111-appb-000068
Figure PCTCN2022124111-appb-000069
Figure PCTCN2022124111-appb-000070
本发明的一些方案中,式(I)所示化合物或其药学上可接受的盐选自式(IV)与式(V)所示化合物或其药学上可接受的盐:
Figure PCTCN2022124111-appb-000071
其中,
环A选自4-10元,环上只有一个杂原子的杂环烷基,所述杂原子是N,
R a选自氧基,羟基,C 1-8烷基,C 3-8环烷基,氟、氯,1-5卤素取代的C 1-8烷基,一个或多个羟基取代的C 1-8烷基,C 1-8烷氧基取代的C 1-8烷基,CN取代的C 1-8烷基,-NHCOC 1-8烷基取代的C 1-8烷基,C 1-8烷氧基,1-5卤素取代的C 1-8烷氧基,一个或多个羟基取代的C 1-8烷氧基,CN,氨基,单或双C 1-8烷基取代的氨基,
n是0,1,2或者3,
R 1”选自
Figure PCTCN2022124111-appb-000072
Figure PCTCN2022124111-appb-000073
Figure PCTCN2022124111-appb-000074
其中,R 7和R 8各自独立地选自H,C1-4烷基和苯甲基,或者R 7和R 8与它们共同连接的N原子一起形成5元或6元杂环烷基,
Y a是O或键,
Q 1’选自N,CH,C-CF 3,C-OH,C-Cl,C-F,C-CH 3,C-OCH 3和C-CN,
Q 2’选自C-R’和N,所述R’选自H,CN,CF 3,OH,卤素,取代或未取代-S-C 1-3烷基,取代或未取代C 1-3烷基和取代或未取代C 1-3烷氧基,取代或未取代C 3-8环烷基,
R 2’选自H,F,OH,CH 3,CN,CF 3,Cl,和OCH 3,
R 3”选自未取代或取代的吡啶基,苯基,苯并[b]噻吩和萘基,这些取代基为一个或多个,选自羟基,氟、氯,C 1-8烷基,C 1-8烷氧基,-NH 2,1-5卤素取代的C 1-8烷基,C 3-6环烷基,C 2-8 烯基,和C 2-8炔基,
R 4’选自H,-CF 3,-OH,-OMe,-OEt,-CH 3,-SCF 3,-OCH(CH 3) 2,-CH(CH 3) 2,-OCF 3,-OCHF 2,环丙基,-NH 2,F和Cl.
本发明的一些方案中,式(IV)中的Q 1’和Q 2’不同时为N.本发明的一些方案中,式(IV)中的Q 1’和Q 2’都不是N.
本发明的一些方案中,式(IV)与式(V)中的Q 1’选自CH,C-CF 3,C-OH,C-Cl,C-F,C-CH 3,C-OCH 3和C-CN.
本发明的一些方案中,式(IV)中的Q 2’选自C-H,C-CH 2CH 3,-C-CH(CH 3) 2,-S-CF 3,C-F,C-OH,C-CH 3,C-CF 3,C-Cl,C-CN,和C-OCH 3.
本发明的一些方案中,式(IV)与式(V)中的Q 1’选自CH,C-CF 3,C-OH,C-Cl,C-F,C-CH 3,C-OCH 3和C-CN,并且Q 2’选自C-H,C-CH 2CH 3,-C-CH(CH 3) 2,-S-CF 3,C-F,C-OH,C-CH 3,C-CF 3,C-Cl,C-CN,和C-OCH 3.
本发明的一些方案中,式(IV)与式(V)中的R 4’选自-CF 3,-OH,-OMe,-OEt,-CH 3,-SCF 3,-OCH(CH 3) 2,-CH(CH 3) 2,-OCF 3,-OCHF 2,环丙基,-NH 2,F和Cl.
本发明的一些方案,R a选自氧基,OH,NH 2,-CH 2OH,CH 3,F,Cl,-CH 2CH 3,-CH(CH 3) 2,环丙基,CN,CF 3,-CH 2OCH 3,-CH 2CN,-CH 2OH,-CH 2NHCOCH 3和OCH 3.
本发明的一些方案中,式(IV)与式(V)中的Q 1’是N.本发明的一些方案中,式(IV)中的Q2”是N.本发明的一些方案中,式(IV)中的R 4’是H.
本发明的一些方案中,环A不是桥连杂环烷基.
本发明的一些方案中,环A选自
Figure PCTCN2022124111-appb-000075
Figure PCTCN2022124111-appb-000076
本发明的一些方案中,R 3”选自
Figure PCTCN2022124111-appb-000077
本发明的一些方案中,式(I)所示化合物或其药学上可接受的盐选自式(VI)与式(VII)所示化合物或其药学上可接受的盐:
Figure PCTCN2022124111-appb-000078
其中,
环A选自4-10元,环上只有一个杂原子的杂环烷基,所述杂原子是N,
R a选自氧基,羟基,C 1-8烷基,C 3-8环烷基,氟、氯,1-5卤素取代的C 1-8烷基,一个或多个羟基取代的C 1-8烷基,C 1-8烷氧基取代的C 1-8烷基,CN取代的C 1-8烷基,-NHCOC 1-8烷基取代的C 1-8烷基,C 1-8烷氧基,1-5卤素取代的C 1-8烷氧基,一个或多个羟基取代的C 1-8烷氧基,CN, 氨基,单或双C 1-8烷基取代的氨基,
n是0,1,2或者3,
R 1”选自
Figure PCTCN2022124111-appb-000079
Figure PCTCN2022124111-appb-000080
Figure PCTCN2022124111-appb-000081
其中,R 7和R 8各自独立地选自H,C1-4烷基和苯甲基,或者R 7和R 8与它们共同连接的N原子一起形成5元或6元杂环烷基,
Y a是O或键,
Q 1’选自N,CH,C-CF 3,C-OH,C-Cl,C-F,C-CH 3,C-OCH 3和C-CN,
R 3”选自未取代或取代的吡啶基,苯基和萘基,这些取代基为一个或多个,选自羟基,氟、氯,C 1-8烷基,C 1-8烷氧基,-NH 2,1-5卤素取代的C 1-8烷基,C 3-6环烷基,C 2-8烯基,和C 2-8炔基,
R 4’选自H,-CF 3,-OH,-OMe,-OEt,-CH 3,-SCF 3,-OCH(CH 3) 2,-CH(CH 3) 2,-OCF 3,-OCHF 2,环丙基,-NH 2,F和Cl.
本发明的一些方案中,式(IV)与式(V)中的R 4’选自-CF 3,-OH,-OMe,-OEt,-CH 3,-SCF 3,-OCH(CH 3) 2,-CH(CH 3) 2,-OCF 3,-OCHF 2,环丙基,-NH 2,F和Cl.
本发明的一些方案,R a选自氧基,OH,NH 2,-CH 2OH,CH 3,F,Cl,-CH 2CH 3,-CH(CH 3) 2,环丙基,CN,CF 3,-CH 2OCH 3,-CH 2CN,-CH 2OH,-CH 2NHCOCH 3和OCH 3.
本发明的一些方案中,式(IV)与式(V)中的Q 1’是N.本发明的一些方案中,式(IV)中的Q2”是N.本发明的一些方案中,式(IV)中的R 4’是H.
本发明的一些方案中,环A选自
Figure PCTCN2022124111-appb-000082
Figure PCTCN2022124111-appb-000083
本发明的一些方案中,R 3”选自
Figure PCTCN2022124111-appb-000084
本发明的一些方案中,式(II)所示化合物或其药学上可接受的盐选自:
Figure PCTCN2022124111-appb-000085
Figure PCTCN2022124111-appb-000086
Figure PCTCN2022124111-appb-000087
Figure PCTCN2022124111-appb-000088
Figure PCTCN2022124111-appb-000089
Figure PCTCN2022124111-appb-000090
Figure PCTCN2022124111-appb-000091
Figure PCTCN2022124111-appb-000092
Figure PCTCN2022124111-appb-000093
或其药学上可接受的盐.
本发明的一些方案中,式(I)所示化合物或其药学上可接受的盐选自:
Figure PCTCN2022124111-appb-000094
Figure PCTCN2022124111-appb-000095
Figure PCTCN2022124111-appb-000096
Figure PCTCN2022124111-appb-000097
,或其药学上可接受的盐.
本发明的另外一些方案1-113包括:
1.式(I)所示化合物或其药学上可接受的盐,
Figure PCTCN2022124111-appb-000098
其中,
R 1选自H,-L-取代或未取代的芳基,-L-取代或未取代的杂芳基,-L-取代或未取代的杂环烷基和-L-取代或未取代的环烷基；
L选自-CH 2-,-C(CH 3)H-,-CH(F)-,-CH 2-CH 2-,-CH 2-CH 2-CH 2-,-CH 2-CH(F)-CH 2-,-CH 2-CF 2-CH 2-,-CH 2-CH(CH 3)-CH 2-,-CH 2-C(CH 3) 2-CH 2-,
Figure PCTCN2022124111-appb-000099
-C＝O-,-C＝-和键；Q 1选自C-R和N,所述R选自H,CN,CF 3,OH,卤素,取代或未取代的C 1-3烷基和取代或未取代的C 1-3烷氧基；
Y选自键,-O-,-S-和-NH-；
Z选自-NR 5R 6和取代或未取代的杂环烷基；
R 5为H,R 6选自取代或未取代的杂环烷基和取代或未取代C 3-6烷基；
X 1选自-OH和C 1-3烷氧基,X 2为乙烯基,所述乙烯基的取代基选自取代或未取代的芳基,取代或未取代的杂环烷基和取代或未取代的杂芳基；
或者X 1和X 2与它们共同连接的碳原子一起形成5元杂芳基,5元或6元杂环烷基,或
Figure PCTCN2022124111-appb-000100
所述5元杂芳基和5元或6元杂环烷基(1)被1个基团取代,所述基团选自取代或未取代的芳基,取代或未取代的杂环烷基和取代或未取代的杂芳基,(2)可以被1个基团取代,所述基团选自C 1-3烷基,CF 3,CN和卤素；
R 3选自取代或未取代的芳基,取代或未取代的杂环烷基和取代或未取代的杂芳基；
R 4选自H,C 1-3烷基,C 3-8环烷基,C 1-3烷氧基,-OCF 3,-OCHF 2,-SCF 3,halo,-NH 2,OH和CF 3；
Q 2选自C-R’和N,所述R’选自H,CN,CF 3,OH,卤素,取代或未取代-S-C 1-3烷基,取代或未取代C 1-3烷基和取代或未取代C 1-3烷氧基,取代或未取代C 3-8环烷基；
或者R’和R 4与它们共同连接的碳原子一起形成取代或未取代的5元或6元杂芳基或取代或未取代5元或6元杂环烷基；
Q 3选自CR 2和N,所述R 2选自H,卤素,OH,CN,取代或未取代C 1-3烷基和取代或未取代C 1-3烷氧基；
前提条件是(1)当Q 1和Q 2为N,R 4为H,Q 3为CR 2,那么(a)Z不是取代或未取代的
Figure PCTCN2022124111-appb-000101
或者(b)如果Z是取代或未取代的
Figure PCTCN2022124111-appb-000102
那么(i)R 3为芳基或杂芳基,所述芳基或杂芳基至少被芳基取代或者(ii)R 1选自-L-取代或未取代的芳基,-L-取代或未取代的杂芳基和-L-取代或未取代的环烷基,所述L选自-C＝O-,-C＝-和键,(2)当Q 1为N,X 1和X 2与它们共同连接的碳原子一起形成5元杂芳基,5元或6元杂环烷基,或
Figure PCTCN2022124111-appb-000103
那么Z不是以N为连接点的,环上至少有另一个选自N,O,和S的杂原子的取代或未取代的8-10元桥连杂环烷基,或者R 1不是取代或未取代的3-6元环烷基,5元或6元饱和杂环烷基和8-10元部分非饱和杂环烷基.
2.根据方案1所述化合物或其药学上可接受的盐，其中当Z为取代或未取代的杂环烷基或-NR 5R 6,R 5为H,R 6选自取代或未取代的杂环烷基,Q 1为N,X 1和X 2与它们共同连接的碳原子一起形成
Figure PCTCN2022124111-appb-000104
那么Q 2和Q 3至少有一个是N.
3.根据方案1所述化合物或其药学上可接受的盐，其中，X 1为-OH,X 2为乙烯基,所述乙烯基的取代基选自取代或未取代的芳基,取代或未取代的杂环烷基和取代或未取代的杂芳基.
4.根据方案1所述化合物或其药学上可接受的盐，其中，X 1为C 1-3烷氧基,X 2为乙烯基,所述乙烯基的取代基选自取代或未取代的芳基,取代或未取代的杂环烷基和取代或未取代的杂芳基.
5.根据方案4所述化合物或其药学上可接受的盐，其中，X 1为-OCH 3.
6.根据方案1和3-5中任一项所述化合物或其药学上可接受的盐，其中，X 2为乙烯基,所述乙烯基的取代基选自取代或未取代的苯基或萘基取代.例如,苯基或萘基可以被OH,苯基,C 1-3烷基,乙炔基或乙烯基取代.
7.根据方案6所述化合物或其药学上可接受的盐，其中,X 2为被苯基或萘基取代的乙烯基,所述苯基或萘基可以被OH,苯基,C 1-3烷基,乙炔基或乙烯基取代.
8.根据方案3-5中任一项所述化合物或其药学上可接受的盐，其中X 2选自
Figure PCTCN2022124111-appb-000105
Figure PCTCN2022124111-appb-000106
9.根据方案1所述化合物或其药学上可接受的盐，其中,X 1和X 2与它们共同连接的碳原子一起形成5元杂芳基,所述5元杂芳基(1)被1个基团取代,所述基团选自取代或未取代 的芳基,取代或未取代的杂环烷基和取代或未取代的杂芳基(2)可以再被1个基团取代,所述基团选自C 1-3烷基,CF 3,CN和卤素.
10.根据方案9所述化合物或其药学上可接受的盐，其中,所述5元杂芳基选自吡唑基、呋喃基、恶唑基、吡咯基和噻吩基,所述吡唑基、呋喃基、恶唑基、吡咯基和噻吩基(1)被1个基团取代,所述基团选自取代或未取代的芳基,取代或未取代的杂环烷基和取代或未取代的杂芳基(2)可以再被1个基团取代,所述基团选自C 1-3烷基,CF 3,CN和卤素.
11.根据方案1所述化合物或其药学上可接受的盐，其中,X 1和X 2与它们共同连接的碳原子一起形成6元杂环烷基,所述6元杂环烷基(1)被1个基团取代,所述基团选自取代或未取代的芳基,取代或未取代的杂环烷基和取代或未取代的杂芳基(2)可以再被1个基团取代,所述基团选自C 1-3烷基,CF 3,CN和卤素.
12.根据方案11所述化合物或其药学上可接受的盐，其中,所述6元杂环烷基选自
Figure PCTCN2022124111-appb-000107
所述
Figure PCTCN2022124111-appb-000108
Figure PCTCN2022124111-appb-000109
被1个基团取代,所述基团选自取代或未取代的芳基,取代或未取代的杂环烷基和取代或未取代的杂芳基(2)可以再被1个基团取代,所述基团选自C 1-3烷基,CF 3,CN和卤素.
13.根据方案9-12中任一项所述化合物或其药学上可接受的盐，其中,X 1和X 2与它们共同连接的碳原子一起形成的5元杂芳基或6元杂环烷基被1个基团取代,所述基团选自
Figure PCTCN2022124111-appb-000110
Figure PCTCN2022124111-appb-000111
Figure PCTCN2022124111-appb-000112
14.根据方案1或2所述化合物或其药学上可接受的盐，其中,X 1和X 2与它们共同连接的碳原子一起形成
Figure PCTCN2022124111-appb-000113
Q 3,R 3,R 4and Q 2如方案1所述.
15.根据方案14所述化合物或其药学上可接受的盐，其中,Q 2为N.
16.根据方案14所述化合物或其药学上可接受的盐，其中,Q 2为CR’,所述R’选自H,CN,CF 3,OH,卤素,取代或未取代-S-C 1-3烷基,取代或未取代C 1-3烷基和取代或未取代C 1-3烷氧基,并且Q 3选自CR 2,所述R 2选自H,卤素,OH,CN,取代或未取代C 1-3烷基和取代或未取代C 1-3烷氧基.
17.根据方案14-16中任一项所述化合物或其药学上可接受的盐，其中,R 4选自C 1-3烷基,C 3-8环烷基,C 1-3烷氧基,-OCF 3,-OCHF 2,-SCF 3,halo,-NH 2,OH和CF 3.
18.根据方案14所述化合物或其药学上可接受的盐，其中,Q 2为CR’,R’和R 4与它们共同连接的碳原子一起形成取代或未取代的5元或6元杂芳基或取代或未取代5元或6元杂环烷基.
19.根据方案14所述化合物或其药学上可接受的盐，其中,Q 2为CR’,R’和R 4与它们共同 连接的碳原子一起形成
Figure PCTCN2022124111-appb-000114
20.根据方案14-19中任一项所述化合物或其药学上可接受的盐，其中,Q 3为N.
21.根据方案14-19中任一项所述化合物或其药学上可接受的盐，其中,Q 3为CR 2,所述R 2选自H,卤素,OH,CN,取代或未取代C 1-3烷基和取代或未取代C 1-3烷氧基.
22.根据方案1-21中任一项所述化合物或其药学上可接受的盐，其中,Q 1为N.
23.根据方案1-21中任一项所述化合物或其药学上可接受的盐,其中,Q 1为CR,R选自H,CN,CF 3,OH,卤素,取代或未取代的C 1-3烷基和取代或未取代的C 1-3烷氧基.
24.根据方案23所述化合物或其药学上可接受的盐，其中,Q 1为CR,R选自H和CN.
25.根据方案1或2所述化合物或其药学上可接受的盐，式(I)所示化合物或其药学上可接受的盐选自式(II)所示化合物或其药学上可接受的盐,
Figure PCTCN2022124111-appb-000115
其中,Q 2’和式(I)Q 2定义一致,R 4’和式(I)R 4定义一致,Z’如方案1的Z所述,Y,R 1,R 2,R 3如方案1所述.
26.根据方案25所述化合物或其药学上可接受的盐,Q 2’为N.
27.根据方案25所述化合物或其药学上可接受的盐,Q 2’为C-H,C-CH 3,C-CH 2CH 3,-C-CH(CH 3) 2,-S-CF 3,C-F or C-Cl.
28.根据方案25-27中任一项所述化合物或其药学上可接受的盐,R 4’选自H.
29.根据方案25-27中任一项所述化合物或其药学上可接受的盐,R 4’选自C 1-3烷基,C 3-8环烷基,C 1-3烷氧基,-OCF 3,-OCHF 2,-SCF 3,halo,-NH 2,OH和CF 3.
30.根据方案29所述化合物或其药学上可接受的盐,R 4’选自-CH 3,-OCH 3,-OCH 2CH 3,-OCH(CH 3) 2,-SCF 3,-CH(CH 3) 2,-OCF 3,OH,-CF 3,-OCHF 2,环丙基,Cl,F,和-NH 2.
31.根据方案25-30中任一项所述化合物或其药学上可接受的盐,R 2选自H,-OH和F.
32.根据方案14-31中任一项所述化合物或其药学上可接受的盐,其中R 3选自选自未取代或取代的吡啶基,苯基,苯并[b]噻吩和萘基,这些取代基为一个或多个,选自羟基,-NH 2,氟、 氯,C 1-8烷基,1-5卤素取代的C 1-8烷基,C 3-6环烷基,C 2-8烯基,和C 2-8炔基.
33.根据方案14-32中任一项所述化合物或其药学上可接受的盐，其中R 3选自
Figure PCTCN2022124111-appb-000116
Figure PCTCN2022124111-appb-000117
Figure PCTCN2022124111-appb-000118
34.根据方案1-33中任一项所述化合物或其药学上可接受的盐，其中,Y为O.
35.根据方案1-33中任一项所述化合物或其药学上可接受的盐，其中,R 1选自L-取代或未取代的9或10元的稠合双环芳基,L-取代或未取代的8-10元的稠合双环杂芳基,L-取代或未取代的3-8元的单环环烷基,L-取代或未取代的7-10元的包含至少一个N原子的稠合双环杂环烷基,和L-取代或未取代的5-7元的包含至少一个N原子的单环杂环烷基.
36.根据方案35所述化合物或其药学上可接受的盐，其中,所述9或10元的稠合双环芳基,8-10元的稠合双环杂芳基,3-8元的单环环烷基,7-10元的包含至少一个N原子的稠合双环杂 环烷基,和5-7元的包含至少一个N原子的单环杂环烷基可以被1个或多个选自F和取代或未取代的C 1-3烷基的基团取代.
37.根据方案36所述化合物或其药学上可接受的盐,其中,R 1选自
Figure PCTCN2022124111-appb-000119
Figure PCTCN2022124111-appb-000120
Figure PCTCN2022124111-appb-000121
其中,R 7和R 8各自独立地选自H,C1-4烷基和苯甲基,或者R 7和R 8与它们共同连接的N原子一起形成5元或6元杂环烷基.
38.根据方案1-37中任一项所述化合物或其药学上可接受的盐，其中,L选自键和CH 2.
39.根据方案1-38中任一项所述化合物或其药学上可接受的盐，其中,Z或Z’为-NR 5R 6,所述R 5为H,R 6选自取代或未取代的杂环烷基和取代或未取代的C 3-6烷基.
40.根据方案39所述化合物或其药学上可接受的盐，其中,Z或Z’为
Figure PCTCN2022124111-appb-000122
Figure PCTCN2022124111-appb-000123
41.根据方案39所述化合物或其药学上可接受的盐，其中,Z或Z’选自
Figure PCTCN2022124111-appb-000124
Figure PCTCN2022124111-appb-000125
42.根据方案1-38中任一项所述化合物或其药学上可接受的盐，其中,Z或Z’为取代或未取 代的杂环烷基.
43.根据方案42所述化合物或其药学上可接受的盐，其中,Z或Z’为取代或未取代的5-7元单环杂环烷基.
44.根据方案43所述化合物或其药学上可接受的盐,其中,Z或Z’选自
Figure PCTCN2022124111-appb-000126
Figure PCTCN2022124111-appb-000127
45.根据方案42所述化合物或其药学上可接受的盐，其中,Z或Z’为取代或未取代的6-10元稠合双环杂环烷基.
46.根据方案45所述化合物或其药学上可接受的盐，其中,Z或Z’选自
Figure PCTCN2022124111-appb-000128
47.根据方案42所述化合物或其药学上可接受的盐，其中,Z或Z’为取代或未取代的6-12元螺合杂环烷基.
48.根据方案47所述化合物或其药学上可接受的盐，其中,Z或Z’为
Figure PCTCN2022124111-appb-000129
49.根据方案42所述化合物或其药学上可接受的盐，其中,Z或Z’为取代或未取代的7-12元桥连杂环烷基.
50.根据方案49所述化合物或其药学上可接受的盐，其中,Z或Z’选自
Figure PCTCN2022124111-appb-000130
Figure PCTCN2022124111-appb-000131
Figure PCTCN2022124111-appb-000132
51.根据方案49所述化合物或其药学上可接受的盐，其中,Z或Z’为取代或未取代的7元桥连杂环烷基.
52.根据方案51所述化合物或其药学上可接受的盐，其中,Z或Z’为取代或未取代的7元桥连包含至少一个N原子的杂环烷基.
53.根据方案52所述化合物或其药学上可接受的盐，其中,Z或Z’为取代或未取代的
Figure PCTCN2022124111-appb-000133
54.根据方案42所述化合物或其药学上可接受的盐，其中,Z或Z’为取代或未取代的环上只有一个选自N,O和S的杂原子的杂环烷基.
55.根据方案54所述化合物或其药学上可接受的盐，其中,Z或Z’为取代或未取代的环上只有一个N杂原子的杂环烷基.
56.根据方案55所述化合物或其药学上可接受的盐，其中,Z或Z’为取代或未取代的氮杂环丁烷基,四氢吡咯基,哌啶基,环己亚胺基,
Figure PCTCN2022124111-appb-000134
Figure PCTCN2022124111-appb-000135
57.根据方案55或56所述化合物或其药学上可接受的盐，其中,环上只有一个N杂原子的氮杂环丁烷基,杂环烷基,四氢吡咯基,哌啶基,环己亚胺基,
Figure PCTCN2022124111-appb-000136
Figure PCTCN2022124111-appb-000137
Figure PCTCN2022124111-appb-000138
的一个或多个取代基选自羟基,氧基,C 1-8烷基,氟、氯,1-5卤素取代的C 1-8烷基,一个或多个羟基取代的C 1-8烷基,一个或多个CN取代的C 1-8烷基,C 1-8烷氧基取代的C 1-8烷基,-NHCOC 1-8烷基取代的C 1-8烷基,C 1-8烷氧基,1-5卤素取代的C 1-8烷氧基,一个或多个羟基取代的C 1-8烷氧基,-CN,氨基,和单或双C 1-8烷基取代的氨基.
58.根据方案57所述化合物或其药学上可接受的盐，其中,环上只有一个N杂原子的氮杂环丁烷基,杂环烷基,四氢吡咯基,哌啶基,环己亚胺基,
Figure PCTCN2022124111-appb-000139
Figure PCTCN2022124111-appb-000140
Figure PCTCN2022124111-appb-000141
包含一个或两个羟基取代基.
59.根据方案56-58中任一项所述化合物或其药学上可接受的盐,其中,Z或Z’为取代或未取代的
Figure PCTCN2022124111-appb-000142
Figure PCTCN2022124111-appb-000143
60.根据方案59所述化合物或其药学上可接受的盐,Z和Z’选自
Figure PCTCN2022124111-appb-000144
Figure PCTCN2022124111-appb-000145
Figure PCTCN2022124111-appb-000146
61.根据方案1所述化合物或其药学上可接受的盐，其中式(I)所示化合物或其药学上可接受的盐选自式(IV)-式(VII)所示化合物或其药学上可接受的盐:
Figure PCTCN2022124111-appb-000147
其中,
环A选自4-10元,环上只有一个杂原子的杂环烷基,所述杂原子是N,R a选自氧基,羟基,C 1-8烷基,C 3-8环烷基,氟、氯,1-5卤素取代的C 1-8烷基,一个或多个羟基取代的C 1-8烷基,C 1-8烷氧基取代的C 1-8烷基,CN取代的C 1-8烷基,-NHCOC 1-8烷基取代的C 1-8烷基,C 1-8烷氧基,1-5卤素取代的C 1-8烷氧基,一个或多个羟基取代的C 1-8烷氧基,CN,氨基,单或双C 1-8烷基取代的氨基,
n是0,1,2或者3,
R 1”选自
Figure PCTCN2022124111-appb-000148
Figure PCTCN2022124111-appb-000149
Figure PCTCN2022124111-appb-000150
其中,R 7和R 8各自独立地选自H,C1-4烷基和苯甲基,或者R 7和R 8与它们共同连接的N原子一起形成5元或6元杂环烷基；
Y a是O或键,
Q 1’选自N,CH,C-CF 3,C-OH,C-Cl,C-F,C-CH 3,C-OCH 3和C-CN,
Q 2’选自C-R’和N,所述R’选自H,CN,CF 3,OH,卤素,取代或未取代-S-C 1-3烷基,取代或未取代C 1-3烷基和取代或未取代C 1-3烷氧基,取代或未取代C 3-8环烷基,
R 2’选自H,F,OH,CH 3,CF 3,Cl,CN,和OCH 3,
R 3”选自未取代或取代的吡啶基,苯基,苯并[b]噻吩和萘基,这些取代基为一个或多个,选自羟基,氟、氯,C 1-8烷基,1-5卤素取代的C 1-8烷基,C 1-8烷氧基,-NH 2,C 3-6环烷基,C 2-8烯基,和C 2-8炔基,
R 4’选自H,-CF 3,-OH,-OMe,OEt,-CH 3,-SCF 3,-OCH(CH 3) 2,-CH(CH 3) 2,-OCF 3,-OCHF 2,环丙基,-NH 2,F和Cl.
62.根据方案61所述化合物或其药学上可接受的盐,其中R a选自氧基,OH,NH 2,-CH 2OH,CH 3,F,Cl,-CH 2CH 3,-CH(CH 3) 2,CN,CF 3,环丙基,-CH 2OCH 3,-CH 2CN,-CH 2OH,-CH 2NHCOCH 3和OCH 3.
63.根据方案61或62所述化合物或其药学上可接受的盐,其中式(IV)与式(V)中的Q 1’是N.
64.根据方案61-63中任一项所述化合物或其药学上可接受的盐,其中式(IV)中的Q 2”是N.
65.根据方案61或62所述化合物或其药学上可接受的盐,式(IV)中的Q 1’和Q 2’不同时为N.
66.根据方案61或62所述化合物或其药学上可接受的盐,式(IV)中的Q 1’和Q 2’都不是N.
67.根据方案61,62,65或66中任一项所述化合物或其药学上可接受的盐,式(IV)与式(V)中的Q 1’选自CH,C-CF 3,C-OH,C-Cl,C-F,C-CH 3,C-OCH 3和C-CN.
68.根据方案61,62,65或66中任一项所述化合物或其药学上可接受的盐,式(IV)中的Q 2’选自C-H,C-CH 2CH 3,-C-CH(CH 3) 2,-S-CF 3,C-F,C-OH,C-CH 3,C-CF 3,C-Cl,C-CN,和C-OCH 3.
69.根据方案61-68中任一项所述化合物或其药学上可接受的盐,其中式(IV)与式(V)中的R 4’是H.
70.根据方案61-68中任一项所述化合物或其药学上可接受的盐,其中式(IV)与式(V)中的R 4’选自-CF 3,-OH,-OMe,-OEt,-CH 3,-SCF 3,-OCH(CH 3) 2,-CH(CH 3) 2,-OCF 3,-OCHF 2,环丙基,-NH 2,F和Cl
71.根据方案61-70中任一项所述化合物或其药学上可接受的盐,其中环A选自
Figure PCTCN2022124111-appb-000151
Figure PCTCN2022124111-appb-000152
72.根据方案61-71中任一项所述化合物或其药学上可接受的盐,其中
Figure PCTCN2022124111-appb-000153
选自
Figure PCTCN2022124111-appb-000154
Figure PCTCN2022124111-appb-000155
Figure PCTCN2022124111-appb-000156
Figure PCTCN2022124111-appb-000157
73.根据方案61-72中任一项所述化合物或其药学上可接受的盐,R 3”选自
Figure PCTCN2022124111-appb-000158
74.根据方案1所述化合物或其药学上可接受的盐，其中,所述式(I)所示化合物或其药学上可接受的盐选自式(III)所示化合物或其药学上可接受的盐:
Figure PCTCN2022124111-appb-000159
其中,
R 1’选自-CH 2-3-12元杂环烷基,所述3-12元杂环烷基可以被-CH 3,F,Cl,-CH 2N(CH 3) 2,-CH 2OC(O)N(CH 3) 2,-CH 2-morpholinyl,-CH 2OC(O)-morpholinyl,和-CF 3取代,
Y’是O或键,
Q 1’选自N,CH,C-CF 3,C-OH,C-Cl,C-F,C-CH 3,C-OCH 3和C-CN,
Z”如方案1的Z所述
R 4’选自H,-CF 3,-OH,OMe,OEt,-CH 3,-SCF 3,-OCH(CH 3) 2,-CH(CH 3) 2,-OCF 3,-OCHF 2,环丙基,-NH 2,F和Cl,
Q 2’选自C-R’和N,所述R’选自H,CN,CF 3,OH,卤素,取代或未取代-S-C 1-3烷基,取代或未取代C 1-3烷基和取代或未取代C 1-3烷氧基,取代或未取代C 3-8环烷基,
R 3’选自取代或未取代的芳基(例如,取代或未取代的苯基,苯并[b]噻吩,蒽基和萘基),取代或未取代的杂环烷基和取代或未取代的杂芳基,
Q 3’选自N,C-H,C-F,C-Cl,C-OH,C-CN,C-CF 3,C-CH 3和C-OCH 3.
75.根据方案74所述化合物或其药学上可接受的盐,当式(III)中的Q 1’为N,Z”为取代或未取代的杂环烷基或-NR 5R 6,R 5为H,R 6选自取代或未取代的杂环烷基,那么Q 2’和Q 3’至少有一个是N.
76.根据方案74或75所述化合物或其药学上可接受的盐,其中,R 1’选自
Figure PCTCN2022124111-appb-000160
Figure PCTCN2022124111-appb-000161
77.根据方案74-76中任一项所述化合物或其药学上可接受的盐,其中R 3’选自
Figure PCTCN2022124111-appb-000162
Figure PCTCN2022124111-appb-000163
Figure PCTCN2022124111-appb-000164
78.根据方案74-77中任一项所述所述化合物或其药学上可接受的盐,其中,Z”为-NR 5R 6,所述R 5为H,R 6选自取代或未取代的杂环烷基和取代或未取代的C 3-6烷基.
79.根据方案78所述所述化合物或其药学上可接受的盐，其中,Z”为
Figure PCTCN2022124111-appb-000165
80.根据方案78所述化合物或其药学上可接受的盐，其中,Z”选自
Figure PCTCN2022124111-appb-000166
Figure PCTCN2022124111-appb-000167
81.根据方案74-77中任一项所述化合物或其药学上可接受的盐，其中,Z”为取代或未取代 的杂环烷基.
82.根据方案81所述化合物或其药学上可接受的盐，其中,Z”为取代或未取代的5-7元单环杂环烷基.
83.根据方案82所述化合物或其药学上可接受的盐,其中,Z”选自
Figure PCTCN2022124111-appb-000168
Figure PCTCN2022124111-appb-000169
84.根据方案81所述化合物或其药学上可接受的盐，其中,Z”为取代或未取代的6-10元稠合双环杂环烷基.
85.根据方案84所述化合物或其药学上可接受的盐，其中,Z”选自
Figure PCTCN2022124111-appb-000170
86.根据方案81所述化合物或其药学上可接受的盐，其中,Z”为取代或未取代的6-12元螺合杂环烷基.
87.根据方案86所述化合物或其药学上可接受的盐，其中,Z”为
Figure PCTCN2022124111-appb-000171
88.根据方案81所述化合物或其药学上可接受的盐，其中,Z”为取代或未取代的7-12元桥连杂环烷基.
89.根据方案88所述化合物或其药学上可接受的盐，其中,Z”选自
Figure PCTCN2022124111-appb-000172
Figure PCTCN2022124111-appb-000173
90.根据方案88所述化合物或其药学上可接受的盐，其中,Z”为取代或未取代的7元桥连杂环烷基.
91.根据方案90所述化合物或其药学上可接受的盐，其中,Z”为取代或未取代的7元桥连包含至少一个N原子的杂环烷基.
92.根据方案91所述化合物或其药学上可接受的盐，其中,Z”为取代或未取代的
Figure PCTCN2022124111-appb-000174
93.根据方案81所述化合物或其药学上可接受的盐，其中,Z”为取代或未取代的环上只有一个选自N,O和S的杂原子的杂环烷基.
94.根据方案93所述化合物或其药学上可接受的盐，其中,Z”为取代或未取代的环上只有一个N杂原子的杂环烷基.
95.根据方案94所述化合物或其药学上可接受的盐，其中,Z”为取代或未取代的氮杂环丁烷基,四氢吡咯基,哌啶基,环己亚胺基,
Figure PCTCN2022124111-appb-000175
Figure PCTCN2022124111-appb-000176
Figure PCTCN2022124111-appb-000177
96.根据方案94或95所述化合物或其药学上可接受的盐，其中,环上只有一个N杂原子的氮杂环丁烷基,杂环烷基,四氢吡咯基,哌啶基,环己亚胺基,
Figure PCTCN2022124111-appb-000178
Figure PCTCN2022124111-appb-000179
Figure PCTCN2022124111-appb-000180
的一个或多个取代基选自羟基,氧基,C 1-8烷基,氟、氯,1-5卤素取代的C 1-8烷基,一个或多个羟基取代的C 1-8烷基,一个或多个CN取代的C 1-8烷基,C 1-8烷氧基取代的C 1-8烷基,-NHCOC 1-8烷基取代的C 1-8烷基,C 1-8烷氧基,1-5卤素取代的C 1-8烷氧基,一个或多个羟基取代的C 1-8烷氧基,CN,氨基,和单或双C 1-8烷基取代的氨基.
97.根据方案96所述化合物或其药学上可接受的盐，其中,环上只有一个N杂原子的氮杂环丁烷基,杂环烷基,四氢吡咯基,哌啶基,环己亚胺基,
Figure PCTCN2022124111-appb-000181
Figure PCTCN2022124111-appb-000182
Figure PCTCN2022124111-appb-000183
包含一个或两个羟基取代基.
98.根据方案94-97中任一项所述化合物或其药学上可接受的盐,其中,Z或Z’为取代或未 取代的
Figure PCTCN2022124111-appb-000184
Figure PCTCN2022124111-appb-000185
99.根据方案98所述化合物或其药学上可接受的盐,Z”选自
Figure PCTCN2022124111-appb-000186
Figure PCTCN2022124111-appb-000187
Figure PCTCN2022124111-appb-000188
Figure PCTCN2022124111-appb-000189
100.根据方案74-99中任一项所述化合物或其药学上可接受的盐,其中,Q 2’选自C-H,C-F,C-OH,C-CH 3,C-CF 3,C-Cl,C-CN,C-CH 2CH 3,-C-CH(CH 3) 2,-S-CF 3,和C-OCH 3.
101.根据方案74-99中任一项所述化合物或其药学上可接受的盐,其中,Q 2’是N.
102.根据方案74-101中任一项所述化合物或其药学上可接受的盐,其中,R 4’选自-CF 3,-OH,OMe,OEt,-CH 3,-SCF 3,-OCH(CH 3) 2,-CH(CH 3) 2,-OCF 3,-OCHF 2,环丙基,-NH 2,F和Cl.
103.根据方案74-102中任一项所述化合物或其药学上可接受的盐,其中Q 1’是N.
104.根据方案74-102中任一项所述化合物或其药学上可接受的盐,其中Q 1’选自CH,C-CF 3,C-OH,C-Cl,C-F,C-CH 3,C-OCH 3和C-CN.
105.根据方案74-104中任一项所述化合物或其药学上可接受的盐,其中Q 3’是N.
106.根据方案74-104中任一项所述化合物或其药学上可接受的盐,其中Q 3’选自C-H,C-F,C-Cl,C-OH,C-CN,C-CF 3,C-CH 3和C-OCH 3.
107.一种药物组合物,包含根据方案1-106中任一项所述化合物或其药学上可接受的盐和药学上可接受的赋形剂.
108.如方案1-106中任一项所述化合物或其药学上可接受的盐或者如方案107所述的药物组合在制备抑制KRAS G12D活性的药物中的用途.
109.如方案1-106中任一项所述化合物或其药学上可接受的盐或者如方案107所述的药物组合在制备治疗与KRAS G12D突变相关的疾病或病症的药物中的用途.
110.根据方案109所述的用途,所述与KRAS G12D突变相关的疾病或病症是癌症.
111.根据方案110所述的用途,所述癌症选自影响上皮组织或腹腔器官内膜的恶性肿瘤(carcinoma),鳞癌、胰腺癌、前列腺癌、直肠癌、结肠癌、结直肠癌、非小细胞肺癌、前列 腺癌、小肠癌、肉瘤、白血病、黑色素瘤和淋巴瘤.
112.根据方案108-111中任一项所述的用途,其特征在于,所述化合物或其药学上可接受的盐与其他抗癌剂,放射疗法或手术联用.
113.根据方案112所述的用途,所述其他抗癌剂选自紫杉醇、顺铂、卡铂和奥沙利铂、PARP抑制剂(如尼拉帕尼、奥拉帕利)、抗PD-1抗体、抗PD-L1抗体、抗CTLA-4抗体、mTOR抑制剂、IGF1R抑制剂、HADC抑制剂、EGFR抑制剂，例如抗EGFR抗体(如帕尼单抗)、HIF-1抑制剂和VEGF/VEGFR抑制剂(如索拉非尼、贝伐珠单抗).
本公开的化合物将抑制KRAS，例如KRAS-G12D，并因此可用在多种疾病和病的治疗和预防中。特别地，本公开的化合物可用在治疗或预防其中KRAS的抑制将提供益处的疾病或病的方法中。这些疾病和病中最重要的是癌症和增生性疾病。例如胰腺癌，结直肠癌，非小细胞肺癌等。
另外，本公开的化合物可能与其他抗癌剂,例如免疫抑制剂例如PD-1或其他药物进行联合使用。
定义和使用说明
取代基左侧的破折号(“-”)用于表示取代基的连接点。例如，-CONH 2是通过碳原子连接的。
波浪线
Figure PCTCN2022124111-appb-000190
表示所述位点与其他基团连接的化学键.例如,
Figure PCTCN2022124111-appb-000191
中的波浪线表示通过该苯基基团中的1位碳原子与其他基团相连。
本文中的术语“烷基”是指含有1-14个碳原子的直链或支链烃链。在术语“烷基”前面的带有数字范围下标的C符号代表烷基中的碳原子的个数。例如，C 1-5烷基代表含有1、2、3、4或5个碳原子的烷基。C 1-5烷基的实例包括但不限于甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基和戊基。
本文中的术语“烯基”是指含有至少一个碳碳双键的不饱和支链或直链烃链。该基团可以在双键的顺式或反式构型中。在术语“烯基”前面的带有数字范围下标的C符号代表烯基中的碳原子的个数。例如，C 2-8烯基表示含有2、3、4、5、6、7或8个碳原子的烯基。示例性的烯基包括但不限于，乙烯基；丙烯基，例如丙-1-烯-1-基、丙-1-烯-2-基、丙-2-烯-1-基(烯丙基)、丙-2-烯-2-基、环丙-1-烯-1-基；环丙-2-烯-1-基；丁烯基，例如丁-烯-1-基、丁-1-烯-2-基、2-甲基-丙-1-烯-1-基、丁-2-烯-1-基、丁-2-烯-1-基,丁-2-烯-2-基,丁-1,3-二烯 -1-基,丁-1,3-二烯-2-基,环丁-1-烯-1-基,环丁-1-烯-3-基,环丁-1,3-二烯-1-基等。在某些实施方案中，烯基具有2至10个碳原子，并且在其他实施方案中，具有2至6个碳原子并含有一个碳碳双键。
本文中的术语“炔基”是指含有至少一个碳碳三键的不饱和支链或直链烃链。术语“炔基”前面的带有数字范围下标的C符号代表炔基中的碳原子的个数。例如，C 2-8炔基代表含有2、3、4、5、6、7或8个碳原子的炔基。示例性的炔基包括但不限于乙炔基；丙炔基，如丙-1-炔-2-基、丙-2-炔-2-基；丁炔基，如丁-1-炔-2-基、丁-1-炔-3-基、丁-3-炔-2-基等。在某些实施例中，炔基具有2至10个碳原子，并且在其他实施例中，具有2至6个碳原子并含有一个碳碳三键。
本文中的术语“烷氧基”是指-O-烷基。在术语“烷氧基”前面的带有数字范围下标的C符号代表烷氧基中的碳原子的个数。例如，C 1-5烷氧基表示含有1、2、3、4或5个碳原子的烷氧基。C 1-5烷氧基的实例包括但不限于甲氧基、乙氧基、丙氧基、丁氧基和戊氧基。
术语“芳基”是指6-10元单环芳烃环，例如苯基。芳基还指螺合、稠合或桥连的双环或多环系统，其中至少一个环是芳族的并且不包含选自O、S和N的杂原子作为环原子，剩余的环可以是饱和的、部分饱和的或芳族的，前提是(1)当剩余的环是芳族时，它不包含选自O、S和N的杂原子作为环原子，和(2)当剩余的环不是芳族时，它可以包含或不包含选自O、S和N的杂原子作为环原子。连接点可以是任何环原子。例如，
Figure PCTCN2022124111-appb-000192
是芳基。芳基的实例包括萘基和蒽基.
本文中的术语“环烷基”是指仅具有碳原子作为环原子的饱和或部分不饱和的3-14元的单环烃基或螺合、稠合或桥连的双环或多环烃基。在术语“环烷基”前面的带有数字范围下标的C符号代表环烷基中的碳环原子的个数。例如，C 3-5环烷基代表含有3、4或5个碳环原子的环烷基，即环丙基、环丁基或环戊基。该环可以是饱和的或具有一个或多个双键(即部分不饱和)，但不是完全共轭的。当环烷基是螺合、稠合或桥连的双环或多环时，没有一个环是芳族的。
术语“杂芳基”是指5-14元单芳香环，例如5元或6元单芳香环，其含有一个或多个选自N、O和S的杂原子，例如，1至4个，或在一些实施例中，1至3个，且其余环原子为碳原子。杂芳基还指7-14元的螺合、稠合或桥连的双环或多环系统，其中至少一个环是芳族的，且包含一个或多个选自N、O和S的杂原子作为环原子，例如，1至4个，或在一些实施方案中，1至3个，其余的环(1)可以或可以不含有选自N、O和S的杂原子作为环 原子，以及(2)可以是饱和的、部分饱和的或芳族的。连接点可以是任何环原子。例如，
Figure PCTCN2022124111-appb-000193
是杂芳基。
进一步的示例性的杂芳基包括但不限于吡啶基、吡嗪基、嘧啶基、吡唑基、咪唑啉基、异恶唑基、恶唑基、噻唑基、噻二唑基、四唑基、噻吩基、苯并噻吩基、呋喃基、苯并呋喃基、苯并咪唑啉基、吲哚基、吡啶基、三唑基、喹啉基和5,6,7,8-四氢异喹啉基
术语“杂环烷基”在本文中是指饱和或部分不饱和的5-14元的单环，或稠合、螺合或桥连的双环或多环，其包含一个或多个选自N、O和S的杂原子，例如，1至4个，或在一些实施例中，1至3个，而其余环原子为碳原子。连接点可以是任何环原子。当杂环烷基是螺合、稠合或桥连的双环或多环时，没有一个环是芳族的。
示例性的杂环烷基包括但不限于吡咯烷基、哌啶基、吗啉基、哌嗪基、四氢呋喃基、5,6,7,8-四氢咪唑并[1,2-a]吡嗪基、四氢-2H-吡喃基、8-氧杂-3-氮杂双环[3.2.1]辛基、3-氧杂-9-氮杂螺[5.5]十一烷基、7-氧杂-2-氮杂螺[3.5]壬基和2-氧杂-7-氮杂螺[3.5]壬基、氮杂环庚烷基、1,2,5-三氮杂环庚烷基,6,7,8,9-四氢-1H,5H-[1,2,4]三唑并[1,2-a][1,2,5]三氮杂环庚烷基、二氮杂环庚烷基、3,6-二氮杂双环[3.1.1]庚烷基,3,8-二氮杂双环[3.2.1]辛烷基,1,2,5-氧杂二氮杂环庚烷基。
“卤素”是指F、Cl、Br或I。
“氧基”指＝(O)基团。
术语“取代或未取代”是指后面被该术语限定基团可被可不被取代基取代.取代基可以选自氧基,C 2-8炔基,C 2-8烯基,芳基,杂芳基,杂环烷基,环烷基,C 1-8烷氧基,-O-苯基,-COOR 7,-NR 7R 8,-OCONR 7R 8,-CONR 7R 8,-COR 7,-SR 7,-CN,-NO 2,-OH,-OCF 3,卤素和C 1-8烷基,所述芳基,杂芳基,杂环烷基,环烷基,C 1-8烷氧基和C 1-8烷基可以被1-5卤素,-CN,-OH,-OCONR 7R 8,-NR 7R 8,-NHCOC 1-8烷基,芳基,杂芳基,杂环烷基,C 1-8烷氧基,C 1-8烷基或环烷基取代,R 7和R 8各自独立地选自H,C 1-4烷基和苯甲基,或者R 7和R 8与它们共同连接的N原子一起形成5元或6元杂环烷基.
“药学上可接受的盐”是指具有至少一个能够形成盐的基团的化合物(例如药物)的盐形式，该盐形式不会对受试者造成显著的不良毒理学作用。药学上可接受的盐包括，例如，取决于化合物(例如药物)的性质，通过与无机酸、有机酸或碱反应制备的盐。无机酸可以是盐酸、氢溴酸、碳酸、硫酸、磷酸等；有机酸可以是富马酸、马来酸、琥珀酸、乙酸、 柠檬酸、酒石酸、甲磺酸等。能与酸性药物形成盐的碱可以是含胺化合物或如氢氧化钠、碳酸钠等的无机碱。合适的药学上可接受的盐形式可以发现于，例如：Handbook of Pharmaceutical Salts:Properties,Selection and Use[药用盐手册：性质、选择和使用]，P.H.Stahl和C.G.Wermuth编辑，Weinheim/Zürich：Wiley-VCH出版社/VHCA，2002。
术语“治疗疾病”或“疾病的治疗”是指减缓或阻止疾病的发展，缓解疾病的症状或副作用，和/或导致疾病的消退。该术语还指与未接受治疗的受试者相比，受试者的发病的减少。
“药学上可接受的赋形剂”指通常安全、无毒且在生物学上或其他方面均无不良作用的可用于制备药物组合物的赋形剂，包括兽用可接受的以及人类药用可接受的赋形剂。说明书和权利要求书中使用的“药学上可接受的赋形剂”包括一种和多于一种这样的赋形剂。
如本文所述的术语“受试者”是指动物(例如哺乳动物)或人。
如本文所述的式(I)和式(II)化合物或其药学上可接受的盐包括但不限于它们的溶剂化物、旋光异构体、外消旋物及其其他混合物。在这些情况下，可以通过不对称合成或通过拆分外消旋物或非对映异构体混合物获得单一对映异构体或非对映异构体，即旋光形式。外消旋体或非对映异构体混合物的拆分可通过例如常规方法完成，例如在拆分剂存在下结晶，或使用例如手性高效液相色谱(HPLC)柱的色谱法。当本文所述的化合物以各种互变异构形式存在时，术语“化合物”旨在包括该化合物的所有互变异构形式。此外，如本文所述的式(I)化合物或其药学上可接受的盐还包括其中式(I)中的某些原子被替换为其相应的同位素的式(I)化合物或其药学上可接受的盐，例如其中某些H被D(氘)取代。
本文公开的化合物(术语“本文公开的化合物”包括其药学上可接受的盐)将通过具有相似效用的药物组合物形式的药剂的任何可接受的给药模式，以治疗有效量给药。本文公开的化合物的治疗有效量的范围可为0.01至500mg/kg受试者体重，其可以每天单次或多次给药。对于口服给药，药物组合物可以以含有1.0至1000mg本文公开的化合物，例如1.0、5.0、10、15、20、25、50、75、100、150、200、250、300、350、400、450、500、550、600、650、700、750、800、850、900和1000mg的片剂或胶囊的形式提供本文公开的化合物。
除了口服给药外，本文公开的化合物还能作为药物组合物通过例如透皮、鼻内、栓剂、肌肉内、静脉内或皮下给药的方式来给药。
因此，还提供了包含本文公开的化合物和药学上可接受的赋形剂(excipient)的药物组合物。当制备为单位剂型时，所述药物组合物能够包含1mg至1000mg本文公开的化 合物。
示例性的固体药物赋形剂包括淀粉、纤维素、滑石粉、葡萄糖、乳糖、蔗糖、明胶、麦芽、大米、面粉、碳酸钙、硅胶、硬脂酸镁、硬脂酸钠、单硬脂酸甘油酯、氯化钠、脱脂奶粉等。液体和半固体赋形剂可以选自甘油、丙二醇、水、乙醇和各种油，包括石油、动物、植物或合成来源的那些，例如，花生油、大豆油、矿物油、芝麻油等。优选的液体赋形剂，特别是用于注射溶液的液体赋形剂，包括水、生理盐水、葡萄糖水溶液和乙二醇类。
其他合适的药物赋形剂和它们的制剂描述于E.W.Martin编辑的雷明顿制药科学(Remington's Pharmaceutical Sciences)(马克出版公司(Mack Publishing Company)，第20版，2000)。
本文进一步提供了在有需要的受试者中抑制KRAS G12D活性的方法，所述方法包括向受试者施用治疗有效量的本文所述的化合物。
本文进一步提供了在有需要的受试者中治疗与KRAS G12D突变相关的疾病或病症的方法，所述方法包括向患者施用治疗有效量的本文所述的化合物。
与KRAS G12D突变相关的疾病或病症可以是癌症。癌症包括但不限于癌、鳞癌、胰腺癌、前列腺癌、直肠癌、结肠癌、结直肠癌、非小细胞肺癌、前列腺癌、小肠癌、肉瘤、白血病、黑色素瘤和淋巴瘤。
本文公开的化合物可以与其他抗癌剂联合给药，或与放射疗法或手术联合给药。其他抗癌剂可以是紫杉醇、顺铂、卡铂和奥沙利铂、PARP抑制剂(如尼拉帕尼、奥拉帕利)、抗PD-1抗体、抗PD-L1抗体、抗CTLA-4抗体、mTOR抑制剂、IGF1R抑制剂、HADC抑制剂、EGFR抑制剂，例如抗EGFR抗体(如帕尼单抗)、HIF-1抑制剂、VEGF/VEGFR抑制剂(如索拉非尼、贝伐珠单抗)
具体实施方式
下面通过实施例对本发明进行详细描述，但并不意味着对本发明任何不利限制。
制备本公开的化合物和/或本公开的中间体的示例性方法在通用方案I和实施例中提供。
通用方案I
在合成起始原料后，下述第一步，与一级胺或二级胺进行N-烷基化反应，或Buchwald反应，或Ullmann反应；第二步，与各种醇进行O-烷基化反应，或Buchwald反应，或Ullmann反应；第三步，与各种芳基硼酸(酯)进行Suzuki偶联，或与锌试剂进行Negishi偶联，或与锡试剂进行Stille偶联，后续或有其它反应操作，如胺基或/和酚等基团 的保护与去保护。其通式如下：
Figure PCTCN2022124111-appb-000194
其中：Q1,Q2选自,例如,CH、N、C-CN、C-羟基、C-卤素、C-烷基、C-烷氧基；X选自,例如,氟、氯、溴、碘、三氟甲磺酸酯、对甲苯磺酸酯、甲砜基等；R1选自,例如,氢、卤素或C1-C3烷基；R2选自,例如,氢、-L-杂芳环或-L-杂环化合物；其中L是,例如,独立的C1-C4碳链，含全氢，以及羟基，羟烷基，甲氧基，胺基等取代基；R3选自,例如,芳环、杂芳环或杂环烷烃。
中间体合成
中间体硼酸酯1：2-(3-(甲氧基甲氧基)萘-1-基)-4,4,5,5-四甲基-1,3,2-二氧硼烷
Figure PCTCN2022124111-appb-000195
步骤1：将4-溴邻苯二甲酸-2-醇(9.5g,42.8mmol)和N,N-二异丙基乙胺(11.0g,85.6mmol)溶于95mL二氯甲烷。冰浴下加入溴(甲氧基)甲烷(5.8g,47.1mmol)，室温搅拌反应4小时。加水(100mL)，二氯甲烷萃取(100mL×3)。合并有机相，无水硫酸钠干燥，过滤，滤液减压浓缩，浓缩剩余物经过柱机(乙酸乙酯/石油醚＝0-1％)纯化得到1-溴-3-(甲氧基甲氧基)萘(11.0g,无色油状液体)，收率：92％。 1H NMR(400MHz,DMSO-d 6)δ8.04(d,J＝7.6Hz,1H),7.89(d,J＝7.6Hz,1H),7.67(s,1H),7.59-7.52(m,3H),5.35(s,2H),3.43(s,3H).
步骤2：将1-溴-3-(甲氧基甲氧基)萘(8.0g,30.0mmol)、醋酸钾(7.4g,75mmol)、1,1'-双二苯基膦二茂铁二氯化钯(1.1g,1.5mmol)、双(频哪醇合)二硼(10.7g,42.0mmol)溶于80mL二氧六环。氮气保护下，90℃搅拌反应4小时。加水(200mL)，乙酸乙酯萃取(200mL×3)。有机相合并，无水硫酸钠干燥，过滤，滤液减压浓缩，浓缩剩余物经过柱机(乙酸乙酯/石油醚＝0-2％)纯化得到2-(3-(甲氧基甲氧基)萘-1-基)-4,4,5,5-四甲基-1,3,2-二氧杂环芳烃(7.5g,黄色油状液体)，收率：80％。 1H NMR(400MHz,DMSO-d 6)δ8.58(d,J＝10.4Hz,1H),7.85(d,J＝11.6Hz,1H),7.67-7.43(m,4H),5.35(s,2H),3.45(s,3H),1.41(s,12H).
中间体硼酸酯2：2-(3-(甲氧基甲氧基)-8-乙烯基萘-1-基)-4,4,5,5-四甲基-1,3,2-二氧杂硼 烷
Figure PCTCN2022124111-appb-000196
步骤1：三异丙基((6-(甲氧基甲氧基)-8-(4,4,5,5-四甲基-1,3,2-二氧硼烷-2-基)萘-1-基)乙炔基)硅烷(1.0g，2.02mmol)溶于DMF(10mL)中，加入氟化铯(619mg，4.07mmol)，室温反应2小时。TLC反应完全。加水稀释，乙酸乙酯(10mL x3)萃取，萃取液水洗(10mL)，饱和食盐水洗(10mL)，无水硫酸钠干燥，浓缩，柱层析(石油醚：乙酸乙酯＝15:1)，得2-(8-乙炔基-3-(甲氧基甲氧基)萘-1-基)-4,4,5,5-四甲基-1,3,2-二氧杂硼烷(731mg，黄色固体)收率97.2％。LC-MS：m/z＝339.2[M+H] +。
步骤2：将2-(8-乙炔基-3-(甲氧基甲氧基)萘-1-基)-4,4,5,5-四甲基-1,3,2-二氧杂硼烷(611mg,1.81mmol)溶于甲醇(10mL)中，加入林德拉催化剂(催化量)，喹啉(催化量)。氢气置换3次，室温反应1小时。TLC原料反应完全。过滤，母液浓缩柱层析得2-(3-(甲氧基甲氧基)-8-乙烯基萘-1-基)-4,4,5,5-四甲基-1,3,2-二氧杂硼烷(571mg，无色油状液体)，收率92.3％。 1H NMR(400MHz,DMSO-d6)δ7.78(dd,J＝6.8,2.8Hz,1H),7.56–7.44(m,3H),7.34(dd,J＝17.2,10.8Hz,1H),7.23(dd,J＝12.4,2.8Hz,1H),5.74(dd,J＝17.2,1.2Hz,1H),5.41(dd,J＝10.8,0.8Hz,1H),5.32(s,2H),3.42(s,3H),1.37(s,12H).
中间体硼酸酯3：2-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯并[d]噻唑-6-酚
Figure PCTCN2022124111-appb-000197
步骤1：将4-氨基苯酚(10.0g,91.7mmol)溶于二氯甲烷(100mL)中，加入咪唑(9.3g,137.6mmol)，降温至0℃，滴加三异丙基氯硅烷(30mL,137.6mmol)，滴毕，升至室温反应5小时。TLC检测显示反应完全。反应液垫硅藻土过滤，滤饼二氯甲烷(20mL)洗涤，滤液浓缩。剩余物经硅胶柱层析纯化得到4-((三异丙基硅基)氧基)苯胺(23.0g， 棕色油)，收率95.8％。LC-MS:m/z＝266.2[M+H] +。
步骤2：将04-((三异丙基硅基)氧基)苯胺(1.0g,3.8mmol)溶于二氯甲烷(10mL)，降温至0℃滴加Br 2/DCM(1.5g,9.4mmol/5mL)，滴毕，保持低温反应2小时。TLC检测显示原料反应完全。反应液用饱和亚硫酸钠溶液洗脱色(20mL)，乙酸乙酯(25mL x3)萃取，饱和食盐水(10mL)洗涤，无水硫酸钠干燥，浓缩，剩余物经硅胶柱层析纯化得到2,6-二溴-4-((三异丙基硅氧基)苯胺(340mg,黄色固体)，收率22％。
步骤3：将2,6-二溴-4-((三异丙基硅氧基)苯胺(340mg,0.8mmol)溶于乙酸(5mL)中，加入醋酸酐(520mg,4.0mmol)，加热至90℃反应1小时。TLC检测显示反应完全。反应液降至室温，加饱和碳酸钠溶液调节pH值至中性，乙酸乙酯(25mL x3)萃取，饱和食盐水(10mL)洗涤，无水硫酸钠干燥，浓缩，得到N-(2,6-二溴-4-((三异丙基硅氧基)苯基)乙酰胺(350mg,黄色固体,粗品)。
步骤4：将N-(2,6-二溴-4-((三异丙基硅氧基)苯基)乙酰胺(350mg,粗品)溶于甲苯(5mL)中，加入劳森试剂(152mg,0.37mmol)，加热至110℃反应2小时。TLC检测显示反应完全。反应液降至室温，加水，乙酸乙酯(15mL x3)萃取，饱和食盐水(10mL)洗涤，无水硫酸钠干燥，浓缩，剩余物经硅胶柱层析纯化得到N-(2,6-二溴-4-((三异丙基硅氧基)苯基)乙硫酰胺(200mg，黄色油)，两步收率52％。
步骤5：将N-(2,6-二溴-4-((三异丙基硅氧基)苯基)乙硫酰胺物(200mg,0.41mmol)溶于乙二醇二甲醚(4mL)中，加入碘化亚铜(10mg,0.04mmol)和1,10-菲啰啉(10mg,0.06mmol)，氮气抽充三次，加热至80℃反应1.5小时。TLC检测显示反应完全。反应液冷却至室温，加水(5mL)，乙酸乙酯(15mL x3)萃取，饱和食盐水(10mL)洗涤，无水硫酸钠干燥，浓缩，剩余物经Prep-TLC纯化得到4-溴-2-甲苯并[d]噻唑-6-酚(47mg，黄色固体)。收率46％。LC-MS:m/z＝245.1[M+H] +。
步骤6：将4-溴-2-甲苯并[d]噻唑-6-酚(47mg,0.1mmol)溶于甲苯(3mL)中，加入联硼酸频那醇酯(119mg,0.47mmol)和醋酸钾(46mg,0.47mmol)和[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(15mg,0.01mmol)，氮气抽充三次，加热至130℃反应2小时。TLC检测显示反应完全。反应液冷却至室温，反应液垫硅藻土过滤，滤饼乙酸乙酯洗涤三次，滤液浓缩，剩余物经Prep-TLC纯化得到2-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯并[d]噻唑-6-酚(28mg，黄色固体)，收率50％。
中间体硼酸酯4：2-(4-甲氧基-[1,1'-联苯]-2-基)-4,4,5,5-四甲基-1,3,2-二氧杂硼烷
Figure PCTCN2022124111-appb-000198
步骤1：间溴苯甲醚(3.0g，16.1mmol)溶于氯仿(15mL)，室温下，加入三氟乙酸银(4.0g，18.2mmol)，碘(4.5g，17.6mmol)，氮气保护下，室温反应12小时，将反应液过滤，滤液加水(30mL)，二氯甲烷(30mL x3)萃取，合并的有机相干燥后浓缩，得2-溴-1-碘-4-苯甲醚(4.7g，黄色油状物)，粗品。
步骤2：2-溴-1-碘-4-苯甲醚(2.5g，7.9mmol)溶于乙二醇二甲醚/水(15mL/5mL)，加入苯硼酸(1.0g，8.2mmol)，二(三苯基磷)二氯化钯(400mg，0.57mmol)，碳酸钾(2.2g，15.9mmol)，氮气保护下，100℃反应12小时后降至室温，加水，乙酸乙酯(30mL x3)萃取，合并的有机相干燥后浓缩，所得残余物用硅胶柱色谱法以洗脱剂(石油醚)纯化后得2-溴-4'-甲氧基联苯(1.6g，黄色油状物)收率：76％。 1H NMR(400MHz,CDCl 3)δ7.43-7.33(m,5H),7.25-7.21(m,2H),6.90(dd,J＝8.0,4.0Hz,1H),3.83(s,3H).
步骤3：2-溴-4'-甲氧基联苯(600mg，2.28mmol)溶于N,N-二甲基甲酰胺(10mL)，加入联硼酸频那醇酯(690mg，2.72mmol)，乙酸钾(1.1g，0.06mmol)，[1,1'-双(二苯基膦基)二茂铁]二氯化钯(150mg，0.18mmol)，氮气保护下，130℃反应2小时，降至室温，加水(10mL)，乙酸乙酯(30mL x3)萃取，合并的有机相干燥后浓缩，所得残余物用硅胶柱色谱法以洗脱剂(乙酸乙酯/石油醚＝0-20％)纯化得到2-(4-甲氧基-[1,1'-联苯]-2-基)-4,4,5,5-四甲基-1,3,2-二氧杂硼烷(400mg，无色油状物)，产率：56％。 1H NMR(400MHz,CDCl 3)δ7.68(s,1H),7.38-7.23(m,6H),6.92-6.90(m,1H),3.86(d,J＝4.0Hz,3H),1.22-1.21(m,12H).
中间体硼酸酯5：三异丙基((6-(甲氧基甲氧基)-8-(4,4,5,5-四甲基-1,3,2-二氧硼烷-2-基)萘-1- 基)乙炔基)硅烷
Figure PCTCN2022124111-appb-000199
步骤1：将间萘二酚(16.5g，103.02mmol)溶于1,4-二氧六环(250mL)中，室温下依次加入(2-溴乙炔基)三异丙基硅烷(32.26g，123.57mmol)，醋酸钾(20.24g，206.03mmol)和二氯双(4-甲基异丙基苯基)钌(II)(6.30g，10.29mmol)，氮气保护下，升温至110℃反应16小时，TLC检测原料反应完全。反应液冷却至室温，垫硅藻土过滤，滤饼二氯甲烷(300mL)洗涤，滤液水洗(300mL)，饱和食盐水(100mL)洗，有机相无水硫酸钠干燥后浓缩，浓缩剩余物经过硅胶柱层析(乙酸乙酯/石油醚＝0-1.5％)纯化得到8-((三异丙基硅基)乙炔基)萘-1,3-二醇(22.0g,褐色油状物)，产率：62.7％。
步骤2：将8-((三异丙基硅基)乙炔基)萘-1,3-二醇(22.0g，64.6mmol)溶于二氯甲烷(500mL)中，室温下加入N,N-二异丙基乙胺(25.0g，193.8mmol)，降温至0℃，缓慢滴加氯甲基甲基醚(7.8g，96.9mmol)，保持0℃，继续搅拌1小时，TLC检测原料反应完全。反应液恢复至室温，有机相用水洗(300mL x1)，饱和食盐水洗涤(100mL x1)，有机相无水硫酸钠干燥后浓缩，浓缩剩余物经过硅胶柱层析(乙酸乙酯/石油醚＝0-2％)纯化得到3-(甲氧基甲氧基)-8-(三异丙基硅基)乙炔基)萘-1-醇(16.9g,黄色油状物)，产率：68％。
步骤3：将3-(甲氧基甲氧基)-8-(三异丙基硅基)乙炔基)萘-1-醇(18.0g，46.8mmol)溶于二氯甲烷(500mL)中，室温下加入N,N-二异丙基乙胺(18.1g，140.4mmol)，降温至-40℃，缓慢滴加三氟甲磺酸酐(26.4g，93.6mmol)，保持-40℃，继续搅拌0.5小时，TLC检测原料反应完全。反应液加入饱和碳酸氢钠溶液(100mL)淬灭，再缓慢恢复至室温，有机相用水洗(300mL x1)，饱和食盐水洗涤(100mL x1)，有机相无水硫酸钠干燥后浓缩，浓缩剩余物经过硅胶柱层析(乙酸乙酯/石油醚＝0-2％)纯化得到3-(甲氧基甲氧基)-8-(三异丙基硅基)乙炔基)萘-1-三氟甲烷磺酸酯(15.0g，黄色油状物)，产率：62％。
步骤4：将3-(甲氧基甲氧基)-8-(三异丙基硅基)乙炔基)萘-1-三氟甲烷磺酸酯(15.0g，29.02mmol)，联硼酸频那醇酯(29.5g，116.08mmol)，醋酸钾(11.4g，116.08mmol)和[1,1'- 双(二苯基膦基)二茂铁]二氯化钯(2.12g，2.90mmol)分散于甲苯(180mL)中，置换氮气三次，升温130℃反应16小时，TLC检测原料反应完全。反应液降至室温，垫硅藻土过滤，滤饼乙酸乙酯(300mL)洗涤，滤液水洗(400mL x2)，饱和食盐水洗涤(100mL x1)，有机相无水硫酸钠干燥后浓缩，浓缩剩余物经过硅胶柱层析(乙酸乙酯/石油醚＝1-3％)纯化得到三异丙基((6-(甲氧基甲氧基)-8-(4,4,5,5-四甲基-1,3,2-二氧硼烷-2-基)萘-1-基)乙炔基)硅烷(8.0g，淡黄色固体)，产率：55.7％。 1H NMR(400MHz,CDCl 3)δ7.68(dd,J＝7.2,2.8Hz,2H),7.46(d,J＝2.4Hz,1H),7.37(d,J＝2.8Hz,1H),7.36-7.32(m,1H),5.28(s,2H),3.50(s,3H),1.43(s,12H),1.15(s,21H).
中间体醇1：(四氢-1H-吡咯嗪-7a(5H)-基)甲醇
Figure PCTCN2022124111-appb-000200
步骤1：Boc-L-脯氨酸甲酯(53.0g，231.1mmol)溶于四氢呋喃(400mL)中，氮气保护下，降温至-60℃，缓慢滴加1M的双三甲基硅基胺基锂(347mL，347mmol)，-60℃反应1小时，再缓慢滴加1-溴-3-氯丙烷(181.0g，1.1mol)，升至室温反应两小时，反应液加水淬灭，用乙酸乙酯萃取。合并的有机相干燥后浓缩，所得残余物用硅胶柱色谱法以洗脱剂(乙酸乙酯/石油醚＝1/20～1/5)纯化后得到1-(叔丁基)2-甲基2-(3-氯丙基)吡咯烷-1,2-二羧酸(59.1g，无色油状)。产率：83％。
步骤2：1-(叔丁基)2-甲基2-(3-氯丙基)吡咯烷-1,2-二羧酸(59.1g，193.2mmol)加入三氟乙酸(100mL)，室温反应2小时，反应液浓缩得粗品，加入二氯甲烷溶解，浓缩得2-(3-氯丙基)吡咯烷-2-羧酸甲酯(102g，无色油状)。粗品。
步骤3：2-(3-氯丙基)吡咯烷-2-羧酸甲酯(102g，粗品)溶于甲醇(100mL)中，加入碘化钾(3.7g，16.4mmol)，碳酸钾(79.2g，38.6mmol)，室温反应2小时，体系变浑浊，反应液浓缩得白色固体，用乙酸乙酯(1000mL)溶解，抽滤，滤液浓缩得粗品，粗品加乙酸乙酯溶解，饱和食盐水洗，乙酸乙酯萃取两次，合并有机相，无水硫酸钠干燥，浓缩得四氢-1H-吡咯嗪-7a(5H)-羧酸甲酯(25g，无色油状)。
步骤4：四氢-1H-吡咯嗪-7a(5H)-羧酸甲酯(25g，148mmol)溶于四氢呋喃(300mL)中，0℃下缓慢加入四氢锂铝(16.1g，424.8mmol)，室温反应2小时，TLC显示反应完全。0℃下依次往反应液滴加水(16.1mL)，15％氢氧化钠水溶液(16.1mL)，水(48.3mL)淬灭，垫硅藻土过滤，乙酸乙酯(500mL)洗涤滤饼，滤液浓缩得(四氢-1H-吡咯嗪-7a(5H)- 基)甲醇(20.2g。无色油状物)。三步产率74％。 1H NMR(400MHz,DMSO-d 6)δ3.04(s,2H),2.86-2.81(m,2H),2.50-2.45(m,2H),1.81-1.59(m,6H),1.41-1.34(m,2H)。
中间体醇2：(八氢-1H-喹啉-9a-基)甲醇
Figure PCTCN2022124111-appb-000201
步骤1：将1-(叔丁基)2-甲基哌啶-1,2-二羧酸酯(28.5g，0.117mol)溶于四氢呋喃(200mL)中，氮气保护下，干冰降温至-60℃后滴加LiHMDS溶液(176mL，0.176mol)，保温搅拌1小时，滴加1-溴-3-氯丙烷(100g，0.583mol)，反应液自然升至室温搅拌2小时，TLC检测反应完全。反应液加水淬灭，用乙酸乙酯萃取，饱和盐水洗涤，有机相干燥后浓缩，残余物经柱层析纯化得到混合物1-(叔丁基)2-甲基2-(4-氯丁基)哌啶-1,2-二羧酸盐(56.8g,粗品)。
步骤2：将混合物1-(叔丁基)2-甲基2-(4-氯丁基)哌啶-1,2-二羧酸盐(56.8g，0.117mol)溶于二氯甲烷(20mL)中，冰浴滴加TFA(50mL)，反应液室温搅拌1小时，TLC检测反应完全。反应液浓缩得到2-(4-氯丁基)哌啶-2-羧酸甲酯(27.3g,粗品)。
步骤3：将粗品2-(4-氯丁基)哌啶-2-羧酸甲酯(27.3g，0.117mol)溶于甲醇(100mL)中，加入碳酸钾(48.5g，0.351mol)和碘化钾(1.94g，11.7mmol)，反应液室温搅拌3小时，TLC检测反应完全。反应液过滤，滤液浓缩后经柱层析纯化得到八氢-9aH-喹啉-9a-羧酸甲酯(9.1g,三步收率39.4％)。 1H NMR(400MHz,CD 3Cl)δ3.69(s,3H),3.17-3.05(m,2H),2.63-2.54(m,2H),2.05-2.00(m,2H),1.68-1.56(m,6H),1.44-1.35(m,2H),1.25-1.11(m,2H)。
步骤4：将氢化铝锂(5.3g，138mmol)溶于四氢呋喃(60mL)中，冰浴下滴加八氢-9aH-喹啉-9a-羧酸甲酯的四氢呋喃溶液(9.1g，46.13mmol)，反应液室温搅拌2小时，TLC检测反应完全。反应液冰浴降温后加水(5mL)淬灭，加15％氢氧化钠水溶液(5mL)，反应液室温搅拌0.5小时，过滤除去固体，滤液浓缩后得到(八氢-9aH-喹啉-9a-基)甲醇(4.3g,收率55.1％)。 1H NMR(400MHz,DMSO-d 6)δ4.13(s,1H),3.64(s,2H),2.64-2.57(m,2H),2.38-2.30(m,2H),1.72-1.69(m,2H),1.54-1.38(m,8H),0.98-0.90(m,2H).
中间体醇3：(反式-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲醇
Figure PCTCN2022124111-appb-000202
步骤1：将(S)-5-氧代吡咯烷-2-甲酸乙酯(300.0g,1.91mol)和3-氯-2-氯甲基丙烯(716.0g,5.73mol)加入到四氢呋喃(2.0L)中，降温至-40℃，氮气保护下，缓慢滴加双三甲基硅基胺基锂(3.82L，3.82mol，1N)，滴加完毕，-40℃搅拌反应1.0小时，加入饱和氯化铵水溶液淬灭，加入乙酸乙酯(1.5L)，分层，水相乙酸乙酯(1.5L)萃取，合并有机相，饱和食盐水洗，无水硫酸钠干燥，浓缩，剩余物经硅胶柱层析纯化得到2-(2-(氯甲基)烯丙基)-5-氧代吡咯烷-2-甲酸乙酯(303.0g,黄色固体)，收率65％。LC-MS:m/z＝246.1[M+H] +.
步骤2：氮气保护下，将氢化钠(74.0g,1.85mol，60％)分批加入冷却至0℃的四氢呋喃(18L)中，再滴加2-(2-(氯甲基)烯丙基)-5-氧代吡咯烷-2-甲酸乙酯(303.0g,1.23mol)的四氢呋喃(3L)，滴加完毕升温至回流反应6.0小时，LCMS监测反应完全。反应液浓缩至(4.0L)，加入饱和氯化铵淬灭(0.5L),乙酸乙酯萃取(2.0L x2)，合并有机相，饱和食盐水洗，浓缩得2-亚甲基-5-氧代四氢-1H-吡咯嗪-7a(5H)-甲酸乙酯(140.0g，棕色油)，收率54％。LC-MS:m/z＝210.2[M+H] +.
步骤3：将2-亚甲基-5-氧代四氢-1H-吡咯嗪-7a(5H)-甲酸乙酯(140.0g,0.67mol)溶于丙酮/水(v/v＝2/1；4.0L)，室温加入二水合锇酸钾(1.2g，3.25mmol)水溶液，搅拌反应30分钟，冷却至0℃分批加入高碘酸钾(572.0g,2.67mol)，加料完毕，升至室温搅拌反应1小时，TLC显示反应完全。过滤，滤液加入水(2.5L)和二氯甲烷(2.5L)分层，水相二氯甲烷萃取(2.0L)，合并有机相，饱和食盐水洗，无水硫酸钠干燥，浓缩，剩余物经硅胶柱层析纯化得到得2,5-二氧四氢-1H-吡咯嗪-7a(5H)-甲酸乙酯(68.6g，棕色油)，收率49％。LC-MS:m/z＝212.1[M+H] +.
步骤4：将2,5-二氧四氢-1H-吡咯嗪-7a(5H)-甲酸乙酯(68.6g,0.32mol)溶于甲醇(1.0L)，冰水浴冷却，0℃分批加入硼氢化钠(3.08g,81.19mmol)，加完，0℃反应1.0h。TLC显示原料反应完。加水(20mL)搅拌1.0h，无水硫酸钠干燥，浓缩，剩余物经硅胶柱层析纯化得到(反式)-2-羟基-5-氧代四氢-1H-吡咯嗪-7a(5H)-甲酸乙酯(32.8g，淡黄色固体)，收 率47％。LC-MS:m/z＝214.1[M+H] +.
步骤5：将(2R,7aR)-2-羟基-5-氧代四氢-1H-吡咯嗪-7a(5H)-羧酸乙酯(32.8g,0.15mol)溶于二氯甲烷(800mL)，-60℃，氮气保护下，缓慢滴加二乙胺基三氟化硫(37.2g，0.23mmol)的DCM(200mL)溶液，滴加完毕升温至室温反应过夜，TLC显示反应完全，加入甲醇淬灭反应，浓缩，剩余物经硅胶柱层析纯化得到(反式)-2-氟-5-氧代四氢-1H-吡咯嗪-7A(5H)-甲酸乙酯(18.8g，黄色油)，收率57％。LC-MS:m/z＝216.1[M+H] +.
步骤6：氮气下，将氢化铝锂(9.95g,0.26mol)加入THF(200ml)中，冰水浴冷却至0℃，滴加(反式)-2-氟-5-氧代四氢-1H-吡咯嗪-7A(5H)-甲酸乙酯(18.8g,87.35mmol)的THF(30mL)溶液，滴完，升温至回流反应4.5小时，LCMS监测反应完全，冷却至零度，依次缓慢滴加水(10mL)，NaOH(15％；10mL)，水(30mL)，搅拌30分钟，反应液垫硅藻土过滤，滤液浓缩，剩余物经硅胶柱层析纯化得到((反式)-2-氟四氢-1H-吡咯里嗪7A(5H)-基)甲醇(6.8g，淡黄色油)，收率49％。 1H NMR(400MHz,CDCl 3)δ5.29-5.24(m,0.5H),5.15-5.10(m,0.5H),3.27(s,2H),3.27-3.10(m,1H),3.09-2.97(m,2H),2.96-2.88(m,1H),2.18-2.20(m,2H),1.96-1.82(m,2H),1.82-1.70(m,2H).
中间体母核1：2,4,7-三氯-8-氟吡啶并[4,3-d]嘧啶
Figure PCTCN2022124111-appb-000203
步骤1：将2-氯-3-氟异烟酸(60.0g，0.34mol)和三乙胺(41.5g，0.41mol)溶于甲苯(200mL)和叔丁醇(300mL)中，0℃下滴加叠氮磷酸二苯酯(103.5g，0.38mol)，反应液室温搅拌0.5小时，然后升温至100℃搅拌2小时，将反应液冷却至室温，加水，乙酸乙酯萃取(50mL x3)，合并的有机相干燥后浓缩，所得残余物用硅胶柱色谱法以洗脱剂(乙酸乙酯/石油醚＝0-5％)纯化得到2-氯-3-氟吡啶-4-氨基甲酸叔丁酯(40.7g，淡黄色油状物)，收率：48％。LC-MS m/z(ESI):247.1[M+H +].
步骤2：2-氯-3-氟吡啶-4-氨基甲酸叔丁酯(40.7g，164.9mmol)溶于乙腈(50mL) 中，加入4M盐酸二氧六环溶液(163mL)，反应液室温搅拌过夜，反应液加水稀释，用1N氢氧化钠水溶液调至pH>7，用乙酸乙酯萃取(50mL x3)，合并的有机相干燥后浓缩，所得残余物用硅胶柱色谱法以洗脱剂(乙酸乙酯/石油醚＝0-25％)纯化得到2-氯-3-氟-4-氨基吡啶(20.3g，淡黄色固体)，收率：84％。
步骤3：2-氯-3-氟-4-氨基吡啶(20.3g，138.5mmol)溶于乙腈(100mL)中，加入N-碘代丁二酰亚胺(37.3g，165.8mmol)和对甲苯磺酸(1.2g，6.9mmol)，反应液升温至70℃搅拌12小时。反应液冷却至室温，加水，乙酸乙酯萃取(30mL x3)，合并的有机相干燥后浓缩，所得残余物用硅胶柱色谱法以洗脱剂(乙酸乙酯/石油醚＝0-20％)纯化得到2-氯-3-氟-4-氨基-5-碘吡啶(30.3g，类白色固体)，收率：80％。LC-MS m/z(ESI):272.9[M+H +]
步骤4：2-氯-3-氟-4-氨基-5-碘吡啶(44.0g，161.5mmol)和三乙胺(58.8g，581.1mmol)溶于乙醇(300mL)中，加入双三苯基磷二氯化钯(11.4g，16.24mmol)，在一氧化碳气体下反应液升温至80℃搅拌40小时，将反应液冷却至室温，加水，乙酸乙酯萃取，合并的有机相干燥后浓缩，所得残余物用硅胶柱色谱法以洗脱剂(二氯甲烷/石油醚＝0-100％)纯化得到4-氨基-6-氯-5-氟烟酸乙酯(28.5g，白色固体)。产率：80％。LC-MS m/z(ESI):219.1[M+H +]
步骤5：4-氨基-6-氯-5-氟烟酸乙酯(22.7g，103.8mmol)溶于四氢呋喃(120mL)中，室温下加入三氯乙酰异氰酸酯(25.4g，134.8mmol)，反应液室温搅拌1小时后，将反应液浓缩，残余物经甲基叔丁基醚(200mL)打浆过滤得6-氯-5-氟-4-(3-(2,2,2-三氯乙酰基)脲基)烟酸乙酯(38.4g,白色固体)，收率：90％。
步骤6：6-氯-5-氟-4-(3-(2,2,2-三氯乙酰基)脲基)烟酸乙酯(38.4g，94.35mmol)溶于甲醇(200mL)中，室温滴加7M氨甲醇溶液(40mL)，反应液从浑浊变澄清又有固体析出，反应液室温搅拌1小时。反应液浓缩，残余物经MTBE打浆得到7-氯-8-氟吡啶[4,3-d]嘧啶-2,4-二醇(20.3g,类白色固体)，收率：100％。LC-MS m/z(ESI):216.0[M+H +].
步骤7：7-氯-8-氟吡啶[4,3-d]嘧啶-2,4-二醇(10.0g，39.7mmol)溶于三氯氧磷(120mL)中，0℃下加入N,N-二异丙基乙胺(24mL，144.8mmol)，体系不溶，升至130℃度回流反应5小时，体系溶清，降至室温，浓缩除去大部分三氯氧磷，加乙酸乙酯稀释后，滴加到20℃水中淬灭三氯氧磷，放热，搅拌30分钟，确认三氯氧磷已完全淬灭。分液，有机层中加入饱和碳酸钠水溶液调至pH＞7，水洗一次，饱和食盐水洗涤，无水硫酸钠干燥，过滤，滤液浓缩，得固体加甲基叔丁基醚(100mL)打浆，过滤得2,4,7-三氯-8-氟吡啶[4,3-d]嘧啶(8.8g，淡黄色固体)，收率75％。
中间体母核2：7-溴-2,4-二氯-6,8-二氟噻唑啉
Figure PCTCN2022124111-appb-000204
步骤1：将3-溴-2,4-二氟苯胺(10.0g，48.3mmol)溶解于50mL醋酸中，加入N-碘代丁二酰亚胺(11.4g，50.7mmol)。室温搅拌反应3小时。加水(200mL)，乙酸乙酯萃取(200mL×3)。合并有机相，无水硫酸钠干燥，过滤，滤液减压浓缩，浓缩剩余物经过柱机(乙酸乙酯/石油醚＝0-5％)纯化得到3-溴-2,4-二氟-6-碘苯胺(15.0g，黄色固体)，产率：85％。 1H NMR(400MHz,DMSO-d 6)δ7.57-7.54(m,1H),5.29(s,2H).
步骤2：将3-溴-2,4-二氟-6-碘苯胺(4.0g,12mmol)、1,1'-双二苯基膦二茂铁二氯化钯(440mg,0.6mmol)、三乙胺(3.3mL,24mmol)溶于20mL乙醇。一氧化碳保护下，70℃搅拌反应3小时。减压浓缩，浓缩剩余物经过柱机(乙酸乙酯/石油醚＝0-5％)纯化得到2-氨基-4-溴-3,5-二氟苯甲酸乙酯(2.6g,黄色固体)，产率：76％。 1H NMR(400MHz,DMSO-d 6)δ7.48-7.46(m,1H),6.65(s,2H),4.32-4.27(m,2H),1.32(t,J＝7.2Hz,3H).
步骤3：将2-氨基-4-溴-3,5-二氟苯甲酸乙酯(2.6g,9.3mmol)溶于甲醇/四氢呋喃/水(26mL/10mL/5mL)。加入一水合氢氧化锂(1.2g,28.0mmol)。室温搅拌反应2小时。减压浓缩去有机溶剂，加水(50mL)，用1M盐酸调节pH<6，过滤得到2-氨基-4-溴-3,5-二氟苯甲酸(2.2g,白色固体)，产率：96％。 1H NMR(400MHz,DMSO-d 6)δ7.47-7.44(m,1H).
步骤4：将尿素(12g,200mmol)加热到150℃直至融化，加入2-氨基-4-溴-3,5-二氟苯甲酸(2.5g,10mmol)，190℃搅拌反应2小时。关闭加热，加水(100mL)搅拌五分钟，冷却至室温，过滤得到7-溴-6,8-二氟喹唑啉-2,4-二醇(1.9g,黄色固体)，收率：70％。 1H NMR(400MHz,DMSO_d 6)δ11.21(brs,2H),7.64-7.61(m,1H).
步骤5：将7-溴-6,8-二氟喹唑啉-2,4-二醇(1.9g,6.9mmol)溶于10mL三氯氧磷。冰浴下滴加N,N-二异丙基乙胺(3.4mL,20.7mmol)，100℃搅拌反应16小时。减压浓缩，浓缩剩余物经过柱机(乙酸乙酯/石油醚＝0-2％)纯化得到7-溴-2,4-二氯-6,8-二氟喹唑啉(1.5g,白色固体)，收率：71％。 1H NMR(400MHz,DMSO-d 6)δ7.83-7.80(m,1H).
中间体母核3：7-溴-2,4-二氯-8-氟-6-甲氧基喹唑啉
Figure PCTCN2022124111-appb-000205
步骤1：0℃下将甲醇钠(1.95g,36.1mmol)缓慢地加入到2-溴-1，3-二氟-4-硝基苯(8.6g,36,1mmol)的甲醇(60mL)溶液里。室温下搅拌3个小时后，将反应液倒入水中，用乙酸乙酯萃取。合并的有机相干燥后浓缩，所得残余物用硅胶柱色谱法以洗脱剂(石油醚/乙酸乙酯＝1/10)纯化后，得到2-溴-3-氟-1-甲氧基-4-硝基苯(4.1g,白色固体)，产率：45％。 1H NMR(400MHz,CDCl 3)δ8.14(dd,J＝9.2,8.0Hz,1H),6.80(dd,J＝9.6,1.6Hz,1H),4.04(s,3H).
步骤2：0℃下将锌粉(9.15g,140.8mmol)和氯化铵(9.5g,176.0mmol)加入到2-溴-3-氟-1-甲氧基-4-硝基苯(4.4g,17.6mmol)的甲醇(80mL)和四氢呋喃(80mL)溶液里。在室温下搅拌半个小时后，向反应液中加入醋酸(3.5mL)。在室温下继续搅拌4个小时后，将反应液倒入水中，用乙酸乙酯萃取。合并的有机相干燥后浓缩，所得残余物用硅胶柱色谱法以洗脱剂(石油醚/乙酸乙酯＝1/10)纯化后，得到3-溴-2-氟-4-甲氧基苯胺(4.1g,浅棕色固体)，产率：86％。 1H NMR(400MHz,CDCl 3)δ6.71(t,J＝9.2Hz,1H),6.56(dd,J＝8.8,2.0Hz,1H),3.83(s,3H)；LC-MS:m/z＝220.0,222.0[M+H] + 。
步骤3：55℃下将水合氯醛(4.87g,29.5mmol)，3N盐酸(6mL)和盐酸羟胺(2.96g)的水溶液(7.7mL)依次加入到3-溴-2-氟-4-甲氧基苯胺(2.95g,13.4mmol)，硫酸钠(15.23g,107.28mmol)和水(38mL)的混合物中。在95℃搅拌1.5小时后，冷却到室温，用乙酸乙酯萃取。合并的有机相干燥后浓缩，所得残余物用硅胶柱色谱法以洗脱剂(石油醚/乙酸乙酯＝1/5)纯化后，得到(E)-N-(3-溴-2-氟-4-甲氧基苯基)-2-(异亚硝基)乙酰胺(2.2g,黄色固体)，产率：57％。 1H NMR(400MHz,DMSO-d6)δ12.26(s,1H),9.83(s,1H),7.68(s,1H),7.64(t,J＝9.2Hz,1H),6.98(dd,J＝9.2,1.6Hz,1H),3.88(s,3H)；LC-MS:m/z＝291.2,292.9[M+H] + 。
步骤4：室温下将(E)-N-(3-溴-2-氟-4-甲氧基苯基)-2-(异亚硝基)乙酰胺(1.8g,6.19 mmol)加入到浓硫酸(9.8mL)中。在85℃下搅拌1.5小时后，冷却到室温，再倒入碎冰中。用乙酸乙酯萃取，合并的有机相干燥后浓缩，所得残余物用硅胶柱色谱法以洗脱剂(石油醚/乙酸乙酯＝1/5)纯化后，得到6-溴-7-氟-5-甲氧基吲唑啉-2,3-二酮(595mg,红色固体)，产率：35％。 1H NMR(400MHz,DMSO-d6)δ11.50(s,1H),7.15(s,1H),3.88(s,3H)
步骤5：0℃下将双氧水(30％,1.2mL)加入到6-溴-7-氟-5-甲氧基吲唑啉-2,3-二酮(690mg,2.52mmol)和2N氢氧化钠(12mL)中。室温下搅拌2小时后，用2N盐酸调节至pH 2。用乙酸乙酯萃取，合并的有机相用饱和食盐水洗后干燥后浓缩，所得残余物即2-氨基-4-溴-3-氟-5-甲氧基苯甲酸(600mg,黄色固体)，产率：90％。 1H NMR(400MHz,DMSO-d6)δ8.45(brs,2H),7.18(d,J＝2.0Hz,1H),3.78(s,3H).
步骤6：氮气保护下，2-氨基-4-溴-3-氟-5-甲氧基苯甲酸(445mg,1.69mmol)和尿素(3.0g,50.6mmol)在180℃下搅拌1.5小时。蒸馏水缓慢加入到反应体系中，然后温度逐渐冷却到室温。抽滤，滤饼减压干燥得到7-溴-8-氟-6-甲氧基喹唑啉-2,4-二醇(460mg,黄色固体)，产率：94％。 1H NMR(400MHz,DMSO-d6)δ11.33(brs,2H),7.29(s,1H),3.92(s,3H).
步骤7：室温下向7-溴-8-氟-6-甲氧基喹唑啉-2,4-二醇(460mg,1.59mmol)和甲苯(12mL)的混合物中依次加入二异丙基乙胺(0.81mL,4.77mmol)和三氯氧磷(1.2mL,12.73mmol)。在110℃下搅拌16个小时后，冷却到室温，浓缩，残留物用flash色谱法洗脱剂(石油醚/乙酸乙酯＝8/92)纯化后，得到7-溴-2,4-二氯-8-氟-6-甲氧基喹唑啉(335mg,淡黄色固体)，产率：65％。
中间体母核4：4,7-二氯-8-氟-2-羟基-1,6-萘啶-3-腈
Figure PCTCN2022124111-appb-000206
步骤1：将2-氯-3-氟异烟酸(60.0g，0.34mol)和三乙胺(41.5g，0.41mol)溶于甲苯(200mL)和叔丁醇(300mL)中，0℃下滴加叠氮磷酸二苯酯(103.5g，0.38mol)，加完升至室温搅拌0.5小时，然后升温至100℃搅拌2小时。反应液冷却至室温，加水(50mL)，乙酸乙酯萃取(50mL x3)，合并有机相，无水硫酸钠干燥，浓缩，所得残余物用硅胶柱色谱法以洗脱剂(乙酸乙酯/石油醚＝0-5％)纯化得到2-氯-3-氟吡啶-4-氨基甲酸叔丁酯(40.7g，淡黄色油状 物)，收率48％。LC-MS:m/z＝247.1[M+H] + 。
步骤2：将2-氯-3-氟吡啶-4-氨基甲酸叔丁酯(40.7g，164.9mmol)溶于乙腈(50mL)中，加入盐酸/1,4-二氧六环溶液(163mL，4M)，室温搅拌过夜。反应液加水稀释(50mL)，用氢氧化钠水溶液(1N)调至pH>7，乙酸乙酯萃取(50mL x3)，合并有机相，无水硫酸钠干燥，浓缩，所得残余物用硅胶柱色谱法以洗脱剂(乙酸乙酯/石油醚＝0-25％)纯化得到2-氯-3-氟-4-氨基吡啶(20.3g，淡黄色固体)，收率：84％。
步骤3：将2-氯-3-氟-4-氨基吡啶(20.3g，138.5mmol)溶于乙腈(100mL)中，室温下加入N-碘代丁二酰亚胺(37.3g，165.8mmol)和对甲苯磺酸(1.2g，6.9mmol)，升温至70℃搅拌12小时。反应液冷却至室温，加水(30mL)，乙酸乙酯萃取(30mL x3)，合并有机相，无水硫酸钠干燥，浓缩，所得残余物用硅胶柱色谱法以洗脱剂(乙酸乙酯/石油醚＝0-20％)纯化得到2-氯-3-氟-4-氨基-5-碘吡啶(30.3g，类白色固体)，收率：80％。LC-MS:m/z＝272.9[M+H] + 。
步骤4：将2-氯-3-氟-4-氨基-5-碘吡啶(44.0g，161.5mmol)和三乙胺(58.8g，581.1mmol)溶于乙醇(300mL)中，室温下加入双三苯基磷二氯化钯(11.4g，16.24mmol)，在一氧化碳气体氛围下升温至80℃搅拌40小时。反应液冷却至室温，加水，乙酸乙酯萃取，合并有机相，无水硫酸钠干燥，浓缩，所得残余物用硅胶柱色谱法以洗脱剂(二氯甲烷/石油醚＝0-100％)纯化得到4-氨基-6-氯-5-氟烟酸乙酯(28.5g，白色固体)。产率：80％。LC-MS:m/z＝219.1[M+H] + 。
步骤5：将4-氨基-6-氯-5-氟烟酸乙酯(10.0g,48.89mmol)，氰乙酸(8.3g,97.75mmol)和吡啶(23.2g,293.34mmol)溶于乙酸乙酯(200mL)，加入1-丙基磷酸酐T 3P(43.8g,0.14mol，50％乙酸乙酯溶液)，室温反应1小时，TLC显示约60％原料剩余。补加氰乙酸(4.2g,48.88mmol)，吡啶(11.6g,146.67mmol)和T 3P(21.9g,0.07mol,50％乙酸乙酯溶液)，TLC显示约30％原料剩余。反应液加水(30mL)淬灭，乙酸乙酯(30mL x3)萃取，合并有机相，无水硫酸钠干燥，浓缩，剩余物经硅胶层析柱纯化得6-氯-4-(2-氰基乙酰胺)-5-氟烟酸乙酯(7.2g,收率：55％)和回收4-氨基-6-氯-5-氟烟酸乙酯(2.0g,9.8mmol)。
步骤6：将6-氯-4-(2-氰基乙酰胺)-5-氟烟酸乙酯(7.2g,26.51mmol)溶解在四氢呋喃(100mL)中，冷却至0℃，加入氢化钠(1.6g,39.77mmol,60％)，维持0℃反应30分钟，TLC显示反应完全。反应液加入少量稀盐酸(1N)淬灭，浓缩得粗品7-氯-8-氟-2,4-二羟基-1,6-二氮杂萘-3-甲腈(7.2g,粗品)，直接用于下一步反应。
步骤7：将粗品7-氯-8-氟-2,4-二羟基-1,6-二氮杂萘-3-甲腈(3.5g,14.61mmol)分散在 三氯氧磷(40mL)中，室温下加入N,N-二异丙基乙胺(7.4g,73.03mmol)和N,N-二甲基甲酰胺(0.2g,2.53mmol)，室温反应1小时，TLC显示反应完全。反应液缓慢加入到冰水(30mL)中，乙酸乙酯(30mL x3)萃取，合并有机相，无水硫酸钠干燥，浓缩得4,7-二氯-8-氟-2-羟基-1,6-二氮杂萘-3-甲腈(2.1g,粗品)，直接用于下一步反应。
中间体母核5：7-溴-2,4-二氯-8-氟-6-碘喹唑啉
Figure PCTCN2022124111-appb-000207
步骤1：在55℃下，将水合氯醛(4.87g,29.5mmol)，3N盐酸(12mL)和盐酸羟胺(20.8g，315.8mmol)的水溶液(20mL)依次加入到3-溴-2-氟苯胺(10.0g，52.6mmol)，硫酸钠(149.5g，1.05mol)和水(80mL)的混合物中，后在90℃下搅拌反应3小时。加水(100mL)，二氯甲烷萃取(100mL×3)。合并有机相，无水硫酸钠干燥，过滤，滤液减压浓缩，浓缩剩余物经过柱机(乙酸乙酯/石油醚＝0-20％)纯化得到(E)-N-(3-溴-2-氟苯基)-2-(羟基亚氨基)乙酰胺(12.4g，黄色固体)，产率：91％。 1H NMR(400MHz,DMSO-d 6)δ12.36(s,1H),9.99(s,1H),7.82(t,J＝7.2Hz,1H),7.74(s,1H),7.52(t,J＝6.8Hz,1H),7.17(t,J＝8.4Hz,1H).
步骤2：将(E)-N-(3-溴-2-氟苯基)-2-(羟基亚氨基)乙酰胺(11.0g,42.5mmol)、缓慢加入300mL浓硫酸中。氮气保护下，90℃搅拌反应3小时。反应液冷却倒入冷水中，用二氯甲烷萃取(50mL×4)，合并有机相，无水硫酸钠干燥，过滤，滤液减压浓缩，浓缩剩余物经过柱机(乙酸乙酯/石油醚＝0-20％)纯化得到6-溴-7-氟吲哚啉-2,3-二酮(9.0g,黄色固体)，产率：87％。 1H NMR(400MHz,DMSO-d 6)δ11.74(s,1H),7.39-7.36(m,1H),7.31(d,J＝7.6Hz,1H).LC-MS:m/z＝243.9,245.9[M+H] +
步骤3：将6-溴-7-氟吲哚啉-2,3-二酮(8.5g,35.1mmol)溶于2N氢氧化钠水溶液(100mL)。0℃加入双氧水(20mL)。0℃搅拌反应2小时。反应完成加入1N盐酸调节至pH 2，固体析出，过滤得到2-氨基-4-溴-3-氟苯甲酸(4.6g,白色固体)，产率：57％。 1H NMR(400MHz,DMSO-d 6)δ13.07(brs,1H),7.47(dd,J＝8.8,1.6Hz,1H),6.78(brs,2H),6.77(dd,J＝8.8,6.4Hz,1H).
步骤4：将2-氨基-4-溴-3-氟苯甲酸(4.5g,19.4mmol)，N-碘代丁二酰亚胺(4.5g,29.1mmol)溶于N,N-二甲基甲酰胺(150mL)中。75℃搅拌反应3小时。反应液冷却，用二氯甲烷萃取(50mL×4)，合并有机相，无水硫酸钠干燥，过滤，滤液减压浓缩，浓缩剩余物经过柱机(乙酸乙酯/石油醚＝0-20％)纯化得到2-氨基-4-溴-3-氟-5-碘苯甲酸(4.7g,黄色固体)，产率：68％。 1H NMR(400MHz,DMSO-d 6)δ13.33(brs,1H),7.99(d,J＝1.6Hz,1H),6.94(brs,2H).LC-MS:m/z＝359.7,361.8[M+H] +.
步骤5：将尿素(12g,26.3mmol)加热到150℃直至熔化，加入2-氨基-4-溴-3-氟-5-碘苯甲酸(4.7g,13.1mmol)，190℃搅拌反应2小时。关闭加热，加水(100mL)搅拌五分钟，冷却至室温，过滤得到7-溴-8-氟-6-碘喹唑啉-2,4-二醇(1.9g,黄色固体)，收率：70％。MS m/z(ESI):382.9,384.8[M-H] +.
步骤6：将7-溴-8-氟-6-碘喹唑啉-2,4-二醇(3.2g,8.4mmol)溶于150mL三氯氧磷。冰浴下滴加N,N-二异丙基乙胺(5.5mL,33.4mmol)，100℃搅拌反应16小时。减压浓缩，浓缩剩余物经过柱机(乙酸乙酯/石油醚＝0-5％)纯化得到7-溴-2,4-二氯-8-氟-6-碘喹唑啉(1.5g,白色固体)，收率：40％。 1H NMR(400MHz,DMSO-d 6)δ8.33-8,34(m,1H).LC-MS:m/z＝420.7,422.7[M+H] +.
中间体母核6：1,3,6-三氯-5-氟-7,9-二氢呋喃[3,4-f]喹唑啉1,3,6-三氯-5-氟-7,9-二氢呋喃[3,4-f] 喹唑啉
Figure PCTCN2022124111-appb-000208
步骤1：将2-氯-3-氟苯甲酸(30.0g，172.0mmol)和醋酸钯(2.0g,8.6mmol)溶解于150mL N,N-二甲基甲酰胺中，加入N-碘代丁二酰亚胺(42.6g,189.2mmol)。氮气保护下，100℃搅拌反应24小时。加水(500mL)，乙酸乙酯萃取(300mL×3)。合并有机 相，无水硫酸钠干燥，过滤，滤液减压浓缩，浓缩剩余物经硅胶柱(乙酸乙酯/石油醚/醋酸＝1/1/0.01)纯化得到2-氯-3-氟-6-碘苯甲酸(35.6g，白色固体)，产率：85％。 1H NMR(400MHz,CDCl 3)δ7.74-7.71(m,1H),7.00-6.96(m,1H).
步骤2：将2-氯-3-氟-6-碘苯甲酸(19.0g,63.0mmol)溶于95mL四氢呋喃。氮气保护下，0℃缓慢滴加硼烷四氢呋喃(1M/四氢呋喃,315mL,315mmol)，加热至70℃搅拌反应20小时。反应液降至0℃，缓慢滴加甲醇(100mL)淬灭，加热至50℃搅拌0.5小时，减压浓缩，浓缩剩余物经过柱机(乙酸乙酯/石油醚＝0-18％)纯化得到(2-氯-3-氟-6-碘苯基)甲醇(10.9g,白色固体)，产率：60％。 1H NMR(400MHz,CDCl 3)δ7.77-7.73(m,1H),6.91-6.87(m,1H),4.99(d,J＝6.0Hz,2H),2.16(t,J＝6.4Hz,1H).
步骤3：将(2-氯-3-氟-6-碘苯基)甲醇(5.0g,17.5mmol)、双(三苯基膦)氯化钯(Ⅱ)(614mg,0.88mmol)和三乙胺(7.3mL，52.5mmol)溶于80mL N,N-二甲基甲酰胺。一氧化碳保护下，90℃搅拌反应3小时。减压浓缩掉大部分有机溶剂，加水(100mL)，乙酸乙酯萃取(100mL×3)。合并有机相，无水硫酸钠干燥，过滤，减压浓缩，浓缩剩余物经过柱机(乙酸乙酯/石油醚＝0-10％)纯化得到4-氯-5-氟异苯并呋喃-1(3H)-酮(2.8g,白色固体)，产率：85％。 1H NMR(400MHz,CDCl 3)δ7.83(dd,J＝8.4,4.4Hz,1H),7.35(t,J＝8.4Hz,1H),5.30(s,2H).
步骤4：将4-氯-5-氟异苯并呋喃-1(3H)-酮(7.2g,38.7mmol)溶于30mL浓硫酸，0℃下缓慢加入浓硝酸(8mL)，室温搅拌反应16小时。加冰水(100mL)乙酸乙酯萃取(100mL×3)，有机相合并，无水硫酸钠干燥，过滤，滤液减压浓缩，浓缩剩余物经过柱机(乙酸乙酯/石油醚＝0-11％)纯化得到4-氯-5-氟-6-硝基异苯并呋喃-1(3H)-酮(7.3g,黄色固体)，粗品。 1H NMR(400MHz,DMSO-d 6)δ8.56(d,J＝6.0Hz,1H),5.60(s,2H)
步骤5：将4-氯-5-氟-6-硝基异苯并呋喃-1(3H)-酮(8.1g,35.0mmol)溶于120mL干燥的甲苯。氮气保护-78℃下滴加二异丁基氢化铝(35mL,1.5M/甲苯,52.6mmol)，-78℃搅拌反应2小时。反应液用饱和酒石酸钾钠水溶液(200mL)淬灭，室温搅拌0.5小时，乙酸乙酯萃取(100mL×3)，有机相合并，无水硫酸钠干燥，过滤，滤液减压浓缩，浓缩剩余物经过柱机(乙酸乙酯/石油醚＝0-18％)纯化得到4-氯-5-氟-6-硝基-1,3-二氢异苯并呋喃-1-醇(4.5g,黄色固体)，收率：55％。 1H NMR(400MHz,CDCl 3)δ8.03(d,J＝6.0Hz,1H),6.59(dd,J＝6.4,2.0Hz,1H),5.31(d,J＝15.2Hz,1H),5.12(d,J＝15.2Hz,1H).
步骤6：将4-氯-5-氟-6-硝基-1,3-二氢异苯并呋喃-1-醇(4.7g,20.0mmol)溶于60mL干燥的二氯甲烷。氮气保护0℃下依次加入三氟化硼乙醚(2mL)、三乙基硅烷(10mL)。 室温搅拌反应2小时。饱和碳酸氢钠水溶液(100mL)淬灭，二氯甲烷萃取(100mL×3)。合并有机相，无水硫酸钠干燥，过滤，滤液减压浓缩，浓缩剩余物经过柱机(乙酸乙酯/石油醚＝0-8％)纯化得到4-氯-5-氟-6-硝基-1,3-二氢异苯并呋喃(3.7g,黄色固体)，收率：84％。 1H NMR(400MHz,CDCl 3)δ7.82(d,J＝5.6Hz,1H),5.20(s,4H).
步骤7：将4-氯-5-氟-6-硝基-1,3-二氢异苯并呋喃(3.5g,16.1mmol)溶于醋酸/乙醇(10mL/40mL)。加入铁粉(2.7g,48.3mmol)，氮气保护下，70℃搅拌反应1小时。反应液降至室温，过滤，乙酸乙酯洗涤(500mL)，滤液减压浓缩，浓缩剩余物经过柱机经过柱机(乙酸乙酯/石油醚＝0-17％)纯化得到7-氯-6-氟-1,3-二氢异苯并呋喃-5-胺(2.4g,白色固体)，收率：80％。 1H NMR(400MHz,CDCl 3)δ6.53(d,J＝7.2Hz,1H),5.04(s,4H),3.79(brs,2H).
步骤8：将7-氯-6-氟-1,3-二氢异苯并呋喃-5-胺(2.4g,12.8mmol)溶于24mL醋酸。加入N-碘代丁二酰亚胺(3.0g,13.4mmol)，室温搅拌反应1小时。反应液倒入水(200mL)中，过滤，用水(100mL)洗涤，滤饼干燥得到7-氯-6-氟-4-碘-1,3-二氢异苯并呋喃-5-胺(3.5g,黄色固体)，收率：88％。 1H NMR(400MHz,CDCl 3)δ5.21(s,2H),4.99(s,2H),4.21(brs,2H).
步骤9：将7-氯-6-氟-4-碘-1,3-二氢异苯并呋喃-5-胺(3.5g,11.2mmol)、1,1'-双二苯基膦二茂铁二氯化钯(820mg,1.12mmol)和三乙胺(3.1mL,22.4mmol)溶于70mL甲醇。一氧化碳保护下，70℃搅拌反应16小时。反应液减压浓缩，浓缩剩余物经过柱机(乙酸乙酯/石油醚＝0-10％)纯化得到5-氨基-7-氯-6-氟-1,3-二氢异苯并呋喃-4-羧酸甲酯(1.7g,白色固体)，收率：63％。 1H NMR(400MHz,DMSO-d 6)δ6.78(s,2H),5.18-5.17(m,2H),4.95-4.94(m,2H),3.81(s,3H).
步骤10：将5-氨基-7-氯-6-氟-1,3-二氢异苯并呋喃-4-羧酸甲酯(1.7g,6.9mmol)溶于甲醇/四氢呋喃/水(20mL/20mL/10mL)。加入一水合氢氧化锂(1.2g,27.6mmol)，室温搅拌反应1小时。反应液浓缩掉大部分有机溶剂，加水(100mL)，1M稀盐酸调节pH<5，过滤，水洗涤(100mL)，滤饼干燥得到5-氨基-7-氯-6-氟-1,3-二氢异苯并呋喃-4-羧酸(1.5g,白色固体)，收率：94％。 1H NMR(400MHz,DMSO-d 6)δ7.01(brs,1H),5.19(s,2H),4.94(s,2H).
步骤11：将尿素(10.1g,169mmol)置于反应瓶中加热至150℃，直至尿素全部溶解。5-氨基-7-氯-6-氟-1,3-二氢异苯并呋喃-4-羧酸(1.3g,5.6mmol)加入反应瓶中，加热至190℃，搅拌反应2小时。停止加热，加水(50mL)，搅拌10分钟，过滤，水洗涤(100 mL)，滤饼干燥得到6-氯-5-氟-7,9-二氢呋喃[3,4-f]喹唑啉-1,3-二醇(1.4g,黄色固体)，收率：100％。 1H NMR(400MHz,DMSO-d 6)δ11.32(brs,2H),5.32(s,2H),5.02(s,2H).
步骤12：将6-氯-5-氟-7,9-二氢呋喃[3,4-f]喹唑啉-1,3-二醇(1.4g,5.5mmol)和三氯氧磷(6.7g,44mmol)溶于30mL干燥的甲苯。0℃下缓慢加入N,N-二异丙基乙胺(3.5g,27.5mmol)，加热至110℃，搅拌反应4小时。反应液浓缩，浓缩剩余物经过柱机(乙酸乙酯/石油醚＝0-5％)纯化得到1,3,6-三氯-5-氟-7,9-二氢呋喃[3,4-f]喹唑啉(1.0g,白色固体)，收率：63％。 1H NMR(400MHz,DMSO-d 6)δ5.39(s,2H),5.13(s,2H).
中间体母核7：4,7,9-三氯-5-氟-3H-[1,2,3]三唑并[4,5-f]喹唑啉
Figure PCTCN2022124111-appb-000209
步骤1：将2-氯-1,3-二氟-4-硝基苯(20.0g，100.0mmol)和三乙胺(12.1g,120.0mmol)溶解于200mL四氢呋喃中，0℃下，加入对甲氧基苄胺(15.1g,110.0mmol)。室温搅拌反应过夜。加水(100mL)，乙酸乙酯萃取(100mL×3)。合并有机相，无水硫酸钠干燥，过滤，滤液减压浓缩，浓缩剩余物经硅胶柱(乙酸乙酯/石油醚＝1/24)纯化得到2-氯-3-氟-N-(4-甲氧基苄基)-6-硝基苯胺(29.0g，白色固体)，产率：91％。 1H NMR(400MHz,DMSO-d 6) δ7.93-7.89(m,1H),7.37(t,J＝6.0Hz,1H),7.14-7.11(m,2H),6.92-6.82(m,3H),4.48(d,J＝6.4Hz,2H),3.70(s,3H).
步骤2：将2-氯-3-氟-N-(4-甲氧基苄基)-6-硝基苯胺(29.0g,93.33mmol)溶于20mL二氯甲烷。室温加入三氟乙酸(40mL)，室温搅拌反应2小时。浓缩反应液，加入200mL二氯甲烷，碳酸氢钠水溶液洗，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，浓缩剩余物经硅胶柱(乙酸乙酯/石油醚＝1/24)纯化得到2-氯-3-氟-6-硝基苯胺(17.0g，白色固体)，产率：96％。 1H NMR(400MHz,DMSO-d 6)δ8.15-8.12(m,1H),7.58(s,2H),6.77(t,J＝9.2Hz,1H).LC-MS:m/z＝188.9[M-H] +.
步骤3：将2-氯-3-氟-6-硝基苯胺(17.0g,89.21mmol)和N-溴代琥珀酰亚胺(17.5g，98.13mmol)溶于60mL N,N-二甲基甲酰胺。90℃搅拌反应2小时。减压浓缩掉大部分有机溶剂，浓缩剩余物经过柱机(乙酸乙酯/石油醚＝0-4％)纯化得到4-溴-2-氯-3-氟-6-硝基苯胺(22.0g,黄色固体)，产率：92％。 1H NMR(400MHz,DMSO-d 6)δ8.36(d,J＝7.2Hz,1H),7.69(s,2H).LC-MS:m/z＝268.8[M-H] +.
步骤4：将4-溴-2-氯-3-氟-6-硝基苯胺(19.5g,72.37mmol)和还原铁粉(20.3g,361.8mmol)溶于200mL乙醇和50mL醋酸，80℃下反应1小时，冷却，加入水(200mL)，乙酸乙酯萃取(150mL×3)，有机相合并，无水硫酸钠干燥，过滤，滤液减压浓缩，浓缩剩余物经过柱机(乙酸乙酯/石油醚＝0-25％)纯化得到5-溴-3-氯-4-氟苯-1,2-二胺(16.7g,黄色固体)，产率：96％。 1H NMR(400MHz,DMSO-d 6)δ6.67(d,J＝6.8Hz,1H),5.19(s,2H),4.92(s,2H).LC-MS:m/z＝238.9[M+H] +.
步骤5：将5-溴-3-氯-4-氟苯-1,2-二胺(16.7g,69.73mmol)溶于60mL醋酸和10mL水，0℃下滴加亚硝酸钠(5.8g,83.67mmol)的水溶液(10mL)。室温搅拌反应2小时。抽滤，固体用水淋洗，干燥得到5-溴-7-氯-6-氟-1H-苯并[d][1,2,3]三唑(13.3g,类白色固体)，收率：76％。 1H NMR(400MHz,DMSO-d 6)δ8.43(d,J＝2.8Hz,1H).LC-MS:m/z＝249.9[M+H] +.
步骤6：将5-溴-7-氯-6-氟-1H-苯并[d][1,2,3]三唑(13.3g,53.10mmol)溶于100mL N,N-二甲基甲酰胺。0℃下加入氢化钠(2.5g,63.72mmol)，0℃下搅拌反应15分钟，然后加入(三甲基硅)乙氧基甲基(10.6g,63.72mmol)，升至室温，搅拌反应2小时。加入氯化铵水溶液(100mL)淬灭反应，乙酸乙酯萃取(200mL)，饱和食盐水(50mL×5)洗，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，浓缩剩余物经过柱机(乙酸乙酯/石油醚＝0-9％)纯化得到5-溴-7-氯-6-氟-1-((2-(三甲基硅基)乙氧基)甲基)-1H-苯并[d][1,2,3] 三唑(19.0g,黄色固体)，收率：94％。 1H NMR(400MHz,DMSO-d 6)δ8.62(d,J＝5.2Hz,1H),6.19(s,2H),3.67(t,J＝8.0Hz,2H),0.93(t,J＝8.0Hz,2H),0.00(s,9H).LC-MS:m/z＝380.0[M+H] +.
步骤7：将5-溴-7-氯-6-氟-1-((2-(三甲基硅基)乙氧基)甲基)-1H-苯并[d][1,2,3]三唑(19.0g,49.90mmol)，二苯甲胺(10.8g,59.88mmol)，三二亚苄基丙酮二钯(2.3g,2.49mmol)，4,5-双二苯基膦-9,9-二甲基氧杂蒽(2.8g,4.99mmol)和碳酸铯(48.6g,149.7mmol)溶于1,4-二氧六环(200mL)。，氮气保护下，80℃搅拌反应2小时。过滤，滤液减压浓缩，浓缩剩余物经过柱机(乙酸乙酯/石油醚＝0-9％)纯化得到二苯基甲基苯胺7-氯-N-(二苯基亚甲基)-6-氟-1-((2-(三甲基硅基)乙氧基)甲基)-1H苯并[d][1,2,3]三唑-5-胺(18.2g,黄色油状物)，收率：76％。LC-MS:m/z＝481.0[M+H] +.
步骤8：将二苯基甲基苯胺7-氯-N-(二苯基亚甲基)-6-氟-1-((2-(三甲基硅基)乙氧基)甲基)-1H苯并[d][1,2,3]三唑-5-胺(18.2g,37.90mmol)，醋酸钾(7.4g,75.80mmol)和盐酸羟胺(5.3g,75.80mmol)溶于180mL甲醇。室温搅拌过夜，反应液减压浓缩，浓缩剩余物经过柱机(乙酸乙酯/石油醚＝0-15％)纯化得到7-氯-6-氟-1-((2-(三甲基硅基)乙氧基)甲基)-1H-苯并[d][1,2,3]三唑-5-胺(6.8g,黄色油状物)，收率：57％。 1H NMR(400MHz,DMSO-d 6)δ6.97(d,J＝7.2Hz,1H),5.93(s,4H),3.73(t,J＝7.6Hz,2H),0.92(t,J＝7.6Hz,2H),0.00(s,9H).LC-MS:m/z＝317.1[M+H] +.
步骤9：将7-氯-6-氟-1-((2-(三甲基硅基)乙氧基)甲基)-1H-苯并[d][1,2,3]三唑-5-胺(2.5g,7.39mmol)溶于20mL N,N-二甲基甲酰胺。室温加入N-碘代丁二酰亚胺(1.9g,8.87mmol)，室温搅拌反应3小时。加入乙酸乙酯(200mL)，饱和食盐水洗(50mL×5)，，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，浓缩剩余物经过柱机(乙酸乙酯/石油醚＝0-15％)纯化得到7-氯-6-氟-4-碘-1-((2-(三甲基硅基)乙氧基)甲基)-1H-苯并[d][1,2,3]三唑-5-胺(1.7g,黄色油状物)，收率：51％。 1H NMR(400MHz,DMSO-d 6)δ6.01(s,2H),5.95(s,2H),3.75(t,J＝8.0Hz,2H),0.92(t,J＝8.0Hz,2H),0.00(s,9H).LC-MS:m/z＝464.8[M+Na] +.
步骤10：将7-氯-6-氟-4-碘-1-((2-(三甲基硅基)乙氧基)甲基)-1H-苯并[d][1,2,3]三唑-5-胺(1.7g,3.34mmol)，[1,1'-双(二苯基膦基)二茂铁]二氯化钯(268mg,0.33mmol)，三乙胺(1.0g,10.02mmol)溶于20mL甲醇。一氧化碳气球保护下，75℃搅拌反应6小时，反应液浓缩，浓缩剩余物经过柱机(乙酸乙酯/石油醚＝0-15％)纯化得到5-氨基-7-氯-6-氟-1-((2-(三甲基硅基)乙氧基)甲基)-1H-苯并[d][1,2,3]三唑-4-羧酸甲酯(1.2g,白色固体)， 收率：96％。 1H NMR(400MHz,DMSO-d 6)δ7.81(s,2H),5.94(s,2H),3.93(t,J＝8.0Hz,2H),0.92(t,J＝8.0Hz,2H),0.00(s,9H).LC-MS:m/z＝397.0[M+Na] +.
步骤11：将5-氨基-7-氯-6-氟-1-((2-(三甲基硅基)乙氧基)甲基)-1H-苯并[d][1,2,3]三唑-4-羧酸甲酯(1.5g,4.00mmol)溶于20mL乙腈，室温加入三氯(异氰酸酯)甲烷(829mg,4.40mmol)，室温反应1小时，过滤，得到白色固体，减压干燥。将白色固体溶于20mL氨甲醇溶液，70℃，搅拌反应2小时。冷却至室温，过滤，滤饼干燥得到三氯(异氰酸酯)甲烷4-氯-5-氟-3-((2-(三甲基硅基)乙氧基)甲基)-3H-[1,2,3]三唑基[4,5-f]喹唑啉-7,9-二醇(1.5g,白色固体)，收率：97％。 1H NMR(400MHz,DMSO-d 6)δ7.22(brs,2H),5.97(s,2H),3.75(t,J＝8.0Hz,2H),0.92(t,J＝8.0Hz,2H),0.00(s,9H).LC-MS:m/z＝384.0[M-H] +.
步骤12：将三氯(异氰酸酯)甲烷4-氯-5-氟-3-((2-(三甲基硅基)乙氧基)甲基)-3H-[1,2,3]三唑基[4,5-f]喹唑啉-7,9-二醇(800mg,2.07mmol溶于4mL二氯甲烷。0℃下加入三氟乙酸(4mL)，室温搅拌反应1小时。反应液浓缩得到4-氯-5-氟-3H-[1,2,3]三唑并[4,5-f]喹唑啉-7,9-二醇(410mg,白色固体)，收率：78％。LC-MS:m/z＝255.9[M+H] +.
步骤13：将4-氯-5-氟-3H-[1,2,3]三唑并[4,5-f]喹唑啉-7,9-二醇(410mg,1.6mmol)溶于10mL三氯氧磷。0℃下加入N,N-二异丙基乙胺(619mg,4.8mmol)，加热至100℃搅拌反应过夜。反应液浓缩，浓缩剩余物经过柱机(乙酸乙酯/石油醚＝0-25％)纯化得到4,7,9-三氯-5-氟-3H-[1,2,3]三唑并[4,5-f]喹唑啉(260mg,白色固体)，收率：56％。LC-MS:m/z＝291.9[M+H] +.
步骤14：将4,7,9-三氯-5-氟-3H-[1,2,3]三唑并[4,5-f]喹唑啉(260mg,0.89mmol)、叔丁基3,8-二氮杂环[3.2.1]辛烷-8-羧酸酯(227mg,1.07mmol)和N,N-二异丙基乙胺(230mg,1.78mmol)溶于4mL N,N-二甲基乙胺。0℃搅拌反应1小时。加入乙酸乙酯(30mL)，饱和食盐水洗(10mL×5),有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，浓缩剩余物经过柱机(甲醇/二氯甲烷＝0-5％)纯化得到叔丁基3-(4,7-二氯-5-氟-1H-[1,2,3]三唑并[4,5-f]喹唑啉-9-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(160mg,白色固体)，收率：37％。 1H NMR(400MHz,DMSO-d 6)δ4.24(brs,4H),3.44(brs,2H),1.94-1.82(m,4H),1.46(s,9H).LC-MS:m/z＝468.0[M+H] +.
步骤15：将(六氢-1H-吡咯利嗪-7a-基)甲醇(59mg,0.42mmol)溶于4mL N,N-二甲基甲酰胺。0℃下加入氢化钠(17mg,0.42mmol)，搅拌15分钟。然后加入叔丁基3-(4,7-二氯-5-氟-1H-[1,2,3]三唑并[4,5-f]喹唑啉-9-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯100mg,0.21mmol)，升温至50℃，搅拌反应7小时。加水淬灭，减压浓缩，浓缩剩余物经 过柱机(甲醇/二氯甲烷＝0-9％)纯化得到叔丁基3-(4-氯-5-氟-7-((六氢-1H-吡咯里嗪-7a-基)甲氧基)-1H-[1,2,3]三唑基[4,5-f]喹唑啉-9-基)-3,8-二氮杂环[3.2.1]辛烷-8-羧酸盐(52mg,黄色固体)，收率：42％。 1H NMR(400MHz,DMSO-d 6)δ4.54(brs,2H),4.23(brs,2H),3.55-3.53(m,2H),3.26-3.22(m,4H),3.13-3.11(m,1H),2.23-1.99(m,11H),1.82-1.80(m,3H),1.41(s,9H).LC-MS:m/z＝573.1[M+H] +.
步骤16：将叔丁基3-(4-氯-5-氟-7-((六氢-1H-吡咯里嗪-7a-基)甲氧基)-1H-[1,2,3]三唑基[4,5-f]喹唑啉-9-基)-3,8-二氮杂环[3.2.1]辛烷-8-羧酸盐(50mg,0.087mmol)溶于2mL N,N-二甲基甲酰胺。0℃下加入氢化钠(5mg,0.13mmol)，搅拌15分钟。然后加入(三甲基硅)乙氧基甲基(22mg,0.13mmol)，室温搅拌反应1小时。加水淬灭，减压浓缩，浓缩剩余物经过柱机(甲醇/二氯甲烷＝0-9％)纯化得到叔丁基3-(4-氯-5-氟-7-((六氢-1H-吡咯里嗪-7a-基)甲氧基)-3-((2-(三甲基硅基)乙氧基)甲基)-3H-[1,2,3]三唑基[4,5-f]喹唑啉-9-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸盐(48mg粗品,黄色固体)。LC-MS:m/z＝703.1[M+H] +.
中间体I50：2,3-反式-3,4-顺式-2-甲基吡咯烷-3,4-二醇盐酸盐
Figure PCTCN2022124111-appb-000210
步骤1:[1-甲基丙-2-烯-1-基]亚氨基二碳酸二叔丁酯
将3-丁烯-2-醇(10.0g,138.7mmol)溶于四氢呋喃(300mL)中，室温下加入三苯基膦(40.0g,152.5mmol)和双(叔丁氧羰基)胺(33.1g,152.5mmol)，氮气保护，降温至0℃，滴入偶氮二甲酸二异丙酯(30.8g,152.5mmol)，滴完升至室温搅拌2小时，TLC显示反应完全。将反应液浓缩干，粗品经硅胶柱层析纯化(EA:PE＝1:50)得白色固体标题化合物I50-1(14.6g,收率39％)。 1H NMR(400MHz,CDCl 3)δ6.05-5.97(m,1H),5.18-5.05(m,2H),4.87-4.77(m,1H),1.49(s,18H),1.40(d,J＝6.8Hz,3H).
步骤2:3-烯-2-基氨基甲酸叔丁酯
将化合物I50-1(14.6g,53.80mmol)溶于二氯甲烷(40mL)中，室温下加入三氟乙酸(30mL)，加毕，室温搅拌2小时，TLC显示反应完全。将反应液浓缩干，粗品加入四氢呋 喃(200mL)溶解，加入二碳酸二叔丁酯(14.1g,64.56mmol)，加毕，将无水碳酸钠固体(17.1g,161.4mmol)溶于水(200mL)中加入至上述反应体系中，室温搅拌16小时，TLC显示反应完全。反应液加入水稀释(500mL)，用乙酸乙酯萃取(500mL x2)，合并有机相，饱和食盐水洗(500mL)，无水硫酸钠干燥，有机相浓缩干经硅胶柱层析纯化(EA:PE＝1:30)得无色油状标题化合物I50-2(7.8g,收率85％)。 1H NMR(400MHz,CDCl 3)δ5.90-5.74(m,1H),5.14(d,J＝17.2Hz,1H),5.05(d,J＝10.4Hz,1H),4.45(br,1H),4.22(br,1H),1.45(s,9H),1.21(d,J＝6.8Hz,3H).
步骤3:烯丙基(叔-3-烯-2-基)氨基甲酸叔丁酯
将化合物I50-2(4.0g,23.36mmol)溶于N,N-二甲基甲酰胺(80mL)中，氮气保护下，降温至0℃，加入氢化钠(1.2g,30.37mmol,wt 60％)，加完升至室温搅拌2小时后降温至0℃，加入3-溴丙烯(4.2g,35.04mmol)，加完升温至30℃搅拌16小时，TLC显示原料剩余少量。反应液加入乙酸乙酯稀释(300mL)，水洗(300mL x3)，饱和食盐水洗(300mL)，无水硫酸钠干燥，浓缩，粗品经硅胶柱层析纯化(EA:PE＝1:40)得无色油状标题化合物I50-3(3.9g,收率79％)。 1H NMR(400MHz,CDCl 3)δ5.93-5.70(m,2H),5.19-4.96(m,4H),4.93-4.28(m,1H),3.88-3.84(m,2H),1.46(s,9H),1.23(d,J＝6.8Hz,3H).
步骤4:2-甲基-2,5-二氢-1H-吡咯-1-羧酸叔丁酯
将化合物I50-3(3.9g,18.46mmol)溶于二氯甲烷(800mL)中，室温下加入1,3-双(2,4,6-三甲基苯基)-2-(咪唑烷亚基)(二氯苯亚甲基)(三环己基膦)钌(783mg,0.923mmol)，室温搅拌16小时，TLC显示反应完全。反应液直接浓缩，粗品经硅胶柱层析纯化(EA:PE＝1:15)得无色油状标题化合物I50-4(3.0g,收率89％)。 1H NMR(400MHz,CDCl 3)δ5.77-5.61(m,2H),4.64-4.42(m,1H),4.26-3.97(m,2H),1.48(d,J＝5.2Hz,9H),1.27(dd,J＝18.4,6.0Hz,3H).
步骤5:2,3-反式-3,4-顺式-3,4-二羟基-2-甲基吡咯烷-1-羧酸叔丁酯
将化合物I50-4(1.0g,5.46mmol)溶于丙酮(30mL)和水(10mL)的混合溶液中，室温下加入N-甲基吗啉氧化物(1.9g,16.37mmol)，将二水合锇酸钾(20mg,0.0546mmol)溶于少量水中加入至上述反应液体系中，加毕，升温至35℃搅拌4小时，TLC显示反应完全。反应液加入乙酸乙酯稀释(200mL)，水洗(200mL)，饱和食盐水洗(200mL)，无水硫酸钠干燥，有机相浓缩，粗品经硅胶柱层析(DCM:MeOH＝40:1)纯化得无色油状标题化合物I50-5(840 mg,收率71％)。
步骤6:2,3-反式-3,4-顺式-2-甲基吡咯烷-3,4-二醇盐酸盐
将化合物I50-5(840mg,3.87mmol)溶于二氯甲烷(4mL)中，室温下加入HCl/1,4-二氧六环溶液(4mL,4M)，室温搅拌2小时，TLC显示反应完全。将反应液浓缩干，加入乙酸乙酯(6mL)打浆，抽滤，滤饼用乙酸乙酯洗(1.5mL x2)，滤饼干燥得黄色固体标题化合物I50(560mg,收率94％)。 1H NMR(400MHz,DMSO-d 6)δ9.61(s,1H),9.11(br,1H),4.11-4.03(m,1H),3.63(dd,J＝8.8,4.0Hz,1H),3.41-3.22(m,2H),3.03-2.90(m,1H),1.31(d,J＝6.8Hz,3H).
中间体I51：反式-氮杂环庚烷-4,5-二醇
Figure PCTCN2022124111-appb-000211
步骤1:8-氧杂-4-氮杂双环[5.1.0]辛烷-4-羧酸苄酯
将化合物I51-0(3.71g,16.01mmol)溶于二氯甲烷(150mL)中，室温下分批加入间氯过氧苯甲酸(9.72g,45.16mmol,80％)，加毕，室温搅拌1小时，TLC检测反应完全。反应液加入饱和亚硫酸钠水溶液(100mL)淬灭，搅拌10分钟，分液，有机层再用1N氢氧化钠(50mL)溶液洗涤，无水硫酸钠干燥，浓缩，粗品经硅胶柱层析(EA:PE＝0-10％)纯化得无色油状标题化合物I51-01(2.43g,产率:60％)。
步骤2:反式-4,5-二羟基氮杂环庚烷-1-羧酸苄酯
将化合物I51-1(2.43g,9.84mmol)溶于丙酮(10mL)中，室温下加入1N硫酸(10mL)溶液，再升至50℃下搅拌12小时，TLC检测反应完全。反应液降至室温，往反应液中加入饱和碳酸钠水溶液碱化至PH＝8-9，乙酸乙酯(100mL x2)萃取，合并有机相，无水硫酸钠干燥，浓缩，粗品经硅胶柱层析(EA:PE＝10％-30％)纯化得无色油状标题化合物51-2(710mg,产率:27％)。 1H NMR(400MHz,DMSO-d 6)δ7.38-7.28(m,5H),5.06(s,2H),3.51-3.40(m,4H),3.33-3.26(m,2H),1.93-1.83(m,2H),1.63-1.50(m,2H)；LC-MS:m/z＝266.2[M+H] +。
步骤3:反式-氮杂环庚烷-4,5-二醇
将化合物I51-2(710mg,2.68mmol)溶于甲醇(50mL)中，室温下加入钯碳(100mg，10％)，氢气保护下，升温至35℃搅拌4小时，TLC检测反应完全。将反应液降至室温，垫 硅藻土过滤，滤饼用甲醇(50mL)洗涤，滤液浓缩得无色油状标题化合物I51-3(280mg,产率:80％)。
中间体I52：6-甲基哌啶-3,4-顺式-二醇盐酸盐
Figure PCTCN2022124111-appb-000212
步骤1:4-烯-2-戊基甲磺酸酯:
4-戊-2-醇(5.0g,58.1mmol)溶于二氯甲烷(50mL)中，室温下加入三乙胺(8.80g,87.1mmol)，加毕，冰浴冷却至0℃，滴加甲基磺酰氯(7.98g,69.7mmol)，加完0℃反应0.5小时。TLC监测原料反应完全，反应液加水(50mL)淬灭，二氯甲烷萃取(100mL x2)，合并有机相，水洗(50mL)，无水硫酸钠干燥，浓缩得到标题化合物I52-1(10.4g，粗品)，直接用于下一步。
步骤2:N-烯丙基戊-4-烯-2-胺:
将化合物I52-1(3.93g,粗品)和烯丙基胺(13.6g,0.24mol)溶于N,N-二甲基甲酰胺(30mL)中，反应液升至55℃反应18小时，TLC检测反应完全。反应液加水(60mL)淬灭，乙酸乙酯萃取(150mL x2)，合并有机相，水洗(50mL)，无水硫酸钠干燥，浓缩得到标题化合物I52-2(2.20g,粗品)，直接用于下一步。
步骤3:烯丙基(4-戊-烯-2-基)氨基甲酸叔丁酯:
将化合物I52-2(2.20g,粗品)溶于二氯甲烷(20mL)中，室温下加入三乙胺(2.66g,26.3mmol)和二碳酸二叔丁酯(4.60g,21.1mmol)，加毕，反应液室温搅拌16小时。TLC检测反应完全。反应液浓缩，粗品经硅胶柱层析(PE:EA＝19:1)纯化得到无色液体标题化合物I52-3(2.63g,三步收率66.4％)。
步骤4:2-甲基-3,6-二氢吡啶-1(2H)-羧酸叔丁酯:
将化合物I52-3(2.63g,11.7mmol)溶于二氯甲烷(30mL)中，室温下加入Grubbs二代催化剂(300mg,0.35mmol)，加毕，反应液室温搅拌16小时。TLC检测反应完全。反应液浓缩，粗品经硅胶柱层析(PE:EA＝19:1)纯化得到棕色液体标题化合物I52-4(2.23g,收率96.8％)。 1H NMR(400MHz,CDCl 3)δ5.73-5.61(m,2H),4.48(s,1H),4.16(d,J＝19.6Hz,1H), 3.52(d,J＝19.2Hz,1H),2.44(d,J＝16.0Hz,1H),1.88-1.80(m,1H),1.47(s,9H),1.11(d,J＝6.8Hz,3H).
步骤5:6-甲基哌啶-3,4-顺式-二醇盐酸盐
将化合物I52-4(650mg,3.29mmol)溶于丙酮(30mL)中，室温下依次加入N-甲基吗啉氧化物(1.16g,9.87mmol)，二水合锇酸钾(121mg,0.33mmol)和水(10mL)，加毕，反应液升至30℃搅拌4小时。TLC检测反应完全。反应液加入饱和亚硫酸钠水溶液(20mL)淬灭，乙酸乙酯萃取(50mL x2)，合并有机相，水洗，无水硫酸钠干燥，浓缩得到粗品(210mg)，粗品溶于4M盐酸/1,4-二氧六环溶液(4mL)，室温反应1小时，TLC检测反应完全，反应液浓缩得到无色液体标题化合物I52(120mg,收率21.8％)。
中间体I53：2-甲基吡咯烷-3,4-二醇盐酸盐
Figure PCTCN2022124111-appb-000213
步骤1:2-甲基-6-氧-3-氮杂双环[3.1.0]己烷-3-羧酸叔丁酯
将化合物I50-4(2.0g,10.91mmol)溶于二氯甲烷(30mL)中，室温下加入间氯过氧苯甲酸(4.4g,21.82mmol,wt 85％)，加毕，室温搅拌16小时，补加间氯过氧苯甲酸(4.4g,21.82mmol,wt 85％)，继续室温搅拌2小时，TLC显示反应完全，将反应液加入二氯甲烷稀释(150mL)，用5％的氢氧化钠水溶液洗(150mL x2)，饱和氯化钠洗，无水硫酸钠干燥，浓缩，粗品经硅胶柱层析纯化(EA:PE＝1:2)得无色油状标题化合物I53-1(380mg,收率17％)。 1H NMR(400MHz,CDCl 3)δ4.18-3.99(m,1H),3.88-3.72(m,1H),3.65-3.62(m,1H),3.40(d,J＝2.8Hz,1H),3.29(dd,J＝12.8,4.0Hz,1H),1.48-1.38(m,9H),1.17(dd,J＝11.6,6.4Hz,3H).
步骤2:(3R,4R)-3,4-二羟基-2-甲基吡咯烷-1-羧酸叔丁酯
将化合物I53-1(150mg,0.753mmol)溶于二甲亚砜(2mL)中，室温下加入氢氧化钾水溶液(2mL,wt 10％)，加完升温至95℃搅拌16小时，TLC显示反应完全。将反应液降至室温，加水稀释(100mL)，乙酸乙酯萃取(100mL x2)，合并有机相，无水硫酸钠干燥，浓缩，粗品经硅胶柱层析纯化(DCM:MeOH＝30:1)得白色固体标题化合物53-2(82mg,收率50％)。 1H NMR(400MHz,DMSO-d 6)δ5.06(br,2H),3.85(br,1H),3.62(br,1H),3.54-3.41(m,2H),3.19-3.06(m,1H),1.39(br,9H),1.29-1.17(m,3H).
步骤3:(3R，4R)-2-甲基吡咯烷-3,4-二醇盐酸盐
将化合物I53-2(225mg,1.04mmol)溶于二氯甲烷(2mL)中，室温下加入盐酸/1,4-二氧六环(2mL)，加毕，室温反应2.5小时，TLC检测反应完全。反应液直接浓缩得透明油状标题化合物I53(117mg,产率:73％)
中间体I54：(3aR,6aS)-5-甲基八氢环戊[c]吡咯-5-醇2,2,2-三氟乙酸盐
Figure PCTCN2022124111-appb-000214
步骤1:(3aR,6aS)-5-羟基-5-甲基六氢环戊并[c]吡咯-2(1H)-羧酸叔丁酯
将(3aR,6aS)-5-氧代六氢环戊并[c]吡咯-2(1H)-羧酸叔丁酯(1.0g,4.44mmol)溶于四氢呋喃(15mL)中，0℃下加入甲基溴化镁(1.57g)，加毕，继续室温反应2小时，TLC(DCM/MeOH＝10/1)检测原料基本反应完全。反应液加水(20mL)稀释，乙酸乙酯萃取(20mL x3)，合并有机相，盐水(20mL)洗涤，无水硫酸钠干燥，浓缩得淡黄色油状液体标题化合物I54-1(500mg,产率46.7％)。
步骤2:(3aR,6aS)-5-甲基八氢环戊[c]吡咯-5-醇2,2,2-三氟乙酸盐
将化合物I54-1(500mg,2.07mmol)溶于二氯甲烷(6mL)中，室温下加入TFA(2mL)，加毕，反应液室温搅拌2小时，TLC检测反应完全。反应液浓缩后得黄色油状标题化合物I54-2(200mg,产率37.9％)。
中间体I55：(R)-4-甲基-N-(哌啶-3-基)哌嗪-1-甲酰胺-三氟乙酸盐
Figure PCTCN2022124111-appb-000215
步骤1:3-(氰甲基)-3-羟基哌啶-1-羧酸叔丁酯
将二异丙胺(1.01g,10mmol)溶于四氢呋喃(20mL)中，-60℃下加入正丁基锂(625mg,9.75mmol)，加毕，反应液升温至-20℃继续搅拌0.5小时，反应液降温至-60℃，加入N-叔丁氧羰基-3-哌啶酮(1.0g,5.0mmol)，加毕，反应液升温至25℃反应12小时，TLC检测原料基本反应完全。反应液加水(60mL)稀释，乙酸乙酯萃取(3x 30mL)，合并有机相，饱和氯化铵水溶液(60mL)洗涤，无水硫酸钠干燥，浓缩得棕黄色油状标题化合物I55-1(830 mg,粗品)，直接用于下一步反应。
步骤2:(R)-4-甲基-N-(哌啶-3-基)哌嗪-1-甲酰胺-三氟乙酸盐
将化合物I55-1(300mg,粗品)溶于二氯甲烷(3mL)中，室温下加入TFA(3mL)，加毕，反应液室温搅拌2小时，TLC检测反应完全。反应液加水(20mL)稀释，饱和碳酸钠水溶液(10mL)碱化至pH＝8-9，二氯甲烷萃取(20mL x3)，合并有机相，盐水(20mL)洗涤，无水硫酸钠干燥，浓缩得黄色油状标题化合物I55(390mg,粗品)，直接用于下一步反应。
中间体I56：6-甲基哌啶-3,4-反式-二醇盐酸盐
Figure PCTCN2022124111-appb-000216
步骤1:4-烯-2-戊基甲磺酸酯
将4-戊烯-2-醇(5.0g,58.0mmol)溶于二氯甲烷(50mL)中，室温下加入三乙胺(8.81g,87.0mmol)，冰浴冷却至0℃，滴加甲基磺酰氯(7.98g,69.7mmol)，加完保持冰浴反应0.5小时。TLC监测原料反应完全，反应液加水(50mL)淬灭，二氯甲烷萃取(100mL x2)，合并有机相，水洗(50mL)，无水硫酸钠干燥，浓缩得到黄色液体标题化合物I56-1(9.5g,收率99.6％)。 1H NMR(400MHz,CDCl 3)δ5.82-5.73(m,1H),5.18(d,J＝4.0Hz,1H),5.14(s,1H),4.87-4.79(m,1H),2.99(s,3H),2.51-2.37(m,2H),1.42(d,J＝6.4Hz,3H).
步骤2:N-烯丙基戊-4-烯-2-胺
将化合物I56-1(9.5g,57.8mmol)和烯丙基胺(33.0g,0.58mol)溶于N,N-二甲基甲酰胺(80mL)中，反应液升至55℃反应48小时，TLC检测原料反应完全。反应液冷却至室温，加水(160mL)淬灭，甲基叔丁基醚萃取(200mL x2)，合并有机相，水洗(100mL)，无水硫酸钠干燥，浓缩得到黄色液体标题化合物I56-2(6.37g,收率88.1％)。
步骤3:烯丙基(4-戊-烯-2-基)氨基甲酸叔丁酯
将化合物I56-2(6.37g,50.8mmol)溶于四氢呋喃(100mL)中，室温下加入二碳酸二叔丁酯(11.1g,50.8mmol)和三乙胺(7.72g,76.3mmol)，加毕，反应液室温搅拌16小时，TLC检测原料反应完全。反应液浓缩，粗品经硅胶柱层析(PE:EA＝20:1)纯化得到黄色液体标题化合物I56-3(10.6g,收率92.4％)。
步骤4:2-甲基-3,6-二氢吡啶-1(2H)-羧酸叔丁酯
将化合物I56-3(10.6g,47.0mmol)溶于二氯甲烷(100mL)中，室温下加入Grubbs二代催化剂(400mg,0.47mmol)，加毕，反应液室温反应16小时，TLC检测原料反应完全。反应液浓缩，粗品经硅胶柱层析(PE:EA＝20:1)纯化得到黄色液体标题化合物I56-4(8.2g,收率88.8％)。 1H NMR(400MHz,CDCl 3)δ5.73-5.62(m,2H),4.48(s,1H),4.19-4.13(m,1H),3.54-3.49(m,1H),2.46-2.41(m,1H),1.87-1.81(m,1H),1.46(s,9H),1.10(d,J＝6.8Hz,3H).
步骤5:4-甲基-7-氧杂-3-氮杂双环[4.1.0]庚烷-3-羧酸叔丁酯
将化合物I56-4(2.77g,14.0mmol)溶于二氯甲烷(50mL)中，冰浴冷却至0℃，分批加入间氯过氧苯甲酸(8.55g,42.1mmol)，加完升至室温反应3小时。TLC检测原料反应完全，反应液加入饱和碳酸氢钠水溶液(50mL)淬灭，二氯甲烷萃取(100mL x2)，合并有机相，无水硫酸钠干燥，浓缩，粗品经硅胶柱层析(PE:EA＝4:1)纯化得到黄色固体标题化合物I56-5(700mg,收率23.4％)。
步骤6:(4S,5S)-4,5-二羟基-2-甲基哌啶-1-羧酸叔丁酯
将化合物I56-5(1.32g,6.10mmol)溶于二甲基亚砜(15mL)中，室温下加入10％氢氧化钾水溶液(15mL)，加毕，反应液升至95℃反应2小时，TLC检测原料反应完全。反应液冷却至室温，加水(10mL)淬灭，乙酸乙酯萃取(20mL x2)，合并有机相，无水硫酸钠干燥，浓缩，粗品经硅胶柱层析(PE:EA＝4:1)纯化得到白色固体标题化合物I56-6(150mg,收率19.8％)。 1H NMR(400MHz,DMSO-d 6)δ4.82(d,J＝3.2Hz,1H),4.72(d,J＝4.0Hz,1H),4.07-4.02(m,1H),3.65-3.55(m,2H),3.43(s,1H),3.17-3.13(m,1H),1.93-1.87(m,1H),1.38(s,9H),1.35-1.30(m,1H),1.18(d,J＝6.8Hz,3H).
步骤7:6-甲基哌啶-3,4-反式-二醇盐酸盐
将化合物I56-6(150mg,0.65mmol)溶于4M盐酸/1,4-二氧六环溶液(4mL)中，反应液室温反应0.5小时，TLC检测原料反应完全。反应液浓缩得到白色固体标题化合物56-7(100mg,收率91.8％)。
中间体I57：2-氮杂双环[4.1.0]庚烷-4-醇
Figure PCTCN2022124111-appb-000217
步骤1:3-羟基-3,4-二氢吡啶-1(2H)-羧酸苄酯
将3-羟基吡啶(5.0g,52.58mmol)和碳酸氢钠(3.5g,42.06mmol)溶于甲醇(80mL)中， 干冰降温至-65℃后分批加入硼氢化钠(5.0g,131.44mmol)，低温搅拌15分钟，滴加氯甲酸苄酯(17.9g,105.15mmol)，滴毕，反应液低温搅拌1.5小时，TLC检测原料反应完全。反应液用1N氢氧化钠水溶液淬灭，乙酸乙酯(30mL x3)萃取，合并有机相，盐水(20mL)洗涤，无水硫酸钠干燥，浓缩，粗品经硅胶柱层析纯化(乙酸乙酯/石油醚＝0-30％)得无色油状标题化合物I57-1(3.8g,产率31.0％)。 1H NMR(400MHz,CDCl 3)δ7.39-7.30(m,5H),6.95-6.78(m,1H),5.23-5.12(m,2H),4.92-4.74(m,1H),4.17-4.07(m,1H),3.68-3.55(m,2H),2.40-2.31(m,1H),2.12-2.03(m,1H).
步骤2:顺式-顺式-4-羟基-2-氮杂双环[4.1.0]庚烷-2-羧酸苄酯
将化合物I57-1(1.0g,4.29mmol)溶于1,2-二氯乙烷(15mL)中，室温下依次滴加1M二乙基锌溶液(12.9mL,12.86mmol)和二碘甲烷(4.6g,17.15mmol)，加毕，反应液室温搅拌过夜，TLC检测原料反应完全。反应液用1N稀盐酸(10mL)淬灭，二氯甲烷萃取(20mL x3)，合并有机相，盐水(20mL)洗涤，无水硫酸钠干燥，浓缩，粗品经硅胶柱层析纯化(乙酸乙酯/石油醚＝0-50％)得淡黄色油状标题化合物I57-2(720mg,产率67.9％)。 1H NMR(400MHz,CDCl 3)δ7.41-7.33(m,5H),5.20(s,2H),4.09-3.50(m,3H),2.95-2.85(m,2H),2.00-1.93(m,2H),1.12-1.06(m,1H),0.90-0.84(m,1H).
步骤3:顺式-顺式-2-氮杂双环[4.1.0]庚烷-4-醇
将化合物I57-2(720mg,2.91mmol)溶于甲醇(10mL)中，室温下加入钯碳(7.2mg,10％)，加毕，反应液室温加氢反应1小时，TLC检测原料反应完全。反应液过滤，滤液浓缩得淡黄色固体标题化合物I57(330mg,产率100％)。
中间体I58：3,5-二甲基哌啶-3-醇三氟乙酸盐
Figure PCTCN2022124111-appb-000218
步骤1:(R)-3-甲基-5-氧代哌啶-1-甲酸叔丁酯
将(R)-3-甲基-5-氧代哌啶-1-甲酸叔丁酯(180mg,0.84mmol)溶于无水四氢呋喃(5mL)中，氮气保护下，冰浴冷却至0℃，滴加3M甲基溴化镁/四氢呋喃溶液(0.54mL,1.68mmol)，加完升至室温反应1小时，TLC检测原料反应完全。反应液加入饱和氯化铵水溶液(20mL)淬灭，乙酸乙酯萃取(50mL x2)，合并有机相，无水硫酸钠干燥，浓缩，粗品经硅胶柱层析(PE:EA＝2:1)纯化得到无色液体标题化合物I58-1(110mg,收率57.1％)。
步骤2:3,5-二甲基哌啶-3-醇三氟乙酸盐
将化合物I58-1(110mg,0.48mmol)溶于三氟乙酸(4mL)中，室温下反应2小时，TLC检测原料反应完全。反应液浓缩得到无色液体标题化合物I58(130mg，粗品)，直接用于下一步。
中间体I59：(5S)-3,5-二甲基哌啶-3-醇三氟乙酸盐
Figure PCTCN2022124111-appb-000219
步骤1:(S)-3-甲基-5-氧代哌啶-1-甲酸叔丁酯
将(R)-3-甲基-5-氧代哌啶-1-甲酸叔丁酯(125mg,0.586mmol)溶于无水四氢呋喃(5mL)中，氮气保护，冰浴冷却至0℃，滴加甲基溴化镁/四氢呋喃溶液(0.54mL,1.68mmol)，加完升至室温反应2小时，TLC检测原料反应完全。反应液加入饱和氯化铵水溶液(20mL)淬灭，乙酸乙酯萃取(50mL x2)，合并有机相，饱和食盐水洗(50mL)，无水硫酸钠干燥，浓缩，粗品经硅胶柱层析(PE:EA＝10:1～3:1)纯化得到无色油状标题化合物I59-1(110mg,收率82％)。
步骤2:(5S)-3,5-二甲基哌啶-3-醇三氟乙酸盐
将化合物I59-1(110mg,0.48mmol)溶于三氟乙酸(6mL)中，室温下反应2小时，TLC检测原料反应完全。反应液直接浓缩，得到无色油状标题化合物I59(130mg，粗品)，直接用于下一步。
中间体I60：2-(8-乙基-7-氟萘-1-基)-4,4,5,5-四甲基-1,3,2-二氧杂硼烷
Figure PCTCN2022124111-appb-000220
步骤1:2-(8-乙炔基-7-氟萘-1-基)-4,4,5,5-四甲基-1,3,2-二氧杂硼烷
将((2-氟-8-(4,4,5,5-四甲基-1,3,2-二氧苯甲醛-2-基)萘-1-基)乙炔基)三异丙基硅烷(2.0g,4.42mmol)溶于N,N-二甲基甲酰胺(30mL)中，25℃下加入氟化铯(13.3g,88.4mmol)，加毕，25℃搅拌4小时，TLC显示原料反应完。反应液加入乙酸乙酯稀释(150mL)，水洗(150mL x3)，饱和食盐水洗(100mL)，无水硫酸钠干燥，浓缩，粗品经硅胶柱层析纯化得黄色固体标题化合物I60-1(1.4g,收率100％)。 1H NMR(400MHz,CD 3OD)δ8.02-7.91(m,2H),7.74(d,J＝6.8Hz,1H),7.54-7.46(m,1H),7.37(t,J＝8.8Hz,1H),4.40(s,1H),1.46(s,12H).
步骤2:2-(8-乙基-7-氟萘-1-基)-4,4,5,5-四甲基-1,3,2-二氧杂硼烷
将化合物I60-1(200mg,0.675mmol)溶于无水甲醇(30mL)中，25℃下加入钯碳(50mg,wt 10％)，氢气置换两次，氢气氛围下25℃搅拌4小时，TLC显示原料反应完。反应液垫硅藻土抽滤，滤饼用甲醇洗(20mL x2)，滤液无水硫酸钠干燥，浓缩得黄色固体标题化合物I60(190mg,收率94％)。
中间体I61：7-(8-乙炔基-7-氟萘-1-基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧 基)吡啶并[4,3-d]嘧啶-4-醇
Figure PCTCN2022124111-appb-000221
步骤1:8-氟-7-(7-氟-8-((三异丙基甲硅烷基)乙炔基)萘-1-基)-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-酚
将4-(苄氧基)-7-氯-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶(430mg,0.964mmol)溶于乙醇(12mL)和水(3mL)的混合溶液中，室温下加入碳酸铯(785mg,2.41mmol)，((2-氟-8-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)萘-1-基)乙炔基)三异丙基硅烷(480mg,1.06mmol)和Ruphos Pd G3(161mg,0.193mmol)，加毕，氮气保护下，置于100℃油浴中反应1小时，TLC检测原料反应完全。反应液冷却至室温，加水(50mL)稀释，乙酸乙酯萃取(50mL x2)，合并有机相，饱和食盐水洗(50mL)，无水硫酸钠干燥，浓缩，粗品经硅胶柱层析纯化(DCM:MeOH＝100:1～9:1)得到黄色固体标题化合物I61-1(297mg,收率48％)。LC-MS:m/z＝647.3[M+H] +.
步骤2:7-(8-乙炔基-7-氟萘-1-基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-酚
将化合物I61-1(297mg,0.459mmol)溶于DMF(12mL)中，室温下加入氟化铯(776mg,5.11mmol)，氮气保护下，室温反应5小时，TLC检测原料反应完全。反应液加水(50mL)稀释，乙酸乙酯萃取(50mL x2)，合并有机相，饱和食盐水洗(50mL)，无水硫酸钠干燥，浓缩，粗品经硅胶柱层析纯化(DCM:MeOH＝100:1～9:1)得到黄色固体标题化合物I61(163mg,收率72％)。LC-MS:m/z＝491.2[M+H] +
中间体I62：(S)-7-(8-乙基-7-氟-3-(甲氧基甲氧基)萘-1-基)-8-氟-2-(1-甲基吡咯烷-2-基)甲氧 基)吡啶并[4,3-d]嘧啶-4-醇
Figure PCTCN2022124111-appb-000222
步骤1:(S)-4-(苄氧基)-7-氯-8-氟-2-(1-甲基吡咯烷-2-基)甲氧基)吡啶并[4,3-d]嘧
将化合物4-苄氧基-7-溴-2,6-二氯-8-氟喹唑啉(500mg,1.54mmol)溶于无水1,4-二氧六环(15mL)中，加入N,N-二异丙基乙胺(596mg,4.62mmol)和N-甲基-L-脯氨醇(888mg,7.71mmol)，氮气保护下，升至100℃反应3小时，TLC检测原料反应完全。将反应液降至室温，加水(100mL)稀释，乙酸乙酯萃取(2x 100mL)，合并有机相，饱和食盐水洗(100mL)，无水硫酸钠干燥，浓缩，粗品经硅胶柱层析(甲醇/二氯甲烷＝0-10％)纯化得黄色固体标题化合物I62-1(550mg,产率:88％)。LC-MS:m/z＝403.1[M+H] +.
步骤2:(S)-4-(苄氧基)-7-(8-乙基-7-氟-3-(甲氧基甲氧基)萘-1-基)-8-氟-2-(1-甲基吡咯烷-2-基)甲氧基)吡啶并[4,3-d]嘧啶
将化合物I62-1(300mg,0.745mmol)溶于1,4-二氧六环(5mL)和水(1.5mL)的混合溶液中，加入2-(8-乙基-7-氟-3-(甲氧基甲氧基)萘-1-基)-4,4,5,5-四甲基-1,3,2-二氧苯甲醛(537mg,1.49mmol)，磷酸钾(474mg,2.235mmol)和甲磺酸[正丁基二(1-金刚烷基)膦](2-氨基-1,1'-联苯-2-基)钯(II)(54mg,0.0745mmol)，氮气保护，升温至95℃反应4小时，TLC检测原料反应完全。将反应液降至室温，加水(100mL)稀释，乙酸乙酯萃取(100mL x2)，合并有机相，无水硫酸钠干燥，浓缩得黄色固体标题化合物I62-2(360mg,粗品)，直接用于下一步。LC-MS:m/z＝601.3[M+H] +.
步骤3:(S)-7-(8-乙基-7-氟-3-(甲氧基甲氧基)萘-1-基)-8-氟-2-(1-甲基吡咯烷-2-基)甲氧基)吡啶并[4,3-d]嘧啶-4-醇
将化合物I62-2(360mg,粗品)溶于乙酸乙酯(100mL)中，25℃下加入钯碳(100mg,wt 10％)，氢气氛下，30℃搅拌4小时，TLC显示原料剩余少量。反应液垫硅藻土抽滤，滤饼甲醇洗，滤液无水硫酸钠干燥，浓缩，粗品经硅胶柱层析纯化(DCM:MeOH＝10:1)得黄色固体标题化合物I62(240mg,两步产率63％)。LC-MS:m/z＝511.2[M+H] +.
中间体I63：(S)-7-(8-乙炔基-7-氟萘-1-基)-8-氟-2-(1-甲基吡咯烷-2-基)甲氧基)吡啶并[4,3-d] 嘧啶-4-醇
Figure PCTCN2022124111-appb-000223
步骤1:(S)-8-氟-7-(7-氟-8-((三异丙基硅基)乙炔基)萘-1-基)-2-((1-甲基吡咯烷-2-基)甲氧基)吡啶并[4,3-d]嘧啶-4-醇
将化合物I61-1(200mg,0.496mmol)溶于乙醇(10mL)和水(3mL)的混合溶液中，加入((2-氟-8-(4,4,5,5-四甲基-1,3,2-二氧苯甲醛-2-基)萘-1-基)乙炔基)三异丙基硅烷(337mg,0.745mmol)，碳酸铯(404mg,1.24mmol)和甲磺酸[正丁基二(1-金刚烷基)膦](2-氨基-1,1'-联苯-2-基)钯(II)(62mg,0.0745mmol)，氮气保护下，升温至100℃反应3小时，TLC检测原料反应完全。将反应液降至室温，加水(100mL)稀释，乙酸乙酯萃取(100mL x2)，合并有机相，饱和食盐水洗(100mL)，无水硫酸钠干燥，浓缩经硅胶柱层析纯化得黄色固体标题化合物I63-1(155mg,收率52％)。LC-MS:m/z＝603.3[M+H] +.
步骤2:(S)-7-(8-乙炔基-7-氟萘-1-基)-8-氟-2-(1-甲基吡咯烷-2-基)甲氧基)吡啶并[4,3-d]嘧啶-4-醇
将化合物I63-1(155mg,0.347mmol)溶于N,N-二甲基甲酰胺(50mL)中，25℃下加入氟化铯(1.05g,6.94mmol)，加毕，继续25℃搅拌4小时，TLC显示原料反应完。反应液加入乙酸乙酯稀释(100mL)，水洗(100mL x3)，饱和食盐水洗(100mL)，无水硫酸钠干燥，有机相浓缩干得黄色固体标题化合物I63(55mg,粗品)，直接用于下一步。
中间体I64：1-(7-溴-6-氯-8-氟-2-氟四氢-1H-吡咯嗪-7a-基)甲氧基喹唑啉-4-基哌啶
Figure PCTCN2022124111-appb-000224
步骤1:7-溴-2,4,6-三氯-8-氟喹唑啉
将4-苄氧基-7-溴-2,6-二氯-8-氟喹唑啉(1.4g,3.48mmol)溶于三氯氧磷(15mL)中，加入N,N-二异丙基乙胺(899mg,6.96mmol)，加完升至125℃反应2小时，TLC检测原料反应完全。反应液冷却至室温，浓缩除去大部分溶剂，粗品加水(40mL)稀释，乙酸乙酯萃取(50mL x2)，合并有机相，水洗(50mL)，无水硫酸钠干燥，浓缩得到白色固体标题化合物I64-1(1.1g，粗品)，直接用于下一步。
步骤2:7-溴-2,6-二氯-8-氟喹唑啉-4-基哌啶
将化合物I64-1(1.1g,粗品)溶于二氯甲烷(20mL)中，冰浴冷却至0℃，加入4-羟基哌啶(510mg,5.0mmol)和N,N-二异丙基乙胺(1.29g,10.0mmol)，加完0℃反应1小时，TLC检测原料反应完全。反应液加水(50mL)淬灭，二氯甲烷萃取(60mL x2)，合并有机相，1M盐酸水溶液洗涤(50mL)，无水硫酸钠干燥，浓缩，粗品经硅胶柱层析(PE:EA＝4:1)纯化得到黄色固体标题化合物I64-2(950mg,两步收率69.8％)。
步骤3:1-(7-溴-6-氯-8-氟-2-氟四氢-1H-吡咯嗪-7a-基)甲氧基喹唑啉-4-基哌啶
将化合物I64-2(100mg,0.25mmol)和((2R,7AS)-2-氟六氢-1H-吡咯嗪-7A-基)甲醇(79mg,0.50mmol)溶于N,N-二甲基甲酰胺(2mL)与四氢呋喃(2mL)中，室温下加入碳酸铯(244mg,0.75mmol)和三乙烯二胺(28mg,0.25mmol)，加完25℃反应16小时，TLC检测原料反应完全。反应液加入1M盐酸水溶液(30mL)淬灭，乙酸乙酯萃取(50mL x2)，合并有机相，水相用饱和碳酸钠水溶液调至PH＝8，乙酸乙酯萃取(50mL x2)，合并有机相，无水硫酸钠干燥，浓缩，粗品经pre-TLC制备(EA＝100％)得到白色固体标题化合物I64(40mg,收率30.9％)。LC-MS:m/z＝517.1[M+H] +
中间体I65：2-(7,8-二氟萘-1-基)-4,4,5,5-四甲基-1,3,2-二氧硼烷
Figure PCTCN2022124111-appb-000225
步骤1:5,6-二氟-1,4-二氢-1,4-环氧萘
将2,3,4-三氟溴苯(10.0g,47.4mmol)和呋喃(6.45g,94.8mmol)溶于甲苯(130mL)中，氮气氛围下降温至-15℃，缓慢加入正丁基锂(3.64g,56.9mmol)，加毕，保持低温反应0.5小时，升至室温(23℃)反应18小时，TLC检测反应完全(PE/EA＝10/1,R f＝0.6)。反应液加水(100mL)稀释，乙酸乙酯(50mL)萃取，收集有机相，饱和食盐水(100mL)洗涤，无水硫酸钠干燥，浓缩，粗品经硅胶柱层析纯化(PE/EA＝30/1～20/1)得淡黄色油状标题化合物I65-1(2.02g,产率：23.6％)。 1H NMR(400MHz,CDCl 3)δ7.08-7.03(m,2H),6.93-6.90(m,1H),6.78-6.72(m,1H),5.97(s,1H),5.71(s,1H).
步骤2:7,8-二氟萘-1-醇
将化合物I65-1(2.0g,11.1mmol)溶于乙醇(30mL)中，加入盐酸(13mL,155.4
mmol)，加毕，升温至80℃反应3小时，TLC检测反应完全(PE/EA＝10/1,R f＝0.5)，反应液加入饱和碳酸氢钠溶液调节至pH约为8，加入乙酸乙酯(50mL x2)萃取，合并有机相，饱和 食盐水(100mL)洗涤，无水硫酸钠干燥，浓缩，粗品经硅胶柱层析纯化(PE/EA＝40/1～20/1)得白色固体标题化合物I65-2(1.80g,产率：90.1％)。 1H NMR(400MHz,CDCl 3)δ761-7.57(m,1H),7.41-7.27(m,3H),7.04-6.96(m,1H),6.63(d,J＝22.0Hz,1H).
步骤3:7,8-二氟萘-1-基三氟甲基磺酸酯
将化合物I65-2(1.5g,8.3mmol)和N,N-二异丙基乙胺(5.4g,41.5mmol)溶于二氯乙烷(15mL)中，室温搅拌10分钟，氮气氛围下降至-40℃，缓慢滴加三氟甲磺酸酐(3.0g,10.8mmol)，加毕，保持低温反应1小时，TLC检测反应完全(PE/EA＝0/1,R f＝0.4)，反应液加水(500mL)稀释，乙酸乙酯(100mL)萃取，收集有机相，饱和食盐水(100mL)洗涤，无水硫酸钠干燥，浓缩，粗品经硅胶柱层析纯化(PE/EA＝100/1～60/1)得淡黄色油状标题化合物I65-3(2.22g,产率：85.7％)。 1H NMR(400MHz,CDCl 3)δ7.89-7.84(m,1H),7.73-7.65(m,1H),7.52(s,3H)；LC-MS:m/z＝311.0[M-H] -
步骤4:2-(7,8-二氟萘-1-基)-4,4,5,5-四甲基-1,3,2-二氧硼烷
将化合物I65-3(2.2g,7.0mmol)、联硼酸频那醇酯(4.4g,17.5mmol)、Pd(dppf)Cl 2(573mg,0.7mmol)和乙酸钾(2.1g,21.0mmol)溶于1,4-二氧六环(15mL)中，氮气氛围下升温至100℃反应18小时，TLC检测反应完全(PE/EA＝10/1,R f＝0.6)。反应液加水(100mL)稀释，乙酸乙酯(100mL)萃取，收集有机相，饱和食盐水(100mL)洗涤，无水硫酸钠干燥，浓缩，粗品经硅胶柱层析纯化(PE/EA＝30/1～20/1)得淡黄色固体标题化合物I65(1.84g,产率：90.0％)。 1H NMR(400MHz,CDCl 3)δ7.84(d,J＝8.0Hz,1H),7.71(d,J＝6.8Hz,1H),7.65-7.55(m,1H),7.51-7.42(m,1H),7.36-7.26(m,1H),1.45(s,12H).
中间体I66：7-(7,8-二氟萘-1-基)-8-氟-2-(2R,7aS)-2-氟四氢-1H-吡咯啉-7a(5H)-基)甲氧基)吡啶 并[4,3-d]嘧啶-4-醇
Figure PCTCN2022124111-appb-000226
步骤5:4-(苄基氧基)-7-(7,8-二氟萘-1-基)-8-氟-2-((2R，7aS)-2-氟四氢-1H-吡咯啉-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶
将化合物I66-0(240mg,0.54mmol)，化合物65(235mg,0.81mmol)，磷酸钾(344mg,1.62mmol)和cataCXium-A-Pd-G3(36mg,0.05mmol)溶于四氢呋喃(4mL)中，加水(1mL)，氮气氛围下升温至65℃反应2小时，TLC检测反应完全(PE/EA＝3/1,R f＝0.1)。反应液加水(100mL)稀释，乙酸乙酯(50mL)萃取，收集有机相，用饱和食盐水(100mL)洗涤，无水硫酸钠干 燥，浓缩，粗品经硅胶柱层析纯化(DCM/MeOH＝50/1～20/1)得白色固体标题化合物I66-1(226mg,产率：72.8％)。LC-MS:m/z＝575.2[M+H] +
步骤6:7-(7,8-二氟萘-1-基)-8-氟-2-(2R,7aS)-2-氟四氢-1H-吡咯啉-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-醇
将化合物I66-1(150mg,0.26mmol)溶于乙酸乙酯(100mL)中，加入Pd/C(30mg,10％)，加毕，升温至30℃搅拌6小时，TLC检测反应完全，反应液减压真空浓缩得白色固体标题化合物I66(120mg,粗品)，直接用于下一步。LC-MS:m/z＝485.2[M+H] +
中间体I67：7-(3-氯-2-环丙基-5-(甲氧基甲氧基)苯基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯啉 -7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-醇
Figure PCTCN2022124111-appb-000227
步骤1:4-(苄氧基)-7-(3-氯-2-环丙基-5-(甲氧基甲氧基)苯基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H))-基)甲氧基)吡啶并[4,3-d]嘧啶
将4-(苄氧基)-7-氯-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶(154mg,0.345mmol)溶于1,4-二氧六环(12mL)和水(3mL)的混合液中，室温下加入化合物ALM-0011-6(175mg,0.517mmol)，磷酸钾(224mg，1.06mmol)和CataCxium A Pd G3(71.2mg，0.098mmol)，氮气保护下，反应液升温至100℃反应1小时，LC-MS显示反应完全。反应液冷却至室温，加水(30mL)淬灭，乙酸乙酯萃取(50mL x2)，合并有机相，饱和食盐水洗涤(50mL)，无水硫酸钠干燥，浓缩，粗品经硅胶柱层析纯化(二氯甲烷/甲醇＝100/1-50/1)得到黄色固体标题化合物I67-1(91mg,收率42％)。LC-MS:m/z＝623.2[M+H] +。
步骤2:7-(3-氯-2-环丙基-5-(甲氧基甲氧基)苯基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯啉-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-醇
将化合物I67-1(126mg,0.202mmol)溶于乙酸乙酯(20mL)中，室温下加入10％湿钯碳(41mg)，加毕，升温至30℃反应5小时，TLC检测反应完全。反应液直接用硅藻土过滤，乙酸乙酯(100mL)洗涤滤饼，浓缩滤液得标题化合物I67(90mg,收率83％)。
中间体I68：(3-氰基-7-氟-4-(8-氟-2-((2R,7aS)-2-氟六氢-1H-吡咯啉-7a-基)甲氧基)-4-羟基吡啶 并[4,3-d]嘧啶-7-基)苯并[b]噻吩-2-基)氨基甲酸叔丁酯
Figure PCTCN2022124111-appb-000228
步骤1:(4-(4-(苄基氧基)-8-氟-2-((2R,7aS)-2-氟六氢-1H-吡咯啉-7a-基)甲氧基)吡啶并[4,3-d]嘧啶-7-基)-3-氰基-7-氟苯并[b]噻吩-2-基)氨基甲酸叔丁酯
将4-(苄氧基)-7-氯-8-氟-2-((2R,7aS)-2-氟六氢-1H-吡咯啉-7a-基)甲氧基)吡啶并[4,3-d]嘧啶(1.1g,2.46mmol)和叔丁基(3-氰基-4-(5,5-二甲基-1,3,2-二氧杂萘-2-基)-7-氟苯并[b]噻吩-2-基)氨基甲酸酯(1.5g,3.69mmol)溶于甲苯(20mL)中，室温下依次加入Ruphos Pd G 3(179mg,0.25mmol)和碳酸铯(2.4g,7.38mmol)，加毕，反应液在氮气保护下升温至100℃搅拌2小时，TLC检测原料反应完全。反应液冷却至室温，加水(50mL)稀释，乙酸乙酯萃取(30mL x3)，合并有机相，盐水(30mL)洗涤，无水硫酸钠干燥，浓缩，粗品经硅胶柱层析纯化(甲醇/二氯甲烷＝0-5％)得淡黄色油状标题化合物I68-1(850mg,产率49.2％)。LC-MS:m/z＝703.2[M+H] +.
步骤2:(3-氰基-7-氟-4-(8-氟-2-((2R,7aS)-2-氟六氢-1H-吡咯啉-7a-基)甲氧基)-4-羟基吡啶并[4,3-d]嘧啶-7-基)苯并[b]噻吩-2-基)氨基甲酸叔丁酯
将化合物I68-1(850mg,1.21mmol)溶于1,4-二氧六环(5mL)中，室温下加入4M氯化氢1,4-二氧六环溶液(10mL)，加毕，反应液室温搅拌3小时，TLC检测原料基本反应完全。反应液加水(20mL)稀释，饱和碳酸钠水溶液(10mL)碱化至pH＝8-9，二氯甲烷萃取(20mL x3)，合并有机相，盐水(20mL)洗涤，无水硫酸钠干燥，浓缩得淡黄色固体标题化合物I68(260mg,产率35.1％)。LC-MS:m/z＝613.1[M+H] +.
中间体I69：7-(8-乙基萘-1-基)-8-氟-2-((2R,7aS)-2-氟四氢-1H-吡咯啉-7a(5H)-基)甲氧基)吡啶 并[4,3-d]嘧啶-4-醇
Figure PCTCN2022124111-appb-000229
步骤1:4-(苄基氧基)-7-(8-乙基萘-1-基)-8-氟-2-((2R,7aS)-2-氟四氢-1H-吡咯啉-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶
将化合物I66-0(400mg,0.897mmol)溶于1,4-二氧六环(15mL)和水(4mL)的混合溶液中，加入2-(8-乙基萘-1-基)-4,4,5,5-四甲基-1,3,2-二氧苯甲醛(506mg,1.794mmol)，磷酸钾(570mg,2.691mmol)和甲磺酸[正丁基二(1-金刚烷基)膦](2-氨基-1,1'-联苯-2-基)钯(II)(65mg, 0.0897mmol)，氮气保护下，升温至90℃反应4小时，TLC检测原料反应完全。将反应液降至室温，加水(100mL)稀释，乙酸乙酯萃取(200mL x2)，合并有机相，无水硫酸钠干燥，浓缩得黄色固体标题化合物I69-1(620mg,粗品)，直接用于下一步。LC-MS:m/z＝567.3[M+H] +.
步骤2:7-(8-乙基萘-1-基)-8-氟-2-((2R,7aS)-2-氟四氢-1H-吡咯啉-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-醇
将化合物I69-2(620mg,1.094mmol)溶于1,4-二氧六环(8mL)中，25℃下加入盐酸/1,4-二氧六环(2mL,8mmol,4M)，加毕，搅拌30分钟，TLC显示反应完全。反应液加入乙酸乙酯(100mL)稀释，饱和碳酸钠溶液调pH至9-10，分液，水相加入乙酸乙酯萃取(100mL)，合并有机相，饱和食盐水(100mL)洗涤，无水硫酸钠干燥，有机相浓缩干经硅胶柱层析纯化(DCM:MeOH＝10:1)得黄色固体标题化合物I69(227mg,两步产率53％)。LC-MS:m/z＝477.2[M+H] +.
中间体I70：8-氟-2-((2R,7aS)-2-氟六氢-1H-吡咯里嗪-7a-基)甲氧基)-7-(5-甲基-1-(四氢-2H-吡 喃-2-基)-1H-吲唑-4-基)吡啶并[4,3-d]嘧啶-4-醇
Figure PCTCN2022124111-appb-000230
步骤1:4-溴-5-甲基-1-(四氢-2H-吡喃-2-基)-1H吲唑
将4-溴-5-甲基-1H-吲唑(5.0g,23.69mmol)溶于二氯甲烷(20mL)中，室温下依次加入3,4-二氢-2H-吡喃(3.98g,47.38mmol)和对甲苯磺酸水合物(455mg,2.37mmol),加毕，室温反应12小时，TLC检测原料反应完全。反应液加水(30mL)淬灭，二氯甲烷(2x30mL)萃取，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥，浓缩，粗品经硅胶柱层析(石油醚/乙酸乙酯＝10:1)纯化得白色固体标题化合物I70-1(6.8g,产率97.6％)。
步骤2:5-甲基-1-(四氢-2H-吡喃-2-基)-4-(4,4,5,5-四甲基-1,3,2-二氧苯并呋喃-2-基)-1H吲唑
将化合物I70-1(1.3g,4.40mmol)和联硼酸频那醇酯(1.7g,6.61mmol)溶于二氧六 环(50mL)中，室温下依次加入Pd(dppf)Cl 2(142mg,0.22mmol)和乙酸钾(864mg，8.80mmol)，加毕，反应液在氮气保护下升温至100℃搅拌12小时，TLC检测原料反应完全。反应液冷却至室温，加水(100mL)稀释，乙酸乙酯萃取(30mL x3)，合并有机相，盐水(30mL)洗涤，无水硫酸钠干燥，浓缩，粗品经硅胶柱层析纯化(乙酸乙酯/石油醚＝10/1)得淡黄色油状标题化合物I70-2(1.4g,产率93.0％)。
步骤3:4-(苄氧基)-8-氟-2-((2R,7aS)-2-氟六氢-1H-吡咯里嗪-7a-基)甲氧基)-7-(5-甲基-1-(四氢-2H-吡喃-2-基)-1H-吲唑-4-基)吡啶并[4,3-d]嘧啶
将4-(苄氧基)-7-氯-8-氟-2-((2R,7aS)-2-氟六氢-1H-吡咯啉-7a-基)甲氧基)吡啶并[4,3-d]嘧啶(800mg,1.79mmol)和化合物I70-2(735mg,2.15mmol)溶于二氧六环(30mL)中，室温下依次加入cataCXium A Pd G 3(130mg,0.18mmol)和磷酸钾(1.1g,5.37mmol)，加毕，反应液在氮气保护下升温至100℃搅拌2小时，TLC检测原料反应完全。反应液冷却至室温，加水(50mL)稀释，乙酸乙酯萃取(30mL x3)，合并有机相，盐水(30mL)洗涤，无水硫酸钠干燥，浓缩，粗品经硅胶柱层析纯化(甲醇/二氯甲烷＝0-5％)得淡黄色油状标题化合物I70-3(650mg,产率57.9％)。
步骤4:8-氟-2-((2R,7aS)-2-氟六氢-1H-吡咯里嗪-7a-基)甲氧基)-7-(5-甲基-1-(四氢-2H-吡喃-2-基)-1H-吲唑-4-基)吡啶并[4,3-d]嘧啶-4-醇
将化合物I70-3(650mg,1.04mmol)溶于乙酸乙酯(20mL)中，室温下加入钯碳(13.0mg,20％)，加毕，反应液室温加氢反应5小时，TLC检测原料反应完全。反应液过滤，滤液浓缩得淡黄色固体标题化合物I70(400mg,产率71.7％)。
中间体I71：7-(8-乙炔基-7-氟-3-(甲氧基甲氧基)萘-1-基)-8-氟-2-((2R,7aS)-2-氟四氢-1H-吡咯 啉-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-醇
Figure PCTCN2022124111-appb-000231
步骤1:8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三异丙基硅基)乙炔基)萘-1-基)-2-((2R,7aS)-2-氟四氢-1H-吡咯啉-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-醇
将化合物I66-0(3.0g,6.72mmol)溶于乙醇(60mL)中，室温下加入((2-氟-6-(甲氧基甲氧基)-8-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)萘-1-基)乙炔基)三异丙基硅烷(4.13g,8.06mmol)，碳酸铯(5.47g,16.8mmol)，甲磺酸(2-二环己基膦基-2',6'-二异丙氧基-1,1'-联苯基)(2- 氨基-1,1'-联苯-2-基)钯(II)(0.84g,1.01mmol)和水(15mL)，反应液氮气保护下升温至100℃回流反应2.5小时，TLC检测反应完全(DCM/MeOH＝15/1,R f＝0.5)，反应液降至室温，加水(200mL)淬灭，乙酸乙酯(200mL x2)萃取，合并有机相，饱和食盐水(200mL)洗涤，无水硫酸钠干燥，浓缩，粗品经硅胶柱层析纯化(DCM/MeOH＝50/1～20/1)得黄色固体标题化合物I77-1(2.24g,产率:47％)。LC-MS:m/z＝707.3[M+H] +
步骤2:7-(8-乙炔基-7-氟-3-(甲氧基甲氧基)萘-1-基)-8-氟-2-((2R,7aS)-2-氟四氢-1H-吡咯啉-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-醇
将化合物I77-1(2.2g,3.11mmol)溶于N,N-二甲基甲酰胺(20mL)中，室温下加入氟化铯(9.5g,62.2mmol)，加毕，室温反应2小时，TLC检测反应完全(DCM/MeOH＝15/1,R f＝0.3)。反应液加水(100mL)淬灭，乙酸乙酯(100mL x2)萃取，合并有机相，饱和食盐水(100mL)洗涤，无水硫酸钠干燥，浓缩，粗品经乙酸乙酯(30mL)打浆，抽滤，滤饼烘干得类白色固体标题化合物I77(1.35g,产率:79％)。 1H NMR(400MHz,DMSO-d 6)δ8.93(s,1H),8.10(dd,J＝9.2,6.0Hz,1H),7.74(d,J＝2.4Hz,1H),7.55(t,J＝8.8Hz,1H),7.36(d,J＝2.4Hz,1H),5.38(s,2H),4.25-4.07(m,3H),3.44(s,3H),3.24-2.98(m,4H),2.91-2.76(m,1H),2.23-1.99(m,3H),1.88-1.73(m,3H)；LC-MS:m/z＝551.2[M+H] +.
中间体I78：7-(8-乙基-7-氟-3-(甲氧基甲氧基)萘-1-基)-6,8-二氟-2-((2R,7aS)-2-氟六氢-1H-吡 咯利嗪-7a-基)甲氧基)喹唑啉-4-醇
Figure PCTCN2022124111-appb-000232
步骤1:4-(苄氧基)-7-溴-2-氯-6,8-二氟喹唑啉
将叔丁醇钠(2.8g,28.67mmol)溶于四氢呋喃(100mL)中，室温下滴加苯甲醇(2.3g,21.03mmol)，室温搅拌1小时后干冰降温至-60℃，分批加入7-溴-2,4-二氯-6,8-二氟喹唑啉(6.0g,19.11mmol)，加毕，反应液低温继续搅拌0.5小时，TLC检测原料反应完全。反应液加冰水(100mL)淬灭，乙酸乙酯萃取(50mL x3)，合并有机相，盐水(50mL)洗涤，无水硫酸 钠干燥，浓缩，粗品经硅胶柱层析纯化(乙酸乙酯/石油醚＝0-3％)得淡黄色固体标题化合物I78-1(6.3g,产率85.5％)。
步骤2:4-(苄氧基)-7-溴-6,8-二氟-2-((2R,7aS)-2-氟六氢-1H-吡咯利嗪-7a-基)甲氧基)喹唑啉
将化合物I78-1(6.0g,15.56mmol)和((2R,7aS)-2-氟六氢-1H-吡咯利嗪-7a-基)甲醇(4.9g,31.12mmol)溶于DMAc(50mL)中，室温下加入氟化钾(2.7g,46.68mmol)，加毕，反应液在氮气保护下升温至100℃搅拌3小时，TLC检测原料基本反应完全。反应液冷却至室温，加水(100mL)稀释，乙酸乙酯萃取(40mL x3)，合并有机相，盐水(30mL)洗涤，无水硫酸钠干燥，浓缩，粗品经硅胶柱层析纯化(甲醇/二氯甲烷＝0-5％)得黄色油状标题化合物I78-2(1.5g,产率19.0％)。
步骤3:4-(苄氧基)-7-(8-乙基-7-氟-3-(甲氧基甲氧基)萘-1-基)-6,8-二氟-2-((2R,7aS)-2-氟六氢-1H-吡咯啉-7a-基)甲氧基)喹唑啉
将化合物I78-2(500mg,0.98mmol)和2-(8-乙基-7-氟-3-(甲氧基甲氧基)萘-1-基)-4,4,5,5-四甲基-1,3,2-二氧苯甲醛(531mg,1.48mmol)溶于二氧六环(30mL)和水(5mL)的混合溶液中，室温下依次加入DPEphosPdCl 2(147mg,0.20mmol)和磷酸钾(623mg,2.94mmol)，加毕，反应液在氮气保护下升温至90℃搅拌1小时，TLC检测原料反应完全。反应液冷却至室温，加水(50mL)稀释，乙酸乙酯萃取(20mL x3)，合并有机相，盐水(30mL)洗涤，无水硫酸钠干燥，浓缩，粗品经硅胶柱层析纯化(甲醇/二氯甲烷＝0-5％)得黄色油状标题化合物I78-3(200mg,产率30.8％)。LC-MS:m/z＝662.2[M+H] +
步骤4:7-(8-乙基-7-氟-3-(甲氧基甲氧基)萘-1-基)-6,8-二氟-2-((2R,7aS)-2-氟六氢-1H-吡咯利嗪-7a-基)甲氧基)喹唑啉-4-醇
将化合物I78-3(200mg,0.30mmol)溶于乙酸乙酯(20mL)中，室温下加入钯碳(20.0mg,10％)，加毕，反应液室温加氢反应5小时，TLC检测原料反应完全。反应液过滤，滤液浓缩，粗品经prep-TLC纯化(甲醇/二氯甲烷＝1/10)得淡黄色固体标题化合物I78(63mg,产率36.7％)。LC-MS:m/z＝572.2[M+H] +
中间体I79：(4-(6-氯-8-氟-2-((2R,7aS)-2-氟四氢-1H-吡咯里嗪-7a(5H)-基)甲氧基)-4-((R)-3-羟 基-3-甲基哌啶-1-基)喹唑啉-7-基)-3-氰基-7-氟苯并[b]噻吩-2-基)氨基甲酸叔丁酯
Figure PCTCN2022124111-appb-000233
步骤1:(R)-1-(7-溴-2,6-二氯-8-氟喹唑啉-4-基)-3-甲基哌啶-3-醇
7-溴-2,4,6-三氯-8-氟喹唑啉(200mg,0.61mmol)溶于二氯甲烷(10mL)中，降至0℃下，加入(3R)-3-甲基哌啶-3-醇盐酸盐(100mg,0.66mmol)的二氯甲烷(5mL)溶液和N,N-二异丙基乙胺(234mg,1.81mmol)，加毕，0℃下继续搅拌30分钟，TLC显示原料消失，反应液加入1N稀盐酸调至PH＝4-5，二氯甲烷(100mL)分液，饱和食盐水洗涤，无水硫酸钠干燥，浓缩得白色固体标题化合物I79-1(198mg,产率:80％)。LC-MS:m/z＝410.0[M+H] +
步骤2:(R)-1-(7-溴-6-氯-8-氟-2-((2R,7aS)-2-氟四氢-1H-吡咯里嗪-7a(5H)-基甲氧基)喹唑啉-4-基)-3-甲基哌啶-3-醇
将化合物I79-1(814mg,1.99mmol)溶于二甲基亚砜(15mL)中，室温下加入((2R,7AS)-2-氟六氢-1H-吡咯嗪-7A-基)甲醇(956mg,6.00mmol)和氟化钾(348mg,6.00mmol)，加毕，氮气保护下升至120℃搅拌12小时，TLC显示原料消失，反应液降至室温，加水(150mL)淬灭，乙酸乙酯(100mL x2)萃取，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥，浓缩，粗品经硅胶柱层析(MeOH：DCM＝0-10％)纯化得白色固体标题化合物I79-2(201mg,产率:19％)。LC-MS:m/z＝531.1[M+H] +
步骤3:(4-(6-氯-8-氟-2-((2R,7aS)-2-氟四氢-1H-吡咯里嗪-7a(5H)-基)甲氧基)-4-((R)-3-羟基-3-甲基哌啶-1-基)喹唑啉-7-基)-3-氰基-7-氟苯并[b]噻吩-2-基)氨基甲酸叔丁酯
将化合物I79-2(90mg,0.17mmol)溶于甲苯(20mL)中，室温下加入015C-184-7(205mg,0.51mmol)，碳酸铯(275mg，0.85mmol)和[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(70mg,0.08mmol)，加毕，氮气保护下，升至100℃反应2小时，送LCMS显示原料消失，反应液降至室温，加水(50mL)淬灭，乙酸乙酯(50mL x2)萃取，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥，浓缩，粗品经Pre-TLC(MeOH:DCM＝1/12)纯化得黄色固体标题化合物I79(72mg,产率:57％)。LC-MS:m/z＝743.2[M+H] +.
中间体I80：(3-氰基-4-(6,8-二氟-2-((2R,7aS)-2-氟四氢-1H-吡咯啉-7a(5H)-基)甲氧基)-4-(4-羟 基哌啶-1-基)喹唑啉-7-基)-7-氟苯并噻吩-2-基)氨基甲酸叔丁酯
Figure PCTCN2022124111-appb-000234
步骤1:1-(7-溴-2-氯-6,8-二氟噻唑啉-4-基)哌啶-4-醇
将7-溴-2,4-二氯-6,8-二氟噻唑啉(500mg,1.59mmol)溶于二氯甲烷(10mL)中，氮气保护下降至0℃，依次加入4-羟基哌啶(161mg,1.59mmol)，N,N-二异丙基乙胺(411mg,3.18mmol)，继续0℃搅拌1小时，TLC显示原料消失。反应液加二氯甲烷(100mL)稀释，1N稀盐酸(20mL)洗涤，水洗(50mL)，饱和食盐水洗涤，无水硫酸钠干燥，浓缩得黄色固体标题化合物I80-1(550mg,产率:91％)。LC-MS:m/z＝380.0[M+H] +.
步骤2:1-(7-溴-6,8-二氟-2-((2R,7aS)-2-氟四氢-1H-吡咯啉-7a(5H)-基)甲氧基)喹唑啉-4-基)哌啶-4-醇
将化合物I80-1(550mg,1.45mmol)溶于四氢呋喃/N,N-二甲基甲酰胺(7mL/7mL)的混合溶液中，20℃下加入((2R,7aS)-2-氟四氢-1H-吡咯啉-7a(5H)-基)甲醇(462mg,2.91mmol)，三乙烯二胺(162mg,1.44mmol)和碳酸铯(1.41g,4.33mmol)，加毕，氮气保护下，20℃搅拌16小时，TLC检测反应完全，反应液加水(50mL)淬灭，乙酸乙酯(150mL)萃取，分液，无水硫酸钠干燥，浓缩，粗品经硅胶柱层析(MeOH:DCM＝0-10％)纯化得白色固体状标题化合物I80-2(180mg,产率:24％)。LC-MS:m/z＝503.1[M+H] +.
步骤3:(3-氰基-4-(6,8-二氟-2-((2R,7aS)-2-氟四氢-1H-吡咯啉-7a(5H)-基)甲氧基)-4-(4-羟基哌啶-1-基)喹唑啉-7-基)-7-氟苯并噻吩-2-基)氨基甲酸叔丁酯
将化合物I80-2(90mg,0.18mmol)溶于甲苯(20mL)中，20℃下加入化合物015C-184-7(217mg,0.53mmol)，碳酸铯(291mg,0.89mmol)和[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(74mg,0.09mmol)，加毕，氮气保护下，升至100℃搅拌2小时，送LCMS显示原料消失。反应液降至室温，加水(50mL)淬灭，乙酸乙酯(100mL)萃取，分液，饱和食盐水洗涤，无水硫酸钠干燥，浓缩，粗品经硅胶柱层析(MeOH:DCM＝0-10％)纯化得白色固体标题化合物I80(85mg,产率:66％)。LC-MS:m/z＝713.2[M+H] +.
化合物合成
实施例1
化合物1:(8-氟-4-(2,6-二氮杂螺[3.3]庚烷-2-基)-2-((四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶 并[4,3-d]嘧啶-7-基)萘-2-醇
Figure PCTCN2022124111-appb-000235
步骤1：将2,4,7-三氯-8-氟吡啶并[4,3-d]嘧啶(400mg,1.5mmol)分散在二氯甲烷中(10mL)，加入N,N-二异丙基乙胺(10mL)，降温至-50℃，加入2,6-二氮杂螺[3.3]庚烷-2-甲酸叔丁酯(316mg,1.6mmol)，搅拌反应50分钟。TLC检测显示反应完全。反应液加水，二氯甲烷萃取两次，饱和食盐水洗涤，无水硫酸钠干燥，浓缩,剩余物经硅胶柱层析纯化(石油醚:乙酸乙酯＝3:1)得到6-(2,7-二氯-8-氟吡啶[4,3-d]嘧啶-4-基)-2,6-二氮螺环[3.3]庚烷-2-羧酸叔丁酯(580mg,黄色固体)，收率88％。
步骤2：将6-(2,7-二氯-8-氟吡啶[4,3-d]嘧啶-4-基)-2,6-二氮螺环[3.3]庚烷-2-羧酸叔丁酯(250mg,0.60mmol)和(四氢-1H-吡咯里嗪-7a(5H)-基)甲醇(127mg，0.90mmol)分散在超干1,4-二氧六环(3mL)中，加入碳酸铯(590mg，1.80mmol)，氮气置换三次，加热至90℃反应12小时。TLC检测显示原料反应完全。反应液降至室温，垫硅藻土过滤，滤饼乙酸乙酯洗涤，滤液浓缩，剩余物经硅胶柱层析纯化(二氯甲烷:甲醇＝10:1)得到叔丁基6-(7-氯-8-氟-2-((四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-2，6-二氮杂螺[3.3]庚烷-2-羧酸盐(174mg,黄色固体)，收率：55％。LC-MS:m/z＝520.2[M+H] +
步骤3：将叔丁基6-(7-氯-8-氟-2-((四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-2，6-二氮杂螺[3.3]庚烷-2-羧酸盐(174mg,mmol)和2-(3-甲氧基萘-1-基)-4,4,5,5-四甲基-1,3,2-二氧硼烷(190mg,0.67mmol)分散在1，4-二氧六环和水(8mL/1mL)中，加入碳酸铯(234mg,0.99mmol)和甲磺酸(2-二环己基膦基-2',6'-二异丙氧基-1,1'-联苯基)(2-氨基-1,1'-联苯-2-基)钯(II)(84mg,0.01mmol),加热至100℃反应2小时。TLC检测显示反应完全。反应液降至室温，垫硅藻土过滤，滤饼甲醇洗涤，滤液浓缩，剩余物经Prep-TLC纯化(二氯甲烷:甲醇＝15:1)得到叔丁基6-(8-氟-7-(3-甲氧基萘-1-基)-2-((四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-yl)-2,6-二氮杂螺[3.3]庚烷-2-羧酸酯(123mg,褐色固 体)，收率：57％。LC-MS:m/z＝641.3[M+H] + .
步骤4：将叔丁基6-(8-氟-7-(3-甲氧基萘-1-基)-2-((四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-yl)-2,6-二氮杂螺[3.3]庚烷-2-羧酸酯(123mg)溶于二氯甲烷(2mL)中，低温下滴加三溴化硼(0.5mL)，滴毕，缓慢升至室温反应1.5小时。TLC检测显示反应完全。反应液加冰水淬灭，加碳酸氢钠饱和液调节pH值至中性，二氯甲烷萃取，饱和食盐水洗涤，无水硫酸钠干燥，浓缩，剩余物经Prep-TLC纯化(二氯甲烷:甲醇:氨甲醇＝16:1:1)得到8-氟-7-(3-甲氧基萘-1-基)-4-(2,6-二氮杂螺[3.3]庚烷-2-基)-2-((四氢-1H-吡咯嗪-7a(5H)-基))甲氧基)吡啶并[4,3-d]嘧啶(8.32mg,棕色固体)，收率8％。 1H NMR(400MHz,CD 3OD)δ9.00(s,1H),7.77(d,J＝8.4Hz,1H),7.51-7.40(m,2H),7.30(d,J＝2.4Hz,1H),7.26-7.19(m,2H),5.09(s,2H),4.68(s,4H),4.41(s,4H),3.76-3.65(m,2H),3.29-3.24(m,2H),2.37-2.05(m,8H).LC-MS:527.2[M+H] +.
其余实施案例基本上沿袭合成通式，化合物2-55的制备用合适的原材料和中间体参考实施例1的具体合成而取得.
化合物2:4-(8-氟-4-(哌嗪-1-基)-2-((四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d] 嘧啶-7-基)萘-2-醇
Figure PCTCN2022124111-appb-000236
1H NMR(400MHz,DMSO-d 6)δ10.10(s,1H),9.60(s,1H),9.29(s,1H),7.81(d,J＝7.6Hz,1H),7.53(d,J＝7.6Hz,1H),7.49-7.39(m,1H),7.37-7.10(m,3H),4.66-4.40(m,2H),4.34-3.98(m,4H),3.55-3.30(m,6H),3.11-2.97(m,2H),2.24-1.79(m,8H).LC-MS:m/z＝515.2[M+H] +.
化合物3:5-乙炔基-4-(8-氟-4-(4-甲基哌嗪-1-基)-2-((四氢-1H-吡咯嗪-7a(5H)-基)甲 氧基)吡啶并[4,3-d]嘧啶-7-基)萘-2-醇
Figure PCTCN2022124111-appb-000237
1H NMR(400MHz,CD 3OD)δ9.02(s,1H),7.82(d,J＝7.6Hz,1H),7.50(d,J＝6.0Hz,1H),7.40(t,J＝8.0Hz,1H),7.33(d,J＝2.4Hz,1H),7.17(d,J＝2.4Hz,1H),4.48(d,J＝1.6Hz,2H),4.12(d,J＝2.8Hz,4H),3.45-3.39(m,2H),3.07-3.00(m,3H),2.68(t,J＝4.8Hz,4H),2.39(s,3H),2.23-1.90(m,8H).LC-MS:m/z＝553.3[M+H] +
化合物4:4-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛烷-3-基)-8-氟-2-((四氢-1H-吡咯嗪 -7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-7-基)-5-乙炔基萘-2-醇
Figure PCTCN2022124111-appb-000238
1H NMR(400MHz,CD 3OD)δ9.08(s,1H),7.83(d,J＝7.6Hz,1H),7.51(d,J＝6.0Hz,1H),7.44-7.37(m,1H),7.34(d,J＝2.4Hz,1H),7.16(d,J＝2.8Hz,1H),4.78(d,J＝13.2Hz,2H),4.68(d,J＝2.8Hz,2H),4.05(s,2H),3.90(s,2H),3.74-3.64(m,3H),3.28(d,J＝5.6Hz,2H),2.33(d,J＝5.6Hz,2H),2.28-1.97(m,11H).LC-MS:m/z＝565.3[M+H] +
化合物5:4-(8-氟-4-(吡咯烷-3-基氨基)-2-((四氢-1H-吡咯烷-7a(5H)-基)甲氧基)吡啶 并[4,3-d]嘧啶-7-基)萘-2-醇
Figure PCTCN2022124111-appb-000239
1H NMR(400MHz,DMSO-d 6)δ9.48(s,1H),8.84-8.81(m,1H),7.80(d,J＝8.4Hz,1H),7.46-7.42(m,2H),7.28(d,J＝2.0Hz,1H),7.25-7.21(m,1H),7.20(d,J＝2.4Hz,1H),4.72-4.70(m,1H),4.08(s,2H),3.18-3.13(m,1H),3.06-2.84(m,5H),2.57-2.50(m,2H),2.15-2.11(m,1H),1.90-1.75(m,8H),1.61-1.54(m,3H).LC-MS:m/z＝515.3[M+H] +
化合物6:4-(4-((1S,4S)-2,5-二氮杂二环[2.2.1]庚烷-2-基)-8-氟-2-((四氢-1H-吡咯嗪 -7a(5H)-基)甲氧基)吡啶基[4,3-d]嘧啶-7-基)萘-2-醇
Figure PCTCN2022124111-appb-000240
1H NMR(400MHz,CD 3OD)δ9.16(s,1H),7.74(d,J＝8.4Hz,1H),7.48(d,J＝8.4Hz,1H),7.41(t,J＝7.2Hz,1H),7.27-7.19(m,3H),5.37(s,1H),4.31-4.24(m,3H),3.92-3.85(m,2H),3.18-3.07(m,4H),2.75-2.69(m,2H),2.12-2.02(m,3H),1.98-1.81(m,5H),1.78-1.70(m,2H).LC-MS:m/z＝527.3[M+H] +
化合物7:4-(4-(3,6-二氮杂双环[3.1.1]庚烷-3-基)-8-氟-2-((四氢-1H-吡咯里嗪7a(5H) -基)甲氧基)吡啶并[4,3-d]嘧啶-7-基)-5-乙基萘-2-醇
Figure PCTCN2022124111-appb-000241
1H NMR(400MHz,CD 3OD)δ9.41(s,1H),7.82(d,J＝8.4Hz,1H),7.51-7.49(m,1H),7.41-7.36(m,1H),7.33(d,J＝2.4Hz,1H),7.17(d,J＝2.4Hz,1H),4.50-4.27(m,6H),3.94(d,J＝6.0Hz,2H),3.27-3.23(m,2H),2.90-2.79(m,3H),2.17-2.11(m,2H),2.04-1.73(m,8H).LC-MS:m/z＝551.3[M+H] +
化合物8:1-(8-氟-7-(3-羟基萘-1-基)-2-((四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并 [4,3-d]嘧啶-4-基)-1,4-二氮杂-6-醇
Figure PCTCN2022124111-appb-000242
1H NMR(400MHz,CD 3OD)δ9.42(s,1H),7.77(d,J＝8.4Hz,1H),7.52(d,J＝8.0Hz,1H),7.43(s,1H),7.30(d,J＝2.0Hz,1H),7.27-7.20(m,2H),4.68(s,2H),4.40-4.28(m,3H),4.28-4.17(m,2H),3.75-3.64(m,2H),3.41(d,J＝4.8Hz,2H),3.30-3.23(m,3H),3.14-3.04(m,1H),2.39-2.29(m,2H),2.27-2.06(m,6H).LC-MS:m/z＝545.2[M+H] +
化合物9:4-(4-((1,4-恶氮杂环-6-基)氨基)-8-氟-2-((四氢-1H-吡咯嗪-7a(5H)-基)甲氧 基)吡啶并[4,3-d]嘧啶-7-基)萘-2-醇
Figure PCTCN2022124111-appb-000243
1H NMR(400MHz,CD 3OD)δ9.36(s,1H),7.76(d,J＝8.0Hz,1H),7.44(d,J＝12.0Hz,2H),7.30(d,J＝2.0Hz,1H),7.27-7.20(m,2H),4.92-4.85(m,2H),4.68(s,2H),4.17-4.10(m,1H),4.01-3.82(m,3H),3.73-3.63(m,2H),3.41-3.33(m,1H),3.29-3.20(m,2H),3.13(s,2H),2.39-2.28(m,2H),2.28-2.04(m,6H).LC-MS:m/z＝545.3[M+H] +
化合物10:4-(8-氟-4-(哌啶-3-基氨基)-2-((四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并 [4,3-d]嘧啶-7-基)萘-2-醇
Figure PCTCN2022124111-appb-000244
1H NMR(400MHz,CD 3OD)δ9.27(s,1H),7.70(d,J＝8.4Hz,1H),7.43(d,J＝8.4Hz,1H),7.40-7.34(m,1H),7.25-7.21(m,1H),7.20-7.14(m,2H),4.51-4.38(m,1H),4.30(s,2H),3.29-3.26(m,1H),3.10-3.04(m,2H),3.02-2.94(m,1H),2.76-2.58(m,4H),2.18-2.01(m,3H),1.99-1.81(m,5H),1.79-1.63(m,4H).LC-MS:m/z＝529.3[M+H] +
化合物11:4-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛烷-8-基)-8-氟-2-((四氢-1H-吡咯嗪 -7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-7-基)萘-2-醇
Figure PCTCN2022124111-appb-000245
1H NMR(400MHz,CD 3OD)δ9.12(s,1H),7.74(d,J＝8.0Hz,1H),7.53(d,J＝8.0Hz,1H),7.41(t,J＝8.0Hz,1H),7.28-7.21(m,3H),5.13(s,2H),4.29(s,2H),3.23-3.08(m,4H), 2.99-2.86(m,2H),2.77-2.71(m,2H),2.11-2.05(m,6H),1.98-1.84(m,4H),1.82-1.72(m,2H).LC-MS:m/z＝541.3[M+H] +
化合物12:(S)-4-(4-((2-氨基丙基)氨基)-8-氟-2-((四氢-1H-吡咯嗪-7a(5H)-基)甲氧基) 吡啶并[4,3-d]嘧啶-7-基)萘-2-醇
Figure PCTCN2022124111-appb-000246
1H NMR(400MHz,CD 3OD)δ9.25(s,1H),7.76(d,J＝8.0Hz,1H),7.48-7.40(m,2H),7.29-7.21(m,3H),4.42(s,2H),3.72(d,J＝6.4Hz,2H),3.47-3.42(m,1H),3.27(d,J＝6.4Hz,2H),2.98-2.87(m,2H),2.18-2.12(m,2H),2.06-1.83(m,6H),1.28(s,3H).LC-MS:m/z＝503.2[M+H] +
化合物13:4-(5-(1,4-二氮杂-1-基)-8-氟-2-((四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶 并[4,3-d]嘧啶-7-基)萘-2-醇
Figure PCTCN2022124111-appb-000247
1H NMR(400MHz,CD 3OD)δ9.19(s,1H),7.75(d,J＝8.4Hz,1H),7.52(d,J＝8.4Hz,1H),7.45-7.39(m,1H),7.31-7.19(m,3H),4.40(s,2H),4.17(dd,J＝10.8,6.0Hz,4H),3.30-3.16(m,4H),2.99-2.87(m,4H),2.19-2.09(m,4H),2.07-1.92(m,4H),1.91-1.82(m,2H).LC-MS:m/z＝529.3[M+H] +
化合物14:4-(4-(6-氨基-3-氮杂双环[3.1.0]己烷-3-基)-8-氟-2-((四氢-1H-吡咯嗪 -7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-7-基)萘-2-醇
Figure PCTCN2022124111-appb-000248
1H NMR(400MHz,DMSO-d 6)δ9.76(br,1H),9.32(s,1H),7.80(d,J＝8.0Hz,1H),7.51(d,J ＝8.0Hz,1H),7.45-7.42(m,1H),7.29-7.28(m,1H),7.26-7.21(m,2H),4.15(d,J＝12.0Hz,2H),4.06(s,2H),2.96-2.91(m,2H),2.57-2.50(m,6H),2.03-1.99(m,1H),1.92-1.84(m,2H),1.82-1.68(m,6H),1.60-1.54(m,2H).LC-MS:m/z＝527.3[M+H] +
化合物15:4-(4-(3,8-二氮杂二环[3.2.1]辛烷-3-基)-6,8-二氟-2-((六氢-1H-吡咯 利嗪-7a-基)甲氧基)喹唑啉-7-基)萘-2-醇二盐酸盐
Figure PCTCN2022124111-appb-000249
1H NMR(400MHz,DMSO-d 6)δ11.01(s,1H),10.21(d,J＝9.2Hz,1H),9.98(s,1H),7.83-7.81(m,2H),7.48-7.24(m,5H),4.59(s,2H),4.50(t,J＝12.0Hz,2H),4.15(s,3H),4.00-3.94(m,2H),3.55-3.50(m,2H),3.23-3.18(m,2H),2.23-1.97(m,12H).LC-MS:m/z＝558.3[M+H] + 。
化合物16:4-(4-(3,8-二氮杂二环[3.2.1]辛烷-3-基)-6,8-二氟-2-((六氢-1H-吡咯 利嗪-7a-基)甲氧基)喹唑啉-7-基)萘-2-醇二盐酸盐
Figure PCTCN2022124111-appb-000250
1H NMR(400MHz,DMSO-d 6)δ11.01(s,1H),10.21(d,J＝9.2Hz,1H),9.98(s,1H),7.83-7.81(m,2H),7.48-7.24(m,5H),4.59(s,2H),4.50(t,J＝12.0Hz,2H),4.15(s,3H),4.00-3.94(m,2H),3.55-3.50(m,2H),3.23-3.18(m,2H),2.23-1.97(m,12H).LC-MS:m/z＝558.3[M+H] + 。
化合物17:4-(4-((3-氮杂双环[3.1.0]己-6-基)氨基)-8-氟-2-((四氢-1H-吡咯嗪-7a(5H)- 基)甲氧基)吡啶并[4,3-d]嘧啶-7-基)萘-2-醇
Figure PCTCN2022124111-appb-000251
1H NMR(400MHz,CD 3OD)δ9.21(s,1H),7.75(d,J＝8.4Hz,1H),7.47-7.40(m,2H), 7.29-7.22(m,3H),4.47(s,2H),3.30-3.24(m,4H),2.99(d,J＝10.6Hz,3H),2.92-2.86(m,2H),2.18-2.12(m,2H),2.06-1.83(m,8H).LC-MS:m/z＝527.3[M+H] +
化合物18:4-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛烷-3-基)-8-氟-2-((八氢-9aH-喹啉 -9a-基)甲氧基)吡啶基[4,3-d]嘧啶-7-基)萘-2-醇
Figure PCTCN2022124111-appb-000252
1H NMR(400MHz,CD 3OD)δ9.09(s,1H),7.75(d,J＝8.4Hz,1H),7.53(d,J＝8.0Hz,1H),7.43-7.38(m,1H),7.31-7.20(m,3H),4.63(d,J＝12.4Hz,2H),3.72-3.64(m,4H),2.87-2.81(m,2H),2.60-2.55(m,2H),1.98-1.91(m,2H),1.90-1.48(m,14H),1.35-1.28(m,2H).LC-MS:m/z＝569.3[M+H] +
化合物19:4-(2-((1H-吡咯并[3,2-b]吡啶-2-基)甲氧基)-4-((1R,5S)-3,8-二氮杂双环 [3.2.1]辛基-3-基)-8-氟吡啶并[4,3-d]嘧啶-7-基)萘-2-醇
Figure PCTCN2022124111-appb-000253
1H NMR(400MHz,DMSO-d 6)δ11.60(s,1H),10.02(s,1H),9.22(s,1H),8.30(dd,J＝4.4,1.2Hz,1H),7.81(d,J＝8.4Hz,1H),7.74(d,J＝8.4Hz,1H),7.57(d,J＝8.0Hz,1H),7.48-7.41(m,1H),7.34-7.20(m,3H),7.10(dd,J＝8.0,4.4Hz,1H),6.67(s,1H),5.65(s,2H),4.63-4.52(m,2H),3.50-3.45(m,1H),3.87-3.69(m,4H),1.70(s,4H).LC-MS:m/z＝548.2[M+H] +.
化合物20:4-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-8-氟-2-((四氢-1H-吡咯嗪 7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-7-基)-5-乙烯基萘-2-醇
Figure PCTCN2022124111-appb-000254
1H NMR(400MHz,CD 3OD)δ9.04(s,1H),7.71(d,J＝8.4Hz,1H),7.39(t,J＝15.6Hz,1H),7.29(d,J＝2.4Hz,1H),7.21(d,J＝7.2Hz,1H),7.12(d,J＝2.4Hz,1H),6.23(dd,J＝17.2,10.8Hz,1H),5.22(dd,J＝17.2,1.6Hz,1H),4.63(t,J＝10.4Hz,2H),4.56(dd,J＝10.8,2.0Hz,1H),3.79-3.67(m,2H),3.17-3.08(m,2H),2.77-2.71(m,2H),2.12-2.02(m,2H),2.01-1.72(m,10H),1.29(s,4H).LC-MS:m/z＝567.3[M+H] +
化合物21:2-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛烷-3-基)-8-氟-2-((四氢-1H-吡咯嗪 -7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-7-基)-[1,1'-联苯]-4-醇
Figure PCTCN2022124111-appb-000255
1H NMR(400MHz,CD 3OD)δ9.08(d,J＝8.0Hz,1H),7.54-7.31(m,2H),7.11-7.08(m,3H),7.03-6.91(m,2H),6.59-6.57(m,1H),4.66-4.63(m,2H),4.57-4.55(m,2H),3.95-3.89(m,2H),3.86-3.83(m,2H),3.63-3.54(m,2H),2.23-2.15(m,2H),2.27-1.83(m,12H).LC-MS:m/z＝567.3[M+H] +
化合物22:4-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛烷-3-基)-8-氟-2-((四氢-1H-吡咯嗪 -7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-7-基)-2-甲基苯并[d]噻唑-6-醇
Figure PCTCN2022124111-appb-000256
1H NMR(400MHz,CD 3OD)δ9.15(s,1H),7.44(d,J＝2.4Hz,1H),7.16(d,J＝2.4Hz,1H),4.89(d,J＝14.8Hz,3H),4.71(s,2H),4.26(s,2H),4.01(d,J＝14.0Hz,2H),3.77-3.66(m,2H),3.33(s,1H),2.72(s,3H),2.42-2.02(m,12H).LC-MS:m/z＝562.2[M+H] +
化合物23:1-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛烷-3-基)-8-氟-2-((四氢-1H-吡咯嗪 -7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-7-基)-1,2,3,4-四氢喹啉-3-醇
Figure PCTCN2022124111-appb-000257
1H NMR(400MHz,DMSO-d 6)δ8.90(s,1H),7.13(d,J＝7.6Hz,1H),7.01(t,J＝7.6Hz,1H),6.87(t,J＝7.6Hz,1H),6.74(dd,J＝7.6,4.4Hz,1H),4.55–4.42(m,2H),4.33(s,2H),4.11(dd,J＝8.8,4.8Hz,1H),3.95(dd,J＝12.4,3.6Hz,1H),3.89(s,2H),3.75(t,J＝13.6Hz,2H),3.61(dd,J＝12.4,7.2Hz,2H),3.10(d,J＝5.2Hz,1H),3.06(d,J＝5.6Hz,1H),2.94(s,3H),2.80-2.66(m,2H),2.07-1.74(m,12H).LC-MS:m/z＝546.3[M+H] +
化合物24:4-(4-(3,6-二氮杂双环[3.1.1]庚烷-3-基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡 咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-7-基)-5-乙炔基萘-2-醇
Figure PCTCN2022124111-appb-000258
1H NMR(400MHz,CD 3OD)δ9.38(s,1H),7.77(d,J＝7.6Hz,1H),7.45-7.43(m,1H),7.36-7.32(m,1H),7.27(d,J＝2.8Hz,1H),7.14(d,J＝2.8Hz,1H),5.36-5.23(m,1H),4.44-4.23(m,6H),3.92(d,J＝6.4Hz,2H),3.24-3.12(m,3H),3.03-3.97(m,1H),2.83-2.77(m,1H),2.33-1.88(m,8H).LC-MS:m/z＝569.2[M+H] +
化合物25:3-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-6-氯-8-氟-2-((四氢-1H-吡咯 嗪-7a(5H)-基)甲氧基)喹唑啉-7-基)苯酚
Figure PCTCN2022124111-appb-000259
1H NMR(400MHz,DMSO-d 6)δ9.74(s,1H),7.87(s,1H),7.32(t,J＝8.0Hz,1H),6.92-6.85(m,1H),6.83-6.73(m,2H),4.45-4.32(m,2H),4.30-4.16(m,2H),3.82(s,2H),3.73-3.61(m,2H),3.44-3.28(m,1H),3.23-3.11(m,2H),2.90-2.73(m,2H),2.09-1.83(m,6H),1.82-1.65(m,6H). LC-MS:m/z＝524.2[M+H] +.
化合物26:4-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛烷-3-基)-8-氟-2-((2-甲基-1,2,3,4-四 氢异喹啉-5-基)氧基)吡啶并[4,3-d]嘧啶-7-基)萘-2-醇
Figure PCTCN2022124111-appb-000260
1H NMR(400MHz,CD 3OD)δ9.08(s,1H),7.75(d,J＝8.4Hz,1H),7.53(d,J＝8.4Hz,1H),7.44-7.40(m,1H),7.28-7.23(m,4H),7.03(d,J＝7.6Hz,2H),4.34(d,J＝12.0Hz,2H),3.66(s,2H),3.54(d,J＝12.4Hz,2H),3.48(s,2H),2.79-2.71(m,4H),2.44(s,3H),1.74-1.57(m,4H).LC-MS:m/z＝563.3[M+H] +
化合物27:4-(8-氟-4-(1,2,5-恶二氮杂-5-基)-2-((四氢-1H-吡咯嗪-7a(5H)-基)甲氧基) 吡啶并[4,3-d]嘧啶-7-基)萘-2-醇
Figure PCTCN2022124111-appb-000261
1H NMR(400MHz,CD 3OD)δ9.23(s,1H),7.76(d,J＝8.4Hz,1H),7.53(d,J＝8.4Hz,1H),7.43(t,J＝7.6Hz,1H),7.30(d,J＝2.0Hz,1H),7.28-7.21(m,2H),4.61(s,2H),4.40-4.30(m,4H),4.13-4.10(m,2H),3.67-3.59(m,2H),3.43-3.40(m,2H),3.27-3.18(m,2H),2.34-2.26(m,2H),2.22-2.02(m,6H).LC-MS:m/z＝531.2[M+H] +
化合物28:4-(8-氟-2-((四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-4-(1,2,5-三氮杂-5-基)吡 啶并[4,3-d]嘧啶-7-基)萘-2-醇二盐酸盐
Figure PCTCN2022124111-appb-000262
1H NMR(400MHz,CD 3OD)δ9.36(s,1H),7.81(d,J＝8.4Hz,1H),7.59(d,J＝8.0Hz,1H), 7.50-7.46(m,1H),7.38-7.31(m,3H),4.84-4.81(m,4H),4.59-4.47(m,4H),3.81-3.71(m,6H),2.41-2.12(m,8H).LC-MS:m/z＝530.3[M+H] +
化合物29:4-(8-氟-4-(3-甲基-5,6,8,9-四氢-1H,7H-[1,2,4]三唑并[1,2-α][1,2,5]三氮杂 -7-基)-2-((四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-7-基)萘-2-醇
Figure PCTCN2022124111-appb-000263
1H NMR(400MHz,DMSO-d 6)δ10.00(s,1H),9.28(s,1H),7.81(d,J＝8.4Hz,1H),7.6(d,J＝8.0Hz,1H),7.46-7.42(m,1H),7.29-7.23(m,3H),4.60-4.53(m,2H),4.30-4.20(m,6H),3.66-3.62(m,2H),3.24-3.11(m,4H),2.86-2.80(m,2H),2.02-1.76(m,11H).LC-MS:m/z＝583.3[M+H] +
化合物30:7-(蒽-9-基)-4-((1R，5S)-3,8-二氮杂环[3.2.1]辛烷-3-基)-8-氟-2-((四氢-1H- 吡咯嗪-7a(5H)-基)甲氧基)吡啶[4,3-d]嘧啶
Figure PCTCN2022124111-appb-000264
1H NMR(400MHz,CD 3OD)δ9.20(s,1H),8.70(s,1H),8.14(d,J＝7.6Hz,2H),7.57-7.47(m,4H),7.45-7.39(m,2H),4.66(t,J＝12.4Hz,2H),4.29(s,2H),3.71(d,J＝12.4Hz,2H),3.63(s,2H),3.14-3.05(m,2H),2.75-2.68(m,2H),2.11-2.03(m,2H),1.95-1.73(m,10H).LC-MS:m/z＝575.3[M+H] +
化合物31:4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛烷-3-基)-7-(二苯并[b,d]呋喃-1-基)-8- 氟-2-((四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶
Figure PCTCN2022124111-appb-000265
1H NMR(400MHz,CD 3OD)δ9.17(s,1H),7.75(d,J＝8.4Hz,1H),7.63(dd,J＝15.2,7.6Hz,2H),7.53(d,J＝7.6Hz,1H),7.48-7.44(m,1H),7.39(d,J＝8.0Hz,1H),7.17(t,J＝8.0Hz,1H),4.65(d,J＝12.4Hz,2H),4.30(s,2H),3.72(d,J＝12.4Hz,2H),3.64(s,2H),3.15-3.10(m,2H),2.77-2.71(m,2H),2.12-2.06(m,2H),1.98-1.76(m,10H).LC-MS:m/z＝565.2[M+H] +
化合物32:4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛烷-3-基)-8-氟-7-(菲-9-基)-2-((四氢 -1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶
Figure PCTCN2022124111-appb-000266
1H NMR(400MHz,CD 3OD)δ9.21(s,1H),8.91-8.85(m,2H),8.01(d,J＝4.0Hz 1H),7.95(s,1H),7.77-7.68(m,4H),7.59-7.55(m,1H),4.73-4.70(m,2H),4.63(s,2H),3.82-3.79(m,4H),3.65-3.62(m,2H),3.25-3.19(m,2H),2.32-2.28(m,2H),2.21-2.05(m,6H),1.93-1.86(m,4H).LC-MS:m/z＝575.3[M+H] +.
化合物33:4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛烷-3-基)-8-氟-7-(苯沙氨酸-4- 基)-2-((四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶
Figure PCTCN2022124111-appb-000267
1H NMR(400MHz,CD 3OD)δ10.54(s,1H),8.87-8.74(m,2H),8.73-8.46(m,4H),8.37-8.30(m,1H),6.06(d,J＝12.4Hz,2H),5.83(s,2H),5.13(d,J＝12.4Hz,2H),5.07(s,2H),4.73-4.70(m,2H),4.39-4.31(m,2H),3.66-3.55(m,2H),3.54-3.12(m,10H).LC-MS:m/z＝597.3[M+H] +
化合物34:4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛烷-3-基)-7-(二苯并[b,d]呋喃-4-基)-8- 氟-2-((四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶
Figure PCTCN2022124111-appb-000268
1H NMR(400MHz,DMSO-d 6)δ9.20(s,1H),8.33(dd,J＝7.6,1.2Hz,1H),8.24(d,J＝7.2Hz,1H),7.83(dd,J＝7.6,0.8Hz,1H),7.72(d,J＝8.0Hz,1H),7.63-7.52(m,2H),7.46(t,J＝7.2Hz,1H),4.45(d,J＝11.6Hz,2H),4.10(s,2H),3.62(d,J＝12.4Hz,2H),3.56(s,2H),3.45-3.40(m,1H),3.01-2.91(m,2H),2.63-2.53(m,2H),1.96-1.87(m,2H),1.85-1.74(m,4H),1.68-1.55(m,6H).LC-MS:m/z＝565.3[M+H] +
化合物35:4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛基-3-基)-7-(二苯并[b,d]噻吩-4-基)-8- 氟-2-((四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶
Figure PCTCN2022124111-appb-000269
1H NMR(400MHz,DMSO-d 6)δ9.26(s,1H),8.55(dd,J＝7.6,0.8Hz,1H),8.48-8.41(m,1H),8.18(d,J＝7.2Hz,1H),8.06-7.99(m,1H),7.73(t,J＝7.6Hz,1H),7.58-7.51(m,2H),4.50(d,J＝11.2Hz,2H),4.21(s,2H),3.77-3.66(m,4H),3.60-3.52(m,1H),3.11-3.02(m,2H),2.76-2.65(m,2H),2.01-1.93(m,2H),1.92-1.78(m,4H),1.76-1.63(m,6H).LC-MS:m/z＝581.3[M+H] +
化合物36:4-(4-(3,8-二氮杂双环[3.2.1]辛烷-3-基)-8-氟-2-((六氢-1H-吡咯利嗪-7a-基) 甲氧基)-6-甲氧基喹唑啉-7-基)萘-2-醇二盐酸盐
Figure PCTCN2022124111-appb-000270
1H NMR(400MHz,DMSO-d6)δ10.95(br,1H),10.31(br,1H),9.89(br,1H),7.77(d,J＝8.4Hz,1H),7.42-7.39(m,1H),7.26(s,1H),7.21-7.16(m,3H),7.07(d,J＝7.6Hz,1H),4.56(s,2H),4.46-4.43(m,2H),4.16(br,2H),3.95-3.88(m,2H),3.80(s,3H),3.43-3.40(m,3H),3.20(br,2H), 2.22-1.93(m,12H)；LC-MS:m/z＝570.4[M+H] + 。
化合物37:4-(4-(1,4-二氮杂环庚-1-基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪 -7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-7-基)-5-乙基萘-2-醇
Figure PCTCN2022124111-appb-000271
1H NMR(400MHz,CD 3OD)δ9.17(s,1H),7.64-7.62(m,1H),7.36(t,J＝8.0Hz,1H),7.30-7.29(m,1H),7.17-7.16(m,1H),7.01-7.00(m,1H),5.53-5.40(m,1H),4.54(s,2H),4.35-4.34(m,2H),4.32-4.25(m,2H),3.66-3.57(m,4H),3.38-3.31(m,4H),2.53-2.14(m,10H),0.89(t,J＝4.0Hz,3H).LC-MS:m/z＝575.3[M+H] +
化合物38:4-(4-(3,9-二氮杂双环[4.2.1]壬烷-3-基)-8-氟-2-((四氢-1H-吡咯嗪-7a(5H)- 基)甲氧基)吡啶并[4,3-d]嘧啶-7-基)萘-2-醇
Figure PCTCN2022124111-appb-000272
1H NMR(400MHz,CD 3OD)δ9.17(s,1H),7.76(d,J＝8.4Hz,1H),7.54(d,J＝8.4Hz,1H),7.44-7.40(m,1H),7.28-7.21(m,3H),4.61(d,J＝12.0Hz,1H),4.36(s,2H),4.23-4.15(m,1H),4.00-3.92(m,1H),3.86-3.75(m,3H),3.24-3.18(m,2H),2.86-2.80(m,2H),2.25-1.78(m,14H).LC-MS:m/z＝555.3[M+H] +
化合物39:4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛烷-3-基)-7-(8-乙炔基-3-羟基萘-1- 基)-8-氟-2-((四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-1,6-萘啶-3-甲腈双三氟乙酸盐
Figure PCTCN2022124111-appb-000273
1H NMR(400MHz,DMSO-d 6)δ10.61(s,1H)，10.27(s,1H)，9.33(d,J＝14.4Hz,2H),9.23(s, 1H),7.91(dd,J＝2.0,7.6Hz,1H),7.46-7.41(m,2H),7.38(d,J＝2.4Hz,1H),7.18(d,J＝2.4Hz,1H),4.72-4.62(m,2H),4.30-4.23(m,3H),4.03-3.96(m,2H),3.83-3.80(m,1H),3.60-3.56(m,3H),3.29-3.23(m,2H),2.43-2.16(m,4H),2.15-1.97(m,8H).LC-MS:m/z＝589.3[M+H] +
化合物40:4-((1R，5S)-3,8-二氮杂环[3.2.1]辛烷-3-基)-8-氟-7-(8-氟-3-羟基萘 -1-基)-2-((四氢-1H-吡咯啉-7a(5H)-基)甲氧基)-1,6-萘啶-3-腈
Figure PCTCN2022124111-appb-000274
1H NMR(400MHz,DMSO-d 6)δ10.40(s,1H),9.30(s,1H),7.68(d,J＝8.4Hz,1H),7.40-7.47(m,2H),7.22(d,J＝2.0Hz,1H),6.99-7.05(m,1H),4.54-4.62(m,2H),4.09-4.11(m,4H),3.92(t,J＝10.0Hz,2H),3.41-3.55(m,4H),3.09(br,2H),2.26-2.34(m,2H),2.12-2.19(m,2H),1.99-2.04(m,5H),1.91-2.06(m,2H).LC-MS:m/z＝583.3[M+H] +
化合物41:4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛烷-3-基)-8-氟-7-(3-羟基萘-1- 基)-2-((四氢-1H-吡咯嗪7a(5H)-基)甲氧基)-1,6-二氮杂萘-3-甲腈双三氟乙酸
Figure PCTCN2022124111-appb-000275
1H NMR(400MHz,DMSO-d 6)δ10.64(s,1H),10.09(s,1H),9.37(s,1H),9.33(s,2H),7.83(d,J＝8.4Hz,1H),7.51-7.44(m,2H),7.33(d,J＝2.0Hz,1H),7.28-7.24(m,2H),4.69(s,2H),4.29(s,2H),4.11(d,J＝13.2Hz,2H),3.98(d,J＝12.4Hz,2H),3.60-3.57(m,2H),3.28-3.24(m,2H),2.35-2.22(m,4H),2.18-1.99(m,8H).LC-MS:m/z＝565.3[M+H] +
化合物42:4-(-3,8-二氮杂环[3.2.1]辛烷-3-基)-8-氟-2-((六氢-1H-吡咯里嗪-7a-基) 甲氧基)-7-(3-羟基萘-1-基)喹唑啉-6-腈三氟乙酸盐
Figure PCTCN2022124111-appb-000276
1H NMR(400MHz,DMSO-d 6)δ10.14(s,1H),9.07-9.35(m,2H),8.52(s,1H),7.86(d,J＝8.4Hz,1H),7.47-7.51(m,1H),7.16-7.36(m,4H),4.58-4.69(m,4H),4.20(s,2H),3.92-3.85(m,2H),3.18(s,4H),1.91-2.19(m,12H).LC-MS:m/z＝565.1[M+H] +.
化合物43:4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛基-3-基)-8-((5-氯-6-氟-1H-吲唑-4-基) 氧基)-2-((四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-1,7-萘啶-3-甲腈
Figure PCTCN2022124111-appb-000277
1H NMR(400MHz,DMSO-d 6)δ13.65(s,1H),7.99(s,1H),7.76(d,J＝3.6Hz,1H),7.60(d,J＝8.8Hz,1H),6.90(d,J＝3.6Hz,1H),4.54(s,2H),4.14(s,2H),4.04(d,J＝12.4Hz,2H),3.72(d,J＝12.0Hz,2H),3.51-3.45(m,3H),3.12(s,2H),2.27(d,J＝7.6Hz,2H),2.22-2.16(m,2H),2.10–2.01(m,6H),1.98-1.94(m,2H).LC-MS:m/z＝589.2[M+H] +.
化合物44:4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛烷-3-基)-8-((5-氯-6-氟-1H-吲唑-4-基) 氧基)-2-(((S)-1-甲基吡咯烷-2-基)甲氧基)-1,7-萘啶-3-甲腈
Figure PCTCN2022124111-appb-000278
1H NMR(400MHz,DMSO-d 6)δ13.62(s,1H),7.95(s,1H),7.73(d,J＝3.6Hz,1H),6.91(d,J＝3.6Hz,1H),6.80(d,J＝8.8Hz,1H),4.26(s,2H),4.09-3.96(m,2H),3.92-3.80(m,2H),3.79-3.62(m,2H),3.16-3.07(m,1H),2.84(s,3H),2.34-2.26(m,2H),2.21-2.04(m,3H), 2.03-1.70(m,3H).LC-MS:m/z＝563.0[M+H] +.
化合物45:4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛烷-3-基)-8-氟-7-(3-羟基萘-1- 基)-2-(((S)-1-甲基吡咯烷-2-基)甲氧基)-1,6-萘啶-3-甲腈三氟乙酸盐
Figure PCTCN2022124111-appb-000279
1H NMR(400MHz,DMSO-d6)δ10.14(s,1H),9.70(s,1H),9.29(s,2H),9.06(s,1H),7.82(d,J＝8.4Hz,1H),7.58(d,J＝8.4Hz,1H),7.46(t,J＝7.6Hz,1H),7.35–7.31(m,1H),7.30–7.24(m,2H),4.67–4.61(m,2H),4.26(s,2H),4.09-3.96(m,2H),3.92-3.80(m,2H),3.79-3.62(m,2H),3.16-3.07(m,1H),2.84(s,3H),2.34-2.26(m,2H),2.21-2.04(m,3H),2.03-1.70(m,3H).LC-MS:m/z＝539.2[M+H] +.
化合物46:3-((λ 2氮杂亚基)-λ 2-甲基)-4-((1R，5S)-3,8-二氮杂双环[3.2.1]辛 烷-3-基)-7-(3-羟基萘-1-基)-1-((四氢-1H-吡咯啉-7a(5H)-基)甲基)-1,6-萘啶-2(1H) -酮三氟乙酸盐
Figure PCTCN2022124111-appb-000280
1H NMR(400MHz,DMSO-d6)10.09(s,1H),9.40(brs,1H),9.27(s,1H),9.26-9.21(m,2H),8.00(s,1H),7.88-7.81(m,2H),7.4(t,J＝8.0Hz,1H),7.31-7.25(m,3H),4.69(s,2H),4.28-4.27(m,2H),4.07-4.04(m,2H),3.95-3.92(m,2H),3.24-3.22(m,2H),2.33-2.32(m,4H),2.11-2.04(m,8H),1.93-1.89(m,2H).LC-MS:m/z＝547.3[M+H] +.
化合物47:4-((1R，5S)-3,8-二氮杂环[3.2.1]辛烷-3-基)-7-(3-羟基萘-1-基)-2- ((四氢-1H-吡咯啉-7a(5H)-基)甲氧基)-1,6-萘啶-3-氰基三氟乙酸盐
Figure PCTCN2022124111-appb-000281
1H NMR(400MHz,DMSO-d6)10.45(s,1H),10.02(s,1H),9.56(s,1H),9.25-9.21(m,2H),7.97-7.95(d,J＝8.8Hz,1H),7.82(t,J＝4.0Hz,1H),7.46(t,J＝7.6Hz,1H),7.31-7.27(m,3H),4.67(s,2H),4.29-4.28(m,2H),4.11-4.08(m,2H),3.97-3.93(m,2H),3.59-3.58(m,2H),3.29-3.26(m,2H),2.37-2.34(m,2H),2.24-2.04(m,2H),2.09-2.05(m,8H).LC-MS:m/z＝547.3[M+H] +.
化合物48:(S)-4-(6-甲基-2-((1-甲基吡咯烷-2-基)甲氧基)-4-(哌嗪-1-基)-5H- 吡喃并[2,3-d]嘧啶-7-基)萘酚
Figure PCTCN2022124111-appb-000282
1H NMR(400MHz,CD 3OD)δ7.75(d,J＝8.4Hz,1H),7.67(d,J＝8.0Hz,1H),7.38(t,J＝14.0Hz,1H),7.29-7.23(m,1H),7.19-7.15(m,1H),7.12-7.08(m,1H),4.34-4.21(m,2H),3.58-3.50(m,4H),3.42(s,2H),3.09-3.02(m,1H),2.99-2.93(m,4H),2.74-2.68(m,1H),2.46(s,3H),2.34-2.28(m,1H),2.09-2.00(m,1H),1.82-1.75(m,2H),1.70-1.63(m,1H),1.59(s,3H).LC-MS:m/z＝488.3[M+H] +.
化合物49:4-(1-甲基-7-(哌嗪-1-基)-5-(四氢-1H-吡咯里嗪-7a(5H-基)甲氧基) -1H-吡唑[4,3-d]嘧啶-3-基)萘酚
Figure PCTCN2022124111-appb-000283
1H NMR(400MHz,DMSO-d 6)δ9.95(s,1H),8.35(d,J＝8.4Hz,1H),7.76(d,J＝8.0Hz,1H), 7.67(d,J＝2.0Hz,1H),7.43(t,J＝2.0Hz,1H),7.31-7.22(m,2H),4.22(s,3H),4.16(s,2H),3.71-3.58(m,6H),3.19-3.13(m,4H),2.86-2.76(m,2H),2.01-1.79(m,8H),1.74-1.69(m,1H).LC-MS:m/z＝500.3[M+H] +.
化合物50:4-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛烷-3-基)-2-((四氢-1H-吡咯嗪 -7a(5H)-基)甲氧基)-5-7,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基)萘-2-醇
Figure PCTCN2022124111-appb-000284
1H NMR(400MHz,CD 3OD)δ8.04(d,J＝8.4Hz,1H),7.63(d,J＝8.2Hz,1H),7.38-7.24(m,3H),6.77(s,1H),4.49-4.24(m,4H),4.16(s,2H),4.15-4.12(m,4H),3.91(d,J＝6.0Hz,2H),3.26(s,2H),3.21-2.87(m,4H),2.42-1.94(m,12H).LC-MS:m/z＝527.3[M+H] +.
化合物51:3-((E)-2-(6-((1R,5S)-3,8-二氮杂双环[3.2.1]辛烷-3-基)-5-甲氧基-2-((四氢 -1H-吡咯烷-7a(5H)-基)甲氧基)嘧啶-4-基)乙烯基)苯酚
Figure PCTCN2022124111-appb-000285
1H NMR(400MHz,CD 3OD)δ7.70(d,J＝16.0Hz,1H),7.30(d,J＝15.6Hz,1H),7.21(t,J＝7.6Hz,1H),7.07(d,J＝8.0Hz,1H),7.03(s,1H),6.78(dd,J＝8.4,2.0Hz,1H),4.43(d,J＝11.6Hz,2H),4.30(s,2H),3.66(s,3H),3.61(s,2H),3.48-3.36(m,2H),3.21(d,J＝12.4Hz,2H),3.05-2.98(m,2H),2.26-2.15(m,2H),2.17-2.98(m,4H),1.98-1.82(m,6H).LC-MS:m/z＝478.3[M+H] +.
化合物52:4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛基-3-基)-6-((E)-3-羟基苯乙烯 基)-2-((四氢-1H-吡咯烷-7a(5H)-基)甲氧基)嘧啶-5-醇盐酸盐
Figure PCTCN2022124111-appb-000286
1H NMR(400MHz,DMSO-d6)δ10.94(s,1H),10.02(s,1H),9.90(brs,1H),9.71(s,1H),7.80(d,J＝15.6Hz,1H),7.46(d,J＝16.0Hz,1H),7.23(t,J＝7.4Hz,1H),7.13-7.02(m,2H),6.81(d,J＝7.2Hz,1H),4.62(brs,2H),4.52(s,2H),4.12(s,2H),3.72-3.51(m,4H),3.24-3.11(m,2H),2.31-1.81(m,12H).LC-MS:m/z＝464.3[M+H] +.
化合物53:4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛基-3-基)-6-((E)-2-(4-羟基-[1,1'-联 苯]-2基)乙烯基)-2-((四氢-1H-吡咯里嗪7A(5H-基)甲氧基)嘧啶-5-醇盐酸盐
Figure PCTCN2022124111-appb-000287
1H NMR(400MHz,CD 3OD)δ7.60(d,J＝16.4Hz,1H),7.46-7.38(m,2H),7.35(d,J＝7.6Hz,1H),7.33-7.29(m,2H),7.26-7.22(m,2H),7.19(d,J＝16.4Hz,1H),6.95(dd,J＝8.4,2.4Hz,1H),5.22(d,J＝14.0Hz,2H),4.67(s,2H),4.24(s,2H),3.78–3.57(m,4H),3.28-3.18(m,2H),2.37–2.01(m,12H).LC-MS:m/z＝540.3[M+H] +.
化合物54:2-((E)-2-(6-((1R,5S)-3,8-二氮杂双环[3.2.1]辛烷-3-基)-5-甲氧基-2-((四氢 -1H-吡咯烷-7a(5H)-基)甲氧基)嘧啶-4-基)乙烯基)-[1,1'-联苯]-4-醇
Figure PCTCN2022124111-appb-000288
1H NMR(400MHz,CD 3OD)δ7.77(d,J＝16.0Hz,1H),7.43-7.36(m,2H),7.35-7.27(m,3H),7.22(d,J＝2.4Hz,1H),7.19(d,J＝9.2Hz,1H),7.16(d,J＝1.2Hz,1H),6.85(dd,J＝8.4,2.4Hz,1H),4.35(d,J＝11.6Hz,2H),4.02(s,2H),3.60(s,3H),3.53(s,2H),3.19-3.08(m,4H),2.82-2.71(m,2H),2.04-1.67(m,12H).LC-MS:m/z＝554.3[M+H] +.
化合物55:4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛基-3-基)-7-(二苯并[b,d]噻吩-1-基)-8- 氟-2-((四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶
Figure PCTCN2022124111-appb-000289
1H NMR(400MHz,CD 3OD)δ9.18(s,1H),8.07(dd,J＝8.0,0.8Hz,1H),7.90(d,J＝8.0Hz,1H),7.62(t,J＝7.6Hz,1H),7.45(dd,J＝7.2,0.8Hz,1H),7.39(td,J＝8.0,0.8Hz,1H),7.11(td,J＝8.0,0.8Hz,1H),7.02(d,J＝8.0,1H),4.65(d,J＝10.8Hz,2H),4.37(s,2H),3.72(d,J＝12.8Hz,2H),3.64(s,2H),3.30-3.19(m,2H),2.93-2.79(m,2H),2.21-2.08(m,2H),2.07-1.73(m,10H).LC-MS:m/z＝581.2[M+H] +.
实施例2
化合物56:3-(7-((1R,5S)-3,8-二氮杂环[3.2.1]辛烷-3-基)-5-((四氢-1H-吡咯里嗪-7a(5H)- 基)甲氧基)恶唑[5,4-d]嘧啶-2-基)苯酚
Figure PCTCN2022124111-appb-000290
步骤1：氨基氰基乙酸乙酯对甲苯磺酸盐(3.75g，12.5mmol)溶于NMP(40mL) 中，加入间甲氧基苯甲酰氯(2.14g，12.5mmol)，室温反应过夜。TLC反应完全。加入乙酸乙酯稀释，饱和碳酸氢钠溶液调碱性，饱和食盐水洗，无水硫酸钠干燥，有机相浓缩得2-氰基-2-(3-甲氧基苯甲酰胺基)乙酸乙酯(2.69g，白色固体)，收率81.5％。LC-MS:m/z＝263.1[M+H] +.
步骤2：2-氰基-2-(3-甲氧基苯甲酰胺基)乙酸乙酯(2.69g，10.26mmol)溶于4M盐酸乙酸乙酯溶液(30mL)中，80℃反应2小时。LC-MS监测反应完全。加入饱和碳酸氢钠溶液调碱性，有机相水洗，饱和食盐水洗，无水硫酸钠干燥，有机相浓缩得5-氨基-2-(3-甲氧基苯基)恶唑-4-羧酸乙酯(2.4g，白色固体)。收率89.2％。LC-MS:m/z＝263.1[M+H] +.
步骤3：5-氨基-2-(3-甲氧基苯基)恶唑-4-羧酸乙酯(1.7g，6.49mmol)溶于THF(20mL)中，室温下加入三氯乙酰异氰酸酯(1.35g，7.14mmol)，室温搅拌10分钟，TLC显示原料反应完，将反应液浓缩干，得2-(3-甲氧基苯基)-5-(3-(2,2,2-三氯乙酰基)脲基)恶唑-4-羧酸乙酯(2.53g，白色固体)，收率86.6％。
步骤4：将2-(3-甲氧基苯基)-5-(3-(2,2,2-三氯乙酰基)脲基)恶唑-4-羧酸乙酯(2.53g,crude)悬浮于甲醇(30mL)，体系浑浊，加入氨甲醇(5mL)，体系澄清，马上有固体析出，室温搅拌2小时，TLC显示原料消失，将反应液抽滤，滤饼用乙醇洗两次，滤饼干燥得2-(3-甲氧基苯基)-5-脲基恶唑-4-羧酸乙酯(1.4g，白色固体)。收率82.4％。LC-MS:m/z＝306.1[M+H] +.
步骤5：将2-(3-甲氧基苯基)-5-脲基恶唑-4-羧酸乙酯5(1.4g，4.59mmol)分散于6％氢氧化钠溶液(20ml)中，回流反应3小时，TLC反应完全。加入1N稀盐酸调酸性，析出固体。过滤，干燥得2-(3-甲氧基苯基)恶唑并[5,4-d]嘧啶-5,7-二醇(1.2g，白色固体)。收率100％。
步骤6：2-(3-甲氧基苯基)恶唑并[5,4-d]嘧啶-5,7-二醇(100mg，0.42mmol)溶于三氯氧磷(6ml)中，加入DIPEA(163mg，1.26mmol)。105℃反应48小时。TLC反应完全。将反应液浓缩除去三氯氧磷，用二氯甲烷(10mL)稀释，加入至冰水中，加入二氯甲烷萃取(10mL x3)，合并有机相，饱和食盐水洗，无水硫酸钠干燥，有机相浓缩干得5,7-二氯-2-(3-甲氧基苯基)恶唑并[5,4-d]嘧啶(143mg，黄色固体)。粗品收率125％。
步骤7：将5,7-二氯-2-(3-甲氧基苯基)恶唑并[5,4-d]嘧啶(143mg，粗品)溶于二氯甲烷(10mL)，氮气保护，降温至-40℃，加入(1R,5S)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸叔丁酯(103mg，0.48mmol)，滴入DIPEA(186mg，1.44mmol)，-40℃搅拌30分钟，TLC原料少量剩余。加入水稀释，用二氯甲烷(10mL x3)萃取，有机相饱和食盐水洗，无水硫酸 钠干燥，浓缩，用硅胶柱色谱法以洗脱剂(石油醚/乙酸乙酯＝1/0～5/1)纯化得叔丁基(1R,5S)-3-(5-氯-2-(3-甲氧基苯基)恶唑并[5,4-d]嘧啶-7-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸盐(120mg，白色固体)。收率52.9％
步骤8：将叔丁基(1R,5S)-3-(5-氯-2-(3-甲氧基苯基)恶唑并[5,4-d]嘧啶-7-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸盐(362mg,0.042mmol)溶于干燥的1，4-二氧六环(10mL)加入叔丁醇钾(172mg，1.54mmol)，(六氢-1H-吡咯啉-7a-基)甲醇(163mg，1.15mmol)，110℃反应过夜，TLC反应完全。加入水稀释，用二氯甲烷萃取(20mL x3)，有机相饱和食盐水洗(10mL)，无水硫酸钠干燥，浓缩，用硅胶柱色谱法以洗脱剂(二氯甲烷/甲醇＝1/0～20/1)纯化得叔丁基(1R,5S)-3-(2-(3-甲氧基苯基)-5-((四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)恶唑并[5,4-d]嘧啶-7-yl)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(132mg，黄色固体)。收率29.9％。LC-MS:m/z＝577.1[M+H] +.
步骤9：将叔丁基(1R,5S)-3-(2-(3-甲氧基苯基)-5-((四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)恶唑并[5,4-d]嘧啶-7-yl)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(70mg，0.12mmol)溶于二氯甲烷(6mL)中，加入三溴化硼(1mL)。室温搅拌1小时。反应液加入二氯甲烷稀释，加入甲醇淬灭。加水，分液，水相加入1N氢氧化钠溶液调碱性，加入二氯甲烷萃取，合并有机相，饱和食盐水洗，无水硫酸钠干燥，有机相浓缩得3-(7-((1R,5S)-3,8-二氮杂双环[3.2.1]辛烷-3-基)-5-((四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)恶唑并[5,4-d]嘧啶-2-基)苯酚(13mg，黄色固体13mg)。收率23.6％。 1H NMR(400MHz,CD 3OD)δ7.53(d,J＝7.6Hz,1H),7.47(s,1H),7.32(t,J＝8.0Hz,1H),6.94(dd,J＝8.2,1.8Hz,1H),5.32(s,1H),4.66(s,1H),4.18(s,2H),3.72(d,J＝12.8Hz,2H),3.63(s,2H),3.22-3.10(m,2H),2.88-2.67(m,2H),2.20-1.66(m,12H).LC-MS:m/z＝463.2[M+H] +.
化合物57-60的制备用合适的原材料和中间体参考实施例1的具体合成而取得.
化合物57:4-(4-((1R,5S)-3,8-二氮杂环[3.2.1]辛烷-8-基)-8-氟-2-((2R,7aS)-2-氟四氢 -1H-吡咯啉-7a(5H)-基)甲氧基)吡啶基[4,3-d]嘧啶-7-基)-5-乙基萘酚
Figure PCTCN2022124111-appb-000291
1H NMR(400MHz,CD 3OD)δ9.08(s,1H),7.62(d,J＝8.4Hz,1H),7.36(t,J＝7.6Hz,1H), 7.28(d,J＝2.4Hz,1H),7.18-7.12(m,1H),7.04-6.99(m,1H),5.43-5.24(m,1H),5.16(s,2H),4.39-4.25(m,2H),3.68-3.61(m,4H),3.28-3.21(m,2H),3.03-2.93(m,2H),2.38-1.97(m,12H),0.89(d,J＝14.4Hz,3H).LC-MS:m/z＝587.3[M+H] +.
化合物58:4-(4-((1R，5S)-3,8-二氮杂环[3.2.1]辛烷-8-基)-8-氟-2-((2R，7aS) -2-氟四氢-1H-吡咯啉-7a(5H)-基)甲氧基)吡啶基[4,3-d]嘧啶-7-基)-5-乙烯基萘酚
Figure PCTCN2022124111-appb-000292
1H NMR(400MHz,CD 3OD)δ9.07(s,1H),7.71(d,J＝8.0Hz,1H),7.38(t,J＝7.2Hz,1H),7.29(d,J＝2.4Hz,1H),7.24-7.18(m,1H),7.15-7.09(m,1H),6.24(dd，J＝16.4,10.8Hz,1H),5.39-5.18(m,2H),5.13(s,2H),4.59-4.55(m,1H),4.31-4.21(m,2H),3.29-3.16(m,6H),2.98-2.93(m,2H),2.26-1.93(m,10H).LC-MS:m/z＝585.4[M+H] +.
化合物59:4-(4-(1,4-二氮杂-1-基)-8-氟-2-((2R，7aS)-2-氟四氢-1H-吡咯里嗪 -7a(5H)-基)甲氧基)吡啶基[4,3-d]嘧啶-7-基)-5-乙烯基萘-2-醇
Figure PCTCN2022124111-appb-000293
1H NMR(400MHz,CD 3OD)9.09(s,1H),7.60(d,J＝8.0Hz,1H),7.28(t,J＝8.0Hz,1H),7.17-7.16(m,1H),7.10-7.07(m,2H),6.27-6.20(m,1H),5.37-5.34(m,0.5H),5.27-5.22(m,1H),5.18-5.17(m,0.5H),4.57-4.52(m,1H),4.31-4.11(m,6H),3.29-3.00(m,5H),2.95-2.88(m,3H),2.24-1.95(m,8H).LC-MS:m/z＝573.3[M+H] +.
化合物60:4-(8-氟-4-(1,2,5-恶二氮杂苯胺-2-基)-2-((四氢-1H-吡咯啉-7a(5H)-基)甲氧 基)吡啶基[4,3-d]嘧啶-7-基)萘酚
Figure PCTCN2022124111-appb-000294
1H NMR(400MHz,CD 3OD)δ9.66(s,1H),7.76(d,J＝8.4Hz,1H),7.52(d,J＝8.4Hz,1H), 7.42(t,J＝15.2Hz,1H),7.31-7.28(m,1H),7.25-7.22(m,2H),4.49(s,2H),4.38-4.28(m,4H),3.50-3.42(m,2H),3.29-3.24(m,2H),3.18-3.09(m,2H),3.06-3.01(m,2H),2.23-2.17(m,2H),2.11-2.01(m,4H),1.97-1.90(m,2H).LC-MS:m/z＝531.2[M+H] +.
实施例3
化合物61:4-(4-((1R,5S)-3,8-二氮杂环[3.2.1]辛烷-3-基)-8-氟-2-((四氢-1H-吡咯里嗪-7a(5H)- 基)甲氧基)吡啶基[4,3-d]嘧啶-7-基)-3,4-二氢喹啉-2(1H)-酮
Figure PCTCN2022124111-appb-000295
步骤1：将(1R，5S)-3-(7-氯-8-氟-2-(甲硫基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸叔丁酯(700mg,1.59mmol)，3,4-二氢-1H-2-喹喔啉酮(457.14mg,3.18mmol)，Pd 2(dba) 3(293.12mg,0.32mmol)，Xantphos(277.15mg,0.48mmol)和碳酸铯(1.55g,4.8mmol)分散于甲苯(50mL)中，升温100℃反应1小时，TLC监测原料反应完全。反应液冷却至室温，加水(100mL)稀释，乙酸乙酯萃取(50mL×3)，合并有机相，无水硫酸钠干燥，浓缩，剩余物经硅胶柱层析(甲醇/DCM＝0-3％)纯化得到(1R,5S)-3-(7-(3-((叔丁基二甲基硅基)氧基)-3,4-二氢-1H-2-喹喔啉酮-8-氟-2-(甲硫基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸叔丁酯(750mg,黄色固体)，产率：85.8％。LC-MS:m/z＝552.2[M+H] + .
步骤2：将(1R,5S)-3-(7-(3-((叔丁基二甲基硅基)氧基)-3,4-二氢-1H-2-喹喔啉酮-8-氟-2-(甲硫基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸叔丁酯(750mg,1.364mmol)溶于二氯甲烷(50mL)中，3-苯基-2-苯基磺酰基-1,2-氧氮杂环丙烷(712.7mg,2.73mmol)，室温(25℃)反应2小时，TLC监测原料反应完毕。反应液加入二氯甲烷稀释(100 mL)，加入饱和碳酸氢钠溶液(40mL)，萃取分液，有机相用饱和食盐水洗(50mL)，无水硫酸钠干燥，浓缩，剩余物经硅胶柱层析(甲醇/DCM＝0-5％)纯化得到(1R,5S-3-(7-(3-((叔丁基二甲基硅基)氧基)-3,4-二氢-1H-2-喹喔啉酮-8-氟-2-(甲基亚磺酰基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸叔丁酯(500mg,黄色固体)，收率64.6％。LC-MS:m/z＝568.2[M+H] + .
步骤3：将(1R,5S-3-(7-(3-((叔丁基二甲基硅基)氧基)-3,4-二氢-1H-2-喹喔啉酮-8-氟-2-(甲基亚磺酰基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸叔丁酯(350mg,0.617mmol)溶于甲苯(20mL)中，加入(四氢-1H-吡咯嗪-7a(5H-基)甲醇(1.3g,9.25mmol)，降温至0℃，一次性加入叔丁醇钾(82.9mg,0.74mmol)，保持零度反应30分钟，TLC监测原料反应完全。反应液浓缩除去甲苯，加入二氯甲烷稀释(50mL)，有机相依次用水洗一次(50mL)，饱和食盐水洗涤一次(50mL)，无水硫酸钠干燥，浓缩，剩余物经硅胶柱层析(甲醇/DCM＝0-7％)纯化得到(1R,5S)-3-(8-氟-7-(3,4-二氢-1H-2-喹喔啉酮)-2-((四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂环[3.2.1]辛烷-8-羧酸叔丁酯(100mg,黄色固体)。收率率：25％。LC-MS:m/z＝645.3[M+H] + .
步骤4：将(1R,5S)-3-(8-氟-7-(3,4-二氢-1H-2-喹喔啉酮)-2-((四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂环[3.2.1]辛烷-8-羧酸叔丁酯(100mg,0.155mmol)溶于二氯甲烷(4mL)中，加入三氟乙酸(4mL)，室温搅拌半小时，TLC监测原料反应完全。反应液浓缩除去三氟乙酸，加入饱和碳酸氢钠溶液(5mL)，加水稀释(20mL)，二氯甲烷萃取(20mL x3)，合并有机相，无水硫酸钠干燥，浓缩，剩余物经硅胶柱层析(甲醇/DCM＝1/10，加5％的氨甲醇)纯化得到4-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛烷-3-基)-8-氟-2-((四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-7-基)-3,4-二氢-1H-2-喹喔啉酮(30mg,白色固体)，产率：35.5％。 1H NMR(400MHz,CD 3OD)δ8.93(s,1H),7.06-7.01(m,2H),6.99–6.94(m,1H),6.92–6.87(m,1H),4.68(d,J＝12.8Hz,2H),4.62(s,2H),4.49(s,2H),3.86(s,2H),3.78(d,J＝13.2Hz,2H),3.70-3.64(m,2H),3.30-3.23(m,2H),2.30(dd,J＝12.0,6.4Hz,2H),2.25-2.14(m,4H),2.11–2.06(m,2H),1.96-1.94(m,2H),1.89–1.82(m,2H).LC-MS:m/z＝545.3[M+H] + .
化合物62-64的制备用合适的原材料和中间体参考实施例1的具体合成而取得.
化合物62:5-乙基-4-(8-氟-2-((2R，7aS)-2-氟四氢-1H-吡咯里嗪-7a(5H)-基) 甲氧基)-4-(1,2,5-恶二氮杂-5-基)吡啶基[4,3-d]嘧啶-7-基)萘酚
Figure PCTCN2022124111-appb-000296
1H NMR(400MHz,CD 3OD)δ9.15(s,1H),7.64(d,J＝7.6Hz,1H),7.36(t,J＝15.2Hz,1H),7.29(d,J＝2.8Hz,1H),7.18-7.13(m,1H),7.04-7.00(m,1H),5.49-5.32(m,1H),4.56(s,2H),4.48-4.36(m,4H),4.31(t,J＝10.8Hz,2H),4.14-4.08(m,2H),3.53-3.48(m,2H),3.44-3.38(m,2H),2.41-2.01(m,8H),0.85(t,J＝14.8Hz,3H).LC-MS:m/z＝577.3[M+H] +.
化合物63:4-(1-((1R,5S)-3,8-二氮杂环[3.2.1]辛烷-3-基)-5-氟-3-((四氢-1H-吡咯里嗪 -7a(5H)-基)甲氧基)-7,9-二氢呋喃[3,4-f]喹唑啉-6-基)萘-2-醇盐酸盐
Figure PCTCN2022124111-appb-000297
1H NMR(400MHz,DMSO-d 6)δ8.19(s,1H),7.78(d,J＝7.6Hz,1H),7.41(t,J＝7.6Hz,1H),7.31-7.21(m,3H),7.13(t,J＝7.2Hz,1H),5.25(s,2H),5.10(s,2H),4.73-4.65(m,2H),4.22-4.18(m,2H),4.07-4.03(m,2H),3.10-3.07(m,2H),2.69-2.60(m,4H),2.02-1.65(m,12H).LC-MS:m/z＝582.4[M+H] +.
化合物64:4-(9-(-3,8-二氮杂环[3.2.1]辛烷-3-基)-5-氟-7-((六氢-1H-吡咯里 嗪-7a-基)甲氧基)-3H-[1,2,3]三唑基[4,5-f]喹唑啉-4-基)萘-2-醇二盐酸盐
Figure PCTCN2022124111-appb-000298
1H NMR(400MHz,DMSO-d 6)δ8.21(s,1H),7.80(d,J＝7.6Hz,1H),7.41(t,J＝7.6Hz,1H),7.29-7.23(m,3H),7.13(t,J＝7.2Hz,1H),4.73-4.65(m,2H),4.20(brs,2H),4.05(brs,2H),3.10-3.07(m,2H),2.69-2.60(m,4H),2.02-1.65(m,12H).LC-MS:m/z＝581.3[M+H] +.
实施例4
化合物65:(3R,4R)-1-(7-(8-乙基-3-羟基萘-1-基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯 嗪-7a(5H)基)甲氧基)吡啶[4,3-d]嘧啶-4-基)吡咯烷-3,4-二醇
Figure PCTCN2022124111-appb-000299
A.中间体2-(8-乙基-3-(甲氧基甲氧基)-萘-1-基)-4,4,5,5-四甲基-1,3,2-二氧硼烷的合成
Figure PCTCN2022124111-appb-000300
将中间体硼酸酯5(730mg,1.47mmol)溶于DMF(15mL)中，室温下加入氟化铯(2.20g,14.5mmol)搅拌2小时，TLC检测原料反应完全。将反应液加水稀释(100mL)乙酸乙酯萃取(100mL x3)，合并有机相，无水硫酸钠干燥，浓缩得黄色油状中间化合物1(500mg，粗品)，直接用于下一步。
将1(500mg,粗品)溶于甲醇(15mL)中，加入Pd/C(50mg,10％)氢气保护下，室温条件下反应12小时，TLC检测原料反应完全。硅藻土过滤，滤液浓缩，所得粗品经硅胶柱层析(乙酸乙酯/石油醚＝1/5)纯化得淡黄色油状中间化合物2-(8-乙基-3-(甲氧基甲氧基)-萘-1-基)-4,4,5,5-四甲基-1,3,2-二氧硼烷(310mg，两步产率：61％).1H NMR(400MHz,CDCl3)δ7.60-7.57(m,1H),7.41-7.33(m,3H),7.25-7.24(m,1H),5.28(s,2H),3.50(s,3H),3.19(q,J＝8.0Hz,2H),1.43(s,12H),1.37-1.33(m,3H).
B.中间体7-(8-乙基-3-(甲氧基甲氧基)-萘-1-基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶[4,3-d]嘧啶-4-醇的合成
Figure PCTCN2022124111-appb-000301
将7-氯-8-氟吡啶并[4,3-D]嘧啶-2,4(1H,3H)-二酮(20.0g,93.4mmol)溶于三氯氧磷(200mL)中，低温下加入N,N-二异丙基乙胺(76mL,468mmol)，加毕，反应液加热至110℃反应2小时。TLC检测原料反应完全。反应液冷却至室温，旋干除去大部分三氯氧磷，加冰水(120mL)淬灭，饱和碳酸氢钠水溶液调节pH值至中性，乙酸乙酯(150mL x2)萃取，合并有机相，饱和食盐水洗涤(150mL)，无水硫酸钠干燥，浓缩，粗品经硅胶柱层析(石油醚:乙酸乙酯＝3:1)纯化得黄色固体中间化合物7(13.6g,收率58％)。
将中间化合物7(10.7g,42.38mmol)溶于二氧六环(50mL)中，室温下加入N,N-二异丙基乙胺(16.41g,127.15mmol)和苄醇(5.04g,46.62mmol)，将反应液缓慢升至60℃继续搅拌3小时，TLC检测原料反应完全，反应液加水(100mL)淬灭，乙酸乙酯(150mL x2)萃取，合并有机相，无水硫酸钠干燥，浓缩，粗品经硅胶柱层析(石油醚：乙酸乙酯＝6％-20％)纯化得白色固体中间化合物8(9.7g,收率70％)。
将中间化合物8(5.1g,15.74mol)溶于二氧六环(75mL)中，加入碳酸铯(12.79g,39.35mmol)和((2R,7aS)-2-氟四氢-1H-吡咯里嗪-7a(5H)-基)甲醇(3.51g,22.07mmol)，氮气保护下，反应液升至80℃继续反应6小时，TLC检测原料反应完全。将反应液降至室温，乙酸乙酯萃取(100mL x3)，合并有机相，无水硫酸钠干燥，浓缩，粗品经硅胶柱层析(甲醇/二氯甲烷＝0-10％)纯化得白色固体中间化合物9(3.8g,产率54％).LC-MS:m/z＝447.2[M+H]+.
将中间化合物9(3.7g,8.29mmol)溶于二氧六环/水(100mL/30mL)的混合液中，加入中间化合物2(5.8g,16.95mmol)，磷酸钾(5.39g,25.42mmol)和甲磺酸[正丁基二(1-金刚烷基)膦](2-氨基-1,1'-联苯-2-基)钯(II)(1.23g,1.69mmol)，氮气保护下，反应液升温至90℃搅拌1.5小时，TLC检测原料反应完全。将反应液降至室温，加水(100mL)淬灭，乙酸乙酯萃取(200mL x3)，合并有机相，无水硫酸钠干燥，浓缩，粗品经硅胶柱层析(甲醇/二氯甲烷 ＝0％-10％)纯化得黄色油状中间化合物10(5.1g,产率98％).LC-MS:m/z＝627.3[M+H]+.
将中间化合物10(1.2g,1.91mmol)溶于乙酸乙酯(50mL)中，室温下加入钯碳(120mg,10％)，氢气保护下，反应液于20℃条件下继续搅拌3小时，TLC检测原料反应完全，反应体系垫硅藻土过滤，滤饼用甲醇(100mL)洗涤，滤液浓缩，粗品经硅胶柱层析(甲醇/二氯甲烷＝0％-10％)纯化得白色固体中间化合物11(770mg,产率77％).LC-MS:m/z＝537.2[M+H]+.
C.化合物65的合成
Figure PCTCN2022124111-appb-000302
将中间化合物11(200mg,0.373mmol)溶于N,N-二甲基乙酰胺(6mL)中，室温条件下，加入N,N-二异丙基乙胺(192mg,1.49mmol)和2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(567mg,1.49mmol)，反应体系于室温条件下继续搅拌1小时，加入反式-3,4-二羟基吡咯烷(3R,4R)-pyrrolidine-3,4-diol(76mg,0.75mmol)，继续室温搅拌12小时，TLC检测原料反应完全，加入乙酸乙酯(100mL)稀释，水洗(50mL)，分液，有机相经无水硫酸钠干燥，浓缩，粗品经硅胶柱层析(甲醇/二氯甲烷＝0-10％)纯化得黄色固体中间化合物12(180mg,产率:78％).LC-MS:m/z＝622.3[M+H]+.
将中间化合物12(180mg,0.28mmol)溶于二氯甲烷(3mL)中，室温条件下，加入盐酸-二氧六环溶液(3mL，4M)，加毕继续搅拌1小时，TLC检测原料反应完全，反应液加入乙酸乙酯(70mL)稀释，体系有大量固体析出，过滤，滤饼经甲醇(10mL)溶解，二氯甲烷(100mL)稀释，饱和碳酸钠水溶液调至pH＝8-9，分液，有机相无水硫酸钠干燥，浓缩，粗品经Prep-HPLC(乙腈/水/甲酸)纯化得白色固体化合物65(含1个甲酸盐)(40mg,产率24％).1H NMR(400MHz,CD3OD)δ9.30-9.27(m,1H),8.45(s,1H),7.63(d,J＝8.0Hz,1H),7.36(t,J＝7.6Hz,1H),7.29-7.28(m,1H),7.16(d,J＝6.8Hz,1H),7.03-7.00(m,1H),5.55-5.42(m,1H),4.64-4.53(m,2H),4.51-4.13(m,4H),4.04-3.95(m,2H),3.87-3.70(m,3H),3.37-3.31(m,1H),2.61-2.42(m,2H),2.36-2.19(m,5H),2.12-2.04(m,1H),0.90-0.86(m,3H).19F NMR(377MHz,CD3OD)δ-135.3,-170.0.LC-MS:m/z＝578.3[M+H]+.
化合物66-72的制备用合适的原材料和中间体11参考实施例4的具体合成而取得.
化合物66:1-(7-(8-乙基-3-羟基萘-1-基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡 咯烷-7a(5H)基)甲氧基)嘧啶[4,3-d]嘧啶-4-基)-4-(羟甲基)哌啶-4-醇
Figure PCTCN2022124111-appb-000303
1H NMR(400MHz,CD 3OD)δ9.07(s,1H),8.48(s,0.86H),7.63(d,J＝8.4Hz,1H),7.36(t,J＝7.6Hz,1H),7.29(d,J＝2.4Hz,1H),7.16(d,J＝6.8Hz,1H),7.01(d,J＝2.4Hz,1H),5.52-5.39(m,1H),4.56-4.46(m,4H),3.85-3.79(m,2H),3.74-3.55(m,3H),3.45(s,2H),3.28-3.24(m,1H),2.47-2.15(m,7H),2.09-2.01(m,1H),1.97-1.90(m,2H),1.78-1.74(m,2H),0.88(t,J＝7.2Hz,3H). 19F NMR(377MHz,CD 3OD)δ-139.6,-173.9.LC-MS:m/z＝606.3[M+H] +.(0.86formic salt).
化合物67:(3S,4S)-1-(7-(8-乙基-3-羟基萘-1-基)-8-氟-2-(((2R,7aS)-2-氟四 氢-1H-吡咯嗪-7a(5H)基)甲氧基)吡啶[4,3-d]嘧啶-4-基)吡咯烷-3,4-二醇
Figure PCTCN2022124111-appb-000304
1H NMR(400MHz,CD 3OD)δ9.25(d,J＝10.4Hz,1H),7.62(d,J＝8.4Hz,1H),7.35(t,J＝7.6Hz,1H),7.29(brs,1H),7.15(d,J＝7.2Hz,1H),7.05(dd,J＝16.8,2.4Hz,1H),5.41-5.28(m,1H),4.49-4.31(m,4H),4.28-4.06(m,2H),4.04-3.90(m,2H),3.48-3.34(m,3H),3.15-3.04(m,1H),2.41-2.14(m,5H),2.10-2.00(m,2H),1.98-1.88(m,1H),0.90-0.85(m,3H). 19F NMR(377MHz,CD 3OD)δ-138.9,-173.7.LC-MS:m/z＝578.3[M+H] +.LC-MS:m/z＝578.3[M+H] +
化合物68:顺式-1-(7-(8-乙基-3-羟基萘-1-基)-8-氟-2-(((2R,7aS)-2-氟四氢 -1H-吡咯嗪-7a(5H)基)甲氧基)吡啶[4,3-d]嘧啶-4-基)吡咯烷-3,4-二醇
Figure PCTCN2022124111-appb-000305
1H NMR(400MHz,CD 3OD)δ9.23(s,1H),7.62(d,J＝8.4Hz,1H),7.35(t,J＝7.6Hz,1H),7.28(d,J＝2.8Hz,1H),7.15(d,J＝6.8Hz,1H),7.02(d,J＝2.0Hz,1H),5.42-5.29(m,1H),4.44-4.23(m,5H),4.13-3.86(m,3H),3.51-3.33(m,3H),3.16-3.05(m,1H),2.45-2.17(m,5H),2.12-2.02(m,2H),1.99-1.89(m,1H),0.90-0.86(m,3H). 19F NMR(377MHz,CD 3OD)δ-139.0,-173.7.LC-MS:m/z＝578.3[M+H] +.
化合物69:反式-1-(7-(8-乙基-3-羟基萘-1-基)-8-氟-2-(((2R，7aS)-2-氟四氢 -1H-吡咯嗪-7a(5H)基)甲氧基)吡啶[4,3-d]嘧啶-4-基)哌啶-3,4-二醇
Figure PCTCN2022124111-appb-000306
1H NMR(400MHz,CD 3OD)δ9.15(s,1H),7.62(d,J＝8.0Hz,1H),7.35(t,J＝7.2Hz,1H),7.28(d,J＝2.4Hz,1H),7.15(d,J＝6.8Hz,1H),7.01(s,1H),5.39-5.26(m,1H),4.38-4.28(m,3H),4.22-4.11(m,1H),3.97-3.89(m,1H),3.79-3.70(m,3H),3.42-3.34(m,3H),3.12-3.04(m,1H),2.38-2.15(m,6H),2.05-1.91(m,3H),1.78-1.65(m,1H),0.89(t,J＝7.2Hz,3H). 19F NMR(377MHz,CD 3OD)δ-139.3,-173.7.LC-MS:m/z＝592.3[M+H] +.
化合物70:(3R,4R)-4-氨基-1-(7-(8-乙基-3-羟基萘-1-基)-8-氟-2-(((2R， 7aS)-2-氟四氢吡咯烷-1H-吡咯嗪-7a(5H)基)甲氧基)吡啶[4,3-d]嘧啶-4-基)吡咯烷-3-醇
Figure PCTCN2022124111-appb-000307
1H NMR(400MHz,CD 3OD)δ9.25(d,J＝4.8Hz,1H),7.62(d,J＝8.4Hz,1H),7.35(t,J＝7.6 Hz,1H),7.28(d,J＝2.4Hz,1H),7.15(d,J＝7.2Hz,1H),7.02(dd,J＝7.2,2.4Hz,1H),5.41-5.28(m,1H),4.52-4.20(m,5H),3.99-3.83(m,2H),3.59-3.34(m,4H),3.15-3.04(m,1H),2.40-2.16(m,5H),2.08-2.01(m,2H),1.98-1.88(m,1H),0.88(t,J＝7.6Hz,3H). 19F NMR(377MHz,CD 3OD)δ-138.9,-173.7.LC-MS:m/z＝577.3[M+H] +.
化合物71:(3R,4R)-1-(7-(8-乙基-3-羟基萘-1-基)-8-氟-2-(((2R,7aS)-2-氟四 氢-1H-吡咯嗪-7a(5H)基)甲氧基)吡啶[4，3-d]嘧啶-4-基)-4-氟吡咯烷-3-醇
Figure PCTCN2022124111-appb-000308
1H NMR(400MHz,CD 3OD)δ9.26(d,J＝8.4Hz,1H),7.62(d,J＝8.0Hz,1H),7.35(t,J＝7.2Hz,1H),7.29(d,J＝2.8Hz,1H),7.15(d,J＝7.2Hz,1H),7.03(dd,J＝7.2,2.4Hz,1H),5.41-5.27(m,1H),5.21-5.09(m,1H),4.55-4.17(m,6H),4.12-4.07(m,1H),3.47-3.31(m,3H),3.12-3.03(m,1H),2.44-2.16(m,5H),2.10-2.01(m,2H),1.98-1.89(m,1H),0.90-0.86(m,3H). 19F NMR(377MHz,CD 3OD)δ-138.8,-173.6.LC-MS:m/z＝580.3[M+H] +.
化合物72:1-(7-(8-乙基-3-羟基萘-1-基)-8-氟-2-(((2R，7aS)-2-氟四氢-1H-吡 咯嗪-7a(5H)基)甲氧基)嘧啶[4,3-d]嘧啶-4-基)-4,4-二氟吡咯烷-3-醇
Figure PCTCN2022124111-appb-000309
1H NMR(400MHz,CD 3OD)δ9.22(d,J＝4.0Hz,1H),7.62(d,J＝8.0Hz,1H),7.35(t,J＝7.6Hz,1H),7.28(d,J＝2.0Hz,1H),7.15(d,J＝6.8Hz,1H),7.01(s,1H),5.44-5.30(m,1H),4.52-4.32(m,6H),4.21-4.10(m,1H),3.54-3.38(m,3H),3.20-3.08(m,1H),2.35-2.20(m,5H),2.13-2.04(m,2H),2.02-1.94(m,1H),0.93-0.82(m,3H). 19F NMR(377MHz,CD 3OD)δ-138.7,-173.7.LC-MS:m/z＝580.3[M+H] +.
化合物73:(3S,4S)-4-氨基-1-(7-(8-乙基-3-羟基萘-1-基)-8-氟-2-((2R,7aS)-2-氟四氢 -1H-吡咯烷-7a(5H)-基)甲氧基)吡啶基[4,3-d]嘧啶-4-基)吡咯烷-3-醇
Figure PCTCN2022124111-appb-000310
1H NMR(400MHz,CD 3OD)δ9.25(d,J＝3.6Hz,1H),7.63(d,J＝8.4Hz,1H),7.35(t,J＝7.6Hz,1H),7.29(d,J＝2.4Hz,1H),7.15(d,J＝6.8Hz,1H),7.02(dd,J＝8.0,2.8Hz,1H),5.42-5.28(m,1H),4.45-4.26(m,4H),3.96-3.89(m,2H),3.65-3.44(m,2H),3.40-3.32(m,3H),3.12-3.06(m,1H),2.42-2.16(m,5H),2.09-1.90(m,3H),0.90-0.86(m,3H). 19F NMR(377MHz,CD3OD)δ-139.0,-173.7.LC-MS:m/z＝577.3[M+H] +.
化合物74:顺式-1-(7-(8-乙基-3-羟基萘-1-基)-8-氟-2-((2R,7aS)-2-氟四氢-1H-吡咯 里嗪-7a(5H)-基)甲氧基)吡啶基[4,3-d]嘧啶-4-基)哌啶-3,4-二醇
Figure PCTCN2022124111-appb-000311
1H NMR(400MHz,CD 3OD)δ9.20(s,1H),7.62(d,J＝8.0Hz,1H),7.35(t,J＝7.6Hz,1H),7.28(d,J＝2.4Hz,1H),7.15(d,J＝6.8Hz,1H),7.01(t,J＝2.8Hz,1H),5.41-5.28(m,1H),4.43-4.27(m,4H),4.01-3.91(m,3H),3.73-3.64(m,1H),3.46-3.34(m,3H),3.14-3.05(m,1H),2.41-2.17(m,5H),2.12-2.01(m,3H),1.97-1.85(m,2H),0.89(t,J＝7.2Hz,3H). 19F NMR(377MHz,CD 3OD)δ-139.4,-173.7.LC-MS:m/z＝592.3[M+H] +.
化合物75:(R)-1-(7-(8-乙基-3-羟基萘-1-基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯里 嗪-7a(5H)-基)甲氧基)吡啶基[4,3-d]嘧啶-4-基)吡咯烷-3-醇
Figure PCTCN2022124111-appb-000312
1H NMR(400MHz,CD 3OD)δ9.26(s,1H),7.62(d,J＝8.0Hz,1H),7.35(t,J＝7.2Hz,1H),7.28(d,J＝2.8Hz,1H),7.15(d,J＝6.8Hz,1H),7.01(dd,J＝9.2,2.8Hz,1H),5.43-5.30(m, 1H),4.67-4.57(m,1H),4.47-4.42(m,1H),4.36-4.33(m,1H),4.30-3.92(m,4H),3.48-3.34(m,3H),3.17-3.07(m,1H),2.46-2.14(m,7H),2.11-2.03(m,2H),2.01-1.90(m,1H),0.91-0.86(m,3H). 19F NMR(377MHz,CD 3OD)δ-139.0,-173.7.LC-MS:m/z＝562.3[M+H] +.
化合物76：(S)-1-(7-(8-乙基-3-羟基萘-1-基)-8-氟-2-((2R，7aS)-2-氟四氢-1H-吡咯里 嗪-7a(5H)-基)甲氧基)吡啶基[4,3-d]嘧啶-4-基)吡咯烷-3-醇
Figure PCTCN2022124111-appb-000313
1H NMR(400MHz,CD 3OD)δ9.30(s,1H),7.63(d,J＝8.0Hz,1H),7.36(t,J＝7.6Hz,1H),7.29(d,J＝2.4Hz,1H),7.16(d,J＝7.2Hz,1H),7.02(dd,J＝8.8,2.4Hz,1H),5.56-5.43(m,1H),4.64-4.54(m,3H),4.40-3.95(m,4H),3.92-3.58(m,3H),3.35-3.33(m,1H),2.58-1.99(m,10H),0.91-0.87(m,3H). 19F NMR(377MHz,CD 3OD)δ-139.37,-173.94.LC-MS:m/z＝562.3[M+H]+.
化合物77:1-(7-(8-乙基-3-羟基萘-1-基)-8-氟-2-((2R,7aS)-2-氟四氢-1H-吡咯里嗪 -7a(5H)-基)甲氧基)吡啶[4,3-d]嘧啶-4-基)哌啶-4-醇
Figure PCTCN2022124111-appb-000314
1H NMR(400MHz,CD 3OD)δ9.06(s,1H),7.63(d,J＝8.0Hz,1H),7.36(t,J＝4.0Hz,1H),7.29(d,J＝2.4Hz,1H),7.16(d,J＝8.0Hz,1H),7.01(d,J＝2.4Hz,1H),5.53-5.41(m,1H),4.59-4.38(m,4H),4.09-4.03(m,1H),3.85-3.66(m,5H),3.34-3.32(m,1H),2.51-2.18(m,7H),2.13-2.02(m,3H),1.83-1.68(m,2H),0.89(t,J＝7.2Hz,3H). 19F NMR(377MHz,CD 3OD)δ-139.59,-173.93.LC-MS:m/z＝576.3[M+H] +.
化合物78:(S)-1-(7-(8-乙基-3-羟基萘-1-基)-8-氟-2-((2R,7aS)-2-氟四氢-1H-吡咯里 嗪-7a(5H)-基)甲氧基)吡啶基[4,3-d]嘧啶-4-基)哌啶-3-醇
Figure PCTCN2022124111-appb-000315
1H NMR(400MHz,CD 3OD)δ9.13(s,1H),7.63(d,J＝8.4Hz,1H),7.36(t,J＝7.6Hz,1H),7.29(d,J＝2.4Hz,1H),7.16(d,J＝6.8Hz,1H),7.01(t,J＝2.4Hz,1H),5.38-5.25(m,1H),4.36-4.22(m,3H),4.05-3.96(m,3H),3.87-3.75(m,1H),3.35-3.32(m,1H),3.29-3.19(m,2H),3.08-3.02(m,1H),2.44-2.13(m,4H),2.12-1.85(m,6H),1.80-1.71(m,2H),0.90(t,J＝7.6Hz,3H). 19F NMR(377MHz,CD 3OD)δ-139.37,-173.69.LC-MS:m/z＝576.3[M+H] +.
化合物79:(R)-1-(7-(8-乙基-3-羟基萘-1-基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯里 嗪-7a(5H)-基)甲氧基)吡啶基[4,3-d]嘧啶-4-基)哌啶-3-醇
Figure PCTCN2022124111-appb-000316
1H NMR(400MHz,CD 3OD)δ9.13(s,1H),7.62(d,J＝8.0Hz,1H),7.35(t,J＝7.2Hz,1H),7.28(d,J＝2.4Hz,1H),7.15(d,J＝7.2Hz,1H),7.01(t,J＝2.8Hz,1H),5.41-5.27(m,1H),4.40-4.37(m,1H),4.32-4.29(m,1H),4.24-4.21(m,1H),4.05-3.92(m,3H),3.86-3.78(m,1H),3.48-3.34(m,3H),3.13-3.04(m,1H),2.39-2.16(m,5H),2.11-2.01(m,4H),1.98-1.89(m,1H),1.79-1.69(m,2H),0.91-0.86(m,3H). 19F NMR(377MHz,CD 3OD)δ-139.4,-173.7.LC-MS:m/z＝576.3[M+H] +.
化合物80:2-(7-(8-乙基-3-羟基萘-1-基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪 -7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-2-氮杂双环[2.2.1]庚烷-5,6-二醇(顺式-消旋 -exo-二醇)
Figure PCTCN2022124111-appb-000317
1H NMR(400MHz,DMSO-d 6)δ9.96(br,1H),9.21(s,1H),7.62(d,J＝7.2Hz,1H),7.35(t,J＝ 8.0Hz,1H),7.29(br,1H),7.13(br,1H),6.94(s,1H),5.44-5.30(m,1H),5.08-4.98(m,3H),4.35-3.64(m,6H),3.34-2.95(m,4H),2.24-1.87(m,10H),1.70-1.63(m,1H),0.86-0.79(m,3H). 19F NMR(377MHz,CD 3OD)δ-139.1,-172.4.LC-MS:m/z＝604.3[M+H] +.
化合物81：(5S，6S)-2-(7-(8-乙基-3-羟基萘-1-基)-8-氟-2-((2R，7aS)-2-氟四氢-1H- 吡咯啉-7a(5H)-基)甲氧基)吡啶[4,3-d]嘧啶-4-基)-2-氮杂双环[2.2.1]庚烷-5,6-二醇((反式-消 旋-二醇)
Figure PCTCN2022124111-appb-000318
1H NMR(400MHz,CD 3OD)δ9.13(s,1H),7.62(d,J＝8.4Hz,1H),7.34(t,J＝7.6Hz,1H),7.27(d,J＝2.0Hz,1H),7.14(d,J＝6.8Hz,1H),6.98(d,J＝12.4Hz,1H),5.39-5.26(m,1H),4.80(br,1H),4.45-4.05(m,5H),3.65-3.55(m,1H),3.30-3.04(m,3H),3.12-3.03(m,1H),2.69(s,1H),2.42-1.92(m,10H),0.90-0.85(m,3H). 19FNMR(377MHz,CD 3OD)δ-138.75,-137.65.LC-MS:m/z＝604.3[M+H] + .
化合物82:8-(7-(8-乙基-3-羟基萘-1-基)-8-氟-2-((2R，7aS)-2-氟四氢-1H-吡咯啉 -7a(5H)-基)甲氧基)吡啶[4,3-d]嘧啶-4-基)-8-氮杂双环[3.2.1]辛烷-2,3-二醇(顺式-消旋-二醇)
Figure PCTCN2022124111-appb-000319
1H NMR(400MHz,CD 3OD)δ9.50-9.45(m,1H),7.63(d,J＝8.0Hz,1H),7.35(t,J＝7.6Hz,1H),7.29(d,J＝2.4Hz,1H),7.16(d,J＝7.2Hz,1H),7.10-6.98(m,1H),5.45-5.15(m,3H),4.40-4.28(m,2H),4.14-4.05(m,1H),3.99-3.95(m,1H),3.45-3.34(m,3H),3.13-3.05(m,1H),2.40-1.86(m,14H),0.99-0.87(m,3H). 19FNMR(377MHz,CD 3OD)δ-139.62,-137.73.LC-MS:m/z＝618.3[M+H] + .
化合物83:1-(7-(8-乙基-3-羟基萘-1-基)-8-氟-2-(((2R，7aS)-2-氟四氢-1H- 吡咯嗪-7a(5H)基)甲氧基)嘧啶[4，3-d]嘧啶-4-基)-4-氟吡咯烷-3，4-二醇二醇(顺式- 消旋-二醇),甲酸盐
Figure PCTCN2022124111-appb-000320
1H NMR(400MHz,DMSO-d6)δ9.90(br,1H),9.22(d,J＝2.8Hz,1H),7.67(d,J＝8.4Hz,1H),7.37(t,J＝7.6Hz,1H),7.28(d,J＝2.0Hz,1H),7.12(d,J＝6.8Hz,1H),6.96(dd,J＝6.0,2.4Hz,1H),5.21-5.35(m,1H),4.81(br,1H),4.30(br,1H),3.97-4.17(m,5H),3.66-3.80(m,2H),3.14(m,2H),3.02(s,1H),2.82-2.84(m,1H),2.13-2.25(m,3H),2.00-2.09(m,2H),1.77-1.86(m,3H),1.31(s,3H),0.82(t,J＝6.8Hz,3H). 19F NMR(377MHz,DMSO-d6)δ-139.1,-172.3.LC-MS:m/z＝592.1[M+H] +.
实施例4
化合物84:8-氟-1-(7-乙炔基-7-氟萘-1-基)-8-氟-2-(2R,7aS)-2-氟四氢-1H-吡咯嗪-7a-基)甲氧 基)-5-甲氧基吡啶并[4,3-d]嘧啶-4-基)-3-甲基哌啶-3-醇
Figure PCTCN2022124111-appb-000321
步骤1:2，6-二氯-3-氟吡啶-4-胺
将4-氨基-2,6-二氯吡啶溶于甲醇(500mL)和水(100mL)的混合溶液中，室温下加入1-氯甲基-4-氟-1,4-二氮杂双环[2.2.2]辛烷二(四氟硼酸)盐(130g,367mmol)，然后升温至45℃反应16小时。LCMS监测原料反应完成后，反应液浓缩后用乙酸乙酯(500mL)稀释，加水(500mL)萃取，有机相用饱和食盐水(500mL)洗，无水硫酸钠干燥，浓缩得灰色标题化合物84-1与原料的混合物粗品(50g)。 1H NMR(400MHz,CDCl 3)δ6.63(d,J＝5.6Hz,1H),4.56(s,2H).
步骤2:叔丁基(叔丁氧羰基)(2，6-二氯-3-氟吡啶-4-基)氨基甲酸酯
将化合物84-1(50g,278mmol)溶解于四氢呋喃(500mL)中，室温下滴加二碳酸二叔丁酯(150g,687mmol)和4-二甲氨基吡啶(2g,16.3mmol)，然后升温至60℃.反应4小时。浓缩反应液,加入甲醇(250mL)打浆得到白色标题化合物粗品84-2(50g)。 1H NMR(400MHz,CDCl 3)δ7.16(d,J＝4.4Hz,1H),1.47(s,18H).
步骤3:4-(叔丁氧羰基)氨基叔丁酯-2，6-二氯-5-氟烟酸酯
将二异丙胺(37.1g,367mmol)溶解在四氢呋喃(300mL)中，在氮气保护-78℃下滴加正丁基锂(146.8mL,367mmol，2.5M)，保持温度搅拌1小时。然后再向上述反应液 中滴加用四氢呋喃(150mL)溶解的84-2(50g,132mmol)，继续反应1小时。反应液用乙酸淬灭至不再冒泡，加入乙酸乙酯(500mL)和水(500mL)萃取，有机相用饱和食盐水(500mL)洗，无水硫酸钠干燥，浓缩。残余物用硅胶层析柱(石油醚:乙酸乙酯＝20:1)得白色固体标题化合物84-3(20g,Yield:40％)。 1H NMR(400MHz,DMSO)δ7.18(s,1H),1.62(s,9H),1.50(s,9H).
步骤4:4-氨基-2，6-二氯-5-氟烟酸
向化合物84-3(10g,26.25mmol)中加入4M HCl/1,4-二氧六环溶液(100mL)，在室温下反应16小时。反应液浓缩得到白色固体标题化合物84-4(5.5g,yield:93％)。LCMS(ESI,M/Z):[M+H]+＝225.0
步骤5:5，7-二氯-8-氟-2-巯基吡啶并[4，3-d]嘧啶-4(3H)-酮
将化合物84-4(5g,22.32mmol)溶解在氯化亚砜(150mL)中，滴加2滴N,N-二甲基甲酰胺，然后升温至90℃反应3小时。LCMS监测原料反应完成后,反应液浓缩然后加入硫氰酸铵(5.10g,66.96mmol)和四氢呋喃(10mL)，在室温下继续反应2小时。反应液用乙酸乙酯(200mL)稀释，加水(200mL)萃取，有机相用饱和食盐水(200mL)洗，无水硫酸钠干燥，浓缩得到黄色固体标题化合物84-5(5.5g,yield:94.82％)。
步骤6:5，7-二氯-8-氟-2-甲硫基吡啶并[4，3-d]嘧啶-4(3H)-酮
将化合物84-5(5.4g,20.3mmol)溶解于甲醇(400mL)和水(400mL)的混合溶液中，加入碘甲烷(5.76g,40.6mmol)和氢氧化钠(1.62g,40.6mmol)，在室温下反应2小时。反应液用水(400mL)稀释，加入2M稀盐酸将pH调至7，过滤，滤饼用水洗，干燥后得到黄色固体标题化合物84-6(3.8g,yield:67.13％)。LCMS(ESI,M/Z):[M+H] +＝279.9
步骤7:7-氯-8-氟-5-甲氧基-2-甲硫基吡啶并[4，3-d]嘧啶-4(3H)-酮
将化合物84-6(2g，7.14mmol)溶于N，N-二甲基乙酰胺(20mL)和甲醇(2mL)，并加入甲醇钠(1.93g，35.70mmol)，混合物在50℃搅拌16小时。LCMS检测原料反应完全。反应液加水(100mL)稀释，然后加入稀盐酸调节pH到7以析出大量固体，将反应液过滤，滤饼干燥后得到黄色固体标题化合物84-7(1.2g，收率：60.96％)。LC-MS:m/z＝275.9[M+H] +.
步骤8:(R)-1-7-氯-8-氟-5-甲氧基-2-甲硫基吡啶并[4，3-d]嘧啶-4-基)-3-甲基哌啶-3-醇
将化合物84-7(800mg，2.90mmol)溶于N，N-二甲基甲酰胺(30mL)，并加入(R)-3- 甲基哌啶-3-醇盐酸盐(1.30g，3.77mmol)，苯并三唑-1-基-氧化三吡咯烷基磷六氟磷酸铵(3.02g，5.80mmol)，和1,8-二氮杂二环[5.4.0]十一碳-7-烯(2.21g，14.51mmol)，混合物在25℃搅拌1小时。反应液加乙酸乙酯(200mL)稀释并加水(200mL)萃取，重复三次。有机相用无水硫酸钠干燥，过滤，真空浓缩滤液。粗品经硅胶柱层析(石油醚/乙酸乙酯＝0-30％)纯化得到黄色固体标题化合物84-8(600mg，收率：55.46％)。LC-MS:m/z＝373.0[M+H] +.
步骤9:(R)-1-(8-氟-7-(7-氟-8-(三异丙基硅基)乙炔基)萘-1-基)-5-甲氧基-2-甲硫基吡啶并[4，3-d]嘧啶-4-基)-3-甲基哌啶-3-醇
将化合物84-8(600mg，1.61mmol)溶于1,4-二氧六环(12mL)和水(3mL)中，并加入(2-氟-8-(4,4,5,5-四甲基-1,3,2-二氧苯并呋喃-2-基)萘-1-基)乙炔基)三异丙基硅烷(946.63mg，2.09mmol)，钯(cas号：1651823-59-4)(234.40mg，0.321mmol)，和磷酸钾(1.02g，4.83mmol)，混合物在95℃搅拌3小时。LCMS检测原料反应完全。反应液加乙酸乙酯(100mL)稀释并加水(100mL)萃取，重复三次。有机相用无水硫酸钠干燥，过滤，真空浓缩滤液。粗品经硅胶柱层析(石油醚/乙酸乙酯＝0-60％)纯化得到黄色泡沫固体标题化合物84-9(620mg，收率：58.12％)。LC-MS:m/z＝663.1[M+H] +.
步骤10:(3R)-1-(8-氟-7-(7-氟-8-(三异丙基硅基)乙炔基)萘-1-基)-5-甲氧基-2-(甲基亚磺酰基)吡啶并[4，3-d]嘧啶-4-基)-3-甲基哌啶-3-醇
将化合物84-9(600mg，0.905mmol)溶于二氯甲烷(10mL)，冷却至0℃，并加入3-氯过氧苯甲酸(202.12g，0.995mmol)，混合物在0℃搅拌30分钟。LCMS检测原料反应完全。反应液加二氯甲烷(100mL)稀释并加水(100mL)萃取，重复三次。有机相用无水硫酸钠干燥，过滤，真空浓缩滤液。粗品经硅胶柱层析(石油醚/乙酸乙酯＝0-100％)纯化得到黄色固体标题化合物84-10(330mg，收率：63.70％)。LC-MS:m/z＝679.1[M+H] +.
步骤11:(R)-1-(8-氟-7-(7-氟-8-(三异丙基硅基)乙炔基)萘-1-基)-2-((2R，7aS)-2-氟四氢-1H-吡啶-7a(5H)-基)甲氧基)-5-甲氧基吡啶并[4，3-d]嘧啶-4-基)-3-甲基哌啶-3-醇
将((2R，7aS)-2-氟四氢呋喃-1H-吡咯啉-7a(5H)-基)甲醇(145.39mg，0.913mmol)溶于四氢呋喃(4mL)中，并加入氢化钠(54.79mg，1.37mmol)，混合物在0℃搅拌30分钟。然后加入84-10(310mg，0.456mmol)，混合物在0℃搅拌30分钟。LCMS检测原料反应完全。反应液加乙酸乙酯(100mL)稀释并加水(100mL)萃取，重复三次。有机相用无水硫酸钠干燥，过滤，真空浓缩滤液。粗品经硅胶柱层析(石油醚/乙酸乙酯＝0-100％)纯化得到黄色固体标题化合物84-11(120mg，收率：33.95％)。LC-MS:m/z＝774.3[M+H] +.
步骤12:8-氟-1-(7-乙炔基-7-氟萘-1-基)-8-氟-2-(2R,7aS)-2-氟四氢-1H-吡咯嗪-7a-基)甲氧基)-5-甲氧基吡啶并[4,3-d]嘧啶-4-基)-3-甲基哌啶-3-醇
将84-11(50mg，0.064mmol)溶于N，N-二甲基甲酰胺(1mL)中，并加入氟化铯(98.13mg，0.645mmol)，混合物在60℃搅拌1小时。LCMS检测原料反应完全。反应液经Prep-HPLC(乙腈/水/碳酸氢铵)纯化得白色固体标题化合物84(16.67mg，收率：41.78％)。 1H NMR(400MHz,DMSO-d6)δ8.24–8.17(m,2H),7.77-7.67(m,2H),7.65-7.57(m,1H),5.28(d,J＝54.0Hz,1H),4.60(s,1H),4.44-4.30(m,1H),4.21-4.03(m,2H),3.98(d,J＝10.4Hz,1H),3.88(d,J＝4.4Hz,3H),3.52-3.46(m,1H),3.20-3.03(m,3H),3.01(s,1H),2.85-2.75(m,1H),2.16-1.97(m,4H),1.89-1.74(m,3H),1.67-1.52(m,3H),1.08(d,J＝20.0Hz,3H). 19F NMR(377MHz,DMSO-d6)δ-105.39(s),-105.53(s),-149.85(s),-150.71(s),-172.09(s),-172.16(s).LC-MS:m/z＝618.2[M+H] +.
实施例5
化合物85:(3R)-1-(7-(8-乙基-7-氟萘-1-基)-6,8-二氟-2-(2R,7aS)-2-氟四氢-1H-吡咯啉-7a(5H)- 基)甲氧基)喹唑啉-4-基)-3-甲基哌啶-3-醇
Figure PCTCN2022124111-appb-000322
步骤1:(R)-1-(7-溴-2-氯-6,8-二氟喹唑啉-4-基)-3-甲基哌啶-3-醇
将化合物7-溴-2，4-二氯-6，8-二氟喹唑啉(1.0g,3.19mmol)溶于二氯甲烷(40mL)中，氮气保护下，降温至0℃，加入(R)-3-甲基哌啶-3-醇盐酸盐(480mg,3.19mmol)，滴入N,N-二异丙基乙胺(1.65g,12.76mmol)，保持0℃条件下继续反应1小时，TLC监测原料反应完全，反应液加入乙酸乙酯稀释(200mL)，1M稀盐酸洗(100mL x2)，饱和食盐水(100mL)洗涤，无水硫酸钠干燥，浓缩得黄色固体标题化合物85-1(1.2g,产率96％)。
步骤2:(R)-1-(7-溴-6,8-二氟-2-((2R,7aS)-2-氟四氢-1H-吡咯啉-7a(5H)-基)甲氧基)喹唑啉-4- 基)-3-甲基哌啶-3-醇.
将化合物85-1(1.7g,4.33mmol)溶于N,N-二甲基甲酰胺(20mL)和四氢呋喃(20mL)的混合液中，加入((2R,7aS)-2-氟四氢-1H-吡咯啉-7a(5H)-基)甲醇(2.07g,12.99mmol)，三乙烯二胺(486mg,4.33mmol)和碳酸铯(4.23g,12.99mmol)，25℃搅拌16小时，TLC监测原料反应完全，反应液加入乙酸乙酯稀释(200mL)，水(200mL x3)洗，饱和食盐水(200mL)洗涤，无水硫酸钠干燥，浓缩得黄色固体标题化合物85-2(2.2g,产率98％)。LC-MS:m/z＝515.1[M+H] +.
步骤3:(3R)-1-(7-(8-乙基-7-氟萘-1-基)-6,8-二氟-2-(2R,7aS)-2-氟四氢-1H-吡咯啉-7a(5H)-基)甲氧基)喹唑啉-4-基)-3-甲基哌啶-3-醇
将化合物85-2(100mg,0.194mmol)溶于1,4-二氧六环(6mL)和水(1.5mL)的混合溶液中，加入化合物2710-2(87mg,0.291mmol)，磷酸钾(123mg,0.582mmol)和甲磺酸[正丁基二(1-金刚烷基)膦](2-氨基-1,1'-联苯-2-基)钯(II)(28mg,0.0388mmol)，氮气保护下，升温至100℃反应18小时，TLC检测原料反应完全。将反应液降至室温，加水(100mL)稀释，乙酸乙酯萃取(100mL x2)，合并有机相，饱和食盐水(100mL)洗涤，无水硫酸钠干燥，浓缩，粗品经硅胶柱层析纯化和prep-HPLC纯化得类白色固体标题化合物85(7mg,收率6％)。 1H NMR(400MHz,CD 3OD)δ7.94(d,J＝8.0Hz,1H),7.82(dd,J＝9.2,6.0Hz,1H),7.72(dd,J＝14.8,10.0Hz,1H),7.44(t,J＝8.0Hz,1H),7.35-7.19(m,2H),5.38-5.18(m,1H),4.37-4.12(m,3H),3.99(d,J＝13.2Hz,1H),3.56-3.24(m,5H),3.11-2.98(m,1H),2.60-2.19(m,4H),2.16-1.83(m,5H),1.79-1.60(m,3H),1.19(s,3H),0.73(q,J＝7.2Hz,3H)； 19F NMR(377MHz,CD 3OD)δ-116.24,-118.15,-125.07,-173.81；LC-MS:m/z＝609.3[M+H] +.
化合物86:(8-反)-3-(7-(8-乙基-3-羟基萘-1-基)-8-氟-2-((2R，7aS)-2-氟四氢 -1H-吡咯利嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3-氮杂双环[3.2.1]辛烷-8-醇
Figure PCTCN2022124111-appb-000323
1H NMR(400MHz,CD 3OD)δ9.03(s,1H),7.62(d,J＝8.0Hz,1H),7.35(t,J＝7.2Hz,1H),7.28(d,J＝2.4Hz,1H),7.15(d,J＝6.8Hz,1H),7.01(d,J＝2.4Hz,1H),5.42-5.24(m,1H), 4.79-4.60(m,2H),4.32(dd,J＝30.4,10.4Hz,2H),4.16(s,1H),3.68-3.56(m,2H),3.43-3.31(m,2H),3.29-3.20(m,1H),3.11-3.00(m,1H),2.47-2.14(m,7H),2.09-1.98(m,2H),1.98-1.85(m,3H),1.58-1.45(m,2H),0.88(td,J＝7.6,2.0Hz,3H). 19F NMR(377MHz,CD 3OD)δ-139.30,-173.70；LC-MS:m/z＝602.3[M+H] +.
化合物87:(8-顺)-3-(7-(8-乙基-3-羟基萘-1-基)-8-氟-2-(2R,7aS)-2-氟四氢-1H- 吡咯嗪-7a(5H)基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3-氮杂双环[3.2.1]辛烷-8-醇
Figure PCTCN2022124111-appb-000324
1H NMR(400MHz,CD 3OD)δ9.10(s,1H),7.62(d,J＝8.4Hz,1H),7.35(t,J＝7.6Hz,1H),7.28(d,J＝2.4Hz,1H),7.15(d,J＝7.2Hz,1H),7.02(d,J＝8.4Hz,1H),5.40-5.27(m,1H),4.55-4.45(m,2H),4.37(d,J＝10.8Hz,1H),4.30(d,J＝10.8Hz,1H),4.13-4.05(m,3H),3.45-3.32(m,2H),3.30-3.25(m,1H),3.10-3.04(m,1H),2.44-1.91(m,10H),1.81-1.78(m,2H),1.59(d,J＝8.4Hz,2H),0.90-0.86(m,3H). 19F NMR(377MHz,CD 3OD)δ-139.30,-173.60；LC-MS:m/z＝602.3[M+H] +.
化合物88:(3-内)-8-(7-(8-乙基-3-羟基萘-1-基)-8-氟-2-(((2R,7aS)-2-氟四氢 -1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-8-氮杂双环[3.2.1]辛-3-醇
Figure PCTCN2022124111-appb-000325
1H NMR(400MHz,CD 3OD)δ9.07(s,1H),7.62(d,J＝8.0Hz,1H),7.34(t,J＝7.6Hz,1H),7.28(d,J＝2.8Hz,1H),7.15(d,J＝6.8Hz,1H),7.01(d,J＝2.4Hz,1H),5.64-5.44(m,1H),5.28-5.21(m,2H),4.43-4.32(m,2H),4.22-4.18(m,1H),3.56-3.38(m,3H),3.19-3.11(m,1H),2.53-2.20(m,9H),2.12-1.92(m,7H),0.92-0.88(m,3H). 19F NMR(377MHz,CD 3OD)δ-139.26,-173.78；LC-MS:m/z＝602.3[M+H] +.
化合物89:(3-外)-8-(7-(8-乙基-3-羟基萘-1-基)-8-氟-2-(((2R,7aS)-2-氟四氢 -1H-吡咯啉-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-8-氮杂双环[3.2.1]辛烷-3-醇
Figure PCTCN2022124111-appb-000326
1H NMR(400MHz,CD 3OD)δ9.11(s,1H),7.62(d,J＝8.0Hz,1H),7.35(t,J＝7.2Hz,1H),7.29(d,J＝2.0Hz,1H),7.16(d,J＝6.8Hz,1H),7.02(d,J＝1.6Hz,1H),5.40-5.27(m,3H),4.45-4.20(m,3H),3.40-3.23(m,3H),3.11-2.99(m,1H),2.42-1.78(m,16H),0.90(t,J＝7.2Hz,3H). 19F NMR(377MHz,CD 3OD)δ-139.03,-173.71；L C-MS:m/z＝602.3[M+H] +.
化合物90:(2-外)-8-(7-(8-乙基-3-羟基萘-1-基)-8-氟-2-(((2R,7aS)-2-氟四氢 -1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-8-氮杂双环[3.2.1]辛-2-醇(exo-)
Figure PCTCN2022124111-appb-000327
1H NMR(400MHz,CD 3OD)δ9.49(s,1H),7.62(d,J＝8.4Hz,1H),7.35(t,J＝7.6Hz,1H),7.28(d,J＝2.4Hz,1H),7.15(d,J＝7.2Hz,1H),7.02-7.00(m,1H),5.48-5.35(m,1H),5.30-5.21(m,2H),4.51-4.37(m,2H),3.99(br,1H),3.65-3.44(m,3H),3.28-3.18(m,1H),2.51-1.86(m,14H),1.71-1.64(m,2H),0.90(t,J＝7.6Hz,3H). 19FNMR(377MHz,CD 3OD)δ-139.93,-173.86；LC-MS:m/z＝602.3[M+H] +.
化合物91:2,3-反式-3,4-顺式-1-(7-(8-乙基-3-羟基萘-1-基)-8-氟 -2-((2R,7aS)-2-氟四氢-1H-吡咯利嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-2-甲基 吡咯烷-3,4-二醇(cis-rac)
Figure PCTCN2022124111-appb-000328
1H NMR(400MHz,CD 3OD)δ9.20(d,J＝4.0Hz,1H),8.49(br,0.86H),7.63(d,J＝8.0Hz,1H),7.36(t,J＝7.6Hz,1H),7.29(d,J＝2.4Hz,1H),7.16(d,J＝7.2Hz,1H),7.02(dd,J＝5.6,2.4Hz,1H),5.55-5.35(m,1H),4.65-4.37(m,5H),4.09-4.03(m,1H),4.00-3.92(m,1H),3.79-3.45(m,3H),3.29-3.20(m,1H),2.64-2.13(m,7H),2.11-1.94(m,1H),1.61-1.45(m,3H),0.93-0.83(m,3H)； 19F NMR(377MHz,CD 3OD)δ-139.19,-173.86；LC-MS:m/z＝592.3[M+H] +.
化合物92:3,4-反式-1-(7-(8-乙基-3-羟基萘-1-基)-8-氟-2-((2R,7aS)-2-氟四氢 -1H-吡咯里嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-4-氟哌啶-3-醇
Figure PCTCN2022124111-appb-000329
1H NMR(400MHz,CD 3OD)δ9.19(s,1H),7.62(d,J＝8.4Hz,1H),7.35(t,J＝7.6Hz,1H),7.29(d,J＝2.4Hz,1H),7.15(d,J＝7.2Hz,1H),7.02-7.01(m,1H),5.42-5.29(m,1H),4.74-4.61(m,1H),4.38(dd,J＝26.4,10.8Hz,2H),4.27-4.23(m,1H),4.12-3.93(m,4H),3.49-3.33(m,3H),3.14-3.08(m,1H),2.46-1.94(m,10H),0.89(t,J＝7.6Hz,3H)； 19F NMR(377MHz,CD 3OD)δ-139.30,-173.78,-187.82；LC-MS:m/z＝594.3[M+H] +.
化合物93:1-(7-(8-乙基-3-羟基萘-1-基)-8-氟-2-((2R,7aS)-2-氟四氢-1H-吡咯 里嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)氮杂环庚烷-4,5-反式-二醇
Figure PCTCN2022124111-appb-000330
1H NMR(400MHz,CD 3OD)δ9.16(s,1H),7.62(d,J＝8.4Hz,1H),7.35(t,J＝7.6Hz,1H),7.29(d,J＝2.4Hz,1H),7.15(d,J＝6.8Hz,1H),7.01(dd,J＝4.0,2.4H z,1H),5.46-5.33(m,1H),4.49-4.35(m,2H),4.17-4.00(m,4H),3.79-3.70(m,2H),3.59-3.40(m,3H),3.20-3.13(m,1H),2.41-2.19(m,7H),2.15-1.97(m,5H),0.93-0.85(m,3H)； 19F NMR(377MHz,CD 3OD)δ-139.3,-173.8；LC-MS:m/z＝606.3[M+H] +.
化合物94:1-(7-(8-乙基-7-氟-3-羟基萘-1-基)-8-氟-2-((2R,7aS)-2-氟四氢-1H- 吡咯里嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)哌啶-4-醇
Figure PCTCN2022124111-appb-000331
1H NMR(400MHz,CD 3OD)δ9.06(s,1H),7.67(dd,J＝8.8,5.6Hz,1H),7.30(d,J＝2.8Hz,1H),7.25(t,J＝9.6Hz,1H),7.05(d,J＝2.4Hz,1H),5.46-5.33(m,1H),4.50-4.34(m,4H),4.09-4.01(m,1H),3.88-3.77(m,2H),3.59-3.40(m,3H),3.23-3.12(m,1H),2.51-2.32(m,3H),2.26-1.99(m,7H),1.81-1.68(m,2H),0.79(t,J＝7.2Hz,3H). 19F NMR(377MHz,CD 3OD)δ-121.1,-139.1,-173.8；LC-MS:m/z＝594.3[M+H] +.
化合物95:1-(7-(8-乙基-3-羟基萘-1-基)-8-氟-2-((2R,7aS)-2-氟四氢-1H-吡咯 里嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)氮杂环庚烷-4,5-顺式-二醇
Figure PCTCN2022124111-appb-000332
1H NMR(400MHz,CD 3OD)δ9.18(s,1H),8.45(s,1.27H),7.63(d,J＝8.4Hz,1H),7.36(t,J＝7.6Hz,1H),7.29(d,J＝2.4Hz,1H),7.16(d,J＝7.2Hz,1H),7.01(d,J＝2.4Hz,1H),5.54-5.41(m,1H),4.62-4.54(m,1H),4.53-4.47(m,1H),4.24-4.13(m,2H),4.10-4.01(m,2H),3.97-3.90(m,2H),3.78-3.58(m,3H),3.39-3.34(m,1H),2.55-2.19(m,9H),2.13-2.02(m,3H),0.92-0.85(m,3H). 19F NMR(377MHz,CD 3OD)δ-139.41,-173.92；LC-MS:m/z＝606.3[M+H] +.
化合物96:2-(7-(8-乙基-3-羟基萘-1-基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯 嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-2-氮杂双环[2.2.2]辛烷-6-反-醇
Figure PCTCN2022124111-appb-000333
1H NMR(400MHz,CD 3OD)δ9.26(s,1H),7.62(d,J＝8.0Hz,1H),7.35(t,J＝8.0Hz,1H),7.28(d,J＝2.4Hz,1H),7.16(d,J＝6.8Hz,1H),7.00(t,J＝2.4Hz,1H),5.52-5.32(m,1H),5.17-4.99(m,1H),4.44-4.30(m,2H),4.30-4.22(m,1H),4.13-3.92(m,2H),3.62-3.46(m,3H),3.23-3.17(m,1H),2.44-2.11(m,10H),2.03-1.93(m,2H),1.87-1.73(m,2H),1.60-1.55(m,1H),0.90(t,J＝7.6Hz,3H).(2个活泼氢未出)； 19FNMR(377MHz,CD 3OD)δ-139.16,-173.80；LC-MS:m/z＝602.3[M+H] +.
化合物97:1-(7-(8-乙基-7-氟-3-羟基萘-1-基)-8-氟-2-((2R,7aS)-2-氟四氢-1H- 吡咯烷-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)吡咯烷-3,4-顺式-二醇
Figure PCTCN2022124111-appb-000334
1H NMR(400MHz,CD 3OD)δ9.27(s,1H),7.68(dd,J＝8.8,5.6Hz,1H),7.31(d,J＝2.4Hz,1H),7.25(t,J＝9.6Hz,1H),7.06(d,J＝2.4Hz,1H),5.48-5.34(m,1H),4.52-4.28(m,5H),4.14-3.90(m,3H),3.64-3.44(m,3H),3.24-3.14(m,1H),2.50-2.23(m,4H),2.20-2.08(m,3H),2.04-1.95(m,1H),0.79(t,J＝3.2Hz,3H). 19F NMR(377M Hz,CD 3OD)δ-121.12,-138.83,-173.81；LC-MS:m/z＝596.3[M+H] +.
化合物98:1-(7-(8-乙基-3-羟基萘-1-基)-8-氟-2-(2R,7aS)-2-氟四氢-1H-吡咯嗪 -7a(5H)基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-6-甲基哌啶-3,4-顺式-二醇(cis-rac)
Figure PCTCN2022124111-appb-000335
1H NMR(400MHz,CD 3OD)δ9.43-9.41(m,1H),7.63(d,J＝8.0Hz,1H),7.36(t,J＝7.6Hz,1H),7.29(d,J＝2.4Hz,1H),7.16(d,J＝7.2Hz,1H),7.01(dd,J＝7.2,2.8Hz,1H),5.56-5.43(m,1H),5.31-5.24(m,1H),4.65-4.51(m,3H),4.13-4.07(m,2H),3.84-3.65(m,4H),2.63-1.96(m,10H),1.78-1.74(m,1H),1.51-1.49(m,3H),0.91-0.86(m,3H). 19F NMR(377MHz,CD 3OD)δ-76.96,-139.92,173.94；LC-MS:m/z＝606.3[M+H] +.
化合物99:2-(7-(8-乙基-3-羟基萘-1-基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯 嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-2-氮杂双环[2.2.2]辛烷-6-顺-醇
Figure PCTCN2022124111-appb-000336
1H NMR(400MHz,CD 3OD)δ9.33(d,J＝2.4Hz,1H),7.62(d,J＝8.0Hz,1H),7.35(t,J＝8.0Hz,1H),7.28(d,J＝2.4Hz,1H),7.15(d,J＝6.8Hz,1H),7.00(t,J＝2.4Hz,1H),5.44-5.30(m,2H),4.49-4.30(m,2H),4.23-3.76(m,3H),3.56-3.31(m,3H),3.16-3.10(m,1H),2.48-1.59(m,15H),0.91-0.88(m,3H). 19FNMR(377MHz,CD 3O D)δ-139.09,-173.77；LC-MS:m/z＝602.3[M+H] +.
化合物100:1-(7-(8-乙炔基-7-氟-3-羟基萘-1-基)-8-氟-2-((2R，7aS)-2-氟四氢 -1H-吡咯啉-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)哌啶-4-醇
Figure PCTCN2022124111-appb-000337
1H NMR(400MHz,CD 3OD)δ8.98(s,1H),7.85(dd,J＝9.2,5.6Hz,1H),7.37-7.26(m,2H),7.22(d,J＝2.4Hz,1H),5.40-5.21(m,1H),4.44-4.34(m,2H),4.34-4.23(m,2H),4.08-3.99(m,1H),3.85-3.74(m,2H),3.40(d,J＝4.8Hz,1H),3.29-3.16(m,3H),3.07-2.97(m,1H),2.40-2.19(m,2H),2.19-1.83(m,6H),1.82-1.69(m,2H). 19F NMR(377MHz,CD 3OD)δ-111.71,-139.87,-173.67；LC-MS:m/z＝590.3[M+H] +.
化合物101:(3R,4S)-1-(7-(8-乙基-3-羟基萘-1-基)-8-氟-2-((2R,7aS)-2-氟四氢 -1H-吡咯里嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)哌啶-3,4-二醇
Figure PCTCN2022124111-appb-000338
1H NMR(400MHz,CD 3OD)δ9.19(s,1H),7.62(d,J＝8.0Hz,1H),7.35(t,J＝7.2Hz,1H),7.28(d,J＝2.8Hz,1H),7.15(d,J＝6.8Hz,1H),7.01(t,J＝2.8Hz,1H),5.42-5.25(m,1H),4.39-4.29(m,4H),4.03-3.86(m,3H),3.71-3.64(m,1H),3.43-3.25(m,3H),3.10-3.04(m,1H),2.43(s,5H),1.88(s,5H),0.91-0.96(m,3H). 19F NMR(377MHz,CD 3OD)δ-139.43,-173.71；LC-MS:m/z＝592.3[M+H] +.
化合物102:6-(7-(8-乙基-3-羟基萘-1-基)-8-氟-2-((2R，7aS)-2-氟四氢-1H-吡咯 里嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-6-氮杂螺环[2.5]辛烷-4-醇
Figure PCTCN2022124111-appb-000339
1H NMR(400MHz,CD 3OD)δ9.29(s,1H),7.63(d,J＝8.0Hz,1H),7.35(t,J＝7.2Hz,1H),7.29(d,J＝2.4Hz,1H),7.15(d,J＝7.2Hz,1H),7.02(d,J＝2.0Hz,1H), 5.52-5.38(m,1H),4.67-4.63(m,1H),4.56-4.43(m,3H),3.88-3.82(m,1H),3.76-3.54(m,4H),3.27-3.23(m,2H),2.59-2.14(m,8H),2.09-2.00(m,1H),1.19-1.13(m,1H),0.91-0.87(m,3H),0.72-0.68(m,1H),0.61-0.58(m,1H),0.55-0.46(m,2H). 19F NMR(377MHz,CD 3OD)δ-73.84,-139.79,-173.91；LC-MS:m/z＝602.3[M+H] +.
化合物103:1-(7-(8-乙基-3-羟基萘-1-基)-8-氟-2-((2R,7aS)-2-氟四氢-1H-吡咯 里嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)氮杂环庚烷-4-醇
Figure PCTCN2022124111-appb-000340
1H NMR(400MHz,CD 3OD)δ9.14(s,1H),7.62(d,J＝8.0Hz,1H),7.35(t,J＝7.2Hz,1H),7.28(d,J＝2.8Hz,1H),7.16(d,J＝7.2Hz,1H),7.01(d,J＝2.4Hz,1H),5.46-5.32(m,1H),4.49-4.42(m,1H),4.41-4.34(m,1H),4.23-4.06(m,3H),4.05-3.92(m,2H),3.59-3.39(m,3H),3.21-2.12(m,1H),2.50-2.18(m,7H),2.14-1.74(m,7H),0.89(t,J＝7.6Hz,3H). 19F NMR(377MHz,CD 3OD)δ-139.2,-173.7；LC-MS:m/z＝590.3[M+H] +.
化合物104:(R)-1-(7-(8-乙基-7-氟-3-羟基萘-1-基)-8-氟-2-((2R,7aS)-2-氟四氢 -1H-吡咯里嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3-甲基哌啶-3-醇
Figure PCTCN2022124111-appb-000341
1H NMR(400MHz,CD 3OD)δ9.22(s,1H),7.67(dd,J＝8.8,5.6Hz,1H),7.30(d,J＝2.8Hz,1H),7.24(t,J＝9.6Hz,1H),7.08-7.03(m,1H),5.43-5.29(m,1H),4.55(d,J＝13.2Hz,1H),4.44-4.24(m,3H),3.67-3.56(m,1H),3.47-3.36(m,4H),3.14-3.08(m,1H),2.49-1.75(m,12H),1.28(d,J＝9.6Hz,3H),0.83-0.77(m,3H). 19F NMR(377MHz,CD 3OD)δ-121.11,-193.30,-173.77；LC-MS:m/z＝608.3[M+H] +.
化合物105:1-(7-(3-氯-2-环丙基-5-羟基苯基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H- 吡咯嗪-7a(5H)-基)甲基)吡啶并[4,3-d]嘧啶-4-基)哌啶-4-醇
Figure PCTCN2022124111-appb-000342
1H NMR(400MHz,CD 3OD)δ9.06(s,1H),6.93(d,J＝2.0Hz,1H),6.75(d,J＝2.4Hz,1H),5.66-5.50(m,1H),4.67-4.58(m,2H),4.38-4.34(m,2H),4.04-3.79(m,6H),3.43-3.41(m,1H),2.58-2.03(m,8H),1.79-1.69(m,3H),0.58-0.57(m,2H),0.04-0.01(m,2H). 19F NMR(377MHz,CD 3OD)δ-76.96,-139.94,-174.13；LC-MS:m/z＝572.2[M+H] +.
化合物106:外-2-(7-(8-乙基-3-羟基萘-1-基)-8-氟-2-((2R,7aS)-2-氟四氢-1H- 吡咯啉-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-2-氮杂双环[2.2.1]庚烷-6-醇
Figure PCTCN2022124111-appb-000343
1H NMR(400MHz,DMSO-d 6)δ9.90(d,J＝5.6Hz,1H),9.18(br,1H),7.67(d,J＝8.0Hz,1H),7.37(t,J＝7.2Hz,1H),7.28(d,J＝2.4Hz,1H),7.16-7.07(m,1H),6.98-6.87(m,1H),5.47-5.22(m,1H),5.07-4.95(m,2H),4.38-3.87(m,4H),3.68-3.53(m,1H),3.27-3.01(m,3H),2.99-2.81(m,1H),2.64-2.55(m,1H),2.36-2.01(m,6H),1.98-1.75(m,4H),1.74-1.62(m,1H),1.59-1.43(m,1H),0.91-0.73(m,3H). 19F NMR(377MHz,DMSO-d 6)δ-139.20,-172.28；LC-MS:m/z＝588.3[M+H] +.
化合物107:1-(7-(8-乙基-7-氟-3-羟基萘-1-基)-8-氟-2-(((2R,7aS)-2-氟四氢 -1H-pyrrolizin-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3-甲基吡咯烷-3-醇
Figure PCTCN2022124111-appb-000344
1H NMR(400MHz,CD 3OD)δ9.26(s,1H),7.68(d,J＝9.2Hz,6.0Hz,1H),7.30(t,J＝2.8Hz,1H),7.25(t,J＝9.6Hz,1H),7.04(dd,J＝9.2Hz,2.4Hz,1H),5.44-5.30(m,1H),4.45-3.96(m,6H),3.54-3.36(m,3H),3.12-3.08(m,1H),2.51-1.92(m,10H),1.54(s,3H),0.82-0.77(m,3H). 19FNMR(377MHz,CD 3OD)δ-121.17,-138.75,-173.77；LC-MS:m/z＝594.3[M+H] +.
化合物108:1-(7-(8-乙炔基-7-氟-3-羟基萘-1-基)-8-氟-2-((2R,7aS)-2-氟四氢 -1H-吡咯啉-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)吡咯烷-3,4-顺式-二醇
Figure PCTCN2022124111-appb-000345
1H NMR(400MHz,CD 3OD)δ9.21(s,1H),7.86(dd,J＝9.2,6.0Hz,1H),7.3-7.28(m,2H),7.22(d,J＝2.4Hz,1H),5.51-5.30(m,1H),4.57-4.24(m,5H),4.17-3.84(m,3H),3.70-3.43(m,3H),3.41(d,J＝3.2Hz,1H),3.27-3.14(m,1H),2.55-2.31(m,2H),2.30-2.20(m,1H),2.20-2.09(m,2H),2.07-1.92(m,1H). 19F NMR(377MHz,CD 3OD)δ-111.67,-139.73,-173.85；LC-MS:m/z＝592.3[M+H] +.
化合物109:(R)-1-(7-(8-乙基-3-羟基萘-1-基)-8-氟-2-(2R,7aS)-2-氟四氢-1H- 吡咯嗪-7a(5H)基)甲氧基吡啶并[4,3-d]嘧啶-4-基)-3-甲基哌啶-3-醇
Figure PCTCN2022124111-appb-000346
1H NMR(400MHz,CD 3OD)δ9.20(d,J＝8.0Hz,1H),7.63(d,J＝8.4Hz,1H),7.35(t,J＝7.6Hz,1H),7.29(d,J＝2.4Hz,1H),7.16(d,J＝7.2Hz,1H),7.00(s,1H), 5.48-5.34(m,1H),4.57-4.28(m,4H),3.67-3.42(m,5H),3.20(s,1H),2.40-1.76(m,12H),1.30-1.27(m,3H),0.92-0.86(m,3H). 19F NMR(377MHz,CD 3OD)δ-139.72,-173.83；LC-MS:m/z＝590.3[M+H] +.
化合物110:(R)-1-(7-(8-乙炔基-7-氟-3-羟基萘-1-基)-8-氟-2-((2R,7aS)-2-氟四 氢-1H-吡咯啉-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3-甲基哌啶-3-醇
Figure PCTCN2022124111-appb-000347
1H NMR(400MHz,DMSO-d 6)δ10.18(d,J＝4.0Hz,1H),9.15(d,J＝62.0Hz,1H),7.98(dd,J＝9.2,6.0Hz,1H),7.50-7.42(m,1H),7.41-7.37(m,1H),7.22(dd,J＝18.0,2.4Hz,1H),5.44-5.20(m,1H),4.76(d,J＝22.8Hz,1H),4.44-4.27(m,1H),4.24-3.90(m,4H),3.59(t,J＝13.2Hz,1H),3.30-2.98(m,4H),2.96-2.78(m,1H),2.25-1.95(m,4H),1.94-1.75(m,3H),1.76-1.58(m,3H),1.17(d,J＝16.0Hz,3H). 19F NMR(377MHz,DMSO-d 6)δ-110.58,-140.49,-172.17；LC-MS:m/z＝604.3[M+H] +.
化合物111:3,4-反式-1-(7-(8-乙基-7-氟-3-羟基萘-1-基)-8-氟-2-((2R,7aS)-2- 氟四氢-1H-吡咯烷-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-4-甲基吡咯烷-3-醇
Figure PCTCN2022124111-appb-000348
1H NMR(400MHz,CD 3OD)δ9.28(s,1H),7.68(dd,J＝8.8,6.0Hz,1H),7.30(d,J＝2.8Hz,1H),7.25(t,J＝9.6Hz,1H),7.05(d,J＝2.0Hz,1H),5.47-5.33(m,1H),4.51-4.14(m,5H),3.88-3.44(m,5H),3.23-3.13(m,1H),2.55-2.31(m,4H),2.24-2.08(m,4H),2.05-1.92(m,1H),1.15(d,J＝6.8Hz,3H),0.79(t,J＝7.2Hz,3H). 19F NMR(377MHz,CD 3OD)δ-121.10,-138.86,-173.83；LC-MS:m/z＝594.3[M+H] +.
化合物112:3,4-顺式-1-(7-(8-乙基-3-羟基萘-1-基)-8-氟-2-((2R,7aS)-2-氟四氢 -1H-吡咯里嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-4-甲基哌啶-3,4-二醇
Figure PCTCN2022124111-appb-000349
1H NMR(400MHz,CD 3OD)δ9.09(s,1H),7.62(d,J＝8.0Hz,1H),7.35(t,J＝7.2Hz,1H),7.28(d,J＝2.8Hz,1H),7.15(d,J＝6.8Hz,1H),7.01(t,J＝2.8Hz,1H),5.34(d,J＝53.6Hz,1H),4.39-4.25(m,4H),3.88(q,J＝6.4Hz,1H),3.76-3.68(t,J＝10.0Hz,1H),3.65-3.62(m,1H),3.48-3.34(m,2H),3.26(s,1H),3.13-3.05(m,1H),2.43-2.16(m,5H),2.08-1.91(m,4H),1.83-1.74(m,1H),1.35(s,3H),0.89(t,J＝7.6Hz,3H). 19FNMR(377MHz,CD 3OD)δ-139.37,-173.73；LC-MS:m/z＝606.3[M+H] +.
化合物113:1-(7-(8-乙基-3-羟基萘-1-基)-8-氟-2-((2R,7aS)-2-氟四氢-1H-吡咯 里嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)哌啶-4-酮
Figure PCTCN2022124111-appb-000350
1H NMR(400MHz,DMSO-d 6)δ9.19(s,1H),8.32(s,1H),7.67(d,J＝8.0Hz,1H),7.37(t,J＝7.6Hz,1H),7.29(s,1H),7.12(d,J＝6.8Hz,1H),6.99(s,1H),5.28(d,J＝54.4Hz,1H),4.27(t,J＝4.8Hz,4H),4.16(d,J＝10.4Hz,1H),4.07(d,J＝10.4Hz,1H),3.09(d,J＝7.2Hz,2H),3.02(s,1H),2.88-2.80(m,1H),2.72(t,J＝5.2Hz,4H),2.32-2.17(m,2H),2.14(s,1H),2.04(d,J＝19.2Hz,2H),1.88-1.71(m,3H),0.82(t,J＝7.2Hz,3H). 19FNMR(377MHz,DMSO-d 6)δ-73.44,-139.34,-172.14；LC-MS:m/z＝574.3[M+H] +.
化合物114:5-乙基-4-(8-氟-2-((2R,7aS)-2-氟四氢-1H-吡咯里嗪-7a(5H)-基)甲 氧基)-4-(4-甲氧基哌啶-1-基)吡啶并[4,3-d]嘧啶-7-基)萘-2-醇
Figure PCTCN2022124111-appb-000351
1H NMR(400MHz,CD 3OD)δ9.05(s,1H),7.66-7.59(m,1H),7.36(t,J＝7.2Hz,1H),7.29(d,J＝2.4Hz,1H),7.16(d,J＝6.8Hz,1H),7.01(d,J＝2.4Hz,1H),5.54-5.33(m,1H),4.52(dd,J＝11.6,3.2Hz,1H),4.45(d,J＝11.6Hz,1H),4.33-4.23(m,2H),3.97-3.86(m,2H),3.73-3.49(m,4H),3.42(s,3H),3.30-3.19(m,1H),2.60-1.96(m,10H),1.89-1.77(m,2H),0.89(t,J＝7.6Hz,3H). 19FNMR(377MHz,CD 3OD)δ-139.55,-173.89；LC-MS:m/z＝590.3[M+H] +.
化合物115:(S)-1-(7-(8-乙基-3-羟基萘-1-基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H- 吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3-甲基哌啶-3-醇
Figure PCTCN2022124111-appb-000352
1H NMR(400MHz,CD 3OD)δ9.25(d,J＝5.6Hz,1H),7.63(d,J＝8.4Hz,1H),7.36(t,J＝7.6Hz,1H),7.30(d,J＝2.4Hz,1H),7.16(d,J＝7.2Hz,1H),7.02(d,J＝2.8Hz,1H),5.56(d,J＝51.6Hz,1H),4.72-4.60(m,3H),4.38-4.33(m,1H),4.12-3.75(m,3H),3.66-3.57(m,1H),3.52-3.37(m,2H),2.78-2.08(m,9H),1.93-1.72(m,3H),1.30(d,J＝9.6Hz,3H),0.92-0.87(m,3H). 19F NMR(377MHz,CD 3OD)δ-139.95,-174.00；LC-MS:m/z＝590.3[M+H] +.
化合物116:3,4-顺式-1-(7-(8-乙基-3-羟基萘-1-基)-8-氟-2-(((2R,7aS)-2-氟四氢 -1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3-甲基哌啶-3,4-二醇
Figure PCTCN2022124111-appb-000353
1H NMR(400MHz,CD 3OD)δ9.30(d,J＝7.6Hz,1H),7.63(d,J＝8.4Hz,1H),7.36(t,J＝7.6Hz,1H),7.30(d,J＝2.4Hz,1H),7.16(d,J＝7.2Hz,1H),7.01(d,J＝2.4Hz,1H),5.57(d,J＝51.2Hz,1H),4.74-4.63(m,3H),4.51-4.38(m,1H),4.01-3.78(m,3H),3.78-3.54(m,2H),3.49-3.42(m,2H),2.74-1.93(m,10H),1.32(d,J＝6.0Hz,3H),0.93-0.83(m,3H). 19F NMR(377MHz,CD 3OD)δ-139.96,-174.06；LC-MS:m/z＝606.3[M+H] +.
化合物117:3,4-反式-1-(7-(8-乙基-3-羟基萘-1-基)-8-氟-2-(((2R,7aS)-2-氟四氢 -1H-吡咯嗪-7a(5H)-基)甲氧基))吡啶并[4,3-d]嘧啶-4-基)-2-甲基哌啶-3,4-二醇
Figure PCTCN2022124111-appb-000354
1H NMR(400MHz,CD 3OD)δ9.31(s,1H),7.64(d,J＝8.0Hz,1H),7.36(t,J＝7.2Hz,1H),7.30(d,J＝2.8Hz,1H),7.16(d,J＝7.2Hz,1H),7.06-7.00(m,1H),5.68-5.48(m,1H),4.80-4.61(m,3H),4.47-4.28(m,2H),4.21-3.80(m,5H),3.52-3.41(m,1H),2.80-2.15(m,8H),1.68-1.50(m,3H),0.89(t,J＝7.6Hz,3H). 19F NMR(377MHz,C D 3OD)δ-139.38,-174.02；LC-MS:m/z＝592.3[M+H] +.
化合物118:(3R,4R)-1-(7-(8-乙基-3-羟基萘-1-基)-8-氟-2-(((2R，7aS) -2-氟四氢-1H-吡咯嗪-7a(5H)基)甲氧基)嘧啶[4，3-d]嘧啶-4-基)-4-氟吡咯烷-3， 4-二醇甲酸盐
Figure PCTCN2022124111-appb-000355
1H NMR(400MHz,DMSO-d6)δ9.87(s,1H),9.27(m,1H),7.67(d,J＝8.0Hz,1H),7.37(t,J＝7.6Hz,1H),7.28(d,J＝2.8Hz,1H),7.12(d,J＝6.8Hz,1H),6.96(dd,J＝6.0,2.4Hz,1H),5.12-5.42(m,3H),4.08-4.19(m,2H),3.81-3.93(m,2H),3.72(m,1H),2.88-3.13(m,4H),2.19-2.33(m,3H),2.03-2.09(m,2H),1.81(m,3H),1.37(s,3H),0.82(m,3H). 19F NMR(377MHz,DMSO-d6)δ-139.3,-172.5；LC-MS:m/z＝592.1[M+H] +.
化合物119:(2R，3S)-7-(7-(8-乙基-3-羟基萘-1-基)-8-氟-2-((2R，7aS) -2-氟四氢-1H-吡咯里嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-7-氮杂双环 [2.2.1]庚烷-2,3-二醇
Figure PCTCN2022124111-appb-000356
1H NMR(400MHz,DMSO-d 6)δ9.87(s,1H),9.30(s,1H),7.66(d,J＝8.0Hz,1H),7.37(t,J＝7.6Hz,1H),7.28(d,J＝2.4Hz,1H),7.12(d,J＝7.2Hz,1H),6.96(d,J＝2.4Hz,1H),5.28(d,J＝53.6Hz,1H),5.12(d,J＝2.0Hz,2H),4.75(t,J＝2.8Hz,2H),4.17-4.13(m,1H),4.07-4.04(m,1H),3.91(t,J＝2.4Hz,2H),3.28-3.08(m,3H),2.83(d,J＝6.4Hz,1H),2.33-2.13(m,3H),2.01-2.00(m,2H),1.86-1.71(m,4H),1.47(d,J＝8.0Hz,2H),1.24(s,1H),0.84-0.80(m,3H). 19F NMR(377MHz,DMSO_d 6)δ-139.66,-172.12；LC-MS:m/z＝604.2[M+H] +.
化合物120:1-(7-(8-乙基-3-羟基萘-1-基)-8-氟-2-((2R，7aS)-2-氟六氢-1H-吡咯 里嗪-7a-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3-甲基哌啶-3-醇
Figure PCTCN2022124111-appb-000357
1H NMR(400MHz,DMSO-d 6)δ9.21(d,J＝8.4Hz,1H),7.66(d,J＝8.0Hz,1H),7.36(t,J＝7.6Hz,1H),7.28(d,J＝2.8Hz,1H),7.12(d,J＝6.8Hz,1H),6.98(d,J＝2.8Hz,1H),5.38(d,J＝54.8Hz,1H),4.77-4.72(m,1H),4.35-4.28(m,1H),4.15-4.00(m,3H),3.65-3.50(m,1H),3.14-3.04(m,2H),3.01(m,1H),2.85-2.79(m,1H),2.33-2.01(m,6H),1.85-1.62(m,6H),1.16(d,J＝10.8Hz,3H),0.84-0.79(m,3H). 19F NMR(377MHz,DMSO-d 6)δ-139.76,-172.13；LC-MS:m/z＝590.3[M+H] +.
化合物121:(3R,6S)-1-(7-(8-乙基-3-羟基萘-1-基)-8-氟-2-((2R,7aS)-2-氟六氢 -1H-吡咯里嗪-7a-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-6-甲基哌啶-3-醇
Figure PCTCN2022124111-appb-000358
1H NMR(400MHz,DMSO-d 6)δ9.93(brs,1H),9.00(s,1H),7.66(d,J＝7.6Hz,1H),7.36(t,J＝7.6Hz,1H),7.28(d,J＝2.4Hz,1H),7.12(d,J＝7.2Hz,1H),6.98(d,J＝10.4Hz,1H),5.26(d,J＝54.8Hz,1H),4.87-4.85(m,1H),4.40-4.37(m,1H),4.19-4.04(m,2H),3.74-3.70(m,1H),3.21-3.15(m,1H),3.11-3.09(m,2H),3.03(s,1H),2.86-2.81(m,1H),2.30-2.13(m,3H),2.10-1.98(m,2H),1.86-1.77(m,5H),1.71-1.65(m,2H),1.44-1.42(m,3H),0.84-0.79(m,3H). 19F NMR(377MHz,DMSO-d 6)δ-139.51,-172.16；LC-MS:m/z＝590.3[M+H] +.
化合物122:(3R,4S)-1-(7-(8-乙基-3-羟基萘-1-基)-8-氟-2-((2R,7aS)-2-氟六氢 -1H-吡咯里嗪-7a-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-4-甲基哌啶-3-醇
Figure PCTCN2022124111-appb-000359
1H NMR(400MHz,DMSO-d 6)δ9.07(s,1H),7.66(d,J＝7.6Hz,1H),7.36(t,J＝8.0Hz,1H),7.28(d,J＝2.4Hz,1H),7.12(d,J＝7.2Hz,1H),6.97(t,J＝2.8Hz,1H),5.28(d,J＝54.4Hz,1H),4.55-4.41(m,2H),4.15-4.03(m,2H),3.38-3.27(m,2H),3.14-3.04(m,3H),3.01(s,1H),2.85-2.80(m,1H),2.30-2.13(m,3H),2.09-1.97(m,2H),1.87-1.74(m,4H),1.64-1.56(m,1H),1.43-1.37(m,1H),1.04(d,J＝6.4Hz,3H),0.81(t,J＝8.0Hz,3H). 19F NMR(377MHz,DMSO-d 6)δ-139.53,-172.14；LC-MS:m/z＝590.3[M+H] +.
化合物123:(2S，4R)-1-(7-(8-乙基-3-羟基萘-1-基)-8-氟-2-((2R，7aS) -2-氟六氢-1H-吡咯里嗪-7a-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-2-甲基哌啶-4-醇
Figure PCTCN2022124111-appb-000360
1H NMR(400MHz,DMSO-d 6)δ8.98(d,J＝2.8Hz,1H),7.66(d,J＝8.0Hz,1H),7.36(t,J＝7.6Hz,1H),7.28(d,J＝2.4Hz,1H),7.12(d,J＝6.8Hz,1H),6.99-6.96(m,1H),5.28(d,J＝53.6Hz,1H),5.01(s,1H),4.39(d,J＝11.6Hz,1H),4.18-4.14(m,1H),4.04(d,J＝10.4Hz,2H),3.18-3.14(m,2H),3.08(d,J＝10.4Hz,2H),3.01(s,1H),2.85-2.82(m,1H),2.26-2.12(m,2H),2.06-2.00(m,2H),1.89-1.77(m,2H),1.61-1.55(m,2H),1.45-1.42(m,3H),1.34-1.28(m,2H),0.95-0.92(m,3H),0.84-0.80(m,3H). 19F NMR(377MHz,DMSO_d 6)δ-139.54,-172.14；LC-MS:m/z＝590.3[M+H] +.
化合物124:(2S,4S)-1-(7-(8-乙基-3-羟基萘-1-基)-8-氟-2-((2R,7aS)-2-氟四氢 -1H-吡咯里嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-2-甲基哌啶-4-醇甲酸盐
Figure PCTCN2022124111-appb-000361
1H NMR(400MHz,DMSO-d 6)δ8.98(s,1H),8.17(s,0.69H),7.66(d,J＝8.0Hz,1H),7.36(t,J＝7.6Hz,1H),7.28(d,J＝2.8Hz,1H),7.12(d,J＝8.4Hz,1H),6.97(dd,J＝2.4,12.0Hz,1H),5.28(d,J＝54.0Hz,1H),4.90-4.80(m,2H),4.23-4.14(m,2H),4.07-4.03(m,2H),3.88-3.80(m,1H),3.14-3.04(m,2H),3.02(s,1H),2.86-2.80(m,1H),2.33-1.71(m,12H),1.61(d,J＝6.4Hz,3H),0.84-0.79(m,3H). 19F NMR(377MHz,DMSO_d 6)δ-139.53,-172.15；LC-MS:m/z＝590.3[M+H] +.
化合物125:(2R,4R)-1-(7-(8-乙基-3-羟基萘-1-基)-8-氟-2-((2R,7aS)-2-氟六氢 -1H-吡咯里嗪-7a-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-2-甲基哌啶-4-醇
Figure PCTCN2022124111-appb-000362
1H NMR(400MHz,DMSO-d 6)δ9.87(s,1H),8.98(s,1H),7.66(d,J＝8.0Hz,1H),7.37(t,J＝7.2Hz,1H),7.28(d,J＝2.8Hz,1H),7.12(d,J＝7.2Hz,1H),6.97(dd,J＝2.4,10.0Hz,1H),5.28(d,J＝53.2Hz,1H),4.87(t,J＝2.8Hz,1H),4.80(brs,1H),4.23-4.05(m,4H),3.88-3.80(m,1H),3.10-3.01(m,3H),2.85-2.79(m,1H),2.33-1.77(m,12H),1.61-1.59(m,3H),0.87-0.80(m,3H). 19F NMR(377MHz,DMSO-d 6)δ-139.57,-172.18；LC-MS:m/z＝590.2[M+H] +.
化合物126:(2R,4S)-1-(7-(8-乙基-3-羟基萘-1-基)-8-氟-2-((2R,7aS)-2-氟四氢 -1H-吡咯里嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-2-甲基哌啶-4-醇
Figure PCTCN2022124111-appb-000363
1H NMR(400MHz,DMSO-d 6)δ9.91(brs,1H),8.98(d,J＝2.4Hz,1H),8.21(s,0.39H),7.66(d,J＝7.6Hz,1H),7.37(t,J＝7.6Hz,1H),7.28(d,J＝2.8Hz,1H),7.12(d,J＝6.8Hz,1H),6.98-6.96(m,1H),5.27(d,J＝53.6Hz,1H),5.01(d,J＝5.6Hz,1H),4.79(brs,1H),4.39(d,J＝12.8Hz,1H),4.14-4.01(m,3H),3.57-3.47(m,1H),3.13-3.01(m,3H),2.85-2.79(m,1H),2.33-1.58(m,10H),1.50-1.49(m,2H),1.44-1.42(m,3H),0.84-0.79(m,3H). 19F NMR(377MHz,DMSO_d 6)δ-139.58,-172.16；LC-MS:m/z＝590.2[M+H] +.
化合物127:(3R,4R)-1-(7-(8-乙基-3-羟基萘-1-基)-8-氟-2-((2R,7aS)-2-氟四氢 -1H-吡咯里嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3-甲基哌啶-4-醇甲酸盐
Figure PCTCN2022124111-appb-000364
1H NMR(400MHz,DMSO-d 6)δ9.88(brs,1H),9.05(d,J＝3.6Hz,1H),8.15(s,0.38H),7.66(d,J＝8.0Hz,1H),7.37(t,J＝7.2Hz,1H),7.28(d,J＝2.4Hz,1H),7.12(d,J＝6.8Hz,1H),6.98(d,J＝2.8Hz,1H),5.28(d,J＝54.0Hz,1H),4.87(brs,1H),4.46-4.32(m,2H),4.18-4.04(m,2H),3.48-3.36(m,2H),3.22-3.05(m,3H),3.02(s,1H),2.86-2.80(m,1H),2.29-1.97(m,6H),1.86-1.57(m,5H),1.00(t,J＝6.0Hz,3H),0.82(t,J＝7.6Hz,3H). 19F NMR(377MHz,DMSO-d 6)δ-139.59,-172.14；LC-MS:m/z＝590.3[M+H] +.
化合物128:1-(7-(8-乙基-3-羟基萘-1-基)-8-氟-2-((2R，7aS)-2-氟四氢 -1H-吡咯里嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-4-甲基哌啶-4-醇
Figure PCTCN2022124111-appb-000365
1H NMR(400MHz,DMSO-d 6)δ9.88(s,1H),9.06(s,1H),7.66(d,J＝8.0Hz,1H),7.36(t,J＝8.4Hz,1H),7.28(d,J＝2.4Hz,1H),7.12(d,J＝4.8Hz,1H),6.97(d,J＝2.4Hz,1H),5.28(d,J＝54.0Hz,1H),4.56(s,1H),4.28-4.15(m,2H),4.14-4.11(m,1H),4.05-4.02(m,1H),3.76-3.69(m,2H),3.10-3.01(m,3H),2.85-2.82(m,1H),2.29-2.12(m,3H),2.06-2.00(m,2H),1.87-1.67(m,7H),1.22(s,3H),0.82(t,J＝7.6Hz,3H). 19F NMR(377MHz,DMSO_d 6)δ-139.64,-172.15；LC-MS:m/z＝590.2[M+H] +.
化合物129:4-(4-(2S，3R)-2,3-二甲基哌啶-1-基)-8-氟-2-((2R，7aS) -2-氟四氢-1H-吡咯啉-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-7-基)-5-乙基萘-2- 醇甲酸盐
Figure PCTCN2022124111-appb-000366
1H NMR(400MHz,DMSO-d 6)δ9.04-8.98(m,1H),8.25(s,0.44H),7.66(d,J＝8.4Hz,1H),7.37(t,J＝7.6Hz,1H),7.28(d,J＝2.4Hz,1H),7.12(d,J＝6.8Hz,1H),6.97(d,J＝9.2Hz,1H),5.28(d,J＝54.0Hz,1H),4.90-4.85(m,1H),4.65-4.63(m,1H),4.38(d,J＝12.9Hz),4.16(t,J＝9.6Hz,1H),4.02(d,J＝10.0Hz,1H),3.71(d,J＝10.8Hz,1H),3.40-2.80(m,5H),2.50-1.50(m,12H),1.45(t,J＝6.4Hz,3H),0.87-0.80(m,3H). 19F NMR(377MHz,DMSO_d 6)δ-139.64,-172.15；LC-MS:m/z＝590.1[M+H] +.
化合物130:(3S，4R)-1-(7-(8-乙基-3-羟基萘-1-基)-8-氟-2-(2R，7aS) -2-氟四氢-1H-吡咯烷-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3-甲基哌啶-4- 醇甲酸盐
Figure PCTCN2022124111-appb-000367
1H NMR(400MHz,DMSO-d 6)δ9.96(brs,1H),9.05(s,1H),8.20(s,0.44H),7.66(d,J＝8.0Hz,1H),7.37(t,J＝7.6Hz,1H),7.28(d,J＝2.4Hz,1H),7.12(d,J＝6.8Hz,1H),6.98(s,1H),5.28(d,J＝54.0Hz,1H),4.80(brs,1H),4.17-3.98(m,4H),3.85-3.80(m,2H),3.75-3.65(m,1H),3.35-3.00(m,3H),2.86-2.82(m,1H),2.31-1.75(m,11H),0.93(t,J＝7.6Hz,3H),0.82(t,J＝7.6Hz,3H). 19F NMR(377MHz,DMSO-d 6)δ-139.68,-172.15；LC-MS:m/z＝590.3[M+H] +.
化合物131:(R)-1-(8-氟-7-(7-氟-8-甲基萘-1-基)-2-((2R,7aS)-2-氟四氢-1H-吡 咯啉-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3-甲基哌啶-3-醇
Figure PCTCN2022124111-appb-000368
1HNMR(400MHz,CD 3OD)δ9.21(d,J＝2.8Hz,1H),8.16-8.13(m,1H),8.07(dd,J＝8.8,5.6Hz,1H),7.70-7.64(m,2H),7.52(t,J＝8.8Hz,1H),5.33(m,1H),4.53(d,J＝12.4Hz,1H),4.37-4.27(m,3H),3.64-3.59(m,1H),3.48-3.36(m,2H),3.26-3.19(m,2H),3.08-3.02(m,1H),2.42-2.24(m,2H),2.19-2.14(m,2H),2.04-1.75(m,6H),1.29(d,J＝8.4Hz,3H). 19F NMR(377MHz,CD 3OD)δ-111.42,-140.11,-173.68；LC-MS:m/z＝598.2[M+H] +.
化合物132:(R)-1-7-(8-乙炔基-7-氟萘-1-基)-8-氟-2-(S)-1-(2R,7aS)-2-氟四氢 -1H-吡咯嗪-7a(5H)基)乙氧基)吡啶并[4,3-d]嘧啶-4-基)-3-甲基哌啶-3-醇
Figure PCTCN2022124111-appb-000369
1H NMR(400MHz,CD 3OD)δ9.23-9.07(m,1H),8.13-8.09(m,2H),7.68-7.62(m,2H),7.46-7.41(m,1H),5.49-5.35(m,1H),5.30-5.22(m,1H),4.67-4.53(m,1H),4.36-4.26(m,1H),3.68-3.35(m,6H),3.20-3.12(m,1H),2.79-2.62(m,1H),2.33-1.92(m,6H),1.85-1.67(m,3H),1.51-1.38(m,3H),1.29-1.24(m,3H). 19F NMR(377MHz,CD 3OD)δ-106.78,-140.16,-173.12；LC-MS:m/z＝602.2[M+H] +.
化合物133:1-(7-(8-乙炔基-7-氟萘-1-基)-8-氟-2-((2R,7aS)-2-氟四氢-1H-吡咯 啉-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3-(甲氧基甲基)哌啶-3-醇
Figure PCTCN2022124111-appb-000370
1H NMR(400MHz,CD 3OD)δ9.15-8.99(m,1H),8.08-7.94(m,2H),7.63-7.50(m,2H),7.39-7.29(m,1H),5.37-5.24(m,1H),4.57-4.23(m,4H),3.74-3.64(m,1H),3.58-3.23(m,9H),3.18-3.01(m,2H),2.43-2.23(m,2H),2.19-1.76(m,6H),1.74-1.59(m,2H). 19F NMR(377MHz,CD 3OD)δ-106.84,-140.23,-173.90；LC-MS:m/z＝618.3[M+H] +.
化合物134:(R)-1-(8-氟-7-(7-氟-8-甲基萘-1-基)-2-((2R,7aS)-2-氟四氢-1H-吡 咯啉-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3-甲基哌啶-3-醇
Figure PCTCN2022124111-appb-000371
1H NMR(400MHz,CD 3OD)δ9.26(d,J＝10.0Hz,1H),8.06(dd,J＝8.0,1.6Hz,1H),7.92(dd,J＝8.8,6.0Hz,1H),7.60-7.50(m,2H),7.36(t,J＝9.2Hz,1H),5.50-5.33(m,1H),4.63-5.54(m,1H), 4.51-4.39(m,2H),4.32(d,J＝13.6Hz,1H),3.69-3.57(m,2H),3.55-3.41(m,3H),3.24-3.16(m,1H),2.55-2.32(m,2H),2.29-2.10(m,4H),2.05-1.98(m,1H),1.93-1.87(m,3H),1.87-1.72(m,3H),1.30(d,J＝9.2Hz,3H). 19FNMR(377MHz,CD 3OD)δ-115.10,-140.47,-173.87；LC-MS:m/z＝578.3[M+H] +.
化合物135:1-(7-(8-乙炔基-7-氟萘-1-基)-6,8-二氟-2-((2R,7aS)-2-氟四氢-1H- 吡咯啉-7a(5H)-基)甲氧基)喹唑啉-4-基)哌啶-4-醇
Figure PCTCN2022124111-appb-000372
1H NMR(400MHz,DMSO-d 6)δ8.28-8.19(m,2H),7.73-7.68(m,1H),7.67-7.59(m,2H),7.54-7.48(m,1H),5.38-5.24(m,1H),4.87(d,J＝4.0Hz,1H),4.20-3.97(m,5H),3.89-3.79(m,1H),3.53-3.42(m,2H),3.23-3.03(m,3H),2.93-2.82(m,1H),2.23-2.02(m,3H),1.97-1.75(m,5H),1.69-1.56(m,2H). 19F NMR(377MHz,CD 3OD)δ-105.12,-118.24,-124.71,-172.19；LC-MS:m/z＝591.2[M+H] +.
化合物136:(R)-1-(7-(3-氯-2-环丙基苯基)-8-氟-2-((2R,7aS)-2-氟四氢-1H-吡 咯啉-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3-甲基哌啶-3-醇
Figure PCTCN2022124111-appb-000373
1H NMR(400MHz,CD 3OD)δ9.25(s,1H),7.55-7.53(m,1H),7.44-7.28(m,2H),5.38(d,J＝53.2Hz,1H),4.55(d,J＝13.6Hz,1H),4.44-4.41(m,2H),4.29(d,J＝13.2Hz,1H),3.61(d,J＝13.6Hz,1H),3.53-3.36(m,4H),3.21-3.06(m,1H),2.49-2.06(m,6H),2.04-1.72(m,5H),1.29(s,3H),0.81-0.62(m,2H),0.15(s,2H). 19F NMR(377MHz,CD 3OD)δ-139.98,-173.81；LC-MS:m/z＝570.3[M+H] +.
化合物137:(3R)-1-(7-(8-乙炔基-7-氟萘-1-基)-6,8-二氟-2-(2R,7aS)-2-氟四氢 -1H-吡咯啉-7a(5H)-基)甲氧基)喹唑啉-4-基)-3-甲基哌啶-3-醇
Figure PCTCN2022124111-appb-000374
1H NMR(400MHz,CD 3OD)δ8.15-8.05(m,2H),7.73-7.61(m,2H),7.57(d,J＝6.8Hz,1H),7.44(t,J＝8.8Hz,1H),5.53-5.28(m,1H),4.53-4.31(m,3H),4.14(d,J＝13.2Hz,1H),3.69-3.42(m,5H),3.39-3.32(m,1H),3.27-3.17(m,1H),2.57-2.23(m,3H),2.21-2.10(m,3H),2.06-1.95(m,1H),1.88-1.68(m,3H),1.26(d,J＝7.6Hz,3H). 19F NMR(377MHz,CD 3OD)δ-106.58,-119.06,-126.71,-173.96；LC-MS:m/z＝605.3[M+H] +.
化合物138:(R)-1-(7-(8-乙炔基-7-氟萘-1-基)-8-氟-2-((四氢-1H-吡咯啉 -7a(5H)-基)甲氧基)喹唑啉-4-基)-3-甲基哌啶-3-醇
Figure PCTCN2022124111-appb-000375
1H NMR(400MHz,CD 3OD)δ8.13-8.04(m,2H),8.00-7.91(m,1H),7.63(t,J＝7.6Hz,1H),7.54(t,J＝8.0Hz,1H),7.45-7.40(m,1H),7.37-7.32(m,1H),4.75-4.55(m,2H),4.45-4.37(m,1H),4.26-4.19(m,1H),3.72-3.51(m,3H),3.50-3.31(m,2H),3.29-3.23(m,2H),2.41-2.00(m,9H),1.91-1.67(m,3H),1.26(d,J＝8.8Hz,3H). 19F NMR(377MHz,CD 3OD)δ-106.85,-130.95；LC-MS:m/z＝569.3[M+H] +.
化合物139:(R)-1-(7-(8-乙炔基-7-氟萘-1-基)-8-氟-2-((2R,7aS)-2-氟四氢-1H- 吡咯啉-7a(5H)-基)甲氧基)喹唑啉-4-基)-3-甲基哌啶-3-醇
Figure PCTCN2022124111-appb-000376
1H NMR(400MHz,CD 3OD)δ8.14-8.03(m,2H),7.97-7.86(m,1H),7.67(s,1H),7.66-7.58(m,1H),7.56-7.49(m,1H),7.46-7.37(m,1H),7.36-7.27(m,1H),5.60-5.36(m,1H),4.67-4.48(m,2H),4.46-4.31(m,1H),4.26-4.14(m,1H),3.90-3.65(m,3H),3.56(t,J＝14.0Hz,1H),3.49-3.34(m,2H),2.68-2.46(m,2H),2.41-2.31(m,1H),2.28-2.12(m,3H),2.09-1.97(m,1H),1.89-1.70(m,3H),1.30-1.25(m,3H). 19F NMR(377MHz,CD 3OD)δ-106.85,-130.69,-174.28；LC-MS:m/z＝587.2[M+H] +.
化合物140:(R)-1-(7-(3-氯-8-乙炔基-7-氟萘-1-基)-8-氟-2-((2R,7aS)-2-氟四氢 -1H-吡咯啉-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3-甲基哌啶-3-醇
Figure PCTCN2022124111-appb-000377
1H NMR(400MHz,CD 3OD)δ9.23-9.11(m,1H),8.17(d,J＝2.4Hz,1H),8.09-8.05(m,1H),7.68-7.63(m,1H),7.52-7.46(m,1H),5.43-5.30(m,1H),4.67-4.55(m,1H),4.45-4.42(m,1H),4.36-4.27(m,2H),3.68-3.61(m,2H),3.52-3.33(m,4H),3.16-3.10(m,1H),2.48-1.70(m,10H),1.29-1.24(m,3H). 19F NMR(377MHz,CD 3OD)δ-106.13,-140.02,-173.79；LC-MS:m/z＝622.2[M+H] +.
化合物141:1-(7-(8-乙炔基-7-氟萘-1-基)-8-氟-2-((2R,7aS)-2-氟四氢-1H-吡咯 啉-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3-甲基氮杂环庚烷-3-醇
Figure PCTCN2022124111-appb-000378
1H NMR(400MHz,CD 3OD)δ9.39(d,J＝31.2Hz,1H),8.13-8.09(m,2H),7.68-7.63(m,2H),7.44(t,J＝9.2Hz,1H),5.38(d,J＝53.2Hz,1H),4.63-4.26(m,4H),4.03-3.73(m,2H),3.68-3.41(m,4H),3.19-3.12(m,1H),2.52-2.30(m,2H),2.30-2.03(m,5H),1.98-1.66(m,5H),1.36(d,J＝8.4Hz,3H). 19F NMR(377MHz,CD 3OD)δ-106.84,-139.80,-173.76；LC-MS:m/z＝602.3[M+H] +.
化合物142:(R)-1-(7-(8-乙炔基-7-氟萘-1-基)-8-氟-2-(S)-1-((2R,7aS)-2-氟四氢 -1H-吡咯啉-7a(5H)-乙氧基)吡啶并[4,3-d]嘧啶-4-基)-3-甲基哌啶-3-醇
Figure PCTCN2022124111-appb-000379
1H NMR(400MHz,CD 3OD)δ9.22-9.08(m,1H),8.13-8.08(m,2H),7.69-7.62(m,2H),7.46-7.41(m,1H),5.37-5.23(m,2H),4.64-4.52(m,1H),4.33-4.24(m,1H),3.67-3.35(m,6H),3.13-3.07(m,1H),2.40-1.95(m,7H),1.88-1.70(m,3H),1.43-1.38(m,3H),1.29-1.24(m,3H). 19F NMR(377MHz,CD 3OD)δ-106.82,-140.31,-173.77；LC-MS:m/z＝602.3[M+H] +.
化合物143:(R)-1-(7-(8-乙炔基-7-氟萘-1-基)-8-氟-2-((四氢-1H-吡咯啉 -7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3-甲基哌啶-3-醇
Figure PCTCN2022124111-appb-000380
1H NMR(400MHz,CD 3OD)δ9.27-9.13(m,1H),8.15-8.10(m,2H),7.70-7.64(m,2H),7.48-7.42(m,1H),4.78-4.58(m,4H),4.40-4.32(m,1H),3.67-3.62(m,2H),3.62-3.59(m,1H),3.45-3.35(m,1H),3.25-3.19(m,2H),2.35-2.03I(m,9H),1.88-1.72(m,3H),1.31-1.26(m,3H). 19F NMR(377 MHz,CD 3OD)δ-106.74,-140.80；LC-MS:m/z＝570.3[M+H] +.
化合物144:(R)-1-(2-(1-(二甲氨基)甲基)环丙基)甲氧基)-7-(8-乙炔基-7-氟萘-1- 基)-8-氟吡啶并[4,3-d]嘧啶-4-基)-3-甲基哌啶-3-醇
Figure PCTCN2022124111-appb-000381
1H NMR(400MHz,CD 3OD)δ9.23-9.09(m,1H),8.15-8.09(m,2H),7.72-7.62(m,2H),7.48-7.40(m,1H),4.86-4.66(m,1H),4.54-4.27(m,3H),3.66-3.33(m,3H),3.00-2.81(m,2H),2.66(s,6H),2.25-2.10(m,1H),1.89-1.70(m,3H),1.27(d,J＝20.0Hz,3H),0.86-0.71(m,4H). 19FNMR(377MHz,CD 3OD)δ-106.76,-140.54；LC-MS:m/z＝558.3[M+H] +.
化合物145:(R)-1-(2-(1-(二甲氨基)甲基)环丙基)甲氧基)-7-(8-乙基-7-氟萘-1-基)-8-氟吡啶并[4,3-d]嘧啶-4-基)-3-甲基哌啶-3-醇
Figure PCTCN2022124111-appb-000382
1H NMR(400MHz,CD 3OD)δ9.25(s,1H),8.06(d,J＝8.0Hz,1H),7.96-7.90(m,1H),7.58-7.52(m,1H),7.49-7.45(m,1H),7.37(t,J＝9.6Hz,1H),4.57(d,J＝12.4Hz,1H),4.44(s,2H),4.35-4.27(m,1H),3.67-3.57(m,1H),3.49-3.40(m,1H),3.14-3.04(m,2H),2.81(s,6H),2.58-2.48(m,1H),2.34-2.24(m,1H),2.20-2.11(m,1H),1.91-1.84(m,1H),1.82-1.75(m,2H),1.29(d,J＝8.8Hz,3H),0.93-0.89(m,2H),0.87-0.77(m,5H). 19F NMR(377MHz,CD 3OD)δ-112.32,-136.14；LC-MS:m/z＝562.3[M+H] +.
化合物146:((R)-1-(7-(8-乙炔基-7-氟萘-1-基)-8-氟-2-((2R,7aS)-2-氟四氢-1H- 吡咯啉-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)哌啶-3-基)甲醇
Figure PCTCN2022124111-appb-000383
1H NMR(400MHz,CD 3OD)δ9.05(s,1H),8.17-8.05(m,2H),7.72-7.58(m,2H),7.44(t,J＝8.8Hz,1H),5.38(d,J＝52.8Hz,1H),4.77-4.50(m,2H),4.46-4.31(m,2H),3.66-3.33(m,8H),3.21-3.08(m,1H),2.52-1.72(m,10H),1.55-1.40(m,1H). 19F NMR(377MHz,CD 3OD)δ-102.88,-136.13,-169.83；LC-MS:m/z＝588.3[M+H] +.
化合物147:1-(7-(8-乙炔基-7-氟萘-1-基)-8-氟-2-((2R,7aS)-2-氟四氢-1H-吡咯 啉-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-4-甲基氮杂环庚烷-4-醇
Figure PCTCN2022124111-appb-000384
1H NMR(400MHz,CD 3OD)δ9.13(d,J＝10.0Hz,1H),8.17-8.06(m,2H),7.71-7.60(m,2H),7.44(t,J＝8.8Hz,1H),5.53-5.40(m,1H),4.58-4.46(m,2H),4.28-4.13(m,2H),4.11-3.94(m,2H),3.82-3.46(m,4H),3.28-3.20(m,1H),2.63-2.36(m,3H),2.33-1.99(m,6H),1.97-1.79(m,2H),1.70-1.61(m,1H),1.29(d,J＝3.6Hz,3H). 19F NMR(377MHz,CD 3OD)δ-106.85,-139.98,-173.84；LC-MS:m/z＝602.3[M+H] +.
化合物148:2-氨基-4-(6,8-二氟-2-((2R,7aS)-2-氟四氢-1H-吡咯里嗪-7a(5H)-基) 甲氧基)-4-((R)-3-羟基-3-甲基哌啶-1-基)喹唑啉-7-基)-7-氟苯并噻吩-3-碳腈
Figure PCTCN2022124111-appb-000385
1H NMR(400MHz,CD 3OD)δ7.75(t,J＝8.8Hz,1H),7.29-7.25(m,1H),7.04(t,J＝9.2Hz,1H),5.41-5.28(d,J＝53.2Hz,1H),4.41-4.20(m,3H),4.04-4.01(d,J＝13.6Hz,1H),3.48-3.34(m,5H),3.13-3.07(m,1H),2.46-1.69(m,10H),1.25(d,J＝5.6Hz,3H). 19F NMR(400MHz, CD 3OD)δ-118.383,-119.463,-125.435,-173.791；LC-MS:m/z＝627.2[M+H] +.
化合物149:(3aR,6aS)-2-(7-(8-乙炔基-7-氟-3-羟基萘-1-基)-8-氟 -2-(2R,7aS)-2-氟六氢-1H-吡咯烷-7a-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-5-甲基八氢环 戊[c]吡咯-5-醇
Figure PCTCN2022124111-appb-000386
1H NMR(400MHz,CD 3OD)δ9.20(s,1H),7.86(dd,J＝8.8,3.2Hz,1H),7.35(d,J＝2.4Hz,1H),7.32(t,J＝8.8Hz,1H),7.21(d,J＝2.4Hz,1H),5.41(d,J＝52.8Hz,1H),4.51-4.39(m,2H),4.35-4.14(m,4H),3.67-3.48(m,3H),3.42-3.41(d,J＝4.4Hz,1H),3.24-3.18(m,1H),3.03(s,2H),2.53-2.32(m,2H),2.28-2.10(m,3H),2.06-2.00(m,3H),1.86-1.82(m,J＝13.6Hz,2H),1.36(s,3H). 19F NMR(377MHz,CD 3OD)δ-111.71,-140.06,-173.85；LC-MS:m/z＝630.3[M+H] +.
化合物150:5-乙炔基-6-氟-4-(8-氟-2-(((2R,7aS)-2-氟四氢 -1H-pyrrolizin-7a(5H)-基)甲氧基)-4-(((S)-2-羟丙基)氨基)吡啶并[4,3-d]嘧啶-7-基)萘-2-醇
Figure PCTCN2022124111-appb-000387
1H NMR(400MHz,DMSO-d 6)δ10.18(s,1H),9.34(s,1H),9.03(s,1H),7.98(dd,J＝9.2,6.0Hz,1H),7.46(t,J＝9.2Hz,1H),7.40(d,J＝2.4Hz,1H),7.16(t,J＝2.4H z,1H),5.43-5.24(m,1H),4.96(dd,J＝8.4,4.8Hz,1H),4.28-3.95(m,4H),3.65-3.58(m,1H),3.46-3.37(m,1H),3.23-2.81(m,4H),2.20-1.75(m,6H),1.16(d,J＝6.4Hz,3H). 19F NMR(377MHz,DMSO-d 6)δ-110.77,-140.54,-172.26；LC-MS:m/z＝564.2[M+H] +.
化合物151:(3R,5S)-1-(7-(8-乙基-7-氟-3-羟基萘-1-基)-8-氟-2-(2R,7aS)-2-氟 四氢-1H-吡咯烷-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-5-氟哌啶-3-醇
Figure PCTCN2022124111-appb-000388
1H NMR(400MHz,CD 3OD)δ9.32(d,J＝5.6Hz,1H),7.68(dd,J＝8.8,6.0Hz,1H),7.31(d,J＝2.4Hz,1H),7.27-7.23(m,1H),7.06(t,J＝2.4Hz,1H),5.46-5.02(m,2H),4.40-4.02(m,7H),3.42-3.34(m,2H),3.29-3.25(m,1H),3.12-3.03(m,1H),2.50-2.16(m,6H),2.18-1.87(m,4H),0.81-0.78(m,3H). 19F NMR(377MHz,CD 3OD)δ-121.12,-138.96,-173.72,-181.79；LC-MS:m/z＝612.3[M+H] +.
化合物152:2-氨基-4-(6-氯-8-氟-2-((2R,7aS)-2-氟四氢-1H-吡咯利嗪-7a(5H)- 基)甲氧基)-4-((R)-3-羟基-3-甲基哌啶-1-基)喹唑啉-7-基)-7-氟苯并噻吩-3-碳腈
Figure PCTCN2022124111-appb-000389
1H NMR(400MHz,CD 3OD)δ8.06(dd,J＝8.4,1.6Hz,1H),7.20(td,J＝9.6,4.4H z,1H),7.05-7.01(m,1H),5.43-5.29(m,1H),4.45-4.36(m,1H),4.35-4.21(m,2H),4.09-4.01(m,1H),3.56-3.34(m,5H),3.17-3.07(m,1H),2.47-2.27(m,2H),2.24-2.02(m,4H),1.98-1.89(m,1H),1.86-1.69(m,3H),1.26-1.22(m,3H). 19F NMR(377MHz,CD 3O D)δ-118.7,-124.1,-173.8；LC-MS:m/z＝643.2[M+H] +.
化合物153:(R)-1-(7-(8-乙基-7-氟-3-羟基萘-1-基)-8-氟-2-((S)-1-甲基吡咯 烷-2-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3-甲基哌啶-3-醇
Figure PCTCN2022124111-appb-000390
1H NMR(400MHz,CD 3OD)δ9.22(d,J＝2.8Hz,1H),7.67(dd,J＝8.8,5.6Hz,1H),7.34-7.19(m,2H),7.06(s,1H),4.61-4.48(m,3H),4.30(t,J＝12.0Hz,1H),3.61(dd,J＝24.0,10.8Hz,1H),3.50-3.39(m,1H),3.27-3.18(m,1H),3.10-2.99(m,1H),2.64(s,3H),2.61-2.40(m,2H),2.26-2.09(m,3H),1.96-1.70(m,6H),1.28(d,J＝9.6Hz,3H),0.81(q,J＝7.2Hz,3H).). 19F NMR(377MHz,CD 3OD)δ-121.11,-139.30；LC-MS:m/z＝564.3[M+H] +.
化合物154:5-乙炔基-6-氟-4-(8-氟-2-((2R，7aS)-2-氟四氢-1H-吡咯啉-7a(5H)- 基)甲氧基)-4-((R)-2-羟丙基)氨基)吡啶并[4,3-d]嘧啶-7-基)萘-2-醇
Figure PCTCN2022124111-appb-000391
1H NMR(400MHz,CD 3OD)δ9.18(d,J＝2.8Hz,1H),7.92-7.81(m,1H),7.42-7.25(m,2H),7.25-7.17(s,1H),5.54-5.41(d,J＝12.4Hz,1H),4.65-4.48(m,2H),4.22-4.13(m,1H),3.85-3.59(m,5H),3.36-3.30(m,2H),2.64-1.98(m,6H),1.30-1.28(m,3H). 19F NMR(377MHz,CD 3OD)δ-111.66,-140.31,-173.99；LC-MS：m/z＝564.2[M+H] +.
化合物155:(2S,4R)-1-(7-(8-乙炔基-7-氟萘-1-基)-8-氟-2-(((2R,7aS)-2-氟四氢 -1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶多[4,3-d]嘧啶-4-基)-2-甲基哌啶-4-醇
Figure PCTCN2022124111-appb-000392
1H NMR(400MHz,CD 3OD)δ8.97(d,J＝8.4Hz,1H),8.14-8.10(m,2H),7.67-7.63 (m,2H),7.45(t,J＝9.2Hz,1H),5.46-5.33(m,1H),5.23-5.11(m,1H),4.63-4.57(m,1H),4.49-4.44(m,1H),4.38-4.34(m,1H),4.24-4.16(m,1H),3.69-3.40(m,5H),3.21-3.13(m,1H),2.46-1.97(m,8H),1.80-1.66(m,2H),1.56(t,J＝6.8Hz,3H). 19F NMR(377MHz,CD 3OD)δ-106.80,-139.92,-173.86；LC-MS:m/z＝588.2[M+H] +.
化合物156:(R)-1-(7-(8-乙炔基-7-氟萘-1-基)-8-氟-2-((2R,7aS)-2-氟四氢-1H- 吡咯啉-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-5,5-二氟哌啶-3-醇
Figure PCTCN2022124111-appb-000393
1H NMR(400MHz,CD 3OD)δ9.22(d,J＝33.2Hz,1H),8.16-8.08(m,2H),7.68-7.66(m,2H),7.45(t,J＝8.8Hz,1H),5.35(d,J＝53.6Hz,1H),4.43-4.21(m,6H),3.80-3.68(m,1H),3.47-3.36(m,4H),3.13-3.05(m,1H),2.60-2.14(m,5H),2.10-1.88(m,3H). 19F NMR(377MHz,CD 3OD)δ-98.76,-106.69,-139.38,-173.78；LC-MS:m/z＝610.3[M+H] +.
化合物157:(3R,4S)-1-(7-(8-乙炔基-7-氟萘-1-基)-8-氟-2-((2R,7aS)-2-氟四氢 -1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)吡咯烷-3,4--二醇
Figure PCTCN2022124111-appb-000394
1H NMR(400MHz,CD 3OD)δ9.21(s,1H),8.14-8.07(m,2H),7.69-7.61(m,2H),7.44(t,J＝8.8Hz,1H),5.40-5.26(m,1H),4.48-4.23(m,5H),4.16-3.84(m,3H),3.55-3.32(m,3H),3.28-3.22(m,1H),3.12-2.99(m,1H),2.42-2.23(m,2H),2.21-2.12(m,1H),2.09-1.99(m,2H),1.96-1.87(m,1H). 19F NMR(377MHz,CD 3OD)δ-106.8,-139.5,-173.7；LC-MS:m/z＝576.2[M+H] +.
化合物158:(3aR,5S,6aS)-2-(7-(8-乙炔基-7-氟萘-1-基)-8-氟-2-((2R,7aS)-2-氟 四氢-1H-吡咯啉-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)八氢环戊[c]吡咯-5-醇
Figure PCTCN2022124111-appb-000395
1H NMR(400MHz,CD 3OD)δ9.20(s,1H),8.13-8.08(m,2H),7.68-7.63(m,2H),7.43(d,J＝8.8Hz,1H),5.41-5.28(m,1H),4.44-4.11(m,7H),3.49(d,J＝4.8Hz,1H),3.46-3.31(m,3H),3.11-3.05(m,1H),2.96-2.88(m,2H),2.44-2.16(m,5H),2.08-1.90(m,3H),1.70-1.66(d,J＝18.1Hz,2H). 19F NMR(377MHz,CD 3OD)δ-106.88,-139.84,-173.70；LC-MS:m/z＝600.2[M+H] +.
化合物159:2-(7-(8-乙炔基-7-氟萘-1-基)-8-氟-2-((2R,7aS)-2-氟四氢-1H-吡咯 啉-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-2-氮杂双环[4.1.0]庚烷-4-醇
Figure PCTCN2022124111-appb-000396
1H NMR(400MHz,CD 3OD)δ9.95(d,J＝8.0Hz,1H),8.18-8.08(m,2H),7.72-7.64(m,2H),7.50-7.41(m,1H),5.55-5.39(m,1H),5.01-4.91(m,1H),4.63-4.47(m,2H),4.31-4.24(m,1H),3.82-3.61(m,3H),3.59-3.45(m,2H),3.30-3.25(m,2H),2.61-2.18(m,6H),2.10-1.89(m,2H),1.73-1.62(m,1H),1.39-1.31(m,1H),1.19-1.03(m,1H). 19F NMR(377MHz,CD 3OD)δ-106.82,-139.91,-173.97；LC-MS:m/z＝586.2[M+H] +
化合物160:(R)-1-(7-(8-乙炔基-7-氟萘-1-基)-8-氟-2-((S)-1-甲基吡咯烷-2-基) 甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3-甲基哌啶-3-醇
Figure PCTCN2022124111-appb-000397
1H NMR(400MHz,CD 3OD)δ9.17(d,J＝51.6Hz,1H),8.17-8.04(m,2H),7.74-7.60(m,2H),7.44(td,J＝9.2,2.8Hz,1H),4.73-4.54(m,3H),4.41-4.26(m,1H),3.70-3.33(m,5H),2.89-2.69(m,4H),2.32-2.10(m,2H),2.08-1.89(m,3H),1.88-1.67(m,3H),1.27(d,J＝20.0Hz,3H). 19F NMR(377MHz,CD 3OD)δ-106.78,-140.16；LC-MS:m/z＝544.2[M+H] +.
化合物161:(3R,5S)-1-(7-(8-乙基-7-氟-3-(甲氧基甲氧基)萘-1-基)-8-氟 -2-(2R,7aS)-2-氟四氢-1H-吡咯啉-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-5-氟哌啶 -3-醇
Figure PCTCN2022124111-appb-000398
1H NMR(400MHz,CD 3OD)δ9.32-9.26(m,1H),8.14-8.10(m,2H),7.70-7.66(m,2H),7.45(t,J＝18.0Hz,1H),5.47-5.37(m,1H),5.05-4.92(m,1H),4.97-4.40(m,2H),4.38-4.31(m,1H),4.18-4.03(m,4H),3.59-3.40(m,4H),3.21-3.15(m,1H),2.52-1.94(m,8H). 19F NMR(377MHz,CD 3OD)δ-106.79,-140.05,-173.84,-181.62；LC-MS:m/z＝592.2[M+H] +
化合物162:(R)-1-(7-(8-乙炔基-7-氟萘-1-基)-8-氟-2-((2R,7aS)-2-氟四氢-1H- 吡咯啉-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)哌啶-3-醇
Figure PCTCN2022124111-appb-000399
1H NMR(400MHz,CD 3OD)δ9.15(d,J＝29.6Hz,1H),8.20-8.06(m,2H),7.76-7.59(m,2H),7.50-7.39m,1H),5.50(d,J＝54.0Hz,1H),4.68-4.49(m,2H),4.27-3.65(m,8H),3.54-3.45(m,1H),3.41-3.33(m,1H),2.69-2.43(m,2H),2.41-1.99(m,6H),1.87-1.69(m,2H). 19F NMR(377MHz,CD 3OD)δ-106.77,-140.31,-174.03；LC-MS:m/z＝574.2[M+H] +.
化合物163:1-(7-(8-乙炔基-7-氟萘-1-基)-8-氟-2-((2R,7aS)-2-氟四氢-1H-吡咯 啉-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)哌啶-4-醇
Figure PCTCN2022124111-appb-000400
1H NMR(400MHz,CD 3OD)δ9.02(s,1H),8.11(dd,J＝8.8,5.6Hz,2H),7.71-7.59(m,2H),7.44(t,J＝9.2Hz,1H),5.39(d,J＝53.2Hz,1H),4.51-4.31(m,4H),4.10-4.01(m,1H),3.89-3.74(m,2H),3.61-3.34(m,4H),3.21-3.11(m,1H),2.49-2.29(m,2H),2.25-1.95(m,6H),1.82-1.70(m,2H). 19F NMR(377MHz,CD 3OD)δ-106.796,-140.026,-173.837；LC-MS:m/z＝574.3[M+H] +.
化合物164:2-氨基-4-(6,8-二氟-2-((2R,7aS)-2-氟四氢-1H-吡咯啉-7a(5H)-基)甲 氧基)-4-(4-羟基哌啶-1-基)喹唑啉-7-基)-7-氟苯并噻吩-3-碳腈
Figure PCTCN2022124111-appb-000401
1H NMR(400MHz,CD 3OD)δ7.46(d,J＝9.6Hz,1H),7.19(dd,J＝8.4,5.2Hz,1H),6.95(t,J＝8.8Hz,1H),5.38-5.25(m,1H),4.45-4.24(m,2H),4.19-4.09(m,2H),3.95-3.83(m,1H),3.60-3.36(m,5H),3.17-3.07(m,1H),2.46-2.14(m,3H),2.11-1.84(m,5H),1.69-1.56(m,2H). 19F NMR(377MHz,CD 3OD)δ-118.2,-118.8,-125.3,-173.9；L C-MS:m/z＝613.3[M+H] +.
化合物165:3-乙基-1-(7-(8-乙炔基-7-氟萘-1-基)-8-氟-2-(2R,7aS)-2-氟四氢 -1H-吡咯啉-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)哌啶-3-醇
Figure PCTCN2022124111-appb-000402
1H NMR(400MHz,CD 3OD)δ9.23-9.08(m,1H),8.13-8.08(m,2H),7.71-7.63(m,2H),7.46-7.41(m,1H),5.37-5.23(m,1H),4.71-4.59(m,1H),4.41-4.22(m,3H),3.66-3.34(m,3H),3.29-3.15(m,3H),3.15-2.98(m,1H),2.38-2.12(m,4H),2.02-1.69(m,6H),1.61-1.45(m,2H),1.02-0.94(m,3H). 19F NMR(377MHz,CD 3OD)δ-106.84,-140.12,-173.67；LC-MS:m/z＝602.3[M+H] +.
化合物166:2-(1-(7-(8-乙炔基-7-氟萘-1-基)-8-氟-2-(2R，7aS)-2-氟四氢-1H- 吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3-羟基哌啶-3-基)乙腈
Figure PCTCN2022124111-appb-000403
1H NMR(400MHz,CD 3OD)δ9.15(d,J＝28.8Hz,1H),8.12-8.06(m,2H),7.70-7.60(m,2H),7.47-7.40(m,1H),5.45-5.31(d,J＝53.2Hz,1H),4.60-4.31(m,4H),3.91-3.81(m,1H),3.65-3.39(m,5H),3.18-3.10(m,1H),2.79-2.73(m,2H),2.49-2.04(m,6H),2.01-1.76(m,4H). 19F NMR(377MHz,CD 3OD)δ-106.81,-140.15,-173.79；LC-MS:m/z＝613.3[M+H] +.
化合物167:(R)-1-(7-(8-乙基-7-氟萘-1-基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡 咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3-甲基哌啶-3-醇
Figure PCTCN2022124111-appb-000404
1H NMR(400MHz,DMSO-d 6)δ9.25(s,1H),8.06(d,J＝7.6Hz,1H),8.06(dd,J＝8.0,6.0Hz,1H),7.45(t,J＝7.6Hz,1H),8.06(d,J＝4.8Hz,1H),7.27(t,J＝9.2H  z,1H),5.39-5.20(m,1H),4.48(d,J＝12.8Hz,1H),4.38-4.19(m,3H),3.57-3.29(m,5H),3.10-3.04(m,1H),2.48-1.66(m,12H),1.23-1.18(m,3H),0.76-0.70(m,3H). 19F NM R(377MHz,CD 3OD)δ-105.75,-140.33,-172.10；LC-MS:m/z＝592.3[M+H] +.
化合物168:2-氨基-4-(6-氯-8-氟-2-(2R，7aS)-2-氟四氢-1H-吡咯嗪-7a-基)甲氧 基)-4-(4-羟基哌啶-1-基)喹唑啉-7-基)-7-氟苯并[b]噻吩-3-甲腈
Figure PCTCN2022124111-appb-000405
1H NMR(400MHz,CD 3OD)δ7.79(s,1H),7.13-7.09(m,1H),6.96-6.92(m,1H),5.41-5.28(m,1H),4.45-4.30(m,2H),4.19-4.15(m,2H),3.93-3.87(m,1H),3.61-3.38(m,5H),3.18-3.10(m,1H),2.48-2.30(m,2H),2.25-2.16(m,1H),2.12-2.04(m,2H),2.01-1.89(m,3H),1.67-1.57(m,2H). 19F NMR(377MHz,CD 3OD)δ-118.58,-124.12,-174.04；LC-MS:m/z＝629.2[M+H] +.
化合物169:1-(7-(8-乙炔基-7-氟萘-1-基)-8-氟-2-((2R,7aS)-2-氟四氢-1H-吡咯 啉-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3-(羟甲基)哌啶-3-醇
Figure PCTCN2022124111-appb-000406
1H NMR(400MHz,CD 3OD)δ9.16-8.99(m,1H),8.08-7.96(m,2H),7.64-7.52(m,2H),7.39-7.29(m,1H),5.34-5.21(m,1H),4.57-4.20(m,4H),3.77-3.67(m,1H),3.60-3.25(m,7H),3.08-2.97(m,1H),2.40-2.21(m,2H),2.17-1.95(m,4H),1.92-1.59(m,4H). 19F NMR(377MHz,CD 3OD)δ-106.8,-140.1,-173.7；LC-MS:m/z＝604.3[M+H] +.
化合物170:(R)-1-(7-(7,8-二氟萘-1-基)-8-氟-2-((2R,7aS)-2-氟四氢-1H-吡咯里 嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3-甲基哌啶-3-醇
Figure PCTCN2022124111-appb-000407
1H NMR(400MHz,CD 3OD)δ9.14(d,J＝4.8Hz,1H),8.01(d,J＝7.6Hz,1H),7.81-7.88(m,1H),7.62-7.53(m,2H),7.47-7.40(m,1H),5.26(d,J＝53.6Hz,1H),4.46(d,J＝12.8Hz,1H),4.33-4.19(m,3H),3.60-3.49(m,1H),3.38-3.23(m,4H),3.04-2.98(m,1H),2.39-2.14(m,2H),2.14-1.75(m,6H),1.75-1.65(m,2H),1.18(s,3H). 19F NM R(377MHz,CD 3OD)δ-141.49,141.72,-144.16,-173.75；LC-MS:m/z＝582.3[M+H] +.
化合物171:(R)-1-(7-(8-乙炔基-7-氟萘-1-基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H- 吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3-甲基哌啶-3-醇甲酸盐
Figure PCTCN2022124111-appb-000408
1H NMR(400MHz,DMSO-d 6)δ9.24-9.11(m,1H),8.50(s,1H).8.14-8.10(m,2H),7.70-7.64(m,2H),7.47-7.42(m,1H),5.50-5.35(m,1H),4.70-4.58(m,1H),4.52-4.48(m,1H),4.43-4.30(m,2H),3.67-3.62(m,2H),3.55-3.35(m,4H),3.23-3.14(m,1H),2.56-2.11(m,6H),2.05-1.96(m,1H),1.86-1.72(m,3H),1.30-1.25(m,3H). 19F NMR(377MHz,CD 3OD)δ-106.80,-140.63,-173.90；LC-MS:m/z＝588.3[M+H] +.
化合物172:8-(7-(8-乙基-3-羟基萘-1-基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡 咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-8-氮杂双环[3.2.1]辛烷-2,3-反式-二醇
Figure PCTCN2022124111-appb-000409
1H NMR(400MHz,CD 3OD)δ9.50(s,1H),7.62(d,J＝8.0Hz,1H),7.34(t,J＝7.6Hz,1H),7.27(d,J＝2.4Hz,1H),7.15(d,J＝7.2Hz,1H),7.02-6.99(m,1H),5.46-5.34(m,1H),5.28-5.22 (m,2H),4.49-4.37(m,2H),3.95(br,1H),3.88-3.83(m,1H),3.64-3.39(m,3H),3.23-3.13(m,1H),2.58-2.23(m,8H),2.16-1.92(m,6H),0.90-0.87(m,3H)； 19FNMR(377MHz,CD 3OD)δ-139.83,-173.83；LC-MS:m/z＝618.3[M+H] +.
化合物173:(3R,4R)-1-(7-(8-乙基-3-羟基萘-1-基)-8-氟-2-氟-2-氟四氢-1H-吡 咯嗪-7a(5H)基)甲氧基吡啶并[4,3-d]嘧啶-4-基)-6-甲基哌啶-3,4-二醇
Figure PCTCN2022124111-appb-000410
1H NMR(400MHz,CD 3OD)δ9.49(s,1H),7.62(d,J＝7.6Hz,1H),7.34(t,J＝7.2Hz,1H),7.28(s,1H),7.15(d,J＝6.8Hz,1H),7.02(d,J＝11.2Hz,1H),5.39-5.26(m,1H),5.02(s,1H),4.43-4.26(m,3H),4.06(t,J＝14.8Hz,1H),3.91(s,2H),3.44-3.38(m,1H),3.30-3.24(m,2H),3.06(s,1H),2.42-1.73(m,10H),1.60(s,3H),0.90-0.88(m,3H). 19F NMR(377MHz,CD 3OD)δ-139.67,-173.69；LC-MS:m/z＝606.3[M+H] +.
化合物174:2,3-顺式-3,5-顺式-2-(7-(8-乙基-3-羟基萘-1-基)-8-氟 -2-((2R,7aS)-2-氟四氢-1H-吡咯里嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-2-氮杂 双环[4.1.0]庚烷-4-醇
Figure PCTCN2022124111-appb-000411
1H NMR(400MHz,CD 3OD)δ9.92(d,J＝11.2Hz,1H),7.62(d,J＝8.0Hz,1H),7.35(t,J＝7.6Hz,1H),7.28(d,J＝2.4Hz,1H),7.17-7.14(m,1H),7.05-7.00(m,1H),5.40-5.23(m,1H),4.97-4.89(m,1H),4.40-4.20(m,3H),3.50-3.33(m,2H),3.30-3.20(m,3H),3.08-3.00(m,1H),2.43-2.11(m,6H),2.05-1.85(m,4H),1.70-1.58(m,1H),1.30-1.23(m,1H),1.13-1.03(m,1H),0.95-0.85(m,3H). 19F NMR(377MHz,CD 3OD)δ-139.05,-173.63；LC-MS:m/z＝588.3 [M+H] +.
化合物175:1-(7-(8-乙基-7-氟-3-羟基萘-1-基)-8-氟-2-((2R,7aS)-2-氟四氢 -1H-吡咯里嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3-(三氟甲基)哌啶-3-醇
Figure PCTCN2022124111-appb-000412
1H NMR(400MHz,CD 3OD)δ9.29(d,J＝1.6Hz,1H),7.68(dd,J＝8.8,5.6Hz,1H),7.32(d,J＝2.4Hz,1H),7.25(t,J＝9.6Hz,1H),7.08(s,1H),5.57(d,J＝52.0Hz,1H),4.83-4.62(m,4H),4.12-3.58(m,4H),3.49-3.37(m,2H),2.81-2.51(m,2H),2.52-2.28(m,4H),2.23-2.16(m,3H),2.12-2.03(m,2H),1.94-1.89(m,1H),0.80(t,J＝7.6Hz,3H). 19F NMR(377MHz,CD 3OD)δ-84.04,-121.03,-139.31,-174.04；LC-MS:m/z＝662.3[M+H] +.
化合物176:1-(7-(8-乙基-7-氟-3-羟基萘-1-基)-8-氟-2-(2R,7aS)-2-氟四氢-1H- 吡咯嗪-7a(5H)基)甲氧基吡啶并[4,3-d]嘧啶-4-基)-3,5-二甲基哌啶-3-醇
Figure PCTCN2022124111-appb-000413
1H NMR(400MHz,CD 3OD)δ9.11(s,1H),7.67(dd,J＝8.8,5.6Hz,1H),7.31(d,J＝2.8Hz,1H),7.25(t,J＝9.2Hz,1H),7.06(dd,J＝10.8,2.0Hz,1H),5.43-5.30(m,1H),4.53-4.32(m,4H),3.50-3.35(m,3H),3.30-3.27(m,1H),3.15-3.03(m,2H),2.51-1.92(m,10H),1.45(t,J＝12.0Hz,1H),1.25(d,J＝30.0Hz,3H),1.06(d,J＝6.4Hz,3H),0.81-0.77(m,3H). 19F NMR(377MHz,CD 3OD)δ-121.05,-138.96,-173.75；LC-MS:m/z＝622.3[M+H] +.
化合物177:5-乙基-4-(8-氟-2-((2R,7aS)-2-氟四氢-1H-吡咯里嗪-7a(5H)-基)甲 氧基)-4-(哌啶-1-基)吡啶并[4,3-d]嘧啶-7-基)萘-2-醇
Figure PCTCN2022124111-appb-000414
1H NMR(400MHz,CD 3OD)δ9.02(s,1H),7.63(d,J＝8.0Hz,1H),7.36(t,J＝7.6Hz,1H),7.29(d,J＝2.4Hz,1H),7.16(d,J＝7.2Hz,1H),7.02(d,J＝2.4Hz,1H),5.43(d,J＝53.2Hz,1H),4.52-4.42(m,2H),4.07(s,4H),3.69-3.45(m,3H),3.25-3.19(m,1H),2.56-2.22(m,5H),2.19-2.09(m,2H),2.07-1.95(m,1H),1.85(s,6H),0.89(t,J＝7.6Hz,3H). 19F NMR(377MHz,CD 3OD)δ-139.58,-173.85；LC-MS:m/z＝560.3[M+H] +.
化合物178:(2S,4R)-1-(7-(8-乙炔基-7-氟-3-羟基萘-1-基)-8-氟-2-((2R,7aS)-2- 氟六氢-1H-吡咯啉-7a-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-2-甲基哌啶-4-醇
Figure PCTCN2022124111-appb-000415
1H NMR(400MHz,CD 3OD)δ8.95(d,J＝9.2Hz,1H),7.88-7.84(m,1H),7.35(d,J＝2.4Hz,1H),7.32(t,J＝9.2Hz,1H),7.22(dd,J＝8.0,2.4Hz,1H),5.45-5.31(m,1H),5.22-5.11(m,1H),4.61-4.57(m,1H),4.46-4.42(m,1H),4.36-4.33(m,1H),4.21-4.16(m,1H),3.69-3.60(m,1H),3.52-3.24(m,4H),3.16-3.13(m,1H),2.47-1.95(m,8H),1.79-1.66(m,2H),1.56(t,J＝7.2Hz,3H). 19F NMR(377MHz,CD 3OD)δ-111.68,-139.91,-173.84；LC-MS:m/z＝604.3[M+H] +.
化合物179:(8-反)-3-(7-(8-乙炔基-7-氟-3-羟基萘-1-基)-8-氟-2-((2R,7aS)-2- 氟四氢-1H-吡咯啉-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3-氮杂双环[3.2.1]辛烷-8- 醇
Figure PCTCN2022124111-appb-000416
1H NMR(400MHz,CD 3OD)δ9.01(s,1H),7.86(dd,J＝9.2,5.6Hz,1H),7.38-7.27(m,2H),7.21(d,J＝2.4Hz,1H),5.50-5.23(m,1H),4.80-4.64(m,2H),4.45-4.27(m,2H),4.17(s,1H),3.69-3.59(m,2H),3.55-3.34(m,3H),3.34-3.31(m,1H),3.20-3.07(m,1H),2.52-2.15(m,5H),2.14-2.02(m,2H),2.01-1.85(m,3H),1.60-1.46(m,2H). 19F NMR(377MHz,CD 3OD)δ-111.65,-139.88,-173.77；LC-MS:m/z＝616.3[M+H] +.
化合物180:(3S,4R)-1-(7-(8-乙炔基-7-氟-3-羟基萘-1-基)-8-氟-2-(2R,7aS)-2- 氟四氢-1H-吡咯烷-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)哌啶-3,4-二醇
Figure PCTCN2022124111-appb-000417
1HNMR(400MHz,CD 3OD)δ9.21-9.10(m,1H),7.88-7.84(m,1H),7.36-7.29(m,2H),7.26-7.21(m,1H),5.48-5.35(m,1H),4.54-4.32(m,4H),3.99-3.91(m,3H),3.72-3.38(m,5H),3.24-3.18(m,1H),2.54-2.25(m,3H),2.18-1.86(m,5H). 19F NMR(377MHz,CD 3OD)δ-111.66,-140.46,-173.88；LC-MS:m/z＝606.2[M+H] +.
化合物181:(4R,5S)-1-(7-(8-乙炔基-7-氟-3-羟基萘-1-基)-8-氟-2-((2R,7aS)-2- 氟四氢-1H-吡咯啉-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)氮杂环庚-4,5-二醇
Figure PCTCN2022124111-appb-000418
1H NMR(400MHz,CD 3OD)δ9.11(s,1H),7.86(dd,J＝9.2,6.0Hz,1H),7.36-7.28(m,2H),7.23(d,J＝2.4Hz,1H),5.51-5.30(m,1H),4.51-4.37(m,2H),4.29-4.15(m,2H),4.12-4.02(m,1H),4.01-3.86(m,3H),3.68-3.43(m,3H),3.40(d,J＝7.2Hz,1H),3.25-3.15(m,1H),2.55-2.21(m,5H),2.20-1.94(m,5H). 19F NMR(377MHz,CD 3OD)δ-111.64,-140.29,-173.89；LC-MS:m/z＝620.3[M+H] +.
化合物182:((3aR,4R,6aS)-消旋)-2-(7-(8-乙基-3-羟基萘-1-基)-8-氟 -2-((2R,7aS)-2-氟四氢-1H-吡咯利嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)八氢环戊 [c]吡咯-4-醇
Figure PCTCN2022124111-appb-000419
1H NMR(400MHz,CD 3OD)δ9.27(s,1H),7.62(d,J＝8.0Hz,1H),7.35(t,J＝7.2Hz,1H),7.28(d,J＝2.8Hz,1H),7.15(d,J＝6.8Hz,1H),7.01(d,J＝2.8Hz,1H),5.44-5.31(m,1H),4.49-4.23(m,5H),4.17-4.06(m,1H),3.93-3.81(m,1H),3.58-3.35(m,3H),3.18-3.09(m,1H),3.03-2.85(m,2H),2.48-2.17(m,5H),2.12-1.91(m,5H),1.89-1.72(m,2H),0.93-0.81(m,3H). 19F NMR(377MHz,CD 3OD)δ-139.2,-173.7；LC-MS:m/z＝602.3[M+H] +.
化合物183:(3R,4S)-1-(7-(8-乙炔基-7-氟-3-羟基萘-1-基)-8-氟-2-(2R,7aS)-2- 氟四氢-1H-吡咯烷-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)哌啶-3,4-二醇
Figure PCTCN2022124111-appb-000420
1H NMR(400MHz,CD 3OD)δ9.15(d,J＝43.6Hz,1H),7.86(dd,J＝9.2,6.0Hz,1H),7.43-7.16(m,3H),5.49-5.29(m,1H),4.58-4.25(m,4H),3.99-3.92(m,3H),3.74-3.34(m,5H),3.22-3.09(m,1H),2.55-2.19(m,3H),2.17-1.82(m,5H). 19F NMR(377MHz,CD 3OD)δ-111.68,-140.14,-173.82；LC-MS:m/z＝606.2[M+H] +.
化合物184:((3aS,4R,6aR)-消旋)-2-(7-(8-乙基-3-羟基萘-1-基)-8-氟 -2-((2R,7aS)-2-氟四氢-1H-吡咯利嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)八氢环戊 [c]吡咯-4-醇
Figure PCTCN2022124111-appb-000421
1H NMR(400MHz,CD 3OD)δ9.26(s,1H),7.63(d,J＝8.4Hz,1H),7.36(t,J＝7.6Hz,1H),7.29(d,J＝2.4Hz,1H),7.16(d,J＝7.2Hz,1H),7.00(d,J＝2.8Hz,1H),5.42(d,J＝53.2Hz,1H),4.53-4.41(m,2H),4.32-4.25(m,2H),4.20-4.16(m,1H),3.99-3.93(m,2H),3.68-3.45(m,3H),3.25-3.05(m,2H),2.78(s,1H),2.55-2.11(m,9H),2.06-1.97(m,1H),1.78-1.57(m,2H),0.88(t,J＝7.2Hz,3H). 19F NMR(377MHz,CD 3OD)δ-139.29,-173.82；LC-MS:m/z＝602.3[M+H] +.
化合物185:(R)-1-(7-(3-氯-2-环丙基-5-羟基苯基)-8-氟-2-(((2R,7aS)-2-氟四氢 -1H-pyrrolizin-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)哌啶-3-酚
Figure PCTCN2022124111-appb-000422
1H NMR(400MHz,CD 3OD)δ9.19(s,1H),6.95(d,J＝2.8Hz,1H),6.77(d,J＝2.8Hz,1H),5.62-5.48(m,1H),4.70-4.59(m,2H),4.19-3.86(m,8H),3.48-3.41(m,1H),2.74-2.52(m,2H),2.42-2.28(m,3H),2.16-2.00(m,3H),1.85-1.71(m,3H),0.60-0.59(m,2H),0.04-0.03(m,2H). 19F NMR(377MHz,CD 3OD)δ-77.07,-140.11,174.13；LC-MS:m/z＝572.2[M+H] +.
化合物186:(3aR,5R,6aS)-2-(7-(8-乙基-3-羟基萘-1-基)-8-氟-2-((2R,7aS)-2-氟 六氢-1H-吡咯利嗪-7a-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)八氢环戊[c]吡咯-5-醇
Figure PCTCN2022124111-appb-000423
1H NMR(400MHz,CD 3OD)δ9.25(s,1H),7.63(d,J＝8.0Hz,1H),7.35(t,J＝7.6Hz,1H),7.29(d,J＝2.0Hz,1H),7.15(d,J＝6.8Hz,1H),7.00(d,J＝2.0Hz,1H),5.49-5.36(m,1H),4.53-4.41(m,3H),4.32-4.27(m,2H),3.92-3.90(m,2H),3.69-3.44(m,3H),3.31-3.19(m,1H),3.11-3.09(m,2H),2.58-1.84(m,12H),0.90-0.86(m,3H). 19F NMR(377MHz,CD 3OD)δ-139.33,-173.81；LC-MS:m/z＝602.3[M+H] +.
化合物187:(R)-1-(7-(3-氯-2-环丙基-5-羟基苯基)-8-氟-2-(((2R,7aS)-2-氟四氢 -1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3-甲基哌啶-3-酚
Figure PCTCN2022124111-appb-000424
1H NMR(400MHz,CD 3OD)δ9.35(s,1H),6.99(d,J＝2.4Hz,1H),6.84-6.77(m,1H),5.58(d,J＝52.0Hz,1H),4.78-4.61(m,3H),4.38(d,J＝13.2Hz,1H),4.10-3.84(m,3H),3.62(d,J＝13.2Hz,1H),3.52-3.39(m,2H),2.79-2.54(m,2H),2.48-2.30(m,3H),2.25-2.10(m,2H),1.92-1.76(m,4H),1.31(s,3H),0.76-0.53(m,2H),0.20-0.02(m,2H) .19F NMR(377MHz,CD 3OD)δ-77.29,-139.77,-174.11；LC-MS:m/z＝586.2[M+H] +.
化合物188:(5S)-1-(7-(8-乙基-7-氟-3-羟基萘-1-基)-8-氟-2-(2R,7aS)-2-氟四氢 -1H-吡咯嗪-7a(5H)基)甲氧基吡啶并[4,3-d]嘧啶-4-基)-3,5-二甲基哌啶-3-醇
Figure PCTCN2022124111-appb-000425
1H NMR(400MHz,CD 3OD)δ9.10(s,1H),7.65(dd,J＝8.8,5.6Hz,1H),7.28(d,J＝2.4Hz,1H),7.23(t,J＝9.2Hz,1H),7.04(dd,J＝9.6,2.4Hz,1H),5.42-5.24(m,1H),4.56-4.42(m,2H),4.39-4.27(m,2H),3.40-3.33(m,1H),3.30-3.19(m,3H),3.12-3.01(m,2H),2.51-1.91(m,10H),1.45(t,J＝12.4Hz,1H),1.30-1.21(m,3H),1.05(d,J＝6.4Hz,3H),0.81-0.76(m,3H). 19F NMR(377MHz,CD 3OD)δ-121.08,-138.95,-173.68；LC-MS:m/z＝622.3[M+H] +.
化合物189:2-氨基-7-氟-4-(8-氟-2-((2R,7aS)-2-氟六氢-1H-吡咯利嗪-7a-基)甲 氧基)-4-((R)-3-羟基-3-甲基哌啶-1-基)吡啶并[4,3-d]嘧啶-7-基)苯并[b]噻吩-3-碳腈
Figure PCTCN2022124111-appb-000426
1HNMR(400MHz,CD 3OD)δ9.22(s,1H),7.43-7.40(m,1H),7.05(t,J＝8.8Hz,1H),5.46-5.33(m,1H),4.55-4.51(m,1H),4.47-4.36(m,2H),4.29-4.28(m,1H),3.64-3.61(m,2H),3.51-3.36(m,3H),3.20-3.12(m,1H),2.52-1.73(m,10H),1.27(s,3H). 19F NMR(377MHz,CD 3OD)δ-117.93,-140.62,-173.86；LC-MS:m/z＝610.2[M+H] +.
化合物190:(3aR，5S，6aS)-2-(7-(8-乙基-3-羟基萘-1-基)-8-氟-2-((2R,7aS)-2- 氟四氢-1H-吡咯利嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)八氢环戊[c]吡咯-5-醇
Figure PCTCN2022124111-appb-000427
1H NMR(400MHz,CD 3OD)δ9.25(s,1H),7.63(d,J＝8.0Hz,1H),7.36(t,J＝8.0Hz,1H),7.29(d,J＝2.4Hz,1H),7.16(d,J＝6.8Hz,1H),7.01(d,J＝2.4Hz,1H),5.50-5.33(m,1H),4.52-4.40(m,3H),4.35-4.25(m,2H),4.20-4.12(m,2H),3.65-3.41(m,3H),3.23-3.13(m,1H),2.93(s,2H),2.54-2.22(m,7H),2.17-1.96(m,3H),1.72-1.64(m,2H),0.93-0.85(m,3H). 19F NMR(377MHz,CD 3OD)δ-139.16,-173.68；LC-MS:m/z＝602.3[M+H] +.
化合物191:(R)-1-(7-(8-乙基萘-1-基)-8-氟-2-((2R,7aS)-2-氟四氢-1H-吡咯啉 -7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3-甲基哌啶-3-醇
Figure PCTCN2022124111-appb-000428
1H NMR(400MHz,CD 3OD)δ9.24(d,J＝10.0Hz,1H),8.49(br,0.58H),8.04(d,J＝8.0Hz,1H),7.86(d,J＝8.0Hz,1H),7.60-7.53(m,1H),7.52-7.36(m,3H),5.54-5.34(m,1H),4.63-4.43(m,3H),4.32(dd,J＝13.2,7.2Hz,1H),3.76-3.50(m,4H),3.49-3.38(m,1H),3.28-3.20(m,1H),2.64-2.25(m,5H),2.24-1.97(m,4H),1.92-1.72(m,3H),1.29(d,J＝10.4Hz,3H),0.92(q,J＝7.2Hz,3H). 19F NMR(377MHz,CD 3OD)δ-139.74,-173.87；LC-MS:m/z＝574.3[M+H] +.
化合物192:(3R)-1-(8-氟-2-((2R,7aS)-2-氟六氢-1H-吡咯里嗪-7a-基)甲氧 基)-7-(5-甲基-1H-吲唑-4-基)吡啶并[4,3-d]嘧啶-4-基)-3-甲基哌啶-3-醇
Figure PCTCN2022124111-appb-000429
1H NMR(400MHz,CD 3OD)δ9.28(s,1H),7.71(s,1H),7.59(d,J＝8.8Hz,1H),7.42(d,J＝8.8Hz,1H),5.33(d,J＝54.0Hz,1H),4.56(d,J＝13.2Hz,1H),4.38(d,J＝10.4Hz,1H),4.29(d,J＝10.8Hz,2H),3.64(d,J＝13.2Hz,1H),3.45-3.37(m,2H),3.28-3.23(m,2H),3.11-3.00(m,1H),2.42-1.75(m,13H),1.28(s,3H). 19F NMR(377MHz,CD 3OD)δ-140.04,-173.71；LC-MS:m/z＝550.3[M+H] +.
化合物193:2-(7-(8-乙基-3-羟基萘-1-基)-8-氟-2-((2R，7aS)-2-氟四氢-1H-吡咯 里嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-2-氮杂螺环[3.3]庚烷-6-醇
Figure PCTCN2022124111-appb-000430
1H NMR(400MHz,DMSO-d 6)δ9.95(s,1H),8.90(s,1H),7.66(d,J＝8.0Hz,1H),7.36(t,J＝7.6Hz,1H),7.28(d,J＝2.8Hz,1H),7.12(d,J＝6.8Hz,1H),6.96(d,J＝2.4Hz,1H),5.36-5.19(m,1H),5.14(d,J＝6.4Hz,1H),4.95-4.65(m,2H),4.45-4.17(m,2H),4.16-3.97(m,3H),3.15-2.98(m,3H),2.87-2.78(m,1H),2.61-2.51(m,2H),2.29-2.14(m,2H),2.13-1.97(m,5H),1.88-1.71(m,3H),0.81(t,J＝7.6Hz,3H) .19F NMR(377MHz,DMSO-d 6)δ-139.17,-172.13；LC-MS:m/z＝588.3[M+H] +.
化合物194:(3R)-1-(7-(8-乙基-7-氟-3-羟基萘-1-基)-6,8-二氟-2-((2R,7aS)-2-氟 六氢-1H-吡咯啉-7a-基)甲氧基)喹唑啉-4-基)-3-甲基哌啶-3-醇
Figure PCTCN2022124111-appb-000431
1H NMR(400MHz,CD 3OD)δ7.82-7.76(m,1H),7.67(dd,J＝8.8,6.0Hz,1H),7.31-7.19(m,2H),6.98(d,J＝2.4Hz,1H),5.41-5.24(m,1H),4.37-4.31(m,1H),4.30-4.18(m,2H),4.06(d,J＝13.2Hz,1H),3.53-3.32(m,3H),3.29-3.20(m,2H),3.09-3.01(m,1H),2.61-1.71(m,12H),1.29-1.25(m,3H),0.86-0.74(m,3H). 19F NMR(377MHz,CD 3OD)δ-118.56,-121.16,-124.88,-173.69；LC-MS:m/z＝625.3[M+H] +.
化合物195:1-(7-(8-乙基-7-氟-3-羟基萘-1-基)-8-氟-2-((2R,7aS)-2-氟四氢 -1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3-异丙基哌啶-3-醇
Figure PCTCN2022124111-appb-000432
1H NMR(400MHz,CD 3OD)δ9.29(dd,J＝15.2,3.6Hz,1H),7.69-7.65(m,1H),7.29(d,J＝2.4Hz,1H),7.24(t,J＝9.6Hz,1H),7.05(t,J＝2.4Hz,1H),5.42-5.28(m,1H),4.76-4.70(m,1H),4.54-4.30(m,3H),3.56-3.33(m,4H),3.28-3.23(m,1H),3.13-3.06(m,1H),2.49-2.27(m,3H),2.23-2.12(m,3H),2.09-2.02(m,2H),1.96-1.70(m,5H),1.02-0.98(m,6H),0.82-0.78(m,3H). 19F NMR(377MHz,CD 3OD)δ-121.13,-139.49,-173.73；LC-MS:m/z＝636.3[M+H] +.
化合物196:N-(1-(7-(8-乙基-7-氟-3-羟基萘-1-基)-8-氟-2-((2R,7aS)-2-氟四氢 -1H-吡咯嗪-7a(5H)基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3-羟基哌啶-3-基)甲基)乙酰胺
Figure PCTCN2022124111-appb-000433
1H NMR(400MHz,CD 3OD)δ9.30(d,J＝17.6Hz,1H),8.35(s,0.12H),7.70(dd,J＝9.2,6.0Hz,1H),7.31-7.23(m,2H),7.05(dd,J＝6.8,2.4Hz,1H),5.58-5.45(m,1H),4.67-4.48(m,3H),4.27(dd,J＝13.6,7.2Hz,1H),3.92-3.36(m,7H),3.25-3.20(m,1H),2.69-1.83(m,15H),0.81-0.77(m,3H). 19F NMR(377MHz,CD 3OD)δ-121.11,-139.60,-174.03；LC-MS:m/z＝665.3[M+H] +.
化合物197:(5S)-1-(7-(8-乙基-7-氟-3-羟基萘-1-基)-8-氟-2-(2R,7aS)-2-氟四氢 -1H-吡咯嗪-7a(5H)基)甲氧基吡啶并[4,3-d]嘧啶-4-基)-2,5-二甲基哌啶-3-醇
Figure PCTCN2022124111-appb-000434
1H NMR(400MHz,DMSO-d 6)δ9.97(d,J＝2.0Hz,1H),9.07(s,1H),7.78-7.75(m,1H),7.37-7.33(m,2H),7.04(s,1H),5.37-5.23(m,1H),4.99-4.86(m,2H),4.29-4.06(m,3H),3.21-2.99(m,3H),2.92-2.81(s,1H),2.40-2.33(m,1H),2.21-1.55(m,12H),1.44-1.41(m,3H),1.13(d,J＝32.4Hz,3H),0.76-0.69(m,3H) .19F NMR(377MHz,CD 3OD)δ-119.62,-139.22,-172.18；LC-MS:m/z＝622.3[M+H] +.
化合物198:1-(7-(8-乙基-3-羟基萘-1-基)-8-氟-2-((2R,7aS)-2-氟四氢吡咯嗪 -7a(5H)基甲氧基)嘧啶[4,3-d]嘧啶-4-基)氮杂环丁烷-3-醇
Figure PCTCN2022124111-appb-000435
1H NMR(400MHz,CD 3OD)δ8.91(s,1H),7.62(d,J＝8.0Hz,1H),7.35(t,J＝7.2Hz,1H),7.28(d,J＝2.8Hz,1H),7.15(d,J＝6.8Hz,1H),7.00(d,J＝2.8Hz,1H),5.42-5.29(m,1H),5.12-4.99(m,1H),4.83-4.79(m,1H),4.56-4.21(m,4H),3.51-3.35(m,3H),3.14-3.08(m,1H),2.46-1.92(m,9H),0.88(t,J＝7.2Hz,3H). 19F NMR(377MHz,CD 3OD)δ-138.96,-173.76；LC-MS:m/z＝548.3[M+H] +.
化合物199:1-(7-(8-乙基-3-羟基萘-1-基)-8-氟-2-((2R,7aS)-2-氟六氢-1H-吡咯 里嗪-7a-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3-甲基氮杂丁-3-醇
Figure PCTCN2022124111-appb-000436
1H NMR(400MHz,CD 3OD)δ8.90(s,1H),7.62(d,J＝8.0Hz,1H),7.35(t,J＝7.6Hz,1H),7.28(d,J＝2.8Hz,1H),7.15(d,J＝7.2Hz,1H),7.00(d,J＝2.4Hz,1H),5.38-5.25(m,1H),4.79-4.55(m,2H),4.44-4.26(m,4H),3.40-3.34(m,1H),3.30-3.22(m,2H),3.07-2.99(m,1H),2.40-2.12(m,5H),2.06-1.87(m,3H),1.60(s,3H),0.90-0.86(m,3H). 19F NMR(377MHz,CD 3OD)δ-138.81,-173.67；LC-MS:m/z＝562.3[M+H] +.
化合物200:(3aR,5S,6aS)-2-(7-(8-乙炔基-7-氟-3-羟基萘-1-基)-8-氟 -2-((2R,7aS)-2-氟六氢-1H-吡咯烷-7a-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)八氢环戊[c]吡咯 -5-醇
Figure PCTCN2022124111-appb-000437
1H NMR(400MHz,CD 3OD)δ9.20(s,1H),7.88-7.83(m,1H),7.36-7.29(m,2H),7.21(d,J＝2.4Hz,1H),5.45-5.29(m,1H),4.45-4.38(m,2H),4.37-4.19(m,4H),4.15-4.09(m,1H),3.57-3.35(m,4H),3.17-3.08(m,1H),2.94(s,2H),2.48-2.18(m,5H),2.12-2.04(m,2H),2.01-1.90(m,1H),1.72-1.64(m,2H). 19F NMR(377MHz,CD 3OD)δ-111.73,-139.91,-173.76；LC-MS:m/z＝616.3[M+H] +.
化合物201:1-(7-(8-乙基-3-羟基萘-1-基)-8-氟-2-((2R,7aS)-2-氟四氢呋喃-1H- 吡咯啉-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)氮杂环庚-3-醇
Figure PCTCN2022124111-appb-000438
1H NMR(400MHz,CD3OD)δ9.23(d,J＝4.8Hz,1H),7.62(d,J＝8.0Hz,1H),7.35(t,J＝7.2Hz,1H),7.28(d,J＝2.4Hz,1H),7.15(d,J＝7.2Hz,1H),7.01(dd,J＝4.8,2.8Hz,1H),5.43-5.24(m,1H),4.47-4.27(m,3H),4.24-4.03(m,3H),3.83-3.71(m,1H),3.45-3.32(m,1H),3.30-3.18(m,2H),3.12-3.02(m,1H),2.45-2.14(m,5H),2.12-1.85(m,7H),1.72-1.60(m,1H),1.53-1.41(m,1H),0.94-0.82(m,3H). 19F NMR(377MHz,CD3OD)δ-138.88,-173.72；LC-MS:m/z＝590.3[M+H] +.
化合物202:(R)-1-(7-(8-乙炔基-7-氟-3-羟基萘-1-基)-8-氟-2-((2R,7aS)-2-氟四 氢-1H-吡咯啉-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-5,5-二氟哌啶-3-醇
Figure PCTCN2022124111-appb-000439
1H NMR(400MHz,CD 3OD)δ9.20(d,J＝35.2Hz,1H),7.86(dd,J＝9.2,6.0Hz,1H),7.40-7.28(m,2H),7.24(dd,J＝8.4,2.4Hz,1H),5.44-5.24(m,1H),4.47-4.14(m,6H),3.82-3.60(m,1H),3.49-3.33(m,4H),3.16-3.01(m,1H),2.61-2.47(m,1H),2.45-2.12(m,4H),2.10-1.85(m,3H). 19F NMR(377MHz,CD 3OD)δ-98.74,-98.86,-111.67,-139.80,-173.79；LC-MS:m/z＝626.2[M+H] +.
化合物203:2-(7-(8-乙基-3-羟基萘-1-基)-8-氟-2-((2R,7aS)-2-氟四氢-1H-吡咯 里嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-2-氮杂螺环[3.4]辛烷-6-醇
Figure PCTCN2022124111-appb-000440
1HNMR(400MHz,CD 3OD)δ8.93(s,1H),7.63(d,J＝8.0Hz,1H),7.36(t,J＝7.6Hz,1H),7.29(d,J＝2.4Hz,1H),7.16(d,J＝6.8Hz,1H),6.99(d,J＝2.4Hz,1H),5.48(d,J＝52.4Hz,1H),4.77(s,2H),4.63-4.31(m,5H),3.90-3.59(m,3H),3.37-3.05(m,1H),2.65-2.42(m,2H),2.38-1.96(m,11H),1.79-1.68(m,1H),0.88(t,J＝7.6Hz,3H). 19F NMR(377MHz,CD 3OD)δ-139.28,-173.97；LC-MS：m/z＝602.3[M+H] +.
化合物204:3,4-顺式-1-(7-(8-乙基-3-羟基萘-1-基)-8-氟-2-((2R，7aS)-2-氟四氢 -1H-吡咯里嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-4-氟哌啶-3-醇(cis-racemic)
Figure PCTCN2022124111-appb-000441
1H NMR(400MHz,CD 3OD)δ9.18(s,1H),7.63(d,J＝8.0Hz,1H),7.35(t,J＝7.6Hz,1H),7.29(d,J＝2.4Hz,1H),7.16(d,J＝7.2Hz,1H),7.01(t,J＝2.4Hz,1H),5.44-5.31(m,1H),4.97-4.80(m,1H),4.45-4.36(m,2H),4.23-3.89(m,5H),3.53-3.31(m,3H),3.17-3.10(m,1H),2.48-2.20(m,6H),2.10-1.92(m,4H),0.91-0.87(m,3H). 19F NMR(377MHz,CD 3OD)δ-139.38,-173.79；LC-MS:m/z＝594.3[M+H] +.
下述化合物可以用合适的原材料和中间体参考以上实施例的具体合成而取得.
Figure PCTCN2022124111-appb-000442
Figure PCTCN2022124111-appb-000443
Figure PCTCN2022124111-appb-000444
生物学测试评价
以下结合测试例进一步描述解释本发明，但这些实施例并未意味着限制本发明的范围。
实施例1
荧光偏振(FP)检测方法
测试原理：带荧光标记的环肽配体与KRAS G12D蛋白结合后，在受到偏振光激发时，荧光分子保持静止，将发出固定偏振平面的发射光(发射光仍保持偏振性)，而非结合状态的环肽分子旋转或翻转速度快，发射光相对于激发光平面将去偏振化。化合物竞争该配体与KRAS G12D结合位点，通过检测发射光偏振程度变化，得到化合物与KRAS G12D的 结合效率。
测试过程：配制1倍反应缓冲液(50mM Tris 7.5国药,Cat.No.30188360)。将KRAS G12D(Purified in house)加入到1倍反应缓冲液中，配制成3倍酶溶液(KRAS G12D终浓度为25nM)，转移20μL该溶液至含有不同浓度化合物(DMSO终浓度1％)的384孔微孔板(Corning 384-well Polystyrene Microplates，Cat.No.3575)中，室温孵育15分钟。将与KRAS G12D特异性结合的环肽配体加入到1倍反应缓冲液中，配制成3倍底物溶液，然后加入20μL底物溶液(环肽配体终浓度5nM)，室温反应一段时间后，将微孔板放置在EnVision仪器上读取毫偏值mp。得到化合物不同浓度的mp原始数据后，按照公式Inh％＝100-(Sample-Min)/(Max-Min)*100％对数据进行标准化处理得到每个浓度点的酶活性抑制率Inh％(其中Max为含酶阳性孔的mp值，Min为不含酶阴性孔的mp值，Sample为化合物处理样品孔的mp值)，然后在EXCEL中输入每个浓度(X)对应的抑制率Inh％(Y)，用Graphpad插件根据内置四参数拟合公式Y＝Bottom+(Top-Bottom)/(1+(IC50/X)*HillSlope)计算出每个化合物的半数抑制浓度IC 50值。
实施例2
细胞内p-ERK检测方法
测试原理：该实验通过测试ERK1/2的内源性磷酸化水平，直接在细胞水平中检测化合物对KRAS G12D抑制作用。RAS-RAF-MEK通路激活后，ERK1/2被磷酸化，细胞膜裂解后，使用2个不同的特异性抗体(一种带Eu3+-Cryptate(供体)标记，另一种带d2(受体)标记)分别识别磷酸化ERK1/2(Thr202/Tyr204)位点和ERK1/2蛋白本身。当发生磷酸化，两个染料靠近，用光源(激光或闪光灯)激发供体向受体的荧光共振能量转移(FRET)，受体在特定位置发出荧光波长(665nm)。特定信号与phospho-ERK1/2(Thr202/Tyr204)水平成正比。
测试过程：表达KRAS G12D突变的GP5d细胞(ECACC，Cat.No.95090715)培养在含10％FBS的DMEM培养基中。将细胞接种到3D assay plate，37℃贴壁3天培养。稀释化合物，使其终浓度含0.5％DMSO,将化合物加入贴壁培养好的细胞中，孵育2小时，去上清，加入1*裂解液裂解细胞，转移裂解产物到新的assay plate，加入预先混合好的抗体溶液(Cisbio，Cat.No.64AERPEH)，室温过夜孵育。将微孔板放置在EnVision仪器上读取吸收光Em665/620荧光信号。按照公式Inh％＝100-(Sample-Min)/(Max-Min)*100％对数据进行标准化处理得到每个浓度点的酶活性抑制率Inh％(其中Max为含酶阳性孔的Em665/620值，Min为不含酶阴性孔的Em665/620值，Sample为化合物处理样品孔的 Em665/620值)，在EXCEL中输入每个浓度(X)对应的抑制率Inh％(Y)，用Graphpad插件根据内置四参数拟合公式Y＝Bottom+(Top-Bottom)/(1+(IC50/X)*HillSlope)计算出每个化合物的半数抑制浓度IC50值。
实施例3
GDP-FRET检测方法
测试原理：该实验采用TR-FRET的原理，带荧光标记的示踪剂与Biotinylated GDP-Loaded recombinant human KRAS G12D蛋白(His-Avi-KRAS 1-185,produced by ChemPartner)结合，与EU标记的streptavidin(Life，PV5899)在受到340nM波长激发光激发后产生FRET现象。化合物竞争该示踪剂配体与KRAS G12D结合位点，通过检测发射光665和620信号值的变化，来反映化合物与KRAS G12D的结合效率。测试过程：将4倍GDP loaded KRAS G12D(Purified in house)和特异的Cy5标记的tracer加入到1倍反应缓冲液中，在该溶液中加入不同浓度的化合物(DMSO终浓度1％)，室温孵育30分钟，然后加入4倍EU标记的strepvadin孵育30min，将微孔板放置在EnVision仪器上读取Em665/620荧光信号。按照公式Inh％＝100-(Sample-Min)/(Max-Min)*100％对数据进行标准化处理得到每个浓度点的酶活性抑制率Inh％(其中Max为含酶阳性孔的Em665/620值，Min为不含酶阴性孔的Em665/620值，Sample为化合物处理样品孔的Em665/620值)，在EXCEL中输入每个浓度(X)对应的抑制率Inh％(Y)，用Graphpad插件根据内置四参数拟合公式Y＝Bottom+(Top-Bottom)/(1+(IC50/X)*HillSlope)计算出每个化合物的半数抑制浓度IC50值。
下表中下列含义适用:“+++”表示IC50<1μM,“++”表示1μM≤IC50<5μM,“+”表示IC50≥5μM.
Figure PCTCN2022124111-appb-000445
Figure PCTCN2022124111-appb-000446
Figure PCTCN2022124111-appb-000447
Figure PCTCN2022124111-appb-000448
Figure PCTCN2022124111-appb-000449
Figure PCTCN2022124111-appb-000450
虽然以上描述了本发明的具体实施方式，但是本领域的技术人员应当理解，这些仅是举例说明，在不背离本发明的原理和实质的前提下，可以对这些实施方式做出多种变更或修改。因此，本发明的保护范围由所附权力要求书限定。

Claims (27)

  1. 式(III)所示化合物或其药学上可接受的盐:
    Figure PCTCN2022124111-appb-100001
    其中,
    R 1’选自-CH 2-5-12元杂环烷基,所述5-12元杂环烷基可以被-CH 3,F,Cl和-CF 3取代,
    Y’是O或键,
    Q 1’选自N,CH,C-CF 3,C-OH,C-Cl,C-F,C-CH 3,C-OCH 3和C-CN,
    Z”为环上只有一个选自N,O和S的杂原子的,包含一个或两个羟基取代基的杂环烷基,或-NR 5R 6,R 5为H,R 6选自取代或未取代的杂环烷基,
    R 4’选自H,-CF 3,-OH,-CH 3,F和Cl,
    Q 2’选自N,-C-H,-C-F,C-OH,C-CH 3,C-CF 3,-C-Cl,和-C-OCH 3,
    R 3’选自取代或未取代的芳基(例如,取代或未取代的苯基,蒽基和萘基),取代或未取代的杂环烷基和取代或未取代的杂芳基,
    Q 3’选自N,C-H,C-F,C-Cl,C-OH,C-CN,C-CH 3和C-OCH 3。
  2. 根据权利要求1所述化合物或其药学上可接受的盐,当式(III)中的Q 1’为N,那么Q 2’和Q 3’至少有一个是N。
  3. 根据权利要求1或2所述化合物或其药学上可接受的盐,其中,R 1’选自
    Figure PCTCN2022124111-appb-100002
    Figure PCTCN2022124111-appb-100003
  4. 根据权利要求1-3中任一项所述化合物或其药学上可接受的盐,其中R 3’选自
    Figure PCTCN2022124111-appb-100004
  5. 根据权利要求1-4中任一项所述所述化合物或其药学上可接受的盐,其中,Z”为-NR 5R 6,所述R 5为H,R 6选自取代或未取代的杂环烷基和取代或未取代的C 3-6烷基。
  6. 根据权利要求5所述化合物或其药学上可接受的盐，其中,Z”为
    Figure PCTCN2022124111-appb-100005
  7. 根据权利要求5所述化合物或其药学上可接受的盐，其中,Z”选自
    Figure PCTCN2022124111-appb-100006
    Figure PCTCN2022124111-appb-100007
  8. 根据权利要求1-4中任一项所述化合物或其药学上可接受的盐，其中,Z”为环上只有一个N杂原子的,包含一个或两个羟基取代基的杂环烷基。
  9. 根据权利要求8所述化合物或其药学上可接受的盐，其中,Z”为包含一个或两个羟基取代基的四氢吡咯基,哌啶基,环己亚胺基,
    Figure PCTCN2022124111-appb-100008
  10. 根据权利要求9所述化合物或其药学上可接受的盐,Z”选自
    Figure PCTCN2022124111-appb-100009
    Figure PCTCN2022124111-appb-100010
  11. 根据权利要求1所述化合物或其药学上可接受的盐，其中,式(III)所示化合物或其药学上可接受的盐选自
    Figure PCTCN2022124111-appb-100011
    Figure PCTCN2022124111-appb-100012
    或其药学上可接受的盐。
  12. 式(IV)与式(V)所示化合物或其药学上可接受的盐:
    Figure PCTCN2022124111-appb-100013
    其中,
    环A选自4-10元,环上只有一个杂原子的杂环烷基,所述杂原子是N,
    R a选自羟基,C 1-8烷基,C 3-8环烷基,氟、氯,1-5卤素取代的C 1-8烷基,一个或多个羟基取代的C 1-8烷基,C 1-8烷氧基,1-5卤素取代的C 1-8烷氧基,一个或多个羟基取代的C 1-8烷氧基, 氨基,单或双C 1-8烷基取代的氨基,
    n是0,1,或者2,
    R 1”选自
    Figure PCTCN2022124111-appb-100014
    Y a是O或键,
    Q 1’选自N,CH,C-CF 3,C-OH,C-Cl,C-F,C-CH 3,C-OCH 3和C-CN,
    Q 2’选自N,C-H,C-F,C-OH,C-CH 3,C-CF 3,C-Cl,C-CN,和C-OCH 3,
    R 2’选自H,F,OH,CH 3,CF 3,Cl,CN,和OCH 3,
    R 3”选自未取代或取代的苯基和萘基,这些取代基为一个或多个,选自羟基,氟、氯,C 1-8烷基,1-5卤素取代的C 1-8烷基,C 3-6环烷基,C 2-8烯基,和C 2-8炔基,
    R 4’选自H,-CF 3,-OH,-OMe,OEt,-CH 3,F和Cl。
  13. 根据权利要求12所述化合物或其药学上可接受的盐,其中R a选自OH,NH 2,-CH 2OH,CH 3,F,Cl,CN,CF 3,环丙基,和OCH 3。
  14. 根据权利要求12或13所述化合物或其药学上可接受的盐,其中式(IV)与式(V)中的Q 1’是N。
  15. 根据权利要求12-14中任一项所述化合物或其药学上可接受的盐,其中式(IV)中的Q 2”是N。
  16. 根据权利要求12-15中任一项所述化合物或其药学上可接受的盐,其中式(IV)中的R 4’是H。
  17. 根据权利要求12-16中任一项所述化合物或其药学上可接受的盐,其中无取代基的环A选自
    Figure PCTCN2022124111-appb-100015
  18. 根据权利要求12-17中任一项所述化合物或其药学上可接受的盐,其中
    Figure PCTCN2022124111-appb-100016
    选自
    Figure PCTCN2022124111-appb-100017
    Figure PCTCN2022124111-appb-100018
  19. 根据权利要求12-18中任一项所述化合物或其药学上可接受的盐,R 3’选自
    Figure PCTCN2022124111-appb-100019
  20. 根据权利要求12所述化合物或其药学上可接受的盐，其中,式(IV)所示化合物或其药学上可接受的盐选自
    Figure PCTCN2022124111-appb-100020
    Figure PCTCN2022124111-appb-100021
    Figure PCTCN2022124111-appb-100022
    Figure PCTCN2022124111-appb-100023
    或其药学上可接受的盐。
  21. 一种药物组合物,包含根据权利要求1-20中任一项所述化合物或其药学上可接受的盐和药学上可接受的赋形剂。
  22. 如权利要求1-20中任一项所述化合物或其药学上可接受的盐或者如权利要求21所述的药物组合在制备抑制KRAS G12D活性的药物中的用途。
  23. 如权利要求1-20中任一项所述化合物或其药学上可接受的盐或者如权利要求21所述的药物组合在制备治疗与KRAS G12D突变相关的疾病或病症的药物中的用途。
  24. 根据权利要求23所述的用途,所述与KRAS G12D突变相关的疾病或病症是癌症。
  25. 根据权利要求24所述的用途,所述癌症选自影响上皮组织或腹腔器官内膜的恶性肿瘤(carcinoma),鳞癌、胰腺癌、前列腺癌、直肠癌、结肠癌、结直肠癌、非小细胞肺癌、前列腺癌、小肠癌、肉瘤、白血病、黑色素瘤和淋巴瘤。
  26. 根据权利要求22-25中任一项所述的用途,其特征在于,所述化合物或其药学上可接受的盐与其他抗癌剂,放射疗法或手术联用。
  27. 根据权利要求26所述的用途,所述其他抗癌剂选自紫杉醇、顺铂、卡铂和奥沙利铂、PARP抑制剂(如尼拉帕尼、奥拉帕利)、抗PD-1抗体、抗PD-L1抗体、抗CTLA-4抗体、mTOR抑制剂、IGF1R抑制剂、HADC抑制剂、EGFR抑制剂，例如抗EGFR抗体(如帕尼单抗)、HIF-1抑制剂和VEGF/VEGFR抑制剂(如索拉非尼、贝伐珠单抗)。
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