[go: up one dir, main page]
More Web Proxy on the site http://driver.im/

WO2023138583A1 - Heterocyclic compound, pharmaceutical composition and use thereof - Google Patents

Heterocyclic compound, pharmaceutical composition and use thereof Download PDF

Info

Publication number
WO2023138583A1
WO2023138583A1 PCT/CN2023/072654 CN2023072654W WO2023138583A1 WO 2023138583 A1 WO2023138583 A1 WO 2023138583A1 CN 2023072654 W CN2023072654 W CN 2023072654W WO 2023138583 A1 WO2023138583 A1 WO 2023138583A1
Authority
WO
WIPO (PCT)
Prior art keywords
ring
membered
substituted
alkyl
aliphatic
Prior art date
Application number
PCT/CN2023/072654
Other languages
French (fr)
Chinese (zh)
Inventor
肖贻崧
谷晓辉
赖焜民
Original Assignee
上海湃隆生物科技有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 上海湃隆生物科技有限公司 filed Critical 上海湃隆生物科技有限公司
Priority to CN202380017933.9A priority Critical patent/CN118556063A/en
Publication of WO2023138583A1 publication Critical patent/WO2023138583A1/en

Links

Classifications

    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
    • 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
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
    • C07D239/94—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • 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
    • C07D471/08—Bridged 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
    • C07D487/08—Bridged 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 relates to a heterocyclic compound, a pharmaceutical composition and applications thereof.
  • KRAS The full name of the KRAS gene is Kirsten rat sarcoma viraloncogene homolog (Kristen rat sarcoma viral oncogene homolog).
  • KRAS plays a pivotal role in the signal regulation of cell growth.
  • the upstream cell surface receptors such as EGFR (ErbB1), HER2 (ErbB2), ErbB3 and ErbB4, after receiving external signals, will pass the signal to the downstream through the RAS protein.
  • EGFR EGFR
  • HER2 HER2
  • ErbB3 and ErbB4 ErbB4
  • the KRAS protein When the KRAS protein is not activated, it is tightly bound to GDP (guanine nucleotide diphosphate).
  • the technical problem to be solved by the present invention is to provide a heterocyclic compound, a pharmaceutical composition and its application in view of the defect that the existing KRAS G12D inhibitor has a single structure.
  • the compound of the present invention has a novel structure, good activity and selectivity.
  • the present invention solves the above-mentioned technical problems through the following technical solutions.
  • the present invention provides a heterocyclic compound represented by formula I-0, a pharmaceutically acceptable salt thereof, a stereoisomer thereof or a solvate thereof (referring to the aforementioned heterocyclic compound represented by formula I-0, a pharmaceutically acceptable salt thereof or a stereoisomer thereof):
  • Ring K is an aromatic ring or a heteroaromatic ring
  • X1 is N, NR X1' or CR X1 ;
  • X2 is N or CR X2 ;
  • R X1 and R X2 Each independently is H, CN, halogen, C 1 -C 6 Alkyl, C substituted by one or more halogens 1 -C 6 Alkyl, substituted by one or more hydroxyl groups C 1 -C 6 Alkyl, PO(C 1 -C 6 alkyl) 2 ⁇ C 3 -C 6 Cycloalkyl, C 3 -C 6 Cycloalkenyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, 6-14 membered aryl, 5-14 membered heteroaryl, one or more X 1-1 Substituted 3-6 membered heterocycloalkyl, replaced by one or more X 1-2 Substituted 5-14 membered heteroaryl, NO 2 , by one or more X 1-3 Substituted 3-6 membered heterocycloalkenyl,
  • X 3 is N or CR X3 , R X3 is H, halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkenyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, halogenated (C 1 -C 6 alkyl), OR a , hydroxyl (C 1 -C 6 alkyl), cyano, nitro, -SO 3 R a , -NR a R b , -C(O)R a , -C(O)OR a , -C(O)NR a R b , -NR a C(O)R a , 5-14 membered heteroaryl, 6-14 membered aryl;
  • R X1 and R X3 and the atoms connected to them together form a C 5 -C 8 cycloalkene structure
  • R X1' and R X3 and the atoms connected to them together form a 5-8 membered heteroaryl ring or a 5-8 membered heteroaryl ring substituted by one or more hydroxyl groups;
  • R 1-3 and R 1-4 are independently halogen
  • X 1 is CR X1 , wherein the C atom in X 1 is connected to the C atom in the aryl or heteroaryl group in R 1 through -O-(CH 2 ) n1 - * , * -NH-(CH 2 ) n2 -, -C ⁇ C-(CH 2 ) n3 -C ⁇ C- * or -(CH 2 ) n4 -O-(CH 2 ) n5 - * , wherein the * end is connected to the C atom in X 1 connected;
  • R 2 is H, halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkenyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, halogenated (C 1 -C 6 alkyl), OR a , hydroxyl (C 1 -C 6 alkyl), cyano, nitro, -SO 3 R a , -NR a R b , -C(O)R a , -C(O)OR a , -C(O)NR a R b , -NR a C(O)R a , 5-14 membered heteroaryl, 6-14 membered aryl;
  • L 2 represents absence, -O-(C 1 -C 6 alkylene) or -NR a -(C 1 -C 6 alkylene);
  • R 1' , R 2' , R 3' , R 4' , R 5' , R 6' , R 7' , R 8' , R 9' , R 10' , R 11' , R 12' Each independently represents hydrogen, halogen, cyano, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, halo(C 1 -C 6 Alkyl), hydroxyl (C 1 -C 6 Alkyl), C 3 -C 6 Cycloalkyl, C 3 -C 6 Cycloalkenyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, -SO 3 R a , -NR a R b , -CO(C 1 -C 6 Alkyl) or -C(O)NR a R b ;
  • substitution refers to being randomly selected from 1-2 members selected from halogen, cyano, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, halo(C 1 -C 6 Alkyl), hydroxyl (C 1 -C 6 Alkyl), C 3 -C 6 Cycloalkyl, C 3 -C 6 Cycloalkenyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, -
  • substitution refers to being randomly selected from 1-2 members selected from halogen, cyano, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, halo(C 1 -C 6 Alkyl), hydroxyl (C 1 -C 6 Alkyl), C 3 -C 6 Cycloalkyl, C 3 -C 6 Cycloalkenyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, -
  • substitution refers to being randomly selected from 1-2 members selected from halogen, cyano, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, halo(C 1 -C 6 Alkyl), hydroxyl (C 1 -C 6 Alkyl), C 3 -C 6 Cycloalkyl, C 3 -C 6 Cycloalkenyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, -
  • substitution refers to being randomly selected from 1-2 members selected from halogen, cyano, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, halo(C 1 -C 6 Alkyl), hydroxyl (C 1 -C 6 Alkyl), C 3 -C 6 Cycloalkyl, C 3 -C 6 Cycloalkenyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, -
  • substitution refers to being randomly selected from 1-2 members selected from halogen, cyano, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, halo(C 1 -C 6 Alkyl), hydroxyl (C 1 -C 6 Alkyl), C 3 -C 6 Cycloalkyl, C 3 -C 6 Cycloalkenyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl,
  • substitution refers to being randomly selected from 1-2 members selected from halogen, cyano, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, halo(C 1 -C 6 Alkyl), hydroxyl (C 1 -C 6 Alkyl), C 3 -C 6 Cycloalkyl, C 3 -C 6 Cycloalkenyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl,
  • R 8' and R 9' together with the atoms connected to it form a C 3 -C 8 aliphatic ring, a C 3 -C 8 carbene ring, a 3-8 membered aliphatic heterocycle, a 3-8 membered carbene ring, a substituted C 3 -C 8 aliphatic ring, a substituted C 3 -C 8 carbene ring, a substituted 3-8 membered aliphatic ring or a substituted 3-8 membered carbene ring;
  • the above substitution refers to being randomly 1-2 selected from halogen, cyano, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, halogenated (C 1 -C 6 alkyl), hydroxyl (C 1 -C 6 alkyl), C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkenyl, 3-6 membered heterocycloalky
  • substitution refers to being randomly selected from 1-2 members selected from halogen, cyano, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, halo(C 1 -C 6 Alkyl), hydroxyl (C 1 -C 6 Alkyl), C 3 -C 6 Cycloalkyl, C 3 -C 6 Cycloalkenyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl,
  • substitution refers to being randomly selected from 1-2 members selected from halogen, cyano, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, halo(C 1 -C 6 Alkyl), hydroxyl (C 1 -C 6 Alkyl), C 3 -C 6 Cycloalkyl, C 3 -C 6 Cycloalkenyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, -
  • R 4 is L 1 -R 5 , L 1 means absent, CR a R b or NR a ;
  • R is any ring structure in the following formula (i), formula (ii) or formula (iii):
  • W 1 represents CR W1 R W2 or NR W1 ;
  • R c and R d together with the atoms connected to them form a C 3 -C 6 aliphatic carbocycle or a C 3 -C 6 aliphatic carbocycle substituted by one or more halogens; or R d and R d' together with the atoms connected to them form a C 3 -C 6 aliphatic carbocycle or a C 3 -C 6 aliphatic carbocycle substituted by one or more halogens;
  • R 1" , R 2" , R 3" , R 4" , R 5" , R 6" , R 7" , R 8" Each independently represents hydrogen, halogen, cyano, nitro, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, halo(C 1 -C 6 Alkyl), hydroxyl (C 1 -C 6 Alkyl), C 3 -C 6 Cycloalkyl, C 3 -C 6 Cycloalkenyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, -OR a ⁇ -SO 3 R a , -NR a R b , -C(O)R a , -C(O)OR a , -C(O)NR a R b , -NR a C(O)R a ;
  • substitution refers to being randomly selected from 1-2 members selected from halogen, cyano, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, halo(C 1 -C 6 Alkyl), hydroxyl (C 1 -C 6 Alkyl), C 3 -C 6 Cycloalkyl, C 3 -C 6 Cycloalkenyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, -
  • substitution refers to being randomly selected from 1-2 members selected from halogen, cyano, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, halo(C 1 -C 6 Alkyl), hydroxyl (C 1 -C 6 Alkyl), C 3 -C 6 Cycloalkyl, C 3 -C 6 Cycloalkenyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, -
  • substitution refers to being randomly selected from 1-2 members selected from halogen, cyano, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, halo(C 1 -C 6 Alkyl), hydroxyl (C 1 -C 6 Alkyl), C 3 -C 6 Cycloalkyl, C 3 -C 6 Cycloalkenyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, -
  • substitution refers to being randomly selected from 1-2 members selected from halogen, cyano, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, halo(C 1 -C 6 Alkyl), hydroxyl (C 1 -C 6 Alkyl), C 3 -C 6 Cycloalkyl, C 3 -C 6 Cycloalkenyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, -
  • substitution refers to being randomly selected from 1-2 members selected from halogen, cyano, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, halo(C 1 -C 6 Alkyl), hydroxyl (C 1 -C 6 Alkyl), C 3 -C 6 Cycloalkyl, C 3 -C 6 Cycloalkenyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl,
  • substitution refers to being randomly selected from 1-2 members selected from halogen, cyano, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, halo(C 1 -C 6 Alkyl), hydroxyl (C 1 -C 6 Alkyl), C 3 -C 6 Cycloalkyl, C 3 -C 6 Cycloalkenyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, -
  • substitution refers to being randomly selected from 1-2 members selected from halogen, cyano, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, halo(C 1 -C 6 Alkyl), hydroxyl (C 1 -C 6 Alkyl), C 3 -C 6 Cycloalkyl, C 3 -C 6 Cycloalkenyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, -
  • substitution refers to being randomly selected from 1-2 members selected from halogen, cyano, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, halo(C 1 -C 6 Alkyl), hydroxyl (C 1 -C 6 Alkyl), C 3 -C 6 Cycloalkyl, C 3 -C 6 Cycloalkenyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, -
  • substitution refers to being randomly selected from 1-2 members selected from halogen, cyano, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, halo(C 1 -C 6 Alkyl), hydroxyl (C 1 -C 6 Alkyl), C 3 -C 6 Cycloalkyl, C 3 -C 6 Cycloalkenyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, -
  • substitution refers to being randomly selected from 1-2 members selected from halogen, cyano, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, halo(C 1 -C 6 Alkyl), hydroxyl (C 1 -C 6 Alkyl), C 3 -C 6 Cycloalkyl, C 3 -C 6 Cycloalkenyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, -
  • substitution refers to being randomly selected from 1-2 members selected from halogen, cyano, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, halo(C 1 -C 6 Alkyl), hydroxyl (C 1 -C 6 Alkyl), C 3 -C 6 Cycloalkyl, C 3 -C 6 Cycloalkenyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl,
  • substitution refers to being randomly selected from 1-2 members selected from halogen, cyano, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, halo(C 1 -C 6 Alkyl), hydroxyl (C 1 -C 6 Alkyl), C 3 -C 6 Cycloalkyl, C 3 -C 6 Cycloalkenyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl,
  • substitution refers to being randomly selected from 1-2 members selected from halogen, cyano, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, halo(C 1 -C 6 Alkyl), hydroxyl (C 1 -C 6 Alkyl), C 3 -C 6 Cycloalkyl, C 3 -C 6 Cycloalkenyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, -
  • R 5 is any ring structure in the following formula (i), formula (ii) or formula (iii):
  • W 2 is N, and when W 1 is NR W1 , R W1 is not H;
  • W 2 is N, W 1 is NR W1 , and when R W1 is H, Y is not ethylene;
  • X 1 is NR X1' , and R X1' and R X3 together with the atoms connected to them form a 5- to 8-membered heteroaromatic ring or are substituted by one or more hydroxyl groups 5-8 membered heteroaromatic rings;
  • X 1 is CR X1 , wherein the C atom in X 1 is connected to the C atom in the aryl or heteroaryl group in R 1 through -O-(CH 2 ) n1 - * , * -NH-(CH 2 ) n2 -, -C ⁇ C-(CH 2 ) n3 -C ⁇ C- * or -(CH 2 ) n4 -O-(CH 2 ) n5 - * , wherein the * terminal is connected to C in X 1 Atoms connected;
  • R 1 is a C 6 -C 14 aryl group substituted by one or more R 1-1 or a 5-14 membered heteroaryl group substituted by one or more R 1-2 ;
  • R 1-3 and R 1-4 are independently halogen
  • the types of heteroatoms in the 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, 5-14-membered heteroaryl, 3-8-membered heterocycloalkyl, 3-6-membered aliphatic heterocycle, 3-6-membered carboalkene ring, 5-8-membered heteroaryl ring, 3-8-membered aliphatic heterocycle, 3-8-membered carbazaene ring, 3-8-membered aliphatic heterocycle and 3-8-membered carbazaene ring are each independently selected from one, two or three of N, O and S;
  • X 1-2 is independently C 1 -C 6 alkyl.
  • X 1-4 is independently H, C 3 -C 8 cycloalkyl, 3-8 membered heterocycloalkyl, C 1 -C 6 alkyl, or C 1 -C 6 alkyl substituted by one or more halogens;
  • X 1-7 is OH or C 1 -C 6 alkyl.
  • X 2 is N or CR X2
  • R X2 is CN
  • X 3 is N or CR X3
  • R X3 is H or C 1 -C 6 alkyl
  • R 2 is halogen, C 1 -C 6 alkyl or C 1 -C 6 alkoxy.
  • L 2 represents -O-(C 1 -C 6 alkylene).
  • R3 is the following ring structure:
  • R 1' , R 2' , R 3' , R 4' , R 5' , R 6' , R 7' , R 8' , R 9' , R 10' , R 11' , R 12' each independently represent hydrogen or halogen;
  • R 3' and R 4' together form a C 3 -C 8 aliphatic carbocyclic ring, a substituted C 3 -C 8 aliphatic carbocyclic ring or a 3-8 membered aliphatic heterocyclic ring, and the substitution refers to being optionally substituted by 1-2 halogens;
  • R 9' and R 10' together form a C 3 -C 8 aliphatic carbocyclic ring, a substituted C 3 -C 8 aliphatic carbocyclic ring or a 3-8 membered aliphatic heterocyclic ring, and the substitution refers to being optionally substituted by 1-2 halogens;
  • R 3' and R 4' together form a C 3 -C 8 aliphatic carbocyclic ring, a substituted C 3 -C 8 aliphatic carbocyclic ring or a 3-8 membered aliphatic heterocyclic ring. Replaced by 1-2 halogens ;
  • R 4' and R 5' together with the atoms connected to them form a C 3 -C 8 aliphatic carbocyclic ring, a substituted C 3 -C 8 aliphatic carbocyclic ring or a 3-8 membered aliphatic heterocyclic ring, and the substitution refers to being optionally substituted by 1-2 halogens;
  • R 8' and R 9' together with the atoms connected to them form a C 3 -C 8 aliphatic carbocycle, a substituted C 3 -C 8 aliphatic carbocycle or a 3-8 membered aliphatic heterocycle, and the substitution refers to being optionally substituted by 1-2 halogens;
  • R 2' and R 3' together with the atoms connected to them form a C 3 -C 8 aliphatic carbocyclic ring, a substituted C 3 -C 8 aliphatic carbocyclic ring or a 3-8 membered aliphatic heterocyclic ring, and the substitution refers to being optionally substituted by 1-2 halogens;
  • R 10' and R 11' together with the atoms connected to them form a C 3 -C 8 aliphatic carbocycle, a substituted C 3 -C 8 aliphatic carbocycle or a 3-8 membered aliphatic heterocycle, and the substitution refers to being optionally substituted by 1-2 halogens.
  • R 4 is L 1 -R 5
  • L 1 represents absence or NR a
  • R a represents hydrogen or C 1 -C 6 alkyl.
  • R is any ring structure of the following formula (i), formula (ii) or formula (iii):
  • W 1 represents CR W1 R W2 or NR W1 ;
  • R a and R b each independently represent hydrogen or C 1 -C 6 alkyl
  • Y is methylene, ethylene, C 3 alkylene, C 2 -C 3 alkenylene, or R c and R d together with the atoms connected to them form a C 3 -C 6 aliphatic carbocycle or a C 3 -C 6 aliphatic carbocycle substituted by one or more halogens; or R d and R d' together with the atoms connected to them form a C 3 -C 6 aliphatic carbocycle or a C 3 -C 6 aliphatic carbocycle substituted by one or more halogens;
  • R 1" , R 2" , R 3" , R 4" , R 5" , R 6" , R 7" , R 8" each independently represent hydrogen or C 1 -C 6 alkyl
  • R 2" and R 3" together with the atoms connected to them form a C 3 -C 8 aliphatic carbocyclic ring, a 3-8 membered aliphatic heterocyclic ring or a substituted 3-8 membered aliphatic heterocyclic ring.
  • R 3" and R 4" together form a C 3 -C 8 aliphatic carbocyclic ring, a 3-8 membered aliphatic heterocyclic ring or a substituted 3-8 membered aliphatic heterocyclic ring with the atoms connected to it.
  • R 4" and R 5" together with the atoms connected to them form a C 3 -C 8 aliphatic carbocyclic ring, a 3-8 membered aliphatic heterocyclic ring or a substituted 3-8 membered aliphatic heterocyclic ring.
  • R 3" and R 4" together with the atom connected to it form a C 3 -C 8 aliphatic carbocyclic ring, a 3-8 membered aliphatic heterocyclic ring or a substituted 3-8 membered aliphatic heterocyclic ring.
  • ring K is an aromatic ring or a heteroaryl ring
  • X 1 is N, NR X1' or CR X1 ,
  • X 1-2 are independently C 1 -C 6 alkyl;
  • X 1-4 are independently H , C 3 -C 8 cycloalkyl, 3-8 membered heterocycloalkyl, C 1 -C 6 alkyl, or C 1 -C 6 alkyl substituted by one or more halogens;
  • X 1-7 is OH or C 1 -C 6 alkyl;
  • R X1' and R X3 and the atoms connected to them together form a 5-8 membered heteroaryl ring or a 5-8 membered heteroaryl ring substituted by one or more hydroxyl groups;
  • R 1 is a C 6 -C 14 aryl group, a C 6 -C 14 aryl group substituted by one or more R 1-1 , a 5-14 membered heteroaryl group or a 5-14 membered heteroaryl group substituted by one or more R 1-2 ;
  • R 1-3 and R 1-4 are independently halogen
  • X 1 is CR X1 , wherein the C atom in X 1 is connected to the C atom in the aryl or heteroaryl group in R 1 through -O-(CH 2 ) n1 - * , * -NH-(CH 2 ) n2 -, -C ⁇ C-(CH 2 ) n3 -C ⁇ C- * or -(CH 2 ) n4 -O-(CH 2 ) n5 - * , wherein the * end is connected to the C atom in X 1 connected;
  • n1, n2, n3, n4 and n5 are each independently 1, 2, 3, 4, 5 or 6;
  • R 2 is halogen, C 1 -C 6 alkyl or C 1 -C 6 alkoxy
  • R 3 is the following ring structure:
  • R 1' , R 2' , R 3' , R 4' , R 5' , R 6' , R 7' , R 8' , R 9' , R 10' , R 11' , R 12' each independently represent hydrogen or halogen;
  • R 3' and R 4' together form a C 3 -C 8 aliphatic carbocyclic ring, a substituted C 3 -C 8 aliphatic carbocyclic ring or a 3-8 membered aliphatic heterocyclic ring, and the substitution refers to being optionally substituted by 1-2 halogens;
  • R 9' and R 10' together form a C 3 -C 8 aliphatic carbocyclic ring, a substituted C 3 -C 8 aliphatic carbocyclic ring or a 3-8 membered aliphatic heterocyclic ring, and the substitution refers to being optionally substituted by 1-2 halogens;
  • R 3' and R 4' together form a C 3 -C 8 aliphatic carbocyclic ring, a substituted C 3 -C 8 aliphatic carbocyclic ring or a 3-8 membered aliphatic heterocyclic ring, the substitution refers to being optionally substituted by 1-2 halogens ; Replaced by 1-2 halogens;
  • R 4' and R 5' together with the atoms connected to them form a C 3 -C 8 aliphatic carbocyclic ring, a substituted C 3 -C 8 aliphatic carbocyclic ring or a 3-8 membered aliphatic heterocyclic ring, and the substitution refers to being optionally substituted by 1-2 halogens;
  • R 8' and R 9' together with the atoms connected to them form a C 3 -C 8 aliphatic carbocycle, a substituted C 3 -C 8 aliphatic carbocycle or a 3-8 membered aliphatic heterocycle, and the substitution refers to being optionally substituted by 1-2 halogens;
  • R 2' and R 3' together with the atoms connected to them form a C 3 -C 8 aliphatic carbocyclic ring, a substituted C 3 -C 8 aliphatic carbocyclic ring or a 3-8 membered aliphatic heterocyclic ring, and the substitution refers to being optionally substituted by 1-2 halogens;
  • R 4 is L 1 -R 5 , L 1 means absent or NR a ,
  • R is any ring structure in the following formula (i), formula (ii) or formula (iii):
  • W 1 represents CR W1 R W2 or NR W1 ;
  • R a and R b each independently represent hydrogen or C 1 -C 6 alkyl
  • W 2 represents CH or N
  • Y is methylene, ethylene, C 3 alkylene, C 2 -C 3 alkenylene, or R c and R d together with the atoms connected to them form a C 3 -C 6 aliphatic carbocycle or a C 3 -C 6 aliphatic carbocycle substituted by one or more halogens; or R d and R d' together with the atoms connected to them form a C 3 -C 6 aliphatic carbocycle or a C 3 -C 6 aliphatic carbocycle substituted by one or more halogens;
  • R 1" , R 2" , R 3" , R 4" , R 5" , R 6" , R 7" , R 8" each independently represent hydrogen or C 1 -C 6 alkyl
  • R 2" and R 3" together with the atoms connected to them form a C 3 -C 8 aliphatic carbocyclic ring, a 3-8 membered aliphatic heterocyclic ring or a substituted 3-8 membered aliphatic heterocyclic ring.
  • R 3" and R 4" together form a C 3 -C 8 aliphatic carbocyclic ring, a 3-8 membered aliphatic heterocyclic ring or a substituted 3-8 membered aliphatic heterocyclic ring with the atoms connected to it.
  • R 5" and R 6" together form a C 3 -C 8 aliphatic carbocyclic ring, a 3-8 membered aliphatic heterocyclic ring or a substituted 3-8 membered aliphatic heterocyclic ring with the atoms connected to it,
  • R 3" and R 4" together with the atoms connected to it form a C 3 -C 8 aliphatic carbocyclic ring, a 3-8 membered aliphatic heterocyclic ring or a substituted 3-8 membered aliphatic heterocyclic ring.
  • R 3 , R 3' and R 4' together form a C 3 -C 8 aliphatic carbocyclic ring, a substituted C 3 -C 8 aliphatic carbocyclic ring or a 3-8 membered aliphatic heterocyclic ring, and the substitution refers to being optionally substituted by 1-2 halogens;
  • R 9' and R 10' together form a C 3 -C 8 aliphatic carbocyclic ring, a substituted C 3 -C 8 aliphatic carbocyclic ring or a 3-8 membered aliphatic heterocyclic ring, and the substitution refers to being optionally substituted by 1-2 halogens;
  • R 3' and R 4' together form a C 3 -C 8 aliphatic carbocyclic ring, a substituted C 3 -C 8 aliphatic carbocyclic ring or a 3-8 membered aliphatic heterocyclic ring. Replaced by 1-2 halogens ;
  • R 4' and R 5' together with the atoms connected to them form a C 3 -C 8 aliphatic carbocycle, a substituted C 3 -C 8 aliphatic carbocycle or a 3-8 membered aliphatic heterocycle, and the substitution refers to being optionally substituted by 1-2 halogens;
  • R 2' and R 3' together with the atoms connected to them form a C 3 -C 8 aliphatic carbocycle, a substituted C 3 -C 8 aliphatic carbocycle or a 3-8 membered aliphatic heterocycle, and the substitution refers to being optionally substituted by 1-2 halogens;
  • R 10' and R 11' together with the atoms connected to them form a C 3 -C 8 aliphatic carbocycle, a substituted C 3 -C 8 aliphatic carbocycle or a 3-8 membered aliphatic heterocycle, and the substitution refers to being optionally substituted by 1-2 halogens;
  • R 5 is any ring structure in the following formula (i), formula (ii) or formula (iii):
  • W 2 is N, and when W 1 is NR W1 , R W1 is not H;
  • W 2 is N, W 1 is NR W1 , and when R W1 is H, Y is not ethylene;
  • X 1 is NR X1' , and R X1' and R X3 together with the atoms connected to them form a 5-8 membered heteroaryl ring or a 5-8 membered heteroaryl ring substituted by one or more hydroxyl groups;
  • X 1 is CR X1 , wherein the C atom in X 1 and the C atom in the aryl or heteroaryl group in R 1 pass through -O-(CH 2 ) n1 - * , * -NH-(CH 2 ) n2 -, -C ⁇ C-(CH 2 ) n3 -C ⁇ C- * or -(CH 2 ) n4 -O-(CH 2 ) n5 - * is connected, where the * end is connected to the C atom in X 1 ;
  • R 1 is a C 6 -C 14 aryl group substituted by one or more R 1-1 or a 5-14 membered heteroaryl group substituted by one or more R 1-2 ;
  • R 1 is a C 6 -C 14 aryl group substituted by one or more R 1-1
  • two adjacent R 1-1 and the atoms connected to it together form a C 3 -C 8 aliphatic carbon ring or a C 3 -C 8 aliphatic carbon ring substituted by one or more R 1-3
  • R 1 is a 5- to 14-membered heteroaryl group substituted by one or more R 1-2
  • two adjacent R 1-2 and their connected atoms together form a C 3 -C 8 aliphatic carbon ring or a C 3 -C 8 aliphatic carbon ring substituted by one or more R 1-4
  • R 1-3 and R 1-4 are independently halogen.
  • X 1-4 is independently C 1 -C 6 alkyl.
  • X 1-7 is C 1 -C 6 alkyl.
  • X 3 is CR X3
  • R X3 is H
  • R X1' and R X3 together with the atoms connected to them form a 5-8 membered heteroaromatic ring.
  • R 1 is a C 6 -C 14 aryl group substituted by one or more R 1-1 or a 5-14 membered heteroaryl group substituted by one or more R 1-2 ;
  • R 2 is halogen
  • R3 is hour
  • ring A, ring B and ring C share one carbon atom with the parent structure, ring D and ring E share two atoms and one bond with the parent structure; ring A, ring B and ring C share one carbon atom with the parent structure, ring D and ring E share two atoms and one bond with the parent structure; ring A, ring B, ring C, ring D and ring E are each independently 3-8 membered aliphatic heterocyclic rings, C 3 -C 8 aliphatic carbocyclic rings, or C 3 -C substituted by one or more halogens 8 aliphatic carbon rings;
  • R 4 is formula (i), formula (ii) or formula (iii):
  • R 1" , R 2" , R 7" and R 8" are each independently hydrogen;
  • W 1 represents CR W1 R W2 or NR W1 ;
  • W 2 represents N;
  • R W1 is CR W1 R W2
  • R W1 and R W2 each independently represent H, a 3-8 membered heterocycloalkyl group or R W1 and R W2 together form a 3-8 membered aliphatic heterocycle together with the atoms connected to it;
  • R W1 is NR W1
  • R W1 is H
  • R 1" , R 2" , R 3" , R 4" , R 7" and R 8" are each independently hydrogen or C 1 -C 6 alkyl
  • R independently represents hydrogen or C 1 -C 6 alkyl
  • R 4 is
  • R 4-2 for C 1 -C 6 Alkyl, R 4-2 The number is one or more
  • R 4-3 and R 4-4 Each independently is H or 3-8 membered heterocycloalkyl, or R 4-3 and R 4-4
  • ring G, ring I and ring J share one carbon atom with the parent structure
  • ring F and ring H share two atoms and one bond with the parent structure
  • ring F, ring G, ring H, ring I and ring J are independently C 3 -C 8 Aliphatic carbon ring, 3-8 membered aliphatic heterocyclic ring, 5-8 membered lactam ring or one or more R e Substituted 3-8 membered
  • the halogens can be independently F, Cl, Br or I, such as Cl.
  • the C 1 -C 6 alkyl group can be independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, preferably methyl.
  • the C 3 -C 6 cycloalkyl group can be cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, preferably cyclopropyl.
  • the C 2 -C 6 alkenyl in R X1 , can be a C 2 -C 4 alkenyl, such as vinyl.
  • the C 2 -C 6 alkynyl can be a C 2 -C 4 alkynyl, such as ethynyl.
  • the 3-6 heterocycloalkyl groups can be independently tetrahydropyrrolyl, oxetanyl, tetrahydropyranyl or piperidinyl, more for example
  • the type of heteroatoms can be N, and the number of heteroatoms can be 2.
  • the 5-14 membered heteroaryl group can be a 5-6 membered heteroaryl group, such as pyrazolyl or imidazolyl, more for example
  • the type of heteroatoms in the 3-6 membered heterocycloalkenyl group, can be independently selected from N and O, and the number of heteroatoms can be independently 1.
  • the 3-6 membered heterocycloalkenyl groups can be independently 6-membered heterocycloalkenyl groups, for example, containing 1 O atom A 6-membered heterocycloalkenyl or a 6-membered heterocycloalkenyl containing 1 N atom, more for example
  • the C 1 -C 6 alkyl group can be independently a C 1 -C 4 alkyl group, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, preferably methyl or ethyl.
  • the C 3 -C 8 cycloalkyl can be a C 3 -C 6 cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, preferably cyclopropyl, cyclopentyl or cyclohexyl.
  • the 3-8 membered heterocycloalkyl group can be 3-6 membered heterocycloalkyl group, such as piperidinyl, morpholinyl or piperazinyl.
  • the C 5 -C 8 cycloalkene can be a C 5 -C 6 cycloalkene, such as cyclopentenone, at this time, Can be
  • the type of heteroatoms in the 5-8 membered heteroaromatic rings can be N independently, and the number of heteroatoms can be 2, 3 or 4 independently.
  • the 5-8 membered heteroaromatic ring can be independently a 5-membered heteroaromatic ring, such as a pyrazole ring, a triazole ring, a tetrazole ring or an oxadiazole ring, at this time, Can be
  • the C 6 -C 14 aryl groups can be independently phenyl or naphthyl, for example
  • the type of heteroatom in the 5- to 14-membered heteroaryl group in R 1 , can be independently N, and the number of heteroatom can be independently 1.
  • the 5-14 membered heteroaryl groups can be independently 5-12 membered heteroaryl groups, such as pyridyl, quinolinyl or isoquinolyl, more for example
  • the halogens can be independently F, Cl, Br or I, such as F or Cl.
  • the C 1 -C 6 alkyl group can be independently a C 1 -C 4 alkyl group, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, preferably methyl or ethyl.
  • the C 1 -C 10 alkyl group can be independently a C 1 -C 9 alkyl group, such as n-nonyl.
  • n2 is 6.
  • n3 is 4.
  • n4 is 1.
  • n5 is 1.
  • R is one or more R 1-1 substituted naphthyl, one or more R 1-1 substituted phenyl, one or more R 1-2 substituted pyridyl, one or more R 1-2 substituted quinolinyl or one or more R 1-2 substituted isoquinolinyl, for example
  • the C 1 -C 6 alkyl group can be a C 1 -C 4 alkyl group, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl.
  • the C 1 -C 6 alkoxy group can be a C 1 -C 4 alkoxy group, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy or tert-butoxy.
  • R 2 is F
  • the C 1 -C 6 alkylene group in L 2 , can be a C 1 -C 3 alkylene group, such as methylene, ethylene or propylene, preferably methylene.
  • the type of heteroatom in the 3-8 membered aliphatic heterocyclic ring, can be independently O, and the number of heteroatom can be independently 1.
  • the 3-8 membered aliphatic heterocyclic ring refers to all 3-8 membered aliphatic heterocyclic rings within the scope of the above definition of R 3 , such as the 3-8 membered aliphatic heterocyclic rings in ring A, ring B, ring C, ring D and ring E.
  • the 3-8 membered aliphatic heterocyclic rings can be independently 4-5 membered aliphatic heterocyclic rings, such as oxetane or tetrahydrofuran rings.
  • the 3-8 membered aliphatic heterocycles can be independently
  • the 3-8 membered aliphatic heterocyclic rings described in ring A, ring B and ring C can be independently
  • the 3-8 membered aliphatic heterocycles can be independently
  • the 3-8 membered aliphatic heterocycles can be independently
  • the C 3 -C 8 aliphatic carbocycles can be independently
  • the C 3 -C 8 aliphatic carbocyclic ring can be independently
  • the C 3 -C 8 aliphatic carbocycles can be independently
  • the C 3 -C 8 aliphatic carbocyclic ring can be independently
  • the halogen in the definition of R 3 , can be F, Cl, Br or I, such as F.
  • the halogen refers to all the halogens mentioned in the definition of R 3 above, such as the halogens in ring A, ring B, ring C, ring D and ring E.
  • the C 1 -C 10 alkyl group in R 4-1 , can be a C 1 -C 9 alkyl group, such as n-nonyl or isopropyl.
  • the type of heteroatoms can be independently selected from N and O, and the number of heteroatoms can be independently 1 or 2.
  • the 3-8 membered heterocycloalkyl groups can be independently 4-6 membered heterocycloalkyl groups, such as tetrahydropyrrolyl, morpholinyl or piperidinyl, more for example
  • the 3-8 membered aliphatic heterocyclic ring can be a 4-5 membered aliphatic heterocyclic ring, such as N-heterocyclobutane, more for example
  • the C 3 -C 8 aliphatic carbocycle can be independently a C 3 -C 6 aliphatic carbocycle, such as cyclopropane, cyclobutane, cyclopentane or cyclohexane, preferably cyclopropane, cyclobutane or cyclohexane.
  • the C 3 -C 8 aliphatic carbocycle refers to all C 3 -C 8 aliphatic carbocycles within the scope of the definition of R 4 above, such as C 3 -C 8 aliphatic carbocycles in ring F, ring G, ring H, ring I and ring J.
  • the C 3 -C 8 aliphatic carbocycles can be independently
  • the C 3 -C 8 aliphatic carbocyclic ring can be independently
  • the C 3 -C 8 aliphatic carbocycles can be independently
  • the C 3 -C 8 aliphatic carbocyclic ring can be independently
  • the 3-8 membered aliphatic heterocyclic rings can be independently 4-5 membered aliphatic heterocyclic rings, such as tetrahydropyrrole ring or N-heterocyclobutane.
  • the 3-8 membered aliphatic heterocyclic ring refers to all 3-8 membered aliphatic heterocyclic rings within the scope of the definition of R 4 above, such as the 3-8 membered aliphatic heterocyclic rings in ring F, ring G, ring H, ring I and ring J.
  • the 3-8 membered aliphatic heterocycles can be independently
  • the 3-8 membered aliphatic heterocycles can be independently
  • the 3-8 membered aliphatic heterocycles can be independently
  • the 3-8 membered aliphatic heterocycles can be independently
  • the 5- to 8-membered lactam rings may be independently 5-membered lactam rings.
  • the 5- to 8-membered lactam rings can be independently
  • the C 1 -C 6 alkyl group can be a C 1 -C 4 alkyl group, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, preferably methyl.
  • X can be F, Cl, Br or I, such as F or Br.
  • R3 is hour
  • X is N
  • Ring A is a 3-8 membered aliphatic heterocycle, a C 3 -C 8 aliphatic carbocycle or a C 3 -C 8 aliphatic carbocycle substituted by one or more halogens, such as oxetane, cyclopropane, or F-substituted cyclopropane, more for example
  • Ring D and ring E are each independently a C 3 -C 8 aliphatic carbocyclic ring, such as cyclopropane, more for example
  • X 1 is CR X1 ;
  • the 3-6 membered heterocycloalkyl is preferably oxetanyl or tetrahydropyrrolyl, for example
  • the 5-14 membered heteroaryl is preferably pyrazolyl, for example
  • Ring A is preferably a C 3 -C 8 aliphatic carbocyclic ring substituted by one or more halogens, such as cyclopropane substituted by F, more for example
  • R 1 is a C 6 -C 14 aryl group substituted by one or more R 1-1 or a 5-14 membered heteroaryl group substituted by one or more R 1-2 ;
  • R 1 is a C 6 -C 14 aryl group substituted by one or more R 1-1
  • two adjacent R 1-1 and the atoms connected to it together form a C 3 -C 8 aliphatic carbon ring or a C 3 -C 8 aliphatic carbon ring substituted by one or more R 1-3
  • R 1 is a 5- to 14-membered heteroaryl group substituted by one or more R 1-2
  • two adjacent R 1-2 and their connected atoms together form a C 3 -C 8 aliphatic carbon ring or a C 3 -C 8 aliphatic carbon ring substituted by one or more R 1-4
  • R 1-3 and R 1-4 are independently halogen.
  • the heterocyclic compound shown in formula I-0 is a heterocyclic compound shown in formula I:
  • X 1 is N or CR X1 , R X1 is CN, halogen, CF 3 , SO 2 Me, POMe 2 or NH 2 ;
  • X 2 is N or CR X2 , R X2 is CN;
  • R 2 is halogen
  • R and R are selected from any of the following schemes:
  • R3 is hour
  • R3 is hour
  • certain groups in the heterocyclic compound represented by formula I, its pharmaceutically acceptable salts, its stereoisomers or their solvates are defined as follows, and the unmentioned groups are the same as those described in any scheme of the present application (referred to as "in a certain scheme of the present invention"), and X1 is N, C-CN, C-Cl, C- CF3 , C- SO2Me , C- POMe2 or C- NH2 .
  • X 2 is N or C-CN.
  • R 2 is F.
  • the compound shown in formula I-0 is a compound shown in formula I-1:
  • X 1 is NR X1' , and R X1' and R X3 together with the atoms connected to them form a 5-8 membered heteroaromatic ring or a 5-8 membered heteroaromatic ring substituted by one or more hydroxyl groups; the definitions of other substituents are as described in any scheme herein;
  • X 1 is CR X1 , wherein, the C atom in X 1 is connected to the C atom in the aryl or heteroaryl group in R 1 through -O-(CH 2 ) n1 - * , * -NH-(CH 2 ) n2 - , -C ⁇ C- (CH 2 ) n3 -C ⁇ C- * or -(CH 2 ) n4 -O-(CH 2 ) n5 - * , where the * end is connected to X 1 C atoms are connected; the definitions of other substituents and the definitions of n1, n2, n3, n4 and n5 are as described in any scheme herein;
  • R 1 is a C 6 -C 14 aryl group substituted by one or more R 1-1
  • two adjacent R 1-1 and the atoms connected to them together form a C 3 -C 8 aliphatic carbon ring or a C 3 -C 8 aliphatic carbon ring substituted by one or more R 1-3
  • R 1 is a 5- to 14-membered heteroaryl group substituted by one or more R 1-2
  • two adjacent R 1-2 and their connected atoms together form a C 3 -C 8 aliphatic carbon ring or a C 3 -C 8 aliphatic carbon ring substituted by one or more R 1-4
  • R 1-3 and R 1-4 are independently halogen
  • the compound shown in formula I-0 is a compound shown in formula I-2:
  • R3 is , wherein, Ring A, Ring B and Ring C share one carbon atom with the parent structure, Ring D and Ring E share two atoms and one bond with the parent structure; Ring A, Ring B, Ring C, Ring D and Ring E are each independently 3-8 membered aliphatic heterocyclic rings, C 3 -C 8 aliphatic carbocyclic rings, or C 3 -C 8 aliphatic carbocyclic rings substituted by one or more halogens;
  • the present invention also provides a heterocyclic compound as shown below, its pharmaceutically acceptable salt, its stereoisomer, or their solvate (referring to the aforementioned heterocyclic compound as shown below, its pharmaceutically acceptable salt or its stereoisomer):
  • the pharmaceutically acceptable salt of the heterocyclic compound is as follows:
  • the present invention also provides a heterocyclic compound as shown below, its pharmaceutically acceptable salt, its stereoisomer or their solvate (referring to the aforementioned heterocyclic compound as shown below, its pharmaceutically acceptable salt or its stereoisomer):
  • the compound whose retention time is 0.660min under the following conditions is One stereoisomer in: Chromatographic column: Chiralpak AD-3, 50mm*4.6mm, 3um; Mobile phase: A phase is carbon dioxide, B phase is 0.05% diethylamine/ethanol; Gradient: keep 50% of B phase for 5 minutes, flow rate: 4 ml/min;
  • the compound whose retention time is 2.311min under the following conditions is One stereoisomer in: Chromatographic column: Chiralpak IG-3 100*4.6mm ID, 3um; Mobile phase: A phase is carbon dioxide, B phase is 0.05% diethylamine/ethanol; Gradient: B phase from 5% to 40% in 4 minutes, keep 40% B phase for 2.5 minutes, keep 5% B phase for 1.5 minutes, flow rate: 2.8 ml/min;
  • the compound whose retention time is 3.397min under the following conditions is One stereoisomer in: Chromatographic column: Chiralpak IG-3 100*4.6mm ID, 3um; Mobile phase: A phase is carbon dioxide, B phase is 0.05% diethylamine/ethanol; Gradient: B phase from 5% to 40% in 4 minutes, keep 40% B phase for 2.5 minutes, keep 5% B phase for 1.5 minutes, flow rate: 2.8 ml/min;
  • the compound whose retention time is 1.942min under the following conditions is One stereoisomer in: chromatographic column: Chiralpak IG-3, 50mm*4.6mm, 3um; mobile phase: phase A is carbon dioxide, phase B is 0.05% diethylamine/ethanol; gradient: phase B is from 5% to 40% in 2 minutes, keep 40% of B phase for 1.2 minutes, keep 5% of B phase for 0.8 minutes, flow rate: 4 ml/min;
  • the compound whose retention time is 2.343min under the following conditions is One stereoisomer in: Chromatographic column: Chiralpak IG-3, 50mm*4.6mm, 3um; Mobile phase: A phase is carbon dioxide, B phase is 0.05% diethylamine/ethanol; Gradient: B phase is from 5% to 40% in 2 minutes, keep 40% of B phase for 1.2 minutes, keep 5% of B phase for 0.8 minutes, flow rate: 4 ml/min;
  • the compound whose retention time is 3.004min under the following conditions is One stereoisomer in: chromatographic column: Chiralpak IG-3, 50mm*4.6mm, 3um; mobile phase: phase A is carbon dioxide, phase B is 0.05% diethylamine/ethanol; gradient: phase B is from 5% to 40% in 2 minutes, keep 40% of B phase for 1.2 minutes, keep 5% of B phase for 0.8 minutes, flow rate: 4 ml/min;
  • the compound whose retention time is 2.414min under the following conditions is A stereoisomer in: Chromatographic column: Chiralpak IC-3, 100mm*4.6mm, 3um; Mobile phase: A phase is carbon dioxide, B phase is 0.05% diethylamine/isopropanol; Gradient: 40% B phase, flow rate: 2.8 ml/min;
  • the compound whose retention time is 1.150min under the following conditions is One stereoisomer in: Chromatographic column: Chiralpak IG-3, 50mm*4.6mm, 3um; Mobile phase: A phase is carbon dioxide, B phase is 0.05% diethylamine/isopropanol; Gradient: keep 40% of B phase, flow rate: 4 ml/min;
  • the compound whose retention time is 2.203min under the following conditions is One stereoisomer in: Chromatographic column: Chiralpak IG-3, 50mm*4.6mm, 3um; Mobile phase: A phase is carbon dioxide, B phase is 0.05% diethylamine/isopropanol; Gradient: keep 40% of B phase, flow rate: 4 ml/min;
  • the compound whose retention time is 1.696min under the following conditions is One stereoisomer in: Chromatographic column: Chiralpak AD-3, 50mm*4.6mm, 3um; mobile phase: phase A is carbon dioxide, phase B is 0.05% diethylamine/ethanol; gradient: phase B is from 5% to 40% in 2 minutes, keep 40% of B phase for 1.2 minutes, keep 5% of B phase for 0.8 minutes; flow rate: 4 ml/min;
  • the compound whose retention time is 2.137min under the following conditions is One stereoisomer in: Chromatographic column: Chiralpak AD-3, 50mm*4.6mm, 3um; Mobile phase: A phase is carbon dioxide, B phase is 0.05% diethylamine/ethanol; Gradient: B phase is from 5% to 40% in 2 minutes, keep 40% B phase for 1.2 minutes, keep 5% B phase for 0.8 minutes; flow rate: 4 ml/min.
  • the compound whose retention time is 1.787min under the following conditions is One stereoisomer in: Chromatographic column: Chiralpak AD-3, 50mm*4.6mm, 3um; mobile phase: phase A is carbon dioxide, phase B is 0.05% diethylamine/ethanol; gradient: phase B is from 5% to 40% in 2 minutes, keep 40% of B phase for 1.2 minutes, keep 5% of B phase for 0.8 minutes; flow rate: 4 ml/min;
  • the compound whose retention time is 2.089min under the following conditions is One stereoisomer in: Chromatographic column: Chiralpak AD-3, 50mm*4.6mm, 3um; mobile phase: phase A is carbon dioxide, phase B is 0.05% diethylamine/ethanol; gradient: phase B is from 5% to 40% in 2 minutes, keep 40% of B phase for 1.2 minutes, keep 5% of B phase for 0.8 minutes; flow rate: 4 ml/min;
  • the compound whose retention time is 0.797min under the following conditions is One stereoisomer in: Chromatographic column: Chiralpak IG-3, 50mm*4.6mm, 3um; Mobile phase: A phase is carbon dioxide, B phase is 0.05% diethylamine/isopropanol; Gradient: keep 40% of B phase; Flow rate: 4 ml/min;
  • the compound whose retention time is 1.943min under the following conditions is One stereoisomer in: Chromatographic column: ChiralPak AD-3, 150*4.6mm, 3um; Mobile phase: A phase is carbon dioxide, B phase is 0.05% diethylamine/ethanol; Gradient: maintain 40% of B phase; Flow rate: 2.5 ml/min;
  • the compound whose retention time is 3.400min under the following conditions is One stereoisomer in: Chromatographic column: ChiralPak AD-3, 150*4.6mm, 3um; Mobile phase: A phase is carbon dioxide, B phase is 0.05% diethylamine/ethanol; Gradient: maintain 40% of B phase; Flow rate: 2.5 ml/min;
  • the compound whose retention time is 6.088min under the following conditions is A mixture of stereoisomers in: chromatographic column: Chiralpak IG-3 100*4.6mm ID, 3um; mobile phase: phase A is carbon dioxide, phase B is 0.05% diethylamine/isopropanol; gradient: maintain 40% phase B, flow rate: 2.8 ml/min;
  • the compound whose retention time is 8.998min under the following conditions is A mixture of stereoisomers in: Chromatographic column: Chiralpak IG-3 100*4.6mm ID, 3um; Mobile phase: Phase A is carbon dioxide, phase B 0.05% diethylamine/isopropanol; gradient: maintain 40% phase B, flow rate: 2.8 ml/min;
  • the compound whose retention time is 1.374min under the following conditions is Two stereoisomer mixtures in: Chromatographic column: Chiralpak IG-3, 100*4.6mm ID, 3um; Mobile phase: A phase is carbon dioxide, B phase is 0.05% diethylamine/ethanol; Gradient: keep 40% of B phase, flow rate: 2.8 ml/min;
  • the compound whose retention time is 2.812min under the following conditions is One stereoisomer in: Chromatographic column: Chiralpak IG-3, 100*4.6mm ID, 3um; Mobile phase: A phase is carbon dioxide, B phase is 0.05% diethylamine/ethanol; Gradient: keep 40% of B phase, flow rate: 2.8 ml/min;
  • the compound whose retention time is 6.215min under the following conditions is One stereoisomer in: Chromatographic column: Chiralpak IG-3, 100*4.6mm ID, 3um; Mobile phase: A phase is carbon dioxide, B phase is 0.05% diethylamine/ethanol; Gradient: keep 40% of B phase, flow rate: 2.8 ml/min;
  • the compound whose retention time is 1.251min under the following conditions is One stereoisomer in: Chromatographic column: Chiralpak AD-3, 50*4.6mm, 3um; Mobile phase: A phase is carbon dioxide, B phase is 0.05% diethylamine/isopropanol; Gradient: maintain 40% of B phase; Flow rate: 4 ml/min;
  • the compound whose retention time is 0.369min under the following conditions is Two stereoisomer mixtures in: Chromatographic column: Chiralpak AD-3, 50mm*4.6mm, 3um; Mobile phase: A phase is carbon dioxide, B phase is 0.05% diethylamine/isopropanol; Gradient: keep B phase at 40%; Flow rate: 4 ml/min;
  • the compound whose retention time is 0.752min under the following conditions is One stereoisomer in: Chromatographic column: Chiralpak AD-3, 50mm*4.6mm, 3um; Mobile phase: A phase is carbon dioxide, B phase is 0.05% diethylamine/isopropanol; Gradient: keep B phase at 40%; Flow rate: 4 ml/min;
  • the compound whose retention time is 1.937min under the following conditions is One stereoisomer in: Chromatographic column: Chiralpak AD-3, 50mm*4.6mm, 3um; Mobile phase: Phase A is carbon dioxide, phase B is 0.05% Diethylamine/isopropanol; gradient: keep phase B at 40%; flow rate: 4 ml/min;
  • the compound whose retention time is 3.692min under the following conditions is One stereoisomer in: Chromatographic column: Chiralpak AD-3, 150mm*4.6mm, 3um; Mobile phase: A phase is carbon dioxide, B phase is 0.05% diethylamine/ethanol; Gradient: B phase is maintained at 40%; Flow rate: 2.5 ml/min.
  • phase A is trifluoroacetic acid/water (1.5mL/4L)
  • phase B is trifluoroacetic acid/acetonitrile (0.75mL/4L)
  • gradient phase B from 1% to 5% in 1 minute, from 5% to 100% in 5 minutes, keep 100% of phase B for 2 minutes, keep 1% of B phase for 2 minutes; flow rate: 1.2 ml/min):
  • the retention time is the compound of 3.539min, which is
  • the retention time is the compound of 3.539min, which is
  • the compound whose retention time is 3.754min under the following conditions is One stereoisomer in: Chromatographic column: ChiralCel OD-3, 150mm*4.6mm, 3um; Mobile phase: A phase is carbon dioxide, B phase is 0.05% diethylamine/isopropanol; keep 40% of B phase; flow rate: 2.5 ml/min;
  • the compound whose retention time is 3.131min under the following conditions is One stereoisomer in: Chromatographic column: ChiralCel OD-3, 150mm*4.6mm, 3um; Mobile phase: A phase is carbon dioxide, B phase is 0.05% diethylamine/isopropanol; keep 40% of B phase; flow rate: 2.5 ml/min;
  • the compound whose retention time is 1.653min under the following conditions is One stereoisomer in: Chromatographic column: ChiralCel OD-3, 50mm*4.6mm, 3um; Mobile phase: A phase is carbon dioxide, B phase is 0.05% diethylamine/ethanol; 2min rises from 5% B phase to 40% B phase, maintains 40% B phase for 1.2min, then maintains 5% B phase for 0.8min; flow rate: 4 ml/min;
  • the compound whose retention time is 1.763min under the following conditions is One stereoisomer in: Chromatographic column: ChiralCel OD-3, 50mm*4.6mm, 3um; Mobile phase: A phase is carbon dioxide, B phase is 0.05% diethylamine/ethanol; 2min rises from 5% B phase to 40% B phase, maintains 40% B phase for 1.2min, then maintains 5% B phase for 0.8min; flow rate: 4 ml/min;
  • the compound whose retention time is 1.343min under the following conditions is One stereoisomer in: Chromatographic column: Cellulose-2 100*4.6mm ID, 3um; Mobile phase: A phase is carbon dioxide, B phase is 0.05% diethylamine/ethanol; Gradient: keep 50% of B phase; Flow rate: 2.8 ml/min;
  • Chromatographic column Cellulose-2 100*4.6mm ID, 3um; Mobile phase: A phase is carbon dioxide, B phase is 0.05% diethylamine/ethanol; Gradient: maintain 50% of B phase; Flow rate: 2.8 ml/min;
  • the compound whose retention time is 1.739min under the following conditions is A stereoisomer in: Chromatographic column: Cellulose-2 100*4.6mm ID3um; Mobile phase: A phase is carbon dioxide, B phase is 0.05% diethylamine/ethanol; Gradient: keep 50% of B phase; Flow rate: 2.8 ml/min;
  • Chromatographic column Cellulose-2 100*4.6mm ID, 3um; Mobile phase: A phase is carbon dioxide, B phase is 0.05% diethylamine/ethanol; Gradient: maintain 50% of B phase; Flow rate: 2.8 ml/min;
  • Chromatographic column Cellulose 2 100*4.6mm ID, 3um; Mobile phase: A phase is carbon dioxide, B phase is 0.05% diethylamine/methanol; Gradient: maintain 50% of B phase; Flow rate: 2.8 ml/min;
  • the compound whose retention time is 4.369min under the following conditions is One stereoisomer in: Chromatographic column: Cellulose 2 100*4.6mm ID, 3um; Mobile phase: A phase is carbon dioxide, B phase is 0.05% diethylamine/methanol; Gradient: maintain 50% of B phase; Flow rate: 2.8 ml/min;
  • the compound whose retention time is 4.500min under the following conditions is One stereoisomer in: Chromatographic column: Chiralpak IC-3 100*4.6mm ID, 3um; Mobile phase: A phase is carbon dioxide, B phase is 0.05% diethylamine/ethanol; Gradient: maintain 50% of B phase; Flow rate: 2.8 ml/min;
  • the compound whose retention time is 2.676min under the following conditions is One stereoisomer in: Chromatographic column: (S, S) Whelk-01 100 ⁇ 4.6mm ID, 5.0um; Mobile phase: A phase is carbon dioxide, B phase is 0.05% diethylamine/isopropanol; Gradient: B phase maintains 60%; Flow rate: 2.5 ml/min;
  • the compound whose retention time is 3.176min under the following conditions is One stereoisomer in: Chromatographic column: (S, S) Whelk-01 100 ⁇ 4.6mm ID, 5.0um; Mobile phase: A phase is carbon dioxide, B phase is 0.05% diethylamine/isopropanol; Gradient: B phase maintains 60%; Flow rate: 2.5 ml/min;
  • the compound whose retention time is 0.634min under the following conditions is One stereoisomer in: Chromatographic column: Chiralpak IG-3 50*4.6mm ID, 3um; Mobile phase: A phase is carbon dioxide, B phase is 0.05% diethylamine/ethanol; Gradient: B phase maintains 40%; Flow rate: 4 ml/min;
  • test conditions of the above retention time are not limited to the compound, as long as the above test conditions are used to measure, the retention time obtained is the same as that described above or within the error range, and the compound is a stereoisomer in the above-mentioned compound limited by the retention time, it falls within the scope of protection of the present invention.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising:
  • heterocyclic compound as described in any one of the preceding items, its pharmaceutically acceptable salt, its stereoisomer or their solvate, and
  • the present invention also provides an application of substance A or the pharmaceutical composition in the preparation of a KRAS G12D inhibitor, wherein the substance A is the heterocyclic compound as described in any one of the preceding items, its pharmaceutically acceptable salt, its stereoisomer or their solvate.
  • the KRAS G12D inhibitor can be used in mammalian organisms; it can also be used in vitro, mainly for experimental purposes, for example: as a standard sample or control sample to provide comparison, or to prepare a kit according to conventional methods in the field to provide rapid detection of KRAS G12D inhibitory effect.
  • the present invention also provides a substance A or the application of the pharmaceutical composition in the preparation of medicines.
  • the substance A is a heterocyclic compound as described in any one of the preceding items, a pharmaceutically acceptable salt thereof, a stereoisomer or a solvate thereof, and the medicine is used for treating cancer, such as colorectal cancer, gastric cancer, pancreatic cancer, non-small cell lung cancer, prostate cancer, breast cancer, etc.
  • pharmaceutically acceptable means that salts, solvents, auxiliary materials, etc. are generally non-toxic, safe and suitable for use by patients.
  • the "patient” is preferably a mammal, more preferably a human.
  • pharmaceutically acceptable salt refers to a salt prepared from a compound of the present invention with a relatively non-toxic, pharmaceutically acceptable acid or base.
  • base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of a pharmaceutically acceptable base either in neat solution or in a suitable inert solvent.
  • Pharmaceutically acceptable base addition salts include, but are not limited to: lithium salts, sodium salts, potassium salts, calcium salts, aluminum salts, magnesium salts, zinc salts, bismuth salts, ammonium salts, diethanolamine salts.
  • solvate refers to a compound of the present invention in combination with a stoichiometric or non-stoichiometric amount of solvent.
  • the solvent molecules in a solvate may exist in an ordered or non-ordered arrangement.
  • the solvent includes but not limited to: water, methanol, ethanol and the like.
  • stereoisomer refers to cis-trans isomers or optical isomers. These stereoisomers can be separated, purified and enriched by asymmetric synthesis methods or chiral separation methods (including but not limited to thin-layer chromatography, rotational chromatography, column chromatography, gas chromatography, high-pressure liquid chromatography, etc.), and can also be obtained by chiral resolution through bond formation (chemical combination, etc.) or salt formation (physical combination, etc.) with other chiral compounds.
  • single “Stereoisomer” means that the mass content of one stereoisomer of the compound of the present invention relative to all stereoisomers of the compound is not less than 95%.
  • tautomers in the terms “compound”, “pharmaceutically acceptable salt”, “solvate” and “solvate of pharmaceutically acceptable salt”, it may exist in the form of a single tautomer or a mixture thereof, preferably in the form of a relatively stable tautomer.
  • cycloalkyl refers to a cyclic, saturated monovalent hydrocarbon group having a specified number of carbon atoms (eg, C 3 -C 6 ). Cycloalkyl groups include, but are not limited to: wait.
  • cycloalkenyl refers to a cyclic, unsaturated monovalent hydrocarbon group with a specified number of carbon atoms (for example, C 3 to C 6 ), which has one or more (for example, 1, 2 or 3) carbon-carbon sp 2 double bonds, which is a single ring and does not have aromaticity.
  • (Monocyclic)cycloalkenyl groups include, but are not limited to: wait.
  • carrier ring satisfies any of the following conditions, and the remaining definitions are the same as the term “cycloalkenyl”: 1. It is connected to the rest of the molecule through more than two single bonds; 2. It shares two atoms and one bond with the rest of the molecule.
  • alkenyl refers to a linear or branched, unsaturated, monovalent hydrocarbon group having a specified number of carbon atoms (eg, C2 - C6 ), which has one or more (eg, 1, 2 or 3) carbon-carbon sp2 double bonds.
  • Alkenyl groups include, but are not limited to: vinyl, wait.
  • alkynyl refers to a straight-chain or branched, unsaturated monovalent hydrocarbon group with a specified number of carbon atoms (for example, C 2 to C 6 ), which has one or more (for example, 1, 2 or 3) carbon-carbon sp 3 triple bonds.
  • Alkynyl includes, but is not limited to, ethynyl and the like.
  • heterocycloalkyl refers to a cyclic, saturated monovalent group having a specified number of ring atoms (for example, 3 to 8 members), a specified number of heteroatoms (for example, 1, 2 or 3), and a specified type of heteroatom (one or more of N, O and S), preferably a monocyclic ring.
  • a heterocycloalkyl group is attached to the rest of the molecule through a carbon atom or a heteroatom.
  • Heterocycloalkyl groups include, but are not limited to: wait.
  • cycloenone examples include, but are not limited to
  • heteroaryl ring satisfies any of the following conditions, and the remaining definitions are the same as the term “heteroaryl”: 1. It is connected to the rest of the molecule through more than two single bonds; 2. It shares two atoms and one bond with the rest of the molecule.
  • aryl refers to a cyclic, unsaturated monovalent hydrocarbon group with a specified number of carbon atoms (for example, C 6 to C 14 ), which is monocyclic or polycyclic (for example, 2 or 3). When it is polycyclic, two atoms and one bond are shared between the single rings, and (at least one ring/each ring) is aromatic. An aryl group is attached to the rest of the molecule through a carbon atom in an aromatic ring.
  • Aryl groups include, but are not limited to: phenyl or naphthyl and the like.
  • aromatic ring satisfies any of the following conditions, and the remaining definitions are the same as the term “aryl”: 1. It is connected to the rest of the molecule through more than two single bonds; 2. It shares two atoms and one bond with the rest of the molecule.
  • heteroalicyclic ring satisfies any of the following conditions, and the remaining definitions are the same as the term “heterocycloalkyl”: 1. It is connected to the rest of the molecule through more than two single bonds; 2. It shares two atoms and one bond with the rest of the molecule.
  • aliphatic carbocycle satisfies any of the following conditions, and the remaining definitions are the same as the term “cycloalkyl”: 1. It is connected to the rest of the molecule through more than two single bonds; 2. It shares two atoms and one bond with the rest of the molecule.
  • alkoxy refers to the group R x -O-, R x is defined the same as the term “alkyl”. Alkoxy includes, but is not limited to: methoxy, ethoxy, n-propoxy, isopropoxy, and the like.
  • the reagents and raw materials used in the present invention are all commercially available.
  • the positive and progressive effect of the present invention is that the compound of the present invention has good cell proliferation inhibitory activity on KRAS G12D mutated gastric cancer AGS cell line and metastatic pancreatic adenocarcinoma AsPC-1 cells. It has good stability of liver microsomes, liver cells, plasma and whole blood, good PK properties, and significant tumor inhibitory effect.
  • HPLC analysis uses SHIMADZU 20A high performance liquid chromatograph.
  • SFC separation uses The Berger MG II, MG III, Sepiatec's Prep SFC 100 system, Waters Prep 80Q SFC SYSTEM, Prep 150 AP SFC SYSTEM, Prep 200 SFC SYSTEM, Prep 350 SFC SYSTEM.
  • Flash column chromatography was performed using a Biotage IsoleraOne flash preparative chromatograph.
  • the thin-layer chromatography silica gel plate uses GF254 acrylic adhesive silica gel plate from Anhui Liangchen Silicon Source Materials Co., Ltd.
  • the specification of the silica gel plate used for thin-layer chromatography (TLC) is 0.25mm, and the specification used for TLC separation and purification products is 0.5mm.
  • Microwave reactions were performed using a Biotage Initiator+ microwave synthesizer.
  • the glove box uses DELLIX custom glove box.
  • the first step N-bromosuccinimide (145g, 815mmol) and silver nitrate (12.6g, 74.2mmol) were slowly added to a solution of ethynyltriisopropylsilane (135g, 742mmol) in acetone (2000mL), and the reaction solution was stirred at 25°C for 16 hours.
  • the reaction solution was concentrated, the residue and petroleum ether (1500 mL) were stirred for 0.5 hours, filtered, and the filtrate was spin-dried to obtain the crude compound (bromoethynyl)triisopropylsilane (171 g) as a yellow oily liquid.
  • 1 H NMR 400MHz, CDCl 3
  • ⁇ ppm 1.13-0.84 m, 21H).
  • Step 2 Dissolve 2-(4-fluorophenyl)acetic acid (200g, 1.30mol), 2,2-dimethyl-1,3-dioxane-4,6-dione (205g, 1.42mol) and 4-dimethylaminopyridine (14g, 114mmol) in acetonitrile (600mL), cool down to 0°C and slowly add diisopropylethylamine (485mL) dropwise, and stir at 0°C for 15 minutes. Control reaction temperature below 30 °C, pivaloyl chloride (175mL) is slowly added dropwise to The reaction solution was stirred at room temperature for 30 minutes, then raised to 50°C and stirred for 16 hours.
  • Step 3 Dissolve 5-(2-(4-fluorophenyl)acetyl)-2,2-dimethyl-1,3-dioxane-4,6-dione (362 g, 1.29 mol) in tert-butanol (930 mL), heat to 90° C. and stir for 2 hours. The reaction solution was spin-dried to obtain the crude compound tert-butyl 4-(4-fluorophenyl)-3-oxobutanoate (280 g) as a yellow solid.
  • Step 4 tert-butyl 4-(4-fluorophenyl)-3-oxobutyrate (278g, 1.10mol) was dissolved in dichloromethane (2480mL), trifluoroacetic acid (575mL, 7.50mol) was added at 0°C, and the reaction was stirred at 25°C for 16 hours. After the reaction was completed, it was concentrated in vacuo to obtain the crude compound 4-(4-fluorophenyl)-3-oxobutanoic acid (231 g) as a white solid.
  • Step 5 4-(4-fluorophenyl)-3-oxobutanoic acid (231 g, 1.18 mol) was dissolved in trifluoromethanesulfonic acid (1230 mL, 13.9 mol), and the reaction was stirred at 25° C. for 24 hours. Slowly add ice water (10L) at 0°C, and extract the reaction solution with ethyl acetate (5L*3). The combined organic phases were washed with water (2 L) and saturated brine (2 L), dried over sodium sulfate, filtered, and the filtrate was spin-dried under reduced pressure.
  • Step 6 Mix 7-fluoronaphthalene-1,3-diol (88g, 494mmol), (bromoethynyl)triisopropylsilane (155g, 592mmol) and potassium acetate (98g, 1.0mol) in dioxane (640mL), add dichloro(p-methylisopropylphenyl)ruthenium(II) dimer (30.2g, 49.6mmol) under nitrogen, and the reaction solution is 110°C Stir for 2 hours.
  • Step 7 7-Fluoro-8-((triisopropylsilyl)ethynyl)naphthalene-1,3-diol (123g, 343mmol) was dissolved in dichloromethane (1230mL), lowered to 0°C, diisopropylethylamine (180mL, 1030mmol) and chloromethyl methyl ether (36.5g, 454mmol) were slowly added to the reaction solution, and the reaction was stirred at 20°C for 16 hours.
  • dichloromethane 1230mL
  • diisopropylethylamine 180mL, 1030mmol
  • chloromethyl methyl ether 36.5g, 454mmol
  • Step 8 Dissolve 7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalene-1-ol (48.0g, 119mmol), diisopropylethylamine (62mL, 357mmol), 4-dimethylaminopyridine (3.00g, 24.5mmol) in dichloromethane (480mL), slowly add pivaloyl chloride (29mL, 238mL) at 0°C mmol), the reaction solution was stirred at 20°C for 2 hours.
  • Step 9 7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalene-1-ylpivalate (50g, 102mmol) was dissolved in N,N-dimethylformamide (916mL), cesium fluoride (167g, 1099mmol) was added, and the reaction was stirred at 20°C for 3 hours. After the reaction, the solvent was removed by concentration under reduced pressure. The crude product was dissolved in ethyl acetate (1000 mL) and water (2000 mL), the organic phase was separated, and the aqueous phase was extracted with ethyl acetate (1000 mL*2).
  • Step 11 Dissolve 8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-ylpivalate (16g, 47.8mmol) in methanol (250mL), add potassium hydroxide (8.50g, 151mmol), and stir the reaction at 20°C for 2 hours.
  • reaction solution was adjusted to pH 6 with dilute hydrochloric acid (1M) at 0°C, extracted with ethyl acetate (200mL*3), combined the organic phases, washed with saturated brine (100ml), dried over sodium sulfate, filtered, and the filtrate was spin-dried, and the residue was purified by flash column chromatography (silica gel, 0-5% gradient ethyl acetate/petroleum ether) to obtain the compound 8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-ol (11g, 43 .9 mmol, yield 92%), as a yellow solid.
  • Step 12 Dissolve 8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-ol (11g, 43.9mmol) and diisopropylethylamine (23mL, 132mmol) in dichloromethane (220mL), slowly add trifluoromethanesulfonic anhydride (11mL, 67.1mmol) dropwise at -40°C, and stir the reaction at -40°C for 2 hours. After the reaction was completed, the reaction was quenched with ice water (200 mL), and extracted with dichloromethane (200 mL*2).
  • the thirteenth step 8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yl trifluoromethanesulfonate (15g, 39.2mmol), bis Alcohol borate (20g, 78.7mmol), potassium acetate (12g, 122mmol) were mixed in toluene (380mL), [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane (3.20g, 3.92mmol) was added under nitrogen, and the reaction was raised to 130°C and stirred for 16 hours. The reaction solution was filtered, and the filtrate was spin-dried.
  • Step 1 To a solution of 7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalene-1-ol (4.93 g, 12.2 mmol) and diisopropylethylamine (7 mL, 40.0 mmol) in dichloromethane (75 mL) was added trifluoromethanesulfonic anhydride (5.19 g, 18.4 mmol) at -40°C. The solution was stirred at -40°C for 1 hour, and the solution was concentrated.
  • Second step Add potassium acetate (3.31 g, 33.7 mmol) and 1, 1-Bis(diphenylphosphino)ferrocenepalladium chloride (0.92g, 1.13mmol). The suspension was stirred at 130°C for 3 hours. The suspension was filtered and concentrated to give a black crude product.
  • Step 1 Dissolve compound 7-fluoro-1-tetralone (18.0g, 109mmol) in acetic acid (300mL) and hydrobromic acid (33% acetic acid solution, 2.5mL), add liquid bromine (19.2g, 120mmol) at 0°C and dissolve in acetic acid (20mL). The reaction was stirred at 25°C for 3 hours. The reaction solution was diluted with dichloromethane (300 mL), washed with water (70 mL*3), dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
  • the crude product was dissolved in dimethylformamide (200 mL), lithium bromide (16.2 g, 186 mmol) and lithium carbonate (13.7 g, 186 mmol) were added, and the reaction was stirred at 160° C. for 3.5 hours.
  • the reaction solution was diluted with ethyl acetate (500 mL), dried with industrial brine (500 mL*2), sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
  • Second step 7-fluoronaphthalen-1-ol (14.3g, 88.2mmol), (bromoethynyl)triisopropylsilane (27.6g, 105mmol), sodium acetate (1.45g, 17.6mmol) and potassium carbonate (12.2g, 88.2mmol) were dissolved in dichloroethane (192mL), and dichloro(p-methylisopropylphenyl) ruthenium (II) dimer ( 8.10 g, 13.2 mmol), and the reaction solution was stirred at 50° C. for 16 hours. After the reaction was completed, filter and spin the filtrate to dryness.
  • Step 3 Dissolve 7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalene-1-ol (28.5g, 83.2mmol), diisopropylethylamine (59.0mL, 338mmol) in dichloromethane (500mL), slowly add trifluoromethanesulfonic anhydride (35.8g, 127mmol) dropwise at -40°C, and stir the reaction at -40°C for 2 hours. After the reaction was completed, it was quenched with ice water (500 mL), and extracted with DCM (200 mL*2).
  • Step 4 Dissolve 7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalene-1-yl trifluoromethanesulfonate (5.20g, 10.9mmol), bis-diancol borate (4.17g, 16.4mmol), potassium acetate (6.18g, 21.9mmol) in toluene (100mL), and add [1,1-bis(diphenylphosphino)ferrocene]diferrocene under nitrogen Palladium chloride in dichloromethane (0.89g, 1.10mmol), the reaction was raised to 130°C and stirred for 3 hours. After the reaction, filter and spin the filtrate to dryness.
  • Step 1 To compound 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (4.00g, 15.84mmol) was added diisopropylethylamine (4mL, 23.77mmol), dichloromethane solution (140mL) and compound (1R,5S)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (3.87 g, 18.22mmol) and stirred at -40°C for 1 hour.
  • Second step To a mixture of compound (1R,5S)-3-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (8.00 g, 18.6 mmol) and 2,2,2-trifluoroethanol (18.6 g, 186.7 mmol) was added diisopropylethylamine (5 mL , 28.0 mmol). The solution was stirred at 80°C for 16 hours.
  • the third step under the protection of nitrogen, the compound tert-butyl (1R, 5S)-3-(7-chloro-8-fluoro-2-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (9.00g, 18.3mmol) and ((2-fluoro-6-(methoxymethoxy)-8-(4 , 4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (10.7 g, 20.9 mmol) in dioxane (200 mL) was added cesium carbonate solution (1.5 M in water, 43 mL) and chloro[(n-butylbis(1-adamantyl)phosphine)-2-(2-aminobiphenyl)]
  • the first step compound tert-butyl(1R,5S)-3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalene-1-yl)-2-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (19.2g , 22.9 mmol) in dimethylformamide (250 mL) was added cesium fluoride (21.6 g, 142.5 mmol). The mixture was stirred at 25°C for 2 hours.
  • the second step under the protection of nitrogen, tert-butyl (1R,5S)-3-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yl)-8-fluoro-2-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (8.00g, 11.6mm ol) in ethyl acetate (200 mL) was added palladium carbon (5%, 4.00 g), and the reaction system was replaced with hydrogen. Stir the mixture at 25°C Stir for 16 hours.
  • Step 1 Compound 2-amino-4-bromo-3-fluorobenzoic acid (25.0g, 107mmol) was dissolved in N,N-dimethylformamide (100mL), N-iodosuccinimide (36.0g, 160mmol) was added, and the mixture was stirred at 80°C for 2 hours. After the reaction solution was cooled to room temperature, it was added to water (3 L), beaten at room temperature for 1 hour, filtered and washed with water (300 mL*3), and the filter cake was vacuum-dried to obtain compound 2-amino-4-bromo-3-fluoro-5-iodobenzoic acid (34.0 g, 94 mmol, yield 88%).
  • LCMS (ESI): [M+H] + 361.9.
  • the second step the compound 2-amino-4-bromo-3-fluoro-5-iodobenzoic acid (30.0 g, 83.3 mmol) and urea (50.0 g, 833 mmol) were added to the reaction flask.
  • the temperature of the reaction system was raised to 200° C. for 4 hours. Cool to room temperature, add water (300mL) and raise the temperature to 80°C for beating and stirring for half an hour, filter while hot, repeat the beating and filtering operation of the filter cake twice, and vacuum dry the filter cake to obtain 7-bromo-8-fluoro-6-iodoquinazoline-2,4-dihydroxyl (26.7g, 69.3mmol, yield 83%).
  • LCMS (ESI): [M+H] + 387.0.
  • the third step the compound 7-bromo-8-fluoro-6-iodoquinazoline-2,4-diol (24.7g, 64.1mmol) was added to phosphorus oxychloride (300mL), diisopropylethylamine (40mL, 224mmol) was added at 0°C, and stirred at 130°C for 4 hours.
  • the fourth step To compound 7-bromo-2,4-dichloro-8-fluoro-6-iodoquinazoline (10.0g, 23.7mmol) in dichloromethane (100mL) solution, add (1R,5S)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate tert-butyl ester (5.54g, 26.1mmol) and triethylamine (10mL, 71mmol), the reaction solution in Stir at 20°C for 2 hours.
  • the fifth step the compound tert-butyl (1R,5S)-3-(7-bromo-2-chloro-8-fluoro-6-iodoquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane- 8-Carboxylate (3.00 g, 5.00 mmol) was added to trifluoroethanol (15 mL), diisopropylethylamine (1560 uL, 8.94 mmol) was added, and the reaction solution was stirred at 50° C. for 3 hours.
  • the first step To the compound tert-butyl (1R,5S)-3-(7-bromo-2-chloro-8-fluoro-6-iodoquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (3.00g, 5.02mmol) in N,N-dimethylacetamide (30mL) solution, add cuprous cyanide (4.50g, 50.2mmol) and zinc under nitrogen atmosphere powder (0.72g, 11.0mmol), and the reaction solution was stirred at 100°C for 16 hours.
  • the second step the compound (1R,5S)-3-(7-bromo-2-chloro-6-cyano-8-fluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (1.48g, 2.98mmol) was added to trifluoroethanol (15mL), diisopropylethylamine (1560uL, 8.94mmol) was added, and the reaction solution was stirred at 50°C 3 hours.
  • the first step Compound 7-bromo-2,4,6-trichloro-8-fluoroquinazoline (0.50g, 1.51mmol) was dissolved in dichloromethane (10mL), added (1R,5S)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate tert-butyl ester (0.32g, 1.51mmol) and triethylamine (630uL, 4.54mmol), stirred at 20°C for 1 6 hours.
  • Second step compound (1R,5S)-3-(7-bromo-2,6-dichloro-8-fluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (90% purity, 550mg, 0.98mmol) and ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol (173mg , 1.09mmol) was added to N,N-dimethylformamide (5mL) and tetrahydrofuran (5mL), cesium carbonate (1.06g, 3.26mmol) and triethylenediamine (24mg, 0.22mmol) were added.
  • the first step the compound 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (3.00g, 11.88mmol) and trifluoroethanol (1.43g, 14.2mmol) were dissolved in toluene (60mL), and sodium tert-butoxide (1.14g, 11.8mmol) was added at 0°C, and the mixture was stirred at 0°C for 2 hours.
  • the second step to compound ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol (0.71g, 4.43mmol), diisopropylethylamine (0.79mL, 4.43mmol) and 4A molecular sieves (1g) in 2-methyltetrahydrofuran (10mL) suspension, 0 °C added 2,7-dichloro-8-fluoro-4-(2,2, 2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (70% purity, 1.00 g, 2.21 mmol). The temperature of the reaction system was raised to 25° C. for 1 hour.
  • the third step the compound 7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (purity 75%, 2.75g, 4.69mmol) was added to dioxane (60mL), and ((2-fluoro-6-(methoxy Methoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (3.21g, 6.27mmol) and cesium carbonate (1.5M in water, 12.5mL, 18.80mmol), added chloro[(n-butylbis(1-adamantyl)phosphine)-2-(2-aminobiphenyl)]palladium(I
  • Step 1 Diisopropylethylamine (21 mL, 126 mmol) was added to a solution of L-proline methyl ester hydrochloride (7.00 g, 42.2 mmol) and (3-(bromomethyl)oxetan-3-yl)methanol (10 g, 55.2 mmol) in N,N-dimethylacetamide (80 mL), and the mixture was heated to 50° C. and stirred for 12 hours under nitrogen protection. The reaction mixture was spin-dried.
  • Second step To ((3-(hydroxymethyl)oxetan-3-yl)methyl)-L-proline methyl ester (1.00g, 4.36mmol) and carbon tetrabromide (1.88g, 5.67mmol) in dichloromethane (25mL) solution at 0°C, triphenylphosphine (1831mg, 6.98mmol) was added in 3 batches, and then the mixture was stirred at 25°C for 3 hours under nitrogen protection. The reaction mixture was spin-dried.
  • the third step under nitrogen protection, ((3-(bromomethyl)oxetan-3-yl)methyl)-L-proline methyl ester (200mg, 0.68mmol) in N,N-dimethylformamide (5mL) and tetrahydrofuran (1mL) solution was cooled to -70°C, and hexamethyldisilazide potassium (1M solution in tetrahydrofuran, 958uL, 0.96mmol) was added at -60°C to -70°C, The mixture was then stirred at -60°C to -70°C for 30 minutes.
  • Step 4 To a solution of methyl dihydro-1'H,3'H-spiro[oxetane-3,2'-pyrrolazine]-7a'(5'H)-carboxylate (150 mg, 0.71 mmol) in tetrahydrofuran (3 mL) under nitrogen protection at -10°C was added lithium aluminum tetrahydride (81 mg, 2.13 mmol), and then the mixture was stirred at -10°C for 30 minutes.
  • Step 1 To a solution of (S)-5-(tert-butoxycarbonyl)-5-azaspiro[2.4]heptane-6-carboxylic acid (8.00 g, 33.16 mmol) and potassium carbonate (9.16 g, 66.3 mmol) in dimethylformamide (80 mL) was slowly added iodomethane (11.7 g, 82.8 mmol) at 0°C. The solution was stirred at 0°C for 1 hour, then the solution was stirred at 25°C for 12 hours. The reaction was quenched with sodium sulfite solution and then concentrated.
  • Step 2 Add 5-(tert-butyl)6-methyl(S)-5-azaspiro[2.4]heptane-5,6-dicarboxylate (8.00g, 29.8mmol) to a solution of lithium diisopropylamide (2M mixed solution of tetrahydrofuran-n-heptane, 16mL, 32mmol) in tetrahydrofuran (80mL) at -78°C and stir for 1 hour, then add 1-bromo at -78°C -3-Chloropropane (3 mL, 31.3 mmol) and stirred for 2 hours, then at 25 °C for 12 hours.
  • Li diisopropylamide 2M mixed solution of tetrahydrofuran-n-heptane, 16mL, 32mmol
  • 1-bromo at -78°C -3-Chloropropane 3 mL, 31.3 mmol
  • Step 4 Add potassium iodide (340 mg, 2.06 mmol) and potassium carbonate (8.53 g, 61.7 mmol) to a solution of methyl 6-(3-chloropropyl)-5-azaspiro[2.4]heptane-6-carboxylate (85% purity, 4.67 g, 17.1 mmol) in methanol (100 mL) at 25° C. The solution was stirred at 25°C for 16 hours.
  • Step 5 Add dihydro-1'H, 3'H-spiro[cyclopropane-1,2'-pyrrolazine]-7a'(5'H)-methyl carboxylate (purity 85%, 2.00g, 8.72mmol) in tetrahydrofuran (0.50mL) to lithium aluminum hydride (0.58g, 15.3mmol) in tetrahydrofuran (10mL) under a nitrogen atmosphere at 0°C. Stir at 60°C for 4 hours. After cooling to room temperature, the mixture was sequentially quenched with water (600 uL), 15% sodium hydroxide (600 uL) and water (1800 uL).
  • Step 1 To a solution of compound 3-azabicyclo[3.1.0]hexane hydrochloride (15g, 125mmol) and triethylamine (35mL, 250mmol) in dichloromethane (150mL), di-tert-butyl dicarbonate (31.7mL, 137mmol) was added at 20°C. The reaction was stirred at 20°C for 16 hours.
  • the second step the compound tert-butyl 3-azabicyclo[3.1.0]hexane-3-carboxylate (20g, 108mmol) and tetramethylethylenediamine (9150uL, 61.3mmol) were dissolved in tetrahydrofuran (150mL), and sec-butyl lithium (1.3M n-hexane solution, 63mL, 81.9mmol) was added at -65°C under nitrogen protection. The reaction was stirred at -65°C for 3 hours. The nitrogen was replaced with carbon dioxide and the reaction was stirred at -65°C under a carbon dioxide balloon for 1 hour.
  • Step 3 Add iodomethane (5.2 mL, 84.4 mmol) to a suspension of compound 3-(tert-butoxycarbonyl)-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (80% purity, 12 g, 42.2 mmol) and potassium carbonate (17.6 g, 126 mmol) in acetone (150 mL) at 20° C. The reaction was stirred at 20°C for 16 hours. The reaction solution was concentrated under reduced pressure.
  • the reaction was stirred at -65°C for 2 hours and then warmed to 0°C, saturated ammonium chloride solution (200 mL) was added, then extracted with ethyl acetate (100 mL*2), the organic layer was dried over anhydrous magnesium sulfate, filtered, and the organic layer was concentrated under reduced pressure.
  • Step 5 Compound 3-(tert-butyl) 2-methyl 2-(3-chloropropyl)-3-azabicyclo[3.1.0]hexane-2,3-dicarboxylate (purity 80%, 2.70g, 6.81mmol) was dissolved in dichloromethane (60mL), and hydrogen chloride (4M solution in dioxane, 15mL, 60 mmol). The reaction was stirred at 25°C for 16 hours. Concentration under reduced pressure gave crude compound 2-(3-chloropropyl)-3-azabicyclo[3.1.0]hexane-2-carboxylic acid methyl ester (1.72 g) as a yellow oil.
  • LCMS (ESI): [M+H] + 218.1.
  • Step 6 The compound 2-(3-chloropropyl)-3-azabicyclo[3.1.0]hexane-2-carboxylate methyl ester (1.72g, 6.81mmol) was dissolved in methanol (50mL), and potassium carbonate (8.57g, 62.0mmol) and potassium iodide (0.34g, 2.07mmol) were added at 20°C. The reaction was stirred at 20°C for 16 hours. The reaction solution was filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 0-10% gradient of methanol/dichloromethane) to yield two intermediates.
  • Step 7 Dissolve lithium aluminum tetrahydride (35 mg, 0.91 mmol) in tetrahydrofuran (6 mL), and add trans-hexahydrocyclopropane[a]pyrrolazine-6a(4H)-methyl carboxylate (110 mg, 0.61 mmol) in tetrahydrofuran (0.5 mL) under a nitrogen atmosphere at -40°C. The reaction was stirred at -10°C for 1 hour. Water (110uL) and 15% aqueous sodium hydroxide solution (110uL) were added to the reaction solution at 0°C, and then water (330uL) was added.
  • Step 1 Add furan-2-carbaldehyde (50 g, 520 mmol) and ethyl azidoacetate (80.6 g, 624 mmol) to a solution of sodium ethoxide (44.2 g, 650 mmol) in ethanol (1000 mL) at 0°C. The reaction mixture was stirred at 25°C for 16 hours. The mixture was diluted with saturated ammonium chloride (1 L) and extracted with ethyl acetate (1 L*3).
  • the second step a toluene solution of ethyl 2-azido-3-(furan-2-yl)acrylate (24 g, 115 mmol) was stirred at 115° C. for 3 hours, and a large amount of gas was released during the reaction. After the reaction was completed, it was concentrated in vacuo to obtain ethyl 4H-furo[3,2-b]pyrrole-5-carboxylate (16 g, 89.3 mmol, yield 77%) as a brown solid compound.
  • LCMS (ESI): [M+H] + 180.1.
  • Step 3 To a solution of ethyl 4H-furo[3,2-b]pyrrole-5-carboxylate (16.5 g, 92.1 mmol) in acetonitrile (160 mL) was added 4-dimethylaminopyridine (1.07 g, 8.75 mmol) and di-tert-butyl dicarbonate (27.7 g, 127 mmol) at 0°C. The reaction was stirred at 25°C for 16 hours.
  • Step 4 To a solution of 4-(tert-butyl)5-ethyl 4H-furo[3,2-b]pyrrole-4,5-dicarboxylate (8 g, 28.6 mmol) in ethanol (200 mL) was added palladium on carbon (10% purity, 6.10 g, 5.73 mmol). The reaction was stirred at 60°C under 50 psi hydrogen atmosphere for 16 hours. The mixture was filtered, and the filtrate was concentrated in vacuo to obtain 4-(tert-butyl)5-ethylhexahydro-4H-furo[3,2-b]pyrrole-4,5-dicarboxylate (7.86 g, 27.5 mmol, yield 96%) as a yellow oil.
  • LCMS (ESI): [M+Na] + 308.1.
  • Step 6 To a solution of 4-(tert-butyl)5-ethyl 5-(3-chloropropyl)hexahydro-4H-furo[3,2-b]pyrrole-4,5-dicarboxylate (1.62 g, 4.48 mmol) in dichloromethane (16 mL) was added trifluoroacetic acid (4 mL) at 0°C. The reaction was stirred at 20°C for 2 hours. The mixture was concentrated in vacuo to afford crude compound ethyl 5-(3-chloropropyl)hexahydro-2H-furo[3,2-b]pyrrole-5-carboxylate (1.10 g) as a yellow oily liquid.
  • LCMS (ESI): [M+H] + 262.1.
  • Step 7 Potassium carbonate (1.74 g, 12.6 mmol) and potassium iodide (0.07 g, 0.42 mmol) were added to a solution of ethyl 5-(3-chloropropyl)hexahydro-2H-furo[3,2-b]pyrrole-5-carboxylate (1.10 g, 4.21 mmol) in ethanol (50 mL). The mixture was stirred at 25°C for 16 hours.
  • Step 8 To a solution of ethyl hexahydro-2H-furo[2,3-b]pyrrolazine-7a(5H)-carboxylate (0.86 g, 3.82 mmol) in THF (9.00 mL) was added lithium aluminum tetrahydrogen (156 mg, 4.12 mmol) at -40°C. The mixture was stirred at -10°C for 1 hour. Water (160uL) was slowly added to the mixture, then 15% sodium hydroxide solution (160uL) and water (480uL) were added, anhydrous sodium sulfate was added and stirred, filtered and the filter cake was washed with tetrahydrofuran.
  • Step 1 Add lithium bistrimethylsilylamide (1M solution in tetrahydrofuran) to a solution of (3R)-2-tert-butyl-3-ethyl-2-azabicyclo[3.1.0]hexane-2,3-dicarboxylate (950mg, 3.72mmol) and 1-bromo-3-chloropropane (1.76g, 11.1mmol) in tetrahydrofuran (10mL) under a nitrogen atmosphere at -65°C. 7.44 mL, 7.44 mmol). The reaction was stirred at 25°C for 16 hours.
  • Second step To a solution of 2-tert-butyl-3-ethyl-3-(3-chloropropyl)-2-azabicyclo[3.1.0]hexane-2,3-dicarboxylate (610 mg, 1.84 mmol) in dichloromethane (6 mL) was added hydrogen chloride (4M in dioxane, 1.38 mL, 5.51 mmol). The reaction was stirred at 25°C for 16 hours. The mixture was concentrated in vacuo to afford crude compound ethyl 3-(3-chloropropyl)-2-azabicyclo[3.1.0]hexane-3-carboxylate (60% purity, 690 mg) as a colorless oil.
  • LCMS (ESI): [M+H] + 232.2.
  • Step 3 To a solution of ethyl 3-(3-chloropropyl)-2-azabicyclo[3.1.0]hexane-3-carboxylate (60% purity, 670 mg, 1.73 mmol) in ethanol (26 mL) was added potassium iodide (29 mg, 0.17 mmol) and potassium carbonate (719 mg, 5.20 mmol). The reaction was stirred at 25°C for 16 hours. The mixture was filtered and concentrated.
  • Step 4 To a solution of ethyl hexahydrocyclopropane[b]pyrrolazine-5a(3H)-carboxylate (95% purity, 310 mg, 1.50 mmol) in THF (3 mL) was added lithium aluminum tetrahydride (72 mg, 1.91 mmol) at -40°C. The mixture was stirred at -10°C for 1 hour. Water (72uL) and 15% aqueous sodium hydroxide solution (72uL) were added to the reaction, followed by water (216uL). Add anhydrous sodium sulfate to dry.
  • the first step Compound 1-(tert-butyl) 2-methyl(S)-4-methylenepyrrolidine-1,2-dicarboxylate (2.80g, 11.6mmol) and trimethyl(trifluoromethyl)silane (4.12g, 29.0mmol) were dissolved in tetrahydrofuran (100mL), and sodium iodide (0.87g, 5.81mmol) was added under nitrogen. The reaction was stirred at 60°C for 16 hours.
  • the second step the compound 5-(tert-butyl) 6-methyl(6S)-1,1-difluoro-5-azaspiro[2.4]heptane-5,6-dicarboxylate (purity 80%, 4.00g, 11.0mmol) was dissolved in tetrahydrofuran (65mL) and dropped to -70°C, and diisopropylamide lithium (2M tetrahydrofuran Heptane mixed solution, 10.3mL, 20.6mmol), the reaction was stirred at -70°C for 1 hour.
  • the third step the compound cis 5-(tert-butyl) 6-methyl-6-(3-chloropropyl)-1,1-difluoro-5-azaspiro[2.4]heptane-5,6-dicarboxylate (1.20g, 3.26mmol) was dissolved in dichloromethane (4mL), hydrogen chloride (4M solution in dioxane, 2mL, 9.78mmol) was added at 20°C, and the reaction solution was stirred at 20°C for 2 hours.
  • the fourth step the compound cis-6-(3-chloropropyl)-1,1-difluoro-5-azaspiro[2.4]heptane-6-carboxylate methyl ester (0.83g, 3.11mmol) was dissolved in methanol (2mL), and potassium iodide (62mg, 0.37mmol) and potassium carbonate (1.55g, 11.21mmol) were added at 25°C. The reaction was stirred at 25°C for 16 hours.
  • Step 5 The compound cis-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolazine]-7a'(5'H)-methyl carboxylate (0.25g, 1.08mmol) was dissolved in tetrahydrofuran (4mL), and lithium aluminum tetrahydride (61mg, 1.62mmol) was added at 0°C. The reaction was stirred at 60°C for 2 hours.
  • Step 1 To a solution of (S)-1-(tert-butoxycarbonyl)-4-methylenepyrrolidine-2-carboxylic acid (90 g, 396 mmol) in dimethylformamide (1.8 L) was added cesium carbonate (168 g, 514 mmol) and benzyl bromide (88 g, 514 mmol) at 0°C. The suspension was stirred at 25°C for 16 hours.
  • reaction solution was diluted with water (1.8 L), extracted with ethyl acetate (1 L*3), the organic layer was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by flash column chromatography (silica gel, 0-25% gradient tetrahydrofuran/petroleum ether) to obtain 2-benzyl 1-(tert-butyl)(S)-4-methylenepyrrolidine-1,2-dicarboxylate (120 g, 378 mmol, yield 95%) as a colorless oil.
  • Second step To a solution of 2-benzyl 1-(tert-butyl)(S)-4-methylenepyrrolidine-1,2-dicarboxylate (8.00 g, 25.2 mmol) and trimethyl(trifluoromethyl)silane (8.96 g, 63.0 mmol) in THF (300 mL) was added sodium iodide (1.89 g, 12.6 mmol) under nitrogen, and the mixture was stirred at 60° C. for 16 hours. The mixture was quenched with saturated ammonium chloride (50 mL), diluted with water (100 mL), extracted with ethyl acetate (50 mL*3).
  • Step 3 To a solution of 6-benzyl 5-(tert-butyl)(3R,6S)-1,1-difluoro-5-azaspiro[2.4]heptane-5,6-dicarboxylate (15g, 40.8mmol) in THF (150mL) was added potassium bis(trimethylsilyl)amide (2M solution in THF, 41mL, 82mmol) at -78°C under a nitrogen atmosphere. The reaction was stirred at -78°C for 1 hour. 1-Bromo-3-chloropropane (13 g, 81.6 mmol) was added to the solution and The solution was stirred at -78°C for 1 hour. It was then stirred at 25°C for 14 hours.
  • 2-benzyl 5-(tert-butyl)(3R,6S)-1,1-difluoro-5-azaspiro[2.4]heptane-5,6-dicarboxylate 15g, 40.8mmol
  • Step 4 To a solution of compound 6-benzyl 5-(tert-butyl)(3R,6S)-6-(3-chloropropyl)-1,1-difluoro-5-azaspiro[2.4]heptane-5,6-dicarboxylate (6 g, 18.1 mmol) in dichloromethane (200 mL) was added hydrogen chloride (4M in dioxane, 100 mL, 400 mmol) at 25°C. The reaction was stirred at 25°C for 16 hours.
  • Step 5 To a methanol (500 mL) solution of compound (3R,6S)-6-(3-chloropropyl)-1,1-difluoro-5-azaspiro[2.4]heptane-6-carboxylate (16 g, 46.5 mmol) was added potassium iodide (0.77 g, 4.65 mmol) and potassium carbonate (19.3 g, 139 mmol) at 25°C. The solution was stirred at 25°C for 16 hours.
  • compound (3R,6S)-6-(3-chloropropyl)-1,1-difluoro-5-azaspiro[2.4]heptane-6-carboxylate (16 g, 46.5 mmol) was added potassium iodide (0.77 g, 4.65 mmol) and potassium carbonate (19.3 g, 139 mmol) at 25°C. The solution was stirred at 25°C for 16 hours.
  • Step 6 To a solution of benzyl (1R,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolazine]-7a'(5'H)-carboxylate (350 mg, 1.14 mmol) in tetrahydrofuran (4 mL) was added lithium aluminum tetrahydride (259 mg, 6.83 mmol) at 0°C. The suspension was stirred at 60°C for 2 hours. The suspension was quenched sequentially with water (260 uL), 15% sodium hydroxide solution (260 uL) and water (780 uL).
  • Step 1 To a solution of 4-((tert-butoxycarbonyl)amino)-6-chloro-5-fluoronicotinic acid (10.0g, 34.40mmol) in dichloromethane (50mL), hydrogen chloride (4M solution in dioxane, 172mL, 688mmol) was added at 0°C, and stirred at 20°C for 16 hours. The mixture was spin-dried to afford the crude compound 4-amino-6-chloro-5-fluoronicotinic acid (9.00 g) as a white solid.
  • LCMS (ESI): [M+H] + 191.0.
  • the second step 4-amino-6-chloro-5-fluoronicotinic acid (9.00g, 34.40mmol) was dissolved in phosphorus oxychloride (50mL), and the mixture was nitrogen Stir at 90°C for 2 hours under protection. Spin dry.
  • LCMS (ESI) of the methyl ester obtained by quenching with methanol during detection: [M+H] + 205.1.
  • Step 3 Ammonium thiocyanate (11.8 g, 155.02 mmol) was added to a solution of 4-amino-6-chloro-5-fluoronicotinoyl chloride (10.0 g, 34.40 mmol) in tetrahydrofuran (100 mL), and the mixture was stirred at 20° C. for 12 hours under nitrogen protection. Water (100 mL) was added, extracted with ethyl acetate (100 mL*3), the organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and spin-dried.
  • Step 4 To a solution of 7-chloro-8-fluoro-2-thioxo-2,3-dihydropyrido[4,3-d]pyrimidin-4(1H)-one (5.60 g, 24.18 mmol) in N,N-dimethylformamide (56 mL), sodium methoxide (1.44 g, 26.59 mmol) and methyl iodide (3.26 g, 22.97 mmol) were added. The mixture was stirred at 20° C. for 2 hours under nitrogen protection.
  • Step 5 Dissolve 7-chloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4(3H)-one (1.10 g, 4.48 mmol) in phosphorus oxychloride (10.0 mL), and add diisopropylethylamine (2.23 mL, 13.43 mmol). The mixture was stirred at 95 °C for 16 hours under nitrogen protection.
  • Step 1 To a solution of 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (500mg, 1.68mmol) and diisopropylethylamine (350uL, 2.02mmol) in dichloromethane (5mL) at -40°C was added tert-butyl ((1R,5S,8S)-3-azabicyclo[3.2.1]octyl-8-yl)carbamate (381 mg, 1.68 mmol). The solution was stirred at -40°C for 1 hour.
  • Second step To a solution of tert-butyl ((1R,5S,8S)-3-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]oct-8-yl)carbamate (800 mg, 2.30 mmol) in dioxane (9 mL) was added (tetrahydro-1H-pyrrolazin-7a(5H)-yl) at 25°C Methanol (459 mg, 3.26 mmol) and diisopropylethylamine (850 mL, 4.88 mmol). The solution was stirred at 80°C for 16 hours.
  • the third step in a nitrogen atmosphere, to tert-butyl ((1R,5S,8S)-3-(7-chloro-8-fluoro-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octyl-8-yl)carbamate (304mg, 0.56mmol), 2-(8- Ethyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (200mg, 0.56mmol), potassium phosphate (1.5M in water, 1120uL, 1.68mmol) in dioxane (4mL) was added [n-butylbis(1-adamantyl)phosphine](2-amino-1,1-biphenyl-2
  • the fourth step tert-butyl ((1R,5S,8S)-3-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yl)-8-fluoro-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]oct-8-yl)carbamate
  • Example 3 4-(4-(2,5-diazabicyclo[4.1.0]hept-2-yl)-8-fluoro-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol
  • the first step compound 8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalene-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (150mg, 0.19 mmol) and diisopropylethylamine (113uL, 0.65mmol) were added to dimethylsulfoxide (1.2mL), 4-(pyrrolidin-1-yl)piperidine (30mg, 0.19mmol) was added, and stirred at 90°C for 3 hours.
  • the second step compound 8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalene-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4-(4-(pyrrolidin-1-yl)piperidin-1-yl)pyrido[4,3-d]pyrimidine (13 0 mg, 0.15 mmol) was added to N,N-dimethylformamide (2 mL), cesium fluoride (234 mg, 1.54 mmol) was added, and stirred at 20°C for 1 hour.
  • the third step compound 7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4-(4-(pyrrolidin-1-yl)piperidin-1-yl)pyrido[4,3-d]pyrimidine (100mg, 0.13mmol) was added into trifluoroacetic acid/dichloromethane (volume ratio 4:1, 2.5 mL), and stirred at 20°C for 2 hours.
  • Example 12 4-(4-([1,4'-bispiperidin]-1'-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol
  • Example 14 5-ethynyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4-((3aR,6aS))-5-methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalene-2 -alcohol formate
  • Example 16 4-(4-((1R,2R,4S,5S)-3,3-difluoro-7,9-diazatricyclo[3.3.1.0 2,4 ]non-7-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol
  • Second step Benzoyl chloride (1.65 mL, 14.2 mmol) was added to a solution of compound (1R,5S)-3,8-diazabicyclo[3.2.1]oct-6-ene (1.20 g, 3.55 mmol) and diisopropylethylamine (5.8 mL, 35.5 mmol) in dichloromethane (12 mL), and the reaction was stirred at 25° C. for 16 hours.
  • the third step the compound ((1R,5S)-3,8-diazabicyclo[3.2.1]oct-6-ene-3,8-diyl)bis(phenyl ketone) (400mg, 1.25mmol), tetrabutylammonium bromide (40mg, 0.13mmol) was dissolved in toluene (5mL), and (bromodifluoromethyl)trimethylsilane (5.10g, 25.1mmol) was added under nitrogen protection. Stir at 110°C for 16 hours.
  • Step 4 The compound ((1R,2R,4S,5S)-3,3-difluoro-7,9-diazatricyclo[3.3.1.0 2,4 ]nonane-7,9-diyl)bis(phenyl ketone) (200mg, 0.25mmol) was dissolved in 6M hydrochloric acid (2mL), and the reaction was stirred at 100°C for 16 hours.
  • Example 17 5-ethynyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4-((1R,2R,4S,5S)-3-(trimethylsilyl)-7,9-diazatricyclo[3.3.1.0 2,4 ]non-7-yl)pyrido[4 ,3-d]pyrimidin-7-yl)naphthalene-2-ol
  • Second step Di-tert-butyl dicarbonate (5.00 mL, 23.1 mmol) was added to a solution of compound (1R,5S)-3,8-diazabicyclo[3.2.1]oct-6-ene (1.20 g, 1.31 mmol) and diisopropylethylamine (5.36 mL, 38.4 mmol) in dichloromethane (12 mL), and the reaction was stirred at 25° C. for 16 hours.
  • Step 4 The compounds (1R, 2R, 4S, 5S) -3- (triangular silicon-based) -7,9-two-nitrogen miscellaneous three rings [3.3.1.0 2,4 ] mesexane-7,9-di-carboxylic acid two uncle (100 mg, 0.25 mmol), add hydrogen chloride (4m solution of 4m, 6m, 6, 6 30ul), stirred at 20 ° C for 1 hour. The reaction solution was concentrated under reduced pressure to obtain the crude compound (1R,2R,4S,5S)-3-(trimethylsilyl)-7,9-diazatricyclo[3.3.1.0 2,4 ]nonane (dihydrochloride, 65mg) as a yellow oily liquid.
  • LCMS (ESI): [M+H] + 197.1.
  • Example 18 4-(4-((1R,5S)-8-Azabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol formate
  • the first step In the glove box, add 4,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidine (500mg, 1.89mmol), tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-8-azabicyclo[3.2.1]oct-2-ene-8-carboxylate (825mg, 2.46 mmol) in 1,4-dioxane (15 mL), potassium phosphate (1.5 M in water, 3.16 mL, 4.73 mmol) and [n-butylbis(1-adamantyl)phosphine](2-amino-1,1-biphenyl-2-yl)palladium(II) methanesulfonate (69 mg, 0.09 mmol) were added.
  • the mixture was stirred at 50° C. for 16 hours under nitrogen protection.
  • the reaction solution was filtered, the filtrate was diluted with water (2 mL), extracted with ethyl acetate (10 mL*3), the combined organic phases were dried over anhydrous sodium sulfate, filtered, and spin-dried.
  • the second step at -15°C, to a solution of tert-butyl (1S,5R)-3-(7-chloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-8-azabicyclo[3.2.1]oct-2-ene-8-carboxylate (2.00g, 4.58mmol) in dichloromethane (120mL), add triethylsilane (4.40mL , 27.46mmol) and trifluoroacetic acid (6.80mL, 91.55mmol). The mixture was stirred at 25°C for 16 hours under nitrogen protection.
  • Step 3 To a solution of 4-((1R,3s,5S)-8-azabicyclo[3.2.1]oct-3-yl)-7-chloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidine (2.00g, 4.58mmol) in dichloromethane (20mL) was added triethylamine (1.97mL, 14.17mmol) and di-tert-butyl dicarbonate (2.0 3 mL, 8.85 mmol). The mixture was stirred at 20° C. for 16 hours under nitrogen protection, and then spin-dried.
  • Step 4 In a glove box, add tert-butyl (1R,3s,5S)-3-(7-chloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate (500 mg, 1.14 mmol), ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl -1,3,2-Dioxygen To a solution of xaboran-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (701 mg, 1.37 mmol) and cesium carbonate (1113 mg, 3.42 mmol) in dioxane (10 mL) and water (2 mL) was added chloro[(n-butylbis(1-adamantyl)phosphine)-2-(2-aminobiphenyl)]palladium
  • the mixture was stirred at 100° C. for 3 hours under nitrogen protection.
  • the reaction solution was filtered, the filtrate was diluted with water (4 mL), extracted with ethyl acetate (10 mL*3), the combined organic phases were dried over anhydrous sodium sulfate, filtered, and spin-dried.
  • the fifth step to tert-butyl(1R,3s,5S)-3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalene-1-yl)-2-(methylthio))pyrido[4,3-d]pyrimidin-4-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate (400mg, 0.51mm ol) in dichloromethane (10 mL), add m-chloroperoxybenzoic acid (85% content, 257 mg, 1.27 mmol). The mixture was stirred at 25°C for 2 hours under nitrogen protection.
  • the sixth step at 25°C, to tert-butyl (1R,3s,5S)-3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalene-1-yl)-2-(methylsulfonyl)pyrido[4,3-d]pyrimidin-4-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate (600 mg, 0.73mmol) and diisopropylethylamine (510uL, 3.65mmol) in dioxane (6.00mL) were added ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol (357mg, 2.24mmol), and the mixture was stirred at 80°C for 4 hours.
  • the eighth step at 25°C, tert-butyl (1R,3s,5S)-3-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-8-azabicyclo [3.2.1] Octane-8-carboxylate (360 mg, 0.48 mmol) was dissolved in trifluoroacetic acid/dichloromethane (volume ratio 1/4, 4.00 mL), and stirred for 2 hours.
  • Example 19 (isobutyryloxy)methyl(1R,5S)-3-(2-((2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolazin]-7a'(5'H)-yl)methoxy)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3, 8-Diazabicyclo[3.2.1]octane-8-carboxylate
  • the first step at 20°C, compound 4-nitrophenol (5.00g, 35.94mmol) was added to tetrahydrofuran (65.0mL), chloromethyl chloroformate (5.10g, 39.54mmol) was added, and N,N-diisopropylethylamine (6.91mL, 39.54mmol) was slowly added dropwise, and the reaction was stirred at 20°C for 2 hours.
  • the second step the compound (4-nitrophenyl) chloromethyl carbonate (5.00g, 21.59mmol) was added to acetone (100mL), sodium iodide (9.71g, 64.77mmol) and 4A molecular sieves (5.00g) were added at 20°C, and the reaction was stirred at 40°C for 16 hours. The reaction was cooled to room temperature and filtered through celite.
  • the third step add isobutyric acid (5.00g, 56.75mmol) into acetonitrile (200mL), add silver oxide (4.76 g, 34.05 mmol), stirred at 70°C for 6 hours in the dark. The mixture was cooled to ambient temperature and filtered through celite. The filtrate was freed of volatiles by vacuum to give the compound silver isobutyrate (1.00 g, 5.12 mmol, 9% yield) as a tan solid.
  • Step 4 Add the compound iodomethyl (4-nitrophenyl) carbonate (414 mg, 1.28 mmol) into toluene (7.00 mL), add silver isobutyrate (500 mg, 2.56 mmol), and stir at 55° C. for 16 hours. The reaction solution was cooled to room temperature and filtered through diatomaceous earth.
  • the fifth step at 25°C, to tert-butyl(1R,5S)-3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalene-1-yl)-2-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxy
  • Add ((1R,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolazin]-7a'(5'H)-yl)methanol (121mg, 0.59mmol) and sodium tert-butoxide (115mg, 0.89mmol) to a tetrahydrofuran (5.00mL) solution of acid ester (500m
  • Step 6 At 25°C, add tert-butyl (1R,5S)-3-(2-(((1R,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolazin]-7a'(5'H)-yl)methoxy)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl )naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (350mg, 0.37mmol) in dimethylformamide (3.50mL) was added cesium fluoride (562mg, 3.70mmol), and the solution was stirred at 25°C for 2 hours.
  • cesium fluoride 562mg, 3.70m
  • the seventh step at 25°C, to tert-butyl (1R,5S)-3-(2-(((1R,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolazin]-7a'(5'H)-yl)methoxy)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yl)-8-fluoropyrido[ 4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (50.0mg, 0.06mmol) in acetonitrile (1.00mL) was added hydrogen chloride (4M solution in dioxane, 317uL, 1.27mmol), and the solution was stirred at 20°C for 2 hours.
  • hydrogen chloride 4M solution in dioxane, 317uL
  • the eighth step at 20°C, add 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(((1R,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolazin]-7a'(5'H)-yl)methoxy)-8-fluoropyrido[4,3-d ]Pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalene-2-ol (purity 50%, 50.0mg, 0.04mmol) in dimethylformamide (1.00mL) was added (((4-nitrophenoxy)carbonyl)oxy)methyl isobutyrate (19.8mg, 0.07mmol), and the solution was stirred at 20°C for 2 hours.
  • Example 20 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)quinolin-2-ol
  • Example 21 7a'-(((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)tetrahydro-1'H,3'H-spiro[oxetane-3,2'-pyrrolazine]
  • the first step tert-butyl (1R,5S)-3-(7-chloro-2-((dihydro-1'H,3'H-spiro[oxetane-3,2'-pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (200mg, 0.
  • To azabicyclo[3.2.1]octane-8-carboxylate (220mg, 0.25mmol), add trifluoroacetic acid/dichloromethane 1:4 (4.4mL).
  • the third step 7a'-(((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl))naphthalene-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)tetrahydro-1'H,3'H-spiro[oxetane-3, 2'-Pyrrolazine] (200 mg, 0.25 mmol) in N,N dimethylformamide (2 mL) was added cesium fluoride (4468 mg, 26.1 mmol).
  • Example 22 7-(6-Amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinazoline-6-carbonitrile
  • Step 1 To 6-bromo-4-methylpyridin-2-amine (1.00g, 5.35mmol) in N,N-dimethylformamide (17mL), add 60% sodium hydrogen (1.10g, 27.5mmol) at 0°C, stir at 25°C for 1 hour, then add 1-(chloromethyl)-4-methoxybenzene (1.90g, 12.1mmol) at 0°C, and place the mixture under nitrogen protection Stir at 25°C for 2 hours. Add saturated ammonium chloride solution (17 mL) to quench at 0°C, extract 5 times with ethyl acetate (25 mL), combine organic phases, wash with brine (50 mL), dry over anhydrous sodium sulfate, filter and spin dry.
  • the third step In the glove box, add tert-butyl(1R,5S)-3-(7-bromo-6-cyano-8-fluoro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (615mg, 1.10mmol), N,N-bis(4-methoxybenzyl)-4-methyl-6-(tributyltin To a solution of alkyl)pyridin-2-amines (1.40 g, 2.2 mmol), cuprous iodide (63 mg, 0.33 mmol) and lithium chloride (116 mg, 2.75 mmol) in 1,4-dioxane (18 mL) was added tetrakis(triphenylphosphine)palladium (254 mg, 0.22 mmol).
  • the fourth step acetonitrile (16 mL) solution, N-iodosuccinimide (1060 mg, 4.71 mmol) and p-toluenesulfonic acid (6 mg, 0.04 mmol) were added.
  • the mixture was stirred at 25 °C for 5 hours under nitrogen protection.
  • the mixture was spin-dried, added brine (10mL), extracted with ethyl acetate (20mL) Take 3 times, the combined organic phases are dried with anhydrous sodium sulfate, filtered and spin-dried.
  • the residue was purified by flash column chromatography (silica gel, gradient 0-20% tetrahydrofuran/petroleum ether).
  • the fifth step N to tert-butyl (1R,5S)-3-(7-(6-(bis(4-methoxybenzyl)amino)-3-iodo-4-methylpyridin-2-yl)-6-cyano-8-fluoro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (700mg, 0.73mmol) , To a solution of N-dimethylacetamide (17.5 mL), add methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (3525 mg, 18.3 mmol) and cuprous iodide (1677 mg, 8.81 mmol).
  • Step 6 To tert-butyl (1R,5S)-3-(7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-cyano-8-fluoro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (150mg, 0.17mm ol) and ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol (70mg, 0.44mmol) in tetrahydrofuran (3mL) was added sodium tert-butoxide (24mg, 0.25mmol).
  • the seventh step tert-butyl (1R,5S)-3-(7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-cyano-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[ 3.2.1]
  • Octane-8-carboxylate (220mg, 0.16mmol) was dissolved in trifluoroacetic acid (3mL), and the mixture was stirred at 50°C for 2 hours under nitrogen protection. Then spin dry.
  • the first step under the protection of nitrogen, the compound tert-butyl (1R,5S)-3-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (300mg, 0.54 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalene-2-ol (176mg, 0.65mmol) in dioxane (5.00mL) were added potassium phosphate (1.5M in water, 1.09mL, 1.63mmol), methanesulfonic acid [n-butylbis(1-adamantyl)phosphine] (2-amino-1,1'-biphen
  • the fourth step at 25°C, to (4-(4-((1R,5S)-8-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]oct)-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalene-2 -yl) boronic acid (76.0 mg, 0.11 mmol) in acetonitrile (1600 uL) was added hydrogen chloride (4M in dioxane, 277 uL, 1.11 mmol).
  • Example 24 7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolazine]-7a'(5'H)- Base) methoxy) -8-fluoro-quinazoline-6-carbonitrile
  • Example 24 was prepared by the synthetic route method of Example 22, using intermediates to tert-butyl (1R,5S)-3-(7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-cyano-8-fluoro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane -8-carboxylates and intermediates (1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolazin]-7a'(5'H)-yl)methanol A16-2A
  • Example 25 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-1-fluoronaphthalen-2-ol
  • Step 1 To a solution of 4-bromonaphthalene-2-ol (2.00 g, 8.96 mmol) in dichloromethane (30 mL) was added bis(benzenesulfonyl)fluoroamine (9.33 g, 29.59 mmol) and zirconium tetrachloride (0.10 g, 0.45 mmol) at 0°C. The solution was stirred at 25°C for 16 hours. The solution was concentrated and purified by flash column chromatography (silica gel, 0-20% gradient of petroleum ether/ethyl acetate) to give brown solid compound 4-bromo-1-fluoronaphthalen-2-ol (0.94 g, 3.50 mmol, yield 39%).
  • LCMS (ESI): [MH] + 240.8.
  • Step 2 Add bis(triphenylphosphine)palladium(II) chloride (44.0mg, 0.06mmol) to a solution of 4-bromo-1-fluoronaphthalen-2-ol (300mg, 1.24mmol), bis-pinacol borate (475mg, 1.87mmol) and potassium acetate (367mg, 3.73mmol) in dioxane (6000uL) at 25°C under nitrogen protection. The solution was stirred at 110°C for 3 hours.
  • the third step 1-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalene-2-ol (157mg, 0.54mmol) and tert-butyl (1R,5S)-3-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl )methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (150mg, 0.27mmol) in dioxane (3.00mL) was added potassium carbonate (2.0M in water, 409uL, 0.82mmol) and tetrakis(triphenylphosphine)palladium (32.0mg, 0.03mmol).
  • the fourth step at 25°C, to tert-butyl (1R,5S)-3-(8-fluoro-7-(4-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyridin[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-
  • To a solution of the carboxylate (200 mg, 0.30 mmol) in acetonitrile (4000 uL) was added hydrogen chloride (4M in dioxane, 739 uL, 2.96 mmol).
  • Example 26 7-(3-amino-7,8-difluoroisoquinolin-1-yl)-4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinazoline-6-carbonitrile
  • Step 1 To a solution of 2-bromo-3,4-difluorobenzoic acid (25.0 g, 105.49 mmol) in tetrahydrofuran (100 mL) was added dropwise a solution of borane in tetrahydrofuran (422 mL, 422 mmol) at 0°C. Warm to room temperature and stir for 16 hours. The solution was cooled with an ice bath, and then 10% aqueous sodium carbonate solution (180 mL) was added slowly. The suspension was concentrated in vacuo to give a white solid. Acidify with 3 mol/L aqueous hydrochloric acid (600 mL), dilute with dichloromethane (300 mL), and filter the mixture through celite.
  • Step 3 To a solution of 2-bromo-3,4-difluorobenzyl methanesulfonate (29.0 g, 96.31 mmol) in acetonitrile (300 mL) was added potassium carbonate (26.0 g, 192 mmol) and trimethylsilyl cyanide (19.0 g, 192 mmol) at 0°C. The reaction was stirred at 80 °C for 16 hours. The mixture was diluted with water (200 mL) and extracted with ethyl acetate (200 mL), the organic phase was washed with brine (200 mL), dried over anhydrous magnesium sulfate and filtered.
  • Step 7 To a solution of tert-butyl (1R,5S)-3-(7-bromo-6-cyano-8-fluoro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (250 mg, 0.45 mmol) in dioxane (5 mL) was added 7,8-difluoro-1-(tributyl Stannyl)isoquinolin-3-amine (251 mg, 0.54 mmol), cuprous iodide (25.5 mg, 0.13 mmol), lithium chloride (47 mg, 1.11 mmol) and tetrakis(triphenylphosphine)palladium (103 mg, 0.09 mmol).
  • Step 8 Add 4A molecular sieves to a solution of tert-butyl (1R,5S)-3-(7-(3-amino-7,8-difluoroisoquinolin-1-yl)-6-cyano-8-fluoro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (60mg, 91umol) in tetrahydrofuran (1mL) (60 mg), sodium tert-butoxide (11 mg, 0.11 mmol) and ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol (17 mg, 0.11 mmol).
  • the ninth step to tert-butyl (1R,5S)-3-(7-(3-amino-7,8-difluoroisoquinolin-1-yl)-6-cyano-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (4 To a solution of 7.3 mg, 66 umol) in acetonitrile (1 mL) was added hydrogen chloride (4M in dioxane, 330 uL, 1.3 mmol).
  • Example 27 6-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine
  • Example 29 6-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-4-methyl-5-(perfluoroethyl)pyridin-2-amine
  • the first step In the glove box, tert-butyl (1R,5S)-3-(7-chloro-8-fluoro-2-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.40g, 2.85mmol), N,N-bis(4-methoxybenzyl)-4-methyl-6-( To a solution of tributylstannyl)pyridin-2-amine (3.27g, 5.12mmol), cuprous iodide (163mg, 0.85mmol) and lithium chloride (302mg, 7.12mmol) in dioxane (28mL) was added tetrakis(triphenylphosphine)palladium (657mg, 0.57mmol).
  • the second step Ethanol to tert-butyl (1R,5S)-3-(7-(6-(bis(4-methoxybenzyl)amino)-4-methylpyridin-2-yl)-8-fluoro-2-(2,2,2-trifluoroethoxy))pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (500mg, 0.62mmol) To a solution of nitrile (10 mL), N-iodosuccinimide (700 mg, 3.11 mmol) and p-toluenesulfonic acid (4.30 mg, 0.02 mmol) were added.
  • the mixture was stirred under nitrogen protection at 25°C for 12 hours.
  • the mixture was spin-dried, brine (10 mL) was added, extracted with ethyl acetate (20 mL*3), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried.
  • the residue was purified by flash column chromatography (silica gel, gradient 0-30% ethyl acetate/petroleum ether) to give the crude product.
  • the third step tert-butyl(1R,5S)-3-(7-(6-(bis(4-methoxybenzyl)amino)-3-iodo-4-methylpyridin-2-yl)-8-fluoro-2-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (290mg, 0.31mmol ) and cuprous iodide (178mg, 0.94mmol) in N,N-dimethylacetamide (7.2mL) solution, 2,2-difluoro-2-(fluorosulfonyl)acetate trimethylsilyl ester (468mg, 1.87mmol) was added at 0°C.
  • the fifth step tert-butyl (1R,5S)-3-(7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diaze Heterobicyclo[3.2.1]octane-8-carboxylate and tert-butyl (1R,5S)-3-(7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(perfluoroethyl)pyridin-2-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl
  • Example 27 (6-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-4-methyl-5-(trifluoromethyl)pyridine pyridin-2-amine) (43.98mg, 0.07mmol, yield 30%) as a white solid.
  • Example 29 (6-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-4-methyl-5-(perfluoroethyl)pyridine pyridin-2-amine) (5.26 mg, 8.2 umol, yield 3%) as a white solid.
  • LCMS(ESI):[M+H] + 641.2.
  • Example 28 N-(6-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-4-methyl-5-(trifluoromethyl)pyridine-2- base) acetamide
  • the third step at 0°C, the compound tert-butyl (1R,5S)-3-(7-(6-acetylamino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-8- Fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrroline-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (35.0 mg, 0.05 mmol) was dissolved in acetonitrile (1 mL), and hydrogen chloride (4M in dioxane, 239 u L, 0.96 mmol), and the reaction was stirred at 20°C for 2 hours.
  • Example 30 4-(4-(-3,8-diazabicyclo[3.2.1]oct-3-yl-2-((dihydro-1'H,3'H-spiro[oxetane-3,2'-pyrrolazin]-7a'(5'H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol
  • the second step In the glove box, add tert-butyl-3-(7-chloro-2-((dihydro-1'H,3'H-spiro[oxetane-3,2'-pyrrolazin]-7a'(5'H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (110mg, 0.19 mmol) and 2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (83mg, 0.23mmol) in dioxane (2.2mL) were added potassium phosphate (1.5M in water, 386uL, 0.58mmol) and methanesulfonic acid [n-butylbis(1-adamanty
  • the third step to tert-butyl-3-(2-((dihydro-1'H,3'H-spiro[oxetane-3,2'-pyrrolazin]-7a'(5'H)-yl)methoxy)-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1 ] To a solution of octane-8-carboxylate (110 mg, 0.14 mmol) in dichloromethane (1760 uL) was added trifluoroacetic acid (440 uL).
  • Example 31A and Example 31B 4-(4-((1R,5S)-(3,8-diazabicyclo[3.2.1]oct-3-yl-2-((dihydro-1'H,3'H-spiro[oxetane-3,2'-pyrrolazin]-7a'(5'H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-5-eth Base-6-fluoronaphthalen-2-ol, and
  • Example 30 was separated by SFC (column: DAICEL CHIRALPAK AD (250mm*30mm, 10um); mobile phase: phase A was carbon dioxide, phase B was 0.1% ammonia water/ethanol; phase B was maintained at 50%; flow rate: 80 ml/min), and the target compound was obtained.
  • SFC column: DAICEL CHIRALPAK AD (250mm*30mm, 10um); mobile phase: phase A was carbon dioxide, phase B was 0.1% ammonia water/ethanol; phase B was maintained at 50%; flow rate: 80 ml/min), and the target compound was obtained.
  • Example 32 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-((hexahydro-2H-furo[2,3-b]pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol dicarboxylate
  • the first step to tert-butyl(1R,5S)-3-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yl)-8-fluoro-2-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (800mg, 1.16mmol) and (hexahydro- To a solution of 2H-furo[2,3-b]pyrrolazin-7a(5H)-yl)methanol (106 mg, 0.58 mmol) in tetrahydrofuran (5 mL) was added sodium tert-butoxide (375 mg, 2.90 mmol).
  • the second step at 0°C, add tert-butyl(1R,5S)-3-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yl)-8-fluoro-2-((hexahydro-2H-furo[2,3-b]pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.
  • Example 33B cis-4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-((hexahydrocyclopropane[a]pyrrolazin-6a(4H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol
  • Example 34 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-((dihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolazin]-7a'(5'H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalene-2- Alcohol formate
  • Example 35 trans-4-(4-((1S,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolazin]-7a'(5'H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrim Pyridin-7-yl)-5-ethyl-6-fluoronaphthalene-2-ol
  • Example 35A and Example 35B 4-(4-((1S,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolazin]-7a'(5'H)-yl)methoxy)-8-fluoropyrido[4,3 -d] pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol, and
  • Example 36 cis-4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(((1R,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolazin]-7a'(5'H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrim Pyridin-7-yl)-5-ethyl-6-fluoronaphthalene-2-ol
  • Example 37 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-((hexahydrocyclopropane[b]pyrrolazin-5a(3H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol
  • Step 1 To a solution of (1R,5S)-tert-butyl 3-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (200 mg, 0.47 mmol) in dioxane (5 mL) was added (hexahydrocyclopropane[b]pyrrolazin-5a(3H)-yl)methanol (85% purity, 257 mg, 1.40 mmol), diisopropylethylamine (0.39 mL, 2.33 mmol). The reaction was stirred at 80°C for 16 hours. The mixture was concentrated in vacuo.
  • the second step under nitrogen atmosphere, dioxane (2mL ) and water (0.40 mL) were added ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalene-1-yl)ethynyl)triisopropylsilane (135mg, 0.26mmol), cesium carbonate (215mg, 0.66mmol) and [(bis(1-adamantyl)-N-butylphosphine)-2- (2-aminobiphenyl)palladium(II) chloride (14.72 mg, 0.02 mmol), and the mixture was stirred at 100° C.
  • the third step to tert-butyl(1R,5S)-3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalene-1-yl)-2-((hexahydrocyclopropane[b]pyrrolazin-5a(3H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1] To a solution of octane-8-carboxylate (40 mg, 0.04 mmol) in dichloromethane (400 uL) was added trifluoroacetic acid (80 uL) at 0°C.
  • the fourth step to 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-((hexahydrocyclopropane[b]pyrrolazin-5a(3H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-6-fluoro-5-((triisopropylsilyl)ethynyl)naphthalene-2-ol (40mg, 0 .05mmol) in dimethylformamide (400uL) was added cesium fluoride (162mg, 1.07mmol). The reaction was stirred at 20°C for 2 hours.
  • Example 38 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-((dihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolazin]-7a'(5'H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalene- 2-ol
  • Example 40A 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(((1R,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolazin]-7a'(5'H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidine- 7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol
  • the third step tert-butyl (1R,5S)-3-(2-(((1R,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolazin]-7a'(5'H)-yl)methoxy)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy))naphthalene-1-yl)-8-fluoropyrido[4 ,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (purity 79%, 370 mg, 0.37 mmol) was dissolved in trifluoroacetic acid/dichloromethane (volume ratio 1/4, 4 mL) and stirred for 2 hours.
  • Example 41 4-(2-((1'H, 3'H, 5'H-dithiacyclo[oxetane-3,2'-pyrrolidine-6', 3'-oxetane-7a'(7'H)-ylmethoxy)-4-((1R,5S)-3,8-diazacyclo[3.2.1]octane-3-yl)-8-fluoropyridin[4,3-d]pyrimidine-7- Base)-5-ethynyl-6-fluoronaphthalene-2-ol
  • Step 5 At 0°C, LiAlH4 (80mg, 2.24mmol) was added to a solution containing 1'H, 3'H, 5'H-ethyl dithiocyanate [oxetane-3,2'-pyrrolizine-6', 3'-oxetane]-7a'(7'H)-ethyl carboxylate (600mg, 2.24mmol) and THF (6mL), and the reaction solution was stirred at room temperature for 1 hour, Add excess sodium sulfate water to the reaction solution, stir for 30 minutes and then filter, and the filtrate is concentrated to obtain compound (1'H,3'H,5'H-dipyrrole[oxetane-3,2'-pyrrolidine-6',3'-oxetane]-7a'(7'H)-yl)methanol (210mg) as a yellow oily product.
  • LCMS (ESI): [M+H]+ 226.2.
  • the seventh step at 0°C, trifluoroacetic acid (0.5 mL) was added to the solution containing tert-butyl (1R, 5S)-3-(2-((1'H, 3'H, 5'H-bispiro[oxetane-3,2'-pyrrolizine-6', 3'-oxetane]-7a'(7'H)-ylmethoxy)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8- ((triisopropylsilyl)ethynyl)naphthalene-1-yl)pyridin[4,3-d]pyrimidin-4-yl)-3,8-diazacyclo[3.2.1]octane-8-carboxylate (50mg, 0.052mmol) and dichloromethane (3mL) in the reaction solution, the reaction solution was stirred at 0°C for 30 minutes, triethylamine (1mL)
  • Step 8 Containing 4-(2-((1'H, 3'H, 5'H-dithiacyclo[oxetane-3,2'-pyrrolidine-6', 3'-oxetane-7a'(7'H)-yl)methoxy)-4-((1R,5S)-3,8-diazacyclo[3.2.1]octane-3-yl)-8-fluoropyridin[4,3-d]pyrimidine-7-
  • a reaction solution of -6-fluoro-5-((triisopropylsilyl)ethynyl)naphthalene-2-ol (30mg, 0.036mmol), cesium fluoride (28mg, 0.18mmol) and DMF (1mL) was stirred at 50°C for 2 hours, the reaction solution was poured into water (20mL) and extracted with EA (20mL x 3), the organic phase was dried over anhydrous Na2SO4, filtered and concentrated, and purified
  • Step 5 Under nitrogen protection at 20°C, triphenylphosphine (385mg, 1.47mmol) and carbon tetrabromide (491mg, 1.47mmol) were added to a solution of methyl 6- ⁇ [(hydroxymethyl)cyclopropyl]methyl ⁇ -6-azaspiro[2.4]heptane-5-carboxylate (270mg, 1.13mmol) in dichloromethane (5ml), and the reaction solution was stirred at 20°C for 2 hours.
  • triphenylphosphine 385mg, 1.47mmol
  • carbon tetrabromide 491mg, 1.47mmol
  • Step 6 Dissolve methyl 6- ⁇ [(bromomethyl)cyclopropyl]methyl ⁇ -6-azaspiro[2.4]heptane-5-carboxylate (300mg, 0.99mmol) in N,N-dimethylformamide (15mL) and tetrahydrofuran (5mL) at 20°C, replace with nitrogen three times, and cool to -70°C, dropwise add bis(trimethylsilyl)potassium amide (1.4mL, 1.39 mmol, 1M), and the reaction solution was stirred at this temperature for 50 minutes.
  • Step 7 Add lithium aluminum hydride (15mg, 0.39mmol) to 1'hydrogen, 3'hydrogen, 5'hydrogen-dispiro[cyclopropane-1,2'-pyrrolizine-6',1"-cyclopropanyl]-7a'(7'hydrogen)-methyl formate (30mg, 0.15mmol) in tetrahydrofuran (2mL) at 0°C, and stir the reaction solution at 0°C for 1 hour. Add to the reaction solution for 1 hour. Lithium aluminum hydride (15mg, 3eq) was added and stirred at 20°C for 1 hour. Water (30ul) and 15% sodium hydroxide solution (90uL) were added to the reaction solution, and stirred at 20°C for 10 minutes.
  • reaction solution was stirred at 20°C for 4 hours.
  • sodium tert-butoxide (2mg x 3) to the reaction solution 3 times, and stir at 60°C for 2 hours.
  • water (2mL) to the reaction solution and extract with ethyl acetate (2mL x 3).
  • the organic phase is dried over anhydrous sodium sulfate, filtered and concentrated to obtain a residue.
  • Step 9 Add cesium fluoride (61mg, 0.40mmol) to (1R,5S)-3-(2-((1'hydrogen,3'hydrogen,5'hydrogen-dispiro[cyclopropane-1,2'-pyrrolizine-6',1"-cyclopropanyl]-7a'(7'hydrogen)-yl)methoxy)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-(( Triisopropylsilyl)ethynyl)naphthalene-1-yl)pyridyl[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (37mg, 0.039mmol) in N,N-dimethylformamide (3mL).
  • reaction solution was stirred at 20°C for 1.5 hours.
  • the reaction solution was diluted with ethyl acetate (2mL) and diluted with water (1mL x 2 ) was washed.
  • the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to obtain a residue, and the residue was purified by column chromatography (silica gel, 0-50% gradient ethyl acetate/petroleum ether, 0-5% gradient methanol/dichloromethane) to obtain a colorless viscous liquid (1R, 5S)-3-(2-((1'hydrogen, 3'hydrogen, 5'hydrogen-dispiro[cyclopropane-1,2'-pyrrolizine-6',1"-cyclopropanyl]-7a'( 7'H)-yl)methoxy)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-
  • reaction solution was concentrated, diluted with acetonitrile (1mL), adjusted to pH 7 with triethylamine, and purified by reverse phase column chromatography (C18, 5- 95% acetonitrile/water gradient) to 4-(2-((1'hydrogen, 3'hydrogen, 5'hydrogen-dispiro[cyclopropane-1,2'-pyrrolizine-6',1"-ring Propanyl]-7a'(7'hydrogen)-yl)methoxy)-4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoropyridin[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalene-2-ol (1.80 mg, yield 32%).
  • LCMS (ESI): [M+H]+ 635.4.
  • Step 1 To a solution of 2-chloro-3-fluoroisonicotinic acid (100 g, 569 mmol) and triethylamine (158 mL, 1133 mmol) in toluene (500 mL) and tert-butanol (500 mL) under nitrogen atmosphere, di-tert-butyl dicarbonate (13 mL, 56.5 mmol) and diphenylphosphoryl azide (147 mL, 682 mmol) were added, and the solution was stirred at 80° C. for 16 hours. The mixture was concentrated and added with 500 mL of saturated brine, and extracted with 500 mL of ethyl acetate.
  • Second step A solution of tert-butyl (2-chloro-3-fluoropyridin-4-yl)carbamate (50 g, 202 mmol) and tetramethylethylenediamine (70.6 g, 608 mmol) in anhydrous methyl tert-butyl ether (500 mL) was cooled to -70°C. And n-butyllithium (2.5M in n-hexane, 203 mL, 506 mmol) was slowly added to the mixture.
  • Step 3 Triphosgene (7.45 g, 25.1 mmol) was added to a solution of 4-((tert-butoxycarbonyl)amino)-6-chloro-5-fluoronicotinic acid (10 g, 34.4 mmol) in dioxane (100 mL), and the mixture was stirred at 100° C. for 4 hours. The reaction solution was concentrated in vacuo, and the residue was slurried with petroleum ether to obtain 7-chloro-8-fluoro-2H-pyrido[4,3-d][1,3]oxazine-2,4(1H)-dione (7.40 g, 34.4 mmol, yield 99%) as a white solid.
  • 1 H NMR 400MHz,DMSO-d 6 ) ⁇ ppm 12.84(br s,1H),8.73(s,1H).
  • Step 5 7-Chloro-8-fluoro-2,4-dioxo-1,2,3,4-tetrahydro-1,6-naphthyridine-3-carbonitrile (5.80 g, 24.2 mmol) was carefully added to phosphorus oxychloride (50 mL, 536 mmol). The reaction was stirred at 90°C for 16 hours. The mixture was concentrated in vacuo, the residue was dissolved in ethyl acetate (100ml), washed with saturated sodium bicarbonate (100ml), and the aqueous phase was extracted with ethyl acetate (50ml*3). The combined organic layers were dried over anhydrous magnesium sulfate and filtered.
  • Step 6 Under -70 ° C to 2,4,7-trigloin-8-fluorine -1,6-pyrimidine-3-metada (2.00g, 7.23 mmol) dichloromethane (30ml) solution (1R, 5S) -Ixin 3,8-two-nitrogen miscellaneous two-ring [3.2.1] Ectane-8-carboxylic acid ester (1.38g, 6.5 6.5, 6.5 1mmol) dichloromethane (10ml) solution. A solution of triethylamine (2.52 mL, 18.1 mmol) in dichloromethane (10 mL) was then added slowly. The reaction was stirred at -70°C for 0.5 hours.
  • Step 7 Add 4A molecular sieves (1.00 g) to a solution of tert-butyl (1R,5S)-3-(2,7-dichloro-3-cyano-8-fluoro-1,6-naphthyridin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.00 g, 2.21 mmol) in tetrahydrofuran (20 mL), ((2R,7aS)-2-fluoro Tetrahydro-lH-pyrrolazin-7a(5H)-yl)methanol (0.35 g, 2.21 mmol) and sodium tert-butoxide (0.32 g, 3.32 mmol).
  • Step 8 In a nitrogen atmosphere, add tert-butyl(1R,5S)-3-(7-chloro-3-cyano-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-1,6-naphthyridin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (500mg, 0.87 mmol), ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (535 mg, 1.04 mmol) and cesium carbonate (850 mg, 2.61 mmol) in dioxane (5 mL) and water (1 mL) was added chloro[(n-
  • the ninth step to tert-butyl (1R,5S)-3-(3-cyano-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalene-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-1,6-naphthyridin-4-yl)-3,8-
  • diazabicyclo[3.2.1]octane-8-carboxylate 750 mg, 0.81 mmol
  • dimethylformamide 7.5 mL
  • cesium fluoride 2.40 g, 15.8 mmol
  • Step 10 To dichloromethane (7.20 mL) in trifluoroacetic acid (1.80 mL) was added tert-butyl(1R,5S)-3-(3-cyano-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)- 1,6-Naphthyridin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (450 mg, 0.59 mmol).
  • the first step to the compound tert-butyl (1R,5S)-3-(7-bromo-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (150mg, 0.19mmol) and (2-fluoro-6- Sodium carbonate (76mg, 0.72mmol) was added to a solution of hydroxyphenyl)boronic acid (59mg, 0.38mmol) in dioxane (3mL) and water (600uL), and (2-dicyclohexylphosphino-2,6-diisopropoxy-1,1-biphenyl)[2-(2-amino-1,1-biphenyl)]palladium(II) (17mg, 0.02m
  • the second step compound tert-butyl (1R,5S)-3-(6-chloro-8-fluoro-7-(2-fluoro-6-hydroxyphenyl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (30.0mg, 0.03mmol ) was dissolved in dichloromethane/trifluoroacetic acid (volume ratio 4:1, 600uL), and the reaction solution was stirred at 20°C for 2 hours.
  • Example 45 4-(4-((1R,5S)-3,8-Diazabicyclo[3.2.1]oct-3-yl)-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol and
  • Example 46 1-(8 -(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-2-fluoro-6-hydroxynaphthalen-1-yl)ethan-1-one
  • Example 45 and Example 46 were prepared by the synthetic route method of Example 44, using intermediate ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalene-1-yl)ethynyl)triisopropylsilane and intermediate tert-butyl (1R,5S)-3-(7-bromo-6-chloro-8-fluoro-2-(((2R, 7aS)-2-Fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate
  • the third and fourth steps were combined into one step, and deprotected with TFA/DCM to obtain the main product 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1
  • Example 47 4-((1R,5S)-3,8-Diazabicyclo[3.2.1]oct-3-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinazolin-6-carbonitrile
  • the first step compound tert-butyl (1R,5S)-3-(7-bromo-6-cyano-8-fluoro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (80% purity, 292mg, 0.57mmol) was added to dioxane (5mL) and water (1mL), and ((2-fluoro-6 -(Methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)naphthalene-1-yl)ethynyl)triisopropylsilane (200mg, 0.29mmol) and potassium phosphate (182mg, 0.86mmol), methanesulfonyloxy(diadamantyl-n-butylphosphino)-2-amino-1,1-biphenyl
  • the second step compound tert-butyl(1R,5S)-3-(6-cyano-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalene-1-yl)-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (70% purity, 147 mg, 0.12mmol) into tetrahydrofuran (2mL), add ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol (57mg, 0.36mmol) and sodium tert-butoxide (17mg, 0.18mmol), and stir at 50°C for 2 hours.
  • the third step compound tert-butyl(1R,5S)-3-(6-cyano-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalene-1-yl)-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (66% purity, 156 mg, 0.11 mmol) was added to N,N-dimethylformamide (2 mL), cesium fluoride (169 mg, 1.11 mmol) was added, and stirred at 20°C for 1 hour.
  • the fourth step the compound tert-butyl (1R,5S)-3-(6-cyano-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane- 8-Carboxylate (60% purity, 135mg, 0.10mmol) was added to trifluoroacetic acid/dichloromethane (volume ratio 4:1, 2.5mL), stirred at 20°C Mix for 2 hours.
  • Examples 48A ⁇ 48D 4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(((1R,7a'R)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolazin]-7a'(5'H)-yl)methoxy)-7-(R)-(8-ethynyl-7- Fluoro-3-hydroxynaphthalen-1-yl)-8-fluoroquinazoline-6-carbonitrile, 4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(((1R,7a'R)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolazin]-7a'(5'H)-yl)methoxy)-7-(S
  • Example 50 4-(4-((1R,5S)-3,8-Diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-6-(trifluoromethyl)quinazolin-7-yl)naphthalen-2-ol
  • the first step the compound tert-butyl(1R,5S)-3-(7-bromo-8-fluoro-6-iodo-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.00g, 1.51mmol) was dissolved in N,N-dimethylformamide (15mL), in a nitrogen atmosphere, 2,2-difluoro - Methyl 2-(fluorosulfonyl)acetate (2.03g, 10.5mmol) and cuprous iodide (2.02g, 10.5mmol). The reaction was stirred at 60°C for 16 hours.
  • Second step To a solution of tert-butyl(1R,5S)-3-(7-bromo-8-fluoro-2-(2,2,2-trifluoroethoxy)-6-(trifluoromethyl)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (200 mg, 0.33 mmol) in THF (3 mL) was added 4-(4,4,5,5 -Tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalene-2-ol (107 mg, 0.40 mmol), potassium phosphate (1.5 M in water, 663 uL, 0.99 mmol), palladium (2-dicyclohexylphosphine-2,4,6-triisopropyl-1,1-biphenyl)[2-(2-amino-1,1-biphenyl]methanesulfonate (28 mg, 0.03 mmol).
  • Step 3 Dissolve tert-butyl(1R,5S)-3-(8-fluoro-7-(3-hydroxynaphthalene-1-yl)-2-(2,2,2-trifluoroethoxy)-6-(trifluoromethyl)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (170mg, 0.26mmol) in dichloromethane (3mL) to 0°C, and slowly pour into the reaction solution Diisopropylethylamine (133uL, 0.77mmol) and bromomethylmethyl ether (27uL, 0.33mmol) were added and the reaction was stirred at 25°C for 16 hours.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

Provided in the present invention are a heterocyclic compound, a pharmaceutical composition and the use thereof. Specifically disclosed are a heterocyclic compound as represented by formula (I-0), a pharmaceutically acceptable salt or stereoisomer of the heterocyclic compound, or a solvate thereof. The compound of the present invention has a novel structure and relatively good activity and selectivity.

Description

杂环类化合物、药物组合物及其应用Heterocyclic compound, pharmaceutical composition and application thereof
本申请要求申请日为2022/1/21的中国专利申请2022100698643的优先权；申请日为2022/5/6的中国专利申请2022105001306的优先权；申请日为2022/7/28的中国专利申请202210900237X的优先权；申请日为2022/9/28的中国专利申请2022111939164的优先权；申请日为2023/1/4的中国专利申请2023100101425的优先权。本申请引用上述中国专利申请的全文。This application claims the priority of Chinese patent application 2022100698643 with a filing date of 2022/1/21; the priority of Chinese patent application 2022105001306 with a filing date of 2022/5/6; the priority of Chinese patent application 202210900237X with a filing date of 2022/7/28; Priority of 11939164; priority of Chinese patent application 2023100101425 with a filing date of 2023/1/4. This application cites the full text of the above-mentioned Chinese patent application.
技术领域technical field
本发明涉及一种杂环类化合物、药物组合物及其应用。The invention relates to a heterocyclic compound, a pharmaceutical composition and applications thereof.
背景技术Background technique
RAS癌基因突变是人类癌症中最常见的激活突变，发生在30％的人类肿瘤中。RAS基因家族包括三个亚型(KRAS、HRAS和NRAS),其中85％的RAS驱动的癌症是由KRAS亚型突变引起的。KRAS突变常见于实体肿瘤中，如：肺腺癌、胰腺导管癌和结直肠癌等。在KRAS突变肿瘤中，80％的致癌突变发生在密码子12上，最常见的突变包括：p.G12D(41％)、p.G12V(28％)和p.G12C(14％)。RAS oncogene mutations are the most common activating mutations in human cancers, occurring in 30% of human tumors. The RAS gene family includes three subtypes (KRAS, HRAS and NRAS), and 85% of RAS-driven cancers are caused by mutations in KRAS subtypes. KRAS mutations are commonly found in solid tumors, such as lung adenocarcinoma, pancreatic ductal carcinoma, and colorectal cancer. In KRAS-mutated tumors, 80% of oncogenic mutations occurred at codon 12, and the most common mutations included: p.G12D (41%), p.G12V (28%), and p.G12C (14%).
KRAS基因的全名是Kirsten rat sarcoma viraloncogene homolog(Kristen大鼠肉瘤病毒癌基因同源物)。KRAS在细胞生长的信号调控中起着一个枢纽的作用，上游的EGFR(ErbBl),HER2(ErbB2)、ErbB3和ErbB4等细胞表面受体，在接受了外界信号之后，会通过RAS蛋白，把信号传递到下游。KRAS蛋白没有被激活的时候，与GDP(鸟嘌呤核苷酸二磷酸)紧密结合。在被SOSl等鸟嘌呤核苷酸交换因子激活后，与GTP(鸟嘌呤核苷酸三磷酸)结合，变成激酶活性的状态。KRAS基因突变后，可以不依赖于上游生长因子受体信号，独立向下游通路传输生长和増殖的信号，造成不受控制的细胞生长和肿瘤进展，同时KRAS基因是否有突变，也是肿瘤预后的一个重要指标。统计结果显示，在KRAS的亚型中，KRAS G12D也是一种常见的亚突变，其中结直肠癌占12％，胰腺癌占36％，非小细胞肺癌占4％，因此开发一种新型KRAS G12D抑制剂是非常有必要，它有很大的潜力可以成为肿瘤治疗领域的新治疗手段，因此需要开发更有效，更安全，药代性质更好的KRAS G12D抑制剂以满足临床需求。The full name of the KRAS gene is Kirsten rat sarcoma viraloncogene homolog (Kristen rat sarcoma viral oncogene homolog). KRAS plays a pivotal role in the signal regulation of cell growth. The upstream cell surface receptors such as EGFR (ErbB1), HER2 (ErbB2), ErbB3 and ErbB4, after receiving external signals, will pass the signal to the downstream through the RAS protein. When the KRAS protein is not activated, it is tightly bound to GDP (guanine nucleotide diphosphate). After being activated by guanine nucleotide exchange factors such as SOS1, it binds to GTP (guanine nucleotide triphosphate) and becomes a kinase active state. After KRAS gene mutation, it can independently transmit growth and proliferation signals to downstream pathways independently of upstream growth factor receptor signals, resulting in uncontrolled cell growth and tumor progression. At the same time, whether KRAS gene is mutated is also an important indicator of tumor prognosis. The statistical results show that KRAS G12D is also a common submutation in KRAS subtypes, of which colorectal cancer accounts for 12%, pancreatic cancer accounts for 36%, and non-small cell lung cancer accounts for 4%. Therefore, it is very necessary to develop a new KRAS G12D inhibitor, which has great potential to become a new treatment in the field of tumor treatment. Therefore, it is necessary to develop more effective, safer, and better pharmacokinetic KRAS G12D inhibitors to meet clinical needs.
发明内容Contents of the invention
本发明所要解决的技术问题是针对现有KRAS G12D抑制剂结构较为单一的缺陷，提供了一种杂环类化合物、药物组合物及其应用，本发明化合物结构新颖，活性和选择性较好。The technical problem to be solved by the present invention is to provide a heterocyclic compound, a pharmaceutical composition and its application in view of the defect that the existing KRAS G12D inhibitor has a single structure. The compound of the present invention has a novel structure, good activity and selectivity.
本发明是通过下述技术方案来解决上述技术问题的。The present invention solves the above-mentioned technical problems through the following technical solutions.
本发明提供了一种如式I-0所示的杂环类化合物、其药学上可接受的盐、其立体异构体或它们(指前述如式I-0所示的杂环类化合物、其药学上可接受的盐或其立体异构体)的溶剂合物：
The present invention provides a heterocyclic compound represented by formula I-0, a pharmaceutically acceptable salt thereof, a stereoisomer thereof or a solvate thereof (referring to the aforementioned heterocyclic compound represented by formula I-0, a pharmaceutically acceptable salt thereof or a stereoisomer thereof):
其中，环K为芳环或杂芳环；Wherein, Ring K is an aromatic ring or a heteroaromatic ring;
X1为N、NRX1’或CRX1；X2为N或CRX2； X1 is N, NR X1' or CR X1 ; X2 is N or CR X2 ;
RX1和RX2各自独立地为H、CN、卤素、C1-C6烷基、被一个或多个卤素取代的C1-C6烷基、被一个或多个羟基取代C1-C6烷基、PO(C1-C6烷基)2、C3-C6环烷基、C3-C6环烯基、C2-C6烯基、C2-C6炔基、3～6元杂环烷基、3～6元杂环烯基、6-14元芳基、5～14元杂芳基、被一个或多个X1-1取代的3～6元杂环烷基、被一个或多个X1-2取代的5～14元杂芳基、NO2、被一个或多个X1-3取代的3～6元杂环烯基、ORa、SF5、C(＝O)X1-4、C(＝O)ORa、-NRaC(O)Ra、NX1-5X1-6或SO2X1-7；RX1and RX2Each independently is H, CN, halogen, C1-C6Alkyl, C substituted by one or more halogens1-C6Alkyl, substituted by one or more hydroxyl groups C1-C6Alkyl, PO(C1-C6alkyl)2、C3-C6Cycloalkyl, C3-C6Cycloalkenyl, C2-C6Alkenyl, C2-C6Alkynyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, 6-14 membered aryl, 5-14 membered heteroaryl, one or more X1-1Substituted 3-6 membered heterocycloalkyl, replaced by one or more X1-2Substituted 5-14 membered heteroaryl, NO2, by one or more X1-3Substituted 3-6 membered heterocycloalkenyl, ORa, SF5, C(=O)X1-4, C(=O)ORa, -NRaC(O)Ra、NX1-5x1-6or SO2x1-7;
X1-1和X1-3各自独立地为(C＝O)-C1-C6烷基；X1-2独立地为C1-C6烷基；X1-4独立地为H、C3-C8环烷基、3～8元杂环烷基、C1-C6烷基、或被一个或多个卤素取代的C1-C6烷基；X1-5和X1-6各自独立地为H、C1-C6烷基、C3-C6环烷基、SO2-C1-C6烷基或(C＝O)-C1-C6烷基，或者X1-5和X1-6一起与与之相连的原子形成C3-C6脂碳环、C3-C6碳烯环、3～6元脂杂环或3～6元碳杂烯环；X1-7为ORa或C1-C6烷基；x1-1and x1-3Each independently is (C=O)-C1-C6Alkyl; X1-2independently for C1-C6Alkyl; X1-4independently H, C3-C8Cycloalkyl, 3-8 membered heterocycloalkyl, C1-C6Alkyl, or C substituted by one or more halogens1-C6Alkyl; X1-5and x1-6Each independently is H, C1-C6Alkyl, C3-C6Cycloalkyl, SO2-C1-C6Alkyl or (C=O)-C1-C6Alkyl, or X1-5and x1-6together with the atoms it is attached to form C3-C6Aliphatic ring, C3-C6Carbene ring, 3-6 membered aliphatic ring or 3-6 membered carbene ring; X1-7for ORaor C1-C6alkyl;
X3为N或CRX3，RX3为H、卤素、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C6环烷基、C3-C6环烯基、3～6元杂环烷基、3～6元杂环烯基、卤代(C1-C6烷基)、ORa、羟基(C1-C6烷基)、氰基、硝基、-SO3Ra、-NRaRb、-C(O)Ra、-C(O)ORa、-C(O)NRaRb、-NRaC(O)Ra、5-14元杂芳基、6-14元芳基；X 3 is N or CR X3 , R X3 is H, halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkenyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, halogenated (C 1 -C 6 alkyl), OR a , hydroxyl (C 1 -C 6 alkyl), cyano, nitro, -SO 3 R a , -NR a R b , -C(O)R a , -C(O)OR a , -C(O)NR a R b , -NR a C(O)R a , 5-14 membered heteroaryl, 6-14 membered aryl;
Ra和Rb各自独立地表示氢、C1-C6烷基或C3-C6环烷基；或者Ra、Rb一起与与之相连的原子形成C3-C6脂碳环、C3-C6碳烯环、3～6元脂杂环或3～6元碳杂烯环；R a and R b each independently represent hydrogen, C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl; or R a and R b together form a C 3 -C 6 aliphatic carbocyclic ring, a C 3 -C 6 carbene ring, a 3-6 membered aliphatic heterocyclic ring or a 3-6 membered carboalkene ring;
或者RX1与RX3和其相连的原子共同形成C5-C8环烯酮结构；Or R X1 and R X3 and the atoms connected to them together form a C 5 -C 8 cycloalkene structure;
或者RX1’与RX3和其相连的原子共同形成5～8元杂芳环或被一个或多个羟基取代的5～8元杂芳环；Or R X1' and R X3 and the atoms connected to them together form a 5-8 membered heteroaryl ring or a 5-8 membered heteroaryl ring substituted by one or more hydroxyl groups;
R1为C6～C14的芳基、被一个或多个R1-1取代的C6～C14的芳基、5～14元杂芳基或被一个或多个R1-2取代的5～14元杂芳基；R 1 is a C 6 -C 14 aryl group, a C 6 -C 14 aryl group substituted by one or more R 1-1 , a 5-14 membered heteroaryl group or a 5-14 membered heteroaryl group substituted by one or more R 1-2 ;
R1-1和R1-2各自独立地为卤素、OH、CN、NO2、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C6环烷基、C3-C6环烯基、3～6元杂环烷基、3～6元杂环烯基、被一个或多个卤素取代的C1-C6烷基、被一个或多个羟基取代的C1-C6烷基、ORa、B(OH)2、O(C＝O)-C1-C10烷基、SO3Ra、NRaRb、CORa、CONRaRb、C(O)ORa、NRaCORa；R 1-1 and R 1-2 are each independently halogen, OH, CN, NO 2 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkenyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, C 1 -C 6 alkyl substituted by one or more halogens, C 1 - C 6 alkyl, OR a , B(OH) 2 , O(C=O)-C 1 -C 10 alkyl, SO 3 R a , NR a R b , COR a , CONR a R b , C(O)OR a , NR a COR a ;
或者，相邻的两个R1-1与其相连的原子一起形成C3-C8脂碳环或被一个或多个R1-3取代的C3-C8脂碳环，其余R1-1独立地为卤素、OH、CN、NO2、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C6环烷基、C3-C6环烯基、3～6元杂环烷基、3～6元杂环烯基、被一个或多个卤素取代的C1-C6烷基、被一个或多个羟基取代的C1-C6烷基、ORa、B(OH)2、O(C＝O)-C1-C10烷基、SO3Ra、NRaRb、CORa、CONRaRb、 C(O)ORa、NRaCORa；或者，相邻的两个R 1-1与其相连的原子一起形成C 3 -C 8脂碳环或被一个或多个R 1-3取代的C 3 -C 8脂碳环，其余R 1-1独立地为卤素、OH、CN、NO 2 、C 1 -C 6烷基、C 2 -C 6烯基、C 2 -C 6炔基、C 3 -C 6环烷基、C 3 -C 6环烯基、3～6元杂环烷基、3～6元杂环烯基、被一个或多个卤素取代的C 1 -C 6烷基、被一个或多个羟基取代的C 1 -C 6烷基、OR a 、B(OH) 2 、O(C＝O)-C 1 -C 10烷基、SO 3 R a 、NR a R b 、COR a 、CONR a R b 、 C(O)OR a , NR a COR a ;
或者，相邻的两个R1-2与其相连的原子一起形成C3-C8脂碳环或被一个或多个R1-4取代的C3-C8脂碳环，其余R1-2独立地为卤素、OH、CN、NO2、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C6环烷基、C3-C6环烯基、3～6元杂环烷基、3～6元杂环烯基、被一个或多个卤素取代的C1-C6烷基、被一个或多个羟基取代的C1-C6烷基、ORa、B(OH)2、O(C＝O)-C1-C10烷基、SO3Ra、NRaRb、CORa、CONRaRb、C(O)ORa、NRaCORa；Or, adjacent two R1-2Together with its attached atoms form C3-C8Aliphatic carbocycle or by one or more R1-4Replaced C3-C8Aliphatic carbocycle, the rest R1-2independently halogen, OH, CN, NO2、C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, C3-C6Cycloalkyl, C3-C6Cycloalkenyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, C substituted by one or more halogens1-C6Alkyl, C substituted by one or more hydroxyl groups1-C6Alkyl, ORa, B(OH)2, O(C=O)-C1-C10Alkyl, SO3Ra、NRaRb、CORa、CONRaRb, C(O)ORa、NRaCORa;
R1-3和R1-4独立地为卤素；R 1-3 and R 1-4 are independently halogen;
或者X1为CRX1，其中，X1中的C原子与R1中的芳基或杂芳基中的C原子通过-O-(CH2)n1-*、*-NH-(CH2)n2-、-C≡C-(CH2)n3-C≡C-*或-(CH2)n4-O-(CH2)n5-*相连，其中，*端与X1中的C原子相连；Or X 1 is CR X1 , wherein the C atom in X 1 is connected to the C atom in the aryl or heteroaryl group in R 1 through -O-(CH 2 ) n1 - * , * -NH-(CH 2 ) n2 -, -C≡C-(CH 2 ) n3 -C≡C- * or -(CH 2 ) n4 -O-(CH 2 ) n5 - * , wherein the * end is connected to the C atom in X 1 connected;
n1、n2、n3、n4和n5各自独立地为1、2、3、4、5或6；n1, n2, n3, n4 and n5 are each independently 1, 2, 3, 4, 5 or 6;
R2为H、卤素、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C6环烷基、C3-C6环烯基、3～6元杂环烷基、3～6元杂环烯基、卤代(C1-C6烷基)、ORa、羟基(C1-C6烷基)、氰基、硝基、-SO3Ra、-NRaRb、-C(O)Ra、-C(O)ORa、-C(O)NRaRb、-NRaC(O)Ra、5-14元杂芳基、6-14元芳基；R 2 is H, halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkenyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, halogenated (C 1 -C 6 alkyl), OR a , hydroxyl (C 1 -C 6 alkyl), cyano, nitro, -SO 3 R a , -NR a R b , -C(O)R a , -C(O)OR a , -C(O)NR a R b , -NR a C(O)R a , 5-14 membered heteroaryl, 6-14 membered aryl;
L2表示不存在、-O-(C1-C6亚烷基)或-NRa-(C1-C6亚烷基)；L 2 represents absence, -O-(C 1 -C 6 alkylene) or -NR a -(C 1 -C 6 alkylene);
R3为 R3 is
其中，R1'、R2'、R3'、R4'、R5'、R6'、R7'、R8'、R9'、R10'、R11'、R12'各自独立地表示氢、卤素、氰基、C1-C6烷基、C2-C6烯基、C2-C6炔基、卤代(C1-C6烷基)、羟基(C1-C6烷基)、C3-C6环烷基、C3-C6环烯基、3～6元杂环烷基、3～6元杂环烯基、-SO3Ra、-NRaRb、-CO(C1-C6烷基)或-C(O)NRaRb；Among them, R1', R2', R3', R4', R5', R6', R7', R8', R9', R10', R11', R12'Each independently represents hydrogen, halogen, cyano, C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, halo(C1-C6Alkyl), hydroxyl (C1-C6Alkyl), C3-C6Cycloalkyl, C3-C6Cycloalkenyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, -SO3Ra, -NRaRb, -CO(C1-C6Alkyl) or -C(O)NRaRb;
或者R1'与R2'一起与与之相连的原子形成C3-C8脂碳环、C3-C8碳烯环、3-8元脂杂环、3-8元碳杂烯环、取代的C3-C8脂碳环、取代的C3-C8碳烯环、取代的3-8元脂杂环或取代的3-8元碳杂烯环；所述的取代是指任意地被1-2个选自卤素、氰基、C1-C6烷基、C2-C6烯基、C2-C6炔基、卤代(C1-C6烷基)、羟基(C1-C6烷基)、C3-C6环烷基、C3-C6环烯基、3～6元杂环烷基、3～6元杂环烯基、-ORa、-SO3Ra、-NRaRb、-C(O)Ra、-C(O)ORa、-C(O)NRaRb、-NRaC(O)Ra的取代基所取代；或者所述环中任意的CH2被C＝O所取代；or R1'with R2'together with the atoms it is attached to form C3-C8Aliphatic ring, C3-C8Carbene ring, 3-8 membered aliphatic ring, 3-8 membered carbene ring, substituted C3-C8Aliphatic ring, substituted C3-C8Carbene ring, substituted 3-8 membered aliphatic heterocyclic ring or substituted 3-8 membered carbene ring; said substitution refers to being randomly selected from 1-2 members selected from halogen, cyano, C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, halo(C1-C6Alkyl), hydroxyl (C1-C6Alkyl), C3-C6Cycloalkyl, C3-C6Cycloalkenyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, -ORa、-SO3Ra, -NRaRb, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, -NRaC(O)RaSubstituents; or any CH in the ring2replaced by C=O;
或者R3'与R4'一起与与之相连的原子形成C3-C8脂碳环、C3-C8碳烯环、3-8元脂杂环、3-8元碳杂烯环、取代的C3-C8脂碳环、取代的C3-C8碳烯环、取代的3-8元脂杂环或取代的3-8元碳杂烯环；所述的取代是指任意地被1-2个选自卤素、氰基、C1-C6烷基、C2-C6烯基、C2-C6炔基、卤代(C1-C6烷基)、羟基(C1-C6烷基)、C3-C6环烷基、C3-C6环烯基、3～6元杂环烷基、3～6元杂环烯基、-ORa、-SO3Ra、-NRaRb、-C(O)Ra、-C(O)ORa、-C(O)NRaRb、-NRaC(O)Ra的取代基所取代；或者所述环中任意的CH2被C＝O所取代；or R3'with R4'together with the atoms it is attached to form C3-C8Aliphatic ring, C3-C8Carbene ring, 3-8 membered aliphatic ring, 3-8 membered carbene ring, substituted C3-C8Aliphatic ring, substituted C3-C8Carbene ring, substituted 3-8 membered aliphatic heterocyclic ring or substituted 3-8 membered carbene ring; said substitution refers to being randomly selected from 1-2 members selected from halogen, cyano, C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, halo(C1-C6Alkyl), hydroxyl (C1-C6Alkyl), C3-C6Cycloalkyl, C3-C6Cycloalkenyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, -ORa、-SO3Ra, -NRaRb, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, -NRaC(O)Rasubstituted by substituents; or any CH in the ring2replaced by C=O;
或者R5'与R6'一起与与之相连的原子形成C3-C8脂碳环、C3-C8碳烯环、3-8元脂杂环、3-8元碳杂 烯环、取代的C3-C8脂碳环、取代的C3-C8碳烯环、取代的3-8元脂杂环或取代的3-8元碳杂烯环；所述的取代是指任意地被1-2个选自卤素、氰基、C1-C6烷基、C2-C6烯基、C2-C6炔基、卤代(C1-C6烷基)、羟基(C1-C6烷基)、C3-C6环烷基、C3-C6环烯基、3～6元杂环烷基、3～6元杂环烯基、-ORa、-SO3Ra、-NRaRb、-C(O)Ra、-C(O)ORa、-C(O)NRaRb、-NRaC(O)Ra的取代基所取代；或者所述环中任意的CH2被C＝O所取代；Or R 5' and R 6' together form C 3 -C 8 aliphatic carbon ring, C 3 -C 8 carbene ring, 3-8 membered aliphatic heterocyclic ring, 3-8 membered carbon heterocycle烯环、取代的C 3 -C 8脂碳环、取代的C 3 -C 8碳烯环、取代的3-8元脂杂环或取代的3-8元碳杂烯环；所述的取代是指任意地被1-2个选自卤素、氰基、C 1 -C 6烷基、C 2 -C 6烯基、C 2 -C 6炔基、卤代(C 1 -C 6烷基)、羟基(C 1 -C 6烷基)、C 3 -C 6环烷基、C 3 -C 6环烯基、3～6元杂环烷基、3～6元杂环烯基、-OR a 、-SO 3 R a 、-NR a R b 、-C(O)R a 、-C(O)OR a 、-C(O)NR a R b 、-NR a C(O)R a的取代基所取代；或者所述环中任意的CH 2被C＝O所取代；
或者R7'与R8'一起与与之相连的原子形成C3-C8脂碳环、C3-C8碳烯环、3-8元脂杂环、3-8元碳杂烯环、取代的C3-C8脂碳环、取代的C3-C8碳烯环、取代的3-8元脂杂环或取代的3-8元碳杂烯环；所述的取代是指任意地被1-2个选自卤素、氰基、C1-C6烷基、C2-C6烯基、C2-C6炔基、卤代(C1-C6烷基)、羟基(C1-C6烷基)、C3-C6环烷基、C3-C6环烯基、3～6元杂环烷基、3～6元杂环烯基、-ORa、-SO3Ra、-NRaRb、-C(O)Ra、-C(O)ORa、-C(O)NRaRb、-NRaC(O)Ra的取代基所取代；或者所述环中任意的CH2被C＝O所取代；or R7'with R8'together with the atoms it is attached to form C3-C8Aliphatic ring, C3-C8Carbene ring, 3-8 membered aliphatic ring, 3-8 membered carbene ring, substituted C3-C8Aliphatic ring, substituted C3-C8Carbene ring, substituted 3-8 membered aliphatic heterocyclic ring or substituted 3-8 membered carbene ring; said substitution refers to being randomly selected from 1-2 members selected from halogen, cyano, C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, halo(C1-C6Alkyl), hydroxyl (C1-C6Alkyl), C3-C6Cycloalkyl, C3-C6Cycloalkenyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, -ORa、-SO3Ra, -NRaRb, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, -NRaC(O)RaSubstituents; or any CH in the ring2replaced by C=O;
或者R9'与R10'一起与与之相连的原子形成C3-C8脂碳环、C3-C8碳烯环、3-8元脂杂环、3-8元碳杂烯环、取代的C3-C8脂碳环、取代的C3-C8碳烯环、取代的3-8元脂杂环或取代的3-8元碳杂烯环；所述的取代是指任意地被1-2个选自卤素、氰基、C1-C6烷基、C2-C6烯基、C2-C6炔基、卤代(C1-C6烷基)、羟基(C1-C6烷基)、C3-C6环烷基、C3-C6环烯基、3～6元杂环烷基、3～6元杂环烯基、-ORa、-SO3Ra、-NRaRb、-C(O)Ra、-C(O)ORa、-C(O)NRaRb、-NRaC(O)Ra的取代基所取代；或者所述环中任意的CH2被C＝O所取代；or R9'with R10'together with the atoms it is attached to form C3-C8Aliphatic ring, C3-C8Carbene ring, 3-8 membered aliphatic ring, 3-8 membered carbene ring, substituted C3-C8Aliphatic ring, substituted C3-C8Carbene ring, substituted 3-8 membered aliphatic heterocyclic ring or substituted 3-8 membered carbene ring; said substitution refers to being randomly selected from 1-2 members selected from halogen, cyano, C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, halo(C1-C6Alkyl), hydroxyl (C1-C6Alkyl), C3-C6Cycloalkyl, C3-C6Cycloalkenyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, -ORa、-SO3Ra, -NRaRb, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, -NRaC(O)RaSubstituents; or any CH in the ring2replaced by C=O;
或者R11'与R12'一起与与之相连的原子形成C3-C8脂碳环、C3-C8碳烯环、3-8元脂杂环、3-8元碳杂烯环、取代的C3-C8脂碳环、取代的C3-C8碳烯环、取代的3-8元脂杂环或取代的3-8元碳杂烯环；所述的取代是指任意地被1-2个选自卤素、氰基、C1-C6烷基、C2-C6烯基、C2-C6炔基、卤代(C1-C6烷基)、羟基(C1-C6烷基)、C3-C6环烷基、C3-C6环烯基、3～6元杂环烷基、3～6元杂环烯基、-ORa、-SO3Ra、-NRaRb、-C(O)Ra、-C(O)ORa、-C(O)NRaRb、-NRaC(O)Ra的取代基所取代；或者所述环中任意的CH2被C＝O所取代；or R11'with R12'together with the atoms it is attached to form C3-C8Aliphatic ring, C3-C8Carbene ring, 3-8 membered aliphatic ring, 3-8 membered carbene ring, substituted C3-C8Aliphatic ring, substituted C3-C8Carbene ring, substituted 3-8 membered aliphatic heterocyclic ring or substituted 3-8 membered carbene ring; said substitution refers to being randomly selected from 1-2 members selected from halogen, cyano, C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, halo(C1-C6Alkyl), hydroxyl (C1-C6Alkyl), C3-C6Cycloalkyl, C3-C6Cycloalkenyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, -ORa、-SO3Ra, -NRaRb, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, -NRaC(O)RaSubstituents; or any CH in the ring2replaced by C=O;
或者R2'、R3'一起与与之相连的原子形成C3-C8脂碳环、C3-C8碳烯环、3-8元脂杂环、3-8元碳杂烯环、取代的C3-C8脂碳环、取代的C3-C8碳烯环、取代的3-8元脂杂环或取代的3-8元碳杂烯环；所述的取代是指任意地被1-2个选自卤素、氰基、C1-C6烷基、C2-C6烯基、C2-C6炔基、卤代(C1-C6烷基)、羟基(C1-C6烷基)、C3-C6环烷基、C3-C6环烯基、3～6元杂环烷基、3～6元杂环烯基、-ORa、-SO3Ra、-NRaRb、-C(O)Ra、-C(O)ORa、-C(O)NRaRb、-NRaC(O)Ra的取代基所取代；或者所述环中任意的CH2被C＝O所取代；or R2', R3'together with the atoms it is attached to form C3-C8Aliphatic ring, C3-C8Carbene ring, 3-8 membered aliphatic ring, 3-8 membered carbene ring, substituted C3-C8Aliphatic ring, substituted C3-C8Carbene ring, substituted 3-8 membered aliphatic heterocyclic ring or substituted 3-8 membered carbene ring; said substitution refers to being randomly selected from 1-2 members selected from halogen, cyano, C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, halo(C1-C6Alkyl), hydroxyl (C1-C6Alkyl), C3-C6Cycloalkyl, C3-C6Cycloalkenyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, -ORa、-SO3Ra, -NRaRb, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, -NRaC(O)RaSubstituents; or any CH in the ring2replaced by C=O;
或者R4'、R5'一起与与之相连的原子形成C3-C8脂碳环、C3-C8碳烯环、3-8元脂杂环、3-8元碳杂烯环、取代的C3-C8脂碳环、取代的C3-C8碳烯环、取代的3-8元脂杂环或取代的3-8元碳杂烯环；所述的取代是指任意地被1-2个选自卤素、氰基、C1-C6烷基、C2-C6烯基、C2-C6炔基、卤代(C1-C6烷基)、羟基(C1-C6烷基)、C3-C6环烷基、C3-C6环烯基、3～6元杂环烷基、3～6元杂环烯基、-ORa、-SO3Ra、-NRaRb、-C(O)Ra、-C(O)ORa、-C(O)NRaRb、-NRaC(O)Ra的取代基所取代；或者所述环中任意的CH2被C＝O所取代；or R4', R5'together with the atoms it is attached to form C3-C8Aliphatic ring, C3-C8Carbene ring, 3-8 membered aliphatic ring, 3-8 membered carbene ring, substituted C3-C8Aliphatic ring, substituted C3-C8Carbene ring, substituted 3-8 membered aliphatic heterocyclic ring or substituted 3-8 membered carbene ring; said substitution refers to being randomly selected from 1-2 members selected from halogen, cyano, C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, halo(C1-C6Alkyl), hydroxyl (C1-C6Alkyl), C3-C6Cycloalkyl, C3-C6Cycloalkenyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, -ORa、-SO3Ra, -NRaRb, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, -NRaC(O)RaSubstituents; or any CH in the ring2replaced by C=O;
或者R8'、R9'一起与与之相连的原子形成C3-C8脂碳环、C3-C8碳烯环、3-8元脂杂环、3-8元碳杂烯环、取代的C3-C8脂碳环、取代的C3-C8碳烯环、取代的3-8元脂杂环或取代的3-8元碳杂烯环；所 述的取代是指任意地被1-2个选自卤素、氰基、C1-C6烷基、C2-C6烯基、C2-C6炔基、卤代(C1-C6烷基)、羟基(C1-C6烷基)、C3-C6环烷基、C3-C6环烯基、3～6元杂环烷基、3～6元杂环烯基、-ORa、-SO3Ra、-NRaRb、-C(O)Ra、-C(O)ORa、-C(O)NRaRb、-NRaC(O)Ra的取代基所取代；或者所述环中任意的CH2被C＝O所取代；Or R 8' and R 9' together with the atoms connected to it form a C 3 -C 8 aliphatic ring, a C 3 -C 8 carbene ring, a 3-8 membered aliphatic heterocycle, a 3-8 membered carbene ring, a substituted C 3 -C 8 aliphatic ring, a substituted C 3 -C 8 carbene ring, a substituted 3-8 membered aliphatic ring or a substituted 3-8 membered carbene ring; The above substitution refers to being randomly 1-2 selected from halogen, cyano, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, halogenated (C 1 -C 6 alkyl), hydroxyl (C 1 -C 6 alkyl), C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkenyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, -OR a , -SO 3 R a , -NR a R b , -C(O)R a , -C(O)OR a , -C(O)NR a R b , -NR a C(O)R a are substituted by substituents; or any CH 2 in the ring is replaced by C=O;
或者R10'、R11'一起与与之相连的原子形成C3-C8脂碳环、C3-C8碳烯环、3-8元脂杂环、3-8元碳杂烯环、取代的C3-C8脂碳环、取代的C3-C8碳烯环、取代的3-8元脂杂环或取代的3-8元碳杂烯环；所述的取代是指任意地被1-2个选自卤素、氰基、C1-C6烷基、C2-C6烯基、C2-C6炔基、卤代(C1-C6烷基)、羟基(C1-C6烷基)、C3-C6环烷基、C3-C6环烯基、3～6元杂环烷基、3～6元杂环烯基、-ORa、-SO3Ra、-NRaRb、-C(O)Ra、-C(O)ORa、-C(O)NRaRb、-NRaC(O)Ra的取代基所取代；或者所述环中任意的CH2被C＝O所取代；or R10', R11'together with the atoms it is attached to form C3-C8Aliphatic ring, C3-C8Carbene ring, 3-8 membered aliphatic ring, 3-8 membered carbene ring, substituted C3-C8Aliphatic ring, substituted C3-C8Carbene ring, substituted 3-8 membered aliphatic heterocyclic ring or substituted 3-8 membered carbene ring; said substitution refers to being randomly selected from 1-2 members selected from halogen, cyano, C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, halo(C1-C6Alkyl), hydroxyl (C1-C6Alkyl), C3-C6Cycloalkyl, C3-C6Cycloalkenyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, -ORa、-SO3Ra, -NRaRb, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, -NRaC(O)Rasubstituted by substituents; or any CH in the ring2replaced by C=O;
或者R3'与R4'一起与与之相连的原子形成C3-C8脂碳环、C3-C8碳烯环、3-8元脂杂环、3-8元碳杂烯环、取代的C3-C8脂碳环、取代的C3-C8碳烯环、取代的3-8元脂杂环或取代的3-8元碳杂烯环；所述的取代是指任意地被1-2个选自卤素、氰基、C1-C6烷基、C2-C6烯基、C2-C6炔基、卤代(C1-C6烷基)、羟基(C1-C6烷基)、C3-C6环烷基、C3-C6环烯基、3～6元杂环烷基、3～6元杂环烯基、-ORa、-SO3Ra、-NRaRb、-C(O)Ra、-C(O)ORa、-C(O)NRaRb、-NRaC(O)Ra的取代基所取代；或者所述环中任意的CH2被C＝O所取代；且R9'与R10'一起与与之相连的原子形成C3-C8脂碳环、C3-C8碳烯环、3-8元脂杂环、3-8元碳杂烯环、取代的C3-C8脂碳环、取代的C3-C8碳烯环、取代的3-8元脂杂环或取代的3-8元碳杂烯环；所述的取代是指任意地被1-2个选自卤素、氰基、C1-C6烷基、C2-C6烯基、C2-C6炔基、卤代(C1-C6烷基)、羟基(C1-C6烷基)、C3-C6环烷基、C3-C6环烯基、3～6元杂环烷基、3～6元杂环烯基、-SO3Ra、-NRaRb、-C(O)Ra、-C(O)ORa、-C(O)NRaRb、-NRaC(O)Ra的取代基所取代；或者所述环中任意的CH2被C＝O所取代；or R3'with R4'together with the atoms it is attached to form C3-C8Aliphatic ring, C3-C8Carbene ring, 3-8 membered aliphatic ring, 3-8 membered carbene ring, substituted C3-C8Aliphatic ring, substituted C3-C8Carbene ring, substituted 3-8 membered aliphatic heterocyclic ring or substituted 3-8 membered carbene ring; said substitution refers to being randomly selected from 1-2 members selected from halogen, cyano, C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, halo(C1-C6Alkyl), hydroxyl (C1-C6Alkyl), C3-C6Cycloalkyl, C3-C6Cycloalkenyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, -ORa、-SO3Ra, -NRaRb, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, -NRaC(O)Rasubstituted by substituents; or any CH in the ring2is replaced by C=O; and R9'with R10'together with the atoms it is attached to form C3-C8Aliphatic ring, C3-C8Carbene ring, 3-8 membered aliphatic ring, 3-8 membered carbene ring, substituted C3-C8Aliphatic ring, substituted C3-C8Carbene ring, substituted 3-8 membered aliphatic heterocyclic ring or substituted 3-8 membered carbene ring; said substitution refers to being randomly selected from 1-2 members selected from halogen, cyano, C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, halo(C1-C6Alkyl), hydroxyl (C1-C6Alkyl), C3-C6Cycloalkyl, C3-C6Cycloalkenyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, -SO3Ra, -NRaRb, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, -NRaC(O)Rasubstituted by substituents; or any CH in the ring2replaced by C=O;
R4为L1-R5，L1表示不存在、CRaRb或NRa；R 4 is L 1 -R 5 , L 1 means absent, CR a R b or NR a ;
R5为以下式(i)、式(ii)或式(iii)的中的任意一种环状结构：
 R is any ring structure in the following formula (i), formula (ii) or formula (iii):
其中，W1表示CRW1RW2或NRW1；Among them, W 1 represents CR W1 R W2 or NR W1 ;
其中，RW1、RW2各自独立地表示氢、卤素、氰基、硝基、C1-C6烷基、C2-C6烯基、C2-C6炔基、卤代(C1-C6烷基)、羟基(C1-C6烷基)、C3-C6环烷基、C3-C6环烯基、3～6元杂环烷基、3～6元杂环烯基、-ORa、-SO3Ra、NRaRb、C(O)Ra、C(O)ORa、C(O)NRaRb、NRaC(O)Ra或(C＝O)-O-C1-C6亚烷基O-(C＝O)-C1-C10烷基；或者RW1、RW2一起与与之相连的原子共同形成3～8元脂杂环；Among them, RW1, RW2Each independently represents hydrogen, halogen, cyano, nitro, C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, halo(C1-C6Alkyl), hydroxyl (C1-C6Alkyl), C3-C6Cycloalkyl, C3-C6Cycloalkenyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, -ORa、-SO3Ra、NRaRb, C(O)Ra, C(O)ORa, C(O)NRaRb、NRaC(O)Raor (C=O)-O-C1-C6Alkylene O-(C=O)-C1-C10Alkyl; or RW1, RW2Together with the atoms connected to it together form a 3-8 membered aliphatic heterocyclic ring;
其中，W2表示CH或N； Wherein, W 2 represents CH or N;
其中，Y为亚甲基、亚乙基、C3亚烷基、C2-C3亚烯基、或 Wherein, Y is methylene, ethylene, C 3 alkylene, C 2 -C 3 alkenylene, or
Rc和Rd与与其相连的原子共同形成C3-C6脂碳环或被一个或多个卤素取代的C3-C6脂碳环；或者Rd和Rd’和与之相连的原子一起形成C3-C6脂碳环或被一个或多个卤素取代的C3-C6脂碳环；R c and R d together with the atoms connected to them form a C 3 -C 6 aliphatic carbocycle or a C 3 -C 6 aliphatic carbocycle substituted by one or more halogens; or R d and R d' together with the atoms connected to them form a C 3 -C 6 aliphatic carbocycle or a C 3 -C 6 aliphatic carbocycle substituted by one or more halogens;
其中，R1”、R2”、R3”、R4”、R5”、R6”、R7”、R8”各自独立地表示氢、卤素、氰基、硝基、C1-C6烷基、C2-C6烯基、C2-C6炔基、卤代(C1-C6烷基)、羟基(C1-C6烷基)、C3-C6环烷基、C3-C6环烯基、3～6元杂环烷基、3～6元杂环烯基、-ORa、-SO3Ra、-NRaRb、-C(O)Ra、-C(O)ORa、-C(O)NRaRb、-NRaC(O)Ra；Among them, R1", R2", R3", R4", R5", R6", R7", R8"Each independently represents hydrogen, halogen, cyano, nitro, C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, halo(C1-C6Alkyl), hydroxyl (C1-C6Alkyl), C3-C6Cycloalkyl, C3-C6Cycloalkenyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, -ORa、-SO3Ra, -NRaRb, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, -NRaC(O)Ra;
或者R1”与R2”一起与与之相连的原子形成C3-C8脂碳环、C3-C8碳烯环、3-8元脂杂环、3-8元碳杂烯环、取代的C3-C8脂碳环、取代的C3-C8碳烯环、取代的3-8元脂杂环或取代的3-8元碳杂烯环；所述的取代是指任意地被1-2个选自卤素、氰基、C1-C6烷基、C2-C6烯基、C2-C6炔基、卤代(C1-C6烷基)、羟基(C1-C6烷基)、C3-C6环烷基、C3-C6环烯基、3～6元杂环烷基、3～6元杂环烯基、-ORa、-SO3Ra、-NRaRb、-C(O)Ra、-C(O)ORa、-C(O)NRaRb、-NRaC(O)Ra的取代基所取代；或者所述环中任意的CH2被C＝O所取代；or R1"with R2"together with the atoms it is attached to form C3-C8Aliphatic ring, C3-C8Carbene ring, 3-8 membered aliphatic ring, 3-8 membered carbene ring, substituted C3-C8Aliphatic ring, substituted C3-C8Carbene ring, substituted 3-8 membered aliphatic heterocyclic ring or substituted 3-8 membered carbene ring; said substitution refers to being randomly selected from 1-2 members selected from halogen, cyano, C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, halo(C1-C6Alkyl), hydroxyl (C1-C6Alkyl), C3-C6Cycloalkyl, C3-C6Cycloalkenyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, -ORa、-SO3Ra, -NRaRb, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, -NRaC(O)RaSubstituents; or any CH in the ring2replaced by C=O;
或者R3”与R4”一起与与之相连的原子形成C3-C8脂碳环、C3-C8碳烯环、3-8元脂杂环、3-8元碳杂烯环、取代的C3-C8脂碳环、取代的C3-C8碳烯环、取代的3-8元脂杂环或取代的3-8元碳杂烯环；所述的取代是指任意地被1-2个选自卤素、氰基、C1-C6烷基、C2-C6烯基、C2-C6炔基、卤代(C1-C6烷基)、羟基(C1-C6烷基)、C3-C6环烷基、C3-C6环烯基、3～6元杂环烷基、3～6元杂环烯基、-ORa、-SO3Ra、-NRaRb、-C(O)Ra、-C(O)ORa、-C(O)NRaRb、-NRaC(O)Ra的取代基所取代；或者所述环中任意的CH2被C＝O所取代；or R3"with R4"together with the atoms it is attached to form C3-C8Aliphatic ring, C3-C8Carbene ring, 3-8 membered aliphatic ring, 3-8 membered carbene ring, substituted C3-C8Aliphatic ring, substituted C3-C8Carbene ring, substituted 3-8 membered aliphatic heterocyclic ring or substituted 3-8 membered carbene ring; said substitution refers to being randomly selected from 1-2 members selected from halogen, cyano, C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, halo(C1-C6Alkyl), hydroxyl (C1-C6Alkyl), C3-C6Cycloalkyl, C3-C6Cycloalkenyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, -ORa、-SO3Ra, -NRaRb, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, -NRaC(O)Rasubstituted by substituents; or any CH in the ring2replaced by C=O;
或者R5”与R6”一起与与之相连的原子形成C3-C8脂碳环、C3-C8碳烯环、3-8元脂杂环、3-8元碳杂烯环、取代的C3-C8脂碳环、取代的C3-C8碳烯环、取代的3-8元脂杂环或取代的3-8元碳杂烯环；所述的取代是指任意地被1-2个选自卤素、氰基、C1-C6烷基、C2-C6烯基、C2-C6炔基、卤代(C1-C6烷基)、羟基(C1-C6烷基)、C3-C6环烷基、C3-C6环烯基、3～6元杂环烷基、3～6元杂环烯基、-ORa、-SO3Ra、-NRaRb、-C(O)Ra、-C(O)ORa、-C(O)NRaRb、-NRaC(O)Ra的取代基所取代；或者所述环中任意的CH2被C＝O所取代；or R5"with R6"together with the atoms it is attached to form C3-C8Aliphatic ring, C3-C8Carbene ring, 3-8 membered aliphatic ring, 3-8 membered carbene ring, substituted C3-C8Aliphatic ring, substituted C3-C8Carbene ring, substituted 3-8 membered aliphatic heterocyclic ring or substituted 3-8 membered carbene ring; said substitution refers to being randomly selected from 1-2 members selected from halogen, cyano, C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, halo(C1-C6Alkyl), hydroxyl (C1-C6Alkyl), C3-C6Cycloalkyl, C3-C6Cycloalkenyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, -ORa、-SO3Ra, -NRaRb, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, -NRaC(O)Rasubstituted by substituents; or any CH in the ring2replaced by C=O;
或者R7”与R8”一起与与之相连的原子形成C3-C8脂碳环、C3-C8碳烯环、3-8元脂杂环、3-8元碳杂烯环、取代的C3-C8脂碳环、取代的C3-C8碳烯环、取代的3-8元脂杂环或取代的3-8元碳杂烯环；所述的取代是指任意地被1-2个选自卤素、氰基、C1-C6烷基、C2-C6烯基、C2-C6炔基、卤代(C1-C6烷基)、羟基(C1-C6烷基)、C3-C6环烷基、C3-C6环烯基、3～6元杂环烷基、3～6元杂环烯基、-ORa、-SO3Ra、-NRaRb、-C(O)Ra、-C(O)ORa、-C(O)NRaRb、-NRaC(O)Ra的取代基所取代；或者所述环中任意的CH2被C＝O所取代；or R7"with R8"together with the atoms it is attached to form C3-C8Aliphatic ring, C3-C8Carbene ring, 3-8 membered aliphatic ring, 3-8 membered carbene ring, substituted C3-C8Aliphatic ring, substituted C3-C8Carbene ring, substituted 3-8 membered aliphatic heterocyclic ring or substituted 3-8 membered carbene ring; said substitution refers to being randomly selected from 1-2 members selected from halogen, cyano, C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, halo(C1-C6Alkyl), hydroxyl (C1-C6Alkyl), C3-C6Cycloalkyl, C3-C6Cycloalkenyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, -ORa、-SO3Ra, -NRaRb, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, -NRaC(O)Rasubstituted by substituents; or any CH in the ring2replaced by C=O;
或者R2”、R3”一起与与之相连的原子形成C3-C8脂碳环、C3-C8碳烯环、3-8元脂杂环、3-8元碳杂烯环、取代的C3-C8脂碳环、取代的C3-C8碳烯环、取代的3-8元脂杂环或取代的3-8元碳杂烯环；所述的取代是指任意地被1-2个选自卤素、氰基、C1-C6烷基、C2-C6烯基、C2-C6炔基、卤代(C1-C6烷基)、羟基(C1-C6烷基)、C3-C6环烷基、C3-C6环烯基、3～6元杂环烷基、3～6元杂环烯基、-ORa、-SO3Ra、-NRaRb、-C(O)Ra、-C(O)ORa、-C(O)NRaRb、-NRaC(O)Ra的取代基所取代；或者所述环中任意的CH2 被C＝O所取代；或者R 2” 、R 3”一起与与之相连的原子形成C 3 -C 8脂碳环、C 3 -C 8碳烯环、3-8元脂杂环、3-8元碳杂烯环、取代的C 3 -C 8脂碳环、取代的C 3 -C 8碳烯环、取代的3-8元脂杂环或取代的3-8元碳杂烯环；所述的取代是指任意地被1-2个选自卤素、氰基、C 1 -C 6烷基、C 2 -C 6烯基、C 2 -C 6炔基、卤代(C 1 -C 6烷基)、羟基(C 1 -C 6烷基)、C 3 -C 6环烷基、C 3 -C 6环烯基、3～6元杂环烷基、3～6元杂环烯基、-OR a 、-SO 3 R a 、-NR a R b 、-C(O)R a 、-C(O)OR a 、-C(O)NR a R b 、-NR a C(O)R a的取代基所取代；或者所述环中任意的CH 2 replaced by C=O;
或者R4”、R5”一起与与之相连的原子形成C3-C8脂碳环、C3-C8碳烯环、3-8元脂杂环、3-8元碳杂烯环、取代的C3-C8脂碳环、取代的C3-C8碳烯环、取代的3-8元脂杂环或取代的3-8元碳杂烯环；所述的取代是指任意地被1-2个选自卤素、氰基、C1-C6烷基、C2-C6烯基、C2-C6炔基、卤代(C1-C6烷基)、羟基(C1-C6烷基)、C3-C6环烷基、C3-C6环烯基、3～6元杂环烷基、3～6元杂环烯基、-ORa、-SO3Ra、-NRaRb、-C(O)Ra、-C(O)ORa、-C(O)NRaRb、-NRaC(O)Ra的取代基所取代；或者所述环中任意的CH2被C＝O所取代；or R4", R5"together with the atoms it is attached to form C3-C8Aliphatic ring, C3-C8Carbene ring, 3-8 membered aliphatic ring, 3-8 membered carbene ring, substituted C3-C8Aliphatic ring, substituted C3-C8Carbene ring, substituted 3-8 membered aliphatic heterocyclic ring or substituted 3-8 membered carbene ring; said substitution refers to being randomly selected from 1-2 members selected from halogen, cyano, C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, halo(C1-C6Alkyl), hydroxyl (C1-C6Alkyl), C3-C6Cycloalkyl, C3-C6Cycloalkenyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, -ORa、-SO3Ra, -NRaRb, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, -NRaC(O)RaSubstituents; or any CH in the ring2replaced by C=O;
或者R6”、R7”一起与与之相连的原子形成C3-C8脂碳环、C3-C8碳烯环、3-8元脂杂环、3-8元碳杂烯环、取代的C3-C8脂碳环、取代的C3-C8碳烯环、取代的3-8元脂杂环或取代的3-8元碳杂烯环；所述的取代是指任意地被1-2个选自卤素、氰基、C1-C6烷基、C2-C6烯基、C2-C6炔基、卤代(C1-C6烷基)、羟基(C1-C6烷基)、C3-C6环烷基、C3-C6环烯基、3～6元杂环烷基、3～6元杂环烯基、-ORa、-SO3Ra、-NRaRb、-C(O)Ra、-C(O)ORa、-C(O)NRaRb、-NRaC(O)Ra的取代基所取代；或者所述环中任意的CH2被C＝O所取代；or R6", R7"together with the atoms it is attached to form C3-C8Aliphatic ring, C3-C8Carbene ring, 3-8 membered aliphatic ring, 3-8 membered carbene ring, substituted C3-C8Aliphatic ring, substituted C3-C8Carbene ring, substituted 3-8 membered aliphatic heterocyclic ring or substituted 3-8 membered carbene ring; said substitution refers to being randomly selected from 1-2 members selected from halogen, cyano, C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, halo(C1-C6Alkyl), hydroxyl (C1-C6Alkyl), C3-C6Cycloalkyl, C3-C6Cycloalkenyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, -ORa、-SO3Ra, -NRaRb, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, -NRaC(O)RaSubstituents; or any CH in the ring2replaced by C=O;
或者R3”与R4”一起与与之相连的原子形成C3-C8脂碳环、C3-C8碳烯环、3-8元脂杂环、3-8元碳杂烯环、取代的C3-C8脂碳环、取代的C3-C8碳烯环、取代的3-8元脂杂环或取代的3-8元碳杂烯环；所述的取代是指任意地被1-2个选自卤素、氰基、C1-C6烷基、C2-C6烯基、C2-C6炔基、卤代(C1-C6烷基)、羟基(C1-C6烷基)、C3-C6环烷基、C3-C6环烯基、3～6元杂环烷基、3～6元杂环烯基、-ORa、-SO3Ra、-NRaRb、-C(O)Ra、-C(O)ORa、-C(O)NRaRb、-NRaC(O)Ra的取代基所取代；或者所述环中任意的CH2被C＝O所取代；且R5”与R6”一起与与之相连的原子形成C3-C8脂碳环、C3-C8碳烯环、3-8元脂杂环、3-8元碳杂烯环、取代的C3-C8脂碳环、取代的C3-C8碳烯环、取代的3-8元脂杂环或取代的3-8元碳杂烯环；所述的取代是指任意地被1-2个选自卤素、氰基、C1-C6烷基、C2-C6烯基、C2-C6炔基、卤代(C1-C6烷基)、羟基(C1-C6烷基)、C3-C6环烷基、C3-C6环烯基、3～6元杂环烷基、3～6元杂环烯基、-ORa、-SO3Ra、-NRaRb、-C(O)Ra、-C(O)ORa、-C(O)NRaRb、-NRaC(O)Ra的取代基所取代；或者所述环中任意的CH2被C＝O所取代；or R3"with R4"together with the atoms it is attached to form C3-C8Aliphatic ring, C3-C8Carbene ring, 3-8 membered aliphatic ring, 3-8 membered carbene ring, substituted C3-C8Aliphatic ring, substituted C3-C8Carbene ring, substituted 3-8 membered aliphatic heterocyclic ring or substituted 3-8 membered carbene ring; said substitution refers to being randomly selected from 1-2 members selected from halogen, cyano, C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, halo(C1-C6Alkyl), hydroxyl (C1-C6Alkyl), C3-C6Cycloalkyl, C3-C6Cycloalkenyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, -ORa、-SO3Ra, -NRaRb, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, -NRaC(O)Rasubstituted by substituents; or any CH in the ring2is replaced by C=O; and R5"with R6"together with the atoms it is attached to form C3-C8Aliphatic ring, C3-C8Carbene ring, 3-8 membered aliphatic ring, 3-8 membered carbene ring, substituted C3-C8Aliphatic ring, substituted C3-C8Carbene ring, substituted 3-8 membered aliphatic heterocyclic ring or substituted 3-8 membered carbene ring; said substitution refers to being randomly selected from 1-2 members selected from halogen, cyano, C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, halo(C1-C6Alkyl), hydroxyl (C1-C6Alkyl), C3-C6Cycloalkyl, C3-C6Cycloalkenyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, -ORa、-SO3Ra, -NRaRb, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, -NRaC(O)Rasubstituted by substituents; or any CH in the ring2replaced by C=O;
其满足下述至少一个条件：It meets at least one of the following conditions:
条件1：R3中，R1'与R2'一起与与之相连的原子形成C3-C8脂碳环、C3-C8碳烯环、3-8元脂杂环、3-8元碳杂烯环、取代的C3-C8脂碳环、取代的C3-C8碳烯环、取代的3-8元脂杂环或取代的3-8元碳杂烯环所述的取代是指任意地被1-2个选自卤素、氰基、C1-C6烷基、C2-C6烯基、C2-C6炔基、卤代(C1-C6烷基)、羟基(C1-C6烷基)、C3-C6环烷基、C3-C6环烯基、3～6元杂环烷基、3～6元杂环烯基、-ORa、-SO3Ra、-NRaRb、-C(O)Ra、-C(O)ORa、-C(O)NRaRb、-NRaC(O)Ra的取代基所取代；或者所述环中任意的CH2被C＝O所取代；Condition 1: R3in, R1'with R2'together with the atoms it is attached to form C3-C8Aliphatic ring, C3-C8Carbene ring, 3-8 membered aliphatic ring, 3-8 membered carbene ring, substituted C3-C8Aliphatic ring, substituted C3-C8The substitution of carbene ring, substituted 3-8 membered aliphatic heterocyclic ring or substituted 3-8 membered carbene ring refers to being randomly selected from 1-2 members selected from halogen, cyano, C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, halo(C1-C6Alkyl), hydroxyl (C1-C6Alkyl), C3-C6Cycloalkyl, C3-C6Cycloalkenyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, -ORa、-SO3Ra, -NRaRb, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, -NRaC(O)RaSubstituents; or any CH in the ring2replaced by C=O;
或者R3'与R4'一起与与之相连的原子形成C3-C8脂碳环、C3-C8碳烯环、3-8元脂杂环、3-8元碳杂烯环、取代的C3-C8脂碳环、取代的C3-C8碳烯环、取代的3-8元脂杂环或取代的3-8元碳杂烯环；所述的取代是指任意地被1-2个选自卤素、氰基、C1-C6烷基、C2-C6烯基、C2-C6炔基、卤代(C1-C6烷基)、羟基(C1-C6烷基)、C3-C6环烷基、C3-C6环烯基、3～6元杂环烷基、3～6元杂环烯基、-ORa、-SO3Ra、-NRaRb、-C(O)Ra、-C(O)ORa、-C(O)NRaRb、-NRaC(O)Ra的取代基所取代；或者所述环中任意的CH2被C＝O所取代； or R3'with R4'together with the atoms it is attached to form C3-C8Aliphatic ring, C3-C8Carbene ring, 3-8 membered aliphatic ring, 3-8 membered carbene ring, substituted C3-C8Aliphatic ring, substituted C3-C8Carbene ring, substituted 3-8 membered aliphatic heterocyclic ring or substituted 3-8 membered carbene ring; said substitution refers to being randomly selected from 1-2 members selected from halogen, cyano, C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, halo(C1-C6Alkyl), hydroxyl (C1-C6Alkyl), C3-C6Cycloalkyl, C3-C6Cycloalkenyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, -ORa、-SO3Ra, -NRaRb, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, -NRaC(O)RaSubstituents; or any CH in the ring2replaced by C=O;
或者R5'与R6'一起与与之相连的原子形成C3-C8脂碳环、C3-C8碳烯环、3-8元脂杂环、3-8元碳杂烯环、取代的C3-C8脂碳环、取代的C3-C8碳烯环、取代的3-8元脂杂环或取代的3-8元碳杂烯环；所述的取代是指任意地被1-2个选自卤素、氰基、C1-C6烷基、C2-C6烯基、C2-C6炔基、卤代(C1-C6烷基)、羟基(C1-C6烷基)、C3-C6环烷基、C3-C6环烯基、3～6元杂环烷基、3～6元杂环烯基、-ORa、-SO3Ra、-NRaRb、-C(O)Ra、-C(O)ORa、-C(O)NRaRb、-NRaC(O)Ra的取代基所取代；或者所述环中任意的CH2被C＝O所取代；or R5'with R6'together with the atoms it is attached to form C3-C8Aliphatic ring, C3-C8Carbene ring, 3-8 membered aliphatic ring, 3-8 membered carbene ring, substituted C3-C8Aliphatic ring, substituted C3-C8Carbene ring, substituted 3-8 membered aliphatic heterocyclic ring or substituted 3-8 membered carbene ring; said substitution refers to being randomly selected from 1-2 members selected from halogen, cyano, C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, halo(C1-C6Alkyl), hydroxyl (C1-C6Alkyl), C3-C6Cycloalkyl, C3-C6Cycloalkenyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, -ORa、-SO3Ra, -NRaRb, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, -NRaC(O)RaSubstituents; or any CH in the ring2replaced by C=O;
或者R7'与R8'一起与与之相连的原子形成C3-C8脂碳环、C3-C8碳烯环、3-8元脂杂环、3-8元碳杂烯环、取代的C3-C8脂碳环、取代的C3-C8碳烯环、取代的3-8元脂杂环或取代的3-8元碳杂烯环；所述的取代是指任意地被1-2个选自卤素、氰基、C1-C6烷基、C2-C6烯基、C2-C6炔基、卤代(C1-C6烷基)、羟基(C1-C6烷基)、C3-C6环烷基、C3-C6环烯基、3～6元杂环烷基、3～6元杂环烯基、-ORa、-SO3Ra、-NRaRb、-C(O)Ra、-C(O)ORa、-C(O)NRaRb、-NRaC(O)Ra的取代基所取代；或者所述环中任意的CH2被C＝O所取代；or R7'with R8'together with the atoms it is attached to form C3-C8Aliphatic ring, C3-C8Carbene ring, 3-8 membered aliphatic ring, 3-8 membered carbene ring, substituted C3-C8Aliphatic ring, substituted C3-C8Carbene ring, substituted 3-8 membered aliphatic heterocyclic ring or substituted 3-8 membered carbene ring; said substitution refers to being randomly selected from 1-2 members selected from halogen, cyano, C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, halo(C1-C6Alkyl), hydroxyl (C1-C6Alkyl), C3-C6Cycloalkyl, C3-C6Cycloalkenyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, -ORa、-SO3Ra, -NRaRb, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, -NRaC(O)Rasubstituted by substituents; or any CH in the ring2replaced by C=O;
或者R9'与R10'一起与与之相连的原子形成C3-C8脂碳环、C3-C8碳烯环、3-8元脂杂环、3-8元碳杂烯环、取代的C3-C8脂碳环、取代的C3-C8碳烯环、取代的3-8元脂杂环或取代的3-8元碳杂烯环；所述的取代是指任意地被1-2个选自卤素、氰基、C1-C6烷基、C2-C6烯基、C2-C6炔基、卤代(C1-C6烷基)、羟基(C1-C6烷基)、C3-C6环烷基、C3-C6环烯基、3～6元杂环烷基、3～6元杂环烯基、-ORa、-SO3Ra、-NRaRb、-C(O)Ra、-C(O)ORa、-C(O)NRaRb、-NRaC(O)Ra的取代基所取代；或者所述环中任意的CH2被C＝O所取代；or R9'with R10'together with the atoms it is attached to form C3-C8Aliphatic ring, C3-C8Carbene ring, 3-8 membered aliphatic ring, 3-8 membered carbene ring, substituted C3-C8Aliphatic ring, substituted C3-C8Carbene ring, substituted 3-8 membered aliphatic heterocyclic ring or substituted 3-8 membered carbene ring; said substitution refers to being randomly selected from 1-2 members selected from halogen, cyano, C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, halo(C1-C6Alkyl), hydroxyl (C1-C6Alkyl), C3-C6Cycloalkyl, C3-C6Cycloalkenyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, -ORa、-SO3Ra, -NRaRb, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, -NRaC(O)RaSubstituents; or any CH in the ring2replaced by C=O;
或者R11'与R12'一起与与之相连的原子形成C3-C8脂碳环、C3-C8碳烯环、3-8元脂杂环、3-8元碳杂烯环、取代的C3-C8脂碳环、取代的C3-C8碳烯环、取代的3-8元脂杂环或取代的3-8元碳杂烯环；所述的取代是指任意地被1-2个选自卤素、氰基、C1-C6烷基、C2-C6烯基、C2-C6炔基、卤代(C1-C6烷基)、羟基(C1-C6烷基)、C3-C6环烷基、C3-C6环烯基、3～6元杂环烷基、3～6元杂环烯基、-ORa、-SO3Ra、-NRaRb、-C(O)Ra、-C(O)ORa、-C(O)NRaRb、-NRaC(O)Ra的取代基所取代；或者所述环中任意的CH2被C＝O所取代；or R11'with R12'together with the atoms it is attached to form C3-C8Aliphatic ring, C3-C8Carbene ring, 3-8 membered aliphatic ring, 3-8 membered carbene ring, substituted C3-C8Aliphatic ring, substituted C3-C8Carbene ring, substituted 3-8 membered aliphatic heterocyclic ring or substituted 3-8 membered carbene ring; said substitution refers to being randomly selected from 1-2 members selected from halogen, cyano, C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, halo(C1-C6Alkyl), hydroxyl (C1-C6Alkyl), C3-C6Cycloalkyl, C3-C6Cycloalkenyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, -ORa、-SO3Ra, -NRaRb, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, -NRaC(O)RaSubstituents; or any CH in the ring2replaced by C=O;
或者R2'、R3'一起与与之相连的原子形成C3-C8脂碳环、C3-C8碳烯环、3-8元脂杂环、3-8元碳杂烯环、取代的C3-C8脂碳环、取代的C3-C8碳烯环、取代的3-8元脂杂环或取代的3-8元碳杂烯环；所述的取代是指任意地被1-2个选自卤素、氰基、C1-C6烷基、C2-C6烯基、C2-C6炔基、卤代(C1-C6烷基)、羟基(C1-C6烷基)、C3-C6环烷基、C3-C6环烯基、3～6元杂环烷基、3～6元杂环烯基、-ORa、-SO3Ra、-NRaRb、-C(O)Ra、-C(O)ORa、-C(O)NRaRb、-NRaC(O)Ra的取代基所取代；或者所述环中任意的CH2被C＝O所取代；or R2', R3'together with the atoms it is attached to form C3-C8Aliphatic ring, C3-C8Carbene ring, 3-8 membered aliphatic ring, 3-8 membered carbene ring, substituted C3-C8Aliphatic ring, substituted C3-C8Carbene ring, substituted 3-8 membered aliphatic heterocyclic ring or substituted 3-8 membered carbene ring; said substitution refers to being randomly selected from 1-2 members selected from halogen, cyano, C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, halo(C1-C6Alkyl), hydroxyl (C1-C6Alkyl), C3-C6Cycloalkyl, C3-C6Cycloalkenyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, -ORa、-SO3Ra, -NRaRb, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, -NRaC(O)Rasubstituted by substituents; or any CH in the ring2replaced by C=O;
或者R4'、R5'一起与与之相连的原子形成C3-C8脂碳环、C3-C8碳烯环、3-8元脂杂环、3-8元碳杂烯环、取代的C3-C8脂碳环、取代的C3-C8碳烯环、取代的3-8元脂杂环或取代的3-8元碳杂烯环；所述的取代是指任意地被1-2个选自卤素、氰基、C1-C6烷基、C2-C6烯基、C2-C6炔基、卤代(C1-C6烷基)、羟基(C1-C6烷基)、C3-C6环烷基、C3-C6环烯基、3～6元杂环烷基、3～6元杂环烯基、-ORa、-SO3Ra、-NRaRb、-C(O)Ra、-C(O)ORa、-C(O)NRaRb、-NRaC(O)Ra的取代基所取代；或者所述环中任意的CH2被C＝O所取代；or R4', R5'together with the atoms it is attached to form C3-C8Aliphatic ring, C3-C8Carbene ring, 3-8 membered aliphatic ring, 3-8 membered carbene ring, substituted C3-C8Aliphatic ring, substituted C3-C8Carbene ring, substituted 3-8 membered aliphatic heterocyclic ring or substituted 3-8 membered carbene ring; said substitution refers to being randomly selected from 1-2 members selected from halogen, cyano, C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, halo(C1-C6Alkyl), hydroxyl (C1-C6Alkyl), C3-C6Cycloalkyl, C3-C6Cycloalkenyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, -ORa、-SO3Ra, -NRaRb, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, -NRaC(O)RaSubstituents; or any CH in the ring2replaced by C=O;
或者R8'、R9'一起与与之相连的原子形成C3-C8脂碳环、C3-C8碳烯环、3-8元脂杂环、3-8元碳杂 烯环、取代的C3-C8脂碳环、取代的C3-C8碳烯环、取代的3-8元脂杂环或取代的3-8元碳杂烯环；所述的取代是指任意地被1-2个选自卤素、氰基、C1-C6烷基、C2-C6烯基、C2-C6炔基、卤代(C1-C6烷基)、羟基(C1-C6烷基)、C3-C6环烷基、C3-C6环烯基、3～6元杂环烷基、3～6元杂环烯基、-ORa、-SO3Ra、-NRaRb、-C(O)Ra、-C(O)ORa、-C(O)NRaRb、-NRaC(O)Ra的取代基所取代；或者所述环中任意的CH2被C＝O所取代；Or R 8' and R 9' together with the atoms connected to it form a C 3 -C 8 aliphatic carbocyclic ring, a C 3 -C 8 carbene ring, a 3-8 membered aliphatic ring, a 3-8 membered carbocyclic烯环、取代的C 3 -C 8脂碳环、取代的C 3 -C 8碳烯环、取代的3-8元脂杂环或取代的3-8元碳杂烯环；所述的取代是指任意地被1-2个选自卤素、氰基、C 1 -C 6烷基、C 2 -C 6烯基、C 2 -C 6炔基、卤代(C 1 -C 6烷基)、羟基(C 1 -C 6烷基)、C 3 -C 6环烷基、C 3 -C 6环烯基、3～6元杂环烷基、3～6元杂环烯基、-OR a 、-SO 3 R a 、-NR a R b 、-C(O)R a 、-C(O)OR a 、-C(O)NR a R b 、-NR a C(O)R a的取代基所取代；或者所述环中任意的CH 2被C＝O所取代；
或者R10'、R11'一起与与之相连的原子形成C3-C8脂碳环、C3-C8碳烯环、3-8元脂杂环、3-8元碳杂烯环、取代的C3-C8脂碳环、取代的C3-C8碳烯环、取代的3-8元脂杂环或取代的3-8元碳杂烯环；所述的取代是指任意地被1-2个选自卤素、氰基、C1-C6烷基、C2-C6烯基、C2-C6炔基、卤代(C1-C6烷基)、羟基(C1-C6烷基)、C3-C6环烷基、C3-C6环烯基、3～6元杂环烷基、3～6元杂环烯基、-ORa、-SO3Ra、-NRaRb、-C(O)Ra、-C(O)ORa、-C(O)NRaRb、-NRaC(O)Ra的取代基所取代；或者所述环中任意的CH2被C＝O所取代；or R10', R11'together with the atoms it is attached to form C3-C8Aliphatic ring, C3-C8Carbene ring, 3-8 membered aliphatic ring, 3-8 membered carbene ring, substituted C3-C8Aliphatic ring, substituted C3-C8Carbene ring, substituted 3-8 membered aliphatic heterocyclic ring or substituted 3-8 membered carbene ring; said substitution refers to being randomly selected from 1-2 members selected from halogen, cyano, C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, halo(C1-C6Alkyl), hydroxyl (C1-C6Alkyl), C3-C6Cycloalkyl, C3-C6Cycloalkenyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, -ORa、-SO3Ra, -NRaRb, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, -NRaC(O)RaSubstituents; or any CH in the ring2replaced by C=O;
或者R3'与R4'一起与与之相连的原子形成C3-C8脂碳环、C3-C8碳烯环、3-8元脂杂环、3-8元碳杂烯环、取代的C3-C8脂碳环、取代的C3-C8碳烯环、取代的3-8元脂杂环或取代的3-8元碳杂烯环；所述的取代是指任意地被1-2个选自卤素、氰基、C1-C6烷基、C2-C6烯基、C2-C6炔基、卤代(C1-C6烷基)、羟基(C1-C6烷基)、C3-C6环烷基、C3-C6环烯基、3～6元杂环烷基、3～6元杂环烯基、-ORa、-SO3Ra、-NRaRb、-C(O)Ra、-C(O)ORa、-C(O)NRaRb、-NRaC(O)Ra的取代基所取代；或者所述环中任意的CH2被C＝O所取代；且R9'与R10'一起与与之相连的原子形成C3-C8脂碳环、C3-C8碳烯环、3-8元脂杂环、3-8元碳杂烯环、取代的C3-C8脂碳环、取代的C3-C8碳烯环、取代的3-8元脂杂环或取代的3-8元碳杂烯环；所述的取代是指任意地被1-2个选自卤素、氰基、C1-C6烷基、C2-C6烯基、C2-C6炔基、卤代(C1-C6烷基)、羟基(C1-C6烷基)、C3-C6环烷基、C3-C6环烯基、3～6元杂环烷基、3～6元杂环烯基、-ORa、-SO3Ra、-NRaRb、-C(O)Ra、-C(O)ORa、-C(O)NRaRb、-NRaC(O)Ra的取代基所取代；或者所述环中任意的CH2被C＝O所取代；or R3'with R4'together with the atoms it is attached to form C3-C8Aliphatic ring, C3-C8Carbene ring, 3-8 membered aliphatic ring, 3-8 membered carbene ring, substituted C3-C8Aliphatic ring, substituted C3-C8Carbene ring, substituted 3-8 membered aliphatic heterocyclic ring or substituted 3-8 membered carbene ring; said substitution refers to being randomly selected from 1-2 members selected from halogen, cyano, C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, halo(C1-C6Alkyl), hydroxyl (C1-C6Alkyl), C3-C6Cycloalkyl, C3-C6Cycloalkenyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, -ORa、-SO3Ra, -NRaRb, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, -NRaC(O)Rasubstituted by substituents; or any CH in the ring2is replaced by C=O; and R9'with R10'together with the atoms it is attached to form C3-C8Aliphatic ring, C3-C8Carbene ring, 3-8 membered aliphatic ring, 3-8 membered carbene ring, substituted C3-C8Aliphatic ring, substituted C3-C8Carbene ring, substituted 3-8 membered aliphatic heterocyclic ring or substituted 3-8 membered carbene ring; said substitution refers to being randomly selected from 1-2 members selected from halogen, cyano, C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, halo(C1-C6Alkyl), hydroxyl (C1-C6Alkyl), C3-C6Cycloalkyl, C3-C6Cycloalkenyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, -ORa、-SO3Ra, -NRaRb, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, -NRaC(O)Rasubstituted by substituents; or any CH in the ring2replaced by C=O;
条件2：R5为以下式(i)、式(ii)或式(iii)的中的任意一种环状结构：
Condition 2: R 5 is any ring structure in the following formula (i), formula (ii) or formula (iii):
其中，式(ii)中，W2为N，W1为NRW1时，RW1不为H；Wherein, in formula (ii), W 2 is N, and when W 1 is NR W1 , R W1 is not H;
式(iii)中，W2为N，W1为NRW1，RW1为H时，Y不为亚乙基；In formula (iii), W 2 is N, W 1 is NR W1 , and when R W1 is H, Y is not ethylene;
条件3：X1为CRX1，RX1为C1-C6烷基、被一个或多个卤素取代的C1-C6烷基、PO(C1-C6烷基)2、C2-C6烯基、C2-C6炔基、被一个或多个X1-1取代的3～6元杂环烷基、6-14元芳基、5～14元杂芳基、被一个或多个X1-2取代的5～14元杂芳基、NO2、C3-C6环烷基、C3-C6环烯基、3～6元杂环烷基、3～6元杂环烯基、被一个或多个X1-3取代的3～6元杂环烯基、SF5、C(＝O)X1-4、C(＝O)ORa、-NRaC(O)Ra、NX1-5X1-6或SO2X1-7；或者，RX1与RX3和其相连的原子共同形成C5-C8环烯酮结构；Condition 3: X1for CRX1, RX1for C1-C6Alkyl, C substituted by one or more halogens1-C6Alkyl, PO(C1-C6alkyl)2、C2-C6Alkenyl, C2-C6Alkynyl, by one or more X1-1Substituted 3-6 membered heterocycloalkyl, 6-14-membered aryl, 5-14-membered heteroaryl, replaced by one or more X1-2Substituted 5-14 membered heteroaryl, NO2、C3-C6Cycloalkyl, C3-C6Cycloalkenyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, with one or more X1-3Substituted 3-6 membered heterocycloalkenyl, SF5, C(=O)X1-4, C(=O)ORa, -NRaC(O)Ra、NX1-5x1-6or SO2x1-7; or, RX1with RX3Together with its attached atoms form C5-C8Cycloenone structure;
或者，X1为NRX1’，RX1’与RX3和其相连的原子共同形成5～8元杂芳环或被一个或多个羟基取代 的5～8元杂芳环；Alternatively, X 1 is NR X1' , and R X1' and R X3 together with the atoms connected to them form a 5- to 8-membered heteroaromatic ring or are substituted by one or more hydroxyl groups 5-8 membered heteroaromatic rings;
或者，X1为CRX1，其中，X1中的C原子与R1中的芳基或杂芳基中的C原子通过-O-(CH2)n1-*、*-NH-(CH2)n2-、-C≡C-(CH2)n3-C≡C-*或-(CH2)n4-O-(CH2)n5-*相连，其中，*端与X1中的C原子相连；Alternatively, X 1 is CR X1 , wherein the C atom in X 1 is connected to the C atom in the aryl or heteroaryl group in R 1 through -O-(CH 2 ) n1 - * , * -NH-(CH 2 ) n2 -, -C≡C-(CH 2 ) n3 -C≡C- * or -(CH 2 ) n4 -O-(CH 2 ) n5 - * , wherein the * terminal is connected to C in X 1 Atoms connected;
条件4：R1为被一个或多个R1-1取代的C6～C14的芳基或被一个或多个R1-2取代的5～14元杂芳基；Condition 4: R 1 is a C 6 -C 14 aryl group substituted by one or more R 1-1 or a 5-14 membered heteroaryl group substituted by one or more R 1-2 ;
当R1为被一个或多个R1-1取代的C6～C14的芳基时，相邻的两个R1-1与其相连的原子一起形成C3-C8脂碳环或被一个或多个R1-3取代的C3-C8脂碳环，其余R1-1独立地为卤素、OH、CN、NO2、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C6环烷基、C3-C6环烯基、3～6元杂环烷基、3～6元杂环烯基、被一个或多个卤素取代的C1-C6烷基、被一个或多个羟基取代的C1-C6烷基、ORa、B(OH)2、O(C＝O)-C1-C10烷基、SO3Ra、NRaRb、CORa、CONRaRb、C(O)ORa、NRaCORa；When R1for one or more R1-1Replaced C6~C14When the aryl group, two adjacent R1-1Together with its attached atoms form C3-C8Aliphatic carbocycle or by one or more R1-3Replaced C3-C8Aliphatic carbocycle, the rest R1-1independently halogen, OH, CN, NO2、C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, C3-C6Cycloalkyl, C3-C6Cycloalkenyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, C substituted by one or more halogens1-C6Alkyl, C substituted by one or more hydroxyl groups1-C6Alkyl, ORa, B(OH)2, O(C=O)-C1-C10Alkyl, SO3Ra、NRaRb、CORa、CONRaRb, C(O)ORa、NRaCORa;
当R1为被一个或多个R1-2取代的5～14元杂芳基时，相邻的两个R1-2与其相连的原子一起形成C3-C8碳环或被一个或多个R1-4取代的C3-C8碳环，其余R1-2独立地为卤素、OH、CN、NO2、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C6环烷基、C3-C6环烯基、3～6元杂环烷基、3～6元杂环烯基、被一个或多个卤素取代的C1-C6烷基、被一个或多个羟基取代的C1-C6烷基、ORa、B(OH)2、O(C＝O)-C1-C10烷基、SO3Ra、NRaRb、CORa、CONRaRb、C(O)ORa、NRaCORa；When R1for one or more R1-2When a substituted 5- to 14-membered heteroaryl group, two adjacent R1-2Together with its attached atoms form C3-C8Carbocycle or by one or more R1-4Replaced C3-C8carbocycle, rest R1-2independently halogen, OH, CN, NO2、C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, C3-C6Cycloalkyl, C3-C6Cycloalkenyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, C substituted by one or more halogens1-C6Alkyl, C substituted by one or more hydroxyl groups1-C6Alkyl, ORa, B(OH)2, O(C=O)-C1-C10Alkyl, SO3Ra、NRaRb、CORa、CONRaRb, C(O)ORa、NRaCORa;
R1-3和R1-4独立地为卤素；R 1-3 and R 1-4 are independently halogen;
其中，所述的3～6元杂环烷基、3～6元杂环烯基、5～14元杂芳基、3～8元杂环烷基、3～6元脂杂环、3～6元碳杂烯环、5～8元杂芳环、3～8元脂杂环、3-8元碳杂烯环、3-8元脂杂环和3-8元碳杂烯环中的杂原子的种类各自独立地选自N、O和S中的一种、两种或三种；所述的3～6元杂环烷基、3～6元杂环烯基、3～8元杂环烷基、3～6元脂杂环、3～6元碳杂烯环、3～8元脂杂环、3-8元碳杂烯环、3-8元脂杂环和3-8元碳杂烯环中的杂原子的个数各自独立地为1个、2个或3个；所述5～14元杂芳基和5～8元杂芳环中杂原子的个数各自独立地为1个、2个、3个或4个。Wherein, the types of heteroatoms in the 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, 5-14-membered heteroaryl, 3-8-membered heterocycloalkyl, 3-6-membered aliphatic heterocycle, 3-6-membered carboalkene ring, 5-8-membered heteroaryl ring, 3-8-membered aliphatic heterocycle, 3-8-membered carbazaene ring, 3-8-membered aliphatic heterocycle and 3-8-membered carbazaene ring are each independently selected from one, two or three of N, O and S; The number of heteroatoms in ~6-membered heterocycloalkyl, 3-6-membered heterocycloalkenyl, 3-8-membered heterocycloalkyl, 3-6-membered aliphatic heterocycle, 3-6-membered carboalkene ring, 3-8-membered aliphatic heterocycle, 3-8-membered carboalkene ring, 3-8-membered aliphatic heterocycle, and 3-8-membered carboalkene ring is independently 1, 2 or 3; the number of heteroatoms in the 5-14-membered heteroaryl and 5-8-membered heteroaryl ring is each independently 1 , 2, 3 or 4.
某一实施方案中，X1为N、NRX1’或CRX1。In a certain embodiment, X 1 is N, NR X1′ or CR X1 .
某一实施方案中，RX1为CN、卤素、C1-C6烷基、被一个或多个卤素取代的C1-C6烷基、PO(C1-C6烷基)2、C3-C6环烷基、C2-C6烯基、C2-C6炔基、3～6元杂环烷基、被一个或多个X1-1取代的3～6元杂环烷基、5～14元杂芳基、被一个或多个X1-2取代的5～14元杂芳基、NO2、3～6元杂环烯基、被一个或多个X1-3取代的3～6元杂环烯基、SF5、C(＝O)X1-4、NX1-5X1-6或SO2X1-7。In one embodiment, RX1is CN, halogen, C1-C6Alkyl, C substituted by one or more halogens1-C6Alkyl, PO(C1-C6alkyl)2、C3-C6Cycloalkyl, C2-C6Alkenyl, C2-C6Alkynyl, 3-6 membered heterocycloalkyl, replaced by one or more X1-1Substituted 3-6 membered heterocycloalkyl, 5-14 membered heteroaryl, replaced by one or more X1-2Substituted 5-14 membered heteroaryl, NO2, 3-6 membered heterocycloalkenyl, replaced by one or more X1-3Substituted 3-6 membered heterocycloalkenyl, SF5, C(=O)X1-4、NX1-5x1-6or SO2x1-7.
某一实施方案中，X1-1和X1-3各自独立地为(C＝O)-C1-C6烷基。In a certain embodiment, X 1-1 and X 1-3 are each independently (C=O)-C 1 -C 6 alkyl.
某一实施方案中，X1-2独立地为C1-C6烷基。In a certain embodiment, X 1-2 is independently C 1 -C 6 alkyl.
某一实施方案中，X1-4独立地为H、C3-C8环烷基、3～8元杂环烷基、C1-C6烷基、或被一个或多个卤素取代的C1-C6烷基；X1-5和X1-6各自独立地为H、C1-C6烷基、SO2-C1-C6烷基或(C＝O)-C1-C6烷基。In a certain embodiment, X 1-4 is independently H, C 3 -C 8 cycloalkyl, 3-8 membered heterocycloalkyl, C 1 -C 6 alkyl, or C 1 -C 6 alkyl substituted by one or more halogens; X 1-5 and X 1-6 are each independently H, C 1 -C 6 alkyl, SO 2 -C 1 -C 6 alkyl or (C=O)-C 1 -C 6 alkyl.
某一实施方案中，X1-5和X1-6各自独立地为H、C1-C6烷基、SO2-C1-C6烷基或(C＝O)-C1-C6烷基。In a certain embodiment, X 1-5 and X 1-6 are each independently H, C 1 -C 6 alkyl, SO 2 -C 1 -C 6 alkyl or (C=O)-C 1 -C 6 alkyl.
某一实施方案中，X1-7为OH或C1-C6烷基。In a certain embodiment, X 1-7 is OH or C 1 -C 6 alkyl.
某一实施方案中，X2为N或CRX2，RX2为CN。In a certain embodiment, X 2 is N or CR X2 , and R X2 is CN.
某一实施方案中，X3为N或CRX3，RX3为H或C1-C6烷基。In a certain embodiment, X 3 is N or CR X3 , and R X3 is H or C 1 -C 6 alkyl.
某一实施方案中，R1-1和R1-2各自独立地为卤素、OH、NH2、CN、C1-C6烷基、(C＝O)C1-C6烷基、C2-C6炔基、被一个或多个卤素取代的C1-C6烷基、B(OH)2或O(C＝O)-C1-C10烷基。 In a certain embodiment, each of R 1-1 and R 1-2 is independently halogen, OH, NH 2 , CN, C 1 -C 6 alkyl, (C=O)C 1 -C 6 alkyl, C 2 -C 6 alkynyl, C 1 -C 6 alkyl substituted by one or more halogens, B(OH) 2 or O(C=O)-C 1 -C 10 alkyl.
某一实施方案中，相邻的两个R1-1与其相连的原子一起形成C3-C8脂碳环或被一个或多个R1-3取代的C3-C8脂碳环，其余R1-1独立地为卤素、OH、NH2、CN、C1-C6烷基、(C＝O)-C1-C6烷基、C2-C6炔基、被一个或多个卤素取代的C1-C6烷基、B(OH)2或O(C＝O)-C1-C10烷基。In a certain embodiment, two adjacent R 1-1 and their connected atoms together form a C 3 -C 8 aliphatic carbon ring or a C 3 -C 8 aliphatic carbon ring substituted by one or more R 1-3 , and the remaining R 1-1 are independently halogen, OH, NH 2 , CN, C 1 -C 6 alkyl, (C=O)-C 1 -C 6 alkyl, C 2 -C 6 alkynyl, C 1 -C substituted by one or more halogens 6 alkyl, B(OH) 2 or O(C=O)-C 1 -C 10 alkyl.
某一实施方案中，相邻的两个R1-2与其相连的原子一起形成C3-C8脂碳环或被一个或多个R1-4取代的C3-C8脂碳环，其余R1-2独立地为卤素、OH、NH2、CN、C1-C6烷基、(C＝O)-C1-C6烷基、C2-C6炔基、被一个或多个卤素取代的C1-C6烷基、B(OH)2或O(C＝O)-C1-C10烷基。In a certain embodiment, two adjacent R 1-2 and their connected atoms together form a C 3 -C 8 aliphatic carbon ring or a C 3 -C 8 aliphatic carbon ring substituted by one or more R 1-4 , and the remaining R 1-2 are independently halogen, OH, NH 2 , CN, C 1 -C 6 alkyl, (C=O)-C 1 -C 6 alkyl, C 2 -C 6 alkynyl, C 1 -C substituted by one or more halogens 6 alkyl, B(OH) 2 or O(C=O)-C 1 -C 10 alkyl.
某一实施方案中，R2为卤素、C1-C6烷基或C1-C6烷氧基。In a certain embodiment, R 2 is halogen, C 1 -C 6 alkyl or C 1 -C 6 alkoxy.
某一实施方案中，L2表示-O-(C1-C6亚烷基)。In a certain embodiment, L 2 represents -O-(C 1 -C 6 alkylene).
某一实施方案中，R3为以下的环状结构：
In a certain embodiment, R3 is the following ring structure:
其中，R1'、R2'、R3'、R4'、R5'、R6'、R7'、R8'、R9'、R10'、R11'、R12'各自独立地表示氢或卤素；Wherein, R 1' , R 2' , R 3' , R 4' , R 5' , R 6' , R 7' , R 8' , R 9' , R 10' , R 11' , R 12' each independently represent hydrogen or halogen;
或者R3'与R4'一起与与之相连的原子形成C3-C8脂碳环、取代的C3-C8脂碳环或3-8元脂杂环，所述的取代是指任意地被1-2个卤素取代；Or R 3' and R 4' together form a C 3 -C 8 aliphatic carbocyclic ring, a substituted C 3 -C 8 aliphatic carbocyclic ring or a 3-8 membered aliphatic heterocyclic ring, and the substitution refers to being optionally substituted by 1-2 halogens;
或者R9'与R10'一起与与之相连的原子形成C3-C8脂碳环、取代的C3-C8脂碳环或3-8元脂杂环，所述的取代是指任意地被1-2个卤素取代；Or R 9' and R 10' together form a C 3 -C 8 aliphatic carbocyclic ring, a substituted C 3 -C 8 aliphatic carbocyclic ring or a 3-8 membered aliphatic heterocyclic ring, and the substitution refers to being optionally substituted by 1-2 halogens;
或者R3'与R4'一起与与之相连的原子形成C3-C8脂碳环、取代的C3-C8脂碳环或3-8元脂杂环，所述的取代是指任意地被1-2个卤素取代；且R9'与R10'一起与与之相连的原子形成C3-C8脂碳环、取代的C3-C8脂碳环或3-8元脂杂环，所述的取代是指任意地被1-2个卤素取代；Or R 3' and R 4' together form a C 3 -C 8 aliphatic carbocyclic ring, a substituted C 3 -C 8 aliphatic carbocyclic ring or a 3-8 membered aliphatic heterocyclic ring. Replaced by 1-2 halogens ;
或者，R4'、R5'一起与与之相连的原子形成C3-C8脂碳环、取代的C3-C8脂碳环或3-8元脂杂环，所述的取代是指任意地被1-2个卤素取代；Alternatively, R 4' and R 5' together with the atoms connected to them form a C 3 -C 8 aliphatic carbocyclic ring, a substituted C 3 -C 8 aliphatic carbocyclic ring or a 3-8 membered aliphatic heterocyclic ring, and the substitution refers to being optionally substituted by 1-2 halogens;
或者，R8'、R9'一起与与之相连的原子形成C3-C8脂碳环、取代的C3-C8脂碳环或3-8元脂杂环，所述的取代是指任意地被1-2个卤素取代；Alternatively, R 8' and R 9' together with the atoms connected to them form a C 3 -C 8 aliphatic carbocycle, a substituted C 3 -C 8 aliphatic carbocycle or a 3-8 membered aliphatic heterocycle, and the substitution refers to being optionally substituted by 1-2 halogens;
或者，R2'、R3'一起与与之相连的原子形成C3-C8脂碳环、取代的C3-C8脂碳环或3-8元脂杂环，所述的取代是指任意地被1-2个卤素取代；Alternatively, R 2' and R 3' together with the atoms connected to them form a C 3 -C 8 aliphatic carbocyclic ring, a substituted C 3 -C 8 aliphatic carbocyclic ring or a 3-8 membered aliphatic heterocyclic ring, and the substitution refers to being optionally substituted by 1-2 halogens;
或者R10'、R11'一起与与之相连的原子形成C3-C8脂碳环、取代的C3-C8脂碳环或3-8元脂杂环，所述的取代是指任意地被1-2个卤素取代。Or R 10' and R 11' together with the atoms connected to them form a C 3 -C 8 aliphatic carbocycle, a substituted C 3 -C 8 aliphatic carbocycle or a 3-8 membered aliphatic heterocycle, and the substitution refers to being optionally substituted by 1-2 halogens.
某一实施方案中，R4为L1-R5，L1表示不存在或NRa,Ra表示氢或C1-C6烷基。In a certain embodiment, R 4 is L 1 -R 5 , L 1 represents absence or NR a , and R a represents hydrogen or C 1 -C 6 alkyl.
某一实施方案中，R5为以下式(i)、式(ii)或式(iii)的中的任意一种环状结构：
In a certain embodiment, R is any ring structure of the following formula (i), formula (ii) or formula (iii):
其中，W1表示CRW1RW2或NRW1；Among them, W 1 represents CR W1 R W2 or NR W1 ;
其中，RW1、RW2各自独立地表示氢、C1-C6烷基、3～6元杂环烷基、NRaRb、或(C＝O)-O-C1-C6亚烷基O-(C＝O)-C1-C10烷基；或者RW1、RW2一起与与之相连的原子共同形成3～8元脂杂环；Wherein, R W1 and R W2 each independently represent hydrogen, C 1 -C 6 alkyl, 3-6 membered heterocycloalkyl, NR a R b , or (C=O)-OC 1 -C 6 alkylene O-(C=O)-C 1 -C 10 alkyl; or R W1 , R W2 together form a 3-8 membered aliphatic heterocycle together with the atoms connected to it;
Ra和Rb各自独立地表示氢或C1-C6烷基；R a and R b each independently represent hydrogen or C 1 -C 6 alkyl;
其中，W2表示CH或N；Wherein, W 2 represents CH or N;
Y为亚甲基、亚乙基、C3亚烷基、C2-C3亚烯基、或Rc和Rd与与其相连的原子共同形成C3-C6脂碳环或被一个或多个卤素取代的C3-C6脂碳环；或者Rd和Rd’和与之相连的原子一起形成C3-C6脂碳环或被一个或多个卤素取代的C3-C6脂碳环；Y is methylene, ethylene, C 3 alkylene, C 2 -C 3 alkenylene, or R c and R d together with the atoms connected to them form a C 3 -C 6 aliphatic carbocycle or a C 3 -C 6 aliphatic carbocycle substituted by one or more halogens; or R d and R d' together with the atoms connected to them form a C 3 -C 6 aliphatic carbocycle or a C 3 -C 6 aliphatic carbocycle substituted by one or more halogens;
其中，R1”、R2”、R3”、R4”、R5”、R6”、R7”、R8”各自独立地表示氢或C1-C6烷基；Wherein, R 1" , R 2" , R 3" , R 4" , R 5" , R 6" , R 7" , R 8" each independently represent hydrogen or C 1 -C 6 alkyl;
或者，R2”、R3”一起与与之相连的原子形成C3-C8脂碳环、3～8元脂杂环或取代的3-8元脂杂环，所述的取代是指任意地被C1-C6烷基取代；或者环中任意的CH2被C＝O所取代；Alternatively, R 2" and R 3" together with the atoms connected to them form a C 3 -C 8 aliphatic carbocyclic ring, a 3-8 membered aliphatic heterocyclic ring or a substituted 3-8 membered aliphatic heterocyclic ring. The substitution refers to any substitution by a C 1 -C 6 alkyl group; or any CH 2 in the ring is substituted by C=O;
或者，R3”与R4”一起与与之相连的原子形成C3-C8脂碳环、3～8元脂杂环或取代的3-8元脂杂环，所述的取代是指任意地被C1-C6烷基取代；或者环中任意的CH2被C＝O所取代；Or, R 3" and R 4" together form a C 3 -C 8 aliphatic carbocyclic ring, a 3-8 membered aliphatic heterocyclic ring or a substituted 3-8 membered aliphatic heterocyclic ring with the atoms connected to it. The substitution refers to any substitution by a C 1 -C 6 alkyl group; or any CH 2 in the ring is substituted by C=O;
或者，R4”、R5”一起与与之相连的原子形成C3-C8脂碳环、3～8元脂杂环或取代的3-8元脂杂环，所述的取代是指任意地被C1-C6烷基取代；或者环中任意的CH2被C＝O所取代；Alternatively, R 4" and R 5" together with the atoms connected to them form a C 3 -C 8 aliphatic carbocyclic ring, a 3-8 membered aliphatic heterocyclic ring or a substituted 3-8 membered aliphatic heterocyclic ring. The substitution refers to any substitution by a C 1 -C 6 alkyl group; or any CH 2 in the ring is substituted by C=O;
或者，R5”与R6”一起与与之相连的原子形成C3-C8脂碳环、3～8元脂杂环或取代的3-8元脂杂环，所述的取代是指任意地被C1-C6烷基取代；或者环中任意的CH2被C＝O所取代；Alternatively, R 5" and R 6" together form a C 3 -C 8 aliphatic carbocyclic ring, a 3-8 membered aliphatic heterocyclic ring or a substituted 3-8 membered aliphatic heterocyclic ring with the atoms connected to it, and the substitution refers to being optionally substituted by a C 1 -C 6 alkyl group; or any CH 2 in the ring is substituted by C=O;
或者，R6”、R7”一起与与之相连的原子形成C3-C8脂碳环、3～8元脂杂环或取代的3-8元脂杂环，所述的取代是指任意地被C1-C6烷基取代；或者环中任意的CH2被C＝O所取代；Or, R 6" and R 7" together with the atoms connected to them form a C 3 -C 8 aliphatic carbocyclic ring, a 3-8 membered aliphatic heterocyclic ring or a substituted 3-8 membered aliphatic heterocyclic ring, and the substitution refers to being optionally substituted by a C 1 -C 6 alkyl group; or any CH 2 in the ring is substituted by C=O;
或者R3”与R4”一起与与之相连的原子形成C3-C8脂碳环、3～8元脂杂环或取代的3-8元脂杂环，所述的取代是指任意地被C1-C6烷基取代；或者环中任意的CH2被C＝O所取代；且R5”与R6”一起与与之相连的原子形成C3-C8脂碳环、3～8元脂杂环或取代的3-8元脂杂环，所述的取代是指任意地被C1-C6烷基取代；或者环中任意的CH2被C＝O所取代。Or R 3" and R 4" together with the atom connected to it form a C 3 -C 8 aliphatic carbocyclic ring, a 3-8 membered aliphatic heterocyclic ring or a substituted 3-8 membered aliphatic heterocyclic ring. For aliphatic heterocycle, the substitution refers to any substitution by C 1 -C 6 alkyl; or any CH 2 in the ring is replaced by C=O .
某一实施方案中，环K为芳环或杂芳环；In a certain embodiment, ring K is an aromatic ring or a heteroaryl ring;
X1为N、NRX1’或CRX1，X 1 is N, NR X1' or CR X1 ,
RX1为CN、卤素、C1-C6烷基、被一个或多个卤素取代的C1-C6烷基、PO(C1-C6烷基)2、C3-C6环烷基、C2-C6烯基、C2-C6炔基、3～6元杂环烷基、被一个或多个X1-1取代的3～6元杂环烷基、5～14元杂芳基、被一个或多个X1-2取代的5～14元杂芳基、NO2、3～6元杂环烯基、被一个或多个X1-3取代的3～6元杂环烯基、SF5、C(＝O)X1-4、NX1-5X1-6或SO2X1-7； RX1is CN, halogen, C1-C6Alkyl, C substituted by one or more halogens1-C6Alkyl, PO(C1-C6alkyl)2、C3-C6Cycloalkyl, C2-C6Alkenyl, C2-C6Alkynyl, 3-6 membered heterocycloalkyl, replaced by one or more X1-1Substituted 3-6 membered heterocycloalkyl, 5-14 membered heteroaryl, replaced by one or more X1-2Substituted 5-14 membered heteroaryl, NO2, 3-6 membered heterocycloalkenyl, replaced by one or more X1-3Substituted 3-6 membered heterocycloalkenyl, SF5, C(=O)X1-4、NX1-5x1-6or SO2x1-7;
X1-1和X1-3各自独立地为(C＝O)-C1-C6烷基；X1-2独立地为C1-C6烷基；X1-4独立地为H、C3-C8环烷基、3～8元杂环烷基、C1-C6烷基、或被一个或多个卤素取代的C1-C6烷基；X1-5和X1-6各自独立地为H、C1-C6烷基、SO2-C1-C6烷基或(C＝O)-C1-C6烷基；X1-7为OH或C1-C6烷基；X 1-1 and X 1-3 are each independently (C=O)-C 1 -C 6 alkyl; X 1-2 are independently C 1 -C 6 alkyl; X 1-4 are independently H , C 3 -C 8 cycloalkyl, 3-8 membered heterocycloalkyl, C 1 -C 6 alkyl, or C 1 -C 6 alkyl substituted by one or more halogens; X 1-5 and X 1-6 are each independently H, C 1 -C 6 alkyl, SO 2 -C 1 -C 6 alkyl or (C=O)-C 1 -C 6 alkyl; X 1-7 is OH or C 1 -C 6 alkyl;
X2为N或CRX2，RX2为CN；X 2 is N or CR X2 , R X2 is CN;
X3为N或CRX3，RX3为H或C1-C6烷基；X 3 is N or CR X3 , R X3 is H or C 1 -C 6 alkyl;
或者RX1与RX3和其相连的原子共同形成C5-C8环烯酮结构；Or R X1 and R X3 and the atoms connected to them together form a C 5 -C 8 cycloalkene structure;
或者RX1’与RX3和其相连的原子共同形成5～8元杂芳环或被一个或多个羟基取代的5～8元杂芳环；Or R X1' and R X3 and the atoms connected to them together form a 5-8 membered heteroaryl ring or a 5-8 membered heteroaryl ring substituted by one or more hydroxyl groups;
R1为C6～C14的芳基、被一个或多个R1-1取代的C6～C14的芳基、5～14元杂芳基或被一个或多个R1-2取代的5～14元杂芳基；R 1 is a C 6 -C 14 aryl group, a C 6 -C 14 aryl group substituted by one or more R 1-1 , a 5-14 membered heteroaryl group or a 5-14 membered heteroaryl group substituted by one or more R 1-2 ;
R1-1和R1-2各自独立地为卤素、OH、NH2、CN、C1-C6烷基、(C＝O)C1-C6烷基、C2-C6炔基、被一个或多个卤素取代的C1-C6烷基、B(OH)2或O(C＝O)-C1-C10烷基，R 1-1 and R 1-2 are each independently halogen, OH, NH 2 , CN, C 1 -C 6 alkyl, (C=O)C 1 -C 6 alkyl, C 2 -C 6 alkynyl, C 1 -C 6 alkyl substituted by one or more halogens, B(OH) 2 or O(C=O ) -C 1 -C 10 alkyl,
或者，相邻的两个R1-1与其相连的原子一起形成C3-C8脂碳环或被一个或多个R1-3取代的C3-C8脂碳环，其余R1-1独立地为卤素、OH、NH2、CN、C1-C6烷基、(C＝O)-C1-C6烷基、C2-C6炔基、被一个或多个卤素取代的C1-C6烷基、B(OH)2或O(C＝O)-C1-C10烷基；Alternatively, two adjacent R 1-1 and their connected atoms together form a C 3 -C 8 aliphatic carbon ring or a C 3 -C 8 aliphatic carbon ring substituted by one or more R 1-3 , and the remaining R 1-1 are independently halogen, OH, NH 2 , CN, C 1 -C 6 alkyl, (C=O)-C 1 -C 6 alkyl, C 2 -C 6 alkynyl, C 1 -C 6 alkyl substituted by one or more halogens, B(OH) 2 or O(C=O)-C 1 -C 10 alkyl;
或者，相邻的两个R1-2与其相连的原子一起形成C3-C8脂碳环或被一个或多个R1-4取代的C3-C8脂碳环，其余R1-2独立地为卤素、OH、NH2、CN、C1-C6烷基、(C＝O)-C1-C6烷基、C2-C6炔基、被一个或多个卤素取代的C1-C6烷基、B(OH)2或O(C＝O)-C1-C10烷基；Alternatively, two adjacent R 1-2 and their connected atoms together form a C 3 -C 8 aliphatic carbon ring or a C 3 -C 8 aliphatic carbon ring substituted by one or more R 1-4 , and the remaining R 1-2 are independently halogen, OH, NH 2 , CN, C 1 -C 6 alkyl, (C=O)-C 1 -C 6 alkyl, C 2 -C 6 alkynyl, C 1 -C 6 alkyl substituted by one or more halogens, B(OH) 2 or O(C=O)-C 1 -C 10 alkyl;
R1-3和R1-4独立地为卤素；R 1-3 and R 1-4 are independently halogen;
或者X1为CRX1，其中，X1中的C原子与R1中的芳基或杂芳基中的C原子通过-O-(CH2)n1-*、*-NH-(CH2)n2-、-C≡C-(CH2)n3-C≡C-*或-(CH2)n4-O-(CH2)n5-*相连，其中，*端与X1中的C原子相连；Or X 1 is CR X1 , wherein the C atom in X 1 is connected to the C atom in the aryl or heteroaryl group in R 1 through -O-(CH 2 ) n1 - * , * -NH-(CH 2 ) n2 -, -C≡C-(CH 2 ) n3 -C≡C- * or -(CH 2 ) n4 -O-(CH 2 ) n5 - * , wherein the * end is connected to the C atom in X 1 connected;
n1、n2、n3、n4和n5各自独立地为1、2、3、4、5或6；n1, n2, n3, n4 and n5 are each independently 1, 2, 3, 4, 5 or 6;
R2为卤素、C1-C6烷基或C1-C6烷氧基；R 2 is halogen, C 1 -C 6 alkyl or C 1 -C 6 alkoxy;
L2表示-O-(C1-C6亚烷基)；L 2 represents -O-(C 1 -C 6 alkylene);
R3为以下的环状结构：
R 3 is the following ring structure:
其中，R1'、R2'、R3'、R4'、R5'、R6'、R7'、R8'、R9'、R10'、R11'、R12'各自独立地表示氢或卤素；Wherein, R 1' , R 2' , R 3' , R 4' , R 5' , R 6' , R 7' , R 8' , R 9' , R 10' , R 11' , R 12' each independently represent hydrogen or halogen;
或者R3'与R4'一起与与之相连的原子形成C3-C8脂碳环、取代的C3-C8脂碳环或3-8元脂杂环，所述的取代是指任意地被1-2个卤素取代；Or R 3' and R 4' together form a C 3 -C 8 aliphatic carbocyclic ring, a substituted C 3 -C 8 aliphatic carbocyclic ring or a 3-8 membered aliphatic heterocyclic ring, and the substitution refers to being optionally substituted by 1-2 halogens;
或者R9'与R10'一起与与之相连的原子形成C3-C8脂碳环、取代的C3-C8脂碳环或3-8元脂杂环，所述的取代是指任意地被1-2个卤素取代； Or R 9' and R 10' together form a C 3 -C 8 aliphatic carbocyclic ring, a substituted C 3 -C 8 aliphatic carbocyclic ring or a 3-8 membered aliphatic heterocyclic ring, and the substitution refers to being optionally substituted by 1-2 halogens;
或者R3'与R4'一起与与之相连的原子形成C3-C8脂碳环、取代的C3-C8脂碳环或3-8元脂杂环，所述的取代是指任意地被1-2个卤素取代；且R9'与R10'一起与与之相连的原子形成C3-C8脂碳环、取代的C3-C8脂碳环或3-8元脂杂环，所述的取代是指任意地被1-2个卤素取代；Or R 3' and R 4' together form a C 3 -C 8 aliphatic carbocyclic ring, a substituted C 3 -C 8 aliphatic carbocyclic ring or a 3-8 membered aliphatic heterocyclic ring, the substitution refers to being optionally substituted by 1-2 halogens ; Replaced by 1-2 halogens;
或者，R4'、R5'一起与与之相连的原子形成C3-C8脂碳环、取代的C3-C8脂碳环或3-8元脂杂环，所述的取代是指任意地被1-2个卤素取代；Alternatively, R 4' and R 5' together with the atoms connected to them form a C 3 -C 8 aliphatic carbocyclic ring, a substituted C 3 -C 8 aliphatic carbocyclic ring or a 3-8 membered aliphatic heterocyclic ring, and the substitution refers to being optionally substituted by 1-2 halogens;
或者，R8'、R9'一起与与之相连的原子形成C3-C8脂碳环、取代的C3-C8脂碳环或3-8元脂杂环，所述的取代是指任意地被1-2个卤素取代；Alternatively, R 8' and R 9' together with the atoms connected to them form a C 3 -C 8 aliphatic carbocycle, a substituted C 3 -C 8 aliphatic carbocycle or a 3-8 membered aliphatic heterocycle, and the substitution refers to being optionally substituted by 1-2 halogens;
或者，R2'、R3'一起与与之相连的原子形成C3-C8脂碳环、取代的C3-C8脂碳环或3-8元脂杂环，所述的取代是指任意地被1-2个卤素取代；Alternatively, R 2' and R 3' together with the atoms connected to them form a C 3 -C 8 aliphatic carbocyclic ring, a substituted C 3 -C 8 aliphatic carbocyclic ring or a 3-8 membered aliphatic heterocyclic ring, and the substitution refers to being optionally substituted by 1-2 halogens;
或者R10'、R11'一起与与之相连的原子形成C3-C8脂碳环、取代的C3-C8脂碳环或3-8元脂杂环，所述的取代是指任意地被1-2个卤素取代；Or R 10' and R 11' together with the atoms connected to them form a C 3 -C 8 aliphatic carbocyclic ring, a substituted C 3 -C 8 aliphatic carbocyclic ring or a 3-8 membered aliphatic heterocyclic ring, and the substitution refers to being optionally substituted by 1-2 halogens;
R4为L1-R5，L1表示不存在或NRa，R 4 is L 1 -R 5 , L 1 means absent or NR a ,
R5为以下式(i)、式(ii)或式(iii)的中的任意一种环状结构：
 R is any ring structure in the following formula (i), formula (ii) or formula (iii):
其中，W1表示CRW1RW2或NRW1；Among them, W 1 represents CR W1 R W2 or NR W1 ;
其中，RW1、RW2各自独立地表示氢、C1-C6烷基、3～6元杂环烷基、NRaRb、或(C＝O)-O-C1-C6亚烷基O-(C＝O)-C1-C10烷基；或者RW1、RW2一起与与之相连的原子共同形成3～8元脂杂环；Wherein, R W1 and R W2 each independently represent hydrogen, C 1 -C 6 alkyl, 3-6 membered heterocycloalkyl, NR a R b , or (C=O)-OC 1 -C 6 alkylene O-(C=O)-C 1 -C 10 alkyl; or R W1 , R W2 together form a 3-8 membered aliphatic heterocycle together with the atoms connected thereto;
Ra和Rb各自独立地表示氢或C1-C6烷基；R a and R b each independently represent hydrogen or C 1 -C 6 alkyl;
其中，W2表示CH或N；Wherein, W 2 represents CH or N;
Y为亚甲基、亚乙基、C3亚烷基、C2-C3亚烯基、或Rc和Rd与与其相连的原子共同形成C3-C6脂碳环或被一个或多个卤素取代的C3-C6脂碳环；或者Rd和Rd’和与之相连的原子一起形成C3-C6脂碳环或被一个或多个卤素取代的C3-C6脂碳环；Y is methylene, ethylene, C 3 alkylene, C 2 -C 3 alkenylene, or R c and R d together with the atoms connected to them form a C 3 -C 6 aliphatic carbocycle or a C 3 -C 6 aliphatic carbocycle substituted by one or more halogens; or R d and R d' together with the atoms connected to them form a C 3 -C 6 aliphatic carbocycle or a C 3 -C 6 aliphatic carbocycle substituted by one or more halogens;
其中，R1”、R2”、R3”、R4”、R5”、R6”、R7”、R8”各自独立地表示氢或C1-C6烷基；Wherein, R 1" , R 2" , R 3" , R 4" , R 5" , R 6" , R 7" , R 8" each independently represent hydrogen or C 1 -C 6 alkyl;
或者，R2”、R3”一起与与之相连的原子形成C3-C8脂碳环、3～8元脂杂环或取代的3-8元脂杂环，所述的取代是指任意地被C1-C6烷基取代；或者环中任意的CH2被C＝O所取代；Alternatively, R 2" and R 3" together with the atoms connected to them form a C 3 -C 8 aliphatic carbocyclic ring, a 3-8 membered aliphatic heterocyclic ring or a substituted 3-8 membered aliphatic heterocyclic ring. The substitution refers to any substitution by a C 1 -C 6 alkyl group; or any CH 2 in the ring is substituted by C=O;
或者，R3”与R4”一起与与之相连的原子形成C3-C8脂碳环、3～8元脂杂环或取代的3-8元脂杂环，所述的取代是指任意地被C1-C6烷基取代；或者环中任意的CH2被C＝O所取代；Or, R 3" and R 4" together form a C 3 -C 8 aliphatic carbocyclic ring, a 3-8 membered aliphatic heterocyclic ring or a substituted 3-8 membered aliphatic heterocyclic ring with the atoms connected to it. The substitution refers to any substitution by a C 1 -C 6 alkyl group; or any CH 2 in the ring is substituted by C=O;
或者，R4”、R5”一起与与之相连的原子形成C3-C8脂碳环、3～8元脂杂环或取代的3-8元脂杂环，所述的取代是指任意地被C1-C6烷基取代；或者环中任意的CH2被C＝O所取代；Alternatively, R 4" and R 5" together with the atoms connected to them form a C 3 -C 8 aliphatic carbocyclic ring, a 3-8 membered aliphatic heterocyclic ring or a substituted 3-8 membered aliphatic heterocyclic ring, and the substitution refers to being optionally substituted by a C 1 -C 6 alkyl group; or any CH 2 in the ring is substituted by C=O;
或者，R5”与R6”一起与与之相连的原子形成C3-C8脂碳环、3～8元脂杂环或取代的3-8元脂杂环， 所述的取代是指任意地被C1-C6烷基取代；或者环中任意的CH2被C＝O所取代；Alternatively, R 5" and R 6" together form a C 3 -C 8 aliphatic carbocyclic ring, a 3-8 membered aliphatic heterocyclic ring or a substituted 3-8 membered aliphatic heterocyclic ring with the atoms connected to it, The substitution refers to any substitution by C 1 -C 6 alkyl; or any CH 2 in the ring is replaced by C=O;
或者，R6”、R7”一起与与之相连的原子形成C3-C8脂碳环、3～8元脂杂环或取代的3-8元脂杂环，所述的取代是指任意地被C1-C6烷基取代；或者环中任意的CH2被C＝O所取代；Or, R 6" and R 7" together with the atoms connected to them form a C 3 -C 8 aliphatic carbocyclic ring, a 3-8 membered aliphatic heterocyclic ring or a substituted 3-8 membered aliphatic heterocyclic ring, and the substitution refers to being optionally substituted by a C 1 -C 6 alkyl group; or any CH 2 in the ring is substituted by C=O;
或者R3”与R4”一起与与之相连的原子形成C3-C8脂碳环、3～8元脂杂环或取代的3-8元脂杂环，所述的取代是指任意地被C1-C6烷基取代；或者环中任意的CH2被C＝O所取代；且R5”与R6”一起与与之相连的原子形成C3-C8脂碳环、3～8元脂杂环或取代的3-8元脂杂环，所述的取代是指任意地被C1-C6烷基取代；或者环中任意的CH2被C＝O所取代；Or R 3" and R 4" together with the atoms connected to it form a C 3 -C 8 aliphatic carbocyclic ring, a 3-8 membered aliphatic heterocyclic ring or a substituted 3-8 membered aliphatic heterocyclic ring. Aliphatic heterocycle, the substitution refers to any substitution by C 1 -C 6 alkyl ; or any CH 2 in the ring is replaced by C=O;
其满足下述至少一个条件：It meets at least one of the following conditions:
条件1：R3中，R3'与R4'一起与与之相连的原子形成C3-C8脂碳环、取代的C3-C8脂碳环或3-8元脂杂环，所述的取代是指任意地被1-2个卤素取代；Condition 1: In R 3 , R 3' and R 4' together form a C 3 -C 8 aliphatic carbocyclic ring, a substituted C 3 -C 8 aliphatic carbocyclic ring or a 3-8 membered aliphatic heterocyclic ring, and the substitution refers to being optionally substituted by 1-2 halogens;
或者R9'与R10'一起与与之相连的原子形成C3-C8脂碳环、取代的C3-C8脂碳环或3-8元脂杂环，所述的取代是指任意地被1-2个卤素取代；Or R 9' and R 10' together form a C 3 -C 8 aliphatic carbocyclic ring, a substituted C 3 -C 8 aliphatic carbocyclic ring or a 3-8 membered aliphatic heterocyclic ring, and the substitution refers to being optionally substituted by 1-2 halogens;
或者R3'与R4'一起与与之相连的原子形成C3-C8脂碳环、取代的C3-C8脂碳环或3-8元脂杂环，所述的取代是指任意地被1-2个卤素取代；且R9'与R10'一起与与之相连的原子形成C3-C8脂碳环、取代的C3-C8脂碳环或3-8元脂杂环，所述的取代是指任意地被1-2个卤素取代；Or R 3' and R 4' together form a C 3 -C 8 aliphatic carbocyclic ring, a substituted C 3 -C 8 aliphatic carbocyclic ring or a 3-8 membered aliphatic heterocyclic ring. Replaced by 1-2 halogens ;
或者，R4'、R5'一起与与之相连的原子形成C3-C8脂碳环、取代的C3-C8脂碳环或3-8元脂杂环，所述的取代是指任意地被1-2个卤素取代；Alternatively, R 4' and R 5' together with the atoms connected to them form a C 3 -C 8 aliphatic carbocycle, a substituted C 3 -C 8 aliphatic carbocycle or a 3-8 membered aliphatic heterocycle, and the substitution refers to being optionally substituted by 1-2 halogens;
或者，R2'、R3'一起与与之相连的原子形成C3-C8脂碳环、取代的C3-C8脂碳环或3-8元脂杂环，所述的取代是指任意地被1-2个卤素取代；Alternatively, R 2' and R 3' together with the atoms connected to them form a C 3 -C 8 aliphatic carbocycle, a substituted C 3 -C 8 aliphatic carbocycle or a 3-8 membered aliphatic heterocycle, and the substitution refers to being optionally substituted by 1-2 halogens;
或者R10'、R11'一起与与之相连的原子形成C3-C8脂碳环、取代的C3-C8脂碳环或3-8元脂杂环，所述的取代是指任意地被1-2个卤素取代；Or R 10' and R 11' together with the atoms connected to them form a C 3 -C 8 aliphatic carbocycle, a substituted C 3 -C 8 aliphatic carbocycle or a 3-8 membered aliphatic heterocycle, and the substitution refers to being optionally substituted by 1-2 halogens;
条件2：R5为以下式(i)、式(ii)或式(iii)的中的任意一种环状结构：
Condition 2: R 5 is any ring structure in the following formula (i), formula (ii) or formula (iii):
其中，式(ii)中，W2为N，W1为NRW1时，RW1不为H；Wherein, in formula (ii), W 2 is N, and when W 1 is NR W1 , R W1 is not H;
式(iii)中，W2为N，W1为NRW1，RW1为H时，Y不为亚乙基；In formula (iii), W 2 is N, W 1 is NR W1 , and when R W1 is H, Y is not ethylene;
条件3：X1为CRX1，RX1为被一个或多个卤素取代的C1-C6烷基、PO(C1-C6烷基)2、C2-C6烯基、C2-C6炔基、NO2、C3-C6环烷基、3～6元杂环烷基、3～6元杂环烯基、被一个或多个X1-1取代的3～6元杂环烷基、被一个或多个X1-2取代的5～14元杂芳基、被一个或多个X1-3取代的3～6元杂环烯基、SF5、C(＝O)X1-4、NX1-5X1-6或SO2X1-7；或者，RX1与RX3和其相连的原子共同形成C5-C8环烯酮结构；Condition 3: X1for CRX1, RX1is C substituted by one or more halogens1-C6Alkyl, PO(C1-C6alkyl)2、C2-C6Alkenyl, C2-C6Alkynyl, NO2、C3-C6Cycloalkyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, replaced by one or more X1-1Substituted 3-6 membered heterocycloalkyl, replaced by one or more X1-2Substituted 5- to 14-membered heteroaryl, replaced by one or more X1-3Substituted 3-6 membered heterocycloalkenyl, SF5, C(=O)X1-4、NX1-5x1-6or SO2x1-7; or, RX1with RX3Together with its attached atoms form C5-C8Cycloenone structure;
或者，X1为NRX1’，RX1’与RX3和其相连的原子共同形成5～8元杂芳环或被一个或多个羟基取代的5～8元杂芳环；Alternatively, X 1 is NR X1' , and R X1' and R X3 together with the atoms connected to them form a 5-8 membered heteroaryl ring or a 5-8 membered heteroaryl ring substituted by one or more hydroxyl groups;
或者，X1为CRX1，其中，X1中的C原子与R1中的芳基或杂芳基中的C原子通过-O-(CH2)n1-*、 *-NH-(CH2)n2-、-C≡C-(CH2)n3-C≡C-*或-(CH2)n4-O-(CH2)n5-*相连，其中，*端与X1中的C原子相连；Alternatively, X 1 is CR X1 , wherein the C atom in X 1 and the C atom in the aryl or heteroaryl group in R 1 pass through -O-(CH 2 ) n1 - * , * -NH-(CH 2 ) n2 -, -C≡C-(CH 2 ) n3 -C≡C- * or -(CH 2 ) n4 -O-(CH 2 ) n5 - * is connected, where the * end is connected to the C atom in X 1 ;
条件4：R1为被一个或多个R1-1取代的C6～C14的芳基或被一个或多个R1-2取代的5～14元杂芳基；Condition 4: R 1 is a C 6 -C 14 aryl group substituted by one or more R 1-1 or a 5-14 membered heteroaryl group substituted by one or more R 1-2 ;
当R1为被一个或多个R1-1取代的C6～C14的芳基时，相邻的两个R1-1与其相连的原子一起形成C3-C8脂碳环或被一个或多个R1-3取代的C3-C8脂碳环，其余R1-1独立地为卤素、OH、NH2、CN、C1-C6烷基、(C＝O)-C1-C6烷基、C2-C6炔基、被一个或多个卤素取代的C1-C6烷基、B(OH)2或O(C＝O)-C1-C10烷基；When R 1 is a C 6 -C 14 aryl group substituted by one or more R 1-1 , two adjacent R 1-1 and the atoms connected to it together form a C 3 -C 8 aliphatic carbon ring or a C 3 -C 8 aliphatic carbon ring substituted by one or more R 1-3 , and the remaining R 1-1 are independently halogen, OH, NH 2 , CN, C 1 -C 6 alkyl, (C=O)-C 1 -C 6 alkyl , C 2 -C 6 alkynyl, C 1 -C 6 alkyl substituted by one or more halogens, B(OH) 2 or O(C=O)-C 1 -C 10 alkyl;
当R1为被一个或多个R1-2取代的5～14元杂芳基时，相邻的两个R1-2与其相连的原子一起形成C3-C8脂碳环或被一个或多个R1-4取代的C3-C8脂碳环，其余R1-2独立地为卤素、OH、NH2、CN、C1-C6烷基、(C＝O)-C1-C6烷基、C2-C6炔基、被一个或多个卤素取代的C1-C6烷基、B(OH)2或O(C＝O)-C1-C10烷基；When R 1 is a 5- to 14-membered heteroaryl group substituted by one or more R 1-2 , two adjacent R 1-2 and their connected atoms together form a C 3 -C 8 aliphatic carbon ring or a C 3 -C 8 aliphatic carbon ring substituted by one or more R 1-4 , and the remaining R 1-2 are independently halogen, OH, NH 2 , CN, C 1 -C 6 alkyl, (C=O)-C 1 -C 6 alkyl, C 2 -C 6 alkynyl, C 1 -C 6 alkyl substituted by one or more halogens, B(OH) 2 or O(C=O)-C 1 -C 10 alkyl;
R1-3和R1-4独立地为卤素。R 1-3 and R 1-4 are independently halogen.
某一实施方案中，RX1为CN、卤素、被一个或多个卤素取代的C1-C6烷基、PO(C1-C6烷基)2、C3-C6环烷基、C2-C6烯基、C2-C6炔基、3～6元杂环烷基、被一个或多个X1-1取代的3～6元杂环烷基、被一个或多个X1-2取代的5～14元杂芳基、NO2、3～6元杂环烯基、被一个或多个X1-3取代的3～6元杂环烯基、C(＝O)X1-4、NX1-5X1-6或SO2X1-7。In one embodiment, RX1is CN, halogen, C substituted by one or more halogens1-C6Alkyl, PO(C1-C6alkyl)2、C3-C6Cycloalkyl, C2-C6Alkenyl, C2-C6Alkynyl, 3-6 membered heterocycloalkyl, replaced by one or more X1-1Substituted 3-6 membered heterocycloalkyl, replaced by one or more X1-2Substituted 5-14 membered heteroaryl, NO2, 3-6 membered heterocycloalkenyl, replaced by one or more X1-3Substituted 3-6 membered heterocycloalkenyl, C(=O)X1-4、NX1-5x1-6or SO2x1-7.
某一实施方案中，X1-4独立地为C1-C6烷基。In a certain embodiment, X 1-4 is independently C 1 -C 6 alkyl.
某一实施方案中，X1-7为C1-C6烷基。In a certain embodiment, X 1-7 is C 1 -C 6 alkyl.
某一实施方案中，X3为CRX3，RX3为H。In a certain embodiment, X 3 is CR X3 , and R X3 is H.
某一实施方案中，RX1’与RX3和其相连的原子共同形成5～8元杂芳环。In a certain embodiment, R X1' and R X3 together with the atoms connected to them form a 5-8 membered heteroaromatic ring.
某一实施方案中，R1为被一个或多个R1-1取代的C6～C14的芳基或被一个或多个R1-2取代的5～14元杂芳基；In a certain embodiment, R 1 is a C 6 -C 14 aryl group substituted by one or more R 1-1 or a 5-14 membered heteroaryl group substituted by one or more R 1-2 ;
R1-1和R1-2各自独立地为卤素、OH、NH2、C1-C6烷基、(C＝O)-C1-C6烷基、C2-C6炔基、被一个或多个卤素取代的C1-C6烷基或B(OH)2；R 1-1 and R 1-2 are each independently halogen, OH, NH 2 , C 1 -C 6 alkyl, (C=O)-C 1 -C 6 alkyl, C 2 -C 6 alkynyl, C 1 -C 6 alkyl substituted by one or more halogens or B(OH) 2 ;
或者，相邻的两个R1-1与其相连的原子一起形成C3-C8脂碳环，其余R1-1独立地为卤素、OH、NH2、C1-C6烷基、(C＝O)-C1-C6烷基、C2-C6炔基、被一个或多个卤素取代的C1-C6烷基或B(OH)2。Alternatively, two adjacent R 1-1 and their connected atoms together form a C 3 -C 8 aliphatic carbon ring, and the remaining R 1-1 are independently halogen, OH, NH 2 , C 1 -C 6 alkyl, (C=O)-C 1 -C 6 alkyl, C 2 -C 6 alkynyl, C 1 -C 6 alkyl substituted by one or more halogens or B(OH) 2 .
某一实施方案中，X1中的C原子与R1中的芳基或杂芳基中的C原子通过-O-(CH2)n1-*或-(CH2)n4-O-(CH2)n5-*相连，其中，*端与X1中的C原子相连；n1、n4和n5各自独立地为1、2、3、4、5或6。In a certain embodiment, the C atom in X1 is connected to the C atom in the aryl or heteroaryl group in R1 through -O-( CH2 ) n1- * or -( CH2 ) n4 -O-( CH2 ) n5- * , wherein the * end is connected to the C atom in X1 ; n1, n4 and n5 are each independently 1, 2, 3, 4, 5 or 6.
某一实施方案中，R2为卤素。In a certain embodiment, R 2 is halogen.
某一实施方案中，R3为 时，In a certain embodiment, R3 is hour,
其中X为卤素，环A、环B和环C与母体结构共用一个碳原子，环D和环E与母体结构共用两个原子和一根键；环A、环B和环C与母体结构共用一个碳原子，环D和环E与母体结构共用两个原子和一根键；环A、环B、环C、环D和环E各自独立地为3～8元脂杂环、C3-C8脂碳环或被一个或多个卤素取代的C3-C8脂碳环；Where X is halogen, ring A, ring B and ring C share one carbon atom with the parent structure, ring D and ring E share two atoms and one bond with the parent structure; ring A, ring B and ring C share one carbon atom with the parent structure, ring D and ring E share two atoms and one bond with the parent structure; ring A, ring B, ring C, ring D and ring E are each independently 3-8 membered aliphatic heterocyclic rings, C 3 -C 8 aliphatic carbocyclic rings, or C 3 -C substituted by one or more halogens 8 aliphatic carbon rings;
较佳地，环A为3～8元脂杂环、C3-C8脂碳环或被1个或2个卤素取代的C3-C8脂碳环；环B和环C各自独立地为3～8元脂杂环；环D为3～8元脂杂环或C3-C8脂碳环；环E为C3-C8脂碳环。Preferably, ring A is a 3-8-membered aliphatic heterocycle, a C 3 -C 8 aliphatic carbocycle, or a C 3 -C 8 aliphatic carbocycle substituted by 1 or 2 halogens; ring B and ring C are each independently a 3-8-membered aliphatic heterocycle; ring D is a 3-8-membered aliphatic heterocycle or a C 3 -C 8 aliphatic carbocycle; ring E is a C 3 -C 8 aliphatic carbocycle.
某一实施方案中，R4为式(i)、式(ii)或式(iii)：
In a certain embodiment, R 4 is formula (i), formula (ii) or formula (iii):
其中，式(i)中，R1”、R2”、R7”和R8”各自独立地为氢；Wherein, in formula (i), R 1" , R 2" , R 7" and R 8" are each independently hydrogen;
R3”与R4”一起与与之相连的原子形成C3-C8脂碳环、3-8元脂杂环或被一个或多个Ra取代的3～8元脂杂环；或者所述环中任意的CH2被C＝O所取代；R 3" and R 4" together form a C 3 -C 8 aliphatic carbocyclic ring, a 3-8 membered aliphatic heterocyclic ring or a 3-8 membered aliphatic heterocyclic ring substituted by one or more R a ; or any CH 2 in the ring is substituted by C=O;
或者，R5”与R6”一起与与之相连的原子形成C3-C8脂碳环、3-8元脂杂环或被一个或多个Ra取代的3～8元脂杂环；或者所述环中任意的CH2被C＝O所取代；Alternatively, R 5" and R 6" together form a C 3 -C 8 aliphatic carbocyclic ring, a 3-8 membered aliphatic heterocyclic ring or a 3-8 membered aliphatic heterocyclic ring substituted by one or more R a ; or any CH 2 in the ring is substituted by C=O;
或者，R3”与R4”一起与与之相连的原子形成C3-C8脂碳环、3-8元脂杂环或被一个或多个Ra取代的3～8元脂杂环；或者所述环中任意的CH2被C＝O所取代；且R5”与R6”一起与与之相连的原子形成C3-C8脂碳环、3-8元脂杂环或被一个或多个Ra取代的3～8元脂杂环；或者所述环中任意的CH2被C＝O所取代；Ra独立地表示氢或C1-C6烷基；Or, R 3" and R 4" together form a C 3 -C 8 aliphatic carbocyclic ring, a 3-8 membered aliphatic heterocyclic ring, or a 3-8 membered aliphatic heterocyclic ring substituted by one or more R a ; or any CH 2 in the ring is substituted by C=O; and R 5" and R 6" together form a C 3 -C 8 aliphatic carbocyclic ring, a 3-8 membered aliphatic heterocyclic ring, or a 3-8 membered aliphatic heterocyclic ring substituted by one or more R a ; Or any CH 2 in the ring is replaced by C=O; R a independently represents hydrogen or C 1 -C 6 alkyl;
其中，式(ii)中，W1表示CRW1RW2或NRW1；W2表示N；Wherein, in formula (ii), W 1 represents CR W1 R W2 or NR W1 ; W 2 represents N;
当W1为CRW1RW2时，RW1、RW2各自独立地表示H、3～8元杂环烷基或者RW1、RW2一起与与之相连的原子共同形成3～8元脂杂环；When W 1 is CR W1 R W2 , R W1 and R W2 each independently represent H, a 3-8 membered heterocycloalkyl group or R W1 and R W2 together form a 3-8 membered aliphatic heterocycle together with the atoms connected to it;
当W1为NRW1时，RW1为H，R1”、R2”、R3”、R4”、R7”和R8”各自独立地为氢或C1-C6烷基；When W 1 is NR W1 , R W1 is H, and R 1" , R 2" , R 3" , R 4" , R 7" and R 8" are each independently hydrogen or C 1 -C 6 alkyl;
或者，R2”、R3”一起与与之相连的原子形成C3-C8脂碳环、3-8元脂杂环或被一个或多个Ra取代的3～8元脂杂环；或者所述环中任意的CH2被C＝O所取代；Alternatively, R 2" and R 3" together with the atoms connected to them form a C 3 -C 8 aliphatic carbocyclic ring, a 3-8 membered aliphatic heterocyclic ring or a 3-8 membered aliphatic heterocyclic ring substituted by one or more R a ; or any CH 2 in the ring is substituted by C=O;
或者R6”、R7”一起与与之相连的原子形成C3-C8脂碳环、3-8元脂杂环或被一个或多个Ra取代的3～8元脂杂环；或者所述环中任意的CH2被C＝O所取代； Or R 6" and R 7" together with the atoms connected to them form a C 3 -C 8 aliphatic carbocyclic ring, a 3-8 membered aliphatic heterocyclic ring or a 3-8 membered aliphatic heterocyclic ring substituted by one or more R a ; or any CH 2 in the ring is substituted by C=O;
或者R5”与R6”一起与与之相连的原子形成C3-C8脂碳环、3-8元脂杂环或被一个或多个Ra取代的3～8元脂杂环；或者所述环中任意的CH2被C＝O所取代；Or R 5" and R 6" together form a C 3 -C 8 aliphatic carbocyclic ring, a 3-8 membered aliphatic heterocyclic ring or a 3-8 membered aliphatic heterocyclic ring substituted by one or more R a ; or any CH 2 in the ring is substituted by C=O;
或者R3”与R4”一起与与之相连的原子形成C3-C8脂碳环、3-8元脂杂环或被一个或多个Ra取代的3～8元脂杂环；或者所述环中任意的CH2被C＝O所取代；Or R 3" and R 4" together form a C 3 -C 8 aliphatic carbocyclic ring, a 3-8 membered aliphatic heterocyclic ring or a 3-8 membered aliphatic heterocyclic ring substituted by one or more R a ; or any CH 2 in the ring is substituted by C=O;
Ra独立地表示氢或C1-C6烷基； R independently represents hydrogen or C 1 -C 6 alkyl;
其中，式(iii)中，W1表示CRW1RW2或NRW1，RW1、RW2各自独立地表示氢、NRaRb、C1-C6烷基或(C＝O)-O-CH2-O-(C＝O)-C1-C10烷基，Ra和Rb各自独立地表示氢或C1-C6烷基；W2表示CH或N；R1”、R2”、R3”和R4”为氢；Y为亚甲基、亚乙基、C3亚烷基、C2-C3亚烯基、或Rc和Rd与与其相连的原子共同形成C3-C6脂碳环或被一个或多个卤素取代的C3-C6脂碳环；或者Rd和Rd’和与之相连的原子一起形成C3-C6脂碳环或被一个或多个卤素取代的C3-C6脂碳环。Wherein, in formula (iii), W 1 represents CR W1 R W2 or NR W1 , R W1 , R W2 each independently represent hydrogen, NR a R b , C 1 -C 6 alkyl or (C=O)-O-CH 2 -O-(C=O)-C 1 -C 10 alkyl, R a and R b each independently represent hydrogen or C 1 -C 6 alkyl; W 2 represents CH or N; R 1 " , R 2" , R 3" and R 4" are hydrogen; Y is methylene, ethylene, C 3 alkylene, C 2 -C 3 alkenylene, or R c and R d and the atoms connected to them together form a C 3 -C 6 aliphatic carbocycle or a C 3 -C 6 aliphatic carbocycle substituted by one or more halogens; or R d and R d' together with the atoms connected to them form a C 3 -C 6 aliphatic carbocycle or a C 3 -C 6 aliphatic carbocycle substituted by one or more halogens.
某一实施方案中，R4为 In a certain embodiment, R 4 is
其中，R4-1为H、C1-C6烷基或(C＝O)-O-CH2-O-(C＝O)-C1-C10烷基；R4-2为C1-C6烷基，R4-2的个数为一个或多个；R4-3和R4-4各自独立地为H或3～8元杂环烷基，或者R4-3和R4-4与其相连的碳原子共同形成3～8元脂杂环；环G、环I和环J与母体结构共用一个碳原子，环F和环H与母体结构共用两个原子和一根键，环F、环G、环H、环I和环J各自独立地为C3-C8脂碳环、3～8元脂杂环、5～8元内酰胺环或被一个或多个Re取代的3～8元脂杂环；Re为C1-C6烷基；Among them, R4-1for H, C1-C6Alkyl or (C=O)-O-CH2-O-(C=O)-C1-C10Alkyl; R4-2for C1-C6Alkyl, R4-2The number is one or more; R4-3and R4-4Each independently is H or 3-8 membered heterocycloalkyl, or R4-3and R4-4The carbon atoms connected to it together form a 3- to 8-membered aliphatic heterocyclic ring; ring G, ring I and ring J share one carbon atom with the parent structure, ring F and ring H share two atoms and one bond with the parent structure, ring F, ring G, ring H, ring I and ring J are independently C3-C8Aliphatic carbon ring, 3-8 membered aliphatic heterocyclic ring, 5-8 membered lactam ring or one or more ReSubstituted 3-8 membered aliphatic heterocycle; Refor C1-C6alkyl;
较佳地，R4-1为H或C1-C6烷基；R4-2为C1-C6烷基，R4-2的个数为一个或多个；R4-3和R4-4各自独立地为H或3～6元杂环烷基，或者R4-3和R4-4与其相连的碳原子共同形成3～6元脂杂环；环G、环I和环J与母体结构共用一个碳原子，环F和环H与母体结构共用两个原子和一根键，环F和环G各自独立地为C3-C8脂碳环；环H为3～8元脂杂环或被一个或多个Re取代的3～8元脂杂环；环I和环J各自独立地为3～8元脂杂环和5～8元内酰胺环；Re为C1-C6烷基。Preferably, R4-1for H or C1-C6Alkyl; R4-2for C1-C6Alkyl, R4-2The number is one or more; R4-3and R4-4Each independently is H or 3-6 membered heterocycloalkyl, or R4-3and R4-4The carbon atoms connected to it together form a 3-6 membered aliphatic heterocyclic ring; ring G, ring I and ring J share one carbon atom with the parent structure, ring F and ring H share two atoms and a bond with the parent structure, ring F and ring G are each independently C3-C8Aliphatic carbon ring; Ring H is a 3-8 membered aliphatic heterocyclic ring or is surrounded by one or more ReSubstituted 3-8 membered aliphatic heterocyclic ring; ring I and ring J are each independently 3-8 membered aliphatic heterocyclic ring and 5-8 membered lactam ring; Refor C1-C6alkyl.
某一实施方案中，RX1中，所述的卤素可独立地为F、Cl、Br或I，例如Cl。In a certain embodiment, in R X1 , the halogens can be independently F, Cl, Br or I, such as Cl.
某一实施方案中，RX1中，所述的C1-C6烷基可独立地为甲基、乙基、正丙基、异丙基、正丁基、异丁基或叔丁基，优选为甲基。In a certain embodiment, in R X1 , the C 1 -C 6 alkyl group can be independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, preferably methyl.
某一实施方案中，RX1中，所述的C3-C6环烷基可为环丙基、环丁基、环戊基或环己基，优选为环丙基。In a certain embodiment, in R X1 , the C 3 -C 6 cycloalkyl group can be cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, preferably cyclopropyl.
某一实施方案中，RX1中，所述的C2-C6烯基可为C2-C4烯基，例如乙烯基。In a certain embodiment, in R X1 , the C 2 -C 6 alkenyl can be a C 2 -C 4 alkenyl, such as vinyl.
某一实施方案中，RX1中，所述的C2-C6炔基可为C2-C4炔基，例如乙炔基。In a certain embodiment, in R X1 , the C 2 -C 6 alkynyl can be a C 2 -C 4 alkynyl, such as ethynyl.
某一实施方案中，RX1中，所述的3～6元杂环烷基中，杂原子的种类可独立地选自N和O，杂原子的个数可独立地为1个；In a certain embodiment, in R X1 , in the 3-6 membered heterocycloalkyl group, the type of heteroatoms can be independently selected from N and O, and the number of heteroatoms can be independently 1;
某一实施方案中，RX1中，所述的3～6杂环烷基可独立地为四氢吡咯基、氧杂环丁烷基、四氢吡喃基或哌啶基，更例如 In a certain embodiment, in R X1 , the 3-6 heterocycloalkyl groups can be independently tetrahydropyrrolyl, oxetanyl, tetrahydropyranyl or piperidinyl, more for example
某一实施方案中，RX1中，所述的5～14元杂芳基中，杂原子的种类可为N，杂原子的个数可为2个。In a certain embodiment, in the 5- to 14-membered heteroaryl group in R X1 , the type of heteroatoms can be N, and the number of heteroatoms can be 2.
某一实施方案中，RX1中，所述的5～14元杂芳基可为5～6元杂芳基，例如吡唑基或咪唑基，更例如 In a certain embodiment, in R X1 , the 5-14 membered heteroaryl group can be a 5-6 membered heteroaryl group, such as pyrazolyl or imidazolyl, more for example
某一实施方案中，RX1中，所述的3～6元杂环烯基中，杂原子的种类可各自独立地选自N和O，杂原子的个数可各自独立地为1个。In a certain embodiment, in R X1 , in the 3-6 membered heterocycloalkenyl group, the type of heteroatoms can be independently selected from N and O, and the number of heteroatoms can be independently 1.
某一实施方案中，RX1中，所述的3～6元杂环烯基可独立地为6元杂环烯基，例如含1个O原子 的6元杂环烯基或含1个N原子的6元杂环烯基，更例如 In a certain embodiment, in R X1 , the 3-6 membered heterocycloalkenyl groups can be independently 6-membered heterocycloalkenyl groups, for example, containing 1 O atom A 6-membered heterocycloalkenyl or a 6-membered heterocycloalkenyl containing 1 N atom, more for example
某一实施方案中，X1-1、X1-2、X1-3、X1-4、X1-5、X1-6和X1-7中，所述的C1-C6烷基可独立地为C1-C4烷基，例如甲基、乙基、正丙基、异丙基、正丁基、异丁基或叔丁基，优选为甲基或乙基。In a certain embodiment, in X 1-1 , X 1-2 , X 1-3 , X 1-4 , X 1-5 , X 1-6 and X 1-7 , the C 1 -C 6 alkyl group can be independently a C 1 -C 4 alkyl group, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, preferably methyl or ethyl.
某一实施方案中，X1-4中，所述的C3-C8环烷基可为C3-C6环烷基，例如环丙基、环丁基、环戊基或环己基，优选为环丙基、环戊基或环己基。In a certain embodiment, in X 1-4 , the C 3 -C 8 cycloalkyl can be a C 3 -C 6 cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, preferably cyclopropyl, cyclopentyl or cyclohexyl.
某一实施方案中，X1-4中，所述的3～8元杂环烷基可为3～6元杂环烷基，例如哌啶基、吗啉基或哌嗪基。In a certain embodiment, in X 1-4 , the 3-8 membered heterocycloalkyl group can be 3-6 membered heterocycloalkyl group, such as piperidinyl, morpholinyl or piperazinyl.
某一实施方案中，当RX1与RX3和其相连的原子共同形成C5-C8环烯酮结构时，所述的C5-C8环烯酮可为C5-C6环烯酮，例如环戊烯酮，此时，可为 In a certain embodiment, when R X1 and R X3 and the atoms connected to them jointly form a C 5 -C 8 cycloalkene structure, the C 5 -C 8 cycloalkene can be a C 5 -C 6 cycloalkene, such as cyclopentenone, at this time, Can be
某一实施方案中，当RX1’与RX3和其相连的原子共同形成5～8元杂芳环时或被一个或多个羟基取代的5～8元杂芳环，所述的5～8元杂芳环中杂原子的种类可独立地为N，所述杂原子的个数可独立地为2个、3个或4个。In a certain embodiment, when R X1' , R X3 and the atoms connected to them jointly form a 5-8 membered heteroaromatic ring or a 5-8 membered heteroaromatic ring substituted by one or more hydroxyl groups, the type of heteroatoms in the 5-8 membered heteroaromatic rings can be N independently, and the number of heteroatoms can be 2, 3 or 4 independently.
某一实施方案中，当RX1’与RX3和其相连的原子共同形成5～8元杂芳环时或被一个或多个羟基取代的5～8元杂芳环，所述的5～8元杂芳环可独立地为5元杂芳环，例如吡唑环、三氮唑环、四氮唑环或恶二唑环，此时，可为 In a certain embodiment, when R X1' and R X3 and the atoms connected to them jointly form a 5-8 membered heteroaromatic ring or a 5-8 membered heteroaromatic ring substituted by one or more hydroxyl groups, the 5-8 membered heteroaromatic ring can be independently a 5-membered heteroaromatic ring, such as a pyrazole ring, a triazole ring, a tetrazole ring or an oxadiazole ring, at this time, Can be
某一实施方案中，RX1为CN、Cl、CF3、NH2、N(CH3)2、NO2、NHSO2CH3、NHCOCH3、PO(CH3)2、SF5、C(＝O)H、C(＝O)CH3、C(＝O)CF3、C(＝O)CH2CH3、SO2CH3、SO3H、环丙基、乙烯基、乙炔基、四氢吡咯基、氧杂环丁烷基、四氢吡喃基、乙酰基取代的哌啶基、甲基取代的咪唑基、甲基取代的吡唑基、含1个O原子的6元杂环烯基、乙酰基取代的含1个N原子的6元杂环烯基、环丙基取代的羰基、环戊基取代的羰基或环己基取代的羰基，例如CN、Cl、CF3、NH2、N(CH3)2、NO2、NHSO2CH3、NHCOCH3、PO(CH3)2、SF5、C(＝O)H、C(＝O)CH3、C(＝O)CF3、C(＝O)CH2CH3、SO2CH3、SO3H、环丙 基、乙烯基、乙炔基、 某一实施方案中，R X1为CN、Cl、CF 3 、NH 2 、N(CH 3 ) 2 、NO 2 、NHSO 2 CH 3 、NHCOCH 3 、PO(CH 3 ) 2 、SF 5 、C(＝O)H、C(＝O)CH 3 、C(＝O)CF 3 、C(＝O)CH 2 CH 3 、SO 2 CH 3 、SO 3 H、环丙基、乙烯基、乙炔基、四氢吡咯基、氧杂环丁烷基、四氢吡喃基、乙酰基取代的哌啶基、甲基取代的咪唑基、甲基取代的吡唑基、含1个O原子的6元杂环烯基、乙酰基取代的含1个N原子的6元杂环烯基、环丙基取代的羰基、环戊基取代的羰基或环己基取代的羰基，例如CN、Cl、CF 3 、NH 2 、N(CH 3 ) 2 、NO 2 、NHSO 2 CH 3 、NHCOCH 3 、PO(CH 3 ) 2 、SF 5 、C(＝O)H、C(＝O)CH 3 、C(＝O)CF 3 、C(＝O)CH 2 CH 3 、SO 2 CH 3 、SO 3 H、环丙base, vinyl, ethynyl,
某一实施方案中，R1中，所述的C6～C14的芳基可独立地为苯基或萘基，例如 In a certain embodiment, in R 1 , the C 6 -C 14 aryl groups can be independently phenyl or naphthyl, for example
某一实施方案中，R1中，所述的5～14元杂芳基中，杂原子的种类可独立地为N，杂原子的个数可独立地为1个。In a certain embodiment, in the 5- to 14-membered heteroaryl group in R 1 , the type of heteroatom can be independently N, and the number of heteroatom can be independently 1.
某一实施方案中，R1中，所述的5～14元杂芳基可独立地为5～12元杂芳基，例如吡啶基、喹啉基或异喹啉基，更例如 In a certain embodiment, in R 1 , the 5-14 membered heteroaryl groups can be independently 5-12 membered heteroaryl groups, such as pyridyl, quinolinyl or isoquinolyl, more for example
某一实施方案中，R1-1、R1-2、R1-3和R1-4中，所述的卤素可独立地为F、Cl、Br或I，例如F或Cl。In a certain embodiment, among R 1-1 , R 1-2 , R 1-3 and R 1-4 , the halogens can be independently F, Cl, Br or I, such as F or Cl.
某一实施方案中，R1-1和R1-2中，所述的C1-C6烷基可独立地为C1-C4烷基，例如甲基、乙基、正丙基、异丙基、正丁基、异丁基或叔丁基，优选为甲基或乙基。In a certain embodiment, in R 1-1 and R 1-2 , the C 1 -C 6 alkyl group can be independently a C 1 -C 4 alkyl group, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, preferably methyl or ethyl.
某一实施方案中，R1-1和R1-2中，所述的C1-C10烷基可独立地为C1-C9烷基，例如正壬基。In a certain embodiment, in R 1-1 and R 1-2 , the C 1 -C 10 alkyl group can be independently a C 1 -C 9 alkyl group, such as n-nonyl.
某一实施方案中，n1为2。In a certain embodiment, n1 is 2.
某一实施方案中，n2为6。In a certain embodiment, n2 is 6.
某一实施方案中，n3为4。In a certain embodiment, n3 is 4.
某一实施方案中，n4为1。In a certain embodiment, n4 is 1.
某一实施方案中，n5为1。In a certain embodiment, n5 is 1.
某一实施方案中，R1为一个或多个R1-1取代的萘基、一个或多个R1-1取代的苯基、被一个或多个R1-2取代的吡啶基、被一个或多个R1-2取代的喹啉基或被一个或多个R1-2取代的异喹啉基，例如
In a certain embodiment, R is one or more R 1-1 substituted naphthyl, one or more R 1-1 substituted phenyl, one or more R 1-2 substituted pyridyl, one or more R 1-2 substituted quinolinyl or one or more R 1-2 substituted isoquinolinyl, for example
某一实施方案中，R2中，所述的卤素可为F、Cl、Br或I，例如F。In a certain embodiment, in R 2 , the halogen can be F, Cl, Br or I, such as F.
某一实施方案中，R2中，所述的C1-C6烷基可为C1-C4烷基，例如甲基、乙基、正丙基、异丙基、正丁基、异丁基或叔丁基。In a certain embodiment, in R 2 , the C 1 -C 6 alkyl group can be a C 1 -C 4 alkyl group, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl.
某一实施方案中，R2中，所述的C1-C6烷氧基可为C1-C4烷氧基，例如甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基或叔丁氧基。In a certain embodiment, in R 2 , the C 1 -C 6 alkoxy group can be a C 1 -C 4 alkoxy group, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy or tert-butoxy.
某一实施方案中，R2为F。In a certain embodiment, R 2 is F.
某一实施方案中，L2中，所述的C1-C6亚烷基可为C1-C3亚烷基，例如亚甲基、亚乙基或亚丙基，优选为亚甲基。In a certain embodiment, in L 2 , the C 1 -C 6 alkylene group can be a C 1 -C 3 alkylene group, such as methylene, ethylene or propylene, preferably methylene.
某一实施方案中，R3定义中，所述的3～8元脂杂环中，杂原子的种类可独立地为O，杂原子的数目可独立地为1个。In a certain embodiment, in the definition of R 3 , in the 3-8 membered aliphatic heterocyclic ring, the type of heteroatom can be independently O, and the number of heteroatom can be independently 1.
本文中，“R3定义中，所述的3～8元脂杂环”指上述R3定义范围内所述的所有的3～8元脂杂环，例如环A、环B、环C、环D和环E中的3～8元脂杂环。Herein, "in the definition of R 3 , the 3-8 membered aliphatic heterocyclic ring" refers to all 3-8 membered aliphatic heterocyclic rings within the scope of the above definition of R 3 , such as the 3-8 membered aliphatic heterocyclic rings in ring A, ring B, ring C, ring D and ring E.
某一实施方案中，R3定义中，所述的3～8元脂杂环可独立地为4～5元脂杂环，例如氧杂环丁烷或四氢呋喃环。 In a certain embodiment, in the definition of R 3 , the 3-8 membered aliphatic heterocyclic rings can be independently 4-5 membered aliphatic heterocyclic rings, such as oxetane or tetrahydrofuran rings.
某一实施方案中，R3定义中，所述的3～8元脂杂环可独立地为例如环A、环B和环C中所述的3～8元脂杂环可独立地为 In a certain embodiment, in the definition of R 3 , the 3-8 membered aliphatic heterocycles can be independently For example, the 3-8 membered aliphatic heterocyclic rings described in ring A, ring B and ring C can be independently
某一实施方案中，R3定义中，所述的3～8元脂杂环可独立地为例如环D和环E中，所述的3～8元脂杂环可独立地为 In a certain embodiment, in the definition of R 3 , the 3-8 membered aliphatic heterocycles can be independently For example, in ring D and ring E, the 3-8 membered aliphatic heterocycles can be independently
某一实施方案中，R3定义中，所述的C3-C8脂碳环可独立地为C3-C6脂碳环，例如环丙烷、环丁烷、环戊烷或环己烷，优选为环丙烷。In a certain embodiment, in the definition of R 3 , the C 3 -C 8 aliphatic carbocycle can be independently a C 3 -C 6 aliphatic carbocycle, such as cyclopropane, cyclobutane, cyclopentane or cyclohexane, preferably cyclopropane.
本文中，“R3定义中，所述的C3-C8脂碳环”指上述R3定义范围内所述的所有的C3-C8脂碳环，例如。Herein, "in the definition of R 3 , the said C 3 -C 8 aliphatic carbocycle" refers to all the C 3 -C 8 aliphatic carbocycles mentioned within the scope of the above definition of R 3 , for example.
某一实施方案中，R3定义中，所述的C3-C8脂碳环可独立地为例如环A、环B和环C中，所述的C3-C8脂碳环可独立地为 In a certain embodiment, in the definition of R 3 , the C 3 -C 8 aliphatic carbocycles can be independently For example, in ring A, ring B and ring C, the C 3 -C 8 aliphatic carbocyclic ring can be independently
某一实施方案中，R3定义中，所述的C3-C8脂碳环可独立地为例如环D和环E中，所述的C3-C8脂碳环可独立地为 In a certain embodiment, in the definition of R 3 , the C 3 -C 8 aliphatic carbocycles can be independently For example, in ring D and ring E, the C 3 -C 8 aliphatic carbocyclic ring can be independently
某一实施方案中，R3定义中，所述的卤素可为F、Cl、Br或I，例如F。In a certain embodiment, in the definition of R 3 , the halogen can be F, Cl, Br or I, such as F.
本文中，“R3定义中，所述的卤素”指上述R3定义范围内所述的所有的卤素，例如环A、环B、环C、环D和环E中的卤素。Herein, "in the definition of R 3 , the halogen" refers to all the halogens mentioned in the definition of R 3 above, such as the halogens in ring A, ring B, ring C, ring D and ring E.
某一实施方案中，R4-1和R4-2中，所述的C1-C6烷基可各自独立地为C1-C4烷基，例如甲基、乙基、正丙基、异丙基、正丁基、异丁基或叔丁基，优选为甲基。In a certain embodiment, in R 4-1 and R 4-2 , the C 1 -C 6 alkyl groups can be independently C 1 -C 4 alkyl groups, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, preferably methyl.
某一实施方案中，R4-1中，所述的C1-C10烷基可为C1-C9烷基，例如正壬基或异丙基。In a certain embodiment, in R 4-1 , the C 1 -C 10 alkyl group can be a C 1 -C 9 alkyl group, such as n-nonyl or isopropyl.
某一实施方案中，RW1、RW2、R4-3和R4-4中，所述的3～8元杂环烷基中，杂原子的种类可独立地选自N和O，杂原子的个数可独立地为1个或2个。In a certain embodiment, among R W1 , R W2 , R 4-3 and R 4-4 , in the 3-8 membered heterocycloalkyl group, the type of heteroatoms can be independently selected from N and O, and the number of heteroatoms can be independently 1 or 2.
某一实施方案中，RW1、RW2、R4-3和R4-4中，所述的3～8元杂环烷基可独立地为4～6元杂环烷基，例如四氢吡咯基、吗啉基或哌啶基，更例如 In a certain embodiment, in R W1 , R W2 , R 4-3 and R 4-4 , the 3-8 membered heterocycloalkyl groups can be independently 4-6 membered heterocycloalkyl groups, such as tetrahydropyrrolyl, morpholinyl or piperidinyl, more for example
某一实施方案中，当RW1和RW2与其相连的原子共同形成3～8元脂杂环或当R4-3和R4-4与其相 连的碳原子共同形成3～8元脂杂环时，所述的3～8元脂杂环可为4～5元脂杂环，例如N杂环丁烷，更例如 In a certain embodiment, when R W1 and R W2 form a 3-8-membered aliphatic heterocyclic ring together with the atoms connected to them or when R 4-3 and R 4-4 correspond to When the connected carbon atoms together form a 3-8 membered aliphatic heterocyclic ring, the 3-8 membered aliphatic heterocyclic ring can be a 4-5 membered aliphatic heterocyclic ring, such as N-heterocyclobutane, more for example
某一实施方案中，R4定义中，所述的C3-C8脂碳环可独立地为C3-C6脂碳环，例如环丙烷、环丁烷、环戊烷或环己烷，优选为环丙烷、环丁烷或环己烷。In a certain embodiment, in the definition of R 4 , the C 3 -C 8 aliphatic carbocycle can be independently a C 3 -C 6 aliphatic carbocycle, such as cyclopropane, cyclobutane, cyclopentane or cyclohexane, preferably cyclopropane, cyclobutane or cyclohexane.
本文中，“R4定义中，所述的C3-C8脂碳环”是指上述R4定义范围内所有的C3-C8脂碳环，例如环F、环G、环H、环I和环J中的C3-C8脂碳环。Herein, "in the definition of R 4 , the C 3 -C 8 aliphatic carbocycle" refers to all C 3 -C 8 aliphatic carbocycles within the scope of the definition of R 4 above, such as C 3 -C 8 aliphatic carbocycles in ring F, ring G, ring H, ring I and ring J.
某一实施方案中，R4定义中，所述的C3-C8脂碳环可独立地为例如环F和环H中，所述的C3-C8脂碳环可独立地为 In a certain embodiment, in the definition of R 4 , the C 3 -C 8 aliphatic carbocycles can be independently For example, in ring F and ring H, the C 3 -C 8 aliphatic carbocyclic ring can be independently
某一实施方案中，R4定义中，所述的C3-C8脂碳环可独立地为例如环G、环I和环J中，所述的C3-C8脂碳环可独立地为 In a certain embodiment, in the definition of R 4 , the C 3 -C 8 aliphatic carbocycles can be independently For example, in ring G, ring I and ring J, the C 3 -C 8 aliphatic carbocyclic ring can be independently
某一实施方案中，R4定义中，所述的3～8元脂杂环可独立地为4～5元脂杂环，例如四氢吡咯环或N杂环丁烷。In a certain embodiment, in the definition of R 4 , the 3-8 membered aliphatic heterocyclic rings can be independently 4-5 membered aliphatic heterocyclic rings, such as tetrahydropyrrole ring or N-heterocyclobutane.
本文中，“R4定义中，所述的3～8元脂杂环”是指上述R4定义范围内所有的3～8元脂杂环，例如环F、环G、环H、环I和环J中的3～8元脂杂环。Herein, "in the definition of R 4 , the 3-8 membered aliphatic heterocyclic ring" refers to all 3-8 membered aliphatic heterocyclic rings within the scope of the definition of R 4 above, such as the 3-8 membered aliphatic heterocyclic rings in ring F, ring G, ring H, ring I and ring J.
某一实施方案中，R4定义中，所述的3～8元脂杂环可独立地为例如环F和环H中，所述的3～8元脂杂环可独立地为 In a certain embodiment, in the definition of R 4 , the 3-8 membered aliphatic heterocycles can be independently For example, in ring F and ring H, the 3-8 membered aliphatic heterocycles can be independently
某一实施方案中，R4定义中，所述的3～8元脂杂环可独立地为例如环G、环I和环J中，所述的3～8元脂杂环可独立地为 In a certain embodiment, in the definition of R 4 , the 3-8 membered aliphatic heterocycles can be independently For example, in Ring G, Ring I and Ring J, the 3-8 membered aliphatic heterocycles can be independently
某一实施方案中，环F、环G、环H、环I和环J中，所述的5～8元内酰胺环可独立地为5元内酰胺环。In a certain embodiment, among ring F, ring G, ring H, ring I and ring J, the 5- to 8-membered lactam rings may be independently 5-membered lactam rings.
某一实施方案中，环G、环I和环J中，所述的5～8元内酰胺环可独立地为 In a certain embodiment, in ring G, ring I and ring J, the 5- to 8-membered lactam rings can be independently
某一实施方案中，Re中，所述的C1-C6烷基可为C1-C4烷基，例如甲基、乙基、正丙基、异丙基、 正丁基、异丁基或叔丁基，优选为甲基。In a certain embodiment, in R e , the C 1 -C 6 alkyl group can be a C 1 -C 4 alkyl group, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, preferably methyl.
某一实施方案中，X可为F、Cl、Br或I，例如F或Br。In a certain embodiment, X can be F, Cl, Br or I, such as F or Br.
某一实施方案中，R3为 时，In a certain embodiment, R3 is hour,
某一实施方案中，R4为 In a certain embodiment, R 4 is
某一实施方案中，当R3为 时；In a certain embodiment, when R 3 is hour;
R4为 R4 is
某一实施方案中，当R3为 时，In a certain embodiment, when R 3 is hour,
R4为 R4 is
某一实施方案中，In one embodiment,
R4为 R4 is
R4-3和R4-4各自独立地为H或3～8元杂环烷基，所述的3～8元杂环烷基较佳地为四氢吡咯基或哌啶基，例如 R 4-3 and R 4-4 are each independently H or 3-8 membered heterocycloalkyl, and said 3-8 membered heterocycloalkyl is preferably tetrahydropyrrolyl or piperidinyl, for example
环H为3～8元脂杂环或被一个或多个Re取代的3～8元脂杂环，较佳地为3～8元脂杂环，例如四氢吡咯环，更例如 Ring H is a 3-8 membered aliphatic heterocyclic ring or a 3-8 membered aliphatic heterocyclic ring substituted by one or more R e , preferably a 3-8 membered aliphatic heterocyclic ring, such as a tetrahydropyrrole ring, more for example
某一实施方案中，X1为N；In a certain embodiment, X is N;
R3为 R3 is
环A为3～8元脂杂环、C3-C8脂碳环或一个或多个卤素取代的C3-C8脂碳环，例如氧杂环丁烷、环丙烷、或F取代的环丙烷，更例如环D和环E各自独立地为为C3-C8脂碳环，例如环丙烷，更例如 Ring A is a 3-8 membered aliphatic heterocycle, a C 3 -C 8 aliphatic carbocycle or a C 3 -C 8 aliphatic carbocycle substituted by one or more halogens, such as oxetane, cyclopropane, or F-substituted cyclopropane, more for example Ring D and ring E are each independently a C 3 -C 8 aliphatic carbocyclic ring, such as cyclopropane, more for example
某一实施方案中，X1为CRX1； In a certain embodiment, X 1 is CR X1 ;
RX1为CN、NO2、卤素、被一个或多个卤素取代的C1-C6烷基、C3-C6环烷基、3～6元杂环烷基、3～6元杂环烯基、C2-C6烯基、C2-C6炔基、PO(C1-C6烷基)2、被一个或多个X1-1取代的3～6元杂环烷基、被一个或多个X1-2取代的5～14元杂芳基、被一个或多个X1-3取代的3～6元杂环烯基、C(＝O)X1- 4、NX1-5X1-6或SO2X1-7；R X1 is CN, NO 2 , halogen, C 1 -C 6 alkyl substituted by one or more halogens, C 3 -C 6 cycloalkyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, PO(C 1 -C 6 alkyl) 2 , 3-6 membered heterocycloalkyl substituted by one or more X 1-1 , substituted by one or more X 1-2 5-14-membered heteroaryl, 3-6-membered heterocycloalkenyl substituted by one or more X 1-3 , C(=O)X 1- 4 , NX 1-5 X 1-6 or SO 2 X 1-7 ;
所述的3～6元杂环烷基较佳地为氧杂环丁烷基或四氢吡咯基，例如 The 3-6 membered heterocycloalkyl is preferably oxetanyl or tetrahydropyrrolyl, for example
所述的5～14元杂芳基较佳地为吡唑基，例如 The 5-14 membered heteroaryl is preferably pyrazolyl, for example
R3为 R3 is
环A较佳地为被一个或多个卤素取代的C3-C8脂碳环，例如被F取代的环丙烷，更例如 Ring A is preferably a C 3 -C 8 aliphatic carbocyclic ring substituted by one or more halogens, such as cyclopropane substituted by F, more for example
某一实施方案中，R1为被一个或多个R1-1取代的C6～C14的芳基或被一个或多个R1-2取代的5～14元杂芳基；In a certain embodiment, R 1 is a C 6 -C 14 aryl group substituted by one or more R 1-1 or a 5-14 membered heteroaryl group substituted by one or more R 1-2 ;
当R1为被一个或多个R1-1取代的C6～C14的芳基时，相邻的两个R1-1与其相连的原子一起形成C3-C8脂碳环或被一个或多个R1-3取代的C3-C8脂碳环，其余R1-1独立地为卤素、OH、NH2、CN、C1-C6烷基、(C＝O)-C1-C6烷基、C2-C6炔基、被一个或多个卤素取代的C1-C6烷基、B(OH)2或O(C＝O)-C1-C10烷基；When R 1 is a C 6 -C 14 aryl group substituted by one or more R 1-1 , two adjacent R 1-1 and the atoms connected to it together form a C 3 -C 8 aliphatic carbon ring or a C 3 -C 8 aliphatic carbon ring substituted by one or more R 1-3 , and the remaining R 1-1 are independently halogen, OH, NH 2 , CN, C 1 -C 6 alkyl, (C=O)-C 1 -C 6 alkyl , C 2 -C 6 alkynyl, C 1 -C 6 alkyl substituted by one or more halogens, B(OH) 2 or O(C=O)-C 1 -C 10 alkyl;
当R1为被一个或多个R1-2取代的5～14元杂芳基时，相邻的两个R1-2与其相连的原子一起形成C3-C8脂碳环或被一个或多个R1-4取代的C3-C8脂碳环，其余R1-2独立地为卤素、OH、NH2、CN、C1-C6烷基、(C＝O)-C1-C6烷基、C2-C6炔基、被一个或多个卤素取代的C1-C6烷基、B(OH)2或O(C＝O)-C1-C10烷基；When R 1 is a 5- to 14-membered heteroaryl group substituted by one or more R 1-2 , two adjacent R 1-2 and their connected atoms together form a C 3 -C 8 aliphatic carbon ring or a C 3 -C 8 aliphatic carbon ring substituted by one or more R 1-4 , and the remaining R 1-2 are independently halogen, OH, NH 2 , CN, C 1 -C 6 alkyl, (C=O)-C 1 -C 6 alkyl, C 2 -C 6 alkynyl, C 1 -C 6 alkyl substituted by one or more halogens, B(OH) 2 or O(C=O)-C 1 -C 10 alkyl;
R1-3和R1-4独立地为卤素。R 1-3 and R 1-4 are independently halogen.
某一实施方案中，所述如式I-0所示的杂环类化合物为如式I所示的杂环类化合物：
In a certain embodiment, the heterocyclic compound shown in formula I-0 is a heterocyclic compound shown in formula I:
其中，in,
X1为N或CRX1，RX1为CN、卤素、CF3、SO2Me、POMe2或NH2；X 1 is N or CR X1 , R X1 is CN, halogen, CF 3 , SO 2 Me, POMe 2 or NH 2 ;
X2为N或CRX2，RX2为CN； X 2 is N or CR X2 , R X2 is CN;
R1为 R1 is
R2为卤素；R 2 is halogen;
R3和R4的定义选自以下任一方案：The definitions of R and R are selected from any of the following schemes:
方案一：Option One:
R3为 时， R3 is hour,
R4为 R4 is
方案二：Option II:
R3为 时， R3 is hour,
R4为 R4 is
在本发明某些优选实施方案中，所述的如式I所示的杂环类化合物、其药学上可接受的盐、其立体异构体或它们的溶剂合物中的某些基团如下定义，未提及的基团同本申请任一方案所述(简称“在本发明某一方案中”)，X1为N、C-CN、C-Cl、C-CF3、C-SO2Me、C-POMe2或C-NH2。In some preferred embodiments of the present invention, certain groups in the heterocyclic compound represented by formula I, its pharmaceutically acceptable salts, its stereoisomers or their solvates are defined as follows, and the unmentioned groups are the same as those described in any scheme of the present application (referred to as "in a certain scheme of the present invention"), and X1 is N, C-CN, C-Cl, C- CF3 , C- SO2Me , C- POMe2 or C- NH2 .
在本发明某一方案中，X2为N或C-CN。In a certain aspect of the present invention, X 2 is N or C-CN.
在本发明某一方案中，R2为F。In a certain aspect of the present invention, R 2 is F.
某一实施方案中，所述如式I-0所示的化合物为如式I-1所示的化合物：
In a certain embodiment, the compound shown in formula I-0 is a compound shown in formula I-1:
其中，R4为J为H或卤素；Among them, R4 is J is H or halogen;
其为以下情况中的任一种：It is any of the following:
1)X1为CRX1，RX1为被一个或多个卤素取代的C1-C6烷基、PO(C1-C6烷基)2、C3-C6环烷基、C2-C6烯基、C2-C6炔基、3～6元杂环烷基、被一个或多个X1-1取代的3～6元杂环烷基、被一个或多个X1- 2取代的5～8元杂芳基、NO2、3～6元杂环烯基、被一个或多个X1-3取代的3～6元杂环烯基、SF5、C(＝O)X1-4、NX1-5X1-6或SO2X1-7；或者RX1与RX3和其相连的原子共同形成C5-C8环烯酮结构；其他取代基的定义均如本文任一方案所述；1)X1for CRX1, RX1is C substituted by one or more halogens1-C6Alkyl, PO(C1-C6alkyl)2、C3-C6Cycloalkyl, C2-C6Alkenyl, C2-C6Alkynyl, 3-6 membered heterocycloalkyl, replaced by one or more X1-1Substituted 3-6 membered heterocycloalkyl, replaced by one or more X1- 2Substituted 5-8 membered heteroaryl, NO2, 3-6 membered heterocycloalkenyl, replaced by one or more X1-3Substituted 3-6 membered heterocycloalkenyl, SF5, C(=O)X1-4、NX1-5x1-6or SO2x1-7; or RX1with RX3Together with its attached atoms form C5-C8Cycloalkene structure; The definitions of other substituents are all as described in any scheme herein;
2)X1为NRX1’，RX1’与RX3和其相连的原子共同形成5～8元杂芳环或被一个或多个羟基取代的5～8元杂芳环；其他取代基的定义均如本文任一方案所述；2) X 1 is NR X1' , and R X1' and R X3 together with the atoms connected to them form a 5-8 membered heteroaromatic ring or a 5-8 membered heteroaromatic ring substituted by one or more hydroxyl groups; the definitions of other substituents are as described in any scheme herein;
3)X1为CRX1，其中，X1中的C原子与R1中的芳基或杂芳基中的C原子通过-O-(CH2)n1-*、*-NH-(CH2)n2-、-C≡C-(CH2)n3-C≡C-*或-(CH2)n4-O-(CH2)n5-*相连，其中，*端与X1中的C原子相连；其他取代基的定义以及n1、n2、n3、n4和n5的定义均如本文任一方案所述；3) X 1 is CR X1 , wherein, the C atom in X 1 is connected to the C atom in the aryl or heteroaryl group in R 1 through -O-(CH 2 ) n1 - * , * -NH-(CH 2 ) n2 - , -C≡C- (CH 2 ) n3 -C≡C- * or -(CH 2 ) n4 -O-(CH 2 ) n5 - * , where the * end is connected to X 1 C atoms are connected; the definitions of other substituents and the definitions of n1, n2, n3, n4 and n5 are as described in any scheme herein;
4)R1为被一个或多个R1-1取代的C6～C14的芳基或被一个或多个R1-2取代的5～14元杂芳基；4) R 1 is a C 6 -C 14 aryl group substituted by one or more R 1-1 or a 5-14 membered heteroaryl group substituted by one or more R 1-2 ;
当R1为被一个或多个R1-1取代的C6～C14的芳基时，相邻的两个R1-1与其相连的原子一起形成C3-C8脂碳环或被一个或多个R1-3取代的C3-C8脂碳环，其余R1-1独立地为卤素、OH、NH2、CN、C1-C6烷基、(C＝O)-C1-C6烷基、C2-C6炔基、被一个或多个卤素取代的C1-C6烷基、B(OH)2或O(C＝O)-C1-C10烷基；When R 1 is a C 6 -C 14 aryl group substituted by one or more R 1-1 , two adjacent R 1-1 and the atoms connected to them together form a C 3 -C 8 aliphatic carbon ring or a C 3 -C 8 aliphatic carbon ring substituted by one or more R 1-3 , and the remaining R 1-1 are independently halogen, OH, NH 2 , CN, C 1 -C 6 alkyl, (C=O)-C 1 -C 6 alkyl , C 2 -C 6 alkynyl, C 1 -C 6 alkyl substituted by one or more halogens, B(OH) 2 or O(C=O)-C 1 -C 10 alkyl;
当R1为被一个或多个R1-2取代的5～14元杂芳基时，相邻的两个R1-2与其相连的原子一起形成C3-C8脂碳环或被一个或多个R1-4取代的C3-C8脂碳环，其余R1-2独立地为卤素、OH、NH2、CN、C1-C6烷基、(C＝O)-C1-C6烷基、C2-C6炔基、被一个或多个卤素取代的C1-C6烷基、B(OH)2或O(C＝O)-C1-C10烷基；When R 1 is a 5- to 14-membered heteroaryl group substituted by one or more R 1-2 , two adjacent R 1-2 and their connected atoms together form a C 3 -C 8 aliphatic carbon ring or a C 3 -C 8 aliphatic carbon ring substituted by one or more R 1-4 , and the remaining R 1-2 are independently halogen, OH, NH 2 , CN, C 1 -C 6 alkyl, (C=O)-C 1 -C 6 alkyl, C 2 -C 6 alkynyl, C 1 -C 6 alkyl substituted by one or more halogens, B(OH) 2 or O(C=O)-C 1 -C 10 alkyl;
R1-3和R1-4独立地为卤素；R 1-3 and R 1-4 are independently halogen;
其余各取代基的定义均如本文任一方案所述。The definitions of all other substituents are as described in any scheme herein.
某一实施方案中，所述如式I-0所示的化合物为如式I-2所示的化合物：
In a certain embodiment, the compound shown in formula I-0 is a compound shown in formula I-2:
其为以下情况中的任一种：It is any of the following:
1)R3为 时，其中，环A、环B和环C与母体结构共用一个碳原子，环D和环E与母体结构共用两个原子和一根键；环A、环B、环C、环D和环E各自独立地为3～8元脂杂环、C3-C8脂碳环或被一个或多个卤素取代的C3-C8脂碳环；1) R3 is , wherein, Ring A, Ring B and Ring C share one carbon atom with the parent structure, Ring D and Ring E share two atoms and one bond with the parent structure; Ring A, Ring B, Ring C, Ring D and Ring E are each independently 3-8 membered aliphatic heterocyclic rings, C 3 -C 8 aliphatic carbocyclic rings, or C 3 -C 8 aliphatic carbocyclic rings substituted by one or more halogens;
R4为 其中，R4-1为H、C1-C6烷基或(C＝O)-O-CH2-O-(C＝O)-C1-C10烷基；R4-2为C1-C6烷基，R4-2的个数为一个或多个；R4-3和R4-4各自独立地为H或3～8元杂环烷基，或者R4-3和R4-4与其相连的碳原子共同形成3～8元脂杂环；环G、环I和环J与母体结构共用一个碳原子，环F和环H与母体结构共用两个原子和一根键，环F、环G、环H、环I和环J各自独立地为C3-C8脂碳环、3～8元脂杂环、5～8元内酰胺环或被一个或多个Re取代的3～8元脂杂环；Re为C1-C6烷基； R4 is 其中，R 4-1为H、C 1 -C 6烷基或(C＝O)-O-CH 2 -O-(C＝O)-C 1 -C 10烷基；R 4-2为C 1 -C 6烷基，R 4-2的个数为一个或多个；R 4-3和R 4-4各自独立地为H或3～8元杂环烷基，或者R 4-3和R 4-4与其相连的碳原子共同形成3～8元脂杂环；环G、环I和环J与母体结构共用一个碳原子，环F和环H与母体结构共用两个原子和一根键，环F、环G、环H、环I和环J各自独立地为C 3 -C 8脂碳环、3～8元脂杂环、5～8元内酰胺环或被一个或多个R e取代的3～8元脂杂环；R e为C 1 -C 6烷基；
其余各取代基的定义均如本文任一方案所述；The definitions of all the other substituents are as described in any scheme herein;
2)R3为 时，其中X为卤素；环A、环B和环C与母体结构共用一个碳原子，环D和环E与母体结构共用两个原子和一根键；环A、环B、环C、环D和环E各自独立地为3～8元脂杂环、C3-C8脂碳环或被一个或多个卤素取代的C3-C8脂碳环；2) R3 is When X is halogen; ring A, ring B and ring C share one carbon atom with the parent structure, ring D and ring E share two atoms and one bond with the parent structure; ring A, ring B, ring C, ring D and ring E are each independently 3-8 membered aliphatic heterocyclic rings, C 3 -C 8 aliphatic carbocyclic rings, or C 3 -C 8 aliphatic carbocyclic rings substituted by one or more halogens;
R4为 其中，X为卤素；R4-1为C1-C6烷基或(C＝O)-O-CH2-O-(C＝O)-C1-C10烷基；R4-3和R4-4各自独立地为H或3～8元杂环烷基，或者R4-3和R4-4与其相连的碳原子共同形成3～8元脂杂环；环G、环I和环J与母体结构共用一个碳原子，环F和环H与母体结构共用两个原子和一根键，环F、环G、环H、环I和环J各自独立地为C3-C8脂碳环、3～8元脂杂环、5～8元内酰胺环或被一个或多个Re取代的3～8元脂杂环；Re为C1-C6烷基； R4 is 其中，X为卤素；R 4-1为C 1 -C 6烷基或(C＝O)-O-CH 2 -O-(C＝O)-C 1 -C 10烷基；R 4-3和R 4-4各自独立地为H或3～8元杂环烷基，或者R 4-3和R 4-4与其相连的碳原子共同形成3～8元脂杂环；环G、环I和环J与母体结构共用一个碳原子，环F和环H与母体结构共用两个原子和一根键，环F、环G、环H、环I和环J各自独立地为C 3 -C 8脂碳环、3～8元脂杂环、5～8元内酰胺环或被一个或多个R e取代的3～8元脂杂环；R e为C 1 -C 6烷基；
其余各取代基的定义均如本文任一方案所述。The definitions of all other substituents are as described in any scheme herein.
本发明还提供了一种如下所示的杂环类化合物、其药学上可接受的盐、其立体异构体、或它们(指前述如下所示的杂环类化合物、其药学上可接受的盐或其立体异构体)的溶剂合物：














The present invention also provides a heterocyclic compound as shown below, its pharmaceutically acceptable salt, its stereoisomer, or their solvate (referring to the aforementioned heterocyclic compound as shown below, its pharmaceutically acceptable salt or its stereoisomer):














在某一优选方案中，所述杂环类化合物的药学上可接受的盐如下所示：


In a preferred embodiment, the pharmaceutically acceptable salt of the heterocyclic compound is as follows:


本发明还提供了一种如下所示的杂环类化合物、其药学上可接受的盐、其立体异构体或它们(指前述如下所示的杂环类化合物、其药学上可接受的盐或其立体异构体)的溶剂合物：The present invention also provides a heterocyclic compound as shown below, its pharmaceutically acceptable salt, its stereoisomer or their solvate (referring to the aforementioned heterocyclic compound as shown below, its pharmaceutically acceptable salt or its stereoisomer):
在下述条件下保留时间为0.660min的化合物，其为中的一个立体异构体：色谱柱:Chiralpak AD-3，50mm*4.6mm，3um；流动相：A相为二氧化碳，B相为0.05％二乙胺/乙醇；梯度：保持50％的B相5分钟，流速：4毫升/分钟； The compound whose retention time is 0.660min under the following conditions is One stereoisomer in: Chromatographic column: Chiralpak AD-3, 50mm*4.6mm, 3um; Mobile phase: A phase is carbon dioxide, B phase is 0.05% diethylamine/ethanol; Gradient: keep 50% of B phase for 5 minutes, flow rate: 4 ml/min;
在下述条件下保留时间为2.147min的化合物，其为中的一个立体异构体：色谱柱:Chiralpak AD-3，50mm*4.6mm，3um；流动相：A相为二氧化碳，B相为0.05％二乙胺/乙醇；梯度：保持50％的B相5分钟，流速：4毫升/分钟；The compound whose retention time is 2.147min under the following conditions is One stereoisomer in: Chromatographic column: Chiralpak AD-3, 50mm*4.6mm, 3um; Mobile phase: A phase is carbon dioxide, B phase is 0.05% diethylamine/ethanol; Gradient: keep 50% of B phase for 5 minutes, flow rate: 4 ml/min;
在下述条件下保留时间为2.311min的化合物，其为中的一个立体异构体：色谱柱:Chiralpak IG-3 100*4.6mm I.D.，3um；流动相：A相为二氧化碳，B相为0.05％二乙胺/乙醇；梯度：B相在4分钟内从5％到40％，保持40％的B相2.5分钟，保持5％的B相1.5分钟，流速：2.8毫升/分钟；The compound whose retention time is 2.311min under the following conditions is One stereoisomer in: Chromatographic column: Chiralpak IG-3 100*4.6mm ID, 3um; Mobile phase: A phase is carbon dioxide, B phase is 0.05% diethylamine/ethanol; Gradient: B phase from 5% to 40% in 4 minutes, keep 40% B phase for 2.5 minutes, keep 5% B phase for 1.5 minutes, flow rate: 2.8 ml/min;
在下述条件下保留时间为3.397min的化合物，其为中的一个立体异构体：色谱柱:Chiralpak IG-3 100*4.6mm I.D.，3um；流动相：A相为二氧化碳，B相为0.05％二乙胺/乙醇；梯度：B相在4分钟内从5％到40％，保持40％的B相2.5分钟，保持5％的B相1.5分钟，流速：2.8毫升/分钟；The compound whose retention time is 3.397min under the following conditions is One stereoisomer in: Chromatographic column: Chiralpak IG-3 100*4.6mm ID, 3um; Mobile phase: A phase is carbon dioxide, B phase is 0.05% diethylamine/ethanol; Gradient: B phase from 5% to 40% in 4 minutes, keep 40% B phase for 2.5 minutes, keep 5% B phase for 1.5 minutes, flow rate: 2.8 ml/min;
在下述条件下保留时间为4.236min的化合物，其为中的一个立体异构体：色谱柱:Chiralpak IE 100*4.6mm 3um；流动相：A相为0.1％二乙胺/正庚烷，B相为异丙醇；梯度：A/B＝60/40，流速：1毫升/分钟； The compound whose retention time is 4.236min under the following conditions is One stereoisomer in: Chromatographic column: Chiralpak IE 100*4.6mm 3um; Mobile phase: A phase is 0.1% diethylamine/n-heptane, B phase is isopropanol; Gradient: A/B=60/40, flow rate: 1 ml/min;
在下述条件下保留时间为1.942min的化合物，其为中的一个立体异构体：色谱柱:Chiralpak IG-3，50mm*4.6mm，3um；流动相：A相为二氧化碳，B相为0.05％二乙胺/乙醇；梯度：B相在2分钟内从5％到40％，保持40％的B相1.2分钟，保持5％的B相0.8分钟，流速：4毫升/分钟；The compound whose retention time is 1.942min under the following conditions is One stereoisomer in: chromatographic column: Chiralpak IG-3, 50mm*4.6mm, 3um; mobile phase: phase A is carbon dioxide, phase B is 0.05% diethylamine/ethanol; gradient: phase B is from 5% to 40% in 2 minutes, keep 40% of B phase for 1.2 minutes, keep 5% of B phase for 0.8 minutes, flow rate: 4 ml/min;
在下述条件下保留时间为2.343min的化合物，其为中的一个立体异构体：色谱柱:Chiralpak IG-3，50mm*4.6mm，3um；流动相：A相为二氧化碳，B相为0.05％二乙胺/乙醇；梯度：B相在2分钟内从5％到40％，保持40％的B相1.2分钟，保持5％的B相0.8分钟，流速：4毫升/分钟；The compound whose retention time is 2.343min under the following conditions is One stereoisomer in: Chromatographic column: Chiralpak IG-3, 50mm*4.6mm, 3um; Mobile phase: A phase is carbon dioxide, B phase is 0.05% diethylamine/ethanol; Gradient: B phase is from 5% to 40% in 2 minutes, keep 40% of B phase for 1.2 minutes, keep 5% of B phase for 0.8 minutes, flow rate: 4 ml/min;
在下述条件下保留时间为3.004min的化合物，其为中的一个立体异构体：色谱柱:Chiralpak IG-3，50mm*4.6mm，3um；流动相：A相为二氧化碳，B相为0.05％二乙胺/乙醇；梯度：B相在2分钟内从5％到40％，保持40％的B相1.2分钟，保持5％的B相0.8分钟，流速：4毫升/分钟；The compound whose retention time is 3.004min under the following conditions is One stereoisomer in: chromatographic column: Chiralpak IG-3, 50mm*4.6mm, 3um; mobile phase: phase A is carbon dioxide, phase B is 0.05% diethylamine/ethanol; gradient: phase B is from 5% to 40% in 2 minutes, keep 40% of B phase for 1.2 minutes, keep 5% of B phase for 0.8 minutes, flow rate: 4 ml/min;
在下述条件下保留时间为2.414min的化合物，其为中的一个立体异构体：色谱柱:Chiralpak IC-3，100mm*4.6mm，3um；流动相：A相为二氧化碳，B相为0.05％二乙胺/异丙醇；梯度：40％的B相，流速：2.8毫升/分钟； The compound whose retention time is 2.414min under the following conditions is A stereoisomer in: Chromatographic column: Chiralpak IC-3, 100mm*4.6mm, 3um; Mobile phase: A phase is carbon dioxide, B phase is 0.05% diethylamine/isopropanol; Gradient: 40% B phase, flow rate: 2.8 ml/min;
在下述条件下保留时间为3.344min的化合物，其为中的一个立体异构体：色谱柱:Chiralpak IC-3，100mm*4.6mm，3um；流动相：A相为二氧化碳，B相为0.05％二乙胺/异丙醇；梯度：40％的B相，流速：2.8毫升/分钟；The compound whose retention time is 3.344min under the following conditions is A stereoisomer in: Chromatographic column: Chiralpak IC-3, 100mm*4.6mm, 3um; Mobile phase: A phase is carbon dioxide, B phase is 0.05% diethylamine/isopropanol; Gradient: 40% B phase, flow rate: 2.8 ml/min;
在下述条件下保留时间为1.150min的化合物，其为中的一个立体异构体：色谱柱:Chiralpak IG-3，50mm*4.6mm，3um；流动相：A相为二氧化碳，B相为0.05％二乙胺/异丙醇；梯度：保持40％的B相，流速：4毫升/分钟；The compound whose retention time is 1.150min under the following conditions is One stereoisomer in: Chromatographic column: Chiralpak IG-3, 50mm*4.6mm, 3um; Mobile phase: A phase is carbon dioxide, B phase is 0.05% diethylamine/isopropanol; Gradient: keep 40% of B phase, flow rate: 4 ml/min;
在下述条件下保留时间为2.203min的化合物，其为中的一个立体异构体：色谱柱:Chiralpak IG-3，50mm*4.6mm，3um；流动相：A相为二氧化碳，B相为0.05％二乙胺/异丙醇；梯度：保持40％的B相，流速：4毫升/分钟；The compound whose retention time is 2.203min under the following conditions is One stereoisomer in: Chromatographic column: Chiralpak IG-3, 50mm*4.6mm, 3um; Mobile phase: A phase is carbon dioxide, B phase is 0.05% diethylamine/isopropanol; Gradient: keep 40% of B phase, flow rate: 4 ml/min;
在下述条件下保留时间为1.696min的化合物，其为中的一个立体异构体：色谱柱:Chiralpak AD-3，50mm*4.6mm，3um；流动相：A相为二氧化碳，B相为0.05％二乙胺/乙醇；梯度：B相在2分钟内从5％到40％，保持40％的B相1.2分钟，保持5％的B相0.8分钟；流速：4毫升/分钟； The compound whose retention time is 1.696min under the following conditions is One stereoisomer in: Chromatographic column: Chiralpak AD-3, 50mm*4.6mm, 3um; mobile phase: phase A is carbon dioxide, phase B is 0.05% diethylamine/ethanol; gradient: phase B is from 5% to 40% in 2 minutes, keep 40% of B phase for 1.2 minutes, keep 5% of B phase for 0.8 minutes; flow rate: 4 ml/min;
在下述条件下保留时间为2.137min的化合物，其为中的一个立体异构体：色谱柱:Chiralpak AD-3，50mm*4.6mm，3um；流动相：A相为二氧化碳，B相为0.05％二乙胺/乙醇；梯度：B相在2分钟内从5％到40％，保持40％的B相1.2分钟，保持5％的B相0.8分钟；流速：4毫升/分钟。The compound whose retention time is 2.137min under the following conditions is One stereoisomer in: Chromatographic column: Chiralpak AD-3, 50mm*4.6mm, 3um; Mobile phase: A phase is carbon dioxide, B phase is 0.05% diethylamine/ethanol; Gradient: B phase is from 5% to 40% in 2 minutes, keep 40% B phase for 1.2 minutes, keep 5% B phase for 0.8 minutes; flow rate: 4 ml/min.
在下述条件下保留时间为1.787min的化合物，其为中的一个立体异构体：色谱柱:Chiralpak AD-3，50mm*4.6mm，3um；流动相：A相为二氧化碳，B相为0.05％二乙胺/乙醇；梯度：B相在2分钟内从5％到40％，保持40％的B相1.2分钟，保持5％的B相0.8分钟；流速：4毫升/分钟；The compound whose retention time is 1.787min under the following conditions is One stereoisomer in: Chromatographic column: Chiralpak AD-3, 50mm*4.6mm, 3um; mobile phase: phase A is carbon dioxide, phase B is 0.05% diethylamine/ethanol; gradient: phase B is from 5% to 40% in 2 minutes, keep 40% of B phase for 1.2 minutes, keep 5% of B phase for 0.8 minutes; flow rate: 4 ml/min;
在下述条件下保留时间为2.089min的化合物，其为中的一个立体异构体：色谱柱:Chiralpak AD-3，50mm*4.6mm，3um；流动相：A相为二氧化碳，B相为0.05％二乙胺/乙醇；梯度：B相在2分钟内从5％到40％，保持40％的B相1.2分钟，保持5％的B相0.8分钟；流速：4毫升/分钟； The compound whose retention time is 2.089min under the following conditions is One stereoisomer in: Chromatographic column: Chiralpak AD-3, 50mm*4.6mm, 3um; mobile phase: phase A is carbon dioxide, phase B is 0.05% diethylamine/ethanol; gradient: phase B is from 5% to 40% in 2 minutes, keep 40% of B phase for 1.2 minutes, keep 5% of B phase for 0.8 minutes; flow rate: 4 ml/min;
在下述条件下保留时间为0.797min的化合物，其为中的一个立体异构体：色谱柱:Chiralpak IG-3，50mm*4.6mm，3um；流动相：A相为二氧化碳，B相为0.05％二乙胺/异丙醇；梯度：保持40％的B相；流速：4毫升/分钟；The compound whose retention time is 0.797min under the following conditions is One stereoisomer in: Chromatographic column: Chiralpak IG-3, 50mm*4.6mm, 3um; Mobile phase: A phase is carbon dioxide, B phase is 0.05% diethylamine/isopropanol; Gradient: keep 40% of B phase; Flow rate: 4 ml/min;
在下述条件下保留时间为2.514min的化合物，其为中的一个立体异构体：色谱柱:Chiralpak IG-3，50mm*4.6mm，3um；流动相：A相为二氧化碳，B相为0.05％二乙胺/异丙醇；梯度：保持40％的B相；流速：4毫升/分钟；The compound whose retention time is 2.514min under the following conditions is One stereoisomer in: Chromatographic column: Chiralpak IG-3, 50mm*4.6mm, 3um; Mobile phase: A phase is carbon dioxide, B phase is 0.05% diethylamine/isopropanol; Gradient: keep 40% of B phase; Flow rate: 4 ml/min;
在下述条件下保留时间为1.943min的化合物，其为中的一个立体异构体：色谱柱:ChiralPak AD-3，150*4.6mm，3um；流动相：A相为二氧化碳，B相为0.05％二乙胺/乙醇；梯度：保持40％的B相；流速：2.5毫升/分钟； The compound whose retention time is 1.943min under the following conditions is One stereoisomer in: Chromatographic column: ChiralPak AD-3, 150*4.6mm, 3um; Mobile phase: A phase is carbon dioxide, B phase is 0.05% diethylamine/ethanol; Gradient: maintain 40% of B phase; Flow rate: 2.5 ml/min;
在下述条件下保留时间为3.400min的化合物，其为中的一个立体异构体：色谱柱:ChiralPak AD-3，150*4.6mm，3um；流动相：A相为二氧化碳，B相为0.05％二乙胺/乙醇；梯度：保持40％的B相；流速：2.5毫升/分钟；The compound whose retention time is 3.400min under the following conditions is One stereoisomer in: Chromatographic column: ChiralPak AD-3, 150*4.6mm, 3um; Mobile phase: A phase is carbon dioxide, B phase is 0.05% diethylamine/ethanol; Gradient: maintain 40% of B phase; Flow rate: 2.5 ml/min;
在下述条件下保留时间为1.729min和1.951min的化合物，其为中的两个立体异构体混合物：色谱柱:Chiralpak IG-3，100*4.6mm I.D.，3um；流动相：A相为二氧化碳，B相为0.05％二乙胺/异丙醇；梯度：保持40％的B相，流速：2.8毫升/分钟；The compounds whose retention times are 1.729min and 1.951min under the following conditions are Two stereoisomer mixtures in: Chromatographic column: Chiralpak IG-3, 100*4.6mm ID, 3um; Mobile phase: A phase is carbon dioxide, B phase is 0.05% diethylamine/isopropanol; Gradient: keep 40% of B phase, flow rate: 2.8 ml/min;
在下述条件下保留时间为6.088min的化合物，其为中的一个立体异构体混合物：色谱柱:Chiralpak IG-3 100*4.6mm I.D.，3um；流动相：A相为二氧化碳，B相为0.05％二乙胺/异丙醇；梯度：保持40％的B相，流速：2.8毫升/分钟；The compound whose retention time is 6.088min under the following conditions is A mixture of stereoisomers in: chromatographic column: Chiralpak IG-3 100*4.6mm ID, 3um; mobile phase: phase A is carbon dioxide, phase B is 0.05% diethylamine/isopropanol; gradient: maintain 40% phase B, flow rate: 2.8 ml/min;
在下述条件下保留时间为8.998min的化合物，其为中的一个立体异构体混合物：色谱柱:Chiralpak IG-3 100*4.6mm I.D.，3um；流动相：A相为二氧化碳，B相 为0.05％二乙胺/异丙醇；梯度：保持40％的B相，流速：2.8毫升/分钟；The compound whose retention time is 8.998min under the following conditions is A mixture of stereoisomers in: Chromatographic column: Chiralpak IG-3 100*4.6mm ID, 3um; Mobile phase: Phase A is carbon dioxide, phase B 0.05% diethylamine/isopropanol; gradient: maintain 40% phase B, flow rate: 2.8 ml/min;
在下述条件下保留时间为1.374min的化合物，其为中的两个立体异构体混合物：色谱柱:Chiralpak IG-3，100*4.6mm I.D.，3um；流动相：A相为二氧化碳，B相为0.05％二乙胺/乙醇；梯度：保持40％的B相，流速：2.8毫升/分钟；The compound whose retention time is 1.374min under the following conditions is Two stereoisomer mixtures in: Chromatographic column: Chiralpak IG-3, 100*4.6mm ID, 3um; Mobile phase: A phase is carbon dioxide, B phase is 0.05% diethylamine/ethanol; Gradient: keep 40% of B phase, flow rate: 2.8 ml/min;
在下述条件下保留时间为2.812min的化合物，其为中的一个立体异构体：色谱柱:Chiralpak IG-3，100*4.6mm I.D.，3um；流动相：A相为二氧化碳，B相为0.05％二乙胺/乙醇；梯度：保持40％的B相，流速：2.8毫升/分钟；The compound whose retention time is 2.812min under the following conditions is One stereoisomer in: Chromatographic column: Chiralpak IG-3, 100*4.6mm ID, 3um; Mobile phase: A phase is carbon dioxide, B phase is 0.05% diethylamine/ethanol; Gradient: keep 40% of B phase, flow rate: 2.8 ml/min;
在下述条件下保留时间为6.215min的化合物，其为中的一个立体异构体：色谱柱:Chiralpak IG-3，100*4.6mm I.D.，3um；流动相：A相为二氧化碳，B相为0.05％二乙胺/乙醇；梯度：保持40％的B相，流速：2.8毫升/分钟；The compound whose retention time is 6.215min under the following conditions is One stereoisomer in: Chromatographic column: Chiralpak IG-3, 100*4.6mm ID, 3um; Mobile phase: A phase is carbon dioxide, B phase is 0.05% diethylamine/ethanol; Gradient: keep 40% of B phase, flow rate: 2.8 ml/min;
在下述条件下保留时间为0.438min的化合物，其为中的一个立体异构体：色谱柱:Chiralpak AD-3,50*4.6mm,3um；流动相：A相为二氧化碳，B相为0.05％二 乙胺/异丙醇；梯度：保持40％的B相；流速：4毫升/分钟；The compound whose retention time is 0.438min under the following conditions is One stereoisomer in: Chromatographic column: Chiralpak AD-3, 50*4.6mm, 3um; Mobile phase: Phase A is carbon dioxide, phase B is 0.05% di Ethylamine/isopropanol; Gradient: maintain 40% phase B; Flow rate: 4 ml/min;
在下述条件下保留时间为1.251min的化合物，其为中的一个立体异构体：色谱柱:Chiralpak AD-3,50*4.6mm,3um；流动相：A相为二氧化碳，B相为0.05％二乙胺/异丙醇；梯度：保持40％的B相；流速：4毫升/分钟；The compound whose retention time is 1.251min under the following conditions is One stereoisomer in: Chromatographic column: Chiralpak AD-3, 50*4.6mm, 3um; Mobile phase: A phase is carbon dioxide, B phase is 0.05% diethylamine/isopropanol; Gradient: maintain 40% of B phase; Flow rate: 4 ml/min;
在下述条件下保留时间为0.369min的化合物，其为中的两个立体异构体混合物：色谱柱:Chiralpak AD-3，50mm*4.6mm，3um；流动相：A相为二氧化碳，B相为0.05％二乙胺/异丙醇；梯度：保持B相在40％；流速：4毫升/分钟；The compound whose retention time is 0.369min under the following conditions is Two stereoisomer mixtures in: Chromatographic column: Chiralpak AD-3, 50mm*4.6mm, 3um; Mobile phase: A phase is carbon dioxide, B phase is 0.05% diethylamine/isopropanol; Gradient: keep B phase at 40%; Flow rate: 4 ml/min;
在下述条件下保留时间为0.752min的化合物，其为中的一个立体异构体：色谱柱:Chiralpak AD-3，50mm*4.6mm，3um；流动相：A相为二氧化碳，B相为0.05％二乙胺/异丙醇；梯度：保持B相在40％；流速：4毫升/分钟；The compound whose retention time is 0.752min under the following conditions is One stereoisomer in: Chromatographic column: Chiralpak AD-3, 50mm*4.6mm, 3um; Mobile phase: A phase is carbon dioxide, B phase is 0.05% diethylamine/isopropanol; Gradient: keep B phase at 40%; Flow rate: 4 ml/min;
在下述条件下保留时间为1.937min的化合物，其为中的一个立体异构体：色谱柱:Chiralpak AD-3，50mm*4.6mm，3um；流动相：A相为二氧化碳，B相为0.05％ 二乙胺/异丙醇；梯度：保持B相在40％；流速：4毫升/分钟；The compound whose retention time is 1.937min under the following conditions is One stereoisomer in: Chromatographic column: Chiralpak AD-3, 50mm*4.6mm, 3um; Mobile phase: Phase A is carbon dioxide, phase B is 0.05% Diethylamine/isopropanol; gradient: keep phase B at 40%; flow rate: 4 ml/min;
在下述条件下保留时间为3.692min的化合物，其为中的一个立体异构体：色谱柱:Chiralpak AD-3，150mm*4.6mm，3um；流动相：A相为二氧化碳，B相为0.05％二乙胺/乙醇；梯度：B相保持在40％；流速：2.5毫升/分钟。The compound whose retention time is 3.692min under the following conditions is One stereoisomer in: Chromatographic column: Chiralpak AD-3, 150mm*4.6mm, 3um; Mobile phase: A phase is carbon dioxide, B phase is 0.05% diethylamine/ethanol; Gradient: B phase is maintained at 40%; Flow rate: 2.5 ml/min.
在下述条件下保留时间为3.586min的化合物，其为The compound whose retention time is 3.586min under the following conditions is
中的一个立体异构体：色谱柱:Ultimate XB-C18,3um,3.0*50mm；流动相：A相为三氟乙酸/水(1.5mL/4L)，B相为三氟乙酸/乙腈(0.75mL/4L)；梯度：B相在1分钟内从1％到5％，在5分钟内从5％到100％，保持100％的B相2分钟，保持1％的B相2分钟；流速：1.2毫升/分钟)： One stereoisomer in: Chromatographic column: Ultimate XB-C18, 3um, 3.0*50mm; Mobile phase: A phase is trifluoroacetic acid/water (1.5mL/4L), B phase is trifluoroacetic acid/acetonitrile (0.75mL/4L); Gradient: B phase from 1% to 5% in 1 minute, from 5% to 100% in 5 minutes, keep 100% of B phase for 2 minutes, keep 1% of B phase 2 minutes; flow rate: 1.2 ml/min):
在下述条件下保留时间为为3.607min的化合物，其为
The compound whose retention time is 3.607min under the following conditions is
中的一个立体异构体：色谱柱:Ultimate XB-C18,3um,3.0*50mm；流动相：A相为三氟乙酸/水(1.5mL/4L)，B相为三氟乙酸/乙腈(0.75mL/4L)；梯度：B相在1分钟内从1％到5％，在5分钟内从5％到100％，保持100％的B相2分钟，保持1％的B相2分钟；流速：1.2毫升/分钟)：One stereoisomer in: Chromatographic column: Ultimate XB-C18, 3um, 3.0*50mm; mobile phase: phase A is trifluoroacetic acid/water (1.5mL/4L), phase B is trifluoroacetic acid/acetonitrile (0.75mL/4L); gradient: phase B from 1% to 5% in 1 minute, from 5% to 100% in 5 minutes, keep 100% of phase B for 2 minutes, keep 1% of B phase for 2 minutes; flow rate: 1.2 ml/min):
在下述条件下保留时间为为3.539min的化合物，其为 Under the following conditions, the retention time is the compound of 3.539min, which is
中的一个立体异构体：色谱柱:Ultimate XB-C18,3um,3.0*50mm；流动相：A相为三氟乙酸/水(1.5mL/4L)，B相为三氟乙酸/乙腈(0.75mL/4L)；梯度：B相在1分钟内从1％到5％，在5分钟内从5％到100％，保持100％的B相2分钟，保持1％的B相2分钟；流速：1.2毫升/分钟)： One stereoisomer in: Chromatographic column: Ultimate XB-C18, 3um, 3.0*50mm; Mobile phase: A phase is trifluoroacetic acid/water (1.5mL/4L), B phase is trifluoroacetic acid/acetonitrile (0.75mL/4L); Gradient: B phase from 1% to 5% in 1 minute, from 5% to 100% in 5 minutes, keep 100% of B phase for 2 minutes, keep 1% of B phase 2 minutes; flow rate: 1.2 ml/min):
在下述条件下保留时间为为3.539min的化合物，其为Under the following conditions, the retention time is the compound of 3.539min, which is
中的一个立体异构体：色谱柱:Ultimate XB-C18,3um,3.0*50mm；流动相：A相为三氟乙酸/水(1.5mL/4L)，B相为三氟乙酸/乙腈(0.75mL/4L)；梯度：B相在1分钟内从1％到5％，在5分钟内从5％到100％，保持100％的B相2分钟，保持1％的B相2分钟；流速：1.2毫升/分钟)：出峰位置为3.565min； One stereoisomer in: Chromatographic column: Ultimate XB-C18, 3um, 3.0*50mm; Mobile phase: A phase is trifluoroacetic acid/water (1.5mL/4L), B phase is trifluoroacetic acid/acetonitrile (0.75mL/4L); Gradient: B phase from 1% to 5% in 1 minute, from 5% to 100% in 5 minutes, keep 100% of B phase for 2 minutes, keep 1% of B phase 2 minutes; flow rate: 1.2 ml/min): the peak position is 3.565 min;
在下述条件下保留时间为3.754min的化合物，其为中的一个立体异构体：色谱柱:ChiralCel OD-3，150mm*4.6mm，3um；流动相：A相为二氧化碳，B相为0.05％二乙胺/异丙醇；保持40％的B相；流速：2.5毫升/分钟； The compound whose retention time is 3.754min under the following conditions is One stereoisomer in: Chromatographic column: ChiralCel OD-3, 150mm*4.6mm, 3um; Mobile phase: A phase is carbon dioxide, B phase is 0.05% diethylamine/isopropanol; keep 40% of B phase; flow rate: 2.5 ml/min;
在下述条件下保留时间为3.131min的化合物，其为中的一个立体异构体：色谱柱:ChiralCel OD-3，150mm*4.6mm，3um；流动相：A相为二氧化碳，B相为0.05％二乙胺/异丙醇；保持40％的B相；流速：2.5毫升/分钟；The compound whose retention time is 3.131min under the following conditions is One stereoisomer in: Chromatographic column: ChiralCel OD-3, 150mm*4.6mm, 3um; Mobile phase: A phase is carbon dioxide, B phase is 0.05% diethylamine/isopropanol; keep 40% of B phase; flow rate: 2.5 ml/min;
在下述条件下保留时间为1.653min的化合物，其为中的一个立体异构体：色谱柱:ChiralCel OD-3，50mm*4.6mm，3um；流动相：A相为二氧化碳，B相为0.05％二乙胺/乙醇；2min从5％的B相升至40％的B相，保持40％的B相1.2min，然后保持5％的B相0.8min；流速：4毫升/分钟；The compound whose retention time is 1.653min under the following conditions is One stereoisomer in: Chromatographic column: ChiralCel OD-3, 50mm*4.6mm, 3um; Mobile phase: A phase is carbon dioxide, B phase is 0.05% diethylamine/ethanol; 2min rises from 5% B phase to 40% B phase, maintains 40% B phase for 1.2min, then maintains 5% B phase for 0.8min; flow rate: 4 ml/min;
在下述条件下保留时间为1.763min的化合物，其为中的一个立体异构体：色谱柱:ChiralCel OD-3，50mm*4.6mm，3um；流动相：A相为二氧化碳，B相为0.05％二乙胺/乙醇；2min从5％的B相升至40％的B相，保持40％的B相1.2min，然后保持5％的B相0.8min；流速：4毫升/分钟； The compound whose retention time is 1.763min under the following conditions is One stereoisomer in: Chromatographic column: ChiralCel OD-3, 50mm*4.6mm, 3um; Mobile phase: A phase is carbon dioxide, B phase is 0.05% diethylamine/ethanol; 2min rises from 5% B phase to 40% B phase, maintains 40% B phase for 1.2min, then maintains 5% B phase for 0.8min; flow rate: 4 ml/min;
在下述条件下保留时间为1.343min的化合物，其为中的一个立体异构体：色谱柱:Cellulose-2 100*4.6mm I.D.,3um；流动相：A相为二氧化碳，B相为0.05％二乙胺/乙醇；梯度：保持50％的B相；流速：2.8毫升/分钟；The compound whose retention time is 1.343min under the following conditions is One stereoisomer in: Chromatographic column: Cellulose-2 100*4.6mm ID, 3um; Mobile phase: A phase is carbon dioxide, B phase is 0.05% diethylamine/ethanol; Gradient: keep 50% of B phase; Flow rate: 2.8 ml/min;
在下述条件下保留时间为1.527min的化合物，其为中的一个立体异构体：色谱柱:Cellulose-2 100*4.6mm I.D.,3um；流动相：A相为二氧化碳，B相为0.05％二乙胺/乙醇；梯度：保持50％的B相；流速：2.8毫升/分钟；The compound whose retention time is 1.527min under the following conditions is One stereoisomer in: Chromatographic column: Cellulose-2 100*4.6mm ID, 3um; Mobile phase: A phase is carbon dioxide, B phase is 0.05% diethylamine/ethanol; Gradient: maintain 50% of B phase; Flow rate: 2.8 ml/min;
在下述条件下保留时间为1.739min的化合物，其为中的一个立体异构体：色谱柱:Cellulose-2 100*4.6mm I.D.3um；流动相：A相为二氧化碳，B相为0.05％二乙胺/乙醇；梯度：保持50％的B相；流速：2.8毫升/分钟； The compound whose retention time is 1.739min under the following conditions is A stereoisomer in: Chromatographic column: Cellulose-2 100*4.6mm ID3um; Mobile phase: A phase is carbon dioxide, B phase is 0.05% diethylamine/ethanol; Gradient: keep 50% of B phase; Flow rate: 2.8 ml/min;
在下述条件下保留时间为2.203min的化合物，其为中的一个立体异构体：色谱柱:Cellulose-2 100*4.6mm I.D.,3um；流动相：A相为二氧化碳，B相为0.05％二乙胺/乙醇；梯度：保持50％的B相；流速：2.8毫升/分钟；The compound whose retention time is 2.203min under the following conditions is One stereoisomer in: Chromatographic column: Cellulose-2 100*4.6mm ID, 3um; Mobile phase: A phase is carbon dioxide, B phase is 0.05% diethylamine/ethanol; Gradient: maintain 50% of B phase; Flow rate: 2.8 ml/min;
在下述条件下保留时间为3.304min的化合物，其为中的一个立体异构体：色谱柱:Cellulose 2 100*4.6mm I.D.,3um；流动相：A相为二氧化碳，B相为0.05％二乙胺/甲醇；梯度：保持50％的B相；流速：2.8毫升/分钟；The compound whose retention time is 3.304min under the following conditions is One stereoisomer in: Chromatographic column: Cellulose 2 100*4.6mm ID, 3um; Mobile phase: A phase is carbon dioxide, B phase is 0.05% diethylamine/methanol; Gradient: maintain 50% of B phase; Flow rate: 2.8 ml/min;
在下述条件下保留时间为4.369min的化合物，其为中的一个立体异构体：色谱柱:Cellulose 2 100*4.6mm I.D.,3um；流动相：A相为二氧化碳，B相为0.05％二乙胺/甲醇；梯度：保持50％的B相；流速：2.8毫升/分钟； The compound whose retention time is 4.369min under the following conditions is One stereoisomer in: Chromatographic column: Cellulose 2 100*4.6mm ID, 3um; Mobile phase: A phase is carbon dioxide, B phase is 0.05% diethylamine/methanol; Gradient: maintain 50% of B phase; Flow rate: 2.8 ml/min;
在下述条件下保留时间为4.500min的化合物，其为中的一个立体异构体：色谱柱:Chiralpak IC-3 100*4.6mm I.D.,3um；流动相：A相为二氧化碳，B相为0.05％二乙胺/乙醇；梯度：保持50％的B相；流速：2.8毫升/分钟；The compound whose retention time is 4.500min under the following conditions is One stereoisomer in: Chromatographic column: Chiralpak IC-3 100*4.6mm ID, 3um; Mobile phase: A phase is carbon dioxide, B phase is 0.05% diethylamine/ethanol; Gradient: maintain 50% of B phase; Flow rate: 2.8 ml/min;
在下述条件下保留时间为5.555min的化合物，其为中的一个立体异构体：色谱柱:Chiralpak IC-3 100*4.6mm I.D.,3um；流动相：A相为二氧化碳，B相为0.05％二乙胺/乙醇；梯度：保持50％的B相；流速：2.8毫升/分钟；The compound whose retention time is 5.555min under the following conditions is One stereoisomer in: Chromatographic column: Chiralpak IC-3 100*4.6mm ID, 3um; Mobile phase: A phase is carbon dioxide, B phase is 0.05% diethylamine/ethanol; Gradient: maintain 50% of B phase; Flow rate: 2.8 ml/min;
在下述条件下保留时间为2.676min的化合物，其为中的一个立体异构体：色谱柱:(S,S)Whelk-01 100×4.6mm I.D.,5.0um；流动相：A相为二氧化碳，B相为0.05％二乙胺/异丙醇；梯度：B相保持60％；流速：2.5毫升/分钟； The compound whose retention time is 2.676min under the following conditions is One stereoisomer in: Chromatographic column: (S, S) Whelk-01 100×4.6mm ID, 5.0um; Mobile phase: A phase is carbon dioxide, B phase is 0.05% diethylamine/isopropanol; Gradient: B phase maintains 60%; Flow rate: 2.5 ml/min;
在下述条件下保留时间为3.176min的化合物，其为中的一个立体异构体：色谱柱:(S,S)Whelk-01 100×4.6mm I.D.,5.0um；流动相：A相为二氧化碳，B相为0.05％二乙胺/异丙醇；梯度：B相保持60％；流速：2.5毫升/分钟；The compound whose retention time is 3.176min under the following conditions is One stereoisomer in: Chromatographic column: (S, S) Whelk-01 100 × 4.6mm ID, 5.0um; Mobile phase: A phase is carbon dioxide, B phase is 0.05% diethylamine/isopropanol; Gradient: B phase maintains 60%; Flow rate: 2.5 ml/min;
在下述条件下保留时间为0.634min的化合物，其为中的一个立体异构体：色谱柱:Chiralpak IG-3 50*4.6mm I.D.,3um；流动相：A相为二氧化碳，B相为0.05％二乙胺/乙醇；梯度：B相保持40％；流速：4毫升/分钟；The compound whose retention time is 0.634min under the following conditions is One stereoisomer in: Chromatographic column: Chiralpak IG-3 50*4.6mm ID, 3um; Mobile phase: A phase is carbon dioxide, B phase is 0.05% diethylamine/ethanol; Gradient: B phase maintains 40%; Flow rate: 4 ml/min;
在下述条件下保留时间为1.129min的化合物，其为中的一个立体异构体：色谱柱::Chiralpak IG-3 50*4.6mm I.D.,3um；流动相：A相为二氧化碳，B相为0.05％二乙胺/乙醇；梯度：B相保持40％；流速：4毫升/分钟；The compound whose retention time is 1.129min under the following conditions is One stereoisomer in: Chromatographic column:: Chiralpak IG-3 50*4.6mm ID, 3um; mobile phase: phase A is carbon dioxide, phase B is 0.05% diethylamine/ethanol; gradient: phase B maintains 40%; flow rate: 4 ml/min;
以上保留时间的测试条件并非对化合物的限定，只要采用上述测试条件进行测定，得到的保留时间与上述记载的相同或在误差范围内，且该化合物为上述用保留时间限定的化合物中的一个立体异构体，则落入本发明的保护范围内。The test conditions of the above retention time are not limited to the compound, as long as the above test conditions are used to measure, the retention time obtained is the same as that described above or within the error range, and the compound is a stereoisomer in the above-mentioned compound limited by the retention time, it falls within the scope of protection of the present invention.
本发明还提供了一种药物组合物，其包括：The present invention also provides a pharmaceutical composition comprising:
(1)如前任一项所述的杂环类化合物、其药学上可接受的盐、其立体异构体或它们的溶剂合物，和 (1) the heterocyclic compound as described in any one of the preceding items, its pharmaceutically acceptable salt, its stereoisomer or their solvate, and
(2)药用辅料。(2) Pharmaceutical excipients.
本发明还提供了一种物质A或所述药物组合物在制备KRAS G12D抑制剂的应用，所述的物质A为如前任一项所述的杂环类化合物、其药学上可接受的盐、其立体异构体或它们的溶剂合物。The present invention also provides an application of substance A or the pharmaceutical composition in the preparation of a KRAS G12D inhibitor, wherein the substance A is the heterocyclic compound as described in any one of the preceding items, its pharmaceutically acceptable salt, its stereoisomer or their solvate.
在所述的应用中，所述的KRAS G12D抑制剂可用于哺乳动物生物体内；也可用于生物体外，主要作为实验用途，例如：作为标准样或对照样提供比对，或按照本领域常规方法制成试剂盒，为KRAS G12D抑制效果提供快速检测。In the above application, the KRAS G12D inhibitor can be used in mammalian organisms; it can also be used in vitro, mainly for experimental purposes, for example: as a standard sample or control sample to provide comparison, or to prepare a kit according to conventional methods in the field to provide rapid detection of KRAS G12D inhibitory effect.
本发明还提供了一种物质A或所述药物组合物在制备药物的应用，所述的物质A为如前任一项所述的杂环类化合物、其药学上可接受的盐、其立体异构体或它们的溶剂合物，所述药物用于治疗癌症，例如结直肠癌，胃癌，胰腺癌，非小细胞肺癌，前列腺癌，乳腺癌等。The present invention also provides a substance A or the application of the pharmaceutical composition in the preparation of medicines. The substance A is a heterocyclic compound as described in any one of the preceding items, a pharmaceutically acceptable salt thereof, a stereoisomer or a solvate thereof, and the medicine is used for treating cancer, such as colorectal cancer, gastric cancer, pancreatic cancer, non-small cell lung cancer, prostate cancer, breast cancer, etc.
如无特别说明，本发明所用术语具有如下含义：Unless otherwise specified, terms used in the present invention have the following meanings:
本领域技术人员可以理解，根据本领域中使用的惯例，本发明描述基团的结构式中所使用的是指，相应的基团通过该位点与化合物中的其它片段、基团进行连接。Those skilled in the art can understand that, according to the practice used in this field, the present invention describes the structural formula used in the group means that the corresponding group is connected with other fragments and groups in the compound through this site.
术语“药学上可接受的”是指盐、溶剂、辅料等一般无毒、安全，并且适合于患者使用。所述的“患者”优选哺乳动物，更优选为人类。The term "pharmaceutically acceptable" means that salts, solvents, auxiliary materials, etc. are generally non-toxic, safe and suitable for use by patients. The "patient" is preferably a mammal, more preferably a human.
术语“药学上可接受的盐”是指本发明化合物与相对无毒的、药学上可接受的酸或碱制备得到的盐。当本发明的化合物中含有相对酸性的功能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的药学上可接受的碱与这类化合物的中性形式接触的方式获得碱加成盐。药学上可接受的碱加成盐包括但不限于：锂盐、钠盐、钾盐、钙盐、铝盐、镁盐、锌盐、铋盐、铵盐、二乙醇胺盐。当本发明的化合物中含有相对碱性的官能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的药学上可接受的酸与这类化合物的中性形式接触的方式获得酸加成盐。所述的药学上可接受的酸包括无机酸，所述无机酸包括但不限于：盐酸、氢溴酸、氢碘酸、硝酸、碳酸、磷酸、亚磷酸、硫酸等。所述的药学上可接受的酸包括有机酸，所述有机酸包括但不限于：乙酸、丙酸、草酸、异丁酸、马来酸、丙二酸、苯甲酸、琥珀酸、辛二酸、反丁烯二酸、乳酸、扁桃酸、邻苯二甲酸、苯磺酸、对甲苯磺酸、柠檬酸、水杨酸、酒石酸、甲磺酸、异烟酸、酸式柠檬酸、油酸、单宁酸、泛酸、酒石酸氢、抗坏血酸、龙胆酸、富马酸、葡糖酸、糖酸、甲酸、乙磺酸、双羟萘酸(即4,4’-亚甲基-双(3-羟基-2-萘甲酸))、氨基酸(例如谷氨酸、精氨酸)等。当本发明的化合物中含有相对酸性和相对碱性的官能团时，可以被转换成碱加成盐或酸加成盐。具体可参见Berge et al.,"Pharmaceutical Salts",Journal of Pharmaceutical Science 66:1-19(1977)、或、Handbook of Pharmaceutical Salts:Properties,Selection,and Use(P.Heinrich Stahl and Camille G.Wermuth,ed.,Wiley-VCH,2002)。The term "pharmaceutically acceptable salt" refers to a salt prepared from a compound of the present invention with a relatively non-toxic, pharmaceutically acceptable acid or base. When compounds of the present invention contain relatively acidic functional groups, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of a pharmaceutically acceptable base either in neat solution or in a suitable inert solvent. Pharmaceutically acceptable base addition salts include, but are not limited to: lithium salts, sodium salts, potassium salts, calcium salts, aluminum salts, magnesium salts, zinc salts, bismuth salts, ammonium salts, diethanolamine salts. When compounds of the present invention contain relatively basic functional groups, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of a pharmaceutically acceptable acid, either neat solution or in a suitable inert solvent. The pharmaceutically acceptable acid includes inorganic acids, including but not limited to: hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, carbonic acid, phosphoric acid, phosphorous acid, sulfuric acid and the like. The pharmaceutically acceptable acids include organic acids, including but not limited to: acetic acid, propionic acid, oxalic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, salicylic acid, tartaric acid, methanesulfonic acid, isonicotinic acid, acid citric acid, oleic acid, tannic acid, pantothenic acid, hydrogen tartaric acid, Ascorbic acid, gentisic acid, fumaric acid, gluconic acid, sugar acid, formic acid, ethanesulfonic acid, pamoic acid (i.e. 4,4’-methylene-bis(3-hydroxy-2-naphthoic acid)), amino acids (e.g. glutamic acid, arginine), etc. When the compounds of the present invention contain relatively acidic and relatively basic functional groups, they can be converted into base addition salts or acid addition salts. For details, see Berge et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science 66:1-19 (1977), or, Handbook of Pharmaceutical Salts: Properties, Selection, and Use (P. Heinrich Stahl and Camille G. Wermuth, ed., Wiley-VCH, 2 002).
术语“溶剂合物”是指本发明化合物与化学计量或非化学计量的溶剂结合形成的物质。溶剂合物中的溶剂分子可以有序或非有序排列的形式存在。所述的溶剂包括但不限于：水、甲醇、乙醇等。The term "solvate" refers to a compound of the present invention in combination with a stoichiometric or non-stoichiometric amount of solvent. The solvent molecules in a solvate may exist in an ordered or non-ordered arrangement. The solvent includes but not limited to: water, methanol, ethanol and the like.
术语“化合物”、“药学上可接受的盐”、“溶剂合物”和“药学上可接受的盐的溶剂合物”如存在立体异构体，则可以以单一的立体异构体或它们的混合物(例如外消旋体)的形式存在。术语“立体异构体”是指顺反异构体或旋光异构体。这些立体异构体可以通过不对称合成方法或手性分离法(包括但不限于薄层色谱、旋转色谱、柱色谱、气相色谱、高压液相色谱等)分离、纯化及富集，还可以通过与其它手性化合物成键(化学结合等)或成盐(物理结合等)等方式进行手性拆分获得。术语“单一的 立体异构体”是指本发明化合物的一种立体异构体相对于该化合物的所有立体异构体的质量含量不低于95％。The terms "compound", "pharmaceutically acceptable salt", "solvate" and "solvate of a pharmaceutically acceptable salt", if stereoisomers exist, may exist as single stereoisomers or mixtures thereof (eg racemates). The term "stereoisomer" refers to cis-trans isomers or optical isomers. These stereoisomers can be separated, purified and enriched by asymmetric synthesis methods or chiral separation methods (including but not limited to thin-layer chromatography, rotational chromatography, column chromatography, gas chromatography, high-pressure liquid chromatography, etc.), and can also be obtained by chiral resolution through bond formation (chemical combination, etc.) or salt formation (physical combination, etc.) with other chiral compounds. The term "single "Stereoisomer" means that the mass content of one stereoisomer of the compound of the present invention relative to all stereoisomers of the compound is not less than 95%.
术语“化合物”、“药学上可接受的盐”、“溶剂合物”和“药学上可接受的盐的溶剂合物”如存在互变异构体，则可以以单一的互变异构体或它们的混合物的形式存在，较佳地以较稳定的互变异构体为主的形式存在。If there are tautomers in the terms "compound", "pharmaceutically acceptable salt", "solvate" and "solvate of pharmaceutically acceptable salt", it may exist in the form of a single tautomer or a mixture thereof, preferably in the form of a relatively stable tautomer.
术语“卤素”是指氟、氯、溴或碘。The term "halogen" refers to fluorine, chlorine, bromine or iodine.
术语“烷基”是指具有指定碳原子数(例如，C1～C6)的、直链或支链的、饱和的一价烃基。烷基包括但不限于：甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、正己基等。The term "alkyl" refers to a linear or branched, saturated monovalent hydrocarbon group having a specified number of carbon atoms (eg, C 1 -C 6 ). Alkyl groups include, but are not limited to: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, and the like.
术语“环烷基”是指具有指定碳原子数(例如，C3～C6)的、环状的、饱和的一价烃基。环烷基包括但不限于：等。The term "cycloalkyl" refers to a cyclic, saturated monovalent hydrocarbon group having a specified number of carbon atoms (eg, C 3 -C 6 ). Cycloalkyl groups include, but are not limited to: wait.
术语“环烯基”是指具有指定碳原子数(例如，C3～C6)的、环状的、不饱和的一价烃基，其具有一个或多个(例如，1个、2个或3个)碳-碳sp2双键，其为单环，不具有芳香性。(单环)环烯基包括但不限于：等。The term "cycloalkenyl" refers to a cyclic, unsaturated monovalent hydrocarbon group with a specified number of carbon atoms (for example, C 3 to C 6 ), which has one or more (for example, 1, 2 or 3) carbon-carbon sp 2 double bonds, which is a single ring and does not have aromaticity. (Monocyclic)cycloalkenyl groups include, but are not limited to: wait.
术语“碳烯环”的满足下述任一条件，其余定义同术语“环烯基”：1、通过两个以上的单键与分子其余部分相连；2、与分子其余部分共用两个原子和一根键。The term "carbene ring" satisfies any of the following conditions, and the remaining definitions are the same as the term "cycloalkenyl": 1. It is connected to the rest of the molecule through more than two single bonds; 2. It shares two atoms and one bond with the rest of the molecule.
术语“烯基”是指具有指定碳原子数(例如，C2-C6)的、直链或支链的、不饱和的一价烃基，其具有一个或多个(例如，1个、2个或3个)碳-碳sp2双键。烯基包括但不限于：乙烯基、 等。The term "alkenyl" refers to a linear or branched, unsaturated, monovalent hydrocarbon group having a specified number of carbon atoms (eg, C2 - C6 ), which has one or more (eg, 1, 2 or 3) carbon-carbon sp2 double bonds. Alkenyl groups include, but are not limited to: vinyl, wait.
术语“炔基”是指具有指定碳原子数(例如，C2～C6)的、直链或支链的、不饱和的一价烃基，其具有一个或多个(例如，1个、2个或3个)碳-碳sp3三键。炔基包括但不限于：乙炔基等。The term "alkynyl" refers to a straight-chain or branched, unsaturated monovalent hydrocarbon group with a specified number of carbon atoms (for example, C 2 to C 6 ), which has one or more (for example, 1, 2 or 3) carbon-carbon sp 3 triple bonds. Alkynyl includes, but is not limited to, ethynyl and the like.
术语“杂环烷基”是指具有指定环原子数(例如，3～8元)的、指定杂原子数(例如，1个、2个或3个)的、指定杂原子种类(N、O和S中的一种或多种)的、环状的、饱和的一价基团，优选为单环。杂环烷基通过碳原子或杂原子与分子其余部分相连。杂环烷基包括但不限于： 等。The term "heterocycloalkyl" refers to a cyclic, saturated monovalent group having a specified number of ring atoms (for example, 3 to 8 members), a specified number of heteroatoms (for example, 1, 2 or 3), and a specified type of heteroatom (one or more of N, O and S), preferably a monocyclic ring. A heterocycloalkyl group is attached to the rest of the molecule through a carbon atom or a heteroatom. Heterocycloalkyl groups include, but are not limited to: wait.
术语“杂芳基”是指具有指定环原子数(例如，5～10元)的、指定杂原子数(例如，1个、2个或3个)的、指定杂原子种类(N、O和S中的一种或多种)的、环状的、不饱和的一价基团，其为单环或多环，单环之间共用两个原子和一根键，且每个环均具有芳香性。杂芳基通过碳原子或杂原子与 分子其余部分相连。杂芳基包括但不限于：等。The term "heteroaryl" refers to a cyclic, unsaturated monovalent group with a specified number of ring atoms (for example, 5 to 10 members), a specified number of heteroatoms (for example, 1, 2 or 3), and a specified heteroatom type (one or more of N, O and S), which is monocyclic or polycyclic, and the single rings share two atoms and a bond, and each ring is aromatic. Heteroaryl through carbon atom or heteroatom and The rest of the molecule is connected. Heteroaryl groups include, but are not limited to: wait.
术语“杂环烯基”是指具有指定环原子数(例如，5～10元)的、指定杂原子数(例如，1个、2个或3个)的、指定杂原子种类(N、O和S中的一种或多种)的、环状的、不饱和的一价烃基，其具有一个或多个(例如，1个、2个或3个)碳-碳sp2双键，其为单环，不具有芳香性。杂环烯基通过碳原子或杂原子与分子其余部分相连。杂环烯基包括但不限于：等。The term "heterocycloalkenyl" refers to a cyclic, unsaturated monovalent hydrocarbon group having a specified number of ring atoms (for example, 5 to 10 members), a specified number of heteroatoms (for example, 1, 2 or 3), and a specified heteroatom type (one or more of N, O and S), which has one or more (for example, 1, 2 or 3) carbon-carbon sp 2 double bonds, which are monocyclic and do not have aromaticity. A heterocycloalkenyl group is attached to the rest of the molecule through a carbon atom or a heteroatom. Heterocyclenyl groups include, but are not limited to: wait.
术语“碳杂烯环”满足下述任一条件，其余定义同术语“杂环烯基”：1、通过两个以上的单键与分子其余部分相连；2、与分子其余部分共用两个原子和一根键。The term "carbaene ring" satisfies any of the following conditions, and the remaining definitions are the same as the term "heterocycloalkenyl": 1. It is connected to the rest of the molecule through more than two single bonds; 2. It shares two atoms and one bond with the rest of the molecule.
术语“环烯酮”的例子包括但不限于 Examples of the term "cycloenone" include, but are not limited to
术语“杂芳环”满足下述任一条件，其余定义同术语“杂芳基”：1、通过两个以上的单键与分子其余部分相连；2、与分子其余部分共用两个原子和一根键。The term "heteroaryl ring" satisfies any of the following conditions, and the remaining definitions are the same as the term "heteroaryl": 1. It is connected to the rest of the molecule through more than two single bonds; 2. It shares two atoms and one bond with the rest of the molecule.
术语“芳基”是指具有指定碳原子数(例如，C6～C14)的、环状的、不饱和的一价烃基，其为单环或多环(例如，2个或3个)，为多环时，单环之间共用两个原子和一根键，且(至少一个环/每个环均)具有芳香性。芳基通过芳香性环中的碳原子与分子其余部分相连。芳基包括但不限于：苯基或萘基等。The term "aryl" refers to a cyclic, unsaturated monovalent hydrocarbon group with a specified number of carbon atoms (for example, C 6 to C 14 ), which is monocyclic or polycyclic (for example, 2 or 3). When it is polycyclic, two atoms and one bond are shared between the single rings, and (at least one ring/each ring) is aromatic. An aryl group is attached to the rest of the molecule through a carbon atom in an aromatic ring. Aryl groups include, but are not limited to: phenyl or naphthyl and the like.
术语“芳环”满足下述任一条件，其余定义同术语“芳基”：1、通过两个以上的单键与分子其余部分相连；2、与分子其余部分共用两个原子和一根键。The term "aromatic ring" satisfies any of the following conditions, and the remaining definitions are the same as the term "aryl": 1. It is connected to the rest of the molecule through more than two single bonds; 2. It shares two atoms and one bond with the rest of the molecule.
术语“脂杂环”满足下述任一条件，其余定义同术语“杂环烷基”：1、通过两个以上的单键与分子其余部分相连；2、与分子其余部分共用两个原子和一根键。The term "heteroalicyclic ring" satisfies any of the following conditions, and the remaining definitions are the same as the term "heterocycloalkyl": 1. It is connected to the rest of the molecule through more than two single bonds; 2. It shares two atoms and one bond with the rest of the molecule.
术语“脂碳环”满足下述任一条件，其余定义同术语“环烷基”：1、通过两个以上的单键与分子其余部分相连；2、与分子其余部分共用两个原子和一根键。The term "aliphatic carbocycle" satisfies any of the following conditions, and the remaining definitions are the same as the term "cycloalkyl": 1. It is connected to the rest of the molecule through more than two single bonds; 2. It shares two atoms and one bond with the rest of the molecule.
术语“烷氧基”是指基团RX-O-，RX的定义同术语“烷基”。烷氧基包括但不限于：甲氧基、乙氧基、正丙氧基、异丙氧基等。The term "alkoxy" refers to the group R x -O-, R x is defined the same as the term "alkyl". Alkoxy includes, but is not limited to: methoxy, ethoxy, n-propoxy, isopropoxy, and the like.
在不违背本领域常识的基础上，上述各优选条件，可任意组合，即得本发明各较佳实例。On the basis of not violating common knowledge in the field, the above-mentioned preferred conditions can be combined arbitrarily to obtain preferred examples of the present invention.
本发明所用试剂和原料均市售可得。The reagents and raw materials used in the present invention are all commercially available.
本发明的积极进步效果在于：本发明化合物对KRAS G12D突变的胃癌AGS细胞系、转移胰腺腺癌AsPC-1细胞具有良好的细胞増殖抑制活性。有良好的肝微粒体、肝细胞、血浆、全血稳定性，有良好的PK性质，并且有显著的抑瘤作用。 The positive and progressive effect of the present invention is that the compound of the present invention has good cell proliferation inhibitory activity on KRAS G12D mutated gastric cancer AGS cell line and metastatic pancreatic adenocarcinoma AsPC-1 cells. It has good stability of liver microsomes, liver cells, plasma and whole blood, good PK properties, and significant tumor inhibitory effect.
具体实施方式Detailed ways
下面通过实施例的方式进一步说明本发明，但并不因此将本发明限制在所述的实施例范围之中。下列实施例中未注明具体条件的实验方法，按照常规方法和条件，或按照商品说明书选择。The present invention is further illustrated below by means of examples, but the present invention is not limited to the scope of the examples. For the experimental methods that do not specify specific conditions in the following examples, select according to conventional methods and conditions, or according to the product instructions.
NMR的测定是用Bruker AVANCE-400核磁仪。测定溶剂在谱图解析中注明。NMR was determined with a Bruker AVANCE-400 nuclear magnetic instrument. The determination solvent is indicated in the spectrum analysis.
MS的测定用Agilent 1200-G1956A/1200-6110A/1200-6140A/1260-6125B/Prime-6125B/1260-6120液质联用仪，SHIMADZU 20A-2010/20A-2020液质联用仪，Waters ACQ-QDA液质联用仪。Agilent 1200-G1956A/1200-6110A/1200-6140A/1260-6125B/Prime-6125B/1260-6120 liquid-mass spectrometer, SHIMADZU 20A-2010/20A-2020 liquid-mass spectrometer, Waters ACQ-QDA liquid-mass spectrometer were used for the determination of MS .
HPLC分析使用SHIMADZU 20A高效液相色谱仪。HPLC analysis uses SHIMADZU 20A high performance liquid chromatograph.
SFC分析测定使用Waters UPCC with PDA Detector and QDa Detector超高效合相色谱仪，Waters UPC2with PDA detector超高效合相色谱仪，Agilent 1260 with DAD detector高效液相色谱仪，Shimadzu LC-20AB with PDA detector高效液相色谱仪，Shimadzu LC-20AD with PDA detector高效液相色谱仪。SFC analysis determine the use of Waters Upcc with PDA DETECTOR and QDA DETECTOR ultra -high -efficiency coexistence, Waters Upc 2 with PDA DETECTOR ultra -efficient syndrome, Agilent 1260 with Dad Detector high -efficiency liquid classes, S S HIMADZU LC-20AB With PDA DETECTOR high-efficiency liquid chromatography, Shimadzu LC-20ad with PDA DETECTOR high-efficiency liquid chromatography.
制备型HPLC分离使用Shimadzu LC-20AP pump,Shimadzu LH-40Liquid Handler,Shimadzu SPD-20A Detector，Gilson GX-281 Liquid Handler,Gilson 322 pump,Gilson 156 UV Detector制备型色谱仪。Preparative HPLC separation using Shimadzu LC-20AP pump, Shimadzu LH-40 Liquid Handler, Shimadzu SPD-20A Detector, Gilson GX-281 Liquid Handler, Gilson 322 pump, Gilson 156 UV Detector preparative chromatography.
SFC分离使用The Berger MG II、MG III，Sepiatec's Prep SFC 100 system，Waters Prep 80Q SFC SYSTEM、Prep 150 AP SFC SYSTEM、Prep 200 SFC SYSTEM、Prep 350 SFC SYSTEM。SFC separation uses The Berger MG II, MG III, Sepiatec's Prep SFC 100 system, Waters Prep 80Q SFC SYSTEM, Prep 150 AP SFC SYSTEM, Prep 200 SFC SYSTEM, Prep 350 SFC SYSTEM.
快速柱色谱分离使用Biotage IsoleraOne快速制备色谱仪。Flash column chromatography was performed using a Biotage IsoleraOne flash preparative chromatograph.
薄层层析硅胶板使用安徽良臣硅源材料有限公司的GF254丙烯酸粘合剂硅胶板，薄层色谱法(TLC)使用的硅胶板采用的规格是0.25mm，薄层层析分离纯化产品采用的规格是0.5mm。The thin-layer chromatography silica gel plate uses GF254 acrylic adhesive silica gel plate from Anhui Liangchen Silicon Source Materials Co., Ltd. The specification of the silica gel plate used for thin-layer chromatography (TLC) is 0.25mm, and the specification used for TLC separation and purification products is 0.5mm.
加压氢化反应氢化瓶和氢气钢瓶。Pressurized hydrogenation reaction hydrogenation cylinders and hydrogen cylinders.
微波反应使用Biotage Initiator+微波合成仪。Microwave reactions were performed using a Biotage Initiator+ microwave synthesizer.
手套箱使用德力斯DELLIX定制手套箱。The glove box uses DELLIX custom glove box.
中间体A1：2-(8-乙基-7-氟-3-(甲氧基甲氧基)萘-1-基)-4,4,5,5-四甲基-1,3,2-二氧硼烷
Intermediate A1: 2-(8-Ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane
第一步：向乙炔基三异丙基硅烷(135g，742mmol)的丙酮(2000mL)溶液中慢慢加入N-溴代丁二酰亚胺(145g，815mmol)和硝酸银(12.6g，74.2mmol)，然后反应液在25℃搅拌16小时。反应液浓缩，残余物和石油醚(1500mL)搅拌0.5小时，过滤，滤液旋干得到粗品化合物(溴乙炔基)三异丙基硅烷(171g)，为黄色油状液体。1H NMR(400MHz,CDCl3)δppm 1.13-0.84(m,21H).The first step: N-bromosuccinimide (145g, 815mmol) and silver nitrate (12.6g, 74.2mmol) were slowly added to a solution of ethynyltriisopropylsilane (135g, 742mmol) in acetone (2000mL), and the reaction solution was stirred at 25°C for 16 hours. The reaction solution was concentrated, the residue and petroleum ether (1500 mL) were stirred for 0.5 hours, filtered, and the filtrate was spin-dried to obtain the crude compound (bromoethynyl)triisopropylsilane (171 g) as a yellow oily liquid. 1 H NMR (400MHz, CDCl 3 ) δppm 1.13-0.84 (m, 21H).
第二步：将2-(4-氟苯基)乙酸(200g，1.30mol)，2,2-二甲基-1,3-二恶烷-4,6-二酮(205g，1.42mol)和4-二甲氨基吡啶(14g，114mmol)溶于乙腈(600mL)，降温到0℃缓慢滴加二异丙基乙胺(485mL)，并在0℃下搅拌15分钟。控制反应温度低于30℃下，特戊酰氯(175mL)缓慢滴加到 反应液中，室温搅拌30分钟，然后升到50℃搅拌16小时。反应降到0℃，缓慢加入到稀盐酸(1M，2000mL)中，然后0℃下反应搅拌2小时，有大量黄色固体产生，过滤，滤饼用乙腈和水的混合液(体积比为1/4，6000mL)洗涤，真空干燥，得到粗品化合物5-(2-(4-氟苯基)乙酰基)-2,2-二甲基-1,3-二恶烷-4,6-二酮(364g)，为白色固体。LCMS(ESI):[M-H]-＝278.9；1H NMR(400MHz,DMSO-d6)δppm 7.36(dd,J＝5.6,8.5Hz,2H),7.16(t,J＝8.9Hz,2H),4.36(s,2H),3.75(s,1H)1.69(s,6H)Step 2: Dissolve 2-(4-fluorophenyl)acetic acid (200g, 1.30mol), 2,2-dimethyl-1,3-dioxane-4,6-dione (205g, 1.42mol) and 4-dimethylaminopyridine (14g, 114mmol) in acetonitrile (600mL), cool down to 0°C and slowly add diisopropylethylamine (485mL) dropwise, and stir at 0°C for 15 minutes. Control reaction temperature below 30 ℃, pivaloyl chloride (175mL) is slowly added dropwise to The reaction solution was stirred at room temperature for 30 minutes, then raised to 50°C and stirred for 16 hours. The reaction was lowered to 0°C, slowly added to dilute hydrochloric acid (1M, 2000mL), then stirred at 0°C for 2 hours, a large amount of yellow solid was produced, filtered, the filter cake was washed with a mixture of acetonitrile and water (volume ratio: 1/4, 6000mL), and dried in vacuo to obtain the crude compound 5-(2-(4-fluorophenyl)acetyl)-2,2-dimethyl-1,3-dioxane-4,6-dione (364g) as a white solid . LCMS (ESI): [MH] - = 278.9; 1 H NMR (400MHz, DMSO-d 6 ) δppm 7.36 (dd, J = 5.6, 8.5 Hz, 2H), 7.16 (t, J = 8.9 Hz, 2H), 4.36 (s, 2H), 3.75 (s, 1H) 1.69 (s, 6H)
第三步：将5-(2-(4-氟苯基)乙酰基)-2,2-二甲基-1,3-二恶烷-4,6-二酮(362g，1.29mol)溶于叔丁醇(930mL)中，加热到90℃搅拌2小时。反应液旋干得到粗品化合物4-(4-氟苯基)-3-氧代丁酸叔丁酯(280g)，为黄色固体。LCMS(ESI):[M-H]-＝250.9；1H NMR(400MHz,DMSO-d6)δppm 7.23-7.19(m,2H),7.17-7.11(m,2H),3.86(s,2H),3.54(s,2H),1.40(s,9H).Step 3: Dissolve 5-(2-(4-fluorophenyl)acetyl)-2,2-dimethyl-1,3-dioxane-4,6-dione (362 g, 1.29 mol) in tert-butanol (930 mL), heat to 90° C. and stir for 2 hours. The reaction solution was spin-dried to obtain the crude compound tert-butyl 4-(4-fluorophenyl)-3-oxobutanoate (280 g) as a yellow solid. LCMS (ESI): [MH] - = 250.9; 1 H NMR (400MHz, DMSO-d 6 ) δppm 7.23-7.19 (m, 2H), 7.17-7.11 (m, 2H), 3.86 (s, 2H), 3.54 (s, 2H), 1.40 (s, 9H).
第四步：4-(4-氟苯基)-3-氧代丁酸叔丁酯(278g，1.10mol)溶于二氯甲烷(2480mL)中，在0℃下加入三氟乙酸(575mL,7.50mol)，反应在25℃搅拌16小时。反应结束后真空浓缩得到粗品化合物4-(4-氟苯基)-3-氧代丁酸(231g)，为白色固体。LCMS(ESI):[M-H]-＝194.8；1H NMR(400MHz,CDCl3)δppm 7.26-7.15(m,2H),7.11-7.01(m,2H),3.85(s,2H),3.56(s,2H)Step 4: tert-butyl 4-(4-fluorophenyl)-3-oxobutyrate (278g, 1.10mol) was dissolved in dichloromethane (2480mL), trifluoroacetic acid (575mL, 7.50mol) was added at 0°C, and the reaction was stirred at 25°C for 16 hours. After the reaction was completed, it was concentrated in vacuo to obtain the crude compound 4-(4-fluorophenyl)-3-oxobutanoic acid (231 g) as a white solid. LCMS (ESI): [MH] - = 194.8; 1 H NMR (400MHz, CDCl 3 ) δppm 7.26-7.15 (m, 2H), 7.11-7.01 (m, 2H), 3.85 (s, 2H), 3.56 (s, 2H)
第五步：将4-(4-氟苯基)-3-氧代丁酸(231g，1.18mol)溶于三氟甲磺酸(1230mL，13.9mol)，反应在25℃搅拌24小时。慢慢加入0℃的冰水中(10L)，反应液用乙酸乙酯(5L*3)萃取。合并的有机相用水(2L)和饱和食盐水洗(2L)洗涤，用硫酸钠干燥，过滤，滤液减压旋干，残留物用快速柱色谱纯化(硅胶，0-20％梯度的乙酸乙酯/石油醚)得到化合物7-氟萘-1,3-二醇(89g，0.5mol，4步收率:38％)，为红色油状液体。LCMS(ESI):[M+H]+＝179.1；1H NMR(400MHz,DMSO-d6)δppm10.26(s,1H),9.55(s,1H),7.67-7.51(m,2H),7.27-7.17(m,1H),6.64(d,J＝2.0Hz,1H),6.55(d,J＝1.8Hz,1H).Step 5: 4-(4-fluorophenyl)-3-oxobutanoic acid (231 g, 1.18 mol) was dissolved in trifluoromethanesulfonic acid (1230 mL, 13.9 mol), and the reaction was stirred at 25° C. for 24 hours. Slowly add ice water (10L) at 0°C, and extract the reaction solution with ethyl acetate (5L*3). The combined organic phases were washed with water (2 L) and saturated brine (2 L), dried over sodium sulfate, filtered, and the filtrate was spin-dried under reduced pressure. The residue was purified by flash column chromatography (silica gel, 0-20% gradient of ethyl acetate/petroleum ether) to obtain compound 7-fluoronaphthalene-1,3-diol (89 g, 0.5 mol, 4-step yield: 38%) as a red oily liquid. LCMS (ESI): [M+H] + = 179.1; 1 H NMR (400MHz, DMSO-d 6 ) δppm 10.26 (s, 1H), 9.55 (s, 1H), 7.67-7.51 (m, 2H), 7.27-7.17 (m, 1H), 6.64 (d, J = 2.0Hz, 1H), 6.55 ( d,J=1.8Hz,1H).
第六步：将7-氟萘-1,3-二醇(88g，494mmol)，(溴乙炔基)三异丙基硅烷(155g，592mmol)和乙酸钾(98g，1.0mol)混合于二氧六环(640mL)中，氮气下加入二氯(对甲基异丙基苯基)钌(II)二聚体(30.2g，49.6mmol)，反应液110℃搅拌2小时。过滤，滤液旋干，残留物用快速柱色谱纯化(硅胶，0-20％梯度的乙酸乙酯/石油醚)得到7-氟-8-((三异丙基甲硅烷基)乙炔基)萘-1,3-二醇(123g，343mmol，收率：69％)。LCMS(ESI):[M-H]-＝357.0；1H NMR(400MHz,CDCl3)δppm 10.06(s,1H),9.18(s,1H),7.60(dd,J＝5.6,9.2Hz,1H),7.22-7.13(m,1H),6.76(d,J＝2.3Hz,1H),6.68(d,J＝2.0Hz,1H),1.23-1.16(m,21H).Step 6: Mix 7-fluoronaphthalene-1,3-diol (88g, 494mmol), (bromoethynyl)triisopropylsilane (155g, 592mmol) and potassium acetate (98g, 1.0mol) in dioxane (640mL), add dichloro(p-methylisopropylphenyl)ruthenium(II) dimer (30.2g, 49.6mmol) under nitrogen, and the reaction solution is 110°C Stir for 2 hours. Filtration, the filtrate was spin-dried, and the residue was purified by flash column chromatography (silica gel, 0-20% gradient ethyl acetate/petroleum ether) to obtain 7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalene-1,3-diol (123g, 343mmol, yield: 69%). LCMS (ESI): [MH] - = 357.0; 1 H NMR (400MHz, CDCl 3 ) δppm 10.06 (s, 1H), 9.18 (s, 1H), 7.60 (dd, J = 5.6, 9.2Hz, 1H), 7.22-7.13 (m, 1H), 6.76 (d, J = 2.3Hz, 1H), 6 .68(d,J=2.0Hz,1H),1.23-1.16(m,21H).
第七步：将7-氟-8-((三异丙基甲硅烷基)乙炔基)萘-1,3-二醇(123g，343mmol)溶于二氯甲烷(1230mL)中，降到0℃，慢慢往反应液中加入二异丙基乙胺(180mL，1030mmol)和氯甲基甲醚(36.5g，454mmol)，反应在20℃搅拌16小时。反应完后用水(1000mL)淬灭，然后用二氯甲烷(500mL*2)萃取，合并有机相，旋干，残留物用快速柱色谱纯化(硅胶，0-5％梯度的乙酸乙酯/石油醚)得到7-氟-3-(甲氧基甲氧基)-8-((三异丙基甲硅烷基)乙炔基)萘-1-醇(48g，119mmol，收率：35％)。LCMS(ESI):[M-H]-＝401.1；1H NMR(400MHz,CDCl3)δppm 9.19-9.08(m,1H),7.71-7.63(m,1H),7.24-7.16(m,1H),6.98(d,J＝2.5Hz,1H),6.82(d,J＝2.0Hz,1H),5.27(s,2H),3.52(s,3H),1.22-1.19(m,21H).Step 7: 7-Fluoro-8-((triisopropylsilyl)ethynyl)naphthalene-1,3-diol (123g, 343mmol) was dissolved in dichloromethane (1230mL), lowered to 0°C, diisopropylethylamine (180mL, 1030mmol) and chloromethyl methyl ether (36.5g, 454mmol) were slowly added to the reaction solution, and the reaction was stirred at 20°C for 16 hours. After the reaction was quenched with water (1000 mL), then extracted with dichloromethane (500 mL*2), the organic phases were combined and spin-dried, and the residue was purified by flash column chromatography (silica gel, 0-5% gradient ethyl acetate/petroleum ether) to obtain 7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalene-1-ol (48 g, 119 mmol, yield: 35%). LCMS (ESI): [MH] - = 401.1; 1 H NMR (400MHz, CDCl 3 ) δppm 9.19-9.08 (m, 1H), 7.71-7.63 (m, 1H), 7.24-7.16 (m, 1H), 6.98 (d, J = 2.5Hz, 1H), 6.82 (d, J = 2.0Hz, 1H),5.27(s,2H),3.52(s,3H),1.22-1.19(m,21H).
第八步：将7-氟-3-(甲氧基甲氧基)-8-((三异丙基甲硅烷基)乙炔基)萘-1-醇(48.0g，119mmol)，二异丙基乙胺(62mL，357mmol)，4-二甲氨基吡啶(3.00g，24.5mmol)溶于二氯甲烷(480mL)，0℃下慢慢加入特戊酰氯(29mL，238mmol)，反应液在20℃下搅拌2小时。向反应液中加入二氯 甲烷(360mL)和水(360mL)，分液，水相用二氯甲烷(200mL*2)萃取，合并有机相，用硫酸钠干燥，过滤，滤液旋干。残留物用快速柱色谱纯化(硅胶，0-5％梯度的乙酸乙酯/石油醚)得到化合物7-氟-3-(甲氧基甲氧基)-8-((三异丙基甲硅烷基)乙炔基)萘-1-基特戊酸酯(50g，102mmol,收率86％)，为黄色油状液体。1HNMR(400MHz,CDCl3)δppm 7.60(dd,J＝5.5,9.1Hz,1H),7.22-7.20(m,1H),7.19-7.13(m,1H),6.76(d,J＝2.3Hz,1H),5.18(s,2H),3.45(s,3H),1.39(s,9H),1.11-1.05(m,21H).Step 8: Dissolve 7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalene-1-ol (48.0g, 119mmol), diisopropylethylamine (62mL, 357mmol), 4-dimethylaminopyridine (3.00g, 24.5mmol) in dichloromethane (480mL), slowly add pivaloyl chloride (29mL, 238mL) at 0°C mmol), the reaction solution was stirred at 20°C for 2 hours. Add dichloride to the reaction solution Methane (360mL) and water (360mL) were separated, the aqueous phase was extracted with dichloromethane (200mL*2), the organic phases were combined, dried over sodium sulfate, filtered, and the filtrate was spin-dried. The residue was purified by flash column chromatography (silica gel, 0-5% gradient ethyl acetate/petroleum ether) to obtain compound 7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalene-1-yl pivalate (50 g, 102 mmol, yield 86%) as a yellow oily liquid. 1 HNMR (400MHz, CDCl 3 ) δppm 7.60(dd,J=5.5,9.1Hz,1H),7.22-7.20(m,1H),7.19-7.13(m,1H),6.76(d,J=2.3Hz,1H),5.18(s,2H),3.45(s,3H),1.39(s, 9H),1.11-1.05(m,21H).
第九步：将7-氟-3-(甲氧基甲氧基)-8-((三异丙基甲硅烷基)乙炔基)萘-1-基特戊酸酯(50g，102mmol)溶于N,N-二甲基甲酰胺(916mL)，加入氟化铯(167g，1099mmol)，反应在20℃搅拌3小时。反应完后，减压浓缩除去溶剂。将粗品溶于乙酸乙酯(1000mL)和水(2000mL)中，分离出有机相，水相用乙酸乙酯(1000mL*2)萃取。合并有机相并用饱和食盐水(1000mL)洗涤，有机相用硫酸钠干燥，过滤，滤液旋干，残留物用快速柱色谱纯化(硅胶，0-5％梯度的乙酸乙酯/石油醚)得到化合物8-乙炔基-7-氟-3-(甲氧基甲氧基)萘-1-基特戊酸酯(19g，57.5mmol，收率56％)，为黄色油状液体。LCMS(ESI):[M+H]+＝331.1；1HNMR(400MHz,CDCl3)δppm 7.66(dd,J＝5.6,9.1Hz,1H),7.24(d,J＝2.4Hz,1H),7.20-7.16(m,1H),6.79(d,J＝2.1Hz,1H),5.19(s,2H),3.50(s,1H),3.43(s,3H),0.99(s,9H).Step 9: 7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalene-1-ylpivalate (50g, 102mmol) was dissolved in N,N-dimethylformamide (916mL), cesium fluoride (167g, 1099mmol) was added, and the reaction was stirred at 20°C for 3 hours. After the reaction, the solvent was removed by concentration under reduced pressure. The crude product was dissolved in ethyl acetate (1000 mL) and water (2000 mL), the organic phase was separated, and the aqueous phase was extracted with ethyl acetate (1000 mL*2). The organic phases were combined and washed with saturated brine (1000 mL), dried over sodium sulfate, filtered, and the filtrate was spin-dried, and the residue was purified by flash column chromatography (silica gel, 0-5% gradient ethyl acetate/petroleum ether) to obtain the compound 8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yl pivalate (19 g, 57.5 mmol, yield 56%) as a yellow oily liquid. LCMS (ESI): [M+H] + = 331.1; 1 HNMR (400MHz, CDCl 3 ) δppm 7.66 (dd, J = 5.6, 9.1Hz, 1H), 7.24 (d, J = 2.4Hz, 1H), 7.20-7.16 (m, 1H), 6.79 (d, J = 2.1Hz, 1H), 5.19 ( s,2H),3.50(s,1H),3.43(s,3H),0.99(s,9H).
第十步：将8-乙炔基-7-氟-3-(甲氧基甲氧基)萘-1-基特戊酸酯(19g，57.5mmol)溶于甲醇(200mL)中，在氮气下加入钯碳(含量10％，2.00g)，反应液用氢气置换3次。反应液在20℃下用氢气球氢化2小时。反应完后过滤，滤液旋干得到粗品化合物8-乙基-7-氟-3-(甲氧基甲氧基)萘-1-基特戊酸酯(16g)。LCMS(ESI):[M+H]+＝335.1；1H NMR(400MHz,CDCl3)δppm 7.51(dd,J＝5.6,9.0Hz,1H),7.23(d,J＝2.5Hz,1H),7.16-7.09(m,1H),6.70(d,J＝2.4Hz,1H),5.18(s,2H),3.43(s,3H),3.04(q,J＝7.5Hz,2H),1.38(s,9H),1.18-1.12(m,3H).Step 10: Dissolve 8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-ylpivalate (19g, 57.5mmol) in methanol (200mL), add palladium on carbon (content 10%, 2.00g) under nitrogen, and replace the reaction solution with hydrogen 3 times. The reaction solution was hydrogenated with a hydrogen balloon at 20°C for 2 hours. After the reaction, it was filtered, and the filtrate was spin-dried to obtain the crude compound 8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yl pivalate (16 g). LCMS (ESI): [M+H] + = 335.1; 1 H NMR (400MHz, CDCl 3 ) δppm 7.51 (dd, J = 5.6, 9.0Hz, 1H), 7.23 (d, J = 2.5Hz, 1H), 7.16-7.09 (m, 1H), 6.70 (d, J = 2.4Hz, 1H), 5.18 ( s,2H),3.43(s,3H),3.04(q,J=7.5Hz,2H),1.38(s,9H),1.18-1.12(m,3H).
第十一步：将8-乙基-7-氟-3-(甲氧基甲氧基)萘-1-基特戊酸酯(16g，47.8mmol)溶于甲醇(250mL)，加入氢氧化钾(8.50g,151mmol)，反应在20℃搅拌2小时。反应完成后将反应液用稀盐酸(1M)在0℃下调到pH为6，用乙酸乙酯(200mL*3)萃取，合并有机相，用饱和食盐水(100ml)洗涤，硫酸钠干燥，过滤，滤液旋干，残留物用快速柱色谱纯化(硅胶，0-5％梯度的乙酸乙酯/石油醚)得到化合物8-乙基-7-氟-3-(甲氧基甲氧基)萘-1-醇(11g，43.9mmol，收率92％)，为黄色固体。LCMS(ESI):[M+H]+＝251.1；1H NMR(400MHz,CDCl3)δppm 7.50(dd,J＝5.6,8.9Hz,1H),7.19(t,J＝9.2Hz,1H),7.00(d,J＝2.3Hz,1H),6.59(d,J＝2.0Hz,1H),5.55-5.45(m,1H),5.30-5.24(m,2H),3.58-3.48(m,3H),3.35(dd,J＝3.0,7.3Hz,2H),1.35-1.26(m,3H).Step 11: Dissolve 8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-ylpivalate (16g, 47.8mmol) in methanol (250mL), add potassium hydroxide (8.50g, 151mmol), and stir the reaction at 20°C for 2 hours. After the reaction was completed, the reaction solution was adjusted to pH 6 with dilute hydrochloric acid (1M) at 0°C, extracted with ethyl acetate (200mL*3), combined the organic phases, washed with saturated brine (100ml), dried over sodium sulfate, filtered, and the filtrate was spin-dried, and the residue was purified by flash column chromatography (silica gel, 0-5% gradient ethyl acetate/petroleum ether) to obtain the compound 8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-ol (11g, 43 .9 mmol, yield 92%), as a yellow solid. LCMS (ESI): [M+H] + =251.1; 1 H NMR (400MHz, CDCl 3 ) δppm 7.50(dd, J=5.6,8.9Hz,1H),7.19(t,J=9.2Hz,1H),7.00(d,J=2.3Hz,1H),6.59(d,J=2.0Hz,1H),5.5 5-5.45(m,1H),5.30-5.24(m,2H),3.58-3.48(m,3H),3.35(dd,J=3.0,7.3Hz,2H),1.35-1.26(m,3H).
第十二步：将8-乙基-7-氟-3-(甲氧基甲氧基)萘-1-醇(11g，43.9mmol)，二异丙基乙胺(23mL,132mmol)溶于二氯甲烷(220mL)，-40℃慢慢滴加三氟甲磺酸酐(11mL，67.1mmol)，反应在-40℃搅拌2小时。反应结束后用冰水(200mL)淬灭反应，用二氯甲烷(200mL*2)萃取。合并有机相，用饱和食盐水(100mL)洗涤，硫酸钠干燥，过滤，滤液旋干。残留物用快速柱色谱纯化(硅胶，0-5％梯度的乙酸乙酯/石油醚)得到化合物8-乙基-7-氟-3-(甲氧基甲氧基)萘-1-基三氟甲磺酸酯(15g，39.2mmol，收率89％)，为黄色油状液体。LCMS(ESI):[M+H]+＝382.9；1H NMR(400MHz,CDCl3)δppm 7.64(dd,J＝5.6,8.9Hz,1H),7.45(d,J＝2.5Hz,1H),7.39(d,J＝2.3Hz,1H),7.34-7.27(m,1H),5.30(s,2H),3.59-3.47(m,3H),3.27(dq,J＝2.8,7.4Hz,2H),1.26(t,J＝7.4Hz,3H).Step 12: Dissolve 8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-ol (11g, 43.9mmol) and diisopropylethylamine (23mL, 132mmol) in dichloromethane (220mL), slowly add trifluoromethanesulfonic anhydride (11mL, 67.1mmol) dropwise at -40°C, and stir the reaction at -40°C for 2 hours. After the reaction was completed, the reaction was quenched with ice water (200 mL), and extracted with dichloromethane (200 mL*2). The organic phases were combined, washed with saturated brine (100 mL), dried over sodium sulfate, filtered, and the filtrate was spin-dried. The residue was purified by flash column chromatography (silica gel, 0-5% gradient ethyl acetate/petroleum ether) to give compound 8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl triflate (15 g, 39.2 mmol, yield 89%) as a yellow oily liquid. LCMS (ESI): [M+H] + = 382.9; 1 H NMR (400MHz, CDCl 3 ) δppm 7.64 (dd, J = 5.6, 8.9 Hz, 1H), 7.45 (d, J = 2.5Hz, 1H), 7.39 (d, J = 2.3Hz, 1H), 7.34-7.27 (m, 1H), 5.30 ( s,2H),3.59-3.47(m,3H),3.27(dq,J=2.8,7.4Hz,2H),1.26(t,J=7.4Hz,3H).
第十三步：将8-乙基-7-氟-3-(甲氧基甲氧基)萘-1-基三氟甲磺酸酯(15g，39.2mmol)，双联嚬哪 醇硼酸酯(20g，78.7mmol)，乙酸钾(12g，122mmol)混合于甲苯(380mL)中，氮气下加入[1,1-双(二苯基膦)二茂铁]二氯化钯二氯甲烷(3.20g，3.92mmol)，反应升到130℃搅拌16小时。反应液过滤，滤液旋干。残留物用快速柱色谱纯化(硅胶，0-5％梯度的乙酸乙酯/石油醚)得到黄色油状粗品，粗品用快速柱色谱纯化(C18，0-100％梯度的乙腈/纯水)得到化合物2-(8-乙基-7-氟-3-(甲氧基甲氧基)萘-1-基)-4,4,5,5-四甲基-1,3,2-二氧硼烷(2.20g，6.11mmol，收率：16％)，为黄色固体。LCMS(ESI):[M+H]+＝361.0；1HNMR(400MHz,CDCl3)δppm 7.49(dd,J＝5.9,8.9Hz,1H),7.38-7.27(m,2H),7.12(t,J＝9.3Hz,1H),5.24-5.16(m,2H),3.49-3.38(m,3H),3.11-2.97(m,2H),1.42-1.33(m,12H),1.19(t,J＝7.5Hz,3H).The thirteenth step: 8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yl trifluoromethanesulfonate (15g, 39.2mmol), bis Alcohol borate (20g, 78.7mmol), potassium acetate (12g, 122mmol) were mixed in toluene (380mL), [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane (3.20g, 3.92mmol) was added under nitrogen, and the reaction was raised to 130°C and stirred for 16 hours. The reaction solution was filtered, and the filtrate was spin-dried. The residue was purified by flash column chromatography (silica gel, 0-5% gradient of ethyl acetate/petroleum ether) to give a crude yellow oil, which was purified by flash column chromatography (C18, 0-100% gradient of acetonitrile/pure water) to give compound 2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (2.20 g, 6.11 mmol, Yield: 16%) as a yellow solid. LCMS (ESI): [M+H] + = 361.0; 1 HNMR (400MHz, CDCl 3 ) δppm 7.49 (dd, J = 5.9, 8.9 Hz, 1H), 7.38-7.27 (m, 2H), 7.12 (t, J = 9.3Hz, 1H), 5.24-5.16 (m, 2H), 3.49-3. 38(m,3H),3.11-2.97(m,2H),1.42-1.33(m,12H),1.19(t,J=7.5Hz,3H).
中间体A2：((2-氟-6-(甲氧基甲氧基)-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
Intermediate A2: ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane
第一步：在-40℃下，向7-氟-3-(甲氧基甲氧基)-8-((三异丙基甲硅烷基)乙炔基)萘-1-醇(4.93g，12.2mmol)和二异丙基乙胺(7mL，40.0mmol)的二氯甲烷(75mL)溶液中加入三氟甲磺酸酐(5.19g，18.4mmol)。溶液在-40℃搅拌1小时，浓缩溶液。残余物通过快速柱色谱(硅胶，0-5％梯度乙酸乙酯/石油醚)纯化，得到黄色油状化合物7-氟-3-(甲氧基甲氧基)-8-((三异丙基甲硅烷基)乙炔基)萘-1-基三氟甲磺酸酯(纯度90％，6g，10.1mmol，收率82％)。1H NMR(400MHz,DMSO-d6)δ＝8.10(dd,J＝5.7,9.2Hz,1H),7.76(d,J＝2.4Hz,1H),7.63(t,J＝9.0Hz,1H),7.49(d,J＝2.2Hz,1H),5.36(s,2H),3.43-3.41(m,3H),1.15-1.04(m,21H).Step 1: To a solution of 7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalene-1-ol (4.93 g, 12.2 mmol) and diisopropylethylamine (7 mL, 40.0 mmol) in dichloromethane (75 mL) was added trifluoromethanesulfonic anhydride (5.19 g, 18.4 mmol) at -40°C. The solution was stirred at -40°C for 1 hour, and the solution was concentrated. The residue was purified by flash column chromatography (silica gel, 0-5% gradient ethyl acetate/petroleum ether) to give yellow oily compound 7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalene-1-yl trifluoromethanesulfonate (purity 90%, 6 g, 10.1 mmol, yield 82%). 1 H NMR (400MHz, DMSO-d 6 )δ=8.10(dd,J=5.7,9.2Hz,1H),7.76(d,J=2.4Hz,1H),7.63(t,J=9.0Hz,1H),7.49(d,J=2.2Hz,1H),5.36(s,2H),3.43-3.41(m,3H ),1.15-1.04(m,21H).
第二步：在25℃的氮气氛围下向7-氟-3-(甲氧基甲氧基)-8-((三异丙基甲硅烷基)乙炔基)萘-1-基三氟甲磺酸酯(纯度90％，6g，10.1mmol)和双联频哪醇硼酸酯(5.70g，22.4mmol)的甲苯(60mL)溶液中加入醋酸钾(3.31g，33.7mmol)和1,1-双(二苯基磷)二茂铁氯化钯(0.92g，1.13mmol)。将悬浮液在130℃下搅拌3小时。过滤悬浮液并浓缩，得到黑色粗品。粗品通过快速柱色谱(硅胶，0-10％梯度乙酸乙酯/石油醚)纯化得到白色固体化合物((2-氟-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)三异丙基硅烷(2.10g，4.10mmol，收率41％)。LCMS(ESI):[M+H]+＝513.0.Second step: Add potassium acetate (3.31 g, 33.7 mmol) and 1, 1-Bis(diphenylphosphino)ferrocenepalladium chloride (0.92g, 1.13mmol). The suspension was stirred at 130°C for 3 hours. The suspension was filtered and concentrated to give a black crude product. The crude product was purified by flash column chromatography (silica gel, 0-10% gradient ethyl acetate/petroleum ether) to give white solid compound ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalene-1-yl)ethynyl)triisopropylsilane (2.10 g, 4.10 mmol, yield 41%). LCMS (ESI): [M+H] + = 513.0.
中间体A3：((2-氟-8-(4,4,5,5-四甲基-1,3,2-二恶硼烷-2-基)萘-1-基)乙炔基)三异丙基硅烷
Intermediate A3: ((2-fluoro-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane
第一步：将化合物7-氟-1-四氢萘酮(18.0g，109mmol)溶于乙酸(300mL)和氢溴酸(33％的乙酸溶液，2.5mL)，0℃下加入液溴(19.2g，120mmol)溶于乙酸(20mL)。反应在25℃下搅拌3小时。反应液用二氯甲烷(300mL)稀释，用水洗涤(70mL*3)，硫酸钠干燥，过滤，滤液减压浓缩。粗品溶于二甲基甲酰胺(200mL)，加入溴化锂(16.2g，186mmol)和碳酸锂(13.7g，186mmol)，反应在160℃下搅拌3.5小时。反应液用乙酸乙酯(500mL)稀释，用工业盐水(500mL*2)，硫酸钠干燥，过滤，滤液减压浓缩。残留物用快速柱色谱纯化(硅胶，0-3％梯度的乙酸乙酯/石油醚)得到黄色固体7-氟萘-1-醇(14.3g，88mmol，收率80％)。LCMS(ESI):[M+H]+＝163.1.1H NMR(400MHz,CDCl3)δppm 7.89-7.76(m,2H),7.46(d,J＝8.3Hz,1H),7.34-7.24(m,2H),6.86(d,J＝7.5Hz,1H),5.41-5.30(m,1H).Step 1: Dissolve compound 7-fluoro-1-tetralone (18.0g, 109mmol) in acetic acid (300mL) and hydrobromic acid (33% acetic acid solution, 2.5mL), add liquid bromine (19.2g, 120mmol) at 0°C and dissolve in acetic acid (20mL). The reaction was stirred at 25°C for 3 hours. The reaction solution was diluted with dichloromethane (300 mL), washed with water (70 mL*3), dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was dissolved in dimethylformamide (200 mL), lithium bromide (16.2 g, 186 mmol) and lithium carbonate (13.7 g, 186 mmol) were added, and the reaction was stirred at 160° C. for 3.5 hours. The reaction solution was diluted with ethyl acetate (500 mL), dried with industrial brine (500 mL*2), sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 0-3% gradient of ethyl acetate/petroleum ether) to give 7-fluoronaphth-1-ol (14.3 g, 88 mmol, 80% yield) as a yellow solid. LCMS (ESI): [M+H] + =163.1.1H NMR (400MHz, CDCl 3 ) δppm 7.89-7.76(m,2H),7.46(d,J=8.3Hz,1H),7.34-7.24(m,2H),6.86(d,J=7.5Hz,1H),5.41-5.30(m, 1H).
第二步：将7-氟萘-1-醇(14.3g，88.2mmol)，(溴乙炔基)三异丙基硅烷(27.6g，105mmol)，乙酸钠(1.45g，17.6mmol)和碳酸钾(12.2g，88.2mmol)溶于二氯乙烷(192mL)，氮气下加入二氯(对甲基异丙基苯基)钌(II)二聚体(8.10g，13.2mmol)，反应液在50℃搅拌16小时。反应完后过滤，滤液旋干。残留物用快速柱色谱纯化(硅胶，0～2％梯度的乙酸乙酯/石油醚)得到7-氟-8-((三异丙基甲硅烷基)乙炔基)萘-1-醇(28.5g，83.2mmol，收率94％)。LCMS(ESI):[M+H]+＝343.3.1H NMR(400MHz,CDCl3)δppm 9.11(s,1H),7.80(dd,J＝5.8,9.3Hz,1H),7.42-7.35(m,2H),7.24(t,J＝8.8Hz,1H),7.08-7.01(m,1H),1.24-1.18(m,21H).Second step: 7-fluoronaphthalen-1-ol (14.3g, 88.2mmol), (bromoethynyl)triisopropylsilane (27.6g, 105mmol), sodium acetate (1.45g, 17.6mmol) and potassium carbonate (12.2g, 88.2mmol) were dissolved in dichloroethane (192mL), and dichloro(p-methylisopropylphenyl) ruthenium (II) dimer ( 8.10 g, 13.2 mmol), and the reaction solution was stirred at 50° C. for 16 hours. After the reaction was completed, filter and spin the filtrate to dryness. The residue was purified by flash column chromatography (silica gel, 0-2% gradient of ethyl acetate/petroleum ether) to give 7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalene-1-ol (28.5 g, 83.2 mmol, yield 94%). LCMS (ESI): [M+H] + =343.3.1H NMR (400MHz, CDCl 3 ) δppm 9.11(s,1H),7.80(dd,J=5.8,9.3Hz,1H),7.42-7.35(m,2H),7.24(t,J=8.8Hz,1H),7.08-7.01(m,1 H),1.24-1.18(m,21H).
第三步：将7-氟-8-((三异丙基甲硅烷基)乙炔基)萘-1-醇(28.5g，83.2mmol)，二异丙基乙胺(59.0mL，338mmol)溶于二氯甲烷(500mL)，-40℃慢慢滴加三氟甲磺酸酐(35.8g，127mmol)，反应在-40℃搅拌2小时。反应完后用冰水(500mL)淬灭，用DCM(200mL*2)萃取。合并有机相用饱和食盐水(100mL)洗，硫酸钠干燥，过滤，滤液减压浓缩。残留物用快速柱色谱纯化(硅胶，0-5％梯度的乙酸乙酯/石油醚)得到黄色油状7-氟-8-((三异丙基甲硅烷基)乙炔基)萘-1-基三氟甲磺酸酯(33g，69.6mmol，收率84％)。1H NMR(400MHz,CDCl3)δppm 7.92-7.77(m,2H),7.60-7.55(m,1H),7.51-7.45(m,1H),7.39(t,J＝8.8Hz,1H),1.28-1.16(m,21H).Step 3: Dissolve 7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalene-1-ol (28.5g, 83.2mmol), diisopropylethylamine (59.0mL, 338mmol) in dichloromethane (500mL), slowly add trifluoromethanesulfonic anhydride (35.8g, 127mmol) dropwise at -40°C, and stir the reaction at -40°C for 2 hours. After the reaction was completed, it was quenched with ice water (500 mL), and extracted with DCM (200 mL*2). The combined organic phases were washed with saturated brine (100 mL), dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 0-5% gradient of ethyl acetate/petroleum ether) to give 7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl triflate (33 g, 69.6 mmol, yield 84%) as yellow oil. 1H NMR (400MHz, CDCl 3 ) δppm 7.92-7.77(m, 2H), 7.60-7.55(m, 1H), 7.51-7.45(m, 1H), 7.39(t, J=8.8Hz, 1H), 1.28-1.16(m, 21H).
第四步：将7-氟-8-((三异丙基甲硅烷基)乙炔基)萘-1-基三氟甲磺酸酯(5.20g，10.9mmol)，双联嚬哪醇硼酸酯(4.17g，16.4mmol)，乙酸钾(6.18g，21.9mmol)溶于甲苯(100mL)，氮气下加入[1,1-双(二苯基膦)二茂铁]二氯化钯二氯甲烷(0.89g，1.10mmol)，反应升到130℃搅拌3小时。反应完过滤，滤液旋干。残留物用快速柱色谱纯化(硅胶，0-5％梯度的四氢呋喃/石油醚)得到黄色固体((2-氟-8-(4,4,5,5-四甲基-1,3,2-二恶硼烷-2-基)萘-1-基)乙炔基)三异丙基硅烷(1.77g，3.91mmol，收率35％)。LCMS(ESI):[M+H]+＝453.3.1H NMR(400MHz,CDCl3)δppm 7.89-7.74(m,3H),7.44(dd,J＝7.0,8.1Hz,1H),7.28-7.25(m,1H),1.46(s,12H),1.25-1.12(m,21H). Step 4: Dissolve 7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalene-1-yl trifluoromethanesulfonate (5.20g, 10.9mmol), bis-diancol borate (4.17g, 16.4mmol), potassium acetate (6.18g, 21.9mmol) in toluene (100mL), and add [1,1-bis(diphenylphosphino)ferrocene]diferrocene under nitrogen Palladium chloride in dichloromethane (0.89g, 1.10mmol), the reaction was raised to 130°C and stirred for 3 hours. After the reaction, filter and spin the filtrate to dryness. The residue was purified by flash column chromatography (silica gel, 0-5% tetrahydrofuran/petroleum ether gradient) to give ((2-fluoro-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalene-1-yl)ethynyl)triisopropylsilane (1.77 g, 3.91 mmol, yield 35%) as a yellow solid. LCMS (ESI): [M+H] + =453.3.1H NMR (400MHz, CDCl 3 ) δppm 7.89-7.74(m,3H),7.44(dd,J=7.0,8.1Hz,1H),7.28-7.25(m,1H),1.46(s,12H),1.25-1.12(m,21 H).
中间体A4：(1R,5S)-叔丁基3-(7-氯-8-氟-2-(((2R,7aS)-2-氟六氢-1H-吡咯嗪-7a-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯
Intermediate A4: (1R,5S)-tert-butyl 3-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolazin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate
第一步：在-40℃下向化合物2,4,7-三氯-8-氟吡啶并[4,3-d]嘧啶(4.00g,15.84mmol)加入二异丙基乙胺(4mL，23.77mmol)，二氯甲烷溶液(140mL)和化合物(1R,5S)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸叔丁酯(3.87g,18.22mmol)溶液并在-40℃搅拌1小时。将混合物用水(20mL)稀释并用乙酸乙酯(20mL*3)萃取，有机相减压浓缩得到黄色色固体(1R,5S)-3-(2,7-二氯-8-氟吡啶并[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(纯度80％，8g，14.94mmol，收率94％)。LCMS(ESI):[M+H]+＝428.1。1H NMR(400MHz,CDCl3-d4)δ＝8.78(s,1H),4.52-4.27(m,4H),3.60(dt,J＝6.6,13.3Hz,2H),1.98-1.82(m,4H),1.47-1.43(m,9H)Step 1: To compound 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (4.00g, 15.84mmol) was added diisopropylethylamine (4mL, 23.77mmol), dichloromethane solution (140mL) and compound (1R,5S)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (3.87 g, 18.22mmol) and stirred at -40°C for 1 hour. The mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL*3), and the organic phase was concentrated under reduced pressure to obtain a yellow solid (1R,5S)-3-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (purity 80%, 8g, 14.94mmol, yield 94%) . LCMS (ESI): [M+H] + = 428.1. 1 H NMR (400MHz, CDCl 3 -d4) δ=8.78(s,1H),4.52-4.27(m,4H),3.60(dt,J=6.6,13.3Hz,2H),1.98-1.82(m,4H),1.47-1.43(m,9H)
第二步：向化合物(1R,5S)-3-(2,7-二氯-8-氟吡啶并[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(纯度80％，1.50g，2.80mmol)加入((2R,7aS)-2-氟六氢-1H-吡咯嗪-7a-基)甲醇(0.56g,3.50mmol)，在25℃下加入二异丙基乙胺(2mL,10.51mmol)和二氧六环(15mL)。溶液在80℃搅拌16小时。反应液用水(5mL)稀释并用乙酸乙酯(5mL*3)萃取，有机相减压浓缩，残余物通过快速柱色谱纯化(硅胶，0-10％二氯甲烷/甲醇)得到黄色固体化合物(1R,5S)-叔丁基3-(7-氯-8-氟-2-(((2R,7aS)-2-氟六氢-1H-吡咯嗪-7a-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(纯度60％，620mg，0.68mmol，收率19％)。LCMS(ESI):[M+H]+＝551.2.1H NMR(400MHz,CDCl3-d4)δ＝8.65(s,1H),4.25-4.20(m,1H),3.96(d,J＝13.0Hz,1H),3.69-3.65(m,1H),3.55-3.48(m,2H),3.45-3.35(m,1H),3.19-3.09(m,2H),2.99-2.91(m,1H),2.66-2.49(m,1H),2.31-2.19(m,3H),1.93-1.84(m,4H),1.78(td,J＝3.2,6.7Hz,2H),1.62(br d,J＝7.8Hz,3H),1.49-1.47(m,1H),1.45(s,9H)The second step: ((2R, 7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methanol (0 .56g, 3.50mmol), diisopropylethylamine (2mL, 10.51mmol) and dioxane (15mL) were added at 25°C. The solution was stirred at 80°C for 16 hours. The reaction solution was diluted with water (5 mL) and extracted with ethyl acetate (5 mL*3), the organic phase was concentrated under reduced pressure, and the residue was purified by flash column chromatography (silica gel, 0-10% dichloromethane/methanol) to obtain a yellow solid compound (1R,5S)-tert-butyl 3-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolazin-7a-yl)methoxy)pyrido[4,3-d]pyrimidine -4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (purity 60%, 620 mg, 0.68 mmol, yield 19%). LCMS(ESI):[M+H] + ＝551.2. 1 H NMR(400MHz,CDCl 3 -d4)δ＝8.65(s,1H),4.25-4.20(m,1H),3.96(d,J＝13.0Hz,1H),3.69-3.65(m,1H),3.55-3.48(m,2H),3.45-3.35(m,1H),3.19-3.09(m,2H),2.99-2.91(m,1H),2.66-2.49(m,1H),2.31-2.19(m,3H),1.93-1.84(m,4H),1.78(td,J＝3.2,6.7Hz,2H),1.62(br d,J＝7.8Hz,3H),1.49-1.47(m,1H),1.45(s,9H)
中间体A5：叔丁基(1R,5S)-3-(8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三异丙基甲硅烷基)乙炔基)萘-1-基)-2-(2,2,2-三氟乙氧基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯
Intermediate A5: tert-butyl(1R,5S)-3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalene-1-yl)-2-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate
第一步：在-40℃下，向化合物2,4,7-三氯-8-氟吡啶并[4,3-d]嘧啶(5.00g，19.8mmol)和二异丙基乙胺(4.2mL，23.7mmol)的二氯甲烷溶液(140mL)中加入化合物(1R,5S)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸叔丁酯(4.20g，19.8mmol)溶液在-40℃搅拌1小时。将混合物用水(20mL)稀释并 用乙酸乙酯(20mL*3)萃取，有机相减压浓缩得到粗品化合物(1R,5S)-3-(2,7-二氯-8-氟吡啶并[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(4.50g)，为黄色固体。LCMS(ESI):[M+H]+＝428.1.1H NMR(400MHz,CDCl3)δppm 8.87(s,1H),4.67-4.30(m,4H),3.93-3.59(m,2H),2.08-1.94(m,2H),1.69(m,2H),1.54(s,9H).The first step: at -40°C, compound (1R,5S)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (4. 20 g, 19.8 mmol) solution was stirred at -40°C for 1 hour. The mixture was diluted with water (20 mL) and Extraction with ethyl acetate (20 mL*3), and concentration of the organic phase under reduced pressure gave the crude compound (1R,5S)-3-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (4.50 g) as a yellow solid. LCMS (ESI): [M+H] + = 428.1. 1 H NMR (400MHz, CDCl 3 ) δppm 8.87(s, 1H), 4.67-4.30(m, 4H), 3.93-3.59(m, 2H), 2.08-1.94(m, 2H), 1.69(m, 2H), 1.54(s, 9H ).
第二步：向化合物(1R,5S)-3-(2,7-二氯-8-氟吡啶并[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(8.00g，18.6mmol)和2,2,2-三氟乙醇(18.6g，186.7mmol)的混合物中加入二异丙基乙胺(5mL，28.0mmol)。溶液在80℃搅拌16小时。反应液用水(5mL)稀释并用乙酸乙酯(5mL*3)萃取，有机相减压浓缩，残余物通过快速柱色谱纯化(硅胶，0-10％甲醇/二氯甲烷)得到黄色固体化合物叔丁基(1R,5S)-3-(7-氯-8-氟-2-(2,2,2-三氟乙氧基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(9.00g，18.3mmol，收率98％)。LCMS(ESI):[M+H]+＝492.0.Second step: To a mixture of compound (1R,5S)-3-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (8.00 g, 18.6 mmol) and 2,2,2-trifluoroethanol (18.6 g, 186.7 mmol) was added diisopropylethylamine (5 mL , 28.0 mmol). The solution was stirred at 80°C for 16 hours. The reaction solution was diluted with water (5 mL) and extracted with ethyl acetate (5 mL*3), the organic phase was concentrated under reduced pressure, and the residue was purified by flash column chromatography (silica gel, 0-10% methanol/dichloromethane) to obtain a yellow solid compound tert-butyl(1R,5S)-3-(7-chloro-8-fluoro-2-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2. 1] Octane-8-carboxylate (9.00 g, 18.3 mmol, yield 98%). LCMS (ESI): [M+H] + = 492.0.
第三步：在氮气保护下，向化合物叔丁基(1R,5S)-3-(7-氯-8-氟-2-(2,2,2-三氟乙氧基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(9.00g，18.3mmol)和((2-氟-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)三异丙基硅烷(10.7g，20.9mmol)的二氧六环(200mL)溶液中加入碳酸铯溶液(1.5M的水溶液，43mL)和氯[(正丁基二(1-金刚烷基)膦)-2-(2-氨基联苯)]钯(II)(1.40g，2.09mmol)。将混合物在80℃下搅拌3小时。反应液用水(200mL)稀释并用乙酸乙酯(200mL*3)萃取，有机相用无水硫酸镁干燥，过滤，滤液减压浓缩得到粗品化合物叔丁基(1R,5S)-3-(8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三异丙基甲硅烷基)乙炔基)萘-1-基)-2-(2,2,2-三氟乙氧基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(19.2g)，为棕色固体。LCMS(ESI):[M+H]+＝842.5.The third step: under the protection of nitrogen, the compound tert-butyl (1R, 5S)-3-(7-chloro-8-fluoro-2-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (9.00g, 18.3mmol) and ((2-fluoro-6-(methoxymethoxy)-8-(4 , 4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (10.7 g, 20.9 mmol) in dioxane (200 mL) was added cesium carbonate solution (1.5 M in water, 43 mL) and chloro[(n-butylbis(1-adamantyl)phosphine)-2-(2-aminobiphenyl)]palladium(II) (1.40 g, 2 .09 mmol). The mixture was stirred at 80°C for 3 hours. The reaction solution was diluted with water (200 mL) and extracted with ethyl acetate (200 mL*3). The organic phase was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude compound tert-butyl(1R,5S)-3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(2,2,2-trifluoroethoxy)pyrido[4 ,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (19.2 g) as a brown solid. LCMS (ESI): [M+H] + = 842.5.
中间体A6：叔丁基(1R,5S)-3-(7-(8-乙基-7-氟-3-(甲氧基甲氧基)萘-1-基)-8-氟-2-(2,2,2-三氟乙氧基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯
Intermediate A6: tert-butyl(1R,5S)-3-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yl)-8-fluoro-2-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate
第一步：化合物叔丁基(1R,5S)-3-(8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三异丙基甲硅烷基)乙炔基)萘-1-基)-2-(2,2,2-三氟乙氧基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(19.2g，22.9mmol)的二甲基甲酰胺(250mL)溶液中加入氟化铯(21.6g，142.5mmol)。混合物在25℃下搅拌2小时。过滤反应液，收集滤液，用二甲基甲酰胺(3mL*50)洗涤滤饼，滤液真空浓缩。残余物通过快速柱色谱纯化(硅胶，0-10％乙酸乙酯/石油醚)得到棕色油状化合物叔丁基(1R,5S)-3-(7-(8-乙炔基-7-氟-3-(甲氧基甲氧基)萘-1-基)-8-氟-2-(2,2,2-三氟乙氧基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(纯度95％，8.50g，11.7mmol，收率51％)。LCMS(ESI):[M+H]+＝686.3.The first step: compound tert-butyl(1R,5S)-3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalene-1-yl)-2-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (19.2g , 22.9 mmol) in dimethylformamide (250 mL) was added cesium fluoride (21.6 g, 142.5 mmol). The mixture was stirred at 25°C for 2 hours. The reaction solution was filtered, the filtrate was collected, the filter cake was washed with dimethylformamide (3 mL*50), and the filtrate was concentrated in vacuo. The residue was purified by flash column chromatography (silica gel, 0-10% ethyl acetate/petroleum ether) to give brown oily compound tert-butyl(1R,5S)-3-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yl)-8-fluoro-2-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1 ] Octane-8-carboxylate (purity 95%, 8.50 g, 11.7 mmol, yield 51%). LCMS (ESI): [M+H] + = 686.3.
第二步：氮气保护下，向叔丁基(1R,5S)-3-(7-(8-乙炔基-7-氟-3-(甲氧基甲氧基)萘-1-基)-8-氟-2-(2,2,2-三氟乙氧基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(8.00g,11.6mmol)的乙酸乙酯(200mL)溶液中加入钯碳(5％，4.00g)，反应体系用氢气置换。将混合物在25℃下搅 拌16小时。过滤反应液并浓缩滤液，得到黄色油状粗品。粗品通过快速柱色谱纯化(硅胶，0-10％的甲醇/二氯甲烷)得到棕色固体化合物叔丁基(1R,5S)-3-(7-(8-乙基-7-氟-3-(甲氧基甲氧基)萘-1-基)-8-氟-2-(2,2,2-三氟乙氧基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(纯度95％，4.20g，5.79mmol，收率50％)。LCMS(ESI):[M+H]+＝689.9.The second step: under the protection of nitrogen, tert-butyl (1R,5S)-3-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yl)-8-fluoro-2-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (8.00g, 11.6mm ol) in ethyl acetate (200 mL) was added palladium carbon (5%, 4.00 g), and the reaction system was replaced with hydrogen. Stir the mixture at 25°C Stir for 16 hours. The reaction solution was filtered and the filtrate was concentrated to obtain a crude product as a yellow oil. The crude product was purified by flash column chromatography (silica gel, 0-10% methanol/dichloromethane) to give brown solid compound tert-butyl(1R,5S)-3-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octano Alkane-8-carboxylate (purity 95%, 4.20 g, 5.79 mmol, yield 50%). LCMS (ESI): [M+H] + = 689.9.
中间体A7：叔丁基(1R,5S)-3-(7-溴-6-碘-8-氟-2-(2,2,2-三氟乙氧基)喹唑啉-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯
Intermediate A7: tert-butyl(1R,5S)-3-(7-bromo-6-iodo-8-fluoro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate
第一步：化合物2-氨基-4-溴-3-氟苯甲酸(25.0g，107mmol)溶于N,N-二甲基甲酰胺(100mL)，加入N-碘代丁二酰亚胺(36.0g，160mmol)，混合物80℃搅拌2小时。反应液冷却至室温后加入到水(3L)中，室温打浆1小时，过滤并用水(300mL*3)洗涤滤饼，滤饼真空干燥得化合物2-氨基-4-溴-3-氟-5-碘苯甲酸(34.0g，94mmol，收率88％)。LCMS(ESI):[M+H]+＝361.9.Step 1: Compound 2-amino-4-bromo-3-fluorobenzoic acid (25.0g, 107mmol) was dissolved in N,N-dimethylformamide (100mL), N-iodosuccinimide (36.0g, 160mmol) was added, and the mixture was stirred at 80°C for 2 hours. After the reaction solution was cooled to room temperature, it was added to water (3 L), beaten at room temperature for 1 hour, filtered and washed with water (300 mL*3), and the filter cake was vacuum-dried to obtain compound 2-amino-4-bromo-3-fluoro-5-iodobenzoic acid (34.0 g, 94 mmol, yield 88%). LCMS (ESI): [M+H] + = 361.9.
第二步：化合物2-氨基-4-溴-3-氟-5-碘苯甲酸(30.0g，83.3mmol)和尿素(50.0g，833mmol)加入到反应瓶。反应体系升温到200℃反应4小时。冷却到室温，加入水(300mL)升温至80℃打浆搅拌半小时，趁热过滤，滤饼重复打浆过滤操作两次，真空干燥滤饼得7-溴-8-氟-6-碘喹唑啉-2,4-二羟基(26.7g，69.3mmol，收率83％)。LCMS(ESI):[M+H]+＝387.0.The second step: the compound 2-amino-4-bromo-3-fluoro-5-iodobenzoic acid (30.0 g, 83.3 mmol) and urea (50.0 g, 833 mmol) were added to the reaction flask. The temperature of the reaction system was raised to 200° C. for 4 hours. Cool to room temperature, add water (300mL) and raise the temperature to 80°C for beating and stirring for half an hour, filter while hot, repeat the beating and filtering operation of the filter cake twice, and vacuum dry the filter cake to obtain 7-bromo-8-fluoro-6-iodoquinazoline-2,4-dihydroxyl (26.7g, 69.3mmol, yield 83%). LCMS (ESI): [M+H] + = 387.0.
第三步：将化合物7-溴-8-氟-6-碘喹唑啉-2,4-二醇(24.7g，64.1mmol)加入到氧氯化磷(300mL)中，0℃下加入二异丙基乙胺(40mL，224mmol)，130℃搅拌4小时。反应液减压浓缩，残留物加入到冰水(500mL)中，二氯甲烷(500mL*3)萃取，有机相用无水硫酸镁干燥，过滤，滤液减压浓缩，残余物用快速柱色谱纯化(硅胶，0-4％梯度的甲醇/二氯甲烷)得化合物7-溴-2,4-二氯-8-氟-6-碘喹唑啉(26.7g，62mmol，收率98％)。LCMS(ESI):[M+H]+＝420.8.The third step: the compound 7-bromo-8-fluoro-6-iodoquinazoline-2,4-diol (24.7g, 64.1mmol) was added to phosphorus oxychloride (300mL), diisopropylethylamine (40mL, 224mmol) was added at 0°C, and stirred at 130°C for 4 hours. The reaction solution was concentrated under reduced pressure, the residue was added to ice water (500 mL), extracted with dichloromethane (500 mL*3), the organic phase was dried over anhydrous magnesium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by flash column chromatography (silica gel, 0-4% gradient of methanol/dichloromethane) to obtain compound 7-bromo-2,4-dichloro-8-fluoro-6-iodoquinazoline (26.7 g, 62 mmol, yield 98%). LCMS (ESI): [M+H] + = 420.8.
第四步：向化合物7-溴-2,4-二氯-8-氟-6-碘喹唑啉(10.0g，23.7mmol)的二氯甲烷(100mL)溶液中，加入(1R,5S)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸叔丁酯(5.54g，26.1mmol)和三乙胺(10mL，71mmol)，反应液在20℃搅拌2小时。反应液减压浓缩，残余用快速柱色谱纯化(硅胶，0-36％梯度的乙酸乙酯/石油醚)得化合物叔丁基(1R,5S)-3-(7-溴-2-氯-8-氟-6-碘喹唑啉-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(3.60g，5.93mmol，收率25％)。LCMS(ESI):[M+H]+＝599.0.The fourth step: To compound 7-bromo-2,4-dichloro-8-fluoro-6-iodoquinazoline (10.0g, 23.7mmol) in dichloromethane (100mL) solution, add (1R,5S)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate tert-butyl ester (5.54g, 26.1mmol) and triethylamine (10mL, 71mmol), the reaction solution in Stir at 20°C for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by flash column chromatography (silica gel, 0-36% gradient ethyl acetate/petroleum ether) to obtain the compound tert-butyl(1R,5S)-3-(7-bromo-2-chloro-8-fluoro-6-iodoquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (3.60g, 5.93mmol, yield 25%). LCMS (ESI): [M+H] + = 599.0.
第五步：将化合物叔丁基(1R,5S)-3-(7-溴-2-氯-8-氟-6-碘喹唑啉-4-基)-3,8-二氮杂双环[3.2.1]辛烷- 8-羧酸酯(3.00g，5.00mmol)加入到三氟乙醇(15mL)，加入二异丙基乙胺(1560uL，8.94mmol)，反应液在50℃搅拌3小时。反应液减压浓缩，残余物用快速柱色谱纯化(硅胶，0-2％梯度的甲醇/二氯甲烷)得化合物叔丁基(1R,5S)-3-(7-溴-6-氰基-8-氟-2-(2,2,2-三氟乙氧基)喹唑啉-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(1.69g，2.55mmol，收率51％)。LCMS(ESI):[M+H]+＝662.2.The fifth step: the compound tert-butyl (1R,5S)-3-(7-bromo-2-chloro-8-fluoro-6-iodoquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane- 8-Carboxylate (3.00 g, 5.00 mmol) was added to trifluoroethanol (15 mL), diisopropylethylamine (1560 uL, 8.94 mmol) was added, and the reaction solution was stirred at 50° C. for 3 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by flash column chromatography (silica gel, 0-2% gradient methanol/dichloromethane) to obtain the compound tert-butyl(1R,5S)-3-(7-bromo-6-cyano-8-fluoro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.69g, 2.55mmol, yield 51 %). LCMS (ESI): [M+H] + = 662.2.
中间体A8：叔丁基(1R,5S)-3-(7-溴-6-氰基-8-氟-2-(2,2,2-三氟乙氧基)喹唑啉-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯
Intermediate A8: tert-butyl(1R,5S)-3-(7-bromo-6-cyano-8-fluoro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate
第一步：向化合物叔丁基(1R,5S)-3-(7-溴-2-氯-8-氟-6-碘喹唑啉-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(3.00g，5.02mmol)的N,N-二甲基乙酰胺(30mL)溶液中，氮气氛围下加入氰化亚铜(4.50g，50.2mmol)和锌粉(0.72g，11.0mmol)，反应液在100℃搅拌16小时。反应液减压浓缩，残余用快速柱色谱纯化(硅胶，0-15％梯度的乙酸乙酯/石油醚)得化合物(1R,5S)-3-(7-溴-2-氯-6-氰基-8-氟喹唑啉-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸叔丁酯(1.70g，3.41mmol，收率68％)。LCMS(ESI):[M+H]+＝498.2.The first step: To the compound tert-butyl (1R,5S)-3-(7-bromo-2-chloro-8-fluoro-6-iodoquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (3.00g, 5.02mmol) in N,N-dimethylacetamide (30mL) solution, add cuprous cyanide (4.50g, 50.2mmol) and zinc under nitrogen atmosphere powder (0.72g, 11.0mmol), and the reaction solution was stirred at 100°C for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by flash column chromatography (silica gel, 0-15% gradient ethyl acetate/petroleum ether) to obtain compound (1R,5S)-3-(7-bromo-2-chloro-6-cyano-8-fluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (1.70 g, 3.41 mmol, yield 68%). LCMS (ESI): [M+H] + = 498.2.
第二步：将化合物(1R,5S)-3-(7-溴-2-氯-6-氰基-8-氟喹唑啉-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸叔丁酯(1.48g，2.98mmol)加入到三氟乙醇(15mL)，加入二异丙基乙胺(1560uL，8.94mmol)，反应液在50℃搅拌3小时。反应液减压浓缩，残余物用快速柱色谱纯化(硅胶，0-2％梯度的甲醇/二氯甲烷)得化合物叔丁基(1R,5S)-3-(7-溴-6-氰基-8-氟-2-(2,2,2-三氟乙氧基)喹唑啉-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(80％纯度，0.90g，1.28mmol，收率43％)。LCMS(ESI):[M+H]+＝562.0.The second step: the compound (1R,5S)-3-(7-bromo-2-chloro-6-cyano-8-fluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (1.48g, 2.98mmol) was added to trifluoroethanol (15mL), diisopropylethylamine (1560uL, 8.94mmol) was added, and the reaction solution was stirred at 50°C 3 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by flash column chromatography (silica gel, 0-2% gradient methanol/dichloromethane) to obtain the compound tert-butyl (1R,5S)-3-(7-bromo-6-cyano-8-fluoro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (80% purity, 0.90g, 1.28mm ol, yield 43%). LCMS (ESI): [M+H] + = 562.0.
中间体A9：叔丁基(1R,5S)-3-(7-溴-6-氯-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)喹唑啉-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯
Intermediate A9: tert-butyl(1R,5S)-3-(7-bromo-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate
第一步：化合物7-溴-2,4,6-三氯-8-氟喹唑啉(0.50g，1.51mmol)溶于二氯甲烷(10mL)，加入(1R,5S)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸叔丁酯(0.32g，1.51mmol)和三乙胺(630uL，4.54mmol)，20℃搅拌16小时。反应液加入到饱和食盐水(10mL)中，用二氯甲烷(10mL)萃取，有机相减压浓缩得化合物(1R,5S)-3-(7-溴-2,6-二氯-8-氟喹唑啉-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸叔丁酯(90％纯度，0.83g，1.48mmol，收率98％)。LCMS(ESI):[M+H]+＝507.2. The first step: Compound 7-bromo-2,4,6-trichloro-8-fluoroquinazoline (0.50g, 1.51mmol) was dissolved in dichloromethane (10mL), added (1R,5S)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate tert-butyl ester (0.32g, 1.51mmol) and triethylamine (630uL, 4.54mmol), stirred at 20°C for 1 6 hours. The reaction solution was added to saturated brine (10 mL), extracted with dichloromethane (10 mL), and the organic phase was concentrated under reduced pressure to obtain compound (1R,5S)-3-(7-bromo-2,6-dichloro-8-fluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (90% purity, 0.83 g, 1.48 mmol, yield 98%). LCMS (ESI): [M+H] + = 507.2.
第二步：化合物(1R,5S)-3-(7-溴-2,6-二氯-8-氟喹唑啉-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸叔丁酯(90％纯度，550mg，0.98mmol)和((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲醇(173mg，1.09mmol)加入到N,N-二甲基甲酰胺(5mL)和四氢呋喃(5mL)中，加入碳酸铯(1.06g，3.26mmol)和三乙烯二胺(24mg，0.22mmol)。反应体系在20℃搅拌16小时。加入水(5mL)，用乙酸乙酯(5mL*3)萃取，有机相减压浓缩得化合物叔丁基(1R,5S)-3-(7-溴-6-氯-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)喹唑啉-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(80％纯度，490mg，0.62mmol，收率63％)。LCMS(ESI):[M+H]+＝629.9.Second step: compound (1R,5S)-3-(7-bromo-2,6-dichloro-8-fluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (90% purity, 550mg, 0.98mmol) and ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol (173mg , 1.09mmol) was added to N,N-dimethylformamide (5mL) and tetrahydrofuran (5mL), cesium carbonate (1.06g, 3.26mmol) and triethylenediamine (24mg, 0.22mmol) were added. The reaction system was stirred at 20°C for 16 hours. Add water (5mL), extract with ethyl acetate (5mL*3), and concentrate the organic phase under reduced pressure to obtain the compound tert-butyl(1R,5S)-3-(7-bromo-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxy Ester (80% purity, 490 mg, 0.62 mmol, yield 63%). LCMS (ESI): [M+H] + = 629.9.
中间体A10：8-氟-7-(7-氟-3-(甲氧基甲氧基)-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)-4-(2,2,2-三氟乙氧基)吡啶并[4,3-d]嘧啶
Intermediate A10: 8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine
第一步：将化合物2,4,7-三氯-8-氟吡啶并[4,3-d]嘧啶(3.00g，11.88mmol)和三氟乙醇(1.43g，14.2mmol)溶于甲苯(60mL)，0℃下加入叔丁醇钠(1.14g，11.8mmol)，混合物在0℃搅拌2小时。反应液通过硅藻土过滤，滤饼用乙酸乙酯洗涤(30mL*3)，滤液用饱和食盐水洗涤(50mL*2)，硫酸钠干燥，过滤，减压浓缩得到粗品化合物2,7-二氯-8-氟-4-(2,2,2-三氟乙氧基)吡啶并[4,3-d]嘧啶(3.76g)。LCMS(ESI):[M+H]+＝315.8.The first step: the compound 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (3.00g, 11.88mmol) and trifluoroethanol (1.43g, 14.2mmol) were dissolved in toluene (60mL), and sodium tert-butoxide (1.14g, 11.8mmol) was added at 0°C, and the mixture was stirred at 0°C for 2 hours. The reaction solution was filtered through diatomaceous earth, the filter cake was washed with ethyl acetate (30mL*3), the filtrate was washed with saturated brine (50mL*2), dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude compound 2,7-dichloro-8-fluoro-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (3.76g). LCMS (ESI): [M+H] + = 315.8.
第二步：向化合物((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲醇(0.71g，4.43mmol)，二异丙基乙胺(0.79mL，4.43mmol)和4A分子筛(1g)的2-甲基四氢呋喃(10mL)悬浊液中，0℃下加入2,7-二氯-8-氟-4-(2,2,2-三氟乙氧基)吡啶并[4,3-d]嘧啶(70％纯度，1.00g，2.21mmol)。反应体系升温到25℃反应1小时。将3个相同量的批次合并，反应液过滤，滤液减压浓缩，残余物用快速柱色谱纯化(硅胶，0-10％梯度的甲醇/二氯甲烷)得黄色油状7-氯-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-4-(2,2,2-三氟乙氧基)吡啶并[4,3-d]嘧啶(纯度75％，3.00g，5.10mmol，收率77％)。LCMS(ESI):[M+H]+＝439.0.The second step: to compound ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol (0.71g, 4.43mmol), diisopropylethylamine (0.79mL, 4.43mmol) and 4A molecular sieves (1g) in 2-methyltetrahydrofuran (10mL) suspension, 0 ℃ added 2,7-dichloro-8-fluoro-4-(2,2, 2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (70% purity, 1.00 g, 2.21 mmol). The temperature of the reaction system was raised to 25° C. for 1 hour. Three batches of the same amount were combined, the reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by flash column chromatography (silica gel, 0-10% gradient of methanol/dichloromethane) to obtain 7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine ( Purity 75%, 3.00 g, 5.10 mmol, yield 77%). LCMS (ESI): [M+H] + = 439.0.
第三步：化合物7-氯-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-4-(2,2,2-三氟乙氧基)吡啶并[4,3-d]嘧啶(纯度75％，2.75g，4.69mmol)加入到二氧六环(60mL)中，加入((2-氟-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)三异丙基硅烷(3.21g，6.27mmol)和碳酸铯(1.5M的水溶液，12.5mL，18.80mmol)，氮气氛围下加入氯[(正丁基二(1-金刚烷基)膦)-2-(2-氨基联苯)]钯(II)(419mg，0.63mmol)，反应液在80℃搅拌3小时。反应液减压浓缩，残余物用快速柱色谱纯化(硅胶，0-10％梯度的甲醇/二氯甲烷)，得到的粗品再用制备型HPLC纯化得到黄色固体化合物8-氟-7-(7-氟-3-(甲氧基甲氧基)-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)-4-(2,2,2-三氟乙氧基)吡啶并[4,3-d]嘧啶(1.50g，1.90mmol，收率40％)。LCMS(ESI):[M+H]+＝789.3.1H NMR(400MHz,CDCl3)δppm 9.27(d,J＝2.3Hz,1H),7.82(dd,J＝5.6,8.9Hz,1H),7.55(d,J＝2.5Hz,1H),7.38-7.29(m,2H),5.57-5.38(m,1H),5.36-5.29(m,2H),5.27-5.17(m,1H),5.11-4.92(m,1H),4.87-4.51(m,2H),3.85(br s,2H),3.54(s,3H),3.49-3.33(m, 1H),3.18(br s,1H),2.66-2.10(m,6H),0.91-0.82(m,18H),0.54(dtd,J＝3.8,7.4,14.8Hz,3H).The third step: the compound 7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (purity 75%, 2.75g, 4.69mmol) was added to dioxane (60mL), and ((2-fluoro-6-(methoxy Methoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (3.21g, 6.27mmol) and cesium carbonate (1.5M in water, 12.5mL, 18.80mmol), added chloro[(n-butylbis(1-adamantyl)phosphine)-2-(2-aminobiphenyl)]palladium(II ) (419mg, 0.63mmol), the reaction solution was stirred at 80°C for 3 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by flash column chromatography (silica gel, 0-10% gradient methanol/dichloromethane), and the obtained crude product was purified by preparative HPLC to obtain the yellow solid compound 8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalene-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazine-7a(5H)- yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (1.50 g, 1.90 mmol, 40% yield). LCMS(ESI):[M+H] + ＝789.3.1H NMR(400MHz,CDCl 3 )δppm 9.27(d,J＝2.3Hz,1H),7.82(dd,J＝5.6,8.9Hz,1H),7.55(d,J＝2.5Hz,1H),7.38-7.29(m,2H),5.57-5.38(m,1H),5.36-5.29(m,2H),5.27-5.17(m,1H),5.11-4.92(m,1H),4.87-4.51(m,2H),3.85(br s,2H),3.54(s,3H),3.49-3.33(m, 1H), 3.18(br s, 1H), 2.66-2.10(m, 6H), 0.91-0.82(m, 18H), 0.54(dtd, J=3.8, 7.4, 14.8Hz, 3H).
中间体A11：(二氢-1'H,3'H-螺[氧杂环丁烷-3,2'-吡咯嗪]-7a'(5'H)-基)-甲醇
Intermediate A11: (dihydro-1'H,3'H-spiro[oxetane-3,2'-pyrrolazin]-7a'(5'H)-yl)-methanol
第一步：向L-脯氨酸甲酯盐酸盐(7.00g，42.2mmol)和(3-(溴甲基)氧杂环丁烷-3-基)甲醇(10g，55.2mmol)的N,N-二甲基乙酰胺(80mL)溶液中加入二异丙基乙基胺(21mL，126mmol)，在氮气保护下，将混合物加热至50℃搅拌12小时。反应混合物旋干。残留物用快速柱色谱纯化(硅胶，0-70％梯度的四氢呋喃/石油醚)得到粗品化合物((3-(羟甲基)氧杂环丁烷-3-基)甲基)-L-脯氨酸甲酯(3g)，为棕色油状液体。LCMS(ESI):[M+H]+＝230.2；Step 1: Diisopropylethylamine (21 mL, 126 mmol) was added to a solution of L-proline methyl ester hydrochloride (7.00 g, 42.2 mmol) and (3-(bromomethyl)oxetan-3-yl)methanol (10 g, 55.2 mmol) in N,N-dimethylacetamide (80 mL), and the mixture was heated to 50° C. and stirred for 12 hours under nitrogen protection. The reaction mixture was spin-dried. The residue was purified by flash column chromatography (silica gel, 0-70% gradient THF/petroleum ether) to give the crude compound ((3-(hydroxymethyl)oxetan-3-yl)methyl)-L-proline methyl ester (3 g) as a brown oily liquid. LCMS (ESI): [M+H] + =230.2;
第二步：在0℃下向((3-(羟甲基)氧杂环丁烷-3-基)甲基)-L-脯氨酸甲酯(1.00g，4.36mmol)和四溴化碳(1.88g，5.67mmol)的二氯甲烷(25mL)溶液中，分3批加入三苯基膦(1831mg，6.98mmol)，然后将混合物氮气保护下在25℃下搅拌3小时。反应混合物旋干。残留物用快速柱色谱纯化(硅胶，0-20％梯度的四氢呋喃/石油醚)得到无色液体化合物((3-(溴甲基)氧杂环丁烷-3-基)甲基)-L-脯氨酸甲酯(400mg，1.37mmol，收率31％)。LCMS(ESI):[M+H]+＝294.0.Second step: To ((3-(hydroxymethyl)oxetan-3-yl)methyl)-L-proline methyl ester (1.00g, 4.36mmol) and carbon tetrabromide (1.88g, 5.67mmol) in dichloromethane (25mL) solution at 0°C, triphenylphosphine (1831mg, 6.98mmol) was added in 3 batches, and then the mixture was stirred at 25°C for 3 hours under nitrogen protection. The reaction mixture was spin-dried. The residue was purified by flash column chromatography (silica gel, 0-20% gradient THF/petroleum ether) to give (3-(bromomethyl)oxetan-3-yl)methyl)-L-proline methyl ester (400 mg, 1.37 mmol, yield 31%) as a colorless liquid. LCMS (ESI): [M+H] + = 294.0.
第三步：氮气保护下，将((3-(溴甲基)氧杂环丁烷-3-基)甲基)-L-脯氨酸甲酯(200mg,0.68mmol)的N,N-二甲基甲酰胺(5mL)和四氢呋喃(1mL)溶液冷却至-70℃，在-60℃至-70℃下加入六甲基二硅基氨基钾(1M的四氢呋喃溶液，958uL，0.96mmol)，然后将混合物在-60℃至-70℃下搅拌30分钟。反应混合物加入水(10mL)，使用乙酸乙酯(10mL*3)萃取，合并有机相，用无水硫酸钠干燥，过滤，滤液旋干。残留物用快速柱色谱纯化(硅胶，0-60％梯度的四氢呋喃/石油醚)得到无色液体化合物二氢-1'H,3'H-螺[氧杂环丁烷-3,2'-吡咯嗪]-7a'(5'H)-羧酸甲酯(20mg，0.09mmol，收率14％)。LCMS(ESI):[M+H]+＝212.1.1H NMR(400MHz,CDCl3)δppm 4.69-4.52(m,4H),3.69(s,3H),3.60(d,J＝9.9Hz,1H),3.10(td,J＝6.5,10.8Hz,1H),2.86-2.75(m,2H),2.73-2.63(m,1H),2.22(td,J＝7.2,12.7Hz,1H),1.88-1.78(m,3H),1.77-1.67(m,1H).The third step: under nitrogen protection, ((3-(bromomethyl)oxetan-3-yl)methyl)-L-proline methyl ester (200mg, 0.68mmol) in N,N-dimethylformamide (5mL) and tetrahydrofuran (1mL) solution was cooled to -70°C, and hexamethyldisilazide potassium (1M solution in tetrahydrofuran, 958uL, 0.96mmol) was added at -60°C to -70°C, The mixture was then stirred at -60°C to -70°C for 30 minutes. Add water (10 mL) to the reaction mixture, extract with ethyl acetate (10 mL*3), combine the organic phases, dry over anhydrous sodium sulfate, filter, and spin the filtrate to dryness. The residue was purified by flash column chromatography (silica gel, 0-60% gradient THF/petroleum ether) to obtain a colorless liquid compound, methyl dihydro-1'H,3'H-spiro[oxetane-3,2'-pyrrolazine]-7a'(5'H)-carboxylate (20mg, 0.09mmol, yield 14%). LCMS (ESI): [M+H] + ＝212.1.1H NMR (400MHz, CDCl 3 ) δppm 4.69-4.52(m, 4H), 3.69(s, 3H), 3.60(d, J＝9.9Hz, 1H), 3.10(td, J＝6.5, 10.8Hz, 1H), 2.86-2.75(m ,2H),2.73-2.63(m,1H),2.22(td,J=7.2,12.7Hz,1H),1.88-1.78(m,3H),1.77-1.67(m,1H).
第四步：在氮气保护，-10℃下，向二氢-1'H,3'H-螺[氧杂环丁烷-3,2'-吡咯嗪]-7a'(5'H)-羧酸甲酯(150mg,0.71mmol)的四氢呋喃(3mL)溶液中加入四氢铝锂(81mg，2.13mmol)，然后将混合物在-10℃下搅拌30分钟。向反应混合物中加入水(81uL)，氢氧化钠(15％的水溶液，81uL)，然后加入水(243uL)，混合物过滤，固体用四氢呋喃洗涤，滤液旋干，得到无色液体化合物(二氢-1'H,3'H-螺[氧杂环丁烷-3,2'-吡咯嗪]-7a'(5'H)-基)-甲醇(120mg，0.66mmol，收率92％)。LCMS(ESI):[M+H]+＝184.1.Step 4: To a solution of methyl dihydro-1'H,3'H-spiro[oxetane-3,2'-pyrrolazine]-7a'(5'H)-carboxylate (150 mg, 0.71 mmol) in tetrahydrofuran (3 mL) under nitrogen protection at -10°C was added lithium aluminum tetrahydride (81 mg, 2.13 mmol), and then the mixture was stirred at -10°C for 30 minutes. Water (81uL), sodium hydroxide (15% aqueous solution, 81uL), and then water (243uL) were added to the reaction mixture, the mixture was filtered, the solid was washed with tetrahydrofuran, and the filtrate was spin-dried to obtain a colorless liquid compound (dihydro-1'H,3'H-spiro[oxetane-3,2'-pyrrolazin]-7a'(5'H)-yl)-methanol (120mg, 0.66mmol, yield 92 %). LCMS (ESI): [M+H] + = 184.1.
中间体A12：(二氢-1'H,3'H-螺[环丙烷-1,2'-吡咯嗪]-7a'(5'H)-基)甲醇
Intermediate A12: (dihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolazin]-7a'(5'H)-yl)methanol
第一步：在0℃下向(S)-5-(叔丁氧基羰基)-5-氮杂螺[2.4]庚烷-6-羧酸(8.00g，33.16mmol)和碳酸钾(9.16g，66.3mmol)的二甲基甲酰胺(80mL)溶液中缓慢加入碘甲烷(11.7g，82.8mmol)。将溶液在0℃搅拌1小时，然后将溶液在25℃下搅拌12小时。反应用亚硫酸钠溶液淬灭后浓缩，粗品通过快速柱色谱(硅胶，0-25％梯度的四氢呋喃/石油醚)纯化，得到无色油状化合物5-(叔丁基)6-甲基(S)-5-氮杂螺[2.4]庚烷-5,6-二羧酸酯(8.10g，30.1mmol，收率91％)。LCMS(ESI):[M+Na]+＝278.1.Step 1: To a solution of (S)-5-(tert-butoxycarbonyl)-5-azaspiro[2.4]heptane-6-carboxylic acid (8.00 g, 33.16 mmol) and potassium carbonate (9.16 g, 66.3 mmol) in dimethylformamide (80 mL) was slowly added iodomethane (11.7 g, 82.8 mmol) at 0°C. The solution was stirred at 0°C for 1 hour, then the solution was stirred at 25°C for 12 hours. The reaction was quenched with sodium sulfite solution and then concentrated. The crude product was purified by flash column chromatography (silica gel, 0-25% gradient tetrahydrofuran/petroleum ether) to obtain 5-(tert-butyl) 6-methyl(S)-5-azaspiro[2.4]heptane-5,6-dicarboxylate (8.10 g, 30.1 mmol, yield 91%) as a colorless oil. LCMS (ESI): [M+Na] + = 278.1.
第二步：在-78℃和氮气保护下，向二异丙基胺基锂(2M的四氢呋喃正庚烷混合溶液，16mL，32mmol)的四氢呋喃(80mL)溶液中加入5-(叔丁基)6-甲基(S)-5-氮杂螺[2.4]庚烷-5,6-二羧酸酯(8.00g，29.8mmol)并搅拌1小时，然后在-78℃下加入1-溴-3-氯丙烷(3mL，31.3mmol)并搅拌2小时，然后在25℃下搅拌12小时。溶液用饱和氯化铵(20mL)淬灭并用乙酸乙酯(10mL*3)萃取。合并的有机层用无水硫酸钠干燥并浓缩，得到粗产物通过快速柱色谱(硅胶，0-20％梯度的四氢呋喃/石油醚)纯化，得到无色油状化合物5-(叔丁基)6-甲基6-(3-氯丙基)-5-氮杂螺[2.4]庚烷-5,6-二羧酸酯(5.80g，17.4mmol，收率58％)。LCMS(ESI):[M+Na]+＝354.0.Step 2: Add 5-(tert-butyl)6-methyl(S)-5-azaspiro[2.4]heptane-5,6-dicarboxylate (8.00g, 29.8mmol) to a solution of lithium diisopropylamide (2M mixed solution of tetrahydrofuran-n-heptane, 16mL, 32mmol) in tetrahydrofuran (80mL) at -78°C and stir for 1 hour, then add 1-bromo at -78°C -3-Chloropropane (3 mL, 31.3 mmol) and stirred for 2 hours, then at 25 °C for 12 hours. The solution was quenched with saturated ammonium chloride (20 mL) and extracted with ethyl acetate (10 mL*3). The combined organic layers were dried over anhydrous sodium sulfate and concentrated to obtain the crude product which was purified by flash column chromatography (silica gel, 0-20% gradient THF/petroleum ether) to obtain 5-(tert-butyl)6-methyl 6-(3-chloropropyl)-5-azaspiro[2.4]heptane-5,6-dicarboxylate (5.80 g, 17.4 mmol, yield 58%) as a colorless oil. LCMS (ESI): [M+Na] + = 354.0.
第三步：在25℃下，向5-(叔丁基)6-甲基(S)-6-(3-氯丙基)-5-氮杂螺[2.4]庚烷-5,6-二羧酸酯(5.80g，17.4mmol)的二氯甲烷溶液(12mL)中加入氯化氢(4M的二氧六环溶液，3mL，12mmol)。溶液在25℃搅拌16小时。将溶液减压浓缩，得到黄色油状化合物6-(3-氯丙基)-5-氮杂螺[2.4]庚烷-6-羧酸甲酯(纯度85％，4.67g，17.1mmol，收率98％)。LCMS(ESI):[M+H]+＝232.1.Third step: To a solution of 5-(tert-butyl)6-methyl(S)-6-(3-chloropropyl)-5-azaspiro[2.4]heptane-5,6-dicarboxylate (5.80 g, 17.4 mmol) in dichloromethane (12 mL) was added hydrogen chloride (4M in dioxane, 3 mL, 12 mmol) at 25°C. The solution was stirred at 25°C for 16 hours. The solution was concentrated under reduced pressure to obtain methyl 6-(3-chloropropyl)-5-azaspiro[2.4]heptane-6-carboxylate (purity 85%, 4.67 g, 17.1 mmol, yield 98%) as a yellow oil. LCMS (ESI): [M+H] + = 232.1.
第四步：在25℃下，向6-(3-氯丙基)-5-氮杂螺[2.4]庚烷-6-羧酸甲酯(纯度85％，4.67g，17.1mmol)的甲醇(100mL)溶液中加入碘化钾(340mg，2.06mmol)和碳酸钾(8.53g，61.7mmol)。溶液在25℃搅拌16小时。将溶液过滤并浓缩，得到棕色油状化合物二氢-1'H,3'H-螺[环丙烷-1,2'-吡咯嗪]-7a'(5'H)-羧酸甲酯(纯度85％，3.90g，17.0mmol，收率99％)。LCMS(ESI):[M+H]+＝196.1.Step 4: Add potassium iodide (340 mg, 2.06 mmol) and potassium carbonate (8.53 g, 61.7 mmol) to a solution of methyl 6-(3-chloropropyl)-5-azaspiro[2.4]heptane-6-carboxylate (85% purity, 4.67 g, 17.1 mmol) in methanol (100 mL) at 25° C. The solution was stirred at 25°C for 16 hours. The solution was filtered and concentrated to obtain methyl dihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolazine]-7a'(5'H)-carboxylate (purity 85%, 3.90 g, 17.0 mmol, yield 99%) as a brown oily compound. LCMS (ESI): [M+H] + = 196.1.
第五步：在0℃的氮气氛围下，向氢化铝锂(0.58g，15.3mmol)的四氢呋喃(10mL)溶液中加入二氢-1'H,3'H-螺[环丙烷-1,2'-吡咯嗪]-7a'(5'H)-羧酸甲酯(纯度85％，2.00g，8.72mmol)的四氢呋喃(0.50mL)溶液，将混合物在60℃搅拌4小时。冷至室温后，混合物依次用水(600uL)，15％氢氧化钠(600uL)和水(1800uL)淬灭。将悬浮液过滤并浓缩，得到棕色油状化合物(二氢-1'H,3'H-螺[环丙烷-1,2'-吡咯嗪]-7a'(5'H)-基)甲醇(1.20g，7.19mmol，收率82％)。LCMS(ESI):[M+H]+＝168.1.Step 5: Add dihydro-1'H, 3'H-spiro[cyclopropane-1,2'-pyrrolazine]-7a'(5'H)-methyl carboxylate (purity 85%, 2.00g, 8.72mmol) in tetrahydrofuran (0.50mL) to lithium aluminum hydride (0.58g, 15.3mmol) in tetrahydrofuran (10mL) under a nitrogen atmosphere at 0°C. Stir at 60°C for 4 hours. After cooling to room temperature, the mixture was sequentially quenched with water (600 uL), 15% sodium hydroxide (600 uL) and water (1800 uL). The suspension was filtered and concentrated to give brown oily compound (dihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolazin]-7a'(5'H)-yl)methanol (1.20 g, 7.19 mmol, yield 82%). LCMS (ESI): [M+H] + = 168.1.
中间体A13-1和A13-2：顺式-六氢环丙[a]吡咯嗪-6a(4H)-基)甲醇A13-1和反式-六氢环丙[a]吡 咯嗪-6a(4H)-基)甲醇A13-2
Intermediates A13-1 and A13-2: cis-hexahydrocyclopropane[a]pyrrolizin-6a(4H)-yl)methanol A13-1 and trans-hexahydrocyclopropane[a]pyrrolidin Alloxazin-6a(4H)-yl)methanol A13-2
第一步：向化合物3-氮杂双环[3.1.0]己烷盐酸盐(15g，125mmol)和三乙胺(35mL，250mmol)的二氯甲烷(150mL)溶液中，20℃下加入二碳酸二叔丁酯(31.7mL，137mmol)。反应在20℃下搅拌16小时。反应液加入饱和氯化铵溶液(200mL)，然后用二氯甲烷(300mL*2)萃取，有机层用无水硫酸镁干燥，过滤，滤液减压浓缩得到白色油状化合物3-氮杂双环[3.1.0]己烷-3-羧酸叔丁酯(20g，109mmol，收率78％)。LCMS(ESI):[M-56+H]+＝128.1.Step 1: To a solution of compound 3-azabicyclo[3.1.0]hexane hydrochloride (15g, 125mmol) and triethylamine (35mL, 250mmol) in dichloromethane (150mL), di-tert-butyl dicarbonate (31.7mL, 137mmol) was added at 20°C. The reaction was stirred at 20°C for 16 hours. The reaction solution was added with saturated ammonium chloride solution (200mL), then extracted with dichloromethane (300mL*2), the organic layer was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a white oily compound 3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (20g, 109mmol, yield 78%). LCMS (ESI): [M-56+H] + = 128.1.
第二步：将化合物3-氮杂双环[3.1.0]己烷-3-羧酸叔丁酯(20g，108mmol)和四甲基乙二胺(9150uL，61.3mmol)溶于四氢呋喃(150mL)，-65℃和氮气保护下加入仲丁基锂(1.3M的正己烷溶液，63mL，81.9mmol)。反应在-65℃下搅拌3小时。用二氧化碳置换氮气并将反应液在-65℃和二氧化碳气球下搅拌1小时。反应液中加入20％硫酸氢钾溶液(300mL)(pH＝7)和水(200mL)。将反应溶液升至室温，减压浓缩除去THF。残余物用乙酸乙酯(300mL*3)萃取，有机层用无水硫酸镁干燥，过滤，有机层减压浓缩得到棕色油状化合物3-(叔丁氧基羰基)-3-氮杂双环[3.1.0]己烷-2-羧酸(纯度80％，12g，42.2mmol，收率43％)。LCMS(ESI):[M-56+H]+＝172.1.The second step: the compound tert-butyl 3-azabicyclo[3.1.0]hexane-3-carboxylate (20g, 108mmol) and tetramethylethylenediamine (9150uL, 61.3mmol) were dissolved in tetrahydrofuran (150mL), and sec-butyl lithium (1.3M n-hexane solution, 63mL, 81.9mmol) was added at -65°C under nitrogen protection. The reaction was stirred at -65°C for 3 hours. The nitrogen was replaced with carbon dioxide and the reaction was stirred at -65°C under a carbon dioxide balloon for 1 hour. To the reaction solution were added 20% potassium hydrogensulfate solution (300 mL) (pH=7) and water (200 mL). The reaction solution was raised to room temperature, and concentrated under reduced pressure to remove THF. The residue was extracted with ethyl acetate (300 mL*3), the organic layer was dried over anhydrous magnesium sulfate, filtered, and the organic layer was concentrated under reduced pressure to obtain brown oily compound 3-(tert-butoxycarbonyl)-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (purity 80%, 12 g, 42.2 mmol, yield 43%). LCMS (ESI): [M-56+H] + = 172.1.
第三步：20℃下，向化合物3-(叔丁氧基羰基)-3-氮杂双环[3.1.0]己烷-2-羧酸(纯度80％，12g，42.2mmol)和碳酸钾(17.6g，126mmol)的丙酮(150mL)悬浊液中，加入碘甲烷(5.2mL，84.4mmol)。反应在20℃下搅拌16小时。反应液减压浓缩。残留物用快速柱色谱纯化(硅胶，0-10％梯度的乙酸乙酯/石油醚)得到黄色油状化合物3-(叔丁基)2-甲基3-氮杂双环[3.1.0]己烷-2,3-二羧酸酯(5g，20.7mmol，收率36％)。LCMS(ESI):[M+Na]+＝264.1.Step 3: Add iodomethane (5.2 mL, 84.4 mmol) to a suspension of compound 3-(tert-butoxycarbonyl)-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (80% purity, 12 g, 42.2 mmol) and potassium carbonate (17.6 g, 126 mmol) in acetone (150 mL) at 20° C. The reaction was stirred at 20°C for 16 hours. The reaction solution was concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 0-10% gradient ethyl acetate/petroleum ether) to give 3-(tert-butyl) 2-methyl 3-azabicyclo[3.1.0]hexane-2,3-dicarboxylate (5 g, 20.7 mmol, yield 36%) as a yellow oil. LCMS (ESI): [M+Na] + = 264.1.
第四步：将化合物3-(叔丁基)2-甲基3-氮杂双环[3.1.0]己烷-2,3-二羧酸酯(5g，20.7mmol)和1-溴-3-氯丙烷(1.2mL，12.4mmol)溶于四氢呋喃(100mL)，-65℃和氮气氛围下加入双(三甲基硅基)氨基锂(1.0M的四氢呋喃溶液，41.4mL，41.4mmol)。反应在-65℃下搅拌2小时然后升温至0℃，加入饱和氯化铵溶液(200mL)，然后用乙酸乙酯(100mL*2)萃取，有机层用无水硫酸镁干燥，过滤，有机层减压浓缩。残余物通过快速柱色谱(硅胶，0-10％梯度的乙酸乙酯/石油醚)得到黄色油状化合物3-(叔丁基)2-甲基2-(3-氯丙基)-3-氮杂双环[3.1.0]己烷-2,3-二羧酸酯(纯度80％，2.70g，6.81mmol，收率33％)。LCMS(ESI):[M+Na]+＝340.1.Step 4: Dissolve compound 3-(tert-butyl) 2-methyl 3-azabicyclo[3.1.0]hexane-2,3-dicarboxylate (5g, 20.7mmol) and 1-bromo-3-chloropropane (1.2mL, 12.4mmol) in tetrahydrofuran (100mL), add bis(trimethylsilyl)amide lithium (1.0M solution in tetrahydrofuran, 41.4mL) at -65°C under nitrogen atmosphere , 41.4 mmol). The reaction was stirred at -65°C for 2 hours and then warmed to 0°C, saturated ammonium chloride solution (200 mL) was added, then extracted with ethyl acetate (100 mL*2), the organic layer was dried over anhydrous magnesium sulfate, filtered, and the organic layer was concentrated under reduced pressure. The residue was subjected to flash column chromatography (silica gel, 0-10% gradient ethyl acetate/petroleum ether) to obtain 3-(tert-butyl) 2-methyl 2-(3-chloropropyl)-3-azabicyclo[3.1.0]hexane-2,3-dicarboxylate (purity 80%, 2.70 g, 6.81 mmol, yield 33%) as a yellow oil. LCMS (ESI): [M+Na] + = 340.1.
第五步：化合物3-(叔丁基)2-甲基2-(3-氯丙基)-3-氮杂双环[3.1.0]己烷-2,3-二羧酸酯(纯度80％，2.70g，6.81mmol)溶于二氯甲烷(60mL)，20℃下加入氯化氢(4M的二氧六环溶液，15mL，60 mmol)。反应在25℃下搅拌16小时。减压浓缩，得到黄色油状的粗品化合物2-(3-氯丙基)-3-氮杂双环[3.1.0]己烷-2-羧酸甲酯(1.72g)。LCMS(ESI):[M+H]+＝218.1.Step 5: Compound 3-(tert-butyl) 2-methyl 2-(3-chloropropyl)-3-azabicyclo[3.1.0]hexane-2,3-dicarboxylate (purity 80%, 2.70g, 6.81mmol) was dissolved in dichloromethane (60mL), and hydrogen chloride (4M solution in dioxane, 15mL, 60 mmol). The reaction was stirred at 25°C for 16 hours. Concentration under reduced pressure gave crude compound 2-(3-chloropropyl)-3-azabicyclo[3.1.0]hexane-2-carboxylic acid methyl ester (1.72 g) as a yellow oil. LCMS (ESI): [M+H] + = 218.1.
第六步：化合物2-(3-氯丙基)-3-氮杂双环[3.1.0]己烷-2-羧酸甲酯(1.72g，6.81mmol)溶于甲醇(50mL)，20℃下加入碳酸钾(8.57g，62.0mmol)和碘化钾(0.34g，2.07mmol)。反应在20℃下搅拌16小时。反应液过滤，减压浓缩。残余物通过快速柱色谱(硅胶，0-10％梯度的甲醇/二氯甲烷)纯化得到两个中间体。极性较小黄色油状液体假定为反式-六氢环丙[a]吡咯嗪-6a(4H)-羧酸甲酯(110mg，0.61mmol，收率8.9％)。LCMS(ESI):[M+H]+＝182.1；极性较大的黄色油状液体假定为顺式-六氢环丙[a]吡咯嗪-6a(4H)-羧酸甲酯(250mg，1.38mmol，收率20％)。LCMS(ESI):[M+H]+＝182.1.Step 6: The compound 2-(3-chloropropyl)-3-azabicyclo[3.1.0]hexane-2-carboxylate methyl ester (1.72g, 6.81mmol) was dissolved in methanol (50mL), and potassium carbonate (8.57g, 62.0mmol) and potassium iodide (0.34g, 2.07mmol) were added at 20°C. The reaction was stirred at 20°C for 16 hours. The reaction solution was filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 0-10% gradient of methanol/dichloromethane) to yield two intermediates. The less polar yellow oily liquid was assumed to be trans-hexahydrocyclopropane[a]pyrrolazine-6a(4H)-carboxylate methyl ester (110 mg, 0.61 mmol, 8.9% yield). LCMS (ESI): [M+H] + =182.1; the more polar yellow oily liquid was assumed to be cis-hexahydrocyclopropane[a]pyrrolazine-6a(4H)-methyl carboxylate (250 mg, 1.38 mmol, yield 20%). LCMS (ESI): [M+H] + = 182.1.
第七步：将四氢铝锂(35mg，0.91mmol)溶于四氢呋喃(6mL)，-40℃的氮气氛围下加入反式-六氢环丙[a]吡咯嗪-6a(4H)-羧酸甲酯(110mg，0.61mmol)的四氢呋喃(0.5mL)溶液。反应在-10℃下搅拌1小时。0℃下反应液中加入水(110uL)和15％氢氧化钠水溶液(110uL)，然后加入水(330uL)。加入无水硫酸钠搅拌，过滤并减压浓缩滤液以得到黄色油状化合物反式-(六氢环丙[a]吡咯嗪-6a(4H)-基)甲醇(中间体A13-1，90mg，0.59mmol，收率96％)。LCMS(ESI):[M+H]+＝154.1.Step 7: Dissolve lithium aluminum tetrahydride (35 mg, 0.91 mmol) in tetrahydrofuran (6 mL), and add trans-hexahydrocyclopropane[a]pyrrolazine-6a(4H)-methyl carboxylate (110 mg, 0.61 mmol) in tetrahydrofuran (0.5 mL) under a nitrogen atmosphere at -40°C. The reaction was stirred at -10°C for 1 hour. Water (110uL) and 15% aqueous sodium hydroxide solution (110uL) were added to the reaction solution at 0°C, and then water (330uL) was added. Anhydrous sodium sulfate was added and stirred, filtered and the filtrate was concentrated under reduced pressure to obtain trans-(hexahydrocyclopropane[a]pyrrolazin-6a(4H)-yl)methanol (intermediate A13-1, 90 mg, 0.59 mmol, yield 96%) as a yellow oil. LCMS (ESI): [M+H] + = 154.1.
顺式-(六氢环丙[a]吡咯嗪-6a(4H)-基)甲醇中间体A13-2在第七步以顺式-六氢环丙[a]吡咯嗪-6a(4H)-羧酸甲酯为原料参照类似反应条件制备得到。LCMS(ESI):[M+H]+＝154.2.The cis-(hexahydrocyclopropane[a]pyrrolazin-6a(4H)-yl)methanol intermediate A13-2 was prepared in the seventh step by using cis-hexahydrocyclopropane[a]pyrrolazin-6a(4H)-carboxylic acid methyl ester as raw material and referring to similar reaction conditions. LCMS (ESI): [M+H] + = 154.2.
中间体A14：(六氢-2H-呋喃[2,3-b]吡咯嗪-7a(5H)-基)甲醇
Intermediate A14: (hexahydro-2H-furo[2,3-b]pyrrolazin-7a(5H)-yl)methanol
第一步：0℃下向乙醇钠(44.2g，650mmol)的乙醇(1000mL)溶液中加入呋喃-2-甲醛(50g，520mmol)和叠氮乙酸乙酯(80.6g，624mmol)。将该反应混合物在25℃下搅拌16小时。混合物用饱和氯化铵(1L)稀释并用乙酸乙酯(1L*3)萃取。真空浓缩有机相，残余物通过快速柱色谱(硅胶，0-30％的二氯甲烷/石油醚)纯化以得到黄色油状化合物2-叠氮基-3-(呋喃-2-基)丙烯酸乙酯(25g，120mmol，收率23％)。1H NMR(400MHz,CDCl3)δppm 7.51(d,J＝1.5Hz,1H),7.12(d,J＝3.5Hz,1H),6.89(s,1H),6.55(dd,J＝1.8,3.5Hz,1H),4.37(q,J＝7.0Hz,2H),1.40(t,J＝7.2Hz,3H).Step 1: Add furan-2-carbaldehyde (50 g, 520 mmol) and ethyl azidoacetate (80.6 g, 624 mmol) to a solution of sodium ethoxide (44.2 g, 650 mmol) in ethanol (1000 mL) at 0°C. The reaction mixture was stirred at 25°C for 16 hours. The mixture was diluted with saturated ammonium chloride (1 L) and extracted with ethyl acetate (1 L*3). The organic phase was concentrated in vacuo, and the residue was purified by flash column chromatography (silica gel, 0-30% dichloromethane/petroleum ether) to give ethyl 2-azido-3-(furan-2-yl)acrylate (25 g, 120 mmol, yield 23%) as a yellow oil. 1 H NMR (400MHz, CDCl 3 ) δppm 7.51(d, J=1.5Hz, 1H), 7.12(d, J=3.5Hz, 1H), 6.89(s, 1H), 6.55(dd, J=1.8, 3.5Hz, 1H), 4.37(q, J=7.0Hz, 2H), 1.40(t, J=7.2Hz, 3H).
第二步：将2-叠氮基-3-(呋喃-2-基)丙烯酸乙酯(24g，115mmol)的甲苯溶液在115℃下搅拌3小时，反应有大量气体放出。反应完成后，真空浓缩，得到呈棕色固体化合物的4H-呋喃[3,2-b]吡咯-5-羧酸乙酯(16g，89.3mmol，收率77％)。LCMS(ESI):[M+H]+＝180.1.The second step: a toluene solution of ethyl 2-azido-3-(furan-2-yl)acrylate (24 g, 115 mmol) was stirred at 115° C. for 3 hours, and a large amount of gas was released during the reaction. After the reaction was completed, it was concentrated in vacuo to obtain ethyl 4H-furo[3,2-b]pyrrole-5-carboxylate (16 g, 89.3 mmol, yield 77%) as a brown solid compound. LCMS (ESI): [M+H] + = 180.1.
第三步：在0℃下，向4H-呋喃[3,2-b]吡咯-5-羧酸乙酯(16.5g，92.1mmol)的乙腈(160mL)溶液加入4-二甲氨基吡啶(1.07g，8.75mmol)和二碳酸二叔丁酯(27.7g，127mmol)。反应在25℃下搅拌16小时。混合物真空浓缩，残余物通过快速柱色谱(硅胶，0-10％梯度的乙酸乙酯/石油醚)纯化得到棕色油状化合物4-(叔丁基)5-乙基4H-呋喃[3,2-b]吡咯-4,5-二羧酸酯(24g，85.9mmol，收率93％)。LCMS(ESI):[M-56+H]+＝224.1. Step 3: To a solution of ethyl 4H-furo[3,2-b]pyrrole-5-carboxylate (16.5 g, 92.1 mmol) in acetonitrile (160 mL) was added 4-dimethylaminopyridine (1.07 g, 8.75 mmol) and di-tert-butyl dicarbonate (27.7 g, 127 mmol) at 0°C. The reaction was stirred at 25°C for 16 hours. The mixture was concentrated in vacuo, and the residue was purified by flash column chromatography (silica gel, 0-10% gradient ethyl acetate/petroleum ether) to give brown oily compound 4-(tert-butyl)5-ethyl 4H-furo[3,2-b]pyrrole-4,5-dicarboxylate (24 g, 85.9 mmol, yield 93%). LCMS (ESI): [M-56+H] + = 224.1.
第四步：向4-(叔丁基)5-乙基4H-呋喃[3,2-b]吡咯-4,5-二羧酸酯(8g，28.6mmol)的乙醇(200mL)溶液中加入钯碳(10％纯度，6.10g，5.73mmol)。反应在60℃及50psi氢气气氛下搅拌16小时。过滤混合物，真空浓缩滤液，得到黄色油状化合物4-(叔丁基)5-乙基六氢-4H-呋喃[3,2-b]吡咯-4,5-二羧酸酯(7.86g，27.5mmol，收率96％)。LCMS(ESI):[M+Na]+＝308.1.Step 4: To a solution of 4-(tert-butyl)5-ethyl 4H-furo[3,2-b]pyrrole-4,5-dicarboxylate (8 g, 28.6 mmol) in ethanol (200 mL) was added palladium on carbon (10% purity, 6.10 g, 5.73 mmol). The reaction was stirred at 60°C under 50 psi hydrogen atmosphere for 16 hours. The mixture was filtered, and the filtrate was concentrated in vacuo to obtain 4-(tert-butyl)5-ethylhexahydro-4H-furo[3,2-b]pyrrole-4,5-dicarboxylate (7.86 g, 27.5 mmol, yield 96%) as a yellow oil. LCMS (ESI): [M+Na] + = 308.1.
第五步：在-65℃和氮气气氛下，向4-(叔丁基)5-乙基六氢-4H-呋喃[3,2-b]吡咯-4,5-二羧酸酯(2g，7.01mmol)和1-溴-3-氯丙烷(3.31g，21.0mmol)的四氢呋喃(20mL)溶液中加入双(三甲硅基)氨基锂(1M的四氢呋喃溶液，14.0mL，14.0mmol)。反应在25℃下搅拌16小时。将混合物加入饱和氯化铵水溶液(15mL)中。然后用乙酸乙酯(15mL*3)萃取。有机相用无水硫酸镁干燥并过滤。滤液真空浓缩。残余物通过快速柱色谱(硅胶，0-10％梯度的四氢呋喃/石油醚)纯化得到无色油状化合物4-(叔丁基)5-乙基5-(3-氯丙基)六氢-4H-呋喃[3,2-b]吡咯-4,5-二羧酸酯(1.62g，4.48mmol，收率64％)。LCMS(ESI):[M-Na]+＝384.2.Step 5: Add bis(trimethylsilyl)amide lithium (1M in tetrahydrofuran) to a solution of 4-(tert-butyl)5-ethylhexahydro-4H-furo[3,2-b]pyrrole-4,5-dicarboxylate (2g, 7.01mmol) and 1-bromo-3-chloropropane (3.31g, 21.0mmol) in tetrahydrofuran (20mL) at -65°C under a nitrogen atmosphere, 14. 0 mL, 14.0 mmol). The reaction was stirred at 25°C for 16 hours. The mixture was added to saturated aqueous ammonium chloride (15 mL). It was then extracted with ethyl acetate (15 mL*3). The organic phase was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated in vacuo. The residue was purified by flash column chromatography (silica gel, 0-10% gradient THF/petroleum ether) to give 4-(tert-butyl)5-ethyl5-(3-chloropropyl)hexahydro-4H-furo[3,2-b]pyrrole-4,5-dicarboxylate (1.62g, 4.48mmol, yield 64%) as a colorless oil. LCMS (ESI): [M-Na] + = 384.2.
第六步：在0℃下，向4-(叔丁基)5-乙基5-(3-氯丙基)六氢-4H-呋喃[3,2-b]吡咯-4,5-二羧酸酯(1.62g，4.48mmol)的二氯甲烷(16mL)溶液中加入三氟乙酸(4mL)。反应在20℃下搅拌2小时。真空浓缩混合物，得到粗品化合物5-(3-氯丙基)六氢-2H-呋喃[3,2-b]吡咯-5-羧酸乙酯(1.10g)，为黄色油状液体。LCMS(ESI):[M+H]+＝262.1.Step 6: To a solution of 4-(tert-butyl)5-ethyl 5-(3-chloropropyl)hexahydro-4H-furo[3,2-b]pyrrole-4,5-dicarboxylate (1.62 g, 4.48 mmol) in dichloromethane (16 mL) was added trifluoroacetic acid (4 mL) at 0°C. The reaction was stirred at 20°C for 2 hours. The mixture was concentrated in vacuo to afford crude compound ethyl 5-(3-chloropropyl)hexahydro-2H-furo[3,2-b]pyrrole-5-carboxylate (1.10 g) as a yellow oily liquid. LCMS (ESI): [M+H] + = 262.1.
第七步：向5-(3-氯丙基)六氢-2H-呋喃[3,2-b]吡咯-5-羧酸乙酯(1.10g，4.21mmol)的乙醇(50mL)溶液中加入碳酸钾(1.74g，12.6mmol)和碘化钾(0.07g，0.42mmol)。将混合物在25℃搅拌16小时。过滤混合物并真空浓缩滤液，残余物通过快速柱色谱(硅胶，0-10％梯度的乙醇/二氯甲烷)纯化得到黄色油状化合物六氢-2H-呋喃[2,3-b]吡咯嗪-7a(5H)-羧酸乙酯(0.86g，3.82mmol，收率91％)。LCMS(ESI):[M+H]+＝226.1.Step 7: Potassium carbonate (1.74 g, 12.6 mmol) and potassium iodide (0.07 g, 0.42 mmol) were added to a solution of ethyl 5-(3-chloropropyl)hexahydro-2H-furo[3,2-b]pyrrole-5-carboxylate (1.10 g, 4.21 mmol) in ethanol (50 mL). The mixture was stirred at 25°C for 16 hours. The mixture was filtered and the filtrate was concentrated in vacuo, and the residue was purified by flash column chromatography (silica gel, 0-10% gradient of ethanol/dichloromethane) to obtain ethyl hexahydro-2H-furo[2,3-b]pyrrolazine-7a(5H)-carboxylate (0.86 g, 3.82 mmol, yield 91%) as a yellow oil. LCMS (ESI): [M+H] + = 226.1.
第八步：在-40℃下，向六氢-2H-呋喃[2,3-b]吡咯嗪-7a(5H)-羧酸乙酯(0.86g，3.82mmol)的四氢呋喃(9.00mL)溶液中加入四氢锂铝(156mg，4.12mmol)。将混合物在-10℃搅拌1小时。向混合物中缓慢加入水(160uL)，然后加入15％氢氧化钠溶液(160uL)以及水(480uL)，加入无水硫酸钠搅拌，过滤并用四氢呋喃洗涤滤饼。真空浓缩滤液，得到棕色油状化合物(六氢-2H-呋喃[2,3-b]吡咯嗪-7a(5H)-基)甲醇(510mg，2.78mmol，收率72％)。LCMS(ESI):[M+H]+＝184.2.1H NMR(400MHz,CD3OD)δppm 4.52-4.48(m,1H),3.98(q,J＝8.1Hz,1H),3.82(dt,J＝4.6,7.6Hz,1H),3.56-3.48(m,1H),3.33(td,J＝1.4,3.1Hz,2H),3.00-2.91(m,1H),2.87-2.77(m,1H),2.19(d,J＝14.3Hz,1H),2.00-1.94(m,2H),1.91-1.82(m,3H),1.81-1.70(m,1H),1.67-1.55(m,1H).Step 8: To a solution of ethyl hexahydro-2H-furo[2,3-b]pyrrolazine-7a(5H)-carboxylate (0.86 g, 3.82 mmol) in THF (9.00 mL) was added lithium aluminum tetrahydrogen (156 mg, 4.12 mmol) at -40°C. The mixture was stirred at -10°C for 1 hour. Water (160uL) was slowly added to the mixture, then 15% sodium hydroxide solution (160uL) and water (480uL) were added, anhydrous sodium sulfate was added and stirred, filtered and the filter cake was washed with tetrahydrofuran. The filtrate was concentrated in vacuo to give (hexahydro-2H-furo[2,3-b]pyrrolazin-7a(5H)-yl)methanol (510 mg, 2.78 mmol, yield 72%) as a brown oil. LCMS(ESI):[M+H] + ＝184.2. 1 H NMR(400MHz,CD 3 OD)δppm 4.52-4.48(m,1H),3.98(q,J＝8.1Hz,1H),3.82(dt,J＝4.6,7.6Hz,1H),3.56-3.48(m,1H),3.33(td,J＝1.4,3.1Hz,2H),3.00-2.91(m,1H),2.87-2.77(m,1H),2.19(d,J＝14.3Hz,1H),2.00-1.94(m,2H),1.91-1.82(m,3H),1.81-1.70(m,1H),1.67-1.55(m,1H).
中间体A15：(六氢环丙[b]吡咯嗪-5a(3H)-基)甲醇
Intermediate A15: (Hexahydrocyclopropane[b]pyrrolazin-5a(3H)-yl)methanol
第一步：在-65℃的氮气环境下，向(3R)-2-叔丁基-3-乙基-2-氮杂双环[3.1.0]己烷-2,3-二羧酸酯(950mg，3.72mmol)和1-溴-3-氯丙烷(1.76g，11.1mmol)的四氢呋喃(10mL)溶液中加入双三甲基硅基胺基锂(1M的四氢呋喃溶液，7.44mL，7.44mmol)。反应在25℃下搅拌16小时。混合物中加入饱和氯化铵溶液(10mL)，然后用乙酸乙酯(10mL*3)萃取，有机层用无水硫酸镁干燥， 过滤，滤液真空浓缩。残余物通过快速柱色谱(硅胶，0-10％梯度的四氢呋喃/二氯甲烷)纯化以得到无色油状化合物2-叔丁基-3-乙基-3-(3-氯丙基)-2-氮杂双环[3.1.0]己烷-2,3-二羧酸酯(630mg，1.90mmol，收率51％)。LCMS(ESI):[M+Na]+＝354.3.Step 1: Add lithium bistrimethylsilylamide (1M solution in tetrahydrofuran) to a solution of (3R)-2-tert-butyl-3-ethyl-2-azabicyclo[3.1.0]hexane-2,3-dicarboxylate (950mg, 3.72mmol) and 1-bromo-3-chloropropane (1.76g, 11.1mmol) in tetrahydrofuran (10mL) under a nitrogen atmosphere at -65°C. 7.44 mL, 7.44 mmol). The reaction was stirred at 25°C for 16 hours. Saturated ammonium chloride solution (10 mL) was added to the mixture, followed by extraction with ethyl acetate (10 mL*3), and the organic layer was dried over anhydrous magnesium sulfate. Filter and concentrate the filtrate in vacuo. The residue was purified by flash column chromatography (silica gel, 0-10% gradient of tetrahydrofuran/dichloromethane) to give compound 2-tert-butyl-3-ethyl-3-(3-chloropropyl)-2-azabicyclo[3.1.0]hexane-2,3-dicarboxylate (630 mg, 1.90 mmol, yield 51%) as colorless oil. LCMS (ESI): [M+Na] + = 354.3.
第二步：向2-叔丁基-3-乙基-3-(3-氯丙基)-2-氮杂双环[3.1.0]己烷-2,3-二羧酸酯(610mg，1.84mmol)的二氯甲烷(6mL)溶液中加入氯化氢(4M的二氧六环溶液，1.38mL，5.51mmol)。反应在25℃下搅拌16小时。真空浓缩混合物，得到无色油状的粗品化合物3-(3-氯丙基)-2-氮杂双环[3.1.0]己烷-3-羧酸乙酯(60％纯度，690mg)。LCMS(ESI):[M+H]+＝232.2.Second step: To a solution of 2-tert-butyl-3-ethyl-3-(3-chloropropyl)-2-azabicyclo[3.1.0]hexane-2,3-dicarboxylate (610 mg, 1.84 mmol) in dichloromethane (6 mL) was added hydrogen chloride (4M in dioxane, 1.38 mL, 5.51 mmol). The reaction was stirred at 25°C for 16 hours. The mixture was concentrated in vacuo to afford crude compound ethyl 3-(3-chloropropyl)-2-azabicyclo[3.1.0]hexane-3-carboxylate (60% purity, 690 mg) as a colorless oil. LCMS (ESI): [M+H] + = 232.2.
第三步：向3-(3-氯丙基)-2-氮杂双环[3.1.0]己烷-3-羧酸乙酯(60％纯度，670mg，1.73mmol)的乙醇(26mL)溶液中加入碘化钾(29mg，0.17mmol)和碳酸钾(719mg，5.20mmol)。反应在25℃下搅拌16小时。将混合物过滤并浓缩。残余物通过快速柱色谱(硅胶，0-10％梯度的乙醇/二氯甲烷)纯化得到黄色油状化合物六氢环丙[b]吡咯嗪-5a(3H)-羧酸乙酯(95％纯度，320mg，1.56mmol，收率90％)。LCMS(ESI):[M+H]+＝196.1.Step 3: To a solution of ethyl 3-(3-chloropropyl)-2-azabicyclo[3.1.0]hexane-3-carboxylate (60% purity, 670 mg, 1.73 mmol) in ethanol (26 mL) was added potassium iodide (29 mg, 0.17 mmol) and potassium carbonate (719 mg, 5.20 mmol). The reaction was stirred at 25°C for 16 hours. The mixture was filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0-10% ethanol/dichloromethane gradient) to obtain ethyl hexahydrocyclopropane[b]pyrrolazine-5a(3H)-carboxylate (95% purity, 320 mg, 1.56 mmol, yield 90%) as a yellow oil. LCMS (ESI): [M+H] + = 196.1.
第四步：在-40℃下，向六氢环丙[b]吡咯嗪-5a(3H)-羧酸乙酯(95％纯度，310mg，1.50mmol)的四氢呋喃(3mL)溶液中加入四氢铝锂(72mg，1.91mmol)。将混合物在-10℃下搅拌1小时。反应加入水(72uL)和15％氢氧化钠水溶液(72uL)，然后加入水(216uL)。加入无水硫酸钠干燥。过滤并用四氢呋喃(30mL)洗涤滤饼，滤液真空浓缩以得到粗品化合物(六氢环丙[b]吡咯嗪-5a(3H)-基)甲醇(230mg)，为黄色油状液体。LCMS(ESI):[M+H]+＝154.1.Step 4: To a solution of ethyl hexahydrocyclopropane[b]pyrrolazine-5a(3H)-carboxylate (95% purity, 310 mg, 1.50 mmol) in THF (3 mL) was added lithium aluminum tetrahydride (72 mg, 1.91 mmol) at -40°C. The mixture was stirred at -10°C for 1 hour. Water (72uL) and 15% aqueous sodium hydroxide solution (72uL) were added to the reaction, followed by water (216uL). Add anhydrous sodium sulfate to dry. After filtering and washing the filter cake with tetrahydrofuran (30 mL), the filtrate was concentrated in vacuo to give crude compound (hexahydrocyclopropane[b]pyrrolazin-5a(3H)-yl)methanol (230 mg) as a yellow oily liquid. LCMS (ESI): [M+H] + = 154.1.
中间体A16-1和A16-2：顺式-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-吡咯嗪]-7a'(5'H)-基)甲醇A16-1和反式-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-吡咯嗪]-7a'(5'H)-基)甲醇A16-2
Intermediate A16-1 and A16-2: Shun-2,2-diofluoride -1'H, 3'h-snail [cycloopropane -1,2' piciazine] -7A '(5'H)-base) methanol A16-1 and translinomous-2,2-dioflurax -1'h, 3'H-snail [cyclopenide-1,2' phenizizin] -7a' (5 '(5' (5 ' H)-base) methanol A16-2
第一步：将化合物1-(叔丁基)2-甲基(S)-4-亚甲基吡咯烷-1,2-二羧酸酯(2.80g，11.6mmol)和三甲基(三氟甲基)硅烷(4.12g，29.0mmol)溶于四氢呋喃(100mL)，氮气下加入碘化钠(0.87g，5.81mmol)。反应在60℃下搅拌16小时。冷却到室温，加入饱和氯化铵(50mL)淬灭，反应液用乙酸乙酯(100mL*2)萃取，合并有机相，依次用用饱和的亚硫酸钠(50mL)和饱和食盐水(50mL)洗涤，硫酸钠干燥，过滤，滤液减压浓缩得到黄色油状化合物5-(叔丁基)6-甲基(6S)-1,1-二氟-5-氮杂螺[2.4]庚烷-5,6-二羧酸酯(纯度80％，4.00g，11.0mmol，收率95％)。LCMS(ESI):[M+Na]+＝313.9.1H NMR(400MHz,CDCl3)δppm 4.58-4.35(m,1H),3.77(m,3H),3.75-3.65(m,1H),3.59-3.44(m,1H),2.57(m,1H),2.13-1.93(m,1H),1.50-1.43(m,9H),1.41-1.30(m,2H).The first step: Compound 1-(tert-butyl) 2-methyl(S)-4-methylenepyrrolidine-1,2-dicarboxylate (2.80g, 11.6mmol) and trimethyl(trifluoromethyl)silane (4.12g, 29.0mmol) were dissolved in tetrahydrofuran (100mL), and sodium iodide (0.87g, 5.81mmol) was added under nitrogen. The reaction was stirred at 60°C for 16 hours. Cooled to room temperature, quenched by adding saturated ammonium chloride (50mL), the reaction solution was extracted with ethyl acetate (100mL*2), the organic phases were combined, washed successively with saturated sodium sulfite (50mL) and saturated brine (50mL), dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain yellow oily compound 5-(tert-butyl) 6-methyl(6S)-1,1-difluoro-5-azaspiro[2.4]heptane-5,6-dicarboxylate (purity 80%, 4.00g, 11.0mmol, yield 95%). LCMS (ESI): [M+Na] + =313.9. 1 H NMR (400MHz, CDCl 3 ) δppm 4.58-4.35 (m, 1H), 3.77 (m, 3H), 3.75-3.65 (m, 1H), 3.59-3.44 (m, 1H), 2.57 (m, 1H), 2.13-1.93 (m,1H),1.50-1.43(m,9H),1.41-1.30(m,2H).
第二步：将化合物5-(叔丁基)6-甲基(6S)-1,1-二氟-5-氮杂螺[2.4]庚烷-5,6-二羧酸酯(纯度80％，4.00g，11.0mmol)溶于四氢呋喃(65mL)降到-70℃，氮气下加入二异丙基氨基锂(2M的四氢呋 喃正庚烷混合溶液，10.3mL，20.6mmol)，反应在-70℃搅拌1小时。加入1-溴-3-氯丙烷(4.32g,27.4mmol)，反应在-70℃搅拌2小时，然后升到25℃反应16小时。反应液用饱和氯化铵(30mL)淬灭，用乙酸乙酯(50mL*2)萃取，合并有机相，用饱和食盐水(50mL)洗涤，硫酸钠干燥，过滤，滤液减压浓缩。残留物用快速柱色谱纯化(硅胶，0-20％梯度的四氢呋喃/石油醚)，得到两个立体异构体。分离得到极性较小的无色油状液体异构体，经二维核磁谱确认为顺式构型：顺式-5-(叔丁基)6-甲基-6-(3-氯丙基)-1,1-二氟-5-氮杂螺[2.4]庚烷-5,6-二羧酸酯(1.20g，3.26mmol，收率30％)。LCMS(ESI):[M+Na]+＝390.3.1H NMR(400MHz,CDCl3)δppm 3.91(m,1H),3.80-3.71(m,3H),3.65-3.44(m,3H),2.48-2.00(m,4H),1.94-1.74(m,2H),1.50-1.42(m,9H),1.41-1.29(m,2H)；分离得到极性较大的异构体，经二维核磁谱确认为反式构型：反式-5-(叔丁基)6-甲基-6-(3-氯丙基)-1,1-二氟-5-氮杂螺[2.4]庚烷-5,6-二羧酸酯(纯度80％，0.70g，1.52mmol，收率14％)。LCMS(ESI):[M-100+H]+＝268.2.1H NMR(400MHz,CDCl3)δppm 3.80-3.73(m,3H),3.71(m,1H),3.67-3.42(m,3H),2.46-2.17(m,3H),2.16-1.73(m,3H),1.50-1.42(m,9H),1.39-1.23(m,2H).The second step: the compound 5-(tert-butyl) 6-methyl(6S)-1,1-difluoro-5-azaspiro[2.4]heptane-5,6-dicarboxylate (purity 80%, 4.00g, 11.0mmol) was dissolved in tetrahydrofuran (65mL) and dropped to -70°C, and diisopropylamide lithium (2M tetrahydrofuran Heptane mixed solution, 10.3mL, 20.6mmol), the reaction was stirred at -70°C for 1 hour. 1-Bromo-3-chloropropane (4.32g, 27.4mmol) was added, and the reaction was stirred at -70°C for 2 hours, then raised to 25°C for 16 hours. The reaction solution was quenched with saturated ammonium chloride (30 mL), extracted with ethyl acetate (50 mL*2), combined organic phases, washed with saturated brine (50 mL), dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, gradient 0-20% tetrahydrofuran/petroleum ether) to afford two stereoisomers. A less polar colorless oily liquid isomer was isolated, which was confirmed to be in the cis configuration by 2D NMR: cis-5-(tert-butyl)6-methyl-6-(3-chloropropyl)-1,1-difluoro-5-azaspiro[2.4]heptane-5,6-dicarboxylate (1.20 g, 3.26 mmol, yield 30%). LCMS(ESI):[M+Na] + ＝390.3. 1 H NMR(400MHz,CDCl 3 )δppm 3.91(m,1H),3.80-3.71(m,3H),3.65-3.44(m,3H),2.48-2.00(m,4H),1.94-1.74(m,2H),1.50-1.42(m,9H),1.41-1.29(m,2H)；分离得到极性较大的异构体，经二维核磁谱确认为反式构型：反式-5-(叔丁基)6-甲基-6-(3-氯丙基)-1,1-二氟-5-氮杂螺[2.4]庚烷-5,6-二羧酸酯(纯度80％，0.70g，1.52mmol，收率14％)。 LCMS (ESI): [M-100+H] + =268.2. 1 H NMR (400MHz, CDCl 3 ) δppm 3.80-3.73 (m, 3H), 3.71 (m, 1H), 3.67-3.42 (m, 3H), 2.46-2.17 (m, 3H), 2.16-1.73 (m, 3H), 1.50-1.42(m,9H),1.39-1.23(m,2H).
第三步：化合物顺式5-(叔丁基)6-甲基-6-(3-氯丙基)-1,1-二氟-5-氮杂螺[2.4]庚烷-5,6-二羧酸酯(1.20g，3.26mmol)溶于二氯甲烷(4mL)，20℃下加入氯化氢(4M的二氧六环溶液，2mL，9.78mmol)，反应液在20℃下搅拌2小时。反应液减压浓缩得到粗品化合物顺式-6-(3-氯丙基)-1,1-二氟-5-氮杂螺[2.4]庚烷-6-羧酸甲酯(0.83g)，为白色固体。LCMS(ESI):[M+H]+＝268.1The third step: the compound cis 5-(tert-butyl) 6-methyl-6-(3-chloropropyl)-1,1-difluoro-5-azaspiro[2.4]heptane-5,6-dicarboxylate (1.20g, 3.26mmol) was dissolved in dichloromethane (4mL), hydrogen chloride (4M solution in dioxane, 2mL, 9.78mmol) was added at 20°C, and the reaction solution was stirred at 20°C for 2 hours. The reaction solution was concentrated under reduced pressure to obtain the crude compound cis-6-(3-chloropropyl)-1,1-difluoro-5-azaspiro[2.4]heptane-6-carboxylic acid methyl ester (0.83 g) as a white solid. LCMS (ESI): [M+H] + = 268.1
第四步：将化合物顺式-6-(3-氯丙基)-1,1-二氟-5-氮杂螺[2.4]庚烷-6-羧酸甲酯(0.83g，3.11mmol)溶于甲醇(2mL)，25℃下加入碘化钾(62mg,0.37mmol)和碳酸钾(1.55g,11.21mmol)。反应在25℃下搅拌16小时。反应液过滤，滤液减压浓缩，残留物用快速柱色谱纯化(硅胶，0-20％梯度的四氢呋喃/石油醚)得到无色油状化合物顺式-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-吡咯嗪]-7a'(5'H)-羧酸甲酯(0.25g，1.08mmol，两步收率：33％)。LCMS(ESI):[M+H]+＝232.1。1H NMR(400MHz,CDCl3)δppm 3.68(s,3H),3.31(d,J＝10.9Hz,1H),3.19-3.10(m,1H),2.75-2.64(m,2H),2.43(d,J＝13.4Hz,1H),2.37-2.30(m,1H),1.91-1.74(m,4H),1.30-1.22(m,2H)The fourth step: the compound cis-6-(3-chloropropyl)-1,1-difluoro-5-azaspiro[2.4]heptane-6-carboxylate methyl ester (0.83g, 3.11mmol) was dissolved in methanol (2mL), and potassium iodide (62mg, 0.37mmol) and potassium carbonate (1.55g, 11.21mmol) were added at 25°C. The reaction was stirred at 25°C for 16 hours. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by flash column chromatography (silica gel, 0-20% gradient tetrahydrofuran/petroleum ether) to obtain the colorless oily compound cis-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolazine]-7a'(5'H)-methyl carboxylate (0.25g, 1.08mmol, two-step yield: 33%). LCMS (ESI): [M+H] + = 232.1. 1 H NMR (400MHz, CDCl 3 ) δppm 3.68(s,3H),3.31(d,J=10.9Hz,1H),3.19-3.10(m,1H),2.75-2.64(m,2H),2.43(d,J=13.4Hz,1H),2.37-2.30(m,1H),1.91 -1.74(m,4H),1.30-1.22(m,2H)
第五步：将化合物顺式-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-吡咯嗪]-7a'(5'H)-羧酸甲酯(0.25g，1.08mmol)溶于四氢呋喃(4mL)，0℃下加入四氢铝锂(61mg，1.62mmol)。反应在60℃下搅拌2小时。向反应液中加入水(61uL)，氢氧化钠(15％水溶液，61uL)，水(183uL)，无水硫酸镁(1g)，搅拌30分钟，反应液过滤，滤液减压浓缩得到无色油状顺式-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-吡咯嗪]-7a'(5'H)-基)甲醇A16-1(0.20g，0.96mmol，收率89％)。LCMS(ESI):[M+H]+＝204.1.1H NMR(400MHz,CDCl3)δppm 3.35-3.28(m,2H),3.23(d,J＝11.0Hz,1H),3.06(td,J＝6.2,10.7Hz,1H),2.82-2.73(m,2H),2.04(d,J＝13.1Hz,1H),1.98-1.69(m,5H),1.36-1.27(m,2H).Step 5: The compound cis-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolazine]-7a'(5'H)-methyl carboxylate (0.25g, 1.08mmol) was dissolved in tetrahydrofuran (4mL), and lithium aluminum tetrahydride (61mg, 1.62mmol) was added at 0°C. The reaction was stirred at 60°C for 2 hours. Add water (61uL), sodium hydroxide (15% aqueous solution, 61uL), water (183uL), anhydrous magnesium sulfate (1g) to the reaction solution, stir for 30 minutes, filter the reaction solution, and concentrate the filtrate under reduced pressure to obtain a colorless oily cis-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolazin]-7a'(5'H)-yl)methanol A16-1 (0.2 0 g, 0.96 mmol, yield 89%). LCMS (ESI): [M+H] + = 204.1. 1 H NMR (400MHz, CDCl 3 ) δppm 3.35-3.28 (m, 2H), 3.23 (d, J = 11.0Hz, 1H), 3.06 (td, J = 6.2, 10.7Hz, 1H), 2.82-2.73 (m, 2H), 2.04 (d,J=13.1Hz,1H),1.98-1.69(m,5H),1.36-1.27(m,2H).
反式-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-吡咯嗪]-7a'(5'H)-基)甲醇A16-2参考中间体A16-1的合成方法，将反式5-(叔丁基)6-甲基-6-(3-氯丙基)-1,1-二氟-5-氮杂螺[2.4]庚烷-5,6-二羧酸酯按类似反应条件制备得到。LCMS(ESI):[M+H]+＝204.1.1H NMR(400MHz,CDCl3)δppm 3.43-3.28(m,2H),3.16-3.04(m,2H),2.81(d,J＝12.3Hz,1H),2.70-2.60(m,1H),2.02-1.94(m,1H),1.92-1.64(m,5H),1.38-1.18(m,2H).Trans-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolazin]-7a'(5'H)-yl)methanol A16-2 Refer to the synthesis method of intermediate A16-1, prepare trans 5-(tert-butyl)6-methyl-6-(3-chloropropyl)-1,1-difluoro-5-azaspiro[2.4]heptane-5,6-dicarboxylate under similar reaction conditions get. LCMS (ESI): [M+H] + =204.1.1 H NMR (400MHz, CDCl 3 ) δppm 3.43-3.28(m,2H),3.16-3.04(m,2H),2.81(d,J=12.3Hz,1H),2.70-2.60(m,1H),2.02-1.94(m, 1H),1.92-1.64(m,5H),1.38-1.18(m,2H).
中间体A16-1A，A16-1B，A16-2A,和A16-2B：(1R,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'- 吡咯嗪]-7a'(5'H)-基)甲醇A16-1A；(1S,7a'R)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-吡咯嗪]-7a'(5'H)-基)甲醇A16-1B；(1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-吡咯嗪]-7a'(5'H)-基)甲醇A16-2A和(1R,7a'R)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-吡咯嗪]-7a'(5'H)-基)甲醇A16-2B
Intermediates A16-1A, A16-1B, A16-2A, and A16-2B: (1R,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'- (1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolazin]-7a'(5'H)-yl)methanol A16-1B; (1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1, 2'-pyrrolazin]-7a'(5'H)-yl)methanol A16-2A and (1R,7a'R)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolazin]-7a'(5'H)-yl)methanol A16-2B
第一步：在0℃下向(S)-1-(叔丁氧基羰基)-4-亚甲基吡咯烷-2-羧酸(90g，396mmol)的二甲基甲酰胺(1.8L)溶液中加入碳酸铯(168g，514mmol)和苄溴(88g，514mmol)。悬浊液在25℃搅拌16小时。反应液用水(1.8L)稀释，乙酸乙酯(1L*3)萃取，有机层用无水硫酸钠干燥，过滤，滤液减压浓缩，残余物通过快速柱色谱(硅胶，0-25％梯度的四氢呋喃/石油醚)纯化，得到无色油状化合物2-苄基1-(叔丁基)(S)-4-亚甲基吡咯烷-1,2-二羧酸酯(120g，378mmol，收率95％)。LCMS(ESI):[M-100+H]+＝218.1.1H NMR(400MHz,CDCl3)δppm 7.35(m,5H),5.29-5.06(m,2H),5.04-4.93(m,2H),4.62-4.41(m,1H),4.16-4.02(m,2H),3.07-2.88(m,1H),2.69-2.56(m,1H),1.55-1.29(m,9H).Step 1: To a solution of (S)-1-(tert-butoxycarbonyl)-4-methylenepyrrolidine-2-carboxylic acid (90 g, 396 mmol) in dimethylformamide (1.8 L) was added cesium carbonate (168 g, 514 mmol) and benzyl bromide (88 g, 514 mmol) at 0°C. The suspension was stirred at 25°C for 16 hours. The reaction solution was diluted with water (1.8 L), extracted with ethyl acetate (1 L*3), the organic layer was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by flash column chromatography (silica gel, 0-25% gradient tetrahydrofuran/petroleum ether) to obtain 2-benzyl 1-(tert-butyl)(S)-4-methylenepyrrolidine-1,2-dicarboxylate (120 g, 378 mmol, yield 95%) as a colorless oil. LCMS (ESI): [M-100+H] + =218.1.1 H NMR (400MHz, CDCl 3 ) δppm 7.35(m,5H),5.29-5.06(m,2H),5.04-4.93(m,2H),4.62-4.41(m,1H),4.16-4.02(m,2H), 3.07-2.88(m,1H),2.69-2.56(m,1H),1.55-1.29(m,9H).
第二步：在氮气下向2-苄基1-(叔丁基)(S)-4-亚甲基吡咯烷-1,2-二羧酸酯(8.00g，25.2mmol)和三甲基(三氟甲基)硅烷(8.96g，63.0mmol)的四氢呋喃(300mL)溶液中加入碘化钠(1.89g，12.6mmol)，并将混合物在60℃下搅拌16小时。混合物用饱和氯化铵(50mL)淬灭，并用水(100mL)稀释，乙酸乙酯(50mL*3)萃取。合并的有机层依次用饱和亚硫酸钠(50mL)和盐水(50mL)洗涤，经无水硫酸钠干燥，过滤并浓缩。粗品通过快速柱色谱(硅胶，0-25％梯度的四氢呋喃/石油醚)纯化，得到两个异构体。极性较小的黄色油状液体产物，由二维核磁谱确认为6-苄基5-(叔丁基)(3S,6S)-1,1-二氟-5-氮杂螺[2.4]庚烷-5,6-二羧酸酯(5.70g，13.2mmol，收率48％)。LCMS(ESI):[M+Na]+＝390.1.1H NMR(400MHz,CDCl3)δppm 7.36(m,5H),5.33-5.05(m,2H),4.62-4.39(m,1H),3.80-3.64(m,1H),3.55-3.37(m,1H),2.65-2.49(m,1H),2.01-1.81(m,1H),1.51-1.23(m,10H),1.23-1.08(m,1H).极性较大的黄色油状液体产物，由二维核磁谱确认为6-苄基5-(叔丁基)(3R,6S)-1,1-二氟-5-氮杂螺[2.4]庚烷-5,6-二羧酸酯(2.70g，7.35mmol，收率27％)。LCMS(ESI):[M+Na]+＝390.1.1H NMR(400MHz,CDCl3)δppm 7.41-7.28(m,5H),5.35-5.01(m,2H),4.61-4.34(m,1H),3.79-3.60(m,1H),3.53-3.38(m,1H),2.50-2.32(m,1H),2.17-2.03(m,1H),1.51-1.28(m,11H).Second step: To a solution of 2-benzyl 1-(tert-butyl)(S)-4-methylenepyrrolidine-1,2-dicarboxylate (8.00 g, 25.2 mmol) and trimethyl(trifluoromethyl)silane (8.96 g, 63.0 mmol) in THF (300 mL) was added sodium iodide (1.89 g, 12.6 mmol) under nitrogen, and the mixture was stirred at 60° C. for 16 hours. The mixture was quenched with saturated ammonium chloride (50 mL), diluted with water (100 mL), extracted with ethyl acetate (50 mL*3). The combined organic layers were washed sequentially with saturated sodium sulfite (50 mL) and brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by flash column chromatography (silica gel, gradient 0-25% THF/petroleum ether) to afford two isomers. The less polar yellow oily liquid product was identified as 6-benzyl 5-(tert-butyl)(3S,6S)-1,1-difluoro-5-azaspiro[2.4]heptane-5,6-dicarboxylate (5.70g, 13.2mmol, yield 48%) by two-dimensional nuclear magnetic spectrum. LCMS(ESI):[M+Na] + ＝390.1. 1 H NMR(400MHz,CDCl 3 )δppm 7.36(m,5H),5.33-5.05(m,2H),4.62-4.39(m,1H),3.80-3.64(m,1H),3.55-3.37(m,1H),2.65-2.49(m,1H),2.01-1.81(m,1H),1.51-1.23(m,10H),1.23-1.08(m,1H).极性较大的黄色油状液体产物，由二维核磁谱确认为6-苄基5-(叔丁基)(3R,6S)-1,1-二氟-5-氮杂螺[2.4]庚烷-5,6-二羧酸酯(2.70g，7.35mmol，收率27％)。 LCMS (ESI): [M+Na] + ＝390.1. 1 H NMR (400MHz, CDCl 3 ) δppm 7.41-7.28 (m, 5H), 5.35-5.01 (m, 2H), 4.61-4.34 (m, 1H), 3.79-3.60 (m, 1H), 3.53-3.38 (m, 1H) ,2.50-2.32(m,1H),2.17-2.03(m,1H),1.51-1.28(m,11H).
第三步：在-78℃氮气氛围下向6-苄基5-(叔丁基)(3R,6S)-1,1-二氟-5-氮杂螺[2.4]庚烷-5,6-二羧酸酯(15g，40.8mmol)的四氢呋喃(150mL)溶液中加入二(三甲基硅)氨基钾(2M的四氢呋喃溶液，41mL，82mmol)。反应液在-78℃搅拌1小时。向溶液中加入1-溴-3-氯丙烷(13g，81.6mmol)并 将溶液在-78℃下搅拌1小时。然后在25℃搅拌14小时。溶液用水(150mL)淬灭，乙酸乙酯(150mL*3)萃取并浓缩，得到粗品化合物6-苄基5-(叔丁基)(3R,6S)-6-(3-氯丙基)-1,1-二氟-5-氮杂螺[2.4]庚烷-5,6-二羧酸酯(20g，含有少量6-苄基5-(叔丁基)(3R,6R)-6-(3-氯丙基)-1,1-二氟-5-氮杂螺[2.4]庚烷-5,6-二羧酸酯)，其为棕色油状液体。LCMS(ESI):[M-56+H]+＝388.1。Step 3: To a solution of 6-benzyl 5-(tert-butyl)(3R,6S)-1,1-difluoro-5-azaspiro[2.4]heptane-5,6-dicarboxylate (15g, 40.8mmol) in THF (150mL) was added potassium bis(trimethylsilyl)amide (2M solution in THF, 41mL, 82mmol) at -78°C under a nitrogen atmosphere. The reaction was stirred at -78°C for 1 hour. 1-Bromo-3-chloropropane (13 g, 81.6 mmol) was added to the solution and The solution was stirred at -78°C for 1 hour. It was then stirred at 25°C for 14 hours. The solution was quenched with water (150 mL), extracted with ethyl acetate (150 mL*3) and concentrated to obtain the crude compound 6-benzyl 5-(tert-butyl)(3R,6S)-6-(3-chloropropyl)-1,1-difluoro-5-azaspiro[2.4]heptane-5,6-dicarboxylate (20 g, containing a small amount of 6-benzyl 5-(tert-butyl)(3R,6R)-6-(3-chloropropyl )-1,1-difluoro-5-azaspiro[2.4]heptane-5,6-dicarboxylate) as a brown oily liquid. LCMS (ESI): [M-56+H] + = 388.1.
第四步：在25℃下向化合物6-苄基5-(叔丁基)(3R,6S)-6-(3-氯丙基)-1,1-二氟-5-氮杂螺[2.4]庚烷-5,6-二羧酸酯(6g，18.1mmol)的二氯甲烷(200mL)溶液中加入氯化氢(4M的二氧六环溶液，100mL，400mmol)。将反应液在25℃搅拌16小时。将溶液浓缩，得到粗品化合物(3R,6S)-6-(3-氯丙基)-1,1-二氟-5-氮杂螺[2.4]庚烷-6-羧酸苄酯(17g)，其为棕色油状液体。LCMS(ESI):[M+H]+＝344.1。Step 4: To a solution of compound 6-benzyl 5-(tert-butyl)(3R,6S)-6-(3-chloropropyl)-1,1-difluoro-5-azaspiro[2.4]heptane-5,6-dicarboxylate (6 g, 18.1 mmol) in dichloromethane (200 mL) was added hydrogen chloride (4M in dioxane, 100 mL, 400 mmol) at 25°C. The reaction was stirred at 25°C for 16 hours. The solution was concentrated to give crude compound (3R,6S)-benzyl 6-(3-chloropropyl)-1,1-difluoro-5-azaspiro[2.4]heptane-6-carboxylate (17 g) as a brown oily liquid. LCMS (ESI): [M+H] + = 344.1.
第五步：在25℃下向化合物(3R,6S)-6-(3-氯丙基)-1,1-二氟-5-氮杂螺[2.4]庚烷-6-羧酸苄酯(16g，46.5mmol)的甲醇(500mL)溶液中加入碘化钾(0.77g，4.65mmol)和碳酸钾(19.3g，139mmol)。溶液在25℃搅拌16小时。将溶液浓缩并通过制备型HPLC纯化，得到棕色油状化合物苄基(1R,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-吡咯嗪]-7a'(5'H)-羧酸酯(350mg，1.14mmol，收率2％)，其构型由二维核磁谱确认。LCMS(ESI):[M+H]+＝308.1.1H NMR(400MHz,CDCl3)δppm 7.43-7.29(m,5H),5.31-5.09(m,2H),3.41(d,J＝10.9Hz,1H),3.32-3.19(m,1H),2.89-2.71(m,2H),2.59(d,J＝13.4Hz,1H),2.46-2.31(m,1H),1.97-1.81(m,4H),1.39-1.27(m,2H).Step 5: To a methanol (500 mL) solution of compound (3R,6S)-6-(3-chloropropyl)-1,1-difluoro-5-azaspiro[2.4]heptane-6-carboxylate (16 g, 46.5 mmol) was added potassium iodide (0.77 g, 4.65 mmol) and potassium carbonate (19.3 g, 139 mmol) at 25°C. The solution was stirred at 25°C for 16 hours. The solution was concentrated and purified by preparative HPLC to give benzyl (1R,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolazine]-7a'(5'H)-carboxylate (350 mg, 1.14 mmol, yield 2%) as a brown oily compound, the configuration of which was confirmed by 2D NMR. LCMS (ESI): [M+H] + =308.1.1 H NMR (400MHz, CDCl 3 ) δppm 7.43-7.29(m,5H),5.31-5.09(m,2H),3.41(d,J=10.9Hz,1H),3.32-3.19(m,1H),2.89-2.71(m, 2H), 2.59(d, J=13.4Hz, 1H), 2.46-2.31(m, 1H), 1.97-1.81(m, 4H), 1.39-1.27(m, 2H).
第六步：在0℃下向苄基(1R,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-吡咯嗪]-7a'(5'H)-羧酸酯(350mg，1.14mmol)的四氢呋喃(4mL)溶液中加入四氢铝锂(259mg，6.83mmol)。悬浮液在60℃下搅拌2小时。悬浮液依次用水(260uL)、15％氢氧化钠(260uL)溶液和水(780uL)淬灭。然后将无水硫酸钠加入悬浮液中，搅拌后过滤并浓缩滤液得到黄色油状化合物((1R,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-吡咯嗪]-7a'(5'H)-基)甲醇A16-1A(纯度60％，300mg，0.89mmol，收率78％)。LCMS(ESI):[M+H]+＝204.1。Step 6: To a solution of benzyl (1R,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolazine]-7a'(5'H)-carboxylate (350 mg, 1.14 mmol) in tetrahydrofuran (4 mL) was added lithium aluminum tetrahydride (259 mg, 6.83 mmol) at 0°C. The suspension was stirred at 60°C for 2 hours. The suspension was quenched sequentially with water (260 uL), 15% sodium hydroxide solution (260 uL) and water (780 uL). Then anhydrous sodium sulfate was added to the suspension, stirred and filtered and the filtrate was concentrated to obtain a yellow oily compound ((1R,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolazin]-7a'(5'H)-yl)methanol A16-1A (purity 60%, 300mg, 0.89mmol, yield 78%). LCMS (ESI): [M+H] + = 204.1.
中间体A16-1B,A16-2A,A16-2B参考中间体A16-1A的合成路线，将中间分离得到的异构体按类似条件制备得到。Intermediates A16-1B, A16-2A, and A16-2B were prepared by referring to the synthetic route of intermediate A16-1A, and the isomers separated in the middle were prepared under similar conditions.
中间体A17:4,7-二氯-8-氟-2-(甲硫基)吡啶并[4,3-d]嘧啶
Intermediate A17: 4,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidine
第一步：向4-((叔丁氧基羰基)氨基)-6-氯-5-氟烟酸(10.0g,34.40mmol)的二氯甲烷(50mL)溶液中，在0℃下加入氯化氢(4M的二氧六环溶液，172mL，688mmol)，在20℃下搅拌16小时。混合物旋干，得到粗品化合物4-氨基-6-氯-5-氟烟酸(9.00g)，为白色固体。LCMS(ESI):[M+H]+＝191.0.Step 1: To a solution of 4-((tert-butoxycarbonyl)amino)-6-chloro-5-fluoronicotinic acid (10.0g, 34.40mmol) in dichloromethane (50mL), hydrogen chloride (4M solution in dioxane, 172mL, 688mmol) was added at 0°C, and stirred at 20°C for 16 hours. The mixture was spin-dried to afford the crude compound 4-amino-6-chloro-5-fluoronicotinic acid (9.00 g) as a white solid. LCMS (ESI): [M+H] + = 191.0.
第二步：将4-氨基-6-氯-5-氟烟酸(9.00g，34.40mmol)溶于三氯氧磷(50mL)，将混合物氮气 保护下在90℃下搅拌2小时。旋干。得到粗品化合物4-氨基-6-氯-5-氟烟酰氯(10.0g)，其为棕色固体。检测时用甲醇淬灭得甲酯的LCMS(ESI):[M+H]+＝205.1.The second step: 4-amino-6-chloro-5-fluoronicotinic acid (9.00g, 34.40mmol) was dissolved in phosphorus oxychloride (50mL), and the mixture was nitrogen Stir at 90°C for 2 hours under protection. Spin dry. The crude compound 4-amino-6-chloro-5-fluoronicotinoyl chloride (10.0 g) was obtained as a brown solid. LCMS (ESI) of the methyl ester obtained by quenching with methanol during detection: [M+H] + =205.1.
第三步：向4-氨基-6-氯-5-氟烟酰氯(10.0g，34.40mmol)的四氢呋喃(100mL)溶液中，加入硫氰酸铵(11.8g，155.02mmol)，然后将混合物氮气保护下在20℃下搅拌12小时。加入水(100mL)，使用乙酸乙酯(100mL*3)萃取，有机相用饱和食盐水(100mL)洗涤，无水硫酸钠干燥，过滤，旋干。残留物用石油醚/乙酸乙酯(体积比为1/3，20mL)打浆，得到白色固体化合物7-氯-8-氟-2-硫代-2,3-二氢吡啶并[4,3-d]嘧啶-4(1H)-酮(5.60g，24.18mmol，收率70％)。LCMS(ESI):[M+H]+＝232.0.Step 3: Ammonium thiocyanate (11.8 g, 155.02 mmol) was added to a solution of 4-amino-6-chloro-5-fluoronicotinoyl chloride (10.0 g, 34.40 mmol) in tetrahydrofuran (100 mL), and the mixture was stirred at 20° C. for 12 hours under nitrogen protection. Water (100 mL) was added, extracted with ethyl acetate (100 mL*3), the organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and spin-dried. The residue was slurried with petroleum ether/ethyl acetate (volume ratio 1/3, 20 mL) to obtain white solid compound 7-chloro-8-fluoro-2-thio-2,3-dihydropyrido[4,3-d]pyrimidin-4(1H)-one (5.60 g, 24.18 mmol, yield 70%). LCMS (ESI): [M+H] + = 232.0.
第四步：向7-氯-8-氟-2-硫代-2,3-二氢吡啶并[4,3-d]嘧啶-4(1H)-酮(5.60g，24.18mmol)的N,N-二甲基甲酰胺(56mL)溶液中，加入甲醇钠(1.44g，26.59mmol)和碘甲烷(3.26g，22.97mmol)。将混合物氮气保护下在20℃下搅拌2小时。反应液倒入水(180mL)中，过滤出固体，真空干燥，得到白色固体化合物7-氯-8-氟-2-(甲硫基)吡啶并[4,3-d]嘧啶-4(3H)-酮(5.10g，20.76mmol，收率86％)。LCMS(ESI):[M+H]+＝246.0.Step 4: To a solution of 7-chloro-8-fluoro-2-thioxo-2,3-dihydropyrido[4,3-d]pyrimidin-4(1H)-one (5.60 g, 24.18 mmol) in N,N-dimethylformamide (56 mL), sodium methoxide (1.44 g, 26.59 mmol) and methyl iodide (3.26 g, 22.97 mmol) were added. The mixture was stirred at 20° C. for 2 hours under nitrogen protection. The reaction solution was poured into water (180 mL), the solid was filtered out, and dried in vacuo to obtain a white solid compound 7-chloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4(3H)-one (5.10 g, 20.76 mmol, yield 86%). LCMS (ESI): [M+H] + = 246.0.
第五步：将7-氯-8-氟-2-(甲硫基)吡啶并[4,3-d]嘧啶-4(3H)-酮(1.10g,4.48mmol)溶于三氯氧磷(10.0mL)，加入二异丙基乙胺(2.23mL，13.43mmol)。将混合物氮气保护下在95℃下搅拌16小时。混合物旋干，加入乙酸乙酯(30mL)然后加入冰水(30mL)并分液，水相用乙酸乙酯(30mL*3)萃取，合并所有有机相，用无水硫酸钠干燥，过滤，旋干。残留物用快速柱色谱纯化(硅胶，0-10％梯度的乙酸乙酯/石油醚)，得到白色固体化合物4,7-二氯-8-氟-2-(甲硫基)吡啶并[4,3-d]嘧啶(1.10g，4.17mmol，收率93％)。LCMS(ESI):[M+H]+＝264.0.Step 5: Dissolve 7-chloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4(3H)-one (1.10 g, 4.48 mmol) in phosphorus oxychloride (10.0 mL), and add diisopropylethylamine (2.23 mL, 13.43 mmol). The mixture was stirred at 95 °C for 16 hours under nitrogen protection. The mixture was spin-dried, ethyl acetate (30 mL) was added and ice water (30 mL) was added and the layers were separated, the aqueous phase was extracted with ethyl acetate (30 mL*3), all organic phases were combined, dried over anhydrous sodium sulfate, filtered, and spin-dried. The residue was purified by flash column chromatography (silica gel, 0-10% gradient ethyl acetate/petroleum ether) to give 4,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidine (1.10 g, 4.17 mmol, yield 93%) as a white solid. LCMS (ESI): [M+H] + = 264.0.
实施例1：4-(4-((1R,5S,8S)-8-氨基-3-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-乙基-6-氟萘-2-醇甲酸盐
 Example 1: 4-(4-((1R,5S,8S)-8-amino-3-azabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol formate
第一步：在-40℃下向2,4,7-三氯-8-氟吡啶并[4,3-d]嘧啶(500mg，1.68mmol)和二异丙基乙胺(350uL，2.02mmol)的二氯甲烷(5mL)溶液中加入((1R,5S,8S)-3-氮杂双环[3.2.1]辛基-8-基)氨基甲酸叔丁酯(381mg，1.68mmol)。将溶液在-40℃下搅拌1小时。加入水(8mL)并用乙酸乙酯(5mL*2)萃取，有机相合并，用硫酸镁干燥，过滤，滤液减压浓缩得到黄色固体化合物叔丁基((1R,5S,8S)-3-(2,7-二氯-8-氟吡啶并[4,3-d]嘧啶-4-基)-3-氮杂双环[3.2.1]辛-8-基)氨基甲酸酯(800mg，2.30mmol，收率86％)。LCMS(ESI):[M+H]+＝442.1Step 1: To a solution of 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (500mg, 1.68mmol) and diisopropylethylamine (350uL, 2.02mmol) in dichloromethane (5mL) at -40°C was added tert-butyl ((1R,5S,8S)-3-azabicyclo[3.2.1]octyl-8-yl)carbamate (381 mg, 1.68 mmol). The solution was stirred at -40°C for 1 hour. Water (8mL) was added and extracted with ethyl acetate (5mL*2), the organic phases were combined, dried over magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a yellow solid compound tert-butyl ((1R,5S,8S)-3-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]oct-8-yl)carbamate (800mg, 2.30mmol, rate of 86%). LCMS (ESI): [M+H] + = 442.1
第二步：在25℃下向叔丁基((1R,5S,8S)-3-(2,7-二氯-8-氟吡啶并[4,3-d]嘧啶-4-基)-3-氮杂双环[3.2.1]辛-8-基)氨基甲酸酯(800mg，2.30mmol)的二氧六环(9mL)溶液中加入(四氢-1H-吡咯嗪-7a(5H)-基)甲醇(459mg，3.26mmol)和二异丙基乙胺(850mL，4.88mmol)。将溶液在80℃搅拌16小时。反应液减压浓缩，残余物用快速柱色谱纯化(硅胶，0-10％梯度的甲醇/二氯甲烷)，得到黄色固体化合物叔丁基((1R,5S,8S)-3-(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)-3-氮杂双环[3.2.1]辛基-8-基)氨基甲酸酯(440mg，0.80mmol，收率35％)。LCMS(ESI):[M+H]+＝547.3.Second step: To a solution of tert-butyl ((1R,5S,8S)-3-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]oct-8-yl)carbamate (800 mg, 2.30 mmol) in dioxane (9 mL) was added (tetrahydro-1H-pyrrolazin-7a(5H)-yl) at 25°C Methanol (459 mg, 3.26 mmol) and diisopropylethylamine (850 mL, 4.88 mmol). The solution was stirred at 80°C for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by flash column chromatography (silica gel, 0-10% gradient methanol/dichloromethane) to obtain a yellow solid compound tert-butyl ((1R,5S,8S)-3-(7-chloro-8-fluoro-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrim Pyridin-4-yl)-3-azabicyclo[3.2.1]octyl-8-yl)carbamate (440 mg, 0.80 mmol, yield 35%). LCMS (ESI): [M+H] + = 547.3.
第三步：在氮气氛围中，向叔丁基((1R,5S,8S)-3-(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)-3-氮杂双环[3.2.1]辛基-8-基)氨基甲酸酯(304mg，0.56mmol)，2-(8-乙基-7-氟-3-(甲氧基甲氧基)萘-1-基)-4,4,5,5-四甲基-1,3,2-二氧硼烷(200mg,0.56mmol)，磷酸钾(1.5M的水溶液，1120uL，1.68mmol)的二氧六环(4mL)溶液中加入甲磺酸[正丁基二(1-金刚烷基)膦](2-氨基-1,1-联苯-2-基)钯(II)(41mg,60umol)，并将混合物在100℃下搅拌3小时。将悬浮液浓缩并通过快速柱色谱纯化(硅胶，0-10％梯度的甲醇/二氯甲烷)得到棕色固体化合物叔丁基((1R,5S,8S)-3-(7-(8-乙基-7-氟-3-(甲氧基甲氧基)萘-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-4-基)-3-氮杂双环[3.2.1]辛-8-基)氨基甲酸叔丁酯(85％纯度，120mg，0.14mmol，收率25％)。LCMS(ESI):[M+H]+＝745.6.The third step: in a nitrogen atmosphere, to tert-butyl ((1R,5S,8S)-3-(7-chloro-8-fluoro-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octyl-8-yl)carbamate (304mg, 0.56mmol), 2-(8- Ethyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (200mg, 0.56mmol), potassium phosphate (1.5M in water, 1120uL, 1.68mmol) in dioxane (4mL) was added [n-butylbis(1-adamantyl)phosphine](2-amino-1,1-biphenyl-2- base) palladium(II) (41mg, 60umol), and the mixture was stirred at 100°C for 3 hours. The suspension was concentrated and purified by flash column chromatography (silica gel, 0-10% gradient of methanol/dichloromethane) to give the brown solid compound tert-butyl((1R,5S,8S)-3-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yl)-8-fluoro-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4- yl)-tert-butyl 3-azabicyclo[3.2.1]oct-8-yl)carbamate (85% purity, 120 mg, 0.14 mmol, yield 25%). LCMS (ESI): [M+H] + = 745.6.
第四步：将叔丁基((1R,5S,8S)-3-(7-(8-乙基-7-氟-3-(甲氧基甲氧基)萘-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-4-基)-3-氮杂双环[3.2.1]辛-8-基)氨基甲酸叔丁酯(110mg，0.15mmol)的二氯甲烷/三氟乙酸(v/v＝4/1，1000uL)溶液在25℃下搅拌1小时。反应液用饱和碳酸氢钠溶液调节pH至7。混合物真空浓缩，残留物通过制备型HPLC通过含有甲酸体系的流动相纯化得到白色固体化合物4-(4-((1R,5S,8S)-8-氨基-3-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-乙基-6-氟萘-2-醇(甲酸盐，2.06mg，3.4umol，收率2％)。LCMS(ESI):[M+H]+＝601.0；1H NMR(400MHz,CD3OD)δppm 9.08(s,1H),8.55(br s,1H),7.68(dd,J＝5.8,9.1Hz,1H),7.34-7.21(m,2H),7.06(d,J＝2.5Hz,1H),4.78(m,J＝10.6Hz,2H),4.48(s,2H),3.69(br dd,J＝7.3,12.6Hz,2H),3.41(s,3H),3.08-2.96(m,2H),2.48(br dd,J＝7.3,13.1Hz,1H),2.34(br s,2H),2.28-1.89(m,11H),1.60(br d,J＝9.0Hz,2H),0.80(t,J＝7.4Hz,3H)The fourth step: tert-butyl ((1R,5S,8S)-3-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yl)-8-fluoro-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]oct-8-yl)carbamate A solution of the ester (110 mg, 0.15 mmol) in dichloromethane/trifluoroacetic acid (v/v = 4/1, 1000 uL) was stirred at 25°C for 1 hour. The pH of the reaction solution was adjusted to 7 with saturated sodium bicarbonate solution. The mixture was concentrated in vacuo, and the residue was purified by preparative HPLC with a mobile phase containing a formic acid system to obtain a white solid compound 4-(4-((1R,5S,8S)-8-amino-3-azabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoro Naphthalene-2-ol (formate salt, 2.06mg, 3.4umol, yield 2%). LCMS(ESI):[M+H] + ＝601.0； 1 H NMR(400MHz,CD 3 OD)δppm 9.08(s,1H),8.55(br s,1H),7.68(dd,J＝5.8,9.1Hz,1H),7.34-7.21(m,2H),7.06(d,J＝2.5Hz,1H),4.78(m,J＝10.6Hz,2H),4.48(s,2H),3.69(br dd,J＝7.3,12.6Hz,2H),3.41(s,3H),3.08-2.96(m,2H),2.48(br dd,J＝7.3,13.1Hz,1H),2.34(br s,2H),2.28-1.89(m,11H),1.60(br d,J＝9.0Hz,2H),0.80(t,J＝7.4Hz,3H)
以下实施例通过实施例1的合成路线方法进行制备：The following examples are prepared by the synthetic route method of Example 1:
实施例2：4-(4-((8-氮杂双环[3.2.1]辛-3-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)-5-乙基-6-氟萘-2-醇
 Example 2: 4-(4-((8-azabicyclo[3.2.1]oct-3-yl)amino)-8-fluoro-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol
LCMS(ESI):[M+H]+＝601.5；1H NMR(400MHz,CD3OD)δppm 9.28(s,1H),7.69(dd,J＝5.9,9.2Hz,1H),7.36-7.21(m,2H),7.05(d,J＝2.5Hz,1H),4.53(br s,1H),4.05(br s,2H),3.51(br s,2H),3.20-3.08(m,2H),2.56-1.92(m,20H),0.79(t,J＝7.3Hz,3H)。LCMS (ESI): [M+H] + = 601.5; 1 H NMR (400MHz, CD 3 OD) δppm 9.28 (s, 1H), 7.69 (dd, J = 5.9, 9.2Hz, 1H), 7.36-7.21 (m, 2H), 7.05 (d, J = 2.5Hz, 1H), 4.53 (br s, 1H) , 4.05 (br s, 2H), 3.51 (br s, 2H), 3.20-3.08 (m, 2H), 2.56-1.92 (m, 20H), 0.79 (t, J=7.3Hz, 3H).
实施例3：4-(4-(2,5-二氮杂双环[4.1.0]庚-2-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-乙基-6-氟萘-2-醇
Example 3: 4-(4-(2,5-diazabicyclo[4.1.0]hept-2-yl)-8-fluoro-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol
LCMS(ESI):[M+H]+＝573.3.1H NMR(400MHz,CD3OD)δppm 9.78-9.71(m,1H),7.63-7.55(m,1H),7.22(br d,J＝2.5Hz,1H),7.19-7.18(m,1H),6.97(br s,1H),4.41(br s,2H),3.31(m,1H),3.13-2.96(m,5H),2.42-2.34(m,1H),2.25-1.91(m,12H),1.53-1.47(m,1H),0.97-0.88(m,1H),0.80(br t,J＝6.8Hz,1H),0.74-0.67(m,3H).LCMS(ESI):[M+H]+=573.3.1H NMR (400MHz, CD3( m,5H),2.42-2.34(m,1H),2.25-1.91(m,12H),1.53-1.47(m,1H),0.97-0.88(m,1H),0.80(br t,J＝6.8Hz,1H),0.74-0.67(m,3H).
实施例4：5-乙基-6-氟-4-(8-氟-4-(八氢喹喔啉-1(2H)-基)-2-((四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶[4,3-d]嘧啶-7-基)萘-2-醇甲酸盐
Example 4: 5-Ethyl-6-fluoro-4-(8-fluoro-4-(octahydroquinoxalin-1(2H)-yl)-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyridin[4,3-d]pyrimidin-7-yl)naphthalene-2-ol formate
LCMS(ESI):[M+H]+＝615.3 1H NMR(400MHz,CD3OD)δppm 9.16-8.98(m,1H),8.53-8.36(m,2H),7.76-7.18(m,2H),7.10-7.00(m,1H),4.72-4.42(m,5H),4.23-4.06(m,1H),3.97-3.61(m,2H),3.28-3.22(m,2H),2.59-1.99(m,13H),1.86(br s,3H),1.51(br s,4H),0.87-0.66(m,3H).LCMS(ESI):[M+H]+=615.31H NMR (400MHz, CD3OD)δppm 9.16-8.98(m,1H),8.53-8.36(m,2H),7.76-7.18(m,2H),7.10-7.00(m,1H),4.72-4.42(m,5H),4.23-4.06(m,1H),3.97-3.61(m,2H),3.2 8-3.22(m,2H),2.59-1.99(m,13H),1.86(br s,3H),1.51(br s,4H),0.87-0.66(m,3H).
实施例5：5-乙基-6-氟-4-(8-氟-4-(5,8-二氮杂螺[3.5]壬-8-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
Example 5: 5-Ethyl-6-fluoro-4-(8-fluoro-4-(5,8-diazaspiro[3.5]non-8-yl)-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalene-2-ol
LCMS(ESI):[M+H]+＝601.3；1H NMR(400MHz,CD3OD)δppm 9.19(s,1H),7.73-7.66(m,1H),7.36-7.21(m,2H),7.09(s,1H),4.69-4.68(m,2H),4.28-4.04(m,4H),3.76-3.65(m,3H),3.10-3.04(m,2H),2.52-2.44(m,1H),2.37-2.29(m,2H),2.26-2.05(m,12H),1.97-1.86(m,2H),0.84-0.74(m,3H)LCMS(ESI):[M+H]+= 601.3;1H NMR (400MHz, CD3OD)δppm 9.19(s,1H),7.73-7.66(m,1H),7.36-7.21(m,2H),7.09(s,1H),4.69-4.68(m,2H),4.28-4.04(m,4H),3.76-3.65(m,3H),3.10-3.04(m,2 H),2.52-2.44(m,1H),2.37-2.29(m,2H),2.26-2.05(m,12H),1.97-1.86(m,2H),0.84-0.74(m,3H)
实施例6：4-(4-(3,9-二氮杂双环[3.3.1]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)-5-乙基-6-氟萘-2-醇甲酸盐
Example 6: 4-(4-(3,9-diazabicyclo[3.3.1]nonan-3-yl)-8-fluoro-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol formate
LCMS(ESI):[M+H]+＝601.3；1H NMR(400MHz,CD3OD)δppm 9.25-9.19(m,1H),8.58-8.46(m,1H),7.75-7.68(m,1H),7.36-7.33(m,1H),7.29(t,J＝9.4Hz,1H),7.10-7.06(m,1H),4.99(br s,2H),4.72-4.70(m,2H),4.10-3.92(m,3H),3.78-3.66(m,3H),3.61(br s,2H),2.54-2.45(m,1H),2.40-2.32(m,2H),2.29-2.04(m,11H),2.00-1.92(m,1H),1.71-1.61(m,1H),0.81(t,J＝7.4Hz,3H)LCMS(ESI):[M+H]+= 601.3;1H NMR (400MHz, CD3OD)δppm 9.25-9.19(m,1H),8.58-8.46(m,1H),7.75-7.68(m,1H),7.36-7.33(m,1H),7.29(t,J＝9.4Hz,1H),7.10-7.06(m,1H),4.99(br s,2H),4.72 -4.70(m,2H),4.10-3.92(m,3H),3.78-3.66(m,3H),3.61(br s,2H),2.54-2.45(m,1H),2.40-2.32(m,2H),2.29-2.04(m,11H),2.00-1.92(m,1H),1 .71-1.61(m,1H),0.81(t,J＝7.4Hz,3H)
实施例7：(S)-5-乙基-6-氟-4-(8-氟-4-(2-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 二甲酸盐
Example 7: (S)-5-Ethyl-6-fluoro-4-(8-fluoro-4-(2-methylpiperazin-1-yl)-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalene-2-ol dicarboxylate
LCMS(ESI):[M+H]+＝575.3；1H NMR(400MHz,CD3OD)δppm 9.12(s,1H),8.46(br s,2H),7.71(dd,J＝5.9,9.0Hz,1H),7.34(d,J＝2.4Hz,1H),7.28(t,J＝9.4Hz,1H),7.12-7.01(m,1H),5.13(br s,1H),4.69(s,2H),4.67-4.58(m,2H),3.90(br s,1H),3.80-3.64(m,2H),3.38(br s,2H),3.31-3.21(m,3H),2.49(br d,J＝6.5Hz,1H),2.42-2.31(m,2H),2.28-2.09(m,7H),1.67(d,J＝7.0Hz,3H),0.90-0.75(m,3H).LCMS(ESI):[M+H]+= 575.3;1H NMR (400MHz, CD3OD)δppm 9.12(s,1H),8.46(br s,2H),7.71(dd,J=5.9,9.0Hz,1H),7.34(d,J=2.4Hz,1H),7.28(t,J=9.4Hz,1H),7.12-7.01(m,1H),5.13(br s,1H),4.69 (s,2H),4.67-4.58(m,2H),3.90(br s,1H),3.80-3.64(m,2H),3.38(br s,2H),3.31-3.21(m,3H),2.49(br d,J＝6.5Hz,1H),2.42-2.31(m,2H),2.28-2 .09(m,7H),1.67(d,J=7.0Hz,3H),0.90-0.75(m,3H).
实施例8：5-乙基-6-氟-4-(8-氟-4-((1R,5S)-8-甲基-3,8-二氮杂双环[3.2.1]基-3-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-醇甲酸盐
Example 8: 5-Ethyl-6-fluoro-4-(8-fluoro-4-((1R,5S)-8-methyl-3,8-diazabicyclo[3.2.1]yl-3-yl)-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalene-2-ol formate
LCMS(ESI):[M+H]+＝601.3；1H NMR(400MHz,CD3OD)δ＝9.14(s,1H),8.44(br s,1H),7.69(dd,J＝6.0,9.0Hz,1H),7.35-7.21(m,2H),7.05(d,J＝2.5Hz,1H),4.68-4.64(m,4H),3.85(br t,J＝14.3Hz,2H),3.70(br d,J＝7.5Hz,2H),3.54(br s,2H),3.29-3.24(m,1H),3.29-3.24(m,1H),2.54-2.42(m,4H),2.34(br dd,J＝6.8,10.8Hz,2H),2.26-2.08(m,9H),1.77(br d,J＝8.0Hz,2H),0.79(t,J＝7.4Hz,3H).LCMS(ESI):[M+H]+= 601.3;1H NMR (400MHz, CD3OD)δ=9.14(s,1H),8.44(br s,1H),7.69(dd,J=6.0,9.0Hz,1H),7.35-7.21(m,2H),7.05(d,J=2.5Hz,1H),4.68-4.64(m,4H),3.85(br t,J=14.3Hz,2H), 1 .77(br d,J=8.0Hz,2H),0.79(t,J=7.4Hz,3H).
实施例9：5-乙基-6-氟-4-(8-氟-4-(2,7-二氮杂螺[3.5]壬-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
Example 9: 5-Ethyl-6-fluoro-4-(8-fluoro-4-(2,7-diazaspiro[3.5]non-7-yl)-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalene-2-ol
LCMS(ESI):[M+H]+＝601.4.1H NMR(400MHz,CD3OD)δppm 9.10(s,1H),7.69(dd,J＝9.17,5.75Hz,1H),7.39-7.18(m,2H),7.05(d,J＝2.45Hz,1H),4.68(s,2H),4.09-4.02(m,6H),3.70(br d,J＝3.79Hz,2H),3.48(br s,2H),2.57-2.28(m,4H),2.26-2.07(m,12H),1.33-1.23(m,3H).LCMS(ESI):[M+H]+=601.4.1H NMR (400MHz, CD3OD)δppm 9.10(s,1H),7.69(dd,J=9.17,5.75Hz,1H),7.39-7.18(m,2H),7.05(d,J=2.45Hz,1H),4.68(s,2H),4.09-4.02(m,6H),3.70(br d,J=3.79Hz,2 H),3.48(br s,2H),2.57-2.28(m,4H),2.26-2.07(m,12H),1.33-1.23(m,3H).
实施例10:5-乙炔基-6-氟-4-(8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-4-(4-(吡咯烷)-1-基)哌啶-1-基)吡啶并[4,3-d]嘧啶-7-基)萘-2-醇甲酸盐
Example 10: 5-ethynyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(4-(pyrrolidin)-1-yl)piperidin-1-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalene-2-ol formate
第一步:化合物8-氟-7-(7-氟-3-(甲氧基甲氧基)-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)-4-(2,2,2-三氟乙氧基)吡啶并[4,3-d]嘧啶(150mg，0.19mmol)和二异丙基乙胺(113uL，0.65mmol)加入到二甲基亚砜(1.2mL)中，加入4-(吡咯烷-1-基)哌啶(30mg，0.19mmol)，90℃搅拌3小时。反应液加入水(3mL)，用乙酸乙酯(3mL*3)萃取，有机相减压浓缩得粗品8-氟-7-(7-氟-3-(甲氧基甲氧基)-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)-4-(4-(吡咯烷-1-基)哌啶-1-基)吡啶并[4,3-d]嘧啶(130mg)。LCMS(ESI):[M+H]+＝843.5.The first step: compound 8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalene-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (150mg, 0.19 mmol) and diisopropylethylamine (113uL, 0.65mmol) were added to dimethylsulfoxide (1.2mL), 4-(pyrrolidin-1-yl)piperidine (30mg, 0.19mmol) was added, and stirred at 90°C for 3 hours. The reaction solution was added with water (3 mL), extracted with ethyl acetate (3 mL*3), and the organic phase was concentrated under reduced pressure to obtain the crude product 8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalene-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4-(4-(pyrrolidine- 1-yl)piperidin-1-yl)pyrido[4,3-d]pyrimidine (130 mg). LCMS (ESI): [M+H] + = 843.5.
第二步：化合物8-氟-7-(7-氟-3-(甲氧基甲氧基)-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)-4-(4-(吡咯烷-1-基)哌啶-1-基)吡啶并[4,3-d]嘧啶(130mg，0.15mmol)加入到N,N-二甲基甲酰胺(2mL)中，加入氟化铯(234mg，1.54mmol)，20℃搅拌1小时。反应液加入水(1500uL)稀释，用乙酸乙酯(3mL*3)萃取，有机相减压浓缩得粗品化合物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-吡咯嗪-7a(5H)-基)甲氧基)-4-(4-(吡咯烷-1-基)哌啶-1-基)吡啶并[4,3-d]嘧啶(100mg)。LCMS(ESI):[M+H]+＝687.4.The second step: compound 8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalene-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4-(4-(pyrrolidin-1-yl)piperidin-1-yl)pyrido[4,3-d]pyrimidine (13 0 mg, 0.15 mmol) was added to N,N-dimethylformamide (2 mL), cesium fluoride (234 mg, 1.54 mmol) was added, and stirred at 20°C for 1 hour. The reaction solution was diluted with water (1500uL), extracted with ethyl acetate (3mL*3), and the organic phase was concentrated under reduced pressure to obtain the crude compound 7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4-(4-(pyrrolidin-1-yl)piper Pyridin-1-yl)pyrido[4,3-d]pyrimidine (100mg). LCMS (ESI): [M+H] + = 687.4.
第三步：化合物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-吡咯嗪-7a(5H)-基)甲氧基)-4-(4-(吡咯烷-1-基)哌啶-1-基)吡啶并[4,3-d]嘧啶(100mg，0.13mmol)加入到三氟乙酸/二氯甲烷(体积比为4:1，2.5mL)中，20℃搅拌2小时。反应液减压浓缩，残留物加入乙腈(500uL)，加入三乙胺调节pH到8，残留物用制备型HPLC纯化，得到黄色固体化合物5-乙炔基-6-氟-4-(8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-4-(4-(吡咯烷)-1-基)哌啶-1-基)吡啶并[4,3-d]嘧啶-7-基)萘-2-醇(甲酸盐，21.1mg，32umol，收率25％)。LCMS(ESI):[M+H]+＝643.0；1H  NMR(400MHz,CD3OD)δppm 9.04(s,1H),8.54(br s,1H),7.89(dd,J＝5.6,9.2Hz,1H),7.44-7.31(m,2H),7.25(s,1H),5.50-5.30(m,1H),4.78(br d,J＝13.1Hz,2H),4.48-4.34(m,2H),3.55-3.37(m,6H),3.26-3.11(m,6H),2.49-2.20(m,5H),2.14-1.87(m,9H).The third step: compound 7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4-(4-(pyrrolidin-1-yl)piperidin-1-yl)pyrido[4,3-d]pyrimidine (100mg, 0.13mmol) was added into trifluoroacetic acid/dichloromethane (volume ratio 4:1, 2.5 mL), and stirred at 20°C for 2 hours. The reaction solution was concentrated under reduced pressure, the residue was added to acetonitrile (500 uL), and triethylamine was added to adjust the pH to 8. The residue was purified by preparative HPLC to obtain a yellow solid compound 5-ethynyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4-(4-(pyrrolidinyl)-1-yl)piperidin-1-yl)pyrido [4,3-d]pyrimidin-7-yl)naphthalene-2-ol (formate salt, 21.1 mg, 32 umol, yield 25%). LCMS (ESI): [M+H] + = 643.0; 1 H NMR(400MHz,CD 3 OD)δppm 9.04(s,1H),8.54(br s,1H),7.89(dd,J＝5.6,9.2Hz,1H),7.44-7.31(m,2H),7.25(s,1H),5.50-5.30(m,1H),4.78(br d,J＝13.1Hz,2H),4.48-4.34(m,2H),3.55-3.37(m,6H),3.26-3.11(m,6H),2.49-2.20(m,5H),2.14-1.87(m,9H).
以下实施例通过实施例10的合成路线方法进行制备：The following examples are prepared by the synthetic route method of Example 10:
实施例11:5-乙炔基-6-氟-4-(8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-4-(4-吗啉哌啶-1-基)吡啶并[4,3-d]嘧啶-7-基)萘-2-醇甲酸盐
Example 11: 5-ethynyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4-(4-morpholinopiperidin-1-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalene-2-ol formate
LCMS(ESI):[M+H]+＝659.3；1H NMR(400MHz,CD3OD)δppm 9.06(s,1H),8.45(br s,1H),7.89(dd,J＝5.7,9.1Hz,1H),7.45-7.31(m,2H),7.26(s,1H),5.65-5.41(m,1H),4.78(br d,J＝13.0Hz,2H),4.63(br s,2H),3.96-3.71(m,7H),3.55-3.35(m,4H),2.90-2.68(m,5H),2.66-2.10(m,8H),1.80(br s,2H).LCMS(ESI):[M+H]+= 659.3;1H NMR (400MHz, CD3OD)δppm 9.06(s,1H),8.45(br s,1H),7.89(dd,J=5.7,9.1Hz,1H),7.45-7.31(m,2H),7.26(s,1H),5.65-5.41(m,1H),4.78(br d,J=13.0Hz,2H),4.63( br s,2H),3.96-3.71(m,7H),3.55-3.35(m,4H),2.90-2.68(m,5H),2.66-2.10(m,8H),1.80(br s,2H).
实施例12：4-(4-([1,4'-双哌啶]-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-乙炔基-6-氟萘-2-醇
Example 12: 4-(4-([1,4'-bispiperidin]-1'-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol
LCMS(ESI):[M+H]+＝657.3；1H NMR(400MHz,CD3OD)δppm 9.00(s,1H),7.88(dd,J＝5.8,9.1Hz,1H),7.40-7.28(m,2H),7.27-7.18(m,1H),5.41-5.22(m,1H),4.77(br d,J＝13.3Hz,2H),4.35-4.22(m,2H),3.47-3.38(m,3H),3.29-3.18(m,3H),3.06-2.97(m,1H),2.80-2.73(m,1H),2.67(br s,4H),2.28-2.21(m,1H),2.14(br d,J＝10.6Hz,3H),2.05-1.89(m,3H),1.84-1.74(m,2H),1.67(br d,J＝4.5Hz,5H),1.53(br d,J＝3.9Hz,2H).LCMS(ESI):[M+H]+= 657.3;1H NMR (400MHz, CD3OD)δppm 9.00(s,1H),7.88(dd,J=5.8,9.1Hz,1H),7.40-7.28(m,2H),7.27-7.18(m,1H),5.41-5.22(m,1H),4.77(br d,J=13.3Hz,2H),4.35-4.22(m,2 H),3.47-3.38(m,3H),3.29-3.18(m,3H),3.06-2.97(m,1H),2.80-2.73(m,1H),2.67(br s,4H),2.28-2.21(m,1H),2.14(br d,J＝10.6Hz,3H),2.05-1 .89(m,3H),1.84-1.74(m,2H),1.67(br d,J=4.5Hz,5H),1.53(br d,J=3.9Hz,2H).
实施例13：5-乙炔基-6-氟-4-(8-氟-2-(((2R，7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-4-(六氢吡咯并[3,4-c]吡咯-2(1H)-基)吡啶并[4,3-d]嘧啶-7-基)萘-2-醇甲酸盐
Example 13: 5-Ethynyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4-(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalene-2-ol formate
LCMS(ESI):[M+H]+＝601.3；1H NMR(400MHz,CD3OD)δppm 9.25(s,1H),8.49(br s,1H),7.89(dd,J＝5.8,9.0Hz,1H),7.41-7.29(m,2H),7.24(d,J＝2.0Hz,1H),5.59-5.37(m,1H),4.61-4.50(m,2H),4.38(br s,2H),4.25-4.10(m,2H),3.85-3.57(m,5H),3.47-3.36(m,5H),3.28(br s,1H),2.66-2.41(m,2H),2.37-2.29(m,1H),2.28-2.17(m,2H),2.15-2.05(m,1H).LCMS(ESI):[M+H]+= 601.3;1H NMR (400MHz, CD3OD)δppm 9.25(s,1H),8.49(br s,1H),7.89(dd,J=5.8,9.0Hz,1H),7.41-7.29(m,2H),7.24(d,J=2.0Hz,1H),5.59-5.37(m,1H),4.61-4.50(m,2H),4.3 8(br s,2H),4.25-4.10(m,2H),3.85-3.57(m,5H),3.47-3.36(m,5H),3.28(br s,1H),2.66-2.41(m,2H),2.37-2.29(m,1H),2.28-2.17(m,2H),2.15 -2.05(m,1H).
实施例14：5-乙炔基-6-氟-4-(8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-4-((3aR,6aS))-5-甲基六氢吡咯并[3,4-c]吡咯-2(1H)-基)吡啶并[4,3-d]嘧啶-7-基)萘-2-醇甲酸盐
Example 14: 5-ethynyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4-((3aR,6aS))-5-methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalene-2 -alcohol formate
LCMS(ESI):[M+H]+＝615.2；1H NMR(400MHz,CD3OD)δppm 9.25(s,1H),8.58-8.26(m,1H),7.99-7.78(m,1H),7.42-7.30(m,2H),7.26-7.15(m,1H),5.66-5.35(m,1H),4.66-4.54(m,2H),4.44-4.33(m,2H),4.26-4.14(m,2H),3.91-3.67(m,3H),3.44-3.41(m,1H),3.41-3.34(m,3H),3.18(br s,4H),2.73-2.65(m,3H),2.64-2.47(m,2H),2.41-2.33(m,1H),2.32-2.22(m,2H),2.18-2.02(m,1H).LCMS(ESI):[M+H]+= 615.2;1H NMR (400MHz, CD3OD)δppm 9.25(s,1H),8.58-8.26(m,1H),7.99-7.78(m,1H),7.42-7.30(m,2H),7.26-7.15(m,1H),5.66-5.35(m,1H),4.66-4.54(m,2H),4.44-4.3 3(m,2H),4.26-4.14(m,2H),3.91-3.67(m,3H),3.44-3.41(m,1H),3.41-3.34(m,3H),3.18(br s,4H),2.73-2.65(m,3H),2.64-2.47(m,2H),2.41-2 .33(m,1H),2.32-2.22(m,2H),2.18-2.02(m,1H).
实施例15：11-(7-(8-乙炔基-7-氟-3-羟基萘-1-基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-2,7,11-三氮杂二螺[3.0.45.34]十二烷-6-一甲酸盐
Example 15: 11-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2,7,11-triazadispiro[3.0.4 5 .3 4 ]dodecane -6-monoformate
LCMS(ESI):[M+H]+＝669.9；1H NMR(400MHz,CD3OD)δppm 9.24(br s,1H),8.47(br s,1H),7.87(dd,J＝9.07,5.82Hz,1H),7.38-7.34(m,2H),7.21(d,J＝2.13Hz,1H),5.60-5.32(m,1H),4.67-4.44(m,5H),4.29-4.09(m,4H),3.79(br d,J＝13.13Hz,1H),3.70-3.62(m,2H),3.55-3.48(m,2H),3.40-3.35(m,1H),2.70-1.93(m,10H). LCMS(ESI):[M+H]+= 669.9;1H NMR (400MHz, CD3OD)δppm 9.24(br s,1H),8.47(br s,1H),7.87(dd,J=9.07,5.82Hz,1H),7.38-7.34(m,2H),7.21(d,J=2.13Hz,1H),5.60-5.32(m,1H),4.67-4.44(m,5H ),4.29-4.09(m,4H),3.79(br d,J＝13.13Hz,1H),3.70-3.62(m,2H),3.55-3.48(m,2H),3.40-3.35(m,1H),2.70-1.93(m,10H).
实施例16：4-(4-((1R,2R,4S,5S)-3,3-二氟-7,9-二氮杂三环[3.3.1.02,4]壬-7-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-6-氟萘-2-醇
Example 16: 4-(4-((1R,2R,4S,5S)-3,3-difluoro-7,9-diazatricyclo[3.3.1.0 2,4 ]non-7-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol
第一步：向化合物(1R,5S)-8-(2-苯基丙-2-基)-3,8-二氮杂双环[3.2.1]辛-6-烯-3-羧酸叔丁酯(2.00g，6.08mmol)的二氯甲烷(32mL)溶液中加入三氟乙酸(8mL)，反应在50℃搅拌16小时。反应液减压浓缩，残余物溶于水中(32mL)，乙酸乙酯洗涤(32mL*2)，水相冻干得到粗品化合物(1R,5S)-3,8-二氮杂双环[3.2.1]辛-6-烯(3.7g)，其为黄色油状液体。LCMS(ESI):[M+H]+＝111.2；The first step: To compound (1R,5S)-8-(2-phenylpropan-2-yl)-3,8-diazabicyclo[3.2.1]oct-6-ene-3-carboxylic acid tert-butyl ester (2.00 g, 6.08 mmol) in dichloromethane (32 mL) was added trifluoroacetic acid (8 mL), and the reaction was stirred at 50° C. for 16 hours. The reaction solution was concentrated under reduced pressure, the residue was dissolved in water (32 mL), washed with ethyl acetate (32 mL*2), and the aqueous phase was lyophilized to obtain the crude compound (1R,5S)-3,8-diazabicyclo[3.2.1]oct-6-ene (3.7 g), which was a yellow oily liquid. LCMS (ESI): [M+H] + =111.2;
第二步：向化合物(1R,5S)-3,8-二氮杂双环[3.2.1]辛-6-烯(1.20g，3.55mmol)和二异丙基乙胺(5.8mL，35.5mmol)的二氯甲烷(12mL)溶液中加入苯甲酰氯(1.65mL，14.2mmol)，反应在25℃搅拌16小时。反应液在0℃下用水(40mL)淬灭，二氯甲烷(20mL*3)萃取，合并的有机相用饱和食盐水(10mL)洗涤，硫酸钠干燥，过滤，减压浓缩，残余物用快速柱色谱纯化(硅胶，0-50％梯 度的四氢呋喃/石油醚)得到白色固体化合物((1R,5S)-3,8-二氮杂双环[3.2.1]辛-6-烯-3,8-二基)双(苯基甲酮)(0.60g，1.18mmol，收率53％)。LCMS(ESI):[M+H]+＝319.0；Second step: Benzoyl chloride (1.65 mL, 14.2 mmol) was added to a solution of compound (1R,5S)-3,8-diazabicyclo[3.2.1]oct-6-ene (1.20 g, 3.55 mmol) and diisopropylethylamine (5.8 mL, 35.5 mmol) in dichloromethane (12 mL), and the reaction was stirred at 25° C. for 16 hours. The reaction solution was quenched with water (40 mL) at 0°C, extracted with dichloromethane (20 mL*3), the combined organic phases were washed with saturated brine (10 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure, and the residue was purified by flash column chromatography (silica gel, 0-50% gradient degrees of tetrahydrofuran/petroleum ether) to obtain a white solid compound ((1R,5S)-3,8-diazabicyclo[3.2.1]oct-6-ene-3,8-diyl)bis(phenyl phenone) (0.60g, 1.18mmol, yield 53%). LCMS (ESI): [M+H] + = 319.0;
第三步：将化合物((1R,5S)-3,8-二氮杂双环[3.2.1]辛-6-烯-3,8-二基)双(苯基甲酮)(400mg，1.25mmol)，四丁基溴化铵(40mg，0.13mmol)溶于甲苯(5mL)，氮气保护下加入(溴二氟甲基)三甲基硅烷(5.10g，25.1mmol)，反应在110℃搅拌16小时。反应液减压浓缩，残余物用快速柱色谱纯化(硅胶，50％梯度的四氢呋喃/石油醚)得到黄色油状化合物((1R,2R,4S,5S)-3,3-二氟-7,9-二氮杂三环[3.3.1.02,4]壬烷-7,9-二基)双(苯基甲酮)(200mg，0.54mmol，收率43％)。LCMS(ESI):[M+H]+＝369.3；The third step: the compound ((1R,5S)-3,8-diazabicyclo[3.2.1]oct-6-ene-3,8-diyl)bis(phenyl ketone) (400mg, 1.25mmol), tetrabutylammonium bromide (40mg, 0.13mmol) was dissolved in toluene (5mL), and (bromodifluoromethyl)trimethylsilane (5.10g, 25.1mmol) was added under nitrogen protection. Stir at 110°C for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by flash column chromatography (silica gel, 50% gradient tetrahydrofuran/petroleum ether) to obtain a yellow oily compound ((1R,2R,4S,5S)-3,3-difluoro-7,9-diazatricyclo[ 3.3.1.02,4 ]nonane-7,9-diyl)bis(phenylphenone) (200mg, 0.54mmol, yield 43%). LCMS (ESI): [M+H] + =369.3;
第四步：将化合物((1R,2R,4S,5S)-3,3-二氟-7,9-二氮杂三环[3.3.1.02,4]壬烷-7,9-二基)双(苯基甲酮)(200mg，0.25mmol)溶于6M的盐酸(2mL)中，反应在100℃搅拌16小时。反应液用EtOAc(2mL*3)洗涤，水相冻干得到粗品化合物(1R,2R,4S,5S)-3,3-二氟-7,9-二氮杂三环[3.3.1.02,4]壬烷(二盐酸盐，120mg)，其为白色固体。1H NMR(400MHz,D2O)δppm 4.53(d,J＝2.0Hz,2H),3.66-3.47(m,4H),2.71(dd,J＝0.9,11.9Hz,2H).Step 4: The compound ((1R,2R,4S,5S)-3,3-difluoro-7,9-diazatricyclo[3.3.1.0 2,4 ]nonane-7,9-diyl)bis(phenyl ketone) (200mg, 0.25mmol) was dissolved in 6M hydrochloric acid (2mL), and the reaction was stirred at 100°C for 16 hours. The reaction solution was washed with EtOAc (2 mL*3), and the aqueous phase was lyophilized to obtain the crude compound (1R,2R,4S,5S)-3,3-difluoro-7,9-diazatricyclo[3.3.1.0 2,4 ]nonane (dihydrochloride, 120 mg) as a white solid. 1 H NMR (400MHz, D 2 O) δppm 4.53(d, J=2.0Hz, 2H), 3.66-3.47(m, 4H), 2.71(dd, J=0.9, 11.9Hz, 2H).
第五步：将化合物8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三异丙基甲硅烷基)乙炔基)萘-1-基)-2-(((2R,7aS)-2-氟四氢-1H-吡咯啉-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-醇(200mg，0.66mmol)，(1R,2R,4S,5S)-3,3-二氟-7,9-二氮杂三环[3.3.1.02,4]壬烷(二盐酸盐，0.43mmol)和二异丙基乙胺(748uL，4.29mmol)溶于二甲基乙酰胺(1.0mL)，0℃下加入苯并三唑-1-氧代-三(二甲氨基磷)六氟磷盐(280mg，0.63mmol)，反应在50℃搅拌2小时。降至在0℃后，反应用饱和碳酸氢钠(10mL)淬灭，乙酸乙酯(10mL*3)萃取，合并的有机相用饱和食盐水(10mL)洗涤，硫酸钠干燥，过滤，减压浓缩得到粗品化合物(1R,2R,4S,5S)-3,3-二氟-7-(8-氟-7-(7-氟-3-(甲氧基甲氧基)-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-基)-7,9-二氮杂三环[3.3.1.02,4]壬烷(200mg)，其为黄色油状液体。LCMS(ESI):[M/2+H]+＝425.0；第五步：将化合物8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三异丙基甲硅烷基)乙炔基)萘-1-基)-2-(((2R,7aS)-2-氟四氢-1H-吡咯啉-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-醇(200mg，0.66mmol)，(1R,2R,4S,5S)-3,3-二氟-7,9-二氮杂三环[3.3.1.0 2,4 ]壬烷(二盐酸盐，0.43mmol)和二异丙基乙胺(748uL，4.29mmol)溶于二甲基乙酰胺(1.0mL)，0℃下加入苯并三唑-1-氧代-三(二甲氨基磷)六氟磷盐(280mg，0.63mmol)，反应在50℃搅拌2小时。降至在0℃后，反应用饱和碳酸氢钠(10mL)淬灭，乙酸乙酯(10mL*3)萃取，合并的有机相用饱和食盐水(10mL)洗涤，硫酸钠干燥，过滤，减压浓缩得到粗品化合物(1R,2R,4S,5S)-3,3-二氟-7-(8-氟-7-(7-氟-3-(甲氧基甲氧基)-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-基)-7,9-二氮杂三环[3.3.1.0 2,4 ]壬烷(200mg)，其为黄色油状液体。 LCMS (ESI): [M/2+H] + =425.0;
第六步：化合物(1R,2R,4S,5S)-3,3-二氟-7-(8-氟-7-(7-氟-3-(甲氧基甲氧基)-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-基)-7,9-二氮杂三环[3.3.1.02,4]壬烷(200mg，0.22mmol)加入到N,N-二甲基甲酰胺(2mL)中，加入氟化铯(343mg，2.20mmol)，20℃搅拌1小时。反应液加入水(2mL)稀释，用乙酸乙酯(3mL*3)萃取，有机相减压浓缩得到粗品化合物(1R,2R,4S,5S)-7-(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-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3,3-二氟-7,9-二氮杂三环[3.3.1.02,4]壬烷(250mg)。LCMS(ESI):[M+H]+＝693.2.第六步：化合物(1R,2R,4S,5S)-3,3-二氟-7-(8-氟-7-(7-氟-3-(甲氧基甲氧基)-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-基)-7,9-二氮杂三环[3.3.1.0 2,4 ]壬烷(200mg，0.22mmol)加入到N,N-二甲基甲酰胺(2mL)中，加入氟化铯(343mg，2.20mmol)，20℃搅拌1小时。 The reaction solution was diluted with water (2 mL), extracted with ethyl acetate (3 mL*3), and the organic phase was concentrated under reduced pressure to obtain the crude compound (1R,2R,4S,5S)-7-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido [4,3-d]pyrimidin-4-yl)-3,3-difluoro-7,9-diazatricyclo[3.3.1.0 2,4 ]nonane (250 mg). LCMS (ESI): [M+H] + = 693.2.
第七步：向化合物(1R,2R,4S,5S)-7-(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-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3,3-二氟-7,9-二氮杂三环[3.3.1.02,4]壬烷(250mg，0.36mmol)的乙腈(0.5mL)溶液中加入氯化氢(4M的二氧六环溶液，340uL)，反应在20℃搅拌1小时。反应液减压浓缩，残留物加入乙腈(500uL)，加入三乙胺调节pH到8，残留物用制备型HPLC纯化，得到黄色固体化合物4-(4-((1R,2R,4S,5S)-3,3-二氟-7,9-二氮杂三环[3.3.1.02,4]壬-7-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-6-氟萘-2-醇(4.71mg，18umol，收率5％)。LCMS(ESI):[M+H]+＝648.8。1H NMR(400MHz,CD3OD)δppm 9.07(s,1H),7.88(dd,J＝5.8,9.3Hz,1H),7.42-7.30(m,2H),7.21(d,J＝2.5Hz,1H),5.45- 5.26(m,1H),4.85-4.68(m,4H),4.41-4.28(m,2H),3.92-3.77(m,4H),3.44(m,2H),3.15-3.04(m,1H),2.45-2.16(m,5H),2.10-1.92(m,3H).第七步：向化合物(1R,2R,4S,5S)-7-(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-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3,3-二氟-7,9-二氮杂三环[3.3.1.0 2,4 ]壬烷(250mg，0.36mmol)的乙腈(0.5mL)溶液中加入氯化氢(4M的二氧六环溶液，340uL)，反应在20℃搅拌1小时。反应液减压浓缩，残留物加入乙腈(500uL)，加入三乙胺调节pH到8，残留物用制备型HPLC纯化，得到黄色固体化合物4-(4-((1R,2R,4S,5S)-3,3-二氟-7,9-二氮杂三环[3.3.1.0 2,4 ]壬-7-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-6-氟萘-2-醇(4.71mg，18umol，收率5％)。 LCMS (ESI): [M+H] + = 648.8. 1 H NMR (400MHz, CD 3 OD) δppm 9.07(s, 1H), 7.88(dd, J=5.8, 9.3Hz, 1H), 7.42-7.30(m, 2H), 7.21(d, J=2.5Hz, 1H), 5.45- 5.26(m,1H),4.85-4.68(m,4H),4.41-4.28(m,2H),3.92-3.77(m,4H),3.44(m,2H),3.15-3.04(m,1H),2.45-2.16(m,5H),2.10-1.92(m,3H).
实施例17：5-乙炔基-6-氟-4-(8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-4-((1R,2R,4S,5S)-3-(三甲基硅基)-7,9-二氮杂三环[3.3.1.02,4]壬-7-基)吡啶并[4,3-d]嘧啶-7-基)萘-2-醇
Example 17: 5-ethynyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4-((1R,2R,4S,5S)-3-(trimethylsilyl)-7,9-diazatricyclo[3.3.1.0 2,4 ]non-7-yl)pyrido[4 ,3-d]pyrimidin-7-yl)naphthalene-2-ol
第一步：向化合物(1R,5S)-8-(2-苯基丙-2-基)-3,8-二氮杂双环[3.2.1]辛-6-烯-3-羧酸叔丁酯(1.00g，3.04mmol)的二氯甲烷(16mL)溶液中加入三氟乙酸(4mL)，反应在50℃搅拌16小时。反应液减压浓缩，残余物溶于水(16mL)中，用乙酸乙酯(16mL*2)洗涤，水相冻干得到粗品化合物(1R,5S)-3,8-二氮杂双环[3.2.1]辛-6-烯(2.80g)，其为黄色油状。LCMS(ESI):[M+H]+＝111.2。1H NMR(500MHz,D2O)δppm 6.37(s,2H),3.48(dd,J＝1.5,14.3Hz,2H),3.38-3.29(m,2H).The first step: To compound (1R,5S)-8-(2-phenylpropan-2-yl)-3,8-diazabicyclo[3.2.1]oct-6-ene-3-carboxylic acid tert-butyl ester (1.00 g, 3.04 mmol) in dichloromethane (16 mL) was added trifluoroacetic acid (4 mL), and the reaction was stirred at 50° C. for 16 hours. The reaction solution was concentrated under reduced pressure, the residue was dissolved in water (16 mL), washed with ethyl acetate (16 mL*2), and the aqueous phase was lyophilized to obtain the crude compound (1R,5S)-3,8-diazabicyclo[3.2.1]oct-6-ene (2.80 g) as a yellow oil. LCMS (ESI): [M+H] + = 111.2. 1 H NMR (500MHz, D 2 O) δppm 6.37(s, 2H), 3.48(dd, J=1.5, 14.3Hz, 2H), 3.38-3.29(m, 2H).
第二步：向化合物(1R,5S)-3,8-二氮杂双环[3.2.1]辛-6-烯(1.20g，1.31mmol)和二异丙基乙胺(5.36mL，38.4mmol)的二氯甲烷(12mL)溶液中加入二碳酸二叔丁酯(5.00mL，23.1mmol)，反应在25℃搅拌16小时。反应液在0℃下用水(40mL)淬灭，二氯甲烷(20mL*3)萃取，合并的有机相用饱和食盐水(10mL)洗涤，硫酸钠干燥，过滤，减压浓缩，残余物用快速柱色谱纯化(硅胶，0-20％梯度的四氢呋喃/石油醚)得到白色固体化合物(1R,5S)-3,8-二氮杂双环[3.2.1]辛-6-烯-3,8-二羧酸二叔丁酯(0.35g，1.12mmol，收率86％)。LCMS(ESI):[M+Na]+＝333.1。1H NMR(400MHz,CDCl3)δppm 6.18(br s,2H),4.56(br s,2H),3.78(br d,J＝12.8Hz,1H),3.64(br d,J＝12.8Hz,1H),3.26-3.02(m,2H),1.50-1.44(m,18H).Second step: Di-tert-butyl dicarbonate (5.00 mL, 23.1 mmol) was added to a solution of compound (1R,5S)-3,8-diazabicyclo[3.2.1]oct-6-ene (1.20 g, 1.31 mmol) and diisopropylethylamine (5.36 mL, 38.4 mmol) in dichloromethane (12 mL), and the reaction was stirred at 25° C. for 16 hours. The reaction solution was quenched with water (40 mL) at 0°C, extracted with dichloromethane (20 mL*3), the combined organic phases were washed with saturated brine (10 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 0-20% gradient THF/petroleum ether) to obtain (1R,5S)-3,8-diazabicyclo[3.2.1]oct-6-ene-3,8-dicarboxylic acid di-tert-butyl as a white solid Ester (0.35 g, 1.12 mmol, 86% yield). LCMS (ESI): [M+Na] + = 333.1. 1 H NMR (400MHz, CDCl 3 ) δppm 6.18(br s,2H),4.56(br s,2H),3.78(br d,J=12.8Hz,1H),3.64(br d,J=12.8Hz,1H),3.26-3.02(m,2H),1.50-1.44(m,18H).
第三步：将化合物(1R,5S)-3,8-二氮杂双环[3.2.1]辛-6-烯-3,8-二羧酸二叔丁酯(200mg，0.61mmol)和(三甲基硅基)重氮甲烷(2M的正己烷溶液，3.00mL，6.10mmol)溶于二氯甲烷(4mL)，氮气保 护下加入醋酸钯(27.0mg，0.12mmol)，反应在20℃搅拌16小时。反应液减压浓缩，残余物用快速柱色谱纯化(硅胶，10％梯度的甲醇/二氯甲烷)得到黄色油状化合物(1R,2R,4S,5S)-3-(三甲基硅基)-7,9-二氮杂三环[3.3.1.02,4]壬烷-7,9-二羧酸二叔丁酯(130mg，0.32mmol，收率53％)。LCMS(ESI):[M+Na]+＝419.0。1H NMR(400MHz,CDCl3)δppm 4.10(br d,J＝19.0Hz,1H),4.01-3.90(m,2H),3.82(br d,J＝12.6Hz,1H),3.20-2.95(m,2H),1.50(m,18H),1.18(br t,J＝5.4Hz,1H),1.11-1.05(m,1H),0.04-0.05(m,9H),-0.50(t,J＝4.8Hz,1H).The third step: the compound (1R,5S)-3,8-diazabicyclo[3.2.1]oct-6-ene-3,8-di-tert-butyl dicarboxylate (200mg, 0.61mmol) and (trimethylsilyl)diazomethane (2M n-hexane solution, 3.00mL, 6.10mmol) were dissolved in dichloromethane (4mL), nitrogen atmosphere Palladium acetate (27.0 mg, 0.12 mmol) was added under protection and the reaction was stirred at 20°C for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by flash column chromatography (silica gel, 10% gradient methanol/dichloromethane) to obtain (1R,2R,4S,5S)-3-(trimethylsilyl)-7,9-diazatricyclo[ 3.3.1.02,4 ]nonane-7,9-dicarboxylate di-tert-butyl (130mg, 0.32mmol, yield 53%) as a yellow oil. LCMS (ESI): [M+Na] + = 419.0. 1 H NMR (400MHz, CDCl 3 ) δppm 4.10(br d,J=19.0Hz,1H),4.01-3.90(m,2H),3.82(br d,J=12.6Hz,1H),3.20-2.95(m,2H),1.50(m,18H),1.18(br t,J=5.4Hz,1H ),1.11-1.05(m,1H),0.04-0.05(m,9H),-0.50(t,J＝4.8Hz,1H).
第四步：将化合物(1R,2R,4S,5S)-3-(三甲基硅基)-7,9-二氮杂三环[3.3.1.02,4]壬烷-7,9-二羧酸二叔丁酯(100mg，0.25mmol)溶于二氯甲烷(1mL)，0℃下加入氯化氢(4M的二氧六环溶液，630uL)，反应在20℃搅拌1小时。反应液减压浓缩得到粗品化合物(1R,2R,4S,5S)-3-(三甲基硅基)-7,9-二氮杂三环[3.3.1.02,4]壬烷(二盐酸盐，65mg)，其为黄色油状液体。LCMS(ESI):[M+H]+＝197.1。Step 4: The compounds (1R, 2R, 4S, 5S) -3- (triangular silicon-based) -7,9-two-nitrogen miscellaneous three rings [3.3.1.0 2,4 ] mesexane-7,9-di-carboxylic acid two uncle (100 mg, 0.25 mmol), add hydrogen chloride (4m solution of 4m, 6m, 6, 6 30ul), stirred at 20 ° C for 1 hour. The reaction solution was concentrated under reduced pressure to obtain the crude compound (1R,2R,4S,5S)-3-(trimethylsilyl)-7,9-diazatricyclo[3.3.1.0 2,4 ]nonane (dihydrochloride, 65mg) as a yellow oily liquid. LCMS (ESI): [M+H] + = 197.1.
第五步：将化合物8-氟-7-(7-氟-3-(甲氧基甲氧基)-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-醇(170mg，0.24mmol)，(1R,2R,4S,5S)-3-(三甲基硅基)-7,9-二氮杂三环[3.3.1.02,4]壬烷(二盐酸盐，65mg，0.24mmol)和二异丙基乙胺(420uL，2.41mmol)溶于二甲基乙酰胺(1.7mL)，0℃下加入苯并三唑-1-氧代-三(二甲氨基磷)六氟磷盐(160mg，0.36mmol)，反应在50℃搅拌2小时。在0℃下用饱和碳酸氢钠(10mL)淬灭，乙酸乙酯(10mL*3)萃取，合并的有机相用饱和食盐水(10mL)洗涤，硫酸钠干燥，过滤，减压浓缩得到粗品化合物(1R,2R,4S,5S)-7-(8-氟-7-(7-氟-3-(甲氧基甲氧基)-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-基)-3-(三甲基硅基)-7,9-二氮杂三环[3.3.1.02,4]壬烷(200mg)，其为黄色油状液体。LCMS(ESI):[M+H]+＝885.6；第五步：将化合物8-氟-7-(7-氟-3-(甲氧基甲氧基)-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-醇(170mg，0.24mmol)，(1R,2R,4S,5S)-3-(三甲基硅基)-7,9-二氮杂三环[3.3.1.0 2,4 ]壬烷(二盐酸盐，65mg，0.24mmol)和二异丙基乙胺(420uL，2.41mmol)溶于二甲基乙酰胺(1.7mL)，0℃下加入苯并三唑-1-氧代-三(二甲氨基磷)六氟磷盐(160mg，0.36mmol)，反应在50℃搅拌2小时。在0℃下用饱和碳酸氢钠(10mL)淬灭，乙酸乙酯(10mL*3)萃取，合并的有机相用饱和食盐水(10mL)洗涤，硫酸钠干燥，过滤，减压浓缩得到粗品化合物(1R,2R,4S,5S)-7-(8-氟-7-(7-氟-3-(甲氧基甲氧基)-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-基)-3-(三甲基硅基)-7,9-二氮杂三环[3.3.1.0 2,4 ]壬烷(200mg)，其为黄色油状液体。 LCMS (ESI): [M+H] + =885.6;
第六步：化合物(1R,2R,4S,5S)-7-(8-氟-7-(7-氟-3-(甲氧基甲氧基)-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-基)-3-(三甲基硅基)-7,9-二氮杂三环[3.3.1.02,4]壬烷(200mg，0.22mmol)加入到N,N-二甲基甲酰胺(2mL)中，加入氟化铯(343mg，2.20mmol)，20℃搅拌1小时。反应液加入水(2mL)稀释，用乙酸乙酯(3mL*3)萃取，有机相减压浓缩，残余物用快速柱色谱纯化(硅胶，0-10％梯度的甲醇/二氯甲烷)得到(1R,2R,4S,5S)-7-(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-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3-(三甲基硅基)-7,9-二氮杂三环[3.3.1.02,4]壬烷(100mg，0.22mmol，收率60％)。LCMS(ESI):[M+H]+＝728.8.第六步：化合物(1R,2R,4S,5S)-7-(8-氟-7-(7-氟-3-(甲氧基甲氧基)-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-基)-3-(三甲基硅基)-7,9-二氮杂三环[3.3.1.0 2,4 ]壬烷(200mg，0.22mmol)加入到N,N-二甲基甲酰胺(2mL)中，加入氟化铯(343mg，2.20mmol)，20℃搅拌1小时。反应液加入水(2mL)稀释，用乙酸乙酯(3mL*3)萃取，有机相减压浓缩，残余物用快速柱色谱纯化(硅胶，0-10％梯度的甲醇/二氯甲烷)得到(1R,2R,4S,5S)-7-(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-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3-(三甲基硅基)-7,9-二氮杂三环[3.3.1.0 2,4 ]壬烷(100mg，0.22mmol，收率60％)。 LCMS (ESI): [M+H] + = 728.8.
第七步：向化合物(1R,2R,4S,5S)-7-(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-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3-(三甲基硅基)-7,9-二氮杂三环[3.3.1.02,4]壬烷(100mg，0.14mmol)的乙腈溶液中加入氯化氢(4M的二氧六环溶液，630uL)，反应在20℃搅拌1小时。反应液减压浓缩，残留物溶于乙腈(500uL)，加入三乙胺调节pH到8，残留物用制备型HPLC纯化，得到黄色固体化合物5-乙炔基-6-氟-4-(8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-4-((1R,2R,4S,5S)-3-(三甲基硅基)-7,9-二氮杂三环[3.3.1.02,4]壬-7-基)吡啶并[4,3-d]嘧啶-7-基)萘-2-醇(4.30mg，6umol，收率4％)。LCMS(ESI):[M+H]+＝685.1。1H NMR(400MHz,DMSO-d6)δppm 10.19(br s,1H),9.14(s,1H),7.98(dd,J＝6.0,8.9Hz,1H),7.47(br t,J＝9.1Hz,1H),7.40(d,J＝2.2Hz,1H),7.17(s,1H),5.40-5.20(m,1H),4.42(br s,2H),4.20-4.11(m,1H),4.03(br d,J＝10.5Hz,1H),3.94(br s,1H),3.67(br s,2H),3.24(br d,J＝9.9Hz,2H),3.18-3.08(m,2H),3.03(br s,1H), 2.85(br d,J＝5.7Hz,1H),2.14-1.76(m,6H),1.32-1.09(m,2H),-0.06(s,9H),-0.20(m,1H).第七步：向化合物(1R,2R,4S,5S)-7-(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-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3-(三甲基硅基)-7,9-二氮杂三环[3.3.1.0 2,4 ]壬烷(100mg，0.14mmol)的乙腈溶液中加入氯化氢(4M的二氧六环溶液，630uL)，反应在20℃搅拌1小时。反应液减压浓缩，残留物溶于乙腈(500uL)，加入三乙胺调节pH到8，残留物用制备型HPLC纯化，得到黄色固体化合物5-乙炔基-6-氟-4-(8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-4-((1R,2R,4S,5S)-3-(三甲基硅基)-7,9-二氮杂三环[3.3.1.0 2,4 ]壬-7-基)吡啶并[4,3-d]嘧啶-7-基)萘-2-醇(4.30mg，6umol，收率4％)。 LCMS (ESI): [M+H] + = 685.1. 1 H NMR(400MHz,DMSO-d 6 )δppm 10.19(br s,1H),9.14(s,1H),7.98(dd,J＝6.0,8.9Hz,1H),7.47(br t,J＝9.1Hz,1H),7.40(d,J＝2.2Hz,1H),7.17(s,1H),5.40-5.20(m,1H),4.42(br s,2H),4.20-4.11(m,1H),4.03(br d,J＝10.5Hz,1H),3.94(br s,1H),3.67(br s,2H),3.24(br d,J＝9.9Hz,2H),3.18-3.08(m,2H),3.03(br s,1H), 2.85(br d,J=5.7Hz,1H),2.14-1.76(m,6H),1.32-1.09(m,2H),-0.06(s,9H),-0.20(m,1H).
实施例18：4-(4-((1R,5S)-8-氮杂双环[3.2.1]辛-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-6-氟萘-2-醇甲酸盐
Example 18: 4-(4-((1R,5S)-8-Azabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol formate
第一步：在手套箱中，向4,7-二氯-8-氟-2-(甲硫基)吡啶并[4,3-d]嘧啶(500mg,1.89mmol)，叔丁基3-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)-8-氮杂双环[3.2.1]辛-2-烯-8-羧酸酯(825mg，2.46mmol)的1,4-二氧六环(15mL)溶液中，加入磷酸钾(1.5M的水溶液，3.16mL，4.73mmol)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)(69mg，0.09mmol)。将混合物氮气保护下在50℃下搅拌16小时。反应液过滤，滤液加入水(2mL)稀释，使用乙酸乙酯(10mL*3)萃取，合并的有机相用无水硫酸钠干燥，过滤，旋干。残留物用快速柱色谱纯化(硅胶，0-10％梯度的乙酸乙酯/石油醚)，得到黄色固体化合物叔丁基(1S,5R)-3-(7-氯-8-氟-2-(甲硫基)吡啶并[4,3-d]嘧啶-4-基)-8-氮杂双环[3.2.1]辛-2-烯-8-羧酸酯(530mg，1.21mmol，收率64％)。LCMS(ESI):[M+H]+＝437.1.The first step: In the glove box, add 4,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidine (500mg, 1.89mmol), tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-8-azabicyclo[3.2.1]oct-2-ene-8-carboxylate (825mg, 2.46 mmol) in 1,4-dioxane (15 mL), potassium phosphate (1.5 M in water, 3.16 mL, 4.73 mmol) and [n-butylbis(1-adamantyl)phosphine](2-amino-1,1-biphenyl-2-yl)palladium(II) methanesulfonate (69 mg, 0.09 mmol) were added. The mixture was stirred at 50° C. for 16 hours under nitrogen protection. The reaction solution was filtered, the filtrate was diluted with water (2 mL), extracted with ethyl acetate (10 mL*3), the combined organic phases were dried over anhydrous sodium sulfate, filtered, and spin-dried. The residue was purified by flash column chromatography (silica gel, 0-10% gradient ethyl acetate/petroleum ether) to give yellow solid compound tert-butyl(1S,5R)-3-(7-chloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-8-azabicyclo[3.2.1]oct-2-ene-8-carboxylate (530mg, 1.21mmol, yield 64%). LCMS (ESI): [M+H] + = 437.1.
第二步：在-15℃度下，向叔丁基(1S,5R)-3-(7-氯-8-氟-2-(甲硫基)吡啶并[4,3-d]嘧啶-4-基)-8-氮杂双环[3.2.1]辛-2-烯-8-羧酸酯(2.00g，4.58mmol)的二氯甲烷(120mL)溶液中，加入三乙基硅烷(4.40mL，27.46mmol)和三氟乙酸(6.80mL，91.55mmol)。混合物在氮气保护下在25℃搅拌16小时。反应液旋干，得到粗品化合物4-((1R,3s,5S)-8-氮杂双环[3.2.1]辛-3-基)-7-氯-8-氟-2-(甲硫基)吡啶并[4,3-d]嘧啶(2.00g)，其为棕色油状液体。LCMS(ESI):[M+H]+＝339.0.The second step: at -15°C, to a solution of tert-butyl (1S,5R)-3-(7-chloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-8-azabicyclo[3.2.1]oct-2-ene-8-carboxylate (2.00g, 4.58mmol) in dichloromethane (120mL), add triethylsilane (4.40mL , 27.46mmol) and trifluoroacetic acid (6.80mL, 91.55mmol). The mixture was stirred at 25°C for 16 hours under nitrogen protection. The reaction solution was spin-dried to obtain the crude compound 4-((1R,3s,5S)-8-azabicyclo[3.2.1]oct-3-yl)-7-chloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidine (2.00 g) as a brown oily liquid. LCMS (ESI): [M+H] + = 339.0.
第三步：向4-((1R,3s,5S)-8-氮杂双环[3.2.1]辛-3-基)-7-氯-8-氟-2-(甲硫基)吡啶并[4,3-d]嘧啶(2.00g，4.58mmol)的二氯甲烷(20mL)溶液中，加入三乙胺(1.97mL，14.17mmol)和二碳酸二叔丁酯(2.03mL，8.85mmol)。混合物在氮气保护下20℃搅拌16小时，然后旋干。加入水(5mL)，使用乙酸乙酯(10mL*3)萃取，有机相用无水硫酸镁干燥，过滤，旋干。残留物用快速柱色谱纯化(硅胶，0-15％梯度的四氢呋喃/石油醚)，得到白色固体化合物叔丁基(1R,3s,5S)-3-(7-氯-8-氟-2-(甲硫基)吡啶并[4,3-d]嘧啶-4-基)-8-氮杂双环[3.2.1]辛烷-8-羧酸酯(1.01g，2.30mmol，收率50％)。LCMS(ESI):[M+H]+＝439.2.Step 3: To a solution of 4-((1R,3s,5S)-8-azabicyclo[3.2.1]oct-3-yl)-7-chloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidine (2.00g, 4.58mmol) in dichloromethane (20mL) was added triethylamine (1.97mL, 14.17mmol) and di-tert-butyl dicarbonate (2.0 3 mL, 8.85 mmol). The mixture was stirred at 20° C. for 16 hours under nitrogen protection, and then spin-dried. Water (5 mL) was added, extracted with ethyl acetate (10 mL*3), the organic phase was dried over anhydrous magnesium sulfate, filtered, and spin-dried. The residue is purified (silicone, 0-15 % gradient tetrahydrofu/petroleum ether) with a quick column color spectrum, and obtained a white solid compound Unbardie (1R, 3S, 5S) -3- (7-chloro-8-fluorine-2- (pyriidine) -8-nitrogen miscellaneous twin ring [3.2.1] Etanane-8-carboxylic acid (1.01g, 2.30 mmol, 50 % revenue). LCMS (ESI): [M+H] + = 439.2.
1H NMR(400MHz,CDCl3)δppm 9.04(s,1H),4.60-4.23(m,2H),4.15-3.90(m,1H),2.67(s,3H),2.40-2.25(m,2H),2.22-2.10(m,2H),1.95-1.83(m,2H),1.74(br dd,J＝1.7,13.8Hz,2H),1.51(s,9H). 1 H NMR (400MHz, CDCl 3 )δppm 9.04(s,1H),4.60-4.23(m,2H),4.15-3.90(m,1H),2.67(s,3H),2.40-2.25(m,2H),2.22-2.10(m,2H),1.95-1.83(m,2H) ,1.74(br dd,J=1.7,13.8Hz,2H),1.51(s,9H).
第四步：在手套箱中，向叔丁基(1R,3s,5S)-3-(7-氯-8-氟-2-(甲硫基)吡啶并[4,3-d]嘧啶-4-基)-8-氮杂双环[3.2.1]辛烷-8-羧酸酯(500mg，1.14mmol)，((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(701mg，1.37mmol)和碳酸铯(1113mg，3.42mmol)的二氧六环(10mL)和水(2mL)溶液中，加入氯[(正丁基二(1-金刚烷基)膦)-2-(2-氨基联苯)]钯(II)(14.7mg，0.02mmol)。将混合物氮气保护下在100℃下搅拌3小时。反应液过滤，滤液加入水(4mL)稀释，使用乙酸乙酯(10mL*3)萃取，合并的有机相用无水硫酸钠干燥，过滤，旋干。残留物用快速柱色谱纯化(硅胶，0-30％梯度的四氢呋喃/石油醚)，得到黄色固体化合物叔丁基(1R,3s,5S)-3-(8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三异丙基甲硅烷基)乙炔基)萘-1-基)-2-(甲硫基))吡啶并[4,3-d]嘧啶-4-基)-8-氮杂双环[3.2.1]辛烷-8-羧酸酯(750mg，0.95mmol，收率83％)。LCMS(ESI):[M+H]+＝789.4.Step 4: In a glove box, add tert-butyl (1R,3s,5S)-3-(7-chloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate (500 mg, 1.14 mmol), ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl -1,3,2-Dioxygen To a solution of xaboran-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (701 mg, 1.37 mmol) and cesium carbonate (1113 mg, 3.42 mmol) in dioxane (10 mL) and water (2 mL) was added chloro[(n-butylbis(1-adamantyl)phosphine)-2-(2-aminobiphenyl)]palladium(II) (14.7 mg, 0.02 mmol). The mixture was stirred at 100° C. for 3 hours under nitrogen protection. The reaction solution was filtered, the filtrate was diluted with water (4 mL), extracted with ethyl acetate (10 mL*3), the combined organic phases were dried over anhydrous sodium sulfate, filtered, and spin-dried. The residue was purified by flash column chromatography (silica gel, 0-30% gradient THF/petroleum ether) to give the yellow solid compound tert-butyl(1R,3s,5S)-3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalene-1-yl)-2-(methylthio))pyrido[4,3-d]pyrimidin-4-yl)-8-azabis Cyclo[3.2.1]octane-8-carboxylate (750 mg, 0.95 mmol, yield 83%). LCMS (ESI): [M+H] + = 789.4.
第五步：向叔丁基(1R,3s,5S)-3-(8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三异丙基甲硅烷基)乙炔基)萘-1-基)-2-(甲硫基))吡啶并[4,3-d]嘧啶-4-基)-8-氮杂双环[3.2.1]辛烷-8-羧酸酯(400mg，0.51mmol)的二氯甲烷(10mL)溶液中，加入间氯过氧化苯甲酸(85％含量，257mg，1.27mmol)。混合物在氮气保护下25℃搅拌2小时。加入水(3mL)，使用二氯甲烷(5mL*3)萃取，合并的有机相用无水硫酸钠干燥，过滤，旋干，得到粗品化合物叔丁基(1R,3s,5S)-3-(8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三异丙基甲硅烷基)乙炔基)萘-1-基)-2-(甲磺酰基))吡啶并[4,3-d]嘧啶-4-基)-8-氮杂双环[3.2.1]辛烷-8-羧酸酯(600mg)，其为黄色固体。LCMS(ESI):[M-56+H]+＝765.1.The fifth step: to tert-butyl(1R,3s,5S)-3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalene-1-yl)-2-(methylthio))pyrido[4,3-d]pyrimidin-4-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate (400mg, 0.51mm ol) in dichloromethane (10 mL), add m-chloroperoxybenzoic acid (85% content, 257 mg, 1.27 mmol). The mixture was stirred at 25°C for 2 hours under nitrogen protection. Added water (3mL), extracted with dichloromethane (5mL*3), dried the combined organic phase with anhydrous sodium sulfate, filtered, and spin-dried to obtain the crude compound tert-butyl(1R,3s,5S)-3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(methylsulfonyl))pyrido[4,3-d]pyrimidine -4-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate (600 mg) as a yellow solid. LCMS (ESI): [M-56+H] + =765.1.
第六步：在25℃下，向叔丁基(1R,3s,5S)-3-(8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三异丙基甲硅烷基)乙炔基)萘-1-基)-2-(甲磺酰基))吡啶并[4,3-d]嘧啶-4-基)-8-氮杂双环[3.2.1]辛烷-8-羧酸酯(600mg，0.73mmol)和二异丙基乙胺(510uL，3.65mmol)的二氧六环(6.00mL)溶液中加入((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲醇(357mg，2.24mmol)，混合物在80℃下搅拌4小时。将溶液浓缩并通过快速柱色谱(硅胶，0-10％梯度甲醇/二氯甲烷)纯化得到棕色油状化合物叔丁基(1R,3s,5S)-3-(8-氟-7-(7-氟-3-(甲氧基甲氧基)-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-基)-8-氮杂双环[3.2.1]辛烷-8-羧酸酯(430mg，0.38mmol，收率52％)。LCMS(ESI):[M+H]+＝900.3。The sixth step: at 25°C, to tert-butyl (1R,3s,5S)-3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalene-1-yl)-2-(methylsulfonyl)pyrido[4,3-d]pyrimidin-4-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate (600 mg, 0.73mmol) and diisopropylethylamine (510uL, 3.65mmol) in dioxane (6.00mL) were added ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol (357mg, 2.24mmol), and the mixture was stirred at 80°C for 4 hours. The solution was concentrated and purified by flash column chromatography (silica gel, 0-10% methanol/dichloromethane gradient) to afford the compound tert-butyl(1R,3s,5S)-3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazine-7a(5H )-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate (430 mg, 0.38 mmol, yield 52%). LCMS (ESI): [M+H] + = 900.3.
第七步：在25℃下，向叔丁基(1R,3s,5S)-3-(8-氟-7-(7-氟-3-(甲氧基甲氧基)-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-基)-8-氮杂双环[3.2.1]辛烷-8-羧酸酯(430mg，0.48mmol)的二甲基甲酰胺(5.00mL)溶液中加入氟化铯(726mg，4.78mmol)。溶液在25℃搅拌16小时。将溶液浓缩，残余物通过快速柱色谱(硅胶，0-10％梯度的甲醇/二氯甲烷)纯化得到棕色油状化合物叔丁基(1R,3s,5S)-3-(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-8-羧酸酯(360mg，0.39mmol，收率81％)。LCMS(ESI):[M+H]+＝744.2.The seventh step: at 25°C, to tert-butyl(1R,3s,5S)-3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalene-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine- To a solution of 4-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate (430 mg, 0.48 mmol) in dimethylformamide (5.00 mL) was added cesium fluoride (726 mg, 4.78 mmol). The solution was stirred at 25°C for 16 hours. The solution was concentrated and the residue was purified by flash column chromatography (silica gel, 0-10% gradient of methanol/dichloromethane) to give tert-butyl(1R,3s,5S)-3-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyroxy)pyridine as a brown oil Pyrido[4,3-d]pyrimidin-4-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate (360 mg, 0.39 mmol, yield 81%). LCMS (ESI): [M+H] + = 744.2.
第八步：在25℃下，将叔丁基(1R,3s,5S)-3-(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-8-羧酸酯(360mg，0.48mmol)溶于三氟乙酸/二氯甲烷(体积比为1/4，4.00mL)，搅拌2小时。溶液用三乙胺(1mL)中和并用水(5mL)稀释，用二氯甲烷(5mL*3)萃取。干燥有机层并浓缩，得到的粗产物通过制备型HPLC纯化得到黄色固体化合物4-(4-((1R,3s,5S)-8-氮杂双环[3.2.1]辛-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-6-氟萘-2-醇(甲酸盐，5.58mg，9.68umol，收率2％)。LCMS(ESI):[M+H]+＝600.2；1H NMR(400MHz,CD3OD)δ＝9.47(s,1H),8.47(s,1H),7.89(dd,J＝5.7,9.1Hz,1H),7.43-7.30(m,2H),7.23(d,J＝2.3Hz,1H),5.48- 5.26(m,1H),4.51-4.44(m,1H),4.24(br s,2H),3.37(br s,5H),3.22-3.17(m,1H),3.15-3.08(m,1H),2.61-1.93(m,14H).The eighth step: at 25°C, tert-butyl (1R,3s,5S)-3-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-8-azabicyclo [3.2.1] Octane-8-carboxylate (360 mg, 0.48 mmol) was dissolved in trifluoroacetic acid/dichloromethane (volume ratio 1/4, 4.00 mL), and stirred for 2 hours. The solution was neutralized with triethylamine (1 mL) and diluted with water (5 mL), extracted with dichloromethane (5 mL*3). The organic layer was dried and concentrated, and the resulting crude product was purified by preparative HPLC to give the compound 4-(4-((1R,3s,5S)-8-azabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyn as a yellow solid yl-6-fluoronaphthalen-2-ol (formate salt, 5.58mg, 9.68umol, yield 2%). LCMS (ESI): [M+H] + = 600.2; 1 H NMR (400MHz, CD 3 OD) δ = 9.47 (s, 1H), 8.47 (s, 1H), 7.89 (dd, J = 5.7, 9.1Hz, 1H), 7.43-7.30 (m, 2H), 7.23 (d, J = 2.3Hz, 1H), 5.4 8- 5.26(m,1H),4.51-4.44(m,1H),4.24(br s,2H),3.37(br s,5H),3.22-3.17(m,1H),3.15-3.08(m,1H),2.61-1.93(m,14H).
实施例19：(异丁酰氧基)甲基(1R,5S)-3-(2-((2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-吡咯嗪]-7a'(5'H)-基)甲氧基)-7-(8-乙炔基-7-氟-3-羟基萘-1-基)-8-氟吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯
Example 19: (isobutyryloxy)methyl(1R,5S)-3-(2-((2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolazin]-7a'(5'H)-yl)methoxy)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3, 8-Diazabicyclo[3.2.1]octane-8-carboxylate
第一步：在20℃下，将化合物4-硝基苯酚(5.00g，35.94mmol)加入到四氢呋喃(65.0mL)中，加入氯甲酸氯甲酯(5.10g，39.54mmol)，然后缓慢滴加N,N-二异丙基乙胺(6.91mL，39.54mmol)，反应在20℃搅拌2小时。将混合物溶于乙酸乙酯(50.0mL)并用饱和碳酸氢钠溶液(50.0mL*2)和盐水(50.0mL*2)洗涤，用无水硫酸镁干燥，过滤并浓缩，得到黄色固体化合物(4-硝基苯基)碳酸氯甲酯(8.10g，34.98mmol，收率97％)。1H NMR(400MHz,CDCl3)δppm 8.39-8.32(m,2H),7.48-7.43(m,2H),5.87(s,2H).The first step: at 20°C, compound 4-nitrophenol (5.00g, 35.94mmol) was added to tetrahydrofuran (65.0mL), chloromethyl chloroformate (5.10g, 39.54mmol) was added, and N,N-diisopropylethylamine (6.91mL, 39.54mmol) was slowly added dropwise, and the reaction was stirred at 20°C for 2 hours. The mixture was dissolved in ethyl acetate (50.0 mL) and washed with saturated sodium bicarbonate solution (50.0 mL*2) and brine (50.0 mL*2), dried over anhydrous magnesium sulfate, filtered and concentrated to give yellow solid compound (4-nitrophenyl)chloromethyl carbonate (8.10 g, 34.98 mmol, yield 97%). 1 H NMR (400MHz, CDCl 3 ) δppm 8.39-8.32(m,2H), 7.48-7.43(m,2H), 5.87(s,2H).
第二步：将化合物(4-硝基苯基)碳酸氯甲酯(5.00g，21.59mmol)加入到丙酮(100mL)中，在20℃下加入碘化钠(9.71g，64.77mmol)和4A分子筛(5.00g)，反应在40℃搅拌16小时。将反应液冷却至室温，并通过硅藻土过滤。滤液减压除去挥发物并将残余物溶解在二氯甲烷(100mL)中，分别用饱和碳酸氢钠溶液(100mL)、水(100mL)和盐水(100mL)洗涤，有机相用无水硫酸镁干燥，过滤并浓缩得到黄色油状化合物碘甲基(4-硝基苯基)碳酸酯(6.76g，20.94mmol，收率97％)。1H NMR(400MHz,CDCl3)δppm 8.36-8.30(m,2H),7.49-7.42(m,2H),6.09(s,2H).The second step: the compound (4-nitrophenyl) chloromethyl carbonate (5.00g, 21.59mmol) was added to acetone (100mL), sodium iodide (9.71g, 64.77mmol) and 4A molecular sieves (5.00g) were added at 20°C, and the reaction was stirred at 40°C for 16 hours. The reaction was cooled to room temperature and filtered through celite. The filtrate was removed of volatiles under reduced pressure and the residue was dissolved in dichloromethane (100mL), washed with saturated sodium bicarbonate solution (100mL), water (100mL) and brine (100mL) respectively, the organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated to give yellow oil compound iodomethyl (4-nitrophenyl) carbonate (6.76g, 20.94mmol, yield 97%). 1 H NMR (400MHz, CDCl 3 ) δppm 8.36-8.30(m,2H), 7.49-7.42(m,2H), 6.09(s,2H).
第三步：把异丁酸(5.00g，56.75mmol)加入到乙腈(200mL)中，在20℃下加入氧化银(4.76 g，34.05mmol)，在70℃避光搅拌6小时。将混合物冷却至环境温度并通过硅藻土过滤。滤液通过真空除去挥发物，得到棕褐色固体化合物异丁酸银(1.00g，5.12mmol，收率9％)。The third step: add isobutyric acid (5.00g, 56.75mmol) into acetonitrile (200mL), add silver oxide (4.76 g, 34.05 mmol), stirred at 70°C for 6 hours in the dark. The mixture was cooled to ambient temperature and filtered through celite. The filtrate was freed of volatiles by vacuum to give the compound silver isobutyrate (1.00 g, 5.12 mmol, 9% yield) as a tan solid.
第四步：将化合物碘甲基(4-硝基苯基)碳酸酯(414mg，1.28mmol)加入到甲苯中(7.00mL)中，加入异丁酸银(500mg，2.56mmol)，在55℃搅拌16小时。将反应液冷却至室温，并通过硅藻土过滤，滤液分别用10％碳酸钾溶液(3mL*2)和盐水(3mL*2)洗涤，有机相用无水硫酸镁干燥，滤液浓缩，残余物通过快速柱色谱(硅胶，0-30％梯度的乙酸乙酯/石油醚)纯化得到黄色油状化合物(((4-硝基苯氧基)羰基)氧基)异丁酸甲酯(220mg，0.78mmol，收率61％)。1H NMR(400MHz,CDCl3)δppm 8.36-8.30(m,2H),7.48-7.41(m,2H),5.91(s,2H),2.69(m,1H),1.29-1.22(m,6H).Step 4: Add the compound iodomethyl (4-nitrophenyl) carbonate (414 mg, 1.28 mmol) into toluene (7.00 mL), add silver isobutyrate (500 mg, 2.56 mmol), and stir at 55° C. for 16 hours. The reaction solution was cooled to room temperature and filtered through diatomaceous earth. The filtrate was washed with 10% potassium carbonate solution (3mL*2) and brine (3mL*2) respectively, the organic phase was dried over anhydrous magnesium sulfate, the filtrate was concentrated, and the residue was purified by flash column chromatography (silica gel, 0-30% gradient ethyl acetate/petroleum ether) to obtain yellow oily compound (((4-nitrophenoxy)carbonyl)oxy)methyl isobutyrate (220mg, 0.78mmol, yield 61% ). 1 H NMR (400MHz, CDCl 3 ) δppm 8.36-8.30(m,2H),7.48-7.41(m,2H),5.91(s,2H),2.69(m,1H),1.29-1.22(m,6H).
第五步：在25℃下，向叔丁基(1R,5S)-3-(8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三异丙基甲硅烷基)乙炔基)萘-1-基)-2-(2,2,2-三氟乙氧基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(500mg，0.59mmol)的四氢呋喃(5.00mL)溶液中加入((1R,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-吡咯嗪]-7a'(5'H)-基)甲醇(121mg，0.59mmol)和叔丁醇钠(115mg，0.89mmol)，将该溶液在25℃搅拌2小时。将反应液浓缩，残余物通过快速柱色谱(硅胶，0-10％梯度的甲醇/二氯甲烷)纯化得到黄色固体化合物叔丁基(1R,5S)-3-(2-(((1R,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-吡咯嗪]-7a'(5'H)-基)甲氧基)-8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三异丙基甲硅烷基)乙炔基)萘-1-基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(350mg，0.37mmol，收率62％)。LCMS(ESI):[M+Na]+＝967.4。The fifth step: at 25°C, to tert-butyl(1R,5S)-3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalene-1-yl)-2-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxy Add ((1R,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolazin]-7a'(5'H)-yl)methanol (121mg, 0.59mmol) and sodium tert-butoxide (115mg, 0.89mmol) to a tetrahydrofuran (5.00mL) solution of acid ester (500mg, 0.59mmol), and the solution was heated at 25°C Stir for 2 hours. The reaction solution was concentrated, and the residue was purified by flash column chromatography (silica gel, 0-10% gradient of methanol/dichloromethane) to obtain yellow solid compound tert-butyl(1R,5S)-3-(2-(((1R,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolazin]-7a'(5'H)-yl)methoxy)-8-fluoro-7-(7-fluoro-3 -(Methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (350 mg, 0.37 mmol, yield 62%). LCMS (ESI): [M+Na] + = 967.4.
第六步：在25℃下，向叔丁基(1R,5S)-3-(2-(((1R,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-吡咯嗪]-7a'(5'H)-基)甲氧基)-8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三异丙基甲硅烷基)乙炔基)萘-1-基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(350mg，0.37mmol)的二甲基甲酰胺(3.50mL)溶液中加入氟化铯(562mg，3.70mmol)，将该溶液在25℃搅拌2小时。将反应液浓缩，残余物通过快速柱色谱(硅胶，0-10％梯度的甲醇/二氯甲烷)纯化得到棕色油状化合物叔丁基(1R,5S)-3-(2-(((1R,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-吡咯嗪]-7a'(5'H)-基)甲氧基)-7-(8-乙炔基-7-氟-3-(甲氧基甲氧基)萘-1-基)-8-氟吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(290mg，0.37umol，收率99％)。LCMS(ESI):[M+H]+＝788.8。Step 6: At 25°C, add tert-butyl (1R,5S)-3-(2-(((1R,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolazin]-7a'(5'H)-yl)methoxy)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl )naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (350mg, 0.37mmol) in dimethylformamide (3.50mL) was added cesium fluoride (562mg, 3.70mmol), and the solution was stirred at 25°C for 2 hours. The reaction solution was concentrated, and the residue was purified by flash column chromatography (silica gel, 0-10% gradient of methanol/dichloromethane) to obtain brown oily compound tert-butyl(1R,5S)-3-(2-(((1R,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolazin]-7a'(5'H)-yl)methoxy)-7-(8-ethynyl-7- Fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (290mg, 0.37umol, yield 99%). LCMS (ESI): [M+H] + = 788.8.
第七步：在25℃下，向叔丁基(1R,5S)-3-(2-(((1R,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-吡咯嗪]-7a'(5'H)-基)甲氧基)-7-(8-乙炔基-7-氟-3-(甲氧基甲氧基)萘-1-基)-8-氟吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(50.0mg，0.06mmol)的乙腈(1.00mL)溶液中加入氯化氢(4M的二氧六环溶液，317uL，1.27mmol)，将该溶液在20℃搅拌2小时。反应液用三乙胺调节pH至7，减压浓缩除去溶剂得到粗品化合物4-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-2-(((1R,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-吡咯嗪]-7a'(5'H)-基)甲氧基)-8-氟吡啶并[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-醇(纯度50％，80.0mg)，其为棕色固体。LCMS(ESI):[M+H]+＝644.9。The seventh step: at 25°C, to tert-butyl (1R,5S)-3-(2-(((1R,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolazin]-7a'(5'H)-yl)methoxy)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yl)-8-fluoropyrido[ 4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (50.0mg, 0.06mmol) in acetonitrile (1.00mL) was added hydrogen chloride (4M solution in dioxane, 317uL, 1.27mmol), and the solution was stirred at 20°C for 2 hours. The reaction solution was adjusted to pH 7 with triethylamine, and concentrated under reduced pressure to remove the solvent to obtain the crude compound 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(((1R,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolazin]-7a'(5'H)-yl)methoxy)-8-fluoro Pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (50% purity, 80.0 mg) as a brown solid. LCMS (ESI): [M+H] + = 644.9.
第八步：在20℃下，向4-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-2-(((1R,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-吡咯嗪]-7a'(5'H)-基)甲氧基)-8-氟吡啶并[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-醇(纯度50％，50.0mg，0.04mmol)的二甲基甲酰胺(1.00mL)溶液中加入(((4-硝基苯氧基)羰基)氧基)异丁酸甲酯(19.8mg，0.07mmol)，将该溶液在20℃搅拌2小时。混合物通过制备型HPLC纯化，得到白色固体化合物(异丁酰氧基)甲基(1R,5S)-3-(2-((2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-吡咯 嗪]-7a'(5'H)-基)甲氧基)-7-(8-乙炔基-7-氟-3-羟基萘-1-基)-8-氟吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(15.26mg，0.02mmol，收率50％)。LCMS(ESI):[M+H]+＝789.4。1H NMR(400MHz,CD3OD)δppm 9.12-9.00(m,1H),7.88(dd,J＝5.6,9.1Hz,1H),7.44-7.29(m,2H),7.23(d,J＝2.3Hz,1H),5.97-5.77(m,2H),4.73(br s,2H),4.58-4.46(m,2H),4.36-4.20(m,2H),3.92-3.69(m,2H),3.40-3.37(m,1H),3.29-3.23(m,1H),3.20-3.09(m,1H),2.96-2.80(m,2H),2.73-2.59(m,1H),2.40-2.28(m,1H),2.17-1.84(m,9H),1.56-1.42(m,2H),1.32-1.15(m,6H).The eighth step: at 20°C, add 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(((1R,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolazin]-7a'(5'H)-yl)methoxy)-8-fluoropyrido[4,3-d ]Pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalene-2-ol (purity 50%, 50.0mg, 0.04mmol) in dimethylformamide (1.00mL) was added (((4-nitrophenoxy)carbonyl)oxy)methyl isobutyrate (19.8mg, 0.07mmol), and the solution was stirred at 20°C for 2 hours. The mixture was purified by preparative HPLC to give the compound (isobutyryloxy)methyl(1R,5S)-3-(2-((2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrole Azine]-7a'(5'H)-yl)methoxy)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (15.26 mg, 0.02 mmol, yield 50%). LCMS (ESI): [M+H] + = 789.4. 1 H NMR(400MHz,CD 3 OD)δppm 9.12-9.00(m,1H),7.88(dd,J＝5.6,9.1Hz,1H),7.44-7.29(m,2H),7.23(d,J＝2.3Hz,1H),5.97-5.77(m,2H),4.73(br s,2H),4.58-4.46(m,2H),4.36-4.20(m,2H),3.92-3.69(m,2H),3.40-3.37(m,1H),3.29-3.23(m,1H),3.20-3.09(m,1H),2.96-2.80(m,2H),2.73-2.59(m,1H),2.40-2.28(m,1H),2.17-1.84(m,9H),1.56-1.42(m,2H),1.32-1.15(m,6H).
实施例20：4-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-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)喹啉-2-醇
Example 20: 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)quinolin-2-ol
第一步：在氮气下向4-溴喹啉-2-醇(500mg，2.23mmol)的二恶烷(25mL)溶液中加入双联频哪醇硼酸酯(681g，2.68mmol)和(1,1-双(二苯基膦)二茂铁)二氯化钯二氯甲烷(273mg，0.37mmol)，2-乙基己酸钾(610mg，3.35mmol)。并将所得混合物在80℃下搅拌1.5小时。将悬浮液过滤并浓缩，得到粗产物，将其通过快速柱色谱(硅胶，0-10％梯度二氯甲烷/甲醇)纯化，得到棕色固体化合物4-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)喹啉-2-醇(220mg，0.56mmol，收率25％)。LCMS(ESI):[M+H]+＝272.1。Step 1: To a solution of 4-bromoquinolin-2-ol (500 mg, 2.23 mmol) in dioxane (25 mL) was added bis-pinacol borate (681 g, 2.68 mmol) and (1,1-bis(diphenylphosphino)ferrocene)dichloropalladium dichloromethane (273 mg, 0.37 mmol), potassium 2-ethylhexanoate (610 mg, 3.35 mmol) under nitrogen. And the resulting mixture was stirred at 80°C for 1.5 hours. The suspension was filtered and concentrated to give a crude product, which was purified by flash column chromatography (silica gel, 0-10% gradient dichloromethane/methanol) to give brown solid compound 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinolin-2-ol (220 mg, 0.56 mmol, yield 25%). LCMS (ESI): [M+H] + = 272.1.
第二步：在氮气下向(1R,5S)-叔丁基3-(7-氯-8-氟-2-(((2R,7aS)-2-氟六氢-1H-吡咯嗪-7a-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(150mg，0.27mmol)和4-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)喹啉-2-醇(74mg，0.27mmol)的二恶烷(2000uL)溶液中加入磷酸钾溶液(549uL，0.82mmol)和甲磺酰氧基(二金刚烷基-正丁基膦基)-2-氨基-1,1-联苯-2-基)钯(II)(20mg，0.03mmol)。将该悬浮液在100℃搅拌2小时。将混合物浓缩并用快速柱色谱(硅胶，0-10％梯度二氯甲烷/甲醇)纯化，得到棕色固体化合物叔丁基(1R,5S)-3-(8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-7-(2-羟基喹啉-4-基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(130mg，0.16mmol，收率58％)。LCMS(ESI):[M+H]+＝660.3。Second step: (1R,5S)-tert-butyl 3-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolazin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (150mg, 0.27mmol) and 4-( To a solution of 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinolin-2-ol (74mg, 0.27mmol) in dioxane (2000uL) was added potassium phosphate solution (549uL, 0.82mmol) and methanesulfonyloxy(diadamantyl-n-butylphosphino)-2-amino-1,1-biphenyl-2-yl)palladium(II) (20mg, 0.03mm ol). The suspension was stirred at 100°C for 2 hours. The mixture was concentrated and purified by flash column chromatography (silica gel, 0-10% gradient dichloromethane/methanol) to give brown solid compound tert-butyl(1R,5S)-3-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-7-(2-hydroxyquinolin-4-yl)pyrido[4,3-d]pyrimidin-4-yl)-3,8 - Diazabicyclo[3.2.1]octane-8-carboxylate (130 mg, 0.16 mmol, yield 58%). LCMS (ESI): [M+H] + = 660.3.
第三步：将叔丁基(1R,5S)-3-(8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-7-(2-羟基喹啉-4-基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(110mg，0.17mmol)的三氟乙酸/二氯甲烷(2200uL)溶液在25℃下搅拌2小时。该溶液用三乙胺(450uL)碱化并用二氯甲烷(2mL*3)萃取。干燥并浓缩合并的有机层。通过制备型HPLC纯化得到白色固体化合物4-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-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)喹啉-2-醇(12.9mg，22umol，收率14％)。LCMS(ESI):[M+H]+＝560.3。1H NMR(400MHz,CD3OD-d4)δ＝9.20(s,1H),7.69-7.57(m,1H),7.52-7.39(m,2H),7.27-7.19(m,1H),6.77(s,1H),5.60-5.40(m,1H),4.81(br s,2H),4.64-4.53(m,2H),4.08(br s,2H),3.91(br d,J＝11.0Hz,2H),3.84-3.61(m,3H),3.39-3.33(m,1H),2.69-1.91(m,10H) The third step: tert-butyl(1R,5S)-3-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-7-(2-hydroxyquinolin-4-yl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (110mg, 0 .17 mmol) in trifluoroacetic acid/dichloromethane (2200 uL) was stirred at 25°C for 2 hours. The solution was basified with triethylamine (450 uL) and extracted with dichloromethane (2 mL*3). The combined organic layers were dried and concentrated. Purification by preparative HPLC afforded white solid compound 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)quinolin-2-ol (12.9mg, 22um ol, yield 14%). LCMS (ESI): [M+H] + = 560.3. 1 H NMR(400MHz,CD 3 OD-d 4 )δ＝9.20(s,1H),7.69-7.57(m,1H),7.52-7.39(m,2H),7.27-7.19(m,1H),6.77(s,1H),5.60-5.40(m,1H),4.81(br s,2H),4.64-4.53(m,2H),4.08(br s,2H),3.91(br d,J＝11.0Hz,2H),3.84-3.61(m,3H),3.39-3.33(m,1H),2.69-1.91(m,10H)
实施例21：7a'-(((4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛烷-3-基)-7-(8-乙炔基-7-氟萘-1-基)-8-氟吡啶并[4,3-d]嘧啶-2-基)氧基)甲基)四氢-1'H,3'H-螺[氧杂环丁烷-3,2'-吡咯嗪]
Example 21: 7a'-(((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)tetrahydro-1'H,3'H-spiro[oxetane-3,2'-pyrrolazine]
第一步：将叔丁基(1R,5S)-3-(7-氯-2-((二氢-1'H,3'H-螺[氧杂环丁烷-3,2'-吡咯烷]-7a'(5'H)-基)甲氧基)-8-氟吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(200mg,0.35mmol)和((2-氟-8-(4,4,5,5-四甲基-1,3,2-二氧硼烷-2-基)萘-1-基)乙炔基)三异丙基硅烷(189mg，0.42mmol)的二氧六环(4mL)溶液，在手套箱中加入1.5M磷酸钾溶液(696uL，1.04mmol)和甲磺酰氧基(二金刚烷基-正丁基膦基)-2-氨基-1,1-联苯-2-基)钯(II)(23mg，0.03mmol)，然后将混合物氮气保护下在100度下搅拌3小时。反应混合物旋干。残留物用快速柱色谱纯化(硅胶，0-7％梯度的甲醇/二氯甲烷)得到白色固体化合物叔丁基(1R,5S)-3-(2-((二氢-1'H,3'H-螺[氧杂环丁烷-3,2'-吡咯嗪]-7a'(5'H)-基)甲氧基)-8-氟-7-(7-氟-8-((三异丙基甲硅烷基)乙炔基)萘-1-基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(230mg，0.27mmol，收率76％)。LCMS(ESI):[M+H]+＝865.6.The first step: tert-butyl (1R,5S)-3-(7-chloro-2-((dihydro-1'H,3'H-spiro[oxetane-3,2'-pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (200mg, 0. 35mmol) and ((2-fluoro-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (189mg, 0.42mmol) in dioxane (4mL), 1.5M potassium phosphate solution (696uL, 1.04mmol) and methanesulfonyloxy(diamantyl-n-butylphosphino) in the glove box -2-amino-1,1-biphenyl-2-yl)palladium(II) (23mg, 0.03mmol), then the mixture was stirred at 100°C for 3 hours under nitrogen protection. The reaction mixture was spin-dried. The residue was purified by flash column chromatography (silica gel, 0-7% gradient of methanol/dichloromethane) to give the compound tert-butyl(1R,5S)-3-(2-((dihydro-1'H,3'H-spiro[oxetane-3,2'-pyrrolazin]-7a'(5'H)-yl)methoxy)-8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl as a white solid ) pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (230 mg, 0.27 mmol, yield 76%). LCMS (ESI): [M+H] + = 865.6.
第二步：将叔丁基(1R,5S)-3-(2-((二氢-1'H,3'H-螺[氧杂环丁烷-3,2'-吡咯嗪]-7a'(5'H)-基)甲氧基)-8-氟-7-(7-氟-8-((三异丙基甲硅烷基)乙炔基)萘-1-基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(220mg，0.25mmol)，加入三氟乙酸/二氯甲烷＝1:4(4.4mL)。混合物在氮气保护下25度搅拌1小时。然后用氮气快速吹干，再油泵旋干。得到棕色油状化合物7a'-(((4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛烷-3-基)-8-氟-7-(7-氟-8-((三异丙基甲硅烷基)乙炔基))萘-1-基)吡啶并[4,3-d]嘧啶-2-基)氧基)甲基)四氢-1'H,3'H-螺[氧杂环丁烷-3,2'-吡咯嗪](200mg，0.25mmol，粗品)。LCMS(ESI):[M+H]+＝765.4.The second step: tert-butyl(1R,5S)-3-(2-((dihydro-1'H,3'H-spiro[oxetane-3,2'-pyrrolazin]-7a'(5'H)-yl)methoxy)-8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-di To azabicyclo[3.2.1]octane-8-carboxylate (220mg, 0.25mmol), add trifluoroacetic acid/dichloromethane=1:4 (4.4mL). The mixture was stirred at 25° C. for 1 hour under nitrogen protection. Then blow dry quickly with nitrogen, and then spin dry with oil pump. Compound 7a'-(((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl))naphthalen-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)tetrahydro-1'H,3'H-spiro[oxetane- 3,2'-Pyrrolizine] (200 mg, 0.25 mmol, crude). LCMS (ESI): [M+H] + = 765.4.
第三步：将7a'-(((4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛烷-3-基)-8-氟-7-(7-氟-8-((三异丙基甲硅烷基)乙炔基))萘-1-基)吡啶并[4,3-d]嘧啶-2-基)氧基)甲基)四氢-1'H,3'H-螺[氧杂环丁烷-3,2'-吡咯嗪](200mg，0.25mmol)的N,N二甲基甲酰胺(2mL)溶液，加入氟化铯(4468mg，26.1mmol)。混合物在氮气保护下25度搅拌2小时。然后过滤。残留物用制备型HPLC纯化，得到黄色固体化合物7a'-(((4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛烷-3-基)-7-(8-乙炔基-7-氟萘-1-基)-8-氟吡啶并[4,3-d]嘧啶-2-基)氧基)甲基)四氢-1'H,3'H-螺[氧杂环丁烷-3,2'-吡咯嗪](55mg，0.09mmol，收率35％)。LCMS(ESI):[M+H]+＝609.3.1H NMR(400MHz,CD3OD)δppm 9.04(s,1H),8.23-8.05(m,2H),7.77-7.58(m,2H),7.46(t,J＝9.0Hz,1H),4.73(br d,J＝6.1Hz,2H),4.68-4.60(m,4H),4.28-4.08(m,2H),3.81-3.62(m,4H),3.53(d,J＝10.4Hz,1H),3.45(d,J＝9.0Hz,1H),3.11-3.01(m,1H),2.97(br d,J＝10.3Hz,1H),2.78(td,J＝5.2,10.6Hz,1H),2.56(dd,J＝1.8,13.3Hz,1H),2.07-1.93(m,3H),1.93-1.76(m,6H).The third step: 7a'-(((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl))naphthalene-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)tetrahydro-1'H,3'H-spiro[oxetane-3, 2'-Pyrrolazine] (200 mg, 0.25 mmol) in N,N dimethylformamide (2 mL) was added cesium fluoride (4468 mg, 26.1 mmol). The mixture was stirred at 25° C. for 2 hours under nitrogen protection. Then filter. The residue was purified by preparative HPLC to give compound 7a'-(((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)tetrahydro-1'H,3'H-spiro[oxetane-3,2' as a yellow solid -pyrrolazine] (55 mg, 0.09 mmol, yield 35%). LCMS(ESI):[M+H] + ＝609.3. 1 H NMR(400MHz,CD 3 OD)δppm 9.04(s,1H),8.23-8.05(m,2H),7.77-7.58(m,2H),7.46(t,J＝9.0Hz,1H),4.73(br d,J＝6.1Hz,2H),4.68-4.60(m,4H),4.28-4.08(m,2H),3.81-3.62(m,4H),3.53(d,J＝10.4Hz,1H),3.45(d,J＝9.0Hz,1H),3.11-3.01(m,1H),2.97(br d,J＝10.3Hz,1H),2.78(td,J＝5.2,10.6Hz,1H),2.56(dd,J＝1.8,13.3Hz,1H),2.07-1.93(m,3H),1.93-1.76(m,6H).
实施例22：7-(6-氨基-4-甲基-3-(三氟甲基)吡啶-2-基)-4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)喹唑啉-6-甲腈
Example 22: 7-(6-Amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinazoline-6-carbonitrile
第一步：向6-溴-4-甲基吡啶-2-胺(1.00g，5.35mmol)的N,N-二甲基甲酰胺(17mL)溶液中，在0℃下加入60％钠氢(1.10g，27.5mmol)，在25℃下搅拌1小时，然后在0℃下加入1-(氯甲基)-4-甲氧基苯(1.90g，12.1mmol)，将混合物氮气保护下在25℃下搅拌2小时。在0℃加入饱和氯化铵溶液(17mL)淬灭，使用乙酸乙酯(25mL)萃取5次，合并有机相，食盐水(50mL)洗涤，无水硫酸钠干燥，过滤旋干。残留物用快速柱色谱纯化(硅胶，0-15％梯度的乙酸乙酯/石油醚)得到黄色固体化合物6-溴-N,N-双(4-甲氧基苄基)-4-甲基吡啶-2-胺(2.00g，4.68mmol，收率79％)。LCMS(ESI):[M+H]+＝427.1.Step 1: To 6-bromo-4-methylpyridin-2-amine (1.00g, 5.35mmol) in N,N-dimethylformamide (17mL), add 60% sodium hydrogen (1.10g, 27.5mmol) at 0°C, stir at 25°C for 1 hour, then add 1-(chloromethyl)-4-methoxybenzene (1.90g, 12.1mmol) at 0°C, and place the mixture under nitrogen protection Stir at 25°C for 2 hours. Add saturated ammonium chloride solution (17 mL) to quench at 0°C, extract 5 times with ethyl acetate (25 mL), combine organic phases, wash with brine (50 mL), dry over anhydrous sodium sulfate, filter and spin dry. The residue was purified by flash column chromatography (silica gel, 0-15% gradient ethyl acetate/petroleum ether) to obtain 6-bromo-N,N-bis(4-methoxybenzyl)-4-methylpyridin-2-amine (2.00 g, 4.68 mmol, yield 79%) as a yellow solid. LCMS (ESI): [M+H] + = 427.1.
第二步：向6-溴-N,N-双(4-甲氧基苄基)-4-甲基吡啶-2-胺(2.00g,4.68mmol)，三环己基膦(0.26g，0.94mmol)和氯化锂(0.99g，23.4mmol)的1,4-二氧六环(13mL)溶液中，加入六丁基二锡(8.14g，14.04mmol)和三(二亚苄基丙酮)二钯(0)(0.43g，9.47mmol)。将混合物氮气保护下在110℃下搅拌5小时，旋干。残留物用快速柱色谱纯化(硅胶，0-10％梯度的乙酸乙酯/石油醚)3次，得到无色油状化合物N,N-双(4-甲氧基苄基)-4-甲基-6-(三丁基锡烷基)吡啶-2-胺(1.80g，2.82mmol，收率60％)。LCMS(ESI):[M+H]+＝639.2.1H NMR(400MHz,CDCl3)δppm 7.24-7.15(m,4H),6.92-6.81(m,4H),6.65-6.43(m,1H),6.17(s,1H),4.71(s,4H),3.81(s,6H),2.24-2.13(m,3H),1.73-1.46(m,6H),1.43-1.24(m,6H),1.20-0.95(m,6H),0.89-0.85(m,9H).Second step: To a solution of 6-bromo-N,N-bis(4-methoxybenzyl)-4-methylpyridin-2-amine (2.00g, 4.68mmol), tricyclohexylphosphine (0.26g, 0.94mmol) and lithium chloride (0.99g, 23.4mmol) in 1,4-dioxane (13mL), add hexabutylditin (8.14g, 14.04mmol) and tri (Dibenzylideneacetone)dipalladium(0) (0.43 g, 9.47 mmol). The mixture was stirred at 110° C. for 5 hours under nitrogen protection, and spin-dried. The residue was purified by flash column chromatography (silica gel, 0-10% gradient ethyl acetate/petroleum ether) three times to obtain the colorless oily compound N,N-bis(4-methoxybenzyl)-4-methyl-6-(tributylstannyl)pyridin-2-amine (1.80 g, 2.82 mmol, yield 60%). LCMS (ESI): [M+H] + ＝639.2. 1 H NMR (400MHz, CDCl 3 ) δppm 7.24-7.15 (m, 4H), 6.92-6.81 (m, 4H), 6.65-6.43 (m, 1H), 6.17 (s, 1H), 4.71 (s, 4H), 3.81 (s, 6H ),2.24-2.13(m,3H),1.73-1.46(m,6H),1.43-1.24(m,6H),1.20-0.95(m,6H),0.89-0.85(m,9H).
第三步：在手套箱中，向叔丁基(1R,5S)-3-(7-溴-6-氰基-8-氟-2-(2,2,2-三氟乙氧基)喹唑啉-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(615mg，1.10mmol)，N,N-双(4-甲氧基苄基)-4-甲基-6-(三丁基甲锡烷基)吡啶-2-胺(1.40g，2.2mmol)，碘化亚铜(63mg，0.33mmol)和氯化锂(116mg，2.75mmol)的1,4-二氧六环(18mL)溶液中，加入四(三苯基磷)钯(254mg，0.22mmol)。将混合物氮气保护下在120℃下搅拌16小时。过滤，加入水(10mL)，使用乙酸乙酯(20mL)萃取3次，合并的有机相用无水硫酸钠干燥，过滤旋干。残留物用快速柱色谱纯化(硅胶，0-20％梯度的四氢呋喃/石油醚)。得到粗品化合物叔丁基(1R,5S)-3-(7-(6-(双(4-甲氧基苄基)氨基)-4-甲基吡啶-2-基)-6-氰基-8-氟-2-(2,2,2-三氟乙氧基)喹唑啉-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(800mg)，为黄色固体。LCMS(ESI):[M+H]+＝828.3.The third step: In the glove box, add tert-butyl(1R,5S)-3-(7-bromo-6-cyano-8-fluoro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (615mg, 1.10mmol), N,N-bis(4-methoxybenzyl)-4-methyl-6-(tributyltin To a solution of alkyl)pyridin-2-amines (1.40 g, 2.2 mmol), cuprous iodide (63 mg, 0.33 mmol) and lithium chloride (116 mg, 2.75 mmol) in 1,4-dioxane (18 mL) was added tetrakis(triphenylphosphine)palladium (254 mg, 0.22 mmol). The mixture was stirred at 120° C. for 16 hours under nitrogen protection. After filtration, water (10 mL) was added, extracted three times with ethyl acetate (20 mL), the combined organic phases were dried over anhydrous sodium sulfate, filtered and spin-dried. The residue was purified by flash column chromatography (silica gel, gradient 0-20% tetrahydrofuran/petroleum ether). The crude compound tert-butyl(1R,5S)-3-(7-(6-(bis(4-methoxybenzyl)amino)-4-methylpyridin-2-yl)-6-cyano-8-fluoro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (800 mg) was obtained as a yellow solid. LCMS (ESI): [M+H] + = 828.3.
第四步：向叔丁基(1R,5S)-3-(7-(6-(双(4-甲氧基苄基)氨基)-4-甲基吡啶-2-基)-6-氰基-8-氟-2-(2,2,2-三氟乙氧基)喹唑啉-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(780mg，0.94mmol)的乙腈(16mL)溶液中，加入N-碘琥珀酰亚胺(1060mg，4.71mmol)和对甲苯磺酸(6mg，0.04mmol)。将混合物氮气保护下在25℃下搅拌5小时。混合物旋干，加入食盐水(10mL)，使用乙酸乙酯(20mL)萃 取3次，合并的有机相用无水硫酸钠干燥，过滤旋干。残留物用快速柱色谱纯化(硅胶，0-20％梯度的四氢呋喃/石油醚)。得到黄色固体化合物叔丁基(1R,5S)-3-(7-(6-(双(4-甲氧基苄基)氨基)-3-碘-4-甲基吡啶-2-基)-6-氰基-8-氟-2-(2,2,2-三氟乙氧基)喹唑啉-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(710mg，0.74mmol，收率79％)。LCMS(ESI):[M+H]+＝954.4.The fourth step: acetonitrile (16 mL) solution, N-iodosuccinimide (1060 mg, 4.71 mmol) and p-toluenesulfonic acid (6 mg, 0.04 mmol) were added. The mixture was stirred at 25 °C for 5 hours under nitrogen protection. The mixture was spin-dried, added brine (10mL), extracted with ethyl acetate (20mL) Take 3 times, the combined organic phases are dried with anhydrous sodium sulfate, filtered and spin-dried. The residue was purified by flash column chromatography (silica gel, gradient 0-20% tetrahydrofuran/petroleum ether). The yellow solid compound tert-butyl(1R,5S)-3-(7-(6-(bis(4-methoxybenzyl)amino)-3-iodo-4-methylpyridin-2-yl)-6-cyano-8-fluoro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (710 mg, 0.74 mmol, yield 79%). LCMS (ESI): [M+H] + = 954.4.
第五步：向叔丁基(1R,5S)-3-(7-(6-(双(4-甲氧基苄基)氨基)-3-碘-4-甲基吡啶-2-基)-6-氰基-8-氟-2-(2,2,2-三氟乙氧基)喹唑啉-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(700mg，0.73mmol)的N,N-二甲基乙酰胺(17.5mL)溶液中，加入2,2-二氟-2-(氟磺酰基)乙酸甲酯(3525mg，18.3mmol)和碘化亚铜(1677mg，8.81mmol)。将混合物氮气保护下在90℃下搅拌12小时。混合物过滤，滤液旋干，加入食盐水(10mL)，使用乙酸乙酯(10mL)萃取3次，合并的有机相用无水硫酸钠干燥，过滤旋干。残留物用快速柱色谱纯化(硅胶，0-20％梯度的四氢呋喃/石油醚)。得到黄色固体化合物叔丁基(1R,5S)-3-(7-(6-(双(4-甲氧基苄基)氨基)-4-甲基-3-(三氟甲基)吡啶-2-基)-6-氰基-8-氟-2-(2,2,2-三氟乙氧基)喹唑啉-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(280mg，0.31mmol，收率43％)。LCMS(ESI):[M+H]+＝897.3.The fifth step: N to tert-butyl (1R,5S)-3-(7-(6-(bis(4-methoxybenzyl)amino)-3-iodo-4-methylpyridin-2-yl)-6-cyano-8-fluoro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (700mg, 0.73mmol) , To a solution of N-dimethylacetamide (17.5 mL), add methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (3525 mg, 18.3 mmol) and cuprous iodide (1677 mg, 8.81 mmol). The mixture was stirred at 90° C. for 12 hours under nitrogen protection. The mixture was filtered, the filtrate was spin-dried, brine (10 mL) was added, extracted three times with ethyl acetate (10 mL), the combined organic phases were dried over anhydrous sodium sulfate, filtered and spin-dried. The residue was purified by flash column chromatography (silica gel, gradient 0-20% tetrahydrofuran/petroleum ether). The yellow solid compound tert-butyl(1R,5S)-3-(7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-cyano-8-fluoro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (280mg, 0.31mm ol, yield 43%). LCMS (ESI): [M+H] + = 897.3.
第六步：向叔丁基(1R,5S)-3-(7-(6-(双(4-甲氧基苄基)氨基)-4-甲基-3-(三氟甲基)吡啶-2-基)-6-氰基-8-氟-2-(2,2,2-三氟乙氧基)喹唑啉-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(150mg，0.17mmol)和((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲醇(70mg，0.44mmol)的四氢呋喃(3mL)溶液中，加入叔丁醇钠(24mg，0.25mmol)。混合物在氮气保护下25℃搅拌2小时。加入水(3mL)，使用乙酸乙酯(3mL)萃取3次，合并的有机相用无水硫酸钠干燥，过滤旋干。得到粗品化合物叔丁基(1R,5S)-3-(7-(6-(双(4-甲氧基苄基)氨基)-4-甲基-3-(三氟甲基)吡啶-2-基)-6-氰基-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)喹唑啉-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(230mg)，其为黄色油状液体。LCMS(ESI):[M+H]+＝955.7.Step 6: To tert-butyl (1R,5S)-3-(7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-cyano-8-fluoro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (150mg, 0.17mm ol) and ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol (70mg, 0.44mmol) in tetrahydrofuran (3mL) was added sodium tert-butoxide (24mg, 0.25mmol). The mixture was stirred at 25°C for 2 hours under nitrogen protection. Water (3 mL) was added, extracted three times with ethyl acetate (3 mL), the combined organic phases were dried over anhydrous sodium sulfate, filtered and spin-dried. The crude compound tert-butyl(1R,5S)-3-(7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-cyano-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[ 3.2.1] Octane-8-carboxylate (230 mg) as a yellow oily liquid. LCMS (ESI): [M+H] + = 955.7.
第七步：将叔丁基(1R,5S)-3-(7-(6-(双(4-甲氧基苄基)氨基)-4-甲基-3-(三氟甲基)吡啶-2-基)-6-氰基-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)喹唑啉-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(220mg，0.16mmol)溶于三氟乙酸(3mL)，混合物在氮气保护下50℃搅拌2小时。然后旋干。加入二氯甲烷(2mL)，使用三乙胺调节pH＝7，旋干。残留物用制备型HPLC纯化，得到白色固体化合物7-(6-氨基-4-甲基-3-(三氟甲基)吡啶-2-基)-4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)喹唑啉-6-甲腈(28.5mg，0.05mmol，收率20％)。LCMS(ESI):[M+H]+＝615.2.1H NMR(400MHz,CD3OD)δppm 8.25(s,1H),6.64(s,1H),5.43-5.21(m,1H),4.53(q,J＝10.4Hz,2H),4.33-4.18(m,2H),3.77-3.60(m,4H),3.31-3.13(m,3H),3.02(dt,J＝5.6,9.3Hz,1H),2.48(d,J＝1.3Hz,3H),2.40-2.09(m,3H),2.05-1.95(m,2H),1.94-1.70(m,5H).The seventh step: tert-butyl (1R,5S)-3-(7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-cyano-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[ 3.2.1] Octane-8-carboxylate (220mg, 0.16mmol) was dissolved in trifluoroacetic acid (3mL), and the mixture was stirred at 50°C for 2 hours under nitrogen protection. Then spin dry. Dichloromethane (2 mL) was added, pH=7 was adjusted with triethylamine, and spin-dried. The residue was purified by preparative HPLC to give the compound 7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinazolin-6- Formaldehyde (28.5 mg, 0.05 mmol, 20% yield). LCMS(ESI):[M+H] + ＝615.2. 1 H NMR(400MHz,CD 3 OD)δppm 8.25(s,1H),6.64(s,1H),5.43-5.21(m,1H),4.53(q,J＝10.4Hz,2H),4.33-4.18(m,2H),3.77-3.60(m,4H),3.31-3.13(m,3H),3.02(dt,J＝5.6,9.3Hz,1H),2.48(d,J＝1.3Hz,3H),2.40-2.09(m,3H),2.05-1.95(m,2H),1.94-1.70(m,5H).
实施例23：(4-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛)-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)萘-2-基)硼酸
Example 23: (4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct)-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-yl)boronic acid
第一步：在氮气保护下，向化合物叔丁基(1R,5S)-3-(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-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(300mg，0.54mmol)和4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)萘-2-醇(176mg，0.65mmol)的二氧六环(5.00mL)溶液中，加入磷酸钾(1.5M的水溶液，1.09mL，1.63mmol)，甲磺酸[正丁基二(1-金刚烷基)膦](2-氨基-1,1'-联苯-2-基)钯(II),(36.4mg，0.05mmol)，将混合物在80℃下搅拌2小时。反应液用水(2mL)稀释并用二氯甲烷(2mL*3)萃取，用无水硫酸镁干燥有机相，过滤，滤液减压浓缩，残余物通过快速柱色谱纯化(硅胶，0-50％石油醚/四氢呋喃，然后0-10％二氯甲烷/甲醇)得到棕色油状化合物叔丁基(1R,5S)-3-(8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-7-(3-羟基萘-1-基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(350mg，0.53mmol，收率98％)。LCMS(ESI):[M+H]+＝659.3.The first step: under the protection of nitrogen, the compound tert-butyl (1R,5S)-3-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (300mg, 0.54 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalene-2-ol (176mg, 0.65mmol) in dioxane (5.00mL) were added potassium phosphate (1.5M in water, 1.09mL, 1.63mmol), methanesulfonic acid [n-butylbis(1-adamantyl)phosphine] (2-amino-1,1'-biphenyl- 2-yl)palladium(II), (36.4mg, 0.05mmol), the mixture was stirred at 80°C for 2 hours. The reaction solution was diluted with water (2 mL) and extracted with dichloromethane (2 mL*3), the organic phase was dried over anhydrous magnesium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by flash column chromatography (silica gel, 0-50% petroleum ether/tetrahydrofuran, then 0-10% dichloromethane/methanol) to obtain brown oily compound tert-butyl(1R,5S)-3-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrole Azin-7a(5H)-yl)methoxy)-7-(3-hydroxynaphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (350 mg, 0.53 mmol, yield 98%). LCMS (ESI): [M+H] + = 659.3.
第二步：将化合物叔丁基(1R,5S)-3-(8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-7-(3-羟基萘-1-基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(300mg，0.46mmol)缓慢加入吡啶(3mL)中，在0℃下加入三氟甲磺酸酐(82.0uL，0.50mmol)，混合物在0℃搅拌1小时。反应液用水(1mL)稀释并用甲苯(1mL*2)萃取，用无水硫酸钠干燥有机相，过滤，滤液减压浓缩，残余物通过快速柱色谱纯化(硅胶，0-10％的二氯甲烷/甲醇)得到棕色固体化合物叔丁基(1R,5S)-3-(8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-7-(3-(((三氟甲基)磺酰基)氧基)萘-1-基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(280mg，0.35mmol，收率78％)。LCMS(ESI):[M+H]+＝791.4.The second step: the compound tert-butyl(1R,5S)-3-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-7-(3-hydroxynaphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (300mg, 0 .46mmol) was slowly added into pyridine (3mL), trifluoromethanesulfonic anhydride (82.0uL, 0.50mmol) was added at 0°C, and the mixture was stirred at 0°C for 1 hour. The reaction solution was diluted with water (1 mL) and extracted with toluene (1 mL*2), the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by flash column chromatography (silica gel, 0-10% dichloromethane/methanol) to obtain brown solid compound tert-butyl(1R,5S)-3-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-7 -(3-(((trifluoromethyl)sulfonyl)oxy)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (280 mg, 0.35 mmol, yield 78%). LCMS (ESI): [M+H] + = 791.4.
第三步：在25℃和氮气保护下向叔丁基(1R,5S)-3-(8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-7-(3-(((三氟甲基)磺酰基)氧基)萘-1-基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(100mg，0.13mmol)，次硼酸(17.0mg，0.19mmol)，三苯基膦(2mg，7.6umol)和二异丙基乙胺(67.0uL，0.38mmol)的异丙醇(1000uL)溶液中加入[1,3-二(二苯基磷)丙烷]氯化镍(3.00mg，3.8umol)，混合物在80℃搅拌16小时。将反应液过滤并浓缩，得到粗品化合物(4-(4-((1R,5S)-8-(叔丁氧羰基)-3,8-二氮杂双环[3.2.1]辛)-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)萘-2-基)硼酸(110mg)，其为棕色固体。LCMS(ESI):[M+H]+＝687.4 The third step: tert-butyl(1R,5S)-3-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-7-(3-(((trifluoromethyl)sulfonyl)oxy)naphthalene-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[ 3.2.1] Octane-8-carboxylate (100mg, 0.13mmol), hypoborinic acid (17.0mg, 0.19mmol), triphenylphosphine (2mg, 7.6umol) and diisopropylethylamine (67.0uL, 0.38mmol) in isopropanol (1000uL) solution, add [1,3-bis(diphenylphospho)propane]nickel chloride (3.00mg, 3.8umol ), and the mixture was stirred at 80°C for 16 hours. The reaction solution was filtered and concentrated to obtain the crude compound (4-(4-((1R,5S)-8-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]oct)-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalene-7-yl) 2-yl)boronic acid (110 mg) as a brown solid. LCMS (ESI): [M+H] + = 687.4
第四步：在25℃下，向(4-(4-((1R,5S)-8-(叔丁氧羰基)-3,8-二氮杂双环[3.2.1]辛)-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)萘-2-基)硼酸(76.0mg，0.11mmol)的乙腈(1600uL)溶液中，加入氯化氢(4M的二氧六环溶液，277uL，1.11mmol)。将该溶液在25℃搅拌1小时。将溶液用三乙胺(155uL，1.11mmol)淬灭，然后浓缩并通过制备型HPLC纯化，得到白色固体化合物(4-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛)-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)萘-2-基)硼酸(甲酸盐，11.19mg，18.7umol，收率17％)。LCMS(ESI):[M+H]+＝587.2 1H NMR(400MHz,CD3OD)δppm 9.16(s,1H),8.46(br s,1H),8.42(br s,1H),8.02(d,J＝8.1Hz,1H),7.94(s,1H),7.67(br d,J＝8.3Hz,1H),7.59-7.43(m,2H),5.57-5.35(m,1H),4.78(br s,2H),4.60-4.47(m,2H),4.02(br s,2H),3.88(br dd,J＝5.6,13.0Hz,2H),3.77-3.51(m,3H),3.29-3.24(m,1H),2.62-2.36(m,2H),2.36-2.13(m,3H),2.12-1.91(m,5H).The fourth step: at 25°C, to (4-(4-((1R,5S)-8-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]oct)-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalene-2 -yl) boronic acid (76.0 mg, 0.11 mmol) in acetonitrile (1600 uL) was added hydrogen chloride (4M in dioxane, 277 uL, 1.11 mmol). The solution was stirred at 25°C for 1 hour. The solution was quenched with triethylamine (155 uL, 1.11 mmol), then concentrated and purified by preparative HPLC to give the compound (4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct)-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyridino as a white solid [4,3-d]pyrimidin-7-yl)naphthalen-2-yl)boronic acid (formate salt, 11.19 mg, 18.7 umol, yield 17%). LCMS(ESI):[M+H] + ＝587.2 1 H NMR(400MHz,CD 3 OD)δppm 9.16(s,1H),8.46(br s,1H),8.42(br s,1H),8.02(d,J＝8.1Hz,1H),7.94(s,1H),7.67(br d,J＝8.3Hz,1H),7.59-7.43(m,2H),5.57-5.35(m,1H),4.78(br s,2H),4.60-4.47(m,2H),4.02(br s,2H),3.88(br dd,J＝5.6,13.0Hz,2H),3.77-3.51(m,3H),3.29-3.24(m,1H),2.62-2.36(m,2H),2.36-2.13(m,3H),2.12-1.91(m,5H).
实施例24：7-(6-氨基-4-甲基-3-(三氟甲基)吡啶-2-基)-4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-吡咯嗪]-7a'(5'H)-基)甲氧基)-8-氟-喹唑啉-6-甲腈
Example 24: 7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolazine]-7a'(5'H)- Base) methoxy) -8-fluoro-quinazoline-6-carbonitrile
实施例24通过实施例22的合成路线方法进行制备，用中间体向叔丁基(1R,5S)-3-(7-(6-(双(4-甲氧基苄基)氨基)-4-甲基-3-(三氟甲基)吡啶-2-基)-6-氰基-8-氟-2-(2,2,2-三氟乙氧基)喹唑啉-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯和中间体(1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-吡咯嗪]-7a'(5'H)-基)甲醇A16-2AExample 24 was prepared by the synthetic route method of Example 22, using intermediates to tert-butyl (1R,5S)-3-(7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-cyano-8-fluoro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane -8-carboxylates and intermediates (1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolazin]-7a'(5'H)-yl)methanol A16-2A
LCMS(ESI):[M+H]+＝659.2；1H NMR(400MHz,CD3OD)δppm 8.26(s,1H),6.65(s,1H),4.62-4.47(m,2H),4.43-4.29(m,2H),3.79-3.56(m,4H),3.32-3.25(m,1H),3.22-3.10(m,1H),2.85(d,J＝12.2Hz,1H),2.78-2.64(m,1H),2.48(br d,J＝0.9Hz,3H),2.28(br dd,J＝6.1,13.4Hz,1H),2.20-2.10(m,1H),2.03(br d,J＝13.6Hz,1H),1.98-1.71(m,7H),1.55-1.36(m,2H).19F NMR(400MHz,CD3OD)δppm-55.85(s,3F),-127.71(br s,1F),-135.41(d,J＝151.1Hz,1F),-138.12(d,J＝151.1Hz,1F).LCMS(ESI):[M+H]+= 659.2;1H NMR (400MHz, CD3OD)δppm 8.26(s,1H),6.65(s,1H),4.62-4.47(m,2H),4.43-4.29(m,2H),3.79-3.56(m,4H),3.32-3.25(m,1H),3.22-3.10(m,1H),2.85(d,J＝12.2 Hz,1H),2.78-2.64(m,1H),2.48(br d,J＝0.9Hz,3H),2.28(br dd,J＝6.1,13.4Hz,1H),2.20-2.10(m,1H),2.03(br d,J＝13.6Hz,1H),1.98-1.71(m,7H),1.5 5-1.36(m,2H).19F NMR (400MHz, CD3OD)δppm-55.85(s,3F),-127.71(br s,1F),-135.41(d,J＝151.1Hz,1F),-138.12(d,J＝151.1Hz,1F).
实施例25：4-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-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)-1-氟萘-2-醇
Example 25: 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-1-fluoronaphthalen-2-ol
第一步：在0℃下向4-溴萘-2-醇(2.00g，8.96mmol)的二氯甲烷(30mL)溶液中加入双(苯磺酰基)氟胺(9.33g，29.59mmol)和四氯化锆(0.10g，0.45mmol)。将该溶液在25℃搅拌16小时。将溶液浓缩并通过快速柱色谱(硅胶，0-20％梯度的石油醚/乙酸乙酯)纯化，得到棕色固体化合物4-溴-1-氟萘-2-醇(0.94g，3.50mmol，收率39％)。LCMS(ESI):[M-H]+＝240.8.Step 1: To a solution of 4-bromonaphthalene-2-ol (2.00 g, 8.96 mmol) in dichloromethane (30 mL) was added bis(benzenesulfonyl)fluoroamine (9.33 g, 29.59 mmol) and zirconium tetrachloride (0.10 g, 0.45 mmol) at 0°C. The solution was stirred at 25°C for 16 hours. The solution was concentrated and purified by flash column chromatography (silica gel, 0-20% gradient of petroleum ether/ethyl acetate) to give brown solid compound 4-bromo-1-fluoronaphthalen-2-ol (0.94 g, 3.50 mmol, yield 39%). LCMS (ESI): [MH] + = 240.8.
第二步：在25℃和氮气保护下，向4-溴-1-氟萘-2-醇(300mg，1.24mmol)，双联频哪醇硼酸酯(475mg，1.87mmol)和醋酸钾(367mg，3.73mmol)的二氧六环(6000uL)溶液中加入双(三苯基膦)氯化钯(II)(44.0mg，0.06mmol)。将该溶液在110℃搅拌3小时。将溶液浓缩并通过快速柱色谱(硅胶，0-25％梯度石油醚/乙酸乙酯)纯化，得到黄色固体化合物1-氟-4-(4,4,5,5-四甲基-1,3,2-二恶硼烷-2-基)萘-2-醇(324mg，1.13mmol，收率90％)。LCMS(ESI):[M-H]+＝287.0.Step 2: Add bis(triphenylphosphine)palladium(II) chloride (44.0mg, 0.06mmol) to a solution of 4-bromo-1-fluoronaphthalen-2-ol (300mg, 1.24mmol), bis-pinacol borate (475mg, 1.87mmol) and potassium acetate (367mg, 3.73mmol) in dioxane (6000uL) at 25°C under nitrogen protection. The solution was stirred at 110°C for 3 hours. The solution was concentrated and purified by flash column chromatography (silica gel, 0-25% petroleum ether/ethyl acetate gradient) to obtain yellow solid compound 1-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalene-2-ol (324 mg, 1.13 mmol, yield 90%). LCMS (ESI): [MH] + = 287.0.
第三步：在25℃和氮气保护下，向1-氟-4-(4,4,5,5-四甲基-1,3,2-二恶硼烷-2-基)萘-2-醇(157mg，0.54mmol)和叔丁基(1R,5S)-3-(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-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(150mg，0.27mmol)的二氧六环(3.00mL)溶液中，加入碳酸钾(2.0M的水溶液，409uL，0.82mmol)和四(三苯基膦)钯(32.0mg，0.03mmol)。将该溶液在85℃搅拌16小时。浓缩溶液并将粗品通过快速柱色谱(硅胶，0-10％梯度二氯甲烷/甲醇)纯化得到棕色固体化合物叔丁基(1R,5S)-3-(8-氟-7-(4-氟-3-羟基萘-1-基)-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)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(210mg，0.26mmol，收率97％)。LCMS(ESI):[M+H]+＝677.2.The third step: 1-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalene-2-ol (157mg, 0.54mmol) and tert-butyl (1R,5S)-3-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl )methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (150mg, 0.27mmol) in dioxane (3.00mL) was added potassium carbonate (2.0M in water, 409uL, 0.82mmol) and tetrakis(triphenylphosphine)palladium (32.0mg, 0.03mmol). The solution was stirred at 85°C for 16 hours. The solution was concentrated and the crude product was purified by flash column chromatography (silica gel, 0-10% gradient dichloromethane/methanol) to give brown solid compound tert-butyl(1R,5S)-3-(8-fluoro-7-(4-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyridin[4,3-d]pyrimidin-4-yl)-3 ,8-diazabicyclo[3.2.1]octane-8-carboxylate (210 mg, 0.26 mmol, yield 97%). LCMS (ESI): [M+H] + = 677.2.
第四步：在25℃下，向叔丁基(1R,5S)-3-(8-氟-7-(4-氟-3-羟基萘-1-基)-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)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(200mg，0.30mmol)的乙腈(4000uL)溶液中加入氯化氢(4M的二氧六环溶液，739uL，2.96mmol)。将该溶液在25℃搅拌1小时。加入三乙胺(206uL，1.48mmol)将pH值调节至8。然后将溶液浓缩并通过制备型HPLC纯化得到白色固体化合物4-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-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)-1-氟萘-2-醇(甲酸盐，77.19mg，0.13mmol，收率45％)。LCMS(ESI):[M+H]+＝577.0.1H NMR(400MHz,CD3OD)δppm 9.15(s,1H),8.48 (s,1H),8.05(d,J＝8.5Hz,1H),7.65-7.51(m,2H),7.42-7.30(m,2H),5.55-5.33(m,1H),4.77(br d,J＝8.5Hz,2H),4.48(q,J＝11.3Hz,2H),3.95(br s,2H),3.89-3.78(m,2H),3.70-3.49(m,3H),3.23(dt,J＝6.0,9.8Hz,1H),2.58-2.23(m,3H),2.21-2.11(m,2H),2.09-1.86(m,5H).The fourth step: at 25°C, to tert-butyl (1R,5S)-3-(8-fluoro-7-(4-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyridin[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- To a solution of the carboxylate (200 mg, 0.30 mmol) in acetonitrile (4000 uL) was added hydrogen chloride (4M in dioxane, 739 uL, 2.96 mmol). The solution was stirred at 25°C for 1 hour. The pH was adjusted to 8 by adding triethylamine (206 uL, 1.48 mmol). The solution was then concentrated and purified by preparative HPLC to afford the white solid compound 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-1-fluoronaphthalen-2-ol (methyl acid salt, 77.19mg, 0.13mmol, yield 45%). LCMS (ESI): [M+H] + =577.0. 1 H NMR (400MHz, CD 3 OD) δppm 9.15 (s, 1H), 8.48 (s,1H),8.05(d,J=8.5Hz,1H),7.65-7.51(m,2H),7.42-7.30(m,2H),5.55-5.33(m,1H),4.77(br d,J=8.5Hz,2H),4.48(q,J=11.3Hz,2H),3.95(br s,2H ),3.89-3.78(m,2H),3.70-3.49(m,3H),3.23(dt,J=6.0,9.8Hz,1H),2.58-2.23(m,3H),2.21-2.11(m,2H),2.09-1.86(m,5H).
实施例26：7-(3-氨基-7,8-二氟异喹啉-1-基)-4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)喹唑啉-6-甲腈
Example 26: 7-(3-amino-7,8-difluoroisoquinolin-1-yl)-4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinazoline-6-carbonitrile
第一步：在0℃下，向2-溴-3,4-二氟苯甲酸(25.0g，105.49mmol)的四氢呋喃(100mL)溶液中滴加硼烷的四氢呋喃溶液(422mL，422mmol)。升温至室温并搅拌16小时。溶液用冰浴冷却，然后缓慢加入10％碳酸钠水溶液(180mL)。将悬浮液真空浓缩，得到白色固体。用3摩尔/升盐酸水溶液(600mL)酸化，用二氯甲烷(300mL)稀释，混合物通过硅藻土过滤。将滤液分液，有机层用无水硫酸钠干燥，然后过滤。将所得滤液真空浓缩，得到(2-溴-3,4-二氟苯基)甲醇(22.0g，98.65mmol，收率94％)，为灰白色固体。1H NMR(400MHz,DMSO-d6)δppm 7.57-7.45(m,1H),7.43-7.31(m,1H),5.58(t,J＝5.6Hz,1H),4.50(br d,J＝5.4Hz,2H).Step 1: To a solution of 2-bromo-3,4-difluorobenzoic acid (25.0 g, 105.49 mmol) in tetrahydrofuran (100 mL) was added dropwise a solution of borane in tetrahydrofuran (422 mL, 422 mmol) at 0°C. Warm to room temperature and stir for 16 hours. The solution was cooled with an ice bath, and then 10% aqueous sodium carbonate solution (180 mL) was added slowly. The suspension was concentrated in vacuo to give a white solid. Acidify with 3 mol/L aqueous hydrochloric acid (600 mL), dilute with dichloromethane (300 mL), and filter the mixture through celite. The filtrate was separated, and the organic layer was dried over anhydrous sodium sulfate, and then filtered. The resulting filtrate was concentrated in vacuo to afford (2-bromo-3,4-difluorophenyl)methanol (22.0 g, 98.65 mmol, 94% yield) as an off-white solid. 1 H NMR (400MHz, DMSO-d 6 ) δppm 7.57-7.45(m, 1H), 7.43-7.31(m, 1H), 5.58(t, J=5.6Hz, 1H), 4.50(br d, J=5.4Hz, 2H).
第二步：在0℃下，向(2-溴-3,4-二氟苯基)甲醇(22.0g，98.65mmol)和三乙胺的二氯甲烷(220mL)溶液中加入甲基磺酸酐(25.78g，148mmol)。将反应在0℃搅拌1小时。向混合物中加入水(200mL)并用二氯甲烷(100mL*3)萃取，有机相用盐水(200mL*1)洗涤。有机层用无水硫酸镁干燥并过滤。将滤液真空浓缩得到棕色油状化合物2-溴-3,4-二氟苄基甲磺酸酯 (29.0g，96.31mmol，收率97％)。1H NMR(400MHz,DMSO-d6)δppm 7.64-7.51(m,2H),5.40-5.32(m,2H),3.32-3.25(m,3H).Second step: To a solution of (2-bromo-3,4-difluorophenyl)methanol (22.0 g, 98.65 mmol) and triethylamine in dichloromethane (220 mL) was added methanesulfonic anhydride (25.78 g, 148 mmol) at 0°C. The reaction was stirred at 0 °C for 1 hour. Water (200 mL) was added to the mixture and extracted with dichloromethane (100 mL*3), and the organic phase was washed with brine (200 mL*1). The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated in vacuo to afford compound 2-bromo-3,4-difluorobenzyl methanesulfonate as a brown oil (29.0 g, 96.31 mmol, 97% yield). 1 H NMR (400MHz,DMSO-d 6 )δppm 7.64-7.51(m,2H),5.40-5.32(m,2H),3.32-3.25(m,3H).
第三步：在0℃下，向2-溴-3,4-二氟苄基甲磺酸酯(29.0g，96.31mmol)的乙腈(300mL)溶液中加入碳酸钾(26.0g，192mmol)和三甲基氰硅烷(19.0g，192mmol)。将反应在80℃搅拌16小时。将混合物用水(200mL)稀释并用乙酸乙酯(200mL)萃取，有机相用盐水(200mL)洗涤，无水硫酸镁干燥并过滤。滤液旋干，得到的残余物通过快速柱色谱(硅胶，0-15％梯度四氢呋喃/石油醚)纯化得到黄色固体化合物2-(2-溴-3,4-二氟苯基)乙腈(9.80g，42mmol，收率44％)。1H NMR(400MHz,DMSO-d6)δppm 7.64-7.52(m,1H),7.50-7.42(m,1H),4.14(s,2H).Step 3: To a solution of 2-bromo-3,4-difluorobenzyl methanesulfonate (29.0 g, 96.31 mmol) in acetonitrile (300 mL) was added potassium carbonate (26.0 g, 192 mmol) and trimethylsilyl cyanide (19.0 g, 192 mmol) at 0°C. The reaction was stirred at 80 °C for 16 hours. The mixture was diluted with water (200 mL) and extracted with ethyl acetate (200 mL), the organic phase was washed with brine (200 mL), dried over anhydrous magnesium sulfate and filtered. The filtrate was spin-dried, and the resulting residue was purified by flash column chromatography (silica gel, 0-15% gradient tetrahydrofuran/petroleum ether) to obtain a yellow solid compound 2-(2-bromo-3,4-difluorophenyl)acetonitrile (9.80 g, 42 mmol, yield 44%). 1 H NMR (400MHz,DMSO-d 6 )δppm 7.64-7.52(m,1H),7.50-7.42(m,1H),4.14(s,2H).
第四步：向2-(2-溴-3,4-二氟苯基)乙腈(9.50g，40.94mmol)的二甲基乙酰胺(100mL)溶液中加入四(三苯基膦)钯(4.73g，4.09mmol)和氰化锌(5.77g，49.13mmol)。混合物在120℃和氮气保护下加热5小时。反应液旋干，残余物通过快速柱色谱(硅胶，0-25％梯度四氢呋喃/石油醚)纯化得到黄色固体化合物6-(氰基甲基)-2,3-二氟苯甲腈(4.50g，25.26mmol，收率62％)。1H NMR(400MHz,DMSO-d6)δppm 8.00-7.84(m,1H),7.52(br dd,J＝4.1,8.4Hz,1H),4.33(s,2H).Step 4: To a solution of 2-(2-bromo-3,4-difluorophenyl)acetonitrile (9.50 g, 40.94 mmol) in dimethylacetamide (100 mL) was added tetrakis(triphenylphosphine)palladium (4.73 g, 4.09 mmol) and zinc cyanide (5.77 g, 49.13 mmol). The mixture was heated at 120°C for 5 hours under nitrogen protection. The reaction solution was spin-dried, and the residue was purified by flash column chromatography (silica gel, 0-25% tetrahydrofuran/petroleum ether gradient) to obtain a yellow solid compound 6-(cyanomethyl)-2,3-difluorobenzonitrile (4.50 g, 25.26 mmol, yield 62%). 1 H NMR (400MHz, DMSO-d 6 ) δppm 8.00-7.84 (m, 1H), 7.52 (br dd, J=4.1, 8.4Hz, 1H), 4.33 (s, 2H).
第五步：在0℃下，将化合物6-(氰基甲基)-2,3-二氟苯甲腈(4.50g，25.26mmol)缓慢溶于33％的氢溴酸/醋酸溶液(45.00mL)，混合物在0℃搅拌0.2小时，然后在20℃搅拌1.5小时。将混合物用水(150mL)稀释并通过饱和碳酸钠溶液碱化。用乙酸乙酯(150mL*3)萃取，有机相用无水硫酸钠干燥，过滤，滤液旋干，残余物通过快速柱色谱(硅胶，0-25％梯度四氢呋喃/石油醚)纯化得到黄色固体化合物1-溴-7,8-二氟异喹啉-3-胺(0.76g，2.90mmol，收率12％)。LCMS(ESI):[M+H]+＝260.8。1H NMR(400MHz,DMSO-d6)δppm 7.63(dt,J＝7.4,9.8Hz,1H),7.49(ddd,J＝1.6,5.0,9.3Hz,1H),6.69(d,J＝2.4Hz,1H),6.49(s,2H).Step 5: Compound 6-(cyanomethyl)-2,3-difluorobenzonitrile (4.50 g, 25.26 mmol) was slowly dissolved in 33% hydrobromic acid/acetic acid solution (45.00 mL) at 0° C., and the mixture was stirred at 0° C. for 0.2 hours and then at 20° C. for 1.5 hours. The mixture was diluted with water (150 mL) and basified by saturated sodium carbonate solution. Extracted with ethyl acetate (150mL*3), the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was spin-dried, and the residue was purified by flash column chromatography (silica gel, 0-25% gradient tetrahydrofuran/petroleum ether) to obtain yellow solid compound 1-bromo-7,8-difluoroisoquinolin-3-amine (0.76g, 2.90mmol, yield 12%). LCMS (ESI): [M+H] + = 260.8. 1 H NMR (400MHz, DMSO-d 6 ) δppm 7.63(dt, J=7.4,9.8Hz,1H), 7.49(ddd,J=1.6,5.0,9.3Hz,1H), 6.69(d,J=2.4Hz,1H), 6.49(s,2H).
第六步：在氮气气氛下，向1-溴-7,8-二氟异喹啉-3-胺(150mg，0.58mmol)的二氧六环(1.5mL)溶液中加入六丁基二锡(1.00g，1.74mmol)，三环己基膦(32.5mg，0.12mmol)，氯化锂(123mg，2.9mmol)和三(二亚苄基丙酮)二钯(53mg，0.06mmol)。反应液在120℃搅拌16小时。混合物减压旋干，残余物通过快速柱色谱(中性氧化铝，0-5％梯度乙酸乙酯/石油醚)纯化得到黄色油状化合物7,8-二氟-1-(三丁基甲锡烷基)异喹啉-3-胺(260mg，0.55mmol，收率95％)。LCMS(ESI):[M+H]+＝471.0.Step 6: Add hexabutylditin (1.00 g, 1.74 mmol), tricyclohexylphosphine (32.5 mg, 0.12 mmol), lithium chloride (123 mg, 2.9 mmol) and tris(dibenzylideneacetone) dipalladium ( 53 mg, 0.06 mmol). The reaction solution was stirred at 120°C for 16 hours. The mixture was spin-dried under reduced pressure, and the residue was purified by flash column chromatography (neutral alumina, 0-5% gradient ethyl acetate/petroleum ether) to obtain yellow oily compound 7,8-difluoro-1-(tributylstannyl)isoquinolin-3-amine (260mg, 0.55mmol, yield 95%). LCMS (ESI): [M+H] + = 471.0.
第七步：在氮气气氛下，向叔丁基(1R,5S)-3-(7-溴-6-氰基-8-氟-2-(2,2,2-三氟乙氧基)喹唑啉-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(250mg，0.45mmol)的二氧六环(5mL)溶液中加入7,8-二氟-1-(三丁基甲锡烷基)异喹啉-3-胺(251mg，0.54mmol)，碘化亚铜(25.5mg，0.13mmol)，氯化锂(47mg，1.11mmol)和四(三苯基膦)钯(103mg，0.09mmol)。反应在氮气气氛和120℃下搅拌16小时。混合物旋干，得到的粗产物通过快速柱色谱(硅胶，0-50％梯度乙酸乙酯/石油醚)纯化得到黄色固体化合物叔丁基(1R,5S)-3-(7-(3-氨基-7,8-二氟异喹啉-1-基)-6-氰基-8-氟-2-(2,2,2-三氟乙氧基)喹唑啉-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(120mg，0.18mmol，收率40％)。LCMS(ESI):[M+H]+＝660.1.Step 7: To a solution of tert-butyl (1R,5S)-3-(7-bromo-6-cyano-8-fluoro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (250 mg, 0.45 mmol) in dioxane (5 mL) was added 7,8-difluoro-1-(tributyl Stannyl)isoquinolin-3-amine (251 mg, 0.54 mmol), cuprous iodide (25.5 mg, 0.13 mmol), lithium chloride (47 mg, 1.11 mmol) and tetrakis(triphenylphosphine)palladium (103 mg, 0.09 mmol). The reaction was stirred under nitrogen atmosphere at 120°C for 16 hours. The mixture was spin-dried, and the obtained crude product was purified by flash column chromatography (silica gel, 0-50% gradient ethyl acetate/petroleum ether) to obtain yellow solid compound 8-Carboxylate (120 mg, 0.18 mmol, 40% yield). LCMS (ESI): [M+H] + = 660.1.
第八步：向叔丁基(1R,5S)-3-(7-(3-氨基-7,8-二氟异喹啉-1-基)-6-氰基-8-氟-2-(2,2,2-三氟乙氧基)喹唑啉-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(60mg，91umol)的四氢呋喃(1mL)溶液中加入4A分子筛(60mg)，叔丁醇钠(11mg，0.11mmol)和((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲醇(17mg，0.11mmol)。将反应在20℃搅拌2小时。混合物用水(2mL)稀释并用乙酸乙酯(2mL*3)萃 取，合并的有机相用饱和食盐水(2mL)洗涤，无水硫酸镁干燥，过滤，滤液浓缩，残余物通过快速柱色谱(硅胶，0-10％梯度甲醇/二氯甲烷)纯化得到棕色固体化合物叔丁基(1R,5S)-3-(7-(3-氨基-7,8-二氟异喹啉-1-基)-6-氰基-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)喹唑啉-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(47.3mg，66umol，收率72％)。LCMS(ESI):[M+H]+＝719.2.Step 8: Add 4A molecular sieves to a solution of tert-butyl (1R,5S)-3-(7-(3-amino-7,8-difluoroisoquinolin-1-yl)-6-cyano-8-fluoro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (60mg, 91umol) in tetrahydrofuran (1mL) (60 mg), sodium tert-butoxide (11 mg, 0.11 mmol) and ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol (17 mg, 0.11 mmol). The reaction was stirred at 20 °C for 2 hours. The mixture was diluted with water (2mL) and extracted with ethyl acetate (2mL*3) The combined organic phases were washed with saturated brine (2 mL), dried over anhydrous magnesium sulfate, filtered, the filtrate was concentrated, and the residue was purified by flash column chromatography (silica gel, 0-10% gradient methanol/dichloromethane) to obtain brown solid compound tert-butyl (1R, 5S)-3-(7-(3-amino-7,8-difluoroisoquinolin-1-yl)-6-cyano-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H -pyrrolazin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (47.3mg, 66umol, yield 72%). LCMS (ESI): [M+H] + = 719.2.
第九步：向叔丁基(1R,5S)-3-(7-(3-氨基-7,8-二氟异喹啉-1-基)-6-氰基-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)喹唑啉-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(47.3mg，66umol)的乙腈(1mL)溶液中加入氯化氢(4M的二氧六环溶液，330uL，1.3mmol)。将反应在20℃搅拌1小时。溶液浓缩后溶于乙腈(1mL)，用三乙胺中和并浓缩。混合物通过制备型HPLC纯化，得到黄色固体化合物7-(3-氨基-7,8-二氟异喹啉-1-基)-4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)喹唑啉-6-甲腈(9.45mg，15.3umol，收率23％)。LCMS(ESI):[M+H]+＝619.1。1H NMR(400MHz,CD3OD)δppm 8.35(s,1H),7.55(br d,J＝5.0Hz,2H),7.01(br s,1H),5.48(br s,1H),4.64(br d,J＝10.5Hz,2H),4.49-4.38(m,2H),3.91-3.79(m,4H),3.48(br d,J＝10.5Hz,3H),3.20(br s,1H),2.46-2.24(m,3H),1.96(br s,7H).The ninth step: to tert-butyl (1R,5S)-3-(7-(3-amino-7,8-difluoroisoquinolin-1-yl)-6-cyano-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (4 To a solution of 7.3 mg, 66 umol) in acetonitrile (1 mL) was added hydrogen chloride (4M in dioxane, 330 uL, 1.3 mmol). The reaction was stirred at 20 °C for 1 hour. The solution was concentrated and dissolved in acetonitrile (1 mL), neutralized with triethylamine and concentrated. The mixture was purified by preparative HPLC to give the compound 7-(3-amino-7,8-difluoroisoquinolin-1-yl)-4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazoline-6-carbonitrile (9. 45mg, 15.3umol, yield 23%). LCMS (ESI): [M+H] + = 619.1. 1 H NMR (400MHz, CD 3 OD) δppm 8.35(s,1H),7.55(br d,J=5.0Hz,2H),7.01(br s,1H),5.48(br s,1H),4.64(br d,J=10.5Hz,2H),4.49-4.38(m,2H),3.91-3.79 (m,4H),3.48(br d,J=10.5Hz,3H),3.20(br s,1H),2.46-2.24(m,3H),1.96(br s,7H).
实施例27：6-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-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)-4-甲基-5-(三氟甲基)吡啶-2-胺Example 27: 6-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine
实施例29：6-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-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)-4-甲基-5-(全氟乙基)吡啶-2-胺 Example 29: 6-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-4-methyl-5-(perfluoroethyl)pyridin-2-amine
第一步：在手套箱中，向叔丁基(1R,5S)-3-(7-氯-8-氟-2-(2,2,2-三氟乙氧基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(1.40g，2.85mmol)，N,N-双(4-甲氧基苄基)-4-甲基-6-(三丁基甲锡烷基)吡啶-2-胺(3.27g，5.12mmol)，碘化亚铜(163mg，0.85mmol)和氯化锂(302mg，7.12mmol)的二氧六环(28mL)溶液中，加入四(三苯基磷)钯(657mg，0.57mmol)。将混合物氮气保护下在120℃下搅拌16小时。过滤，旋干。残留物用快速柱色谱纯化(硅胶，0-30％梯度的乙酸乙酯/石油醚)，得到黄色固体化合物叔丁基(1R,5S)-3-(7-(6-(双(4-甲氧基苄基)氨基)-4-甲基吡啶-2-基)-8-氟-2-(2,2,2-三氟乙氧基))吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(1.80g，2.24mmol，收率79％)。LCMS(ESI):[M+H]+＝804.6.The first step: In the glove box, tert-butyl (1R,5S)-3-(7-chloro-8-fluoro-2-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.40g, 2.85mmol), N,N-bis(4-methoxybenzyl)-4-methyl-6-( To a solution of tributylstannyl)pyridin-2-amine (3.27g, 5.12mmol), cuprous iodide (163mg, 0.85mmol) and lithium chloride (302mg, 7.12mmol) in dioxane (28mL) was added tetrakis(triphenylphosphine)palladium (657mg, 0.57mmol). The mixture was stirred at 120° C. for 16 hours under nitrogen protection. Filter and spin dry. The residue was purified by flash column chromatography (silica gel, 0-30% gradient ethyl acetate/petroleum ether) to give the yellow solid compound tert-butyl(1R,5S)-3-(7-(6-(bis(4-methoxybenzyl)amino)-4-methylpyridin-2-yl)-8-fluoro-2-(2,2,2-trifluoroethoxy))pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3 .2.1] Octane-8-carboxylate (1.80 g, 2.24 mmol, 79% yield). LCMS (ESI): [M+H] + = 804.6.
第二步：向叔丁基(1R,5S)-3-(7-(6-(双(4-甲氧基苄基)氨基)-4-甲基吡啶-2-基)-8-氟-2-(2,2,2-三氟乙氧基))吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(500mg，0.62mmol)的乙腈(10mL)溶液中，加入N-碘琥珀酰亚胺(700mg，3.11mmol)和对甲苯磺酸(4.30mg，0.02mmol)。将混合物在氮气保护和25℃下搅拌12小时。混合物旋干，加入食盐水(10mL)，使用乙酸乙酯(20mL*3)萃取，有机相用无水硫酸钠干燥，过滤，滤液旋干。残留物用快速柱色谱纯化(硅胶，0-30％梯度的乙酸乙酯/石油醚)得到粗品。该粗品加入水(20mL)中，室温搅拌1小时，过滤，并用石油醚(10mL)洗涤，滤饼真空干燥得到粗品化合物叔丁基(1R,5S)-3-(7-(6-(双(4-甲氧基苄基)氨基)-3-碘-4-甲基吡啶-2-基)-8-氟-2-(2,2,2-三氟乙氧基)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 酯(660mg)，其为黄色固体。LCMS(ESI):[M+H]+＝930.3.1HNMR(400MHz,CDCl3)δppm 9.11(s,1H),7.19(d,J＝8.6Hz,4H),6.87(d,J＝8.6Hz,4H),6.52(s,1H),4.92(q,J＝8.3Hz,2H),4.69(s,4H),4.63-4.38(m,4H),3.81(s,6H),3.76(br dd,J＝4.9,12.4Hz,2H),2.39(s,3H),2.05-1.96(m,2H),1.76(br d,J＝7.7Hz,2H),1.55(s,9H).The second step: Ethanol to tert-butyl (1R,5S)-3-(7-(6-(bis(4-methoxybenzyl)amino)-4-methylpyridin-2-yl)-8-fluoro-2-(2,2,2-trifluoroethoxy))pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (500mg, 0.62mmol) To a solution of nitrile (10 mL), N-iodosuccinimide (700 mg, 3.11 mmol) and p-toluenesulfonic acid (4.30 mg, 0.02 mmol) were added. The mixture was stirred under nitrogen protection at 25°C for 12 hours. The mixture was spin-dried, brine (10 mL) was added, extracted with ethyl acetate (20 mL*3), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried. The residue was purified by flash column chromatography (silica gel, gradient 0-30% ethyl acetate/petroleum ether) to give the crude product. The crude product was added into water (20 mL), stirred at room temperature for 1 hour, filtered, washed with petroleum ether (10 mL), and the filter cake was dried in vacuo to obtain the crude compound tert-butyl(1R,5S)-3-(7-(6-(bis(4-methoxybenzyl)amino)-3-iodo-4-methylpyridin-2-yl)-8-fluoro-2-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-4-yl)-3 ,8-Diazabicyclo[3.2.1]octane-8-carboxylic acid Ester (660 mg) as a yellow solid. LCMS(ESI):[M+H] + ＝930.3. 1 HNMR(400MHz,CDCl 3 )δppm 9.11(s,1H),7.19(d,J＝8.6Hz,4H),6.87(d,J＝8.6Hz,4H),6.52(s,1H),4.92(q,J＝8.3Hz,2H),4.69(s,4H),4.63-4.38(m,4H),3.81(s,6H),3.76(br dd,J＝4.9,12.4Hz,2H),2.39(s,3H),2.05-1.96(m,2H),1.76(br d,J＝7.7Hz,2H),1.55(s,9H).
第三步：将叔丁基(1R,5S)-3-(7-(6-(双(4-甲氧基苄基)氨基)-3-碘-4-甲基吡啶-2-基)-8-氟-2-(2,2,2-三氟乙氧基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(290mg,0.31mmol)和碘化亚铜(178mg,0.94mmol)的N,N-二甲基乙酰胺(7.2mL)溶液，在0℃下加入2,2-二氟-2-(氟磺酰基)乙酸三甲基甲硅烷酯(468mg，1.87mmol)。将混合物氮气保护下在20℃下搅拌1小时。加入水(30mL)，使用乙酸乙酯(30mL)萃取3次，无水硫酸钠干燥，过滤旋干。残留物用快速柱色谱纯化(硅胶，0-30％梯度的四氢呋喃/石油醚)。得到化合物叔丁基(1R,5S)-3-(7-(6-(双(4-甲氧基苄基)氨基)-4-甲基-3-(三氟甲基)吡啶-2-基)-8-氟-2-(2,2,2-三氟乙氧基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯和叔丁基(1R,5S)-3-(7-(6-(双(4-甲氧基苄基)氨基)-4-甲基-3-(全氟乙基)吡啶-2-基)-8-氟-2-(2,2,2-三氟乙氧基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯的混合物(150mg)，其为黄色固体。LCMS(ESI):[M+H]+＝872.5；922.7.The third step: tert-butyl(1R,5S)-3-(7-(6-(bis(4-methoxybenzyl)amino)-3-iodo-4-methylpyridin-2-yl)-8-fluoro-2-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (290mg, 0.31mmol ) and cuprous iodide (178mg, 0.94mmol) in N,N-dimethylacetamide (7.2mL) solution, 2,2-difluoro-2-(fluorosulfonyl)acetate trimethylsilyl ester (468mg, 1.87mmol) was added at 0°C. The mixture was stirred at 20° C. for 1 hour under nitrogen protection. Water (30 mL) was added, extracted three times with ethyl acetate (30 mL), dried over anhydrous sodium sulfate, filtered and spin-dried. The residue was purified by flash column chromatography (silica gel, gradient 0-30% tetrahydrofuran/petroleum ether). The compound tert-butyl(1R,5S)-3-(7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-8-fluoro-2-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate and tert-butyl(1R,5 S)-3-(7-(6-(Bis(4-methoxybenzyl)amino)-4-methyl-3-(perfluoroethyl)pyridin-2-yl)-8-fluoro-2-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate mixture (150 mg) as a yellow solid. LCMS (ESI): [M+H] + = 872.5; 922.7.
第四步：向化合物叔丁基(1R,5S)-3-(7-(6-(双(4-甲氧基苄基)氨基)-4-甲基-3-(三氟甲基)吡啶-2-基)-8-氟-2-(2,2,2-三氟乙氧基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯和叔丁基(1R,5S)-3-(7-(6-(双(4-甲氧基苄基)氨基)-4-甲基-3-(全氟乙基)吡啶-2-基)-8-氟-2-(2,2,2-三氟乙氧基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯的混合物(140mg，0.16mmol)及((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲醇(51.0mg，0.32mmol)的四氢呋喃(2.8mL)溶液中，加入叔丁醇钠(23.0mg，0.24mmol)。混合物在氮气保护下20℃搅拌2小时。加入水(5mL)，使用乙酸乙酯(10mL*3)萃取3，合并的有机相用无水硫酸钠干燥，过滤，滤液旋干，得到粗品化合物叔丁基(1R,5S)-3-(7-(6-(双(4-甲氧基苄基)氨基)-4-甲基-3-(三氟甲基)吡啶-2-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)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯和叔丁基(1R,5S)-3-(7-(6-(双(4-甲氧基苄基)氨基)-4-甲基-3-(全氟乙基)吡啶-2-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)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯的混合物(230mg)，其为黄色油状液体。LCMS(ESI):[M+Na]+＝953.7；[M+H]+＝982.5.The fourth step: to the compound tert-butyl (1R,5S)-3-(7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-8-fluoro-2-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate and tert-butyl (1 ( To a solution of (2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol (51.0 mg, 0.32 mmol) in THF (2.8 mL) was added sodium tert-butoxide (23.0 mg, 0.24 mmol). The mixture was stirred at 20°C for 2 hours under nitrogen protection. Water (5 mL) was added, extracted with ethyl acetate (10 mL*3), the combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried to obtain the crude compound tert-butyl(1R,5S)-3-(7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- Pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate and tert-butyl(1R,5S)-3-(7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(perfluoroethyl)pyridin-2-yl)-8-fluoro-2-(((2R,7 aS)-2-Fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate mixture (230 mg) as a yellow oily liquid. LCMS (ESI): [M+Na] + = 953.7; [M+H] + = 982.5.
第五步：将叔丁基(1R,5S)-3-(7-(6-(双(4-甲氧基苄基)氨基)-4-甲基-3-(三氟甲基)吡啶-2-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)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯和叔丁基(1R,5S)-3-(7-(6-(双(4-甲氧基苄基)氨基)-4-甲基-3-(全氟乙基)吡啶-2-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)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯的混合物(230mg，0.16mmol)溶于三氟乙酸(2.3mL)，在氮气保护下50℃搅拌2小时，然后旋干。加入二氯甲烷(0.5mL)，使用三乙胺调节至pH＝7，旋干。残留物用制备型HPLC纯化，得到两个化合物。保留时间较短的化合物为实施例27(6-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-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)-4-甲基-5-(三氟甲基)吡啶-2-胺)(43.98mg，0.07mmol，收率30％)，其为白色固体。LCMS(ESI):[M+H]+＝591.2.1H NMR(400MHz,CD3OD)δppm 9.03(s,1H),6.63(s,1H),5.48-5.16(m,1H),4.70-4.54(m,2H),4.38-4.18(m,2H),3.75-3.59(m,4H),3.31-3.18(m,3H),3.02(dt,J＝5.7,9.4Hz,1H),2.47(br d,J＝1.2Hz,3H),2.40- 2.20(m,2H),2.19-2.11(m,1H),2.07-1.96(m,2H),1.94-1.73(m,5H).The fifth step: tert-butyl (1R,5S)-3-(7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diaze Heterobicyclo[3.2.1]octane-8-carboxylate and tert-butyl (1R,5S)-3-(7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(perfluoroethyl)pyridin-2-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin A mixture of pyridin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylates (230mg, 0.16mmol) was dissolved in trifluoroacetic acid (2.3mL), stirred at 50°C for 2 hours under nitrogen protection, and then spin-dried. Dichloromethane (0.5 mL) was added, adjusted to pH=7 with triethylamine, and spin-dried. The residue was purified by preparative HPLC to afford two compounds. The compound with shorter retention time is Example 27 (6-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-4-methyl-5-(trifluoromethyl)pyridine pyridin-2-amine) (43.98mg, 0.07mmol, yield 30%) as a white solid. LCMS (ESI): [M+H] + ＝591.2. 1 H NMR (400MHz, CD 3 OD) δppm 9.03 (s, 1H), 6.63 (s, 1H), 5.48-5.16 (m, 1H), 4.70-4.54 (m, 2H), 4.38-4.18 (m, 2H), 3.75-3.59 (m,4H),3.31-3.18(m,3H),3.02(dt,J=5.7,9.4Hz,1H),2.47(br d,J=1.2Hz,3H),2.40- 2.20(m,2H),2.19-2.11(m,1H),2.07-1.96(m,2H),1.94-1.73(m,5H).
保留时间较长的化合物为实施例29(6-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-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)-4-甲基-5-(全氟乙基)吡啶-2-胺)(5.26mg，8.2umol，收率3％)，其为白色固体。LCMS(ESI):[M+H]+＝641.2.1H NMR(400MHz,CD3OD)δppm 8.99(s,1H),6.64(s,1H),5.44-5.21(m,1H),4.60(br s,2H),4.37-4.18(m,2H),3.67(br s,4H),3.30-3.14(m,3H),3.03(dt,J＝5.7,9.3Hz,1H),2.47(br s,3H),2.41-2.21(m,2H),2.20-2.11(m,1H),2.07-1.96(m,2H),1.96-1.71(m,5H).The compound with longer retention time is Example 29 (6-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-4-methyl-5-(perfluoroethyl)pyridine pyridin-2-amine) (5.26 mg, 8.2 umol, yield 3%) as a white solid. LCMS(ESI):[M+H] + ＝641.2. 1 H NMR(400MHz,CD 3 OD)δppm 8.99(s,1H),6.64(s,1H),5.44-5.21(m,1H),4.60(br s,2H),4.37-4.18(m,2H),3.67(br s,4H),3.30-3.14(m,3H),3.03(dt,J＝5.7,9.3Hz,1H),2.47(br s,3H),2.41-2.21(m,2H),2.20-2.11(m,1H),2.07-1.96(m,2H),1.96-1.71(m,5H).
实施例28：N-(6-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-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)-4-甲基-5-(三氟甲基)吡啶-2-基)乙酰胺
Example 28: N-(6-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-4-methyl-5-(trifluoromethyl)pyridine-2- base) acetamide
第一步：在25℃下，将化合物6-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-7-基)-5-(三氟甲基)吡啶-2-胺(35.0mg，0.06mmol)加入到二氯甲烷(500uL)中，加入三乙胺(89uL，0.59mmol)和二碳酸二叔丁酯(15uL,0.07mmol)，混合液在25℃搅拌16小时。减压浓缩反应液得到粗品化合物叔丁基(1R,5S)-3-(7-(6-氨基-4-甲基-3-(三氟甲基)吡啶-2-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)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(40mg，0.06mmol，收率98％)。LCMS(ESI):[M+H]+＝691.2。The first step: at 25°C, the compound 6-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrol-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-(trifluoromethyl)pyridin-2-amine (3 5.0mg, 0.06mmol) was added to dichloromethane (500uL), triethylamine (89uL, 0.59mmol) and di-tert-butyl dicarbonate (15uL, 0.07mmol) were added, and the mixture was stirred at 25°C for 16 hours. The reaction solution was concentrated under reduced pressure to obtain the crude compound tert-butyl(1R,5S)-3-(7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2 .1] Octane-8-carboxylate (40 mg, 0.06 mmol, 98% yield). LCMS (ESI): [M+H] + = 691.2.
第二步：在25℃下，将化合物叔丁基(1R,5S)-3-(7-(6-氨基-4-甲基-3-(三氟甲基)吡啶-2-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)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(35.0mg，0.05mmol)溶于二甲基甲酰胺(400uL)，冷却至0℃，加入吡啶(50uL)，然后缓慢加入乙酰氯(7uL，0.10mmol)，混合液升温至25℃搅拌1小时。反应液用乙酸乙酯(1mL)和水(1mL)分液，水层用乙酸乙酯(1mL*2)萃取。合并的有机层用无水硫酸镁干燥，过滤并浓缩滤液得到棕色油状化合物叔丁基(1R,5S)-3-(7-(6-乙酰氨基-4-甲基-3-(三氟甲基)吡啶-2-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)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(37mg，0.05mmol，收率99％)。LCMS(ESI):[M+H]+＝733.2。The second step: at 25°C, the compound tert-butyl (1R, 5S)-3-(7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3 .2.1] Octane-8-carboxylate (35.0mg, 0.05mmol) was dissolved in dimethylformamide (400uL), cooled to 0°C, pyridine (50uL) was added, and then acetyl chloride (7uL, 0.10mmol) was slowly added, and the mixture was heated to 25°C and stirred for 1 hour. The reaction solution was separated with ethyl acetate (1 mL) and water (1 mL), and the aqueous layer was extracted with ethyl acetate (1 mL*2). The combined organic layers were dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated to give the brown oily compound tert-butyl(1R,5S)-3-(7-(6-acetylamino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl )-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (37 mg, 0.05 mmol, yield 99%). LCMS (ESI): [M+H] + = 733.2.
第三步：在0℃下，将化合物叔丁基(1R,5S)-3-(7-(6-乙酰氨基-4-甲基-3-(三氟甲基)吡啶-2-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)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(35.0mg，0.05mmol)溶于乙睛(1mL)，加入氯化氢(4M的二氧六环溶液，239uL，0.96mmol)，反应在20℃下搅拌2小时。真空浓缩反应液，残余物溶于乙睛(500uL)并用三乙胺中和至pH＞7，减压浓缩除去溶剂，残留物用制备型HPLC纯化，得到白色固体N-(6-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛基-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)-4-甲基-5-(三氟甲基)吡啶-2-基)乙酰胺(15.0mg，0.02mmol，收率50％)。LCMS(ESI):[M+H]+＝633.2。1H NMR(400MHz,CD3OD)δppm 9.05(s,1H),8.33(s,1H),5.44-5.19(m,1H),4.60(br d,J＝19.3Hz,3H),4.37-4.21(m,2H),3.77-3.57(m,4H),3.27-3.19(m,2H),3.09-2.97(m,1H),2.71-2.57(m,3H),2.42-2.10(m,6H),2.06-1.97(m,2H),1.95-1.72(m,5H).The third step: at 0°C, the compound tert-butyl (1R,5S)-3-(7-(6-acetylamino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-8- Fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrroline-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (35.0 mg, 0.05 mmol) was dissolved in acetonitrile (1 mL), and hydrogen chloride (4M in dioxane, 239 u L, 0.96 mmol), and the reaction was stirred at 20°C for 2 hours. The reaction solution was concentrated in vacuo, the residue was dissolved in acetonitrile (500uL) and neutralized with triethylamine to pH>7, concentrated under reduced pressure to remove the solvent, and the residue was purified by preparative HPLC to obtain a white solid N-(6-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octyl-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazine-7a( 5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-4-methyl-5-(trifluoromethyl)pyridin-2-yl)acetamide (15.0 mg, 0.02 mmol, 50% yield). LCMS (ESI): [M+H] + = 633.2. 1 H NMR(400MHz,CD 3 OD)δppm 9.05(s,1H),8.33(s,1H),5.44-5.19(m,1H),4.60(br d,J＝19.3Hz,3H),4.37-4.21(m,2H),3.77-3.57(m,4H),3.27-3.19(m,2H),3.09-2.97(m,1H),2.71-2.57(m,3H),2.42-2.10(m,6H),2.06-1.97(m,2H),1.95-1.72(m,5H).
实施例30：4-(4-(-3,8-二氮杂双环[3.2.1]辛-3-基-2-((二氢-1'H,3'H-螺[氧杂环丁烷-3,2'-吡咯嗪]-7a'(5'H)-基)甲氧基)-8-氟吡啶并[4,3-d]嘧啶-7-基)-5-乙基-6-氟萘-2-醇
Example 30: 4-(4-(-3,8-diazabicyclo[3.2.1]oct-3-yl-2-((dihydro-1'H,3'H-spiro[oxetane-3,2'-pyrrolazin]-7a'(5'H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol
第一步：向叔丁基(1R,5S)-3–(2,7-二氯-8-氟吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(269mg,0.63mmol)和(二氢-1'H,3'H-螺[氧杂环丁烷-3,2'-吡咯嗪]-7a'(5'H)-基)-甲醇(115mg，0.63mmol)的二氧六环(2.5mL)溶液中加入二异丙基乙胺(334uL，1.88mmol)，然后将混合物氮气保护下在80℃下搅拌16小时。反应混合物旋干。残留物用快速柱色谱纯化(硅胶，0-5％梯度的甲醇/二氯甲烷)得到黄色固体化合物叔丁基-3-(7-氯-2-((二氢-1'H,3'H-螺[氧杂环丁烷-3,2'-吡咯嗪]-7a'(5'H)-基)甲氧基)-8-氟吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(83mg，0.14mmol，收率23％)。LCMS(ESI):[M+H]+＝575.4.The first step: to tert-butyl (1R,5S)-3–(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (269mg, 0.63mmol) and (dihydro-1'H,3'H-spiro[oxetane-3,2'-pyrrolazine]-7a'(5'H)- Diisopropylethylamine (334uL, 1.88mmol) was added to a solution of methanol (115mg, 0.63mmol) in dioxane (2.5mL), and the mixture was stirred at 80°C for 16 hours under nitrogen protection. The reaction mixture was spin-dried. The residue was purified by flash column chromatography (silica gel, 0-5% gradient of methanol/dichloromethane) to give the compound tert-butyl-3-(7-chloro-2-((dihydro-1'H,3'H-spiro[oxetane-3,2'-pyrrolazin]-7a'(5'H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2. 1] Octane-8-carboxylate (83 mg, 0.14 mmol, yield 23%). LCMS (ESI): [M+H] + = 575.4.
第二步：在手套箱中，向叔丁基-3-(7-氯-2-((二氢-1'H,3'H-螺[氧杂环丁烷-3,2'-吡咯嗪]-7a'(5'H)-基)甲氧基)-8-氟吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(110mg,0.19mmol)和2-(8-乙基-7-氟-3-(甲氧基甲氧基)萘-1-基)-4,4,5,5-四甲基-1,3,2-二氧杂硼烷(83mg，0.23mmol)的二氧六环(2.2mL)溶液中，加入磷酸钾(1.5M的水溶液，386uL，0.58mmol)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)(14mg，0.02mmol)，然后将混合物氮气保护下在100℃下搅拌3小时。反应混合物旋干。残留物用快速柱色谱纯化(硅胶，0-5％梯度的甲醇/二氯甲烷)得到黄色油状化合物叔丁基-3-(2-((二氢-1'H,3'H-螺[氧杂环丁烷-3,2'-吡咯嗪]-7a'(5'H)-基)甲氧基)-7-(8-乙基-7-氟-3-(甲氧基甲氧基)萘-1-基)-8-氟吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(129mg，0.17mmol，收率87％)。LCMS(ESI):[M+H]+＝773.5.The second step: In the glove box, add tert-butyl-3-(7-chloro-2-((dihydro-1'H,3'H-spiro[oxetane-3,2'-pyrrolazin]-7a'(5'H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (110mg, 0.19 mmol) and 2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (83mg, 0.23mmol) in dioxane (2.2mL) were added potassium phosphate (1.5M in water, 386uL, 0.58mmol) and methanesulfonic acid [n-butylbis(1-adamantyl)phosphine] (2- Amino-1,1-biphenyl-2-yl)palladium(II) (14mg, 0.02mmol), then the mixture was stirred at 100°C for 3 hours under nitrogen protection. The reaction mixture was spin-dried. The residue was purified by flash column chromatography (silica gel, 0-5% gradient of methanol/dichloromethane) to give tert-butyl-3-(2-((dihydro-1'H,3'H-spiro[oxetane-3,2'-pyrrolazin]-7a'(5'H)-yl)methoxy)-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3- d] Pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (129 mg, 0.17 mmol, yield 87%). LCMS (ESI): [M+H] + = 773.5.
第三步：向叔丁基-3-(2-((二氢-1'H,3'H-螺[氧杂环丁烷-3,2'-吡咯嗪]-7a'(5'H)-基)甲氧基)-7-(8-乙基-7-氟-3-(甲氧基甲氧基)萘-1-基)-8-氟吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(110mg，0.14mmol)的二氯甲烷(1760uL)溶液中，加入三氟乙酸(440uL)。混合物在25℃搅拌1小时。用氮气流除去大部分溶剂，再用油泵旋干。然后加入三乙胺(0.5mL)和四氢呋喃(0.5mL)，旋干。残留物用制备型HPLC纯化，得到白色固体化合物4-(4-(3,8-二氮杂双环[3.2.1]辛-3-基-2-((二氢- 1'H,3'H-螺[氧杂环丁烷-3,2'-吡咯嗪]-7a'(5'H)-基)甲氧基)-8-氟吡啶并[4,3-d]嘧啶-7-基)-5-乙基-6-氟萘-2-醇(30.6mg，0.05mmol，收率34％)。LCMS(ESI):[M+H]+＝629.3.1H NMR(400MHz,CD3OD)δppm9.07(s,1H),7.69(dd,J＝5.8,9.1Hz,1H),7.32(d,J＝2.5Hz,1H),7.26(t,J＝9.4Hz,1H),7.07(d,J＝2.4Hz,1H),4.73(br d,J＝6.1Hz,2H),4.67-4.58(m,4H),4.28-4.10(m,2H),3.81-3.60(m,4H),3.53(d,J＝10.4Hz,1H),3.04(br dd,J＝6.8,10.6Hz,1H),2.97(d,J＝10.5Hz,1H),2.78(td,J＝5.2,10.8Hz,1H),2.62-2.42(m,2H),2.28-2.12(m,1H),2.05-1.93(m,3H),1.91-1.76(m,6H),0.81(dt,J＝2.4,7.3Hz,3H).The third step: to tert-butyl-3-(2-((dihydro-1'H,3'H-spiro[oxetane-3,2'-pyrrolazin]-7a'(5'H)-yl)methoxy)-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1 ] To a solution of octane-8-carboxylate (110 mg, 0.14 mmol) in dichloromethane (1760 uL) was added trifluoroacetic acid (440 uL). The mixture was stirred at 25°C for 1 hour. Most of the solvent was removed with a stream of nitrogen and then spin-dried with an oil pump. Then triethylamine (0.5 mL) and tetrahydrofuran (0.5 mL) were added and spin-dried. The residue was purified by preparative HPLC to give white solid compound 4-(4-(3,8-diazabicyclo[3.2.1]oct-3-yl-2-((dihydro- 1'H,3'H-spiro[oxetane-3,2'-pyrrolizine]-7a'(5'H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol (30.6 mg, 0.05 mmol, yield 34%). LCMS(ESI):[M+H] + ＝629.3. 1 H NMR(400MHz,CD 3 OD)δppm9.07(s,1H),7.69(dd,J＝5.8,9.1Hz,1H),7.32(d,J＝2.5Hz,1H),7.26(t,J＝9.4Hz,1H),7.07(d,J＝2.4Hz,1H),4.73(br d,J＝6.1Hz,2H),4.67-4.58(m,4H),4.28-4.10(m,2H),3.81-3.60(m,4H),3.53(d,J＝10.4Hz,1H),3.04(br dd,J＝6.8,10.6Hz,1H),2.97(d,J＝10.5Hz,1H),2.78(td,J＝5.2,10.8Hz,1H),2.62-2.42(m,2H),2.28-2.12(m,1H),2.05-1.93(m,3H),1.91-1.76(m,6H),0.81(dt,J＝2.4,7.3Hz,3H).
实施例31A和实施例31B：4-(4-((1R,5S)-(3,8-二氮杂双环[3.2.1]辛-3-基-2-((二氢-1'H,3'H-螺[氧杂环丁烷-3,2'-吡咯嗪]-7a'(5'H)-基)甲氧基)-8-氟吡啶并[4,3-d]嘧啶-7-基)-5-乙基-6-氟萘-2-醇，和Example 31A and Example 31B: 4-(4-((1R,5S)-(3,8-diazabicyclo[3.2.1]oct-3-yl-2-((dihydro-1'H,3'H-spiro[oxetane-3,2'-pyrrolazin]-7a'(5'H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-5-eth Base-6-fluoronaphthalen-2-ol, and
4-(4-((1R,5S)-(3,8-二氮杂双环[3.2.1]辛-3-基-2-((二氢-1'H,3'H-螺[氧杂环丁烷-3,2'-吡咯嗪]-7a'(5'H)-基)甲氧基)-8-氟吡啶并[4,3-d]嘧啶-7-基)-5-乙基-6-氟萘-2-醇
4-(4-((1R,5S)-(3,8-diazabicyclo[3.2.1]oct-3-yl-2-((dihydro-1'H,3'H-spiro[oxetane-3,2'-pyrrolazin]-7a'(5'H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol
实施例30经SFC分离(柱：DAICEL CHIRALPAK AD(250mm*30mm,10um)；流动相：A相为二氧化碳，B相为0.1％氨水/乙醇；B相保持50％；流速：80毫升/分钟)，得到目标化合物。Example 30 was separated by SFC (column: DAICEL CHIRALPAK AD (250mm*30mm, 10um); mobile phase: phase A was carbon dioxide, phase B was 0.1% ammonia water/ethanol; phase B was maintained at 50%; flow rate: 80 ml/min), and the target compound was obtained.
异构体1,实施例31A：LCMS(ESI):[M+H]+＝629.3；SFC分析(柱：Chiralpak AD-3(50mm*4.6mm)，3um；流动相：A相为二氧化碳，B相为0.05％二乙胺/乙醇；梯度：保持50％的B相5分钟，流速：4毫升/分钟)：手性柱出峰位置为0.660min；1H NMR(400MHz,MeOD)δppm 9.07(s,1H),7.69(dd,J＝5.9,9.0Hz,1H),7.32(d,J＝2.6Hz,1H),7.27(t,J＝9.4Hz,1H),7.07(d,J＝2.6Hz,1H),4.73(dd,J＝1.5,6.1Hz,2H),4.68-4.56(m,4H),4.27-4.12(m,2H),3.81-3.63(m,4H),3.54(d,J＝10.4Hz,1H),3.11-3.01(m,1H),2.97(d,J＝10.4Hz,1H),2.78(td,J＝5.3,10.8Hz,1H),2.62-2.42(m,2H),2.24-2.14(m,1H),2.07-1.93(m,3H),1.93-1.75(m,6H),0.81(dt,J＝2.8,7.4Hz,3H).Isomer 1, Example 31A: LCMS (ESI): [M+H]+=629.3; SFC analysis (column: Chiralpak AD-3 (50mm*4.6mm), 3um; mobile phase: phase A is carbon dioxide, phase B is 0.05% diethylamine/ethanol; gradient: keep 50% of phase B for 5 minutes, flow rate: 4 ml/min): the chiral column peak position is 0.660min;1H NMR (400MHz,MeOD)δppm 9.07(s,1H),7.69(dd,J=5.9,9.0Hz,1H),7.32(d,J=2.6Hz,1H),7.27(t,J=9.4Hz,1H),7.07(d,J=2.6Hz,1H),4.73(dd,J=1.5,6.1Hz, 2H), 4.68-4.56(m, 4H), 4.27-4.12(m, 2H), 3.81-3.63(m, 4H), 3.54(d, J=10.4Hz, 1H), 3.11-3.01(m, 1H), 2.97(d, J=10.4Hz, 1H), 2.78(td, J=5.3, 10. 8Hz,1H),2.62-2.42(m,2H),2.24-2.14(m,1H),2.07-1.93(m,3H),1.93-1.75(m,6H),0.81(dt,J＝2.8,7.4Hz,3H).
异构体2，实施例31B：LCMS(ESI):[M+H]+＝629.3；SFC分析(柱：Chiralpak AD-3(50mm*4.6mm)，3um；流动相：A相为二氧化碳，B相为0.05％二乙胺/乙醇；梯度：保持50％的B相5分钟，流速：4毫升/分钟)：手性柱出峰位置为2.147min；1H NMR(400MHz,CD3OD)δppm 9.07(s,1H),7.69(dd,J＝5.8,9.1Hz,1H),7.32(d,J＝2.7Hz,1H),7.27(t,J＝9.4Hz,1H),7.07(d,J＝2.6Hz,1H),4.73(dd,J＝1.3,6.1Hz,2H),4.68-4.56(m,4H),4.30-4.10(m,2H),3.81-3.63(m,4H),3.55(d,J＝10.5Hz,1H),3.13-2.94(m,2H),2.87-2.74(m,1H),2.63-2.43(m,2H),2.25-2.15(m,1H),2.07-1.94(m,3H),1.93-1.77(m,6H),0.82(dt,J＝2.7,7.4Hz,3H).Isomer 2, Example 31B: LCMS (ESI): [M+H]+=629.3; SFC analysis (column: Chiralpak AD-3 (50mm*4.6mm), 3um; mobile phase: phase A is carbon dioxide, phase B is 0.05% diethylamine/ethanol; gradient: keep 50% phase B for 5 minutes, flow rate: 4 ml/min): the chiral column peak position is 2.147min;1H NMR (400MHz, CD3OD)δppm 9.07(s,1H),7.69(dd,J=5.8,9.1Hz,1H),7.32(d,J=2.7Hz,1H),7.27(t,J=9.4Hz,1H),7.07(d,J=2.6Hz,1H),4.73(dd,J=1.3,6.1Hz,2H),4.68-4 .56(m,4H),4.30-4.10(m,2H),3.81-3.63(m,4H),3.55(d,J=10.5Hz,1H),3.13-2.94(m,2H),2.87-2.74(m,1H),2.63-2.43(m,2H),2.25-2.15(m,1H ),2.07-1.94(m,3H),1.93-1.77(m,6H),0.82(dt,J＝2.7,7.4Hz,3H).
实施例32：4-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-8-氟-2-((六氢-2H-呋喃[2,3-b]吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-7-基)-5-乙基-6-氟萘-2-醇 二甲酸盐
Example 32: 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-((hexahydro-2H-furo[2,3-b]pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol dicarboxylate
第一步：向叔丁基(1R,5S)-3-(7-(8-乙基-7-氟-3-(甲氧基甲氧基)萘-1-基)-8-氟-2-(2,2,2-三氟乙氧基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(800mg，1.16mmol)和(六氢-2H-呋喃[2,3-b]吡咯嗪-7a(5H)-基)甲醇(106mg，0.58mmol)的四氢呋喃(5mL)溶液中加入叔丁醇钠(375mg，2.90mmol)。反应在25℃搅拌16小时。过滤混合物并真空浓缩滤液。残余物通过快速柱色谱(硅胶，0-10％梯度的甲醇/二氯甲烷)纯化得到棕色固体化合物叔丁基(1R,5S)-3-(7-(8-乙基-7-氟-3-(甲氧基甲氧基)萘-1-基)-8-氟-2-((六氢-2H-呋喃[2,3-b]吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(70％纯度，430mg，0.39mmol，收率67％)。LCMS(ESI):[M+H]+＝773.4.The first step: to tert-butyl(1R,5S)-3-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yl)-8-fluoro-2-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (800mg, 1.16mmol) and (hexahydro- To a solution of 2H-furo[2,3-b]pyrrolazin-7a(5H)-yl)methanol (106 mg, 0.58 mmol) in tetrahydrofuran (5 mL) was added sodium tert-butoxide (375 mg, 2.90 mmol). The reaction was stirred at 25°C for 16 hours. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by flash column chromatography (silica gel, 0-10% gradient of methanol/dichloromethane) to give brown solid compound tert-butyl(1R,5S)-3-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yl)-8-fluoro-2-((hexahydro-2H-furo[2,3-b]pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine- 4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (70% purity, 430 mg, 0.39 mmol, yield 67%). LCMS (ESI): [M+H] + = 773.4.
第二步：在0℃下，向含有叔丁基(1R,5S)-3-(7-(8-乙基-7-氟-3-(甲氧基甲氧基)萘-1-基)-8-氟-2-((六氢-2H-呋喃[2,3-b]吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(70％纯度，410mg，0.37mmol)的反应瓶中加入三氟乙酸/二氯甲烷混合溶液(体积比为1/4，5mL)。反应在25℃下搅拌1小时。将该混合物用氮气流在室温下吹干，用二氯甲烷(1mL)稀释并加入三乙胺调节pH至7-8。将混合物真空浓缩，残余物用制备型HPLC纯化得到黄色固体化合物4-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-8-氟-2-((六氢-2H-呋喃[2,3-b]吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-7-基)-5-乙基-6-氟萘-2-醇(二甲酸盐，17.6mg，27umol，收率7％)。LCMS(ESI):[M+H]+＝629.3.1H NMR(400MHz,CD3OD)δppm 9.14(s,1H),8.49(s,2H),7.70(dd,J＝6.0,9.0Hz,1H),7.34(d,J＝2.8Hz,1H),7.28(t,J＝9.3Hz,1H),7.07(d,J＝2.5Hz,1H),4.86-4.75(m,2H),4.65-4.58(m,2H),4.55(t,J＝4.3Hz,1H),4.19-4.06(m,3H),4.03-3.90(m,3H),3.90-3.81(m,1H),3.50-3.40(m,1H),3.27(br dd,J＝5.4,10.2Hz,1H),2.57-2.51(m,1H),2.51-2.43(m,1H),2.33-2.02(m,12H),0.84-0.77(m,3H)The second step: at 0°C, add tert-butyl(1R,5S)-3-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yl)-8-fluoro-2-((hexahydro-2H-furo[2,3-b]pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2. 1] To a reaction flask of octane-8-carboxylate (70% purity, 410mg, 0.37mmol) was added trifluoroacetic acid/dichloromethane mixed solution (volume ratio 1/4, 5mL). The reaction was stirred at 25°C for 1 hour. The mixture was blown dry at room temperature with a stream of nitrogen, diluted with dichloromethane (1 mL) and adjusted to pH 7-8 by addition of triethylamine. The mixture was concentrated in vacuo, and the residue was purified by preparative HPLC to give yellow solid compound 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-((hexahydro-2H-furo[2,3-b]pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalene- 2-alcohol (diformate, 17.6mg, 27umol, yield 7%). LCMS(ESI):[M+H] + ＝629.3. 1 H NMR(400MHz,CD 3 OD)δppm 9.14(s,1H),8.49(s,2H),7.70(dd,J＝6.0,9.0Hz,1H),7.34(d,J＝2.8Hz,1H),7.28(t,J＝9.3Hz,1H),7.07(d,J＝2.5Hz,1H),4.86-4.75(m,2H),4.65-4.58(m,2H),4.55(t,J＝4.3Hz,1H),4.19-4.06(m,3H),4.03-3.90(m,3H),3.90-3.81(m,1H),3.50-3.40(m,1H),3.27(br dd,J＝5.4,10.2Hz,1H),2.57-2.51(m,1H),2.51-2.43(m,1H),2.33-2.02(m,12H),0.84-0.77(m,3H)
以下实施例通过实施例32的合成路线方法进行制备：The following examples are prepared by the synthetic route method of Example 32:
实施例33A：反式-4-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-8-氟-2-(((1aR,6aS,6bS)-六氢环丙[a]吡咯嗪-6a(4H)-基)甲氧基)吡啶并[4,3-d]嘧啶-7-基)-5-乙基-6-氟萘-2-醇甲酸盐
Example 33A: trans-4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(((1aR,6aS,6bS)-hexahydrocyclopropane[a]pyrrolazin-6a(4H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalene-2- Alcohol formate
LCMS(ESI):[M+H]+＝599.3.1H NMR(400MHz,CD3OD)δppm 9.12(s,1H),8.64-8.37(m,2H),7.68(dd,J＝9.1,5.8Hz,1H),7.41-7.20(m,2H),7.05(d,J＝2.6Hz,1H),4.78-4.64(m,4H),3.96-3.75(m,4H),3.66(br d,J＝11.4Hz,2H),3.38(br dd,J＝11.7,4.3Hz,2H),2.55-2.15(m,6H),2.03-1.87(m,6H),0.92-0.70(m,5H).LCMS(ESI):[M+H]+=599.3.1H NMR (400MHz, CD3OD)δppm 9.12(s,1H),8.64-8.37(m,2H),7.68(dd,J=9.1,5.8Hz,1H),7.41-7.20(m,2H),7.05(d,J=2.6Hz,1H),4.78-4.64(m,4H),3.96-3.75(m,4H), 3.66(br d,J=11.4Hz,2H),3.38(br dd,J=11.7,4.3Hz,2H),2.55-2.15(m,6H),2.03-1.87(m,6H),0.92-0.70(m,5H).
实施例33B：顺式-4-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-8-氟-2-((六氢环丙[a]吡咯嗪-6a(4H)-基)甲氧基)吡啶并[4,3-d]嘧啶-7-基)-5-乙基-6-氟萘-2-醇
Example 33B: cis-4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-((hexahydrocyclopropane[a]pyrrolazin-6a(4H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol
LCMS(ESI):[M+H]+＝599.3.1H NMR(400MHz,CD3OD)δppm 9.06(s,1H),7.68(dd,J＝9.1,5.9Hz,1H),7.38-7.18(m,2H),7.06(d,J＝2.6Hz,1H),4.73-4.57(m,2H),4.49-4.24(m,2H),3.80-3.63(m,4H),3.44(br dd,J＝11.6,4.10Hz,1H),3.07(br d,J＝5.5Hz,1H),2.90(d,J＝11.6Hz,1H),2.73-2.60(m,1H),2.57-2.42(m,1H),2.25-2.13(m,1H),2.08(br d,J＝3.2Hz,1H),2.02-1.93(m,3H),1.92-1.76(m,5H),1.70(br d,J＝7.6Hz,1H),0.88-0.67(m,4H),0.36-0.25(m,1H).LCMS(ESI):[M+H]+=599.3.1H NMR (400MHz, CD3OD)δppm 9.06(s,1H),7.68(dd,J=9.1,5.9Hz,1H),7.38-7.18(m,2H),7.06(d,J=2.6Hz,1H),4.73-4.57(m,2H),4.49-4.24(m,2H),3.80-3.63(m,4H), 3.44(br dd,J=11.6,4.10Hz,1H),3.07(br d,J=5.5Hz,1H),2.90(d,J=11.6Hz,1H),2.73-2.60(m,1H),2.57-2.42(m,1H),2.25-2.13(m,1H),2.08(br d,J ＝3.2Hz,1H),2.02-1.93(m,3H),1.92-1.76(m,5H),1.70(br d,J＝7.6Hz,1H),0.88-0.67(m,4H),0.36-0.25(m,1H).
实施例34：4-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-2-((二氢-1'H,3'H-螺[环丙烷-1,2'-吡咯嗪]-7a'(5'H)-基)甲氧基)-8-氟吡啶并[4,3-d]嘧啶-7-基)-5-乙基-6-氟萘-2-醇甲酸盐
Example 34: 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-((dihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolazin]-7a'(5'H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalene-2- Alcohol formate
LCMS(ESI):[M+H]+＝613.3.1H NMR(400MHz,CD3OD)δppm 9.12(s,1H),8.54(br s,1H),7.69(dd,J＝6.0,9.0Hz,1H),7.34-7.21(m,2H),7.06(d,J＝2.3Hz,1H),4.67-4.56(m,4H),3.83-3.67(m,7H),3.16(m,1H),2.56-2.05(m,8H),1.88(br s,2H),1.79(br d,J＝8.8Hz,2H),0.87-0.67(m,7H).LCMS(ESI):[M+H]+=613.3.1H NMR (400MHz, CD3OD)δppm 9.12(s,1H),8.54(br s,1H),7.69(dd,J＝6.0,9.0Hz,1H),7.34-7.21(m,2H),7.06(d,J＝2.3Hz,1H),4.67-4.56(m,4H),3.83-3.67(m,7H),3.1 6(m,1H),2.56-2.05(m,8H),1.88(br s,2H),1.79(br d,J＝8.8Hz,2H),0.87-0.67(m,7H).
实施例35：反式-4-(4-((1S,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-吡咯嗪]-7a'(5'H)-基)甲氧基)-8-氟吡啶并[4,3-d]嘧啶-7-基)-5-乙基-6-氟萘-2-醇
Example 35: trans-4-(4-((1S,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolazin]-7a'(5'H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrim Pyridin-7-yl)-5-ethyl-6-fluoronaphthalene-2-ol
LCMS(ESI):[M+H]+＝649.3.1H NMR(400MHz,CDCl3)δppm 9.08(s,1H),7.69(dd,J＝6.0,9.0Hz,1H),7.35-7.24(m,2H),7.07(d,J＝2.5Hz,1H),4.70-4.59(m,2H),4.42-4.35(m,2H),3.78-3.65(m,4H),3.32-3.27(m,1H),3.20-3.14(m,1H),2.86(d,J＝12.3Hz,1H),2.75-2.68(m,1H),2.51(br dd,J＝7.0,15.1Hz,1H),2.33-2.12(m,3H),2.04(d,J＝13.6Hz,1H),1.95-1.77(m,7H),1.52-1.35(m,2H),0.88-0.75(m,3H).LCMS(ESI):[M+H]+=649.3.1H NMR (400MHz, CDCl3)δppm 9.08(s,1H),7.69(dd,J=6.0,9.0Hz,1H),7.35-7.24(m,2H),7.07(d,J=2.5Hz,1H),4.70-4.59(m,2H),4.42-4.35(m,2H),3.78-3.65(m,4H),3 .32-3.27(m,1H),3.20-3.14(m,1H),2.86(d,J=12.3Hz,1H),2.75-2.68(m,1H),2.51(br dd,J=7.0,15.1Hz,1H),2.33-2.12(m,3H),2.04(d,J=13.6Hz,1 H),1.95-1.77(m,7H),1.52-1.35(m,2H),0.88-0.75(m,3H).
实施例35A和实施例35B：4-(4-((1S,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-吡咯嗪]-7a'(5'H)-基)甲氧基)-8-氟吡啶并[4,3-d]嘧啶-7-基)-5-乙基-6-氟萘-2-醇，和Example 35A and Example 35B: 4-(4-((1S,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolazin]-7a'(5'H)-yl)methoxy)-8-fluoropyrido[4,3 -d] pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol, and
4-(4-((1S,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-2-(((1R,7a'R)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-吡咯嗪]-7a'(5'H)-基)甲氧基)-8-氟吡啶并[4,3-d]嘧啶-7-基)-5-乙基-6-氟萘-2-醇
4-(4-((1S,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(((1R,7a'R)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolazin]-7a'(5'H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-5 -Ethyl-6-fluoronaphthalen-2-ol
实施例35经SFC分离(柱：DAICEL CHIRALPAK IG(250mm*30mm,10um)；流动相：A相为二氧化碳，B相为乙醇；B相保持45％；流速：80毫升/分钟)得到出峰时间较短的手性单体35A及出峰时间较长的手性单体35B。Example 35 was separated by SFC (column: DAICEL CHIRALPAK IG (250mm*30mm, 10um); mobile phase: phase A is carbon dioxide, phase B is ethanol; phase B is kept at 45%; flow rate: 80 ml/min) to obtain chiral monomer 35A with a shorter peak time and chiral monomer 35B with a longer peak time.
实施例35A：异构体1，白色固体，LCMS(ESI):[M+H]+＝649.3；SFC分析(柱：Chiralpak IG-3 100*4.6mm I.D.，3um；流动相：A相为二氧化碳，B相为0.05％二乙胺/乙醇；梯度：B相在4分钟内从5％到40％，保持40％的B相2.5分钟，保持5％的B相1.5分钟，流速：2.8毫升/分钟)：RT＝2.311min,ee＝98.68％；1H NMR(400MHz,CD3OD)δppm 8.96(s,1H),7.57(dd,J＝5.9,8.9Hz,1H),7.20(d,J＝2.4Hz,1H),7.14(t,J＝9.4Hz,1H),6.95(d,J＝2.3Hz,1H),4.56-4.48(m,2H),4.31-4.20(m,2H),3.66-3.51(m,4H),3.19-3.16(m,1H),3.09-3.01(m,1H),2.74(br d,J＝12.3Hz,1H),2.63-2.55(m,1H),2.38(br dd,J＝7.1,13.9Hz,1H),2.21-2.01(m,3H),1.96-1.91(m,1H),1.82-1.64(m,7H),1.37-1.28(m,2H),0.69(br t,J＝7.3Hz,3H)。 Example 35A: Isomer 1, white solid, LCMS (ESI): [M+H]+=649.3; SFC analysis (column: Chiralpak IG-3 100*4.6mm I.D., 3um; Mobile phase: A phase is carbon dioxide, B phase is 0.05% diethylamine/ethanol; Gradient: B phase is from 5% to 40% in 4 minutes, keeps 40% B phase 2.5 minutes, keeps 5% B phase 1.5 minutes, flow velocity: 2.8 milliliters/minute): RT=2.311min, ee = 98.68%;1H NMR (400MHz, CD3OD)δppm 8.96(s,1H),7.57(dd,J=5.9,8.9Hz,1H),7.20(d,J=2.4Hz,1H),7.14(t,J=9.4Hz,1H),6.95(d,J=2.3Hz,1H),4.56-4.48(m,2H),4.31-4.20(m, 2H),3.66-3.51(m,4H),3.19-3.16(m,1H),3.09-3.01(m,1H),2.74(br d,J=12.3Hz,1H),2.63-2.55(m,1H),2.38(br dd,J=7.1,13.9Hz,1H),2.21-2.01 (m, 3H), 1.96-1.91 (m, 1H), 1.82-1.64 (m, 7H), 1.37-1.28 (m, 2H), 0.69 (br t, J=7.3Hz, 3H).
实施例35B：异构体2，白色固体，LCMS(ESI):[M+H]+＝649.3；SFC分析(柱：Chiralpak IG-3 100*4.6mm I.D.，3um；流动相：A相为二氧化碳，B相为0.05％二乙胺/乙醇；梯度：B相在4分钟内从5％到40％，保持40％的B相2.5分钟，保持5％的B相1.5分钟，流速：2.8毫升/分钟)：RT＝3.397min,ee＝96.08％；1H NMR(400MHz,CD3OD)δppm 9.00-8.92(m,1H),7.61-7.53(m,1H),7.24-7.10(m,2H),7.00-6.93(m,1H),4.48-4.42(m,2H),4.32-4.23(m,2H),3.66-3.53(m,4H),3.17(br s,1H),3.08-3.03(m,1H),2.78-2.69(m,1H),2.64-2.55(m,1H),2.44-2.33(m,1H),2.23-2.13(m,1H),2.12-2.01(m,2H),1.97-1.92(m,1H),1.83-1.63(m,7H),1.39-1.29(m,2H),0.73-0.65(m,3H).Example 35B: Isomer 2, white solid, LCMS (ESI): [M+H]+=649.3; SFC analysis (column: Chiralpak IG-3 100*4.6mm I.D., 3um; Mobile phase: A phase is carbon dioxide, B phase is 0.05% diethylamine/ethanol; Gradient: B phase is from 5% to 40% in 4 minutes, keeps 40% B phase 2.5 minutes, keeps 5% B phase 1.5 minutes, flow rate: 2.8 milliliters/minute): RT=3.397min, ee = 96.08%;1H NMR (400MHz, CD3OD)δppm 9.00-8.92(m,1H),7.61-7.53(m,1H),7.24-7.10(m,2H),7.00-6.93(m,1H),4.48-4.42(m,2H),4.32-4.23(m,2H),3.66-3.53(m,4H),3.1 1 .83-1.63(m,7H),1.39-1.29(m,2H),0.73-0.65(m,3H).
实施例36：顺式-4-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-2-(((1R,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-吡咯嗪]-7a'(5'H)-基)甲氧基)-8-氟吡啶并[4,3-d]嘧啶-7-基)-5-乙基-6-氟萘-2-醇
Example 36: cis-4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(((1R,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolazin]-7a'(5'H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrim Pyridin-7-yl)-5-ethyl-6-fluoronaphthalene-2-ol
LCMS(ESI):[M+H]+＝649.3.1H NMR(400MHz,CDCl3)δppm 9.01-8.95(m,1H),7.55(dd,J＝5.8,8.8Hz,1H),7.23-7.17(m,2H),7.04(br s,1H),4.68-4.47(m,2H),4.24-4.16(m,2H),3.73-3.57(m,4H),3.28(d,J＝10.5Hz,1H),3.17(td,J＝5.2,10.2Hz,1H),2.86-2.72(m,2H),2.50(br d,J＝6.5Hz,1H),2.41-2.33(m,1H),2.27-2.08(m,3H),2.05-1.83(m,7H),1.39-1.31(m,2H),0.88-0.81(m,3H).LCMS(ESI):[M+H]+=649.3.1H NMR (400MHz, CDCl3)δppm 9.01-8.95(m,1H),7.55(dd,J＝5.8,8.8Hz,1H),7.23-7.17(m,2H),7.04(br s,1H),4.68-4.47(m,2H),4.24-4.16(m,2H),3.73-3.57(m,4H),3 .28(d,J=10.5Hz,1H),3.17(td,J=5.2,10.2Hz,1H),2.86-2.72(m,2H),2.50(br d,J=6.5Hz,1H),2.41-2.33(m,1H),2.27-2.08(m,3H),2.05-1.83(m,7 H),1.39-1.31(m,2H),0.88-0.81(m,3H).
实施例37：4-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-8-氟-2-((六氢环丙[b]吡咯嗪-5a(3H)-基)甲氧基)吡啶并[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-醇
Example 37: 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-((hexahydrocyclopropane[b]pyrrolazin-5a(3H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol
第一步：向(1R,5S)-叔丁基3-(2,7-二氯-8-氟吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(200mg，0.47mmol)的二氧六环(5mL)溶液中加入(六氢环丙[b]吡咯嗪-5a(3H)-基)甲醇 (85％纯度，257mg，1.40mmol)，二异丙基乙胺(0.39mL，2.33mmol)。反应在80℃下搅拌16小时。真空浓缩混合物。残余物通过快速柱色谱(硅胶，0-10％梯度的甲醇/二氯甲烷)纯化得到黄色固体化合物叔丁基(1R,5S)-3-(7-氯-8-氟-2-((六氢环丙[b]吡咯嗪-5a(3H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(130mg，0.24mmol，收率51％)。LCMS(ESI):[M+H]+＝545.3.Step 1: To a solution of (1R,5S)-tert-butyl 3-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (200 mg, 0.47 mmol) in dioxane (5 mL) was added (hexahydrocyclopropane[b]pyrrolazin-5a(3H)-yl)methanol (85% purity, 257 mg, 1.40 mmol), diisopropylethylamine (0.39 mL, 2.33 mmol). The reaction was stirred at 80°C for 16 hours. The mixture was concentrated in vacuo. The residue was purified by flash column chromatography (silica gel, 0-10% gradient of methanol/dichloromethane) to give the yellow solid compound tert-butyl(1R,5S)-3-(7-chloro-8-fluoro-2-((hexahydrocyclopropane[b]pyrrolazin-5a(3H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (13 0 mg, 0.24 mmol, yield 51%). LCMS (ESI): [M+H] + = 545.3.
第二步：在氮气环境下中，向叔丁基(1R,5S)-3-(7-氯-8-氟-2-((六氢环丙[b]吡咯嗪-5a(3H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(120mg，0.22mmol)的二氧六环(2mL)和水(0.40mL)溶液中加入((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(135mg，0.26mmol)，碳酸铯(215mg，0.66mmol)和[(二(1-金刚烷基)-N-丁基膦)-2-(2-氨基联苯)氯化钯(II)(14.72mg，0.02mmol)，并将混合物在100℃下搅拌3小时。将混合物真空浓缩。残余物通过快速柱色谱(硅胶，0-10％梯度的甲醇/二氯甲烷)纯化，得到黄色固体化合物叔丁基(1R,5S)-3-(8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三异丙基甲硅烷基)乙炔基)萘-1-基)-2-((六氢环丙[b]吡咯嗪-5a(3H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(44mg，0.05mmol，收率22％)。LCMS(ESI):[M+H]+＝896.5.The second step: under nitrogen atmosphere, dioxane (2mL ) and water (0.40 mL) were added ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalene-1-yl)ethynyl)triisopropylsilane (135mg, 0.26mmol), cesium carbonate (215mg, 0.66mmol) and [(bis(1-adamantyl)-N-butylphosphine)-2- (2-aminobiphenyl)palladium(II) chloride (14.72 mg, 0.02 mmol), and the mixture was stirred at 100° C. for 3 hours. The mixture was concentrated in vacuo. The residue was purified by flash column chromatography (silica gel, 0-10% gradient of methanol/dichloromethane) to give the yellow solid compound tert-butyl(1R,5S)-3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-((hexahydrocycloprop[b]pyrrolazin-5a(3H)-yl)methoxy)pyrido[4,3- d] Pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (44 mg, 0.05 mmol, yield 22%). LCMS (ESI): [M+H] + = 896.5.
第三步：向叔丁基(1R,5S)-3-(8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三异丙基甲硅烷基)乙炔基)萘-1-基)-2-((六氢环丙[b]吡咯嗪-5a(3H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(40mg，0.04mmol)的二氯甲烷(400uL)溶液中，在0℃下加入三氟乙酸(80uL)。反应在25℃下搅拌2小时。将混合物真空浓缩，得到粗品化合物4-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-8-氟-2-((六氢环丙[b]吡咯嗪-5a(3H)-基)甲氧基)吡啶并[4,3-d]嘧啶-7-基)-6-氟-5-((三异丙基甲硅烷基)乙炔基)萘-2-醇(30mg)，为棕色固体。LCMS(ESI):[M+H]+＝751.4.The third step: to tert-butyl(1R,5S)-3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalene-1-yl)-2-((hexahydrocyclopropane[b]pyrrolazin-5a(3H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1] To a solution of octane-8-carboxylate (40 mg, 0.04 mmol) in dichloromethane (400 uL) was added trifluoroacetic acid (80 uL) at 0°C. The reaction was stirred at 25°C for 2 hours. The mixture was concentrated in vacuo to afford the crude compound 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-((hexahydrocycloprop[b]pyrrolazin-5a(3H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-6-fluoro-5-((triisopropylsilyl)ethynyl)naphthalen-2-ol ( 30mg), as a brown solid. LCMS (ESI): [M+H] + = 751.4.
第四步：向4-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-8-氟-2-((六氢环丙[b]吡咯嗪-5a(3H)-基)甲氧基)吡啶并[4,3-d]嘧啶-7-基)-6-氟-5-((三异丙基甲硅烷基)乙炔基)萘-2-醇(40mg，0.05mmol)的二甲基甲酰胺(400uL)溶液中加入氟化铯(162mg，1.07mmol)。反应在20℃下搅拌2小时。反应液真空浓缩，残余物经过制备型HPLC纯化，得到黄色固体化合物4-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-8-氟-2-((六氢环丙[b]吡咯嗪-5a(3H)-基)甲氧基)吡啶并[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-醇(3.06mg，4.5umol，收率9％)。LCMS(ESI):[M+H]+＝595.3.1HNMR(400MHz,CD3OD)δppm 9.02(s,1H),7.88(dd,J＝5.8,9.0Hz,1H),7.41-7.30(m,2H),7.23(d,J＝2.3Hz,1H),4.28-4.15(m,2H),3.78-3.65(m,4H),3.38(d,J＝3.8Hz,1H),3.28-3.21(m,1H),3.03-2.95(m,1H),2.79-2.71(m,1H),2.23-2.13(m,2H),2.08(br dd,J＝6.1,13.4Hz,1H),2.01-1.77(m,8H),1.65(br dd,J＝5.0,9.0Hz,1H),1.33(br d,J＝18.3Hz,1H),0.69(q,J＝7.7Hz,1H),0.50(br s,1H).The fourth step: to 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-((hexahydrocyclopropane[b]pyrrolazin-5a(3H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-6-fluoro-5-((triisopropylsilyl)ethynyl)naphthalene-2-ol (40mg, 0 .05mmol) in dimethylformamide (400uL) was added cesium fluoride (162mg, 1.07mmol). The reaction was stirred at 20°C for 2 hours. The reaction solution was concentrated in vacuo, and the residue was purified by preparative HPLC to obtain a yellow solid compound 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-((hexahydrocyclopropane[b]pyrrolazin-5a(3H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalene-2-ol (3. 06mg, 4.5umol, yield 9%). LCMS(ESI):[M+H] + ＝595.3. 1 HNMR(400MHz,CD 3 OD)δppm 9.02(s,1H),7.88(dd,J＝5.8,9.0Hz,1H),7.41-7.30(m,2H),7.23(d,J＝2.3Hz,1H),4.28-4.15(m,2H),3.78-3.65(m,4H),3.38(d,J＝3.8Hz,1H),3.28-3.21(m,1H),3.03-2.95(m,1H),2.79-2.71(m,1H),2.23-2.13(m,2H),2.08(br dd,J＝6.1,13.4Hz,1H),2.01-1.77(m,8H),1.65(br dd,J＝5.0,9.0Hz,1H),1.33(br d,J＝18.3Hz,1H),0.69(q,J＝7.7Hz,1H),0.50(br s,1H).
以下实施例通过实施例37的合成路线方法进行制备：The following examples are prepared by the synthetic route method of Example 37:
实施例38：4-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛烷-3-基)-2-((二氢-1'H,3'H-螺[环丙烷-1,2'-吡咯嗪]-7a'(5'H)-基)甲氧基)-8-氟吡啶并[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-醇
Example 38: 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-((dihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolazin]-7a'(5'H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalene- 2-ol
LCMS(ESI):[M+H]+＝609.3.1H NMR(400MHz,CD3OD)δppm 9.02(s,1H),7.86(dd,J＝5.7,9.1Hz,1H),7.38-7.28(m,2H),7.21(d,J＝2.2Hz,1H),4.52-4.32(m,2H),3.79-3.61(m,5H),3.36(br d,J＝4.5Hz,2H),3.23-3.16(m,1H),3.03-2.80(m,3H),2.17-1.78(m,10H),0.70-0.54(m,4H).LCMS(ESI):[M+H]+=609.3.1H NMR (400MHz, CD3OD)δppm 9.02(s,1H),7.86(dd,J=5.7,9.1Hz,1H),7.38-7.28(m,2H),7.21(d,J=2.2Hz,1H),4.52-4.32(m,2H),3.79-3.61(m,5H),3.36(br d,J=4.5Hz, 2H),3.23-3.16(m,1H),3.03-2.80(m,3H),2.17-1.78(m,10H),0.70-0.54(m,4H).
实施例39：4-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛烷-3-基)-2-((二氢-1'H,3'H-螺[氧杂环丁烷-3,2'-吡咯嗪]-7a'(5'H)-基)甲氧基)-8-氟吡啶并[4，3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-醇
Example 39: 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-((dihydro-1'H,3'H-spiro[oxetane-3,2'-pyrrolazin]-7a'(5'H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoro Naphthalene-2-ol
LCMS(ESI):[M+H]+＝625.5.1H NMR(400MHz,CD3OD)δppm 9.02(s,1H),7.87(dd,J＝5.6,9.2Hz,1H),7.39-7.30(m,2H),7.22(d,J＝2.0Hz,1H),4.73(br d,J＝6.0Hz,2H),4.70-4.52(m,4H),4.26-4.10(m,2H),3.79-3.60(m,4H),3.53(d,J＝10.3Hz,1H),3.37(d,J＝9.0Hz,1H),3.09-3.00(m,1H),2.97(br d,J＝10.5Hz,1H),2.83-2.70(m,1H),2.55(dd,J＝2.3,13.3Hz,1H),2.04(s,3H),1.92-1.76(m,6H).LCMS(ESI):[M+H]+=625.5.1H NMR (400MHz, CD3OD)δppm 9.02(s,1H),7.87(dd,J=5.6,9.2Hz,1H),7.39-7.30(m,2H),7.22(d,J=2.0Hz,1H),4.73(br d,J=6.0Hz,2H),4.70-4.52(m,4H),4.26-4.10(m, 2H),3.79-3.60(m,4H),3.53(d,J=10.3Hz,1H),3.37(d,J=9.0Hz,1H),3.09-3.00(m,1H),2.97(br d,J=10.5Hz,1H),2.83-2.70(m,1H),2.55(dd,J=2.3, 13.3Hz,1H),2.04(s,3H),1.92-1.76(m,6H).
实施例40A：4-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-2-(((1R,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-吡咯嗪]-7a'(5'H)-基)甲氧基)-8-氟吡啶并[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-醇
Example 40A: 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(((1R,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolazin]-7a'(5'H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidine- 7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol
第一步：在25℃下向叔丁基(1R,5S)-3-(8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三异丙基甲硅烷基)乙炔基)萘-1-基)-2-(2,2,2-三氟乙氧基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(547mg，0.65mmol)和((1R,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-吡咯嗪]-7a'(5'H)-基)甲醇A16-1A (120mg，0.59mmol)的四氢呋喃(5mL)溶液中加入叔丁醇钠(85mg，0.89mmol)。将溶液在25℃搅拌2小时。将溶液浓缩并通过快速柱色谱(硅胶，0-10％梯度甲醇/二氯甲烷)纯化得到棕色油状化合物叔丁基(1R,5S)-3-(2-(((1R,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-吡咯嗪]-7a'(5'H)-基)甲氧基)-8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三异丙基甲硅烷基)乙炔基)萘-1-基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(纯度50％，470mg，0.25mmol，收率42％)。LCMS(ESI):[M+H]+＝944.9.The first step: tert-butyl (1R,5S)-3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalene-1-yl)-2-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate ( 547 mg, 0.65 mmol) and ((1R,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolazin]-7a'(5'H)-yl)methanol A16-1A (120 mg, 0.59 mmol) in THF (5 mL) was added sodium tert-butoxide (85 mg, 0.89 mmol). The solution was stirred at 25°C for 2 hours. The solution was concentrated and purified by flash column chromatography (silica gel, 0-10% methanol/dichloromethane gradient) to afford the compound tert-butyl(1R,5S)-3-(2-(((1R,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolazin]-7a'(5'H)-yl)methoxy)-8-fluoro-7-(7-fluoro-3-(methyl Oxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (purity 50%, 470 mg, 0.25 mmol, yield 42%). LCMS (ESI): [M+H] + = 944.9.
第二步：在25℃下向叔丁基(1R,5S)-3-(2-(((1R,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-吡咯嗪]-7a'(5'H)-基)甲氧基)-8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三异丙基甲硅烷基)乙炔基)萘-1-基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(纯度50％，470mg，0.25mmol)在二甲基甲酰胺(5mL)中的溶液中加入氟化铯(604mg，3.98mmol)。悬浮液在25℃下搅拌2小时。将溶液浓缩并通过快速柱色谱(硅胶，0-10％梯度二氯甲烷/甲醇)纯化，得到棕色油状化合物叔丁基(1R,5S)-3-(2-(((1R,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-吡咯嗪]-7a'(5'H)-基)甲氧基)-7-(8-乙炔基-7-氟-3-(甲氧基甲氧基))萘-1-基)-8-氟吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(纯度79％，370mg，0.37mmol，收率93％)。LCMS(ESI):[M+H]+＝789.4。The second step: tert-butyl(1R,5S)-3-(2-(((1R,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolazin]-7a'(5'H)-yl)methoxy)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalene To a solution of -1-yl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (50% purity, 470 mg, 0.25 mmol) in dimethylformamide (5 mL) was added cesium fluoride (604 mg, 3.98 mmol). The suspension was stirred at 25°C for 2 hours. The solution was concentrated and purified by flash column chromatography (silica gel, 0-10% gradient dichloromethane/methanol) to give tert-butyl(1R,5S)-3-(2-(((1R,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolazin]-7a'(5'H)-yl)methoxy)-7-(8-ethynyl-7-fluoro-3 -(methoxymethoxy))naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (purity 79%, 370mg, 0.37mmol, yield 93%). LCMS (ESI): [M+H] + = 789.4.
第三步：在25℃下将叔丁基(1R,5S)-3-(2-(((1R,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-吡咯嗪]-7a'(5'H)-基)甲氧基)-7-(8-乙炔基-7-氟-3-(甲氧基甲氧基))萘-1-基)-8-氟吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(纯度79％，370mg，0.37mmol)溶于三氟乙酸/二氯甲烷(体积比为1/4，4mL)并搅拌2小时。溶液用三乙胺(1.5mL)调节至中性并用水(8mL)稀释，乙酸乙酯(4mL*3)萃取。干燥合并的有机层并浓缩，得到的粗产物通过制备型HPLC纯化，得到黄色固体化合物4-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-2-(((1R,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-吡咯嗪]-7a'(5'H)-基)甲氧基)-8-氟吡啶并[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-醇(27.3mg，39.8umol，收率11％)。LCMS(ESI):[M+H]+＝645.3。1H NMR(400MHz,CD3OD)δppm 9.01(s,1H),7.85(dd,J＝5.7,9.2Hz,1H),7.39-7.28(m,2H),7.24-7.19(m,1H),4.69-4.43(m,2H),4.35-4.17(m,2H),3.79-3.62(m,4H),3.36-3.33(m,1H),3.26-3.21(m,1H),3.14-3.07(m,1H),2.92-2.79(m,2H),2.32(dd,J＝5.1,13.4Hz,1H),2.15-1.76(m,9H),1.52-1.39(m,2H).The third step: tert-butyl (1R,5S)-3-(2-(((1R,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolazin]-7a'(5'H)-yl)methoxy)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy))naphthalene-1-yl)-8-fluoropyrido[4 ,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (purity 79%, 370 mg, 0.37 mmol) was dissolved in trifluoroacetic acid/dichloromethane (volume ratio 1/4, 4 mL) and stirred for 2 hours. The solution was adjusted to neutral with triethylamine (1.5 mL) and diluted with water (8 mL), extracted with ethyl acetate (4 mL*3). The combined organic layers were dried and concentrated, and the resulting crude product was purified by preparative HPLC to give compound 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(((1R,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolazin]-7a'(5'H)-yl)methoxy) as a yellow solid -8-fluoropyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (27.3mg, 39.8umol, yield 11%). LCMS (ESI): [M+H] + = 645.3. 1 H NMR(400MHz,CD 3 OD)δppm 9.01(s,1H),7.85(dd,J＝5.7,9.2Hz,1H),7.39-7.28(m,2H),7.24-7.19(m,1H),4.69-4.43(m,2H),4.35-4.17(m,2H),3.79-3.62(m,4H),3.36-3.33(m,1H),3.26-3.21(m,1H),3.14-3.07(m,1H),2.92-2.79(m,2H),2.32(dd,J＝5.1,13.4Hz,1H),2.15-1.76(m,9H),1.52-1.39(m,2H).
以下实施例通过实施例40A的合成路线方法进行制备：The following examples are prepared by the synthetic route method of embodiment 40A:
实施例40B：4-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛烷-3-基)-2-((((1S,7a'R)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-吡咯嗪]-7a'(5'H)-基)甲氧基)-8-氟吡啶并[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-醇
Example 40B: 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-((((1S,7a'R)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolazin]-7a'(5'H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrim Pyridin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol
LCMS(ESI):[M+H]+＝645.3。1H NMR(400MHz,CD3OD)δppm 9.01(s,1H),7.86(br dd,J＝5.8,8.8Hz,1H),7.39-7.29(m,2H),7.21(s,1H),4.68-4.57(m,2H),4.31-4.19(m,2H),3.81-3.61(m,4H),3.36(br d,J＝7.3Hz,1H),3.24(br d,J＝10.8Hz,1H),3.10(br d,J＝5.3Hz,1H),2.95-2.77(m,2H),2.31(br dd,J＝4.8,13.3Hz,1H),2.13-1.79(m,9H),1.52-1.41(m,2H).LCMS (ESI): [M+H] + = 645.3. 1 H NMR(400MHz,CD 3 OD)δppm 9.01(s,1H),7.86(br dd,J＝5.8,8.8Hz,1H),7.39-7.29(m,2H),7.21(s,1H),4.68-4.57(m,2H),4.31-4.19(m,2H),3.81-3.61(m,4H),3.36(br d,J＝7.3Hz,1H),3.24(br d,J＝10.8Hz,1H),3.10(br d,J＝5.3Hz,1H),2.95-2.77(m,2H),2.31(br dd,J＝4.8,13.3Hz,1H),2.13-1.79(m,9H),1.52-1.41(m,2H).
实施例40C：4-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-2-((((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-吡咯嗪]-7a'(5'H)-基)甲氧基)-8-氟吡啶并[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-醇甲酸盐
Example 40C: 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-((((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolazin]-7a'(5'H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidine -7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol formate
LCMS(ESI):[M+H]+＝645.3 1H NMR(400MHz,CD3OD)δppm 9.08(s,1H),8.49(br s,1H),7.89(dd,J＝5.7,9.0Hz,1H),7.42-7.29(m,2H),7.23(d,J＝2.2Hz,1H),4.79(br s,2H),4.58-4.49(m,2H),4.05(br s,2H),3.89(br s,2H),3.60(br dd,J＝6.5,12.3Hz,1H),3.50-3.42(m,1H),3.38(s,1H),3.11(br d,J＝12.2Hz,1H),3.00-2.87(m,1H),2.43(br dd,J＝6.1,13.6Hz,1H),2.27(br dd,J＝5.8,11.7Hz,1H),2.19-1.89(m,8H),1.68-1.52(m,2H).LCMS(ESI):[M+H]+=645.3 1H NMR (400MHz, CD3OD)δppm 9.08(s,1H),8.49(br s,1H),7.89(dd,J=5.7,9.0Hz,1H),7.42-7.29(m,2H),7.23(d,J=2.2Hz,1H),4.79(br s,2H),4.58-4.49(m,2H),4.05(br s,2H),3.89(br s,2H),3.60(br dd,J＝6.5,12.3Hz,1H),3.50-3.42(m,1H),3.38(s,1H),3.11(br d,J＝12.2Hz,1H),3.00-2.87(m,1H),2.43(br dd,J＝6.1 ,13.6Hz,1H),2.27(br dd,J＝5.8,11.7Hz,1H),2.19-1.89(m,8H),1.68-1.52(m,2H).
实施例40D：4-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-2-((((1R,7a'R)-2,2-二氟二氢-1'H),3'H-螺[环丙烷-1,2'-吡咯嗪]-7a'(5'H)-基)甲氧基)-8-氟吡啶并[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-醇 二甲酸盐
Example 40D: 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-((((1R,7a'R)-2,2-difluorodihydro-1'H),3'H-spiro[cyclopropane-1,2'-pyrrolazin]-7a'(5'H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrim Pyridin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol dicarboxylate
LCMS(ESI):[M+H]+＝645.4.1H NMR(400MHz,CD3OD)δppm 9.07(s,1H),8.44(br s,2H),7.88(dd,J＝5.8,9.0Hz,1H),7.39-7.29(m,2H),7.21(d,J＝2.5Hz,1H),4.83-4.73(m,2H),4.62-4.52(m,2H),4.10(br s,2H),3.90(br t,J＝11.4Hz,2H),3.72-3.61(m,1H),3.51(td,J＝5.6,11.2Hz,1H),3.37(s,1H),3.15(d,J＝12.3Hz,1H),3.02-2.91(m,1H),2.45(dd,J＝6.0,13.6Hz,1H),2.28(br dd,J＝6.3,11.3Hz,1H),2.19-1.92(m,8H),1.68-1.55(m,2H). LCMS(ESI):[M+H]+=645.4.1H NMR (400MHz, CD3OD)δppm 9.07(s,1H),8.44(br s,2H),7.88(dd,J=5.8,9.0Hz,1H),7.39-7.29(m,2H),7.21(d,J=2.5Hz,1H),4.83-4.73(m,2H),4.62-4.52(m,2H),4.1 0(br s,2H),3.90(br t,J=11.4Hz,2H),3.72-3.61(m,1H),3.51(td,J=5.6,11.2Hz,1H),3.37(s,1H),3.15(d,J=12.3Hz,1H),3.02-2.91(m,1H),2.45(dd ,J=6.0,13.6Hz,1H),2.28(br dd,J=6.3,11.3Hz,1H),2.19-1.92(m,8H),1.68-1.55(m,2H).
实施例41：4-(2-((1'H，3'H，5'H-二硫杂环[氧杂环丁烷-3,2'-吡咯烷-6'，3'-氧杂环丁烷-7a'(7'H)-基甲氧基)-4-((1R，5S)-3,8-二氮杂环[3.2.1]辛烷-3-基)-8-氟吡啶[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-醇
Example 41: 4-(2-((1'H, 3'H, 5'H-dithiacyclo[oxetane-3,2'-pyrrolidine-6', 3'-oxetane-7a'(7'H)-ylmethoxy)-4-((1R,5S)-3,8-diazacyclo[3.2.1]octane-3-yl)-8-fluoropyridin[4,3-d]pyrimidine-7- Base)-5-ethynyl-6-fluoronaphthalene-2-ol
第一步：N2氛围下,在0℃将(叔丁氧羰基)甘氨酸乙酯(10g,49.20mmol)和3,3-双(溴甲基)氧代烷(14.4g,59.04mmol)溶于DMA(100mL)后缓慢滴加到含有NaH(7.9g,196.81mmol)和DMA(50mL)的反应液中，滴加完成后，反应液在20℃下搅拌2小时，反应液用NH4Cl水溶液淬灭(100mL)然后用EtOAc(100mL x 3)萃取，有机相用无水Na2SO4干燥，过滤并浓缩后经柱层析纯化(硅胶，0-30％梯度的乙酸乙酯/石油醚)得到化合物6-(叔丁基)7-乙基2-氧代-6-氮杂螺环[3.4]辛烷-6,7-二甲酸酯(11.2g),为无色油状液体。TLC(hexanes:EtOAc＝2:1)确认了产物。第一步：N2氛围下,在0℃将(叔丁氧羰基)甘氨酸乙酯(10g,49.20mmol)和3,3-双(溴甲基)氧代烷(14.4g,59.04mmol)溶于DMA(100mL)后缓慢滴加到含有NaH(7.9g,196.81mmol)和DMA(50mL)的反应液中，滴加完成后，反应液在20℃下搅拌2小时，反应液用NH4Cl水溶液淬灭(100mL)然后用EtOAc(100mL x 3)萃取，有机相用无水Na 2 SO 4干燥，过滤并浓缩后经柱层析纯化(硅胶，0-30％梯度的乙酸乙酯/石油醚)得到化合物6-(叔丁基)7-乙基2-氧代-6-氮杂螺环[3.4]辛烷-6,7-二甲酸酯(11.2g),为无色油状液体。 TLC (hexanes:EtOAc=2:1) confirmed the product.
第二步：含有7-[(叔丁基)氧羰基]-2-氧-7-氮杂螺环[3.4]辛烷-6-羧酸乙酯(5g，17.52mmol)、TFA(10mL)和DCM(50mL)的反应液在20℃下搅拌4小时，向反应液中加入三乙胺(4mL)后经浓缩得到化合物2-氧-6-氮杂螺环[3.4]辛烷-7-羧酸乙酯(6.9g)，为黄色油状液体。TLC(DCM:MeOH＝10:1)确认了产物。The second step: the reaction solution containing 7-[(tert-butyl)oxycarbonyl]-2-oxo-7-azaspiro[3.4]octane-6-carboxylate (5g, 17.52mmol), TFA (10mL) and DCM (50mL) was stirred at 20°C for 4 hours, triethylamine (4mL) was added to the reaction solution and concentrated to obtain the compound 2-oxo-6-azaspiro[3.4]octane-7-carboxylate ethyl ester (6.9 g) as a yellow oily liquid. TLC (DCM:MeOH=10:1) confirmed the product.
第三步：含有2-氧-6-氮杂螺环[3.4]辛烷-7-羧酸乙酯(6.9g，37.25mmol)、3-(溴甲基)氧代烷-3-碳醛(8g，44.70mmol)、三乙胺(11.5g，111.76mmol)、和甲醇(50mL)的反应液在20℃下搅拌1h，将反应液倒入水中(100mL)并用EtOAc(100mL x 3)萃取，有机相用无水Na2SO4干燥，过滤并浓缩后经柱层析纯化(硅胶，0-30％梯度的乙酸乙酯/石油醚)得到化合物6-((3-(溴甲基)氧代烷-3-基)甲基)-2-氧代-6-氮杂螺环[3.4]辛烷-7-羧酸乙酯(2.9g)，为无色油状液体。LCMS(ESI):[M+H]+＝348.1。第三步：含有2-氧-6-氮杂螺环[3.4]辛烷-7-羧酸乙酯(6.9g，37.25mmol)、3-(溴甲基)氧代烷-3-碳醛(8g，44.70mmol)、三乙胺(11.5g，111.76mmol)、和甲醇(50mL)的反应液在20℃下搅拌1h，将反应液倒入水中(100mL)并用EtOAc(100mL x 3)萃取，有机相用无水Na 2 SO 4干燥，过滤并浓缩后经柱层析纯化(硅胶，0-30％梯度的乙酸乙酯/石油醚)得到化合物6-((3-(溴甲基)氧代烷-3-基)甲基)-2-氧代-6-氮杂螺环[3.4]辛烷-7-羧酸乙酯(2.9g)，为无色油状液体。 LCMS (ESI): [M+H] + = 348.1.
第四步：-78℃，N2氛围下，将KHMDS(11mL,111.26mmol)滴加到含有6-((3-(溴甲基)氧代烷-3-基)甲基)-2-氧代-6-氮杂螺环[3.4]辛烷-7-羧酸乙酯(2.8g,8.04mmol),THF(18mL)和DMF(90mL)的溶液中，反应液在-78℃下搅拌30分钟，向反应液中加入三乙胺(20mL)后倒入水中(100mL),然后经EA(100mL x 3)萃取，有机相用无水Na2SO4干燥，过滤并浓缩后经柱层析纯化(硅胶，0-100％梯度的乙酸乙酯/石油醚)得到化合物1'H，3'H，5'H-二硫氰酸乙酯[氧杂环丁烷-3,2'-吡咯利嗪-6'，3'-氧杂环丁烷]-7a'(7'H)-羧酸乙酯(640mg)，为黄色油状产物。LCMS(ESI):[M+H]+＝268.1。第四步：-78℃，N2氛围下，将KHMDS(11mL,111.26mmol)滴加到含有6-((3-(溴甲基)氧代烷-3-基)甲基)-2-氧代-6-氮杂螺环[3.4]辛烷-7-羧酸乙酯(2.8g,8.04mmol),THF(18mL)和DMF(90mL)的溶液中，反应液在-78℃下搅拌30分钟，向反应液中加入三乙胺(20mL)后倒入水中(100mL),然后经EA(100mL x 3)萃取，有机相用无水Na 2 SO 4干燥，过滤并浓缩后经柱层析纯化(硅胶，0-100％梯度的乙酸乙酯/石油醚)得到化合物1'H，3'H，5'H-二硫氰酸乙酯[氧杂环丁烷-3,2'-吡咯利嗪-6'，3'-氧杂环丁烷]-7a'(7'H)-羧酸乙酯(640mg)，为黄色油状产物。 LCMS (ESI): [M+H] + = 268.1.
第五步：0℃下，将LiAlH4(80mg,2.24mmol)加入到含有1'H，3'H，5'H-二硫氰酸乙酯[氧杂环丁烷-3,2'-吡咯利嗪-6'，3'-氧杂环丁烷]-7a'(7'H)-羧酸乙酯(600mg,2.24mmol)和THF(6mL)的溶液中，反应液在室温下搅拌1小时，向反应液中加入过量的水水硫酸钠，搅拌30分钟后过滤，滤液经浓缩后得到化合物(1'H，3'H，5'H-二吡咯[氧杂环丁烷-3,2'-吡咯烷-6'，3'-氧杂环丁烷]-7a'(7'H)-基)甲醇(210mg),为黄色油状产物。LCMS(ESI):[M+H]+＝226.2。 Step 5: At 0°C, LiAlH4 (80mg, 2.24mmol) was added to a solution containing 1'H, 3'H, 5'H-ethyl dithiocyanate [oxetane-3,2'-pyrrolizine-6', 3'-oxetane]-7a'(7'H)-ethyl carboxylate (600mg, 2.24mmol) and THF (6mL), and the reaction solution was stirred at room temperature for 1 hour, Add excess sodium sulfate water to the reaction solution, stir for 30 minutes and then filter, and the filtrate is concentrated to obtain compound (1'H,3'H,5'H-dipyrrole[oxetane-3,2'-pyrrolidine-6',3'-oxetane]-7a'(7'H)-yl)methanol (210mg) as a yellow oily product. LCMS (ESI): [M+H]+ = 226.2.
第六步：含有叔丁基(1R，5S)-3-(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-(2,2,2-三氟乙氧基)吡啶[4,3-d]嘧啶-4-基)-3,8-二氮杂二环[3.2.1]辛烷-8-羧酸盐(200mg,0.24mmol),(1'H，3'H，5'H-二吡咯[氧杂环丁烷-3,2'-吡咯烷-6'，3'-氧杂环丁烷]-7a'(7'H)-基)甲醇(54mg,0.24mmol),叔丁醇钠(70mg,0.71mmol)和THF(2mL)的反应液在60℃下搅拌3小时，将反应液倒入水中(20mL)并用EA(20mL x 3)萃取，有机相用无水Na2SO4干燥，过滤并浓缩后经柱层析纯化(硅胶，0-30％梯度的甲醇/二氯甲烷)得到化合物叔丁基(1R，5S)-3-(2-((1'H，3'H，5'H-二螺环[氧杂环丁烷-3,2'-吡咯利嗪-6'，3'-氧杂环丁烷]-7a'(7'H)-基甲氧基)-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)吡啶[4,3-d]嘧啶-4-基)-3,8-二氮杂环[3.2.1]辛烷-8-羧酸盐(50mg)，为黄色油状液体。LCMS(ESI):[M/2+H]+＝484.5。Step 6: Containing tert-butyl(1R,5S)-3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalene-1-yl)-2-(2,2,2-trifluoroethoxy)pyridin[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (200mg, 0 .24mmol), (1'H, 3'H, 5'H-dipyrrole[oxetane-3,2'-pyrrolidine-6', 3'-oxetane]-7a'(7'H)-yl)methanol (54mg, 0.24mmol), sodium tert-butoxide (70mg, 0.71mmol) and THF (2mL) were stirred at 60°C for 3 hours, the reaction solution was poured into water (20mL) and Extracted with EA (20mL x 3), the organic phase was dried over anhydrous Na2SO4, filtered and concentrated, and purified by column chromatography (silica gel, 0-30% gradient of methanol/dichloromethane) to obtain the compound tert-butyl (1R, 5S)-3-(2-((1'H, 3'H, 5'H-bispiro[oxetane-3,2'-pyrrolizine-6', 3'-oxetane]-7a'(7'H) -ylmethoxy)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyridin[4,3-d]pyrimidin-4-yl)-3,8-diazacyclo[3.2.1]octane-8-carboxylate (50 mg) as a yellow oily liquid. LCMS (ESI): [M/2+H]+=484.5.
第七步：在0℃下，将三氟乙酸(0.5mL)加入到含有叔丁基(1R，5S)-3-(2-((1'H，3'H，5'H-二螺环[氧杂环丁烷-3,2'-吡咯利嗪-6'，3'-氧杂环丁烷]-7a'(7'H)-基甲氧基)-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)吡啶[4,3-d]嘧啶-4-基)-3,8-二氮杂环[3.2.1]辛烷-8-羧酸盐(50mg,0.052mmol)和二氯甲烷(3mL)的反应液中，反应液在0℃下搅拌30分钟，三乙胺(1mL)加入到反应液中,反应液倒入水中(20mL),EA萃取(20mL*3),有机相经无水硫酸钠干燥后浓缩得到化合物4-(2-((1'H，3'H，5'H-二硫杂环[氧杂环丁烷-3,2'-吡咯烷-6'，3'-氧杂环丁烷-7a'(7'H)-基)甲氧基)-4-((1R，5S)-3,8-二氮杂环[3.2.1]辛烷-3-基)-8-氟吡啶[4,3-d]嘧啶-7-基)-6-氟-5-((三异丙基硅基)乙炔基)萘-2-醇(30mg),为黄色油状产物。LCMS(ESI):[M/2+H]+＝412.2。The seventh step: at 0°C, trifluoroacetic acid (0.5 mL) was added to the solution containing tert-butyl (1R, 5S)-3-(2-((1'H, 3'H, 5'H-bispiro[oxetane-3,2'-pyrrolizine-6', 3'-oxetane]-7a'(7'H)-ylmethoxy)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8- ((triisopropylsilyl)ethynyl)naphthalene-1-yl)pyridin[4,3-d]pyrimidin-4-yl)-3,8-diazacyclo[3.2.1]octane-8-carboxylate (50mg, 0.052mmol) and dichloromethane (3mL) in the reaction solution, the reaction solution was stirred at 0°C for 30 minutes, triethylamine (1mL) was added to the reaction solution, the reaction solution was poured into water (20mL), extracted with EA (2 0mL*3), the organic phase was dried over anhydrous sodium sulfate and concentrated to obtain the compound 4-(2-((1'H,3'H,5'H-dithiacyclo[oxetane-3,2'-pyrrolidine-6',3'-oxetane-7a'(7'H)-yl)methoxy)-4-((1R,5S)-3,8-diazecyclo[3.2.1]octane-3-yl)-8-fluoropyridine [4,3-d]pyrimidin-7-yl)-6-fluoro-5-((triisopropylsilyl)ethynyl)naphthalene-2-ol (30 mg), a yellow oily product. LCMS (ESI): [M/2+H]+=412.2.
第八步：含有4-(2-((1'H，3'H，5'H-二硫杂环[氧杂环丁烷-3,2'-吡咯烷-6'，3'-氧杂环丁烷-7a'(7'H)-基)甲氧基)-4-((1R，5S)-3,8-二氮杂环[3.2.1]辛烷-3-基)-8-氟吡啶[4,3-d]嘧啶-7-基)-6-氟-5-((三异丙基硅基)乙炔基)萘-2-醇(30mg,0.036mmol),氟化铯(28mg,0.18mmol)和DMF(1mL)的反应液在50℃下搅拌2小时，将反应液倒入水中(20mL)并用EA(20mL x 3)萃取，有机相用无水Na2SO4干燥，过滤并浓缩后经柱层析纯化(C18，0-50％梯度的水/乙腈)得到化合物4-(2-((1'H，3'H，5'H-二硫杂环[氧杂环丁烷-3,2'-吡咯烷-6'，3'-氧杂环丁烷-7a'(7'H)-基甲氧基)-4-((1R，5S)-3,8-二氮杂环[3.2.1]辛烷-3-基)-8-氟吡啶[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-醇(0.85mg),为白色固体产物。LCMS(ESI):[M/2+H]+＝667.4。Step 8: Containing 4-(2-((1'H, 3'H, 5'H-dithiacyclo[oxetane-3,2'-pyrrolidine-6', 3'-oxetane-7a'(7'H)-yl)methoxy)-4-((1R,5S)-3,8-diazacyclo[3.2.1]octane-3-yl)-8-fluoropyridin[4,3-d]pyrimidine-7- A reaction solution of -6-fluoro-5-((triisopropylsilyl)ethynyl)naphthalene-2-ol (30mg, 0.036mmol), cesium fluoride (28mg, 0.18mmol) and DMF (1mL) was stirred at 50°C for 2 hours, the reaction solution was poured into water (20mL) and extracted with EA (20mL x 3), the organic phase was dried over anhydrous Na2SO4, filtered and concentrated, and purified by column chromatography (C18 , 0-50% gradient of water/acetonitrile) yielded the compound 4-(2-((1'H,3'H,5'H-dithiacyclo[oxetane-3,2'-pyrrolidine-6',3'-oxetane-7a'(7'H)-ylmethoxy)-4-((1R,5S)-3,8-diazecyclo[3.2.1]octane-3-yl)-8-fluoropyridin[4,3 -d] pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalene-2-ol (0.85 mg), a white solid product. LCMS (ESI): [M/2+H]+=667.4.
实施例42：4-(2-((1'氢,3'氢,5'氢-二螺[环丙烷-1,2'-吡咯里嗪-6',1”-环丙烷基]-7a'(7'氢)-基)甲氧基)-4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛烷-3-基)-8-氟吡啶[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-醇
Example 42: 4-(2-((1'hydrogen,3'hydrogen,5'hydrogen-dispiro[cyclopropane-1,2'-pyrrolizine-6',1"-cyclopropanyl]-7a'(7'hydrogen)-yl)methoxy)-4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoropyridin[4,3-d]pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol
第一步：在20℃下，将碘甲烷(6.60g,45.59mmol)加到6-[(叔丁基)氧羰基]-6-氮杂螺环[2.4]庚烷-5-甲酸(10.00g,41.44mmol)、碳酸钾(11.70g,82.89mmol)的N,N-二甲基甲酰胺(100mL)溶液中，反应液在20℃下搅拌12小时。将反应液倒入水(300mL)中，用乙酸乙酯(50mL x 3)萃取,将有机相用无水硫酸钠干燥、过滤、浓缩得到淡黄色油状液体6-[(叔丁基)氧羰基]-6-氮杂螺环[2.4]庚烷-5-甲酸甲酯(7.2g，收率68.1％)。LCMS(ESI):[M+H]+＝156.1.The first step: at 20°C, add iodomethane (6.60g, 45.59mmol) to 6-[(tert-butyl)oxycarbonyl]-6-azaspiro[2.4]heptane-5-carboxylic acid (10.00g, 41.44mmol), potassium carbonate (11.70g, 82.89mmol) in N,N-dimethylformamide (100mL) solution, and the reaction solution was stirred at 20°C 12 hours. The reaction solution was poured into water (300mL), extracted with ethyl acetate (50mL x 3), the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain light yellow oily liquid 6-[(tert-butyl)oxycarbonyl]-6-azaspiro[2.4]heptane-5-carboxylic acid methyl ester (7.2g, yield 68.1%). LCMS (ESI): [M+H] + = 156.1.
第二步：在20℃下，将三氟乙酸(15.0mL,195.84mmol)加到6-[(叔丁基)氧羰基]-6-氮杂螺环[2.4]庚烷-5-甲酸甲酯(5.00g,19.58mmol)的二氯甲烷(20mL)溶液中。反应液在20℃下搅拌2小时。将反应液浓缩干得粘稠状黄色液体6-氮杂螺环[2.4]庚烷-5-甲酸甲酯(3.0g,收率99％)。LCMS(ESI):[M+H]+＝156.2.Second step: Trifluoroacetic acid (15.0 mL, 195.84 mmol) was added to a solution of methyl 6-[(tert-butyl)oxycarbonyl]-6-azaspiro[2.4]heptane-5-carboxylate (5.00 g, 19.58 mmol) in dichloromethane (20 mL) at 20°C. The reaction solution was stirred at 20°C for 2 hours. The reaction solution was concentrated to dryness to obtain viscous yellow liquid methyl 6-azaspiro[2.4]heptane-5-carboxylate (3.0 g, yield 99%). LCMS (ESI): [M+H] + = 156.2.
第三步：在20℃下，将碳酸钾(3.40g,24.16mmol)加到6-氮杂螺环[2.4]庚烷-5-甲酸甲酯(1.50g,9.66mmol)、((1-(溴甲基)环丙基)甲氧基)(叔丁基)二苯基硅烷(3.90g,9.66mmol)的乙腈(20mL)溶液中。将反应在60℃下搅拌16小时。将反应液过滤，加入硅胶10g，浓缩后经柱层析(硅胶，0-10％的梯度乙酸乙酯/石油醚)得无色油状液体5-((1-(((叔丁基二苯基硅基)氧基)甲基)环丙基)甲基)-5-氮杂螺环[2.4]庚烷-6-甲酸甲酯(3.8g，收率82.5％)。LCMS(ESI):[M+H]+＝478.4.Step 3: Potassium carbonate (3.40 g, 24.16 mmol) was added to a solution of methyl 6-azaspiro[2.4]heptane-5-carboxylate (1.50 g, 9.66 mmol), ((1-(bromomethyl)cyclopropyl)methoxy)(tert-butyl)diphenylsilane (3.90 g, 9.66 mmol) in acetonitrile (20 mL) at 20°C. The reaction was stirred at 60 °C for 16 hours. The reaction solution was filtered, 10 g of silica gel was added, concentrated and then subjected to column chromatography (silica gel, 0-10% gradient ethyl acetate/petroleum ether) to obtain a colorless oily liquid 5-((1-(((tert-butyldiphenylsilyl)oxy)methyl)cyclopropyl)methyl)-5-azaspiro[2.4]heptane-6-carboxylic acid methyl ester (3.8g, yield 82.5%). LCMS (ESI): [M+H]+=478.4.
第四步：在20℃下，将5-((1-(((叔丁基二苯基硅基)氧基)甲基)环丙基)甲基)-5-氮杂螺环[2.4]庚烷-6-甲酸甲酯(1.5g,3.14mmol)和盐酸二氧六环(15.0mL,60.01mmol)的混合溶液搅拌1小时。将反应液浓缩干得残余物，残余物经柱层析纯化(硅胶，0-50％梯度的乙酸乙酯/石油醚,0-10％梯度的甲醇/二氯甲烷)得1g粗产品。该粗产品再次经柱层析纯化(硅胶，0-3％梯度的甲醇/二氯甲烷)得白色粘稠状固体6-{[(羟甲基)环丙基]甲基}-6-氮杂螺环[2.4]庚烷-5-甲酸甲酯(480mg，收率63.9％)。LCMS(ESI):[M+H]+＝240.2.Step 4: A mixed solution of methyl 5-((1-(((tert-butyldiphenylsilyl)oxy)methyl)cyclopropyl)methyl)-5-azaspiro[2.4]heptane-6-carboxylate (1.5 g, 3.14 mmol) and dioxane hydrochloride (15.0 mL, 60.01 mmol) was stirred for 1 hour at 20°C. The reaction solution was concentrated to dryness to obtain a residue, which was purified by column chromatography (silica gel, 0-50% gradient of ethyl acetate/petroleum ether, 0-10% gradient of methanol/dichloromethane) to obtain 1 g of crude product. The crude product was again purified by column chromatography (silica gel, 0-3% methanol/dichloromethane gradient) to give white viscous solid 6-{[(hydroxymethyl)cyclopropyl]methyl}-6-azaspiro[2.4]heptane-5-carboxylic acid methyl ester (480 mg, yield 63.9%). LCMS (ESI): [M+H]+=240.2.
第五步：在20℃氮气保护下，将三苯基膦(385mg,1.47mmol)、四溴化碳(491mg,1.47mmol)加到6-{[(羟甲基)环丙基]甲基}-6-氮杂螺环[2.4]庚烷-5-甲酸甲酯(270mg,1.13mmol)的二氯甲烷(5ml)溶液中，反应液在20℃下搅拌2小时。将反应液浓缩得残余物，残余物经柱层析(硅胶，0-20％的乙酸乙酯/石油醚,0-5％梯度的甲醇/二氯甲烷)得到无色液体6-{[(溴甲基)环丙基]甲基}-6-氮杂螺环[2.4]庚烷-5-甲酸甲酯(140mg,收率41.2％)。LCMS(ESI):[M+H]+＝302.2. Step 5: Under nitrogen protection at 20°C, triphenylphosphine (385mg, 1.47mmol) and carbon tetrabromide (491mg, 1.47mmol) were added to a solution of methyl 6-{[(hydroxymethyl)cyclopropyl]methyl}-6-azaspiro[2.4]heptane-5-carboxylate (270mg, 1.13mmol) in dichloromethane (5ml), and the reaction solution was stirred at 20°C for 2 hours. The reaction solution was concentrated to obtain a residue, and the residue was subjected to column chromatography (silica gel, 0-20% ethyl acetate/petroleum ether, 0-5% gradient methanol/dichloromethane) to obtain a colorless liquid 6-{[(bromomethyl)cyclopropyl]methyl}-6-azaspiro[2.4]heptane-5-carboxylic acid methyl ester (140 mg, yield 41.2%). LCMS (ESI): [M+H]+=302.2.
第六步：在20℃下，将6-{[(溴甲基)环丙基]甲基}-6-氮杂螺环[2.4]庚烷-5-甲酸甲酯(300mg,0.99mmol)溶于N,N-二甲基甲酰胺(15mL)和四氢呋喃(5mL)中，用氮气置换3次，并冷却至-70℃，向反应液中滴加双(三甲基硅烷基)氨基钾(1.4mL,1.39mmol，1M)，反应液在该温度下搅拌50分钟。向反应液中加入饱和氯化铵溶液(10mL)中用乙酸乙酯(20mL x 3)萃取，有机相经无水硫酸钠干燥，水相用二氯甲烷/甲醇(20mL x 3,20:1)萃取,有机相经无水硫酸钠干燥,有机相经过合并、过滤、浓缩得残余物。残余物经柱层析(硅胶，0-10％梯度的甲醇/二氯甲烷)得灰色油状物1'氢,3'氢,5'氢-二螺[环丙烷-1,2'-吡咯里嗪-6',1”-环丙烷基]-7a'(7'氢)-甲酸甲酯(30mg，收率13.7％)。LCMS(ESI):[M+H]+＝194.2.Step 6: Dissolve methyl 6-{[(bromomethyl)cyclopropyl]methyl}-6-azaspiro[2.4]heptane-5-carboxylate (300mg, 0.99mmol) in N,N-dimethylformamide (15mL) and tetrahydrofuran (5mL) at 20°C, replace with nitrogen three times, and cool to -70°C, dropwise add bis(trimethylsilyl)potassium amide (1.4mL, 1.39 mmol, 1M), and the reaction solution was stirred at this temperature for 50 minutes. Saturated ammonium chloride solution (10 mL) was added to the reaction solution, extracted with ethyl acetate (20 mL x 3), the organic phase was dried over anhydrous sodium sulfate, the aqueous phase was extracted with dichloromethane/methanol (20 mL x 3, 20:1), the organic phase was dried over anhydrous sodium sulfate, the organic phases were combined, filtered, and concentrated to obtain a residue. The residue was subjected to column chromatography (silica gel, 0-10% methanol/dichloromethane gradient) to give gray oil 1'hydrogen, 3'hydrogen, 5'hydrogen-dispiro[cyclopropane-1,2'-pyrrolizine-6',1"-cyclopropanyl]-7a'(7'hydrogen)-methyl formate (30 mg, yield 13.7%). LCMS (ESI): [M+H]+=194.2.
第七步：在0℃下，将氢化铝锂(15mg,0.39mmol)加到1'氢,3'氢,5'氢-二螺[环丙烷-1,2'-吡咯里嗪-6',1”-环丙烷基]-7a'(7'氢)-甲酸甲酯(30mg,0.15mmol)的四氢呋喃(2mL)溶液中，反应液在0℃下搅拌1小时。在1小时。向反应液中补加氢化铝锂(15mg,3eq)，在20℃搅拌1小时。向反应液中加入水(30ul)、15％的氢氧化钠溶液(90uL)，在20℃下搅拌10分钟。将反应混合物过滤、浓缩干得白色固体(1'氢,3'氢,5'氢-二螺[环丙烷-1,2'-吡咯里嗪-6',1”-环丙烷基]-7a'(7'氢)-基)甲醇(25mg，收率99％)。LCMS(ESI):[M+H]+＝.Step 7: Add lithium aluminum hydride (15mg, 0.39mmol) to 1'hydrogen, 3'hydrogen, 5'hydrogen-dispiro[cyclopropane-1,2'-pyrrolizine-6',1"-cyclopropanyl]-7a'(7'hydrogen)-methyl formate (30mg, 0.15mmol) in tetrahydrofuran (2mL) at 0°C, and stir the reaction solution at 0°C for 1 hour. Add to the reaction solution for 1 hour. Lithium aluminum hydride (15mg, 3eq) was added and stirred at 20°C for 1 hour. Water (30ul) and 15% sodium hydroxide solution (90uL) were added to the reaction solution, and stirred at 20°C for 10 minutes. The reaction mixture was filtered and concentrated to dryness to obtain a white solid (1'hydrogen, 3'hydrogen, 5'hydrogen-dispiro[cyclopropane-1,2'-pyrrolizine-6',1"-cyclopropanyl]-7a'(7'hydrogen)-yl ) methanol (25 mg, yield 99%). LCMS(ESI):[M+H]+＝.
第八步：在0℃下，将叔丁醇钠(17mg,0.18mmol)加到(1R,5S)-3-(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-(2,2,2-三氟乙基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-甲酸叔丁酯(78mg,0.093mmol)和(1'氢,3'氢,5'氢-二螺[环丙烷-1,2'-吡咯里嗪-6',1”-环丙烷基]-7a'(7'氢)-基)甲醇(24.00mg,0.12mmol)的四氢呋喃(3mL)的溶液中。反应液在20℃下搅拌4小时。向反应液中补加3次叔丁醇钠(2mg x 3)，在60℃下搅拌2小时。向反应液中加入水(2mL)、用乙酸乙酯(2mL X 3)萃取。有机相经过无水硫酸钠干燥、过滤和浓缩得残余物，残余物经柱层析纯化(硅胶，0-50％梯度的乙酸乙酯/石油醚，0-5％梯度的甲醇/二氯甲烷)的无色油状物(1R,5S)-3-(2-((1'氢,3'氢,5'氢-二螺[环丙烷-1,2'-吡咯里嗪-6',1”-环丙烷基]-7a'(7'氢)-基)甲氧基)-8-氟-7-(7-氟-3-(甲氧甲氧基)-8-((三异丙基硅基)乙炔基)萘-1-基)吡啶基[4,3-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-甲酸叔丁酯(37mg，收率33％)。LCMS(ESI):[M+H]+＝468.5.Step 8: Add sodium tert-butoxide (17mg, 0.18mmol) to (1R,5S)-3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalene-1-yl-2-(2,2,2-trifluoroethyl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[ 3.2.1] Octane-8-carboxylic acid tert-butyl ester (78mg, 0.093mmol) and (1'hydrogen, 3'hydrogen, 5'hydrogen-dispiro[cyclopropane-1,2'-pyrrolizine-6',1"-cyclopropanyl]-7a'(7'hydrogen)-yl)methanol (24.00mg, 0.12mmol) in tetrahydrofuran (3mL) solution. The reaction solution was stirred at 20°C for 4 hours. Add sodium tert-butoxide (2mg x 3) to the reaction solution 3 times, and stir at 60°C for 2 hours. Add water (2mL) to the reaction solution and extract with ethyl acetate (2mL x 3). The organic phase is dried over anhydrous sodium sulfate, filtered and concentrated to obtain a residue. 3-(2-((1'hydrogen,3'hydrogen,5'hydrogen-dispiro[cyclopropane-1,2'-pyrrolizine-6',1"-cyclopropanyl]-7a'(7'hydrogen)-yl)methoxy)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyridyl[4,3-d]pyrimidin-4-yl)-3, tert-butyl 8-diazabicyclo[3.2.1]octane-8-carboxylate (37mg, yield 33%). LCMS (ESI): [M+H]+=468.5.
第九步：在20℃下，将氟化铯(61mg,0.40mmol)加到(1R,5S)-3-(2-((1'氢,3'氢,5'氢-二螺[环丙烷-1,2'-吡咯里嗪-6',1”-环丙烷基]-7a'(7'氢)-基)甲氧基)-8-氟-7-(7-氟-3-(甲氧甲氧基)-8-((三异丙基硅基)乙炔基)萘-1-基)吡啶基[4,3-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-甲酸叔丁酯(37mg,0.039mmol)的N,N-二甲基甲酰胺(3mL)中。反应液在20℃下搅拌1.5小时。反应液用乙酸乙酯(2mL)稀释，用水(1mL x 2)洗。有机相经过无水硫酸钠干燥、过滤和浓缩得残余物，残余物经柱层析纯化(硅胶，0-50％梯度的乙酸乙酯/石油醚，0-5％梯度的甲醇/二氯甲烷)得无色粘稠状液体(1R,5S)-3-(2-((1'氢,3'氢,5'氢-二螺[环丙烷-1,2'-吡咯里嗪-6',1”-环丙烷基]-7a'(7'氢)-基)甲氧基)-7-(8-乙炔基-7-氟-3-(甲氧甲氧基)萘-1-基)-8-氟吡啶[4,3-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-甲酸叔丁酯(29mg,收率62.7％，2批次合并)。LCMS(ESI):[M+H]+＝390.4.Step 9: Add cesium fluoride (61mg, 0.40mmol) to (1R,5S)-3-(2-((1'hydrogen,3'hydrogen,5'hydrogen-dispiro[cyclopropane-1,2'-pyrrolizine-6',1"-cyclopropanyl]-7a'(7'hydrogen)-yl)methoxy)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-(( Triisopropylsilyl)ethynyl)naphthalene-1-yl)pyridyl[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (37mg, 0.039mmol) in N,N-dimethylformamide (3mL). The reaction solution was stirred at 20°C for 1.5 hours. The reaction solution was diluted with ethyl acetate (2mL) and diluted with water (1mL x 2 ) was washed. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to obtain a residue, and the residue was purified by column chromatography (silica gel, 0-50% gradient ethyl acetate/petroleum ether, 0-5% gradient methanol/dichloromethane) to obtain a colorless viscous liquid (1R, 5S)-3-(2-((1'hydrogen, 3'hydrogen, 5'hydrogen-dispiro[cyclopropane-1,2'-pyrrolizine-6',1"-cyclopropanyl]-7a'( 7'H)-yl)methoxy)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyridin[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (29 mg, yield 62.7%, 2 batches combined). LCMS (ESI): [M+H]+=390.4.
第十步：20℃下，向(1R,5S)-3-(2-((1'氢,3'氢,5'氢-二螺[环丙烷-1,2'-吡咯里嗪-6',1”-环丙烷基]-7a'(7'氢)-基)甲氧基)-7-(8-乙炔基-7-氟-3-(甲氧甲氧基)萘-1-基)-8-氟吡啶[4,3-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-甲酸叔丁酯(7mg,0.009mmol)的乙腈(1mL)中加入三氟乙酸(480ul,6.29mmol)，反应液在20℃的氮气下搅拌4小时。将反应液浓缩，用乙腈(1mL)稀释，用三乙胺将pH调至7,经反相柱层析纯化(C18，5-95％乙腈/水的梯度)得4-(2-((1'氢,3'氢,5'氢-二螺[环丙烷-1,2'-吡咯里嗪-6',1”-环 丙烷基]-7a'(7'氢)-基)甲氧基)-4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛烷-3-基)-8-氟吡啶[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-醇(1.80mg,收率32％)。LCMS(ESI):[M+H]+＝635.4.The tenth step: at 20°C, to (1R,5S)-3-(2-((1'hydrogen,3'hydrogen,5'hydrogen-dispiro[cyclopropane-1,2'-pyrrolizine-6',1"-cyclopropanyl]-7a'(7'hydrogen)-yl)methoxy)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yl)-8-fluoropyridin[4,3-d]pyrimidine -4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (7mg, 0.009mmol) in acetonitrile (1mL) was added trifluoroacetic acid (480ul, 6.29mmol), and the reaction solution was stirred at 20°C under nitrogen for 4 hours. The reaction solution was concentrated, diluted with acetonitrile (1mL), adjusted to pH 7 with triethylamine, and purified by reverse phase column chromatography (C18, 5- 95% acetonitrile/water gradient) to 4-(2-((1'hydrogen, 3'hydrogen, 5'hydrogen-dispiro[cyclopropane-1,2'-pyrrolizine-6',1"-ring Propanyl]-7a'(7'hydrogen)-yl)methoxy)-4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoropyridin[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalene-2-ol (1.80 mg, yield 32%). LCMS (ESI): [M+H]+=635.4.
实施例43：4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-7-(8-乙炔基-7-氟-3-羟基萘-1-基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-1,6-萘啶-3-甲腈
Example 43: 4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-1,6-naphthyridine-3-carbonitrile
第一步：在氮气环境下，向2-氯-3-氟异烟酸(100g，569mmol)和三乙胺(158mL，1133mmol)的甲苯(500mL)和叔丁醇(500mL)溶液中加入二碳酸二叔丁酯(13mL，56.5mmol)和叠氮磷酸二苯酯(147mL，682mmol)，将溶液在80℃下搅拌16小时。混合物浓缩并加入500mL饱和食盐水，并用500mL乙酸乙酯萃取。真空浓缩有机层，得到的残余物通过快速柱色谱(硅胶，0-5％梯度的乙酸乙酯/石油醚)纯化得到淡黄色油状化合物(2-氯-3-氟吡啶-4-基)氨基甲酸叔丁酯(112g，454mmol，收率80％)。LCMS(ESI):[M+H]+＝247.1.Step 1: To a solution of 2-chloro-3-fluoroisonicotinic acid (100 g, 569 mmol) and triethylamine (158 mL, 1133 mmol) in toluene (500 mL) and tert-butanol (500 mL) under nitrogen atmosphere, di-tert-butyl dicarbonate (13 mL, 56.5 mmol) and diphenylphosphoryl azide (147 mL, 682 mmol) were added, and the solution was stirred at 80° C. for 16 hours. The mixture was concentrated and added with 500 mL of saturated brine, and extracted with 500 mL of ethyl acetate. The organic layer was concentrated in vacuo, and the resulting residue was purified by flash column chromatography (silica gel, 0-5% gradient of ethyl acetate/petroleum ether) to obtain tert-butyl (2-chloro-3-fluoropyridin-4-yl)carbamate (112 g, 454 mmol, yield 80%) as a pale yellow oil. LCMS (ESI): [M+H] + = 247.1.
第二步：将(2-氯-3-氟吡啶-4-基)氨基甲酸叔丁酯(50g，202mmol)和四甲基乙二胺(70.6g，608mmol)的无水甲基叔丁基醚(500mL)溶液冷却至-70℃。并将正丁基锂(2.5M的正己烷溶液，203mL，506mmol)缓慢加入到混合物中。在-70℃的氮气环境下搅拌1小时，然后将混合物升温至-30℃，氮气环境下搅拌1小时，然后将混合物冷却至-70℃，将含有干燥的二氧化碳的气袋连接到搅拌的溶液中，半小时过后将混合物缓慢升温至20℃并搅拌10小时。向混合物中加入水(500mL)淬灭并静置分液，弃去有机相，将水相冷却至0℃，用稀盐酸(4M)调节pH＝6-7，有白色固体析出，过滤，收集滤饼并真空干燥，得到白色固体化合物4-((叔丁氧基羰基氨基)-6-氯-5-氟烟酸(39.8g，136mmol，收率68％)。LCMS(ESI):[M+H]+＝291.0.Second step: A solution of tert-butyl (2-chloro-3-fluoropyridin-4-yl)carbamate (50 g, 202 mmol) and tetramethylethylenediamine (70.6 g, 608 mmol) in anhydrous methyl tert-butyl ether (500 mL) was cooled to -70°C. And n-butyllithium (2.5M in n-hexane, 203 mL, 506 mmol) was slowly added to the mixture. Stirred at -70°C under nitrogen atmosphere for 1 hour, then warmed the mixture to -30°C, stirred under nitrogen atmosphere for 1 hour, then cooled the mixture to -70°C, attached an air bag containing dry carbon dioxide to the stirred solution, after half an hour the mixture was slowly warmed to 20°C and stirred for 10 hours. Add water (500mL) to the mixture to quench and stand for liquid separation, discard the organic phase, cool the aqueous phase to 0°C, adjust the pH=6-7 with dilute hydrochloric acid (4M), a white solid precipitates, filter, collect the filter cake and vacuum dry to obtain the white solid compound 4-((tert-butoxycarbonylamino)-6-chloro-5-fluoronicotinic acid (39.8g, 136mmol, yield 68%). LCMS (ESI): [M+H] + =291.0.
第三步：向4-((叔丁氧基羰基)氨基)-6-氯-5-氟烟酸(10g，34.4mmol)的二氧六环(100mL)溶液中加入三光气(7.45g，25.1mmol)，混合物在100℃下搅拌4个小时。反应液真空浓缩，残余物用石油醚打浆得到7-氯-8-氟-2H-吡啶并[4,3-d][1,3]恶嗪-2,4(1H)-二酮(7.40g，34.4mmol，收率99％)，为白色固体。1H NMR(400MHz,DMSO-d6)δppm 12.84(br s,1H),8.73(s,1H).Step 3: Triphosgene (7.45 g, 25.1 mmol) was added to a solution of 4-((tert-butoxycarbonyl)amino)-6-chloro-5-fluoronicotinic acid (10 g, 34.4 mmol) in dioxane (100 mL), and the mixture was stirred at 100° C. for 4 hours. The reaction solution was concentrated in vacuo, and the residue was slurried with petroleum ether to obtain 7-chloro-8-fluoro-2H-pyrido[4,3-d][1,3]oxazine-2,4(1H)-dione (7.40 g, 34.4 mmol, yield 99%) as a white solid. 1 H NMR (400MHz,DMSO-d 6 )δppm 12.84(br s,1H),8.73(s,1H).
第四步：向7-氯-8-氟-2H-吡啶并[4,3-d][1,3]恶嗪-2,4(1H)-二酮(5.40g，24.9mmol)的二甲苯(54mL)溶液中加入2-氰基乙酸乙酯(4.23g，37.4mmol)和三乙胺(6.91mL，49.8mmol)。反应在145℃下搅拌5小时。真空浓缩混合物，将残余物用石油醚/乙酸乙酯(体积比为1:1)打浆，得到棕色固 体化合物7-氯-8-氟-2,4-二氧代-1,2,3,4-四氢-1,6-萘啶-3-甲腈(4.30g，17.95mmol，收率72％)。LCMS(ESI):[M+H]+＝239.9.Fourth step: To a solution of 7-chloro-8-fluoro-2H-pyrido[4,3-d][1,3]oxazine-2,4(1H)-dione (5.40 g, 24.9 mmol) in xylene (54 mL) was added ethyl 2-cyanoacetate (4.23 g, 37.4 mmol) and triethylamine (6.91 mL, 49.8 mmol). The reaction was stirred at 145°C for 5 hours. The mixture was concentrated in vacuo, and the residue was slurried with petroleum ether/ethyl acetate (1:1 by volume) to give a brown solid The compound 7-chloro-8-fluoro-2,4-dioxo-1,2,3,4-tetrahydro-1,6-naphthyridine-3-carbonitrile (4.30g, 17.95mmol, yield 72%). LCMS (ESI): [M+H] + = 239.9.
第五步：小心地将7-氯-8-氟-2,4-二氧代-1,2,3,4-四氢-1,6-萘啶-3-甲腈(5.80g，24.2mmol)加入到三氯氧磷(50mL，536mmol)中。反应物在90℃下搅拌16小时。混合物真空浓缩，残留物溶于乙酸乙酯(100ml)，用饱和碳酸氢钠(100ml)洗涤，水相用乙酸乙酯(50ml*3)萃取。合并的有机层用无水硫酸镁干燥并过滤。滤液真空浓缩，得到的残余物通过快速柱色谱(硅胶，0-15％梯度的乙酸乙酯/石油醚)纯化得到黄色固体化合物2,4,7-三氯-8-氟-1,6-萘啶-3-甲腈(3.10g，11.2mmol，收率46％)。LCMS(ESI):[M+H]+＝275.9,277.9.Step 5: 7-Chloro-8-fluoro-2,4-dioxo-1,2,3,4-tetrahydro-1,6-naphthyridine-3-carbonitrile (5.80 g, 24.2 mmol) was carefully added to phosphorus oxychloride (50 mL, 536 mmol). The reaction was stirred at 90°C for 16 hours. The mixture was concentrated in vacuo, the residue was dissolved in ethyl acetate (100ml), washed with saturated sodium bicarbonate (100ml), and the aqueous phase was extracted with ethyl acetate (50ml*3). The combined organic layers were dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated in vacuo, and the resulting residue was purified by flash column chromatography (silica gel, 0-15% gradient of ethyl acetate/petroleum ether) to obtain 2,4,7-trichloro-8-fluoro-1,6-naphthyridine-3-carbonitrile (3.10 g, 11.2 mmol, yield 46%) as a yellow solid. LCMS (ESI): [M+H] + = 275.9, 277.9.
第六步：在-70℃下向2,4,7-三氯-8-氟-1,6-萘啶-3-甲腈(2.00g，7.23mmol)的二氯甲烷(30mL)溶液中加入(1R,5S)-叔丁基3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(1.38g，6.51mmol)的二氯甲烷(10mL)溶液。然后缓慢加入三乙胺(2.52mL，18.1mmol)的二氯甲烷(10mL)溶液。反应在-70℃下搅拌0.5小时。混合物加入水(20ml)，然后用二氯甲烷(20mL*3)萃取，合并的有机相用盐水(20mL)洗涤。有机层用无水硫酸镁干燥并过滤。滤液真空浓缩。残余物通过快速柱色谱(硅胶，0-12％梯度的四氢呋喃/二氯甲烷)纯化得到黄色固体化合物叔丁基(1R,5S)-3-(2,7-二氯-3-氰基-8-氟-1,6-萘啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(2.20g，4.86mmol，收率67％)。LCMS(ESI):[M+H]+＝452.1.Step 6: Under -70 ° C to 2,4,7-trigloin-8-fluorine -1,6-pyrimidine-3-metada (2.00g, 7.23 mmol) dichloromethane (30ml) solution (1R, 5S) -Ixin 3,8-two-nitrogen miscellaneous two-ring [3.2.1] Ectane-8-carboxylic acid ester (1.38g, 6.5 6.5, 6.5 1mmol) dichloromethane (10ml) solution. A solution of triethylamine (2.52 mL, 18.1 mmol) in dichloromethane (10 mL) was then added slowly. The reaction was stirred at -70°C for 0.5 hours. The mixture was added with water (20ml), then extracted with dichloromethane (20mL*3), and the combined organic phases were washed with brine (20mL). The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated in vacuo. The residue was purified by flash column chromatography (silica gel, 0-12% tetrahydrofuran/dichloromethane gradient) to give yellow solid compound tert-butyl(1R,5S)-3-(2,7-dichloro-3-cyano-8-fluoro-1,6-naphthyridin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (2.20g, 4.86mmol, yield 67%). LCMS (ESI): [M+H] + = 452.1.
第七步：向叔丁基(1R,5S)-3-(2,7-二氯-3-氰基-8-氟-1,6-萘啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(1.00g，2.21mmol)的四氢呋喃(20mL)溶液中加入4A分子筛(1.00g)，((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲醇(0.35g，2.21mmol)和叔丁醇钠(0.32g，3.32mmol)。反应在20℃下搅拌2小时。混合物加入水(30mL)，然后用乙酸乙酯(30mL*2)和二氯甲烷(30mL*2)萃取。合并的有机层用无水硫酸镁干燥并过滤。真空浓缩滤液，残余物通过快速柱色谱(硅胶，0-8％梯度的甲醇/二氯甲烷)纯化得到黄色固体化合物叔丁基(1R,5S)-3-(7-氯-3-氰基-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-1,6-萘啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(1.10g，1.91mmol，收率86％)。LCMS(ESI):[M+H]+＝575.3.Step 7: Add 4A molecular sieves (1.00 g) to a solution of tert-butyl (1R,5S)-3-(2,7-dichloro-3-cyano-8-fluoro-1,6-naphthyridin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.00 g, 2.21 mmol) in tetrahydrofuran (20 mL), ((2R,7aS)-2-fluoro Tetrahydro-lH-pyrrolazin-7a(5H)-yl)methanol (0.35 g, 2.21 mmol) and sodium tert-butoxide (0.32 g, 3.32 mmol). The reaction was stirred at 20°C for 2 hours. Water (30 mL) was added to the mixture, followed by extraction with ethyl acetate (30 mL*2) and dichloromethane (30 mL*2). The combined organic layers were dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated in vacuo, and the residue was purified by flash column chromatography (silica gel, 0-8% gradient of methanol/dichloromethane) to give yellow solid compound tert-butyl(1R,5S)-3-(7-chloro-3-cyano-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-1,6-naphthyridin-4-yl)-3,8-diazabicyclo[3 .2.1] Octane-8-carboxylate (1.10 g, 1.91 mmol, 86% yield). LCMS (ESI): [M+H] + = 575.3.
第八步：在氮气环境中，向叔丁基(1R,5S)-3-(7-氯-3-氰基-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-1,6-萘啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(500mg，0.87mmol)，((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(535mg，1.04mmol)和碳酸铯(850mg，2.61mmol)的二氧六环(5mL)和水(1mL)溶液中加入氯[(正丁基二(1-金刚烷基)膦)-2-(2-氨基联苯)]钯(II)(58mg，0.09mmol)，并将混合物在100℃下搅拌3小时。混合物加入水(5mL)，然后用乙酸乙酯(5mL*2)萃取，合并的有机相用盐水(6mL*1)洗涤，无水硫酸镁干燥并过滤。滤液真空浓缩。残余物通过快速柱色谱(硅胶，0-7％梯度的甲醇/二氯甲烷)纯化得到棕色固体化合物叔丁基(1R,5S)-3-(3-氰基-8-氟-7-(7-氟-3-(甲氧基甲氧基)-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)-1,6-萘啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(800mg，0.86mmol，收率99％)。LCMS(ESI):[M+H]+＝925.5Step 8: In a nitrogen atmosphere, add tert-butyl(1R,5S)-3-(7-chloro-3-cyano-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-1,6-naphthyridin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (500mg, 0.87 mmol), ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (535 mg, 1.04 mmol) and cesium carbonate (850 mg, 2.61 mmol) in dioxane (5 mL) and water (1 mL) was added chloro[(n-butylbis(1-adamant Alkyl)phosphine)-2-(2-aminobiphenyl)]palladium(II) (58mg, 0.09mmol), and the mixture was stirred at 100°C for 3 hours. The mixture was added with water (5 mL), then extracted with ethyl acetate (5 mL*2), the combined organic phases were washed with brine (6 mL*1), dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated in vacuo. The residue was purified by flash column chromatography (silica gel, 0-7% gradient of methanol/dichloromethane) to give brown solid compound tert-butyl(1R,5S)-3-(3-cyano-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalene-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazine-7a(5H) -yl)methoxy)-1,6-naphthyridin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (800 mg, 0.86 mmol, yield 99%). LCMS (ESI): [M+H] + =925.5
第九步：向叔丁基(1R,5S)-3-(3-氰基-8-氟-7-(7-氟-3-(甲氧基甲氧基)-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)-1,6-萘啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(750mg，0.81mmol)的二甲基甲酰胺(7.5mL)溶液中加入氟化铯(2.40g，15.8mmol)。 反应在20℃下搅拌2小时。将混合物真空浓缩。残余物通过快速柱色谱法(硅胶，0-3％梯度的甲醇/二氯甲烷)纯化得到叔丁基(1R,5S)-3-(3-氰基-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-吡咯嗪-7a(5H)-基)甲氧基)-1,6-萘啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(450mg，0.59mmol，收率73％)，为棕色固体。LCMS(ESI):[M+H]+＝768.9.The ninth step: to tert-butyl (1R,5S)-3-(3-cyano-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalene-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-1,6-naphthyridin-4-yl)-3,8- To a solution of diazabicyclo[3.2.1]octane-8-carboxylate (750 mg, 0.81 mmol) in dimethylformamide (7.5 mL) was added cesium fluoride (2.40 g, 15.8 mmol). The reaction was stirred at 20°C for 2 hours. The mixture was concentrated in vacuo. The residue was purified by flash column chromatography (silica gel, 0-3% gradient of methanol/dichloromethane) to give tert-butyl(1R,5S)-3-(3-cyano-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-1,6-naphthyridine -4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (450 mg, 0.59 mmol, yield 73%) as a brown solid. LCMS (ESI): [M+H] + = 768.9.
第十步：向溶有三氟乙酸(1.80mL)的二氯甲烷(7.20mL)中添加叔丁基(1R,5S)-3-(3-氰基-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-吡咯嗪-7a(5H)-基)甲氧基)-1,6-萘啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(450mg，0.59mmol)。反应在20℃下搅拌2小时。将混合物真空浓缩得到残余物。将残余物用二氯甲烷(3mL)稀释并加入三乙胺以将pH值调节至7-8。然后真空浓缩，残余物通过制备型HPLC纯化得到黄色固体化合物4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-7-(8-乙炔基-7-氟-3-羟基萘-1-基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-1,6-萘啶-3-甲腈(13.5mg，21umol，收率3.5％)。LCMS(ESI):[M+H]+＝625.2.1H NMR(400MHz,CD3OD)δppm 9.23(s,1H),7.88(dd,J＝5.8,9.0Hz,1H),7.39-7.32(m,2H),7.24(s,1H),5.47-5.26(m,1H),4.47-4.32(m,2H),4.05-3.92(m,2H),3.90-3.78(m,2H),3.70(br s,2H),3.51-3.35(m,2H),3.30-3.14(m,2H),3.12-3.01(m,1H),2.45-1.98(m,10H).Step 10: To dichloromethane (7.20 mL) in trifluoroacetic acid (1.80 mL) was added tert-butyl(1R,5S)-3-(3-cyano-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)- 1,6-Naphthyridin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (450 mg, 0.59 mmol). The reaction was stirred at 20°C for 2 hours. The mixture was concentrated in vacuo to give a residue. The residue was diluted with dichloromethane (3 mL) and triethylamine was added to adjust the pH to 7-8. It was then concentrated in vacuo and the residue was purified by preparative HPLC to give the yellow solid compound 4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-1,6-naphthyridine -3-carbonitrile (13.5 mg, 21 umol, yield 3.5%). LCMS(ESI):[M+H] + ＝625.2. 1 H NMR(400MHz,CD 3 OD)δppm 9.23(s,1H),7.88(dd,J＝5.8,9.0Hz,1H),7.39-7.32(m,2H),7.24(s,1H),5.47-5.26(m,1H),4.47-4.32(m,2H),4.05-3.92(m,2H),3.90-3.78(m,2H),3.70(br s,2H),3.51-3.35(m,2H),3.30-3.14(m,2H),3.12-3.01(m,1H),2.45-1.98(m,10H).
实施例44：2-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-6-氯-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)喹唑啉-7-基)-3-氟苯酚
Example 44: 2-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinazolin-7-yl)-3-fluorophenol
第一步：向化合物叔丁基(1R,5S)-3-(7-溴-6-氯-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)喹唑啉-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(150mg，0.19mmol)和(2-氟-6-羟基苯基)硼酸(59mg，0.38mmol)的二氧六环(3mL)和水(600uL)溶液中加入碳酸钠(76mg，0.72mmol)，氮气氛围下加入(2-二环己基膦基-2,6-二异丙氧基-1,1-联苯基)[2-(2-氨基-1,1-联苯基)]钯(II)(17mg，0.02mmol)和(2-二环己基膦-2,4,6-三异丙基-1,1-联苯)[2-(2-胺基-1,1-联苯]甲磺酸钯(20mg，0.02mmol)，60℃搅拌2小时。反应液减压浓缩，残留物用快速柱色谱纯化(硅胶，0-80％梯度的四氢呋喃/石油醚)得化合物叔丁基(1R,5S)-3-(6-氯-8-氟-7-(2-氟-6-羟基苯基)-2-(((2R,7aS)-2-氟四氢-1H-吡咯烷-7a(5H)-基)甲氧基)喹唑啉-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(67％纯度，40mg，0.04mmol，收率21％)。LCMS(ESI):[M+H]+＝660.0.The first step: to the compound tert-butyl (1R,5S)-3-(7-bromo-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (150mg, 0.19mmol) and (2-fluoro-6- Sodium carbonate (76mg, 0.72mmol) was added to a solution of hydroxyphenyl)boronic acid (59mg, 0.38mmol) in dioxane (3mL) and water (600uL), and (2-dicyclohexylphosphino-2,6-diisopropoxy-1,1-biphenyl)[2-(2-amino-1,1-biphenyl)]palladium(II) (17mg, 0.02mmol) and (2-dicyclohexyl Phosphine-2,4,6-triisopropyl-1,1-biphenyl)[2-(2-amino-1,1-biphenyl]palladium methanesulfonate (20mg, 0.02mmol), stirred at 60°C for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by flash column chromatography (silica gel, 0-80% gradient tetrahydrofuran/petroleum ether) to obtain the compound tert-butyl (1R,5S)-3-(6-chloro-8-fluoro-7-(2-fluoro-6 -Hydroxyphenyl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (67% purity, 40 mg, 0.04 mmol, yield 21%). LCMS (ESI): [M+H]+=660.0.
第二步：化合物叔丁基(1R,5S)-3-(6-氯-8-氟-7-(2-氟-6-羟基苯基)-2-(((2R,7aS)-2-氟四氢-1H-吡咯烷-7a(5H)-基)甲氧基)喹唑啉-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(30.0mg，0.03mmol)溶于二氯甲烷/三氟乙酸(体积比为4:1，600uL)中，反应液在20℃搅拌2小时。反应液减压浓缩，加入乙腈(0.5mL)，然后用三乙胺调节pH到8，浓缩后的残留物用制备型HPLC纯化，得到白色固体化合物2-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-6-氯-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)喹唑啉-7-基)-3-氟苯酚(12.0mg，21.5umol，收率71％)。LCMS(ESI):[M+H]+＝560.1；1H NMR(400MHz,DMSO-d6)δppm 10.49-9.92(m,1H),8.10-7.70(m,1H),7.52-7.23(m,1H),6.99-6.62(m,2H), 5.46-5.03(m,1H),4.27(br t,J＝9.2Hz,2H),4.15-3.93(m,2H),3.51(br s,3H),3.48(br d,J＝4.8Hz,1H),3.08(br d,J＝5.8Hz,2H),3.01(s,1H),2.88-2.75(m,1H),2.16-2.10(m,1H),2.06-1.93(m,2H),1.91-1.71(m,3H),1.62(br s,4H).The second step: compound tert-butyl (1R,5S)-3-(6-chloro-8-fluoro-7-(2-fluoro-6-hydroxyphenyl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (30.0mg, 0.03mmol ) was dissolved in dichloromethane/trifluoroacetic acid (volume ratio 4:1, 600uL), and the reaction solution was stirred at 20°C for 2 hours. The reaction solution was concentrated under reduced pressure, acetonitrile (0.5 mL) was added, and then the pH was adjusted to 8 with triethylamine. The concentrated residue was purified by preparative HPLC to obtain a white solid compound 2-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl) Methoxy)quinazolin-7-yl)-3-fluorophenol (12.0 mg, 21.5 umol, yield 71%). LCMS (ESI): [M+H] + =560.1; 1 H NMR (400MHz, DMSO-d 6 ) δppm 10.49-9.92 (m, 1H), 8.10-7.70 (m, 1H), 7.52-7.23 (m, 1H), 6.99-6.62 (m, 2H), 5.46-5.03(m,1H),4.27(br t,J=9.2Hz,2H),4.15-3.93(m,2H),3.51(br s,3H),3.48(br d,J=4.8Hz,1H),3.08(br d,J=5.8Hz,2H),3.01(s,1H),2.88-2.7 5(m,1H),2.16-2.10(m,1H),2.06-1.93(m,2H),1.91-1.71(m,3H),1.62(br s,4H).
实施例45：4-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-6-氯-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)喹唑啉-7-基)-5-乙炔基-6-氟萘-2-醇和实施例46：1-(8-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-6-氯-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)喹唑啉-7-基)-2-氟-6-羟基萘-1-基)乙-1-酮
Example 45: 4-(4-((1R,5S)-3,8-Diazabicyclo[3.2.1]oct-3-yl)-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol and Example 46: 1-(8 -(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-2-fluoro-6-hydroxynaphthalen-1-yl)ethan-1-one
实施例45和实施例46通过实施例44的合成路线方法进行制备，用中间体((2-氟-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)三异丙基硅烷和中间体叔丁基(1R,5S)-3-(7-溴-6-氯-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)喹唑啉-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯A9反应，第三步和第四步合并成一步，用TFA/DCM脱保护，得到主产物4-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-6-氯-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)喹唑啉-7-基)-5-乙炔基-6-氟萘-2-醇。LCMS(ESI):[M+H]+＝634.4；1H NMR(400MHz,CD3OD)δppm7.89-7.79(m,2H),7.37-7.27(m,2H),7.05(d,J＝2.1Hz,1H),5.45-5.24(m,1H),4.58-4.41(m,2H),4.35-4.20(m,2H),3.68(br s,3H),3.61(br dd,J＝6.2,12.6Hz,1H),3.27(m,4H),3.10-2.99(m,1H),2.44-2.23(m,2H),2.16(m,1H),2.07-1.96(m,2H),1.90(br s,5H).Example 45 and Example 46 were prepared by the synthetic route method of Example 44, using intermediate ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalene-1-yl)ethynyl)triisopropylsilane and intermediate tert-butyl (1R,5S)-3-(7-bromo-6-chloro-8-fluoro-2-(((2R, 7aS)-2-Fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate A9 reaction, the third and fourth steps were combined into one step, and deprotected with TFA/DCM to obtain the main product 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl) -6-Chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol. LCMS(ESI):[M+H] + ＝634.4； 1 H NMR(400MHz,CD 3 OD)δppm7.89-7.79(m,2H),7.37-7.27(m,2H),7.05(d,J＝2.1Hz,1H),5.45-5.24(m,1H),4.58-4.41(m,2H),4.35-4.20(m,2H),3.68(br s,3H),3.61(br dd,J＝6.2,12.6Hz,1H),3.27(m,4H),3.10-2.99(m,1H),2.44-2.23(m,2H),2.16(m,1H),2.07-1.96(m,2H),1.90(br s,5H).
同时得到次产物1-(8-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-6-氯-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)喹唑啉-7-基)-2-氟-6-羟基萘-1-基)乙-1-酮。LCMS(ESI):[M+H]+＝652.3；1HNMR(400MHz,MeOD-d4)δppm 7.98-7.85(m,2H),7.39-7.29(m,2H),7.08(d,J＝2.4Hz,1H),5.44-5.23(m,1H),4.57-4.45(m,2H),4.38-4.19(m,2H),3.79-3.62(m,4H),3.50-3.37(m,1H),3.31-3.21(m,2H),3.14-2.99(m,1H),2.46-2.31(m,1H),2.30-2.16(m,2H),2.13(s,3H),2.08-1.98(m,2H),1.96-1.77(m,5H).At the same time, the secondary product 1-(8-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinazolin-7-yl)-2-fluoro-6-hydroxynaphthalen-1-yl)ethan-1-one was obtained. LCMS(ESI):[M+H] + ＝652.3； 1 HNMR(400MHz,MeOD-d 4 )δppm 7.98-7.85(m,2H),7.39-7.29(m,2H),7.08(d,J＝2.4Hz,1H),5.44-5.23(m,1H),4.57-4.45(m,2H),4.38-4.19(m,2H),3.79-3.62(m,4H),3.50-3.37(m,1H),3.31-3.21(m,2H),3.14-2.99(m,1H),2.46-2.31(m,1H),2.30-2.16(m,2H),2.13(s,3H),2.08-1.98(m,2H),1.96-1.77(m,5H).
实施例47：4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-7-(8-乙炔基-7-氟-3-羟基萘-1-基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)喹唑啉-6-甲腈
Example 47: 4-((1R,5S)-3,8-Diazabicyclo[3.2.1]oct-3-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinazolin-6-carbonitrile
第一步：化合物叔丁基(1R,5S)-3-(7-溴-6-氰基-8-氟-2-(2,2,2-三氟乙氧基)喹唑啉-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(80％纯度，292mg，0.57mmol)加入到二氧六环(5mL)和水(1mL)中，加入((2-氟-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)三异丙基硅烷(200mg，0.29mmol)和磷酸钾(182mg，0.86mmol)，氮气氛围下加入甲磺酰氧基(二金刚烷基-正丁基膦基)-2-氨基-1,1-联苯-2-基)钯(II)(41mg，0.06mmol)，反应液在100℃搅拌2小时。反应液减压浓缩，残余物用快速柱色谱纯化(硅胶，0-2％梯度的甲醇/二氯甲烷)得化合物叔丁基(1R,5S)-3-(6-氰基-8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三异丙基甲硅烷基)乙炔基)萘-1-基)-2-(2,2,2-三氟乙氧基)喹唑啉-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(70％纯度，187mg，0.14mmol，收率53％)。LCMS(ESI):[M+H]+＝866.5.The first step: compound tert-butyl (1R,5S)-3-(7-bromo-6-cyano-8-fluoro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (80% purity, 292mg, 0.57mmol) was added to dioxane (5mL) and water (1mL), and ((2-fluoro-6 -(Methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)naphthalene-1-yl)ethynyl)triisopropylsilane (200mg, 0.29mmol) and potassium phosphate (182mg, 0.86mmol), methanesulfonyloxy(diadamantyl-n-butylphosphino)-2-amino-1,1-biphenyl-2-yl)palladium(II) was added under nitrogen atmosphere (41mg, 0.06mmol), and the reaction solution was stirred at 100°C for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by flash column chromatography (silica gel, 0-2% gradient methanol/dichloromethane) to obtain the compound tert-butyl(1R,5S)-3-(6-cyano-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalene-1-yl)-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazepine Heterobicyclo[3.2.1]octane-8-carboxylate (70% purity, 187 mg, 0.14 mmol, yield 53%). LCMS (ESI): [M+H] + = 866.5.
第二步：化合物叔丁基(1R,5S)-3-(6-氰基-8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三异丙基甲硅烷基)乙炔基)萘-1-基)-2-(2,2,2-三氟乙氧基)喹唑啉-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(70％纯度，147mg，0.12mmol)加入到四氢呋喃(2mL)中，加入((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲醇(57mg，0.36mmol)和叔丁醇钠(17mg，0.18mmol)，50℃搅拌2小时。反应液加入水(3mL)，用乙酸乙酯(3mL*3)萃取，有机相减压浓缩得化合物叔丁基(1R,5S)-3-(6-氰基-8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三异丙基甲硅烷基)乙炔基)萘-1-基)-2-(2,2,2-三氟乙氧基)喹唑啉-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(66％纯度，156mg，0.11mmol，收率93％)。LCMS(ESI):[M+H]+＝924.9.The second step: compound tert-butyl(1R,5S)-3-(6-cyano-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalene-1-yl)-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (70% purity, 147 mg, 0.12mmol) into tetrahydrofuran (2mL), add ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol (57mg, 0.36mmol) and sodium tert-butoxide (17mg, 0.18mmol), and stir at 50°C for 2 hours. The reaction solution was added with water (3 mL), extracted with ethyl acetate (3 mL*3), and the organic phase was concentrated under reduced pressure to obtain the compound tert-butyl(1R,5S)-3-(6-cyano-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalene-1-yl)-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabis Cyclo[3.2.1]octane-8-carboxylate (66% purity, 156 mg, 0.11 mmol, 93% yield). LCMS (ESI): [M+H] + =924.9.
第三步：化合物叔丁基(1R,5S)-3-(6-氰基-8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三异丙基甲硅烷基)乙炔基)萘-1-基)-2-(2,2,2-三氟乙氧基)喹唑啉-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(66％纯度，156mg，0.11mmol)加入到N,N-二甲基甲酰胺(2mL)中，加入氟化铯(169mg，1.11mmol)，20℃搅拌1小时。反应液加入水(500uL)稀释，用乙酸乙酯(1mL*3)萃取，有机相减压浓缩得化合物叔丁基(1R,5S)-3-(6-氰基-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-吡咯嗪-7a(5H)-基)甲氧基)喹唑啉-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(60％纯度，135mg，0.10mmol，收率94％)。LCMS(ESI):[M+H]+＝769.3.The third step: compound tert-butyl(1R,5S)-3-(6-cyano-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalene-1-yl)-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (66% purity, 156 mg, 0.11 mmol) was added to N,N-dimethylformamide (2 mL), cesium fluoride (169 mg, 1.11 mmol) was added, and stirred at 20°C for 1 hour. The reaction solution was diluted with water (500uL), extracted with ethyl acetate (1mL*3), and the organic phase was concentrated under reduced pressure to obtain the compound tert-butyl(1R,5S)-3-(6-cyano-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy) Quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (60% purity, 135 mg, 0.10 mmol, yield 94%). LCMS (ESI): [M+H] + = 769.3.
第四步：化合物叔丁基(1R,5S)-3-(6-氰基-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-吡咯嗪-7a(5H)-基)甲氧基)喹唑啉-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(60％纯度，135mg，0.10mmol)加入到三氟乙酸/二氯甲烷(体积比为4:1，2.5mL)中，20℃搅 拌2小时。反应液减压浓缩，残留物加入乙腈(500uL)，加入三乙胺调节pH到8，残留物用制备型HPLC纯化，得到黄色固体化合物4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-7-(8-乙炔基-7-氟-3-羟基萘-1-基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)喹唑啉-6-甲腈(9.11mg，15umol，收率14％)。LCMS(ESI):[M+H]+＝624.9；1H NMR(400MHz,DMSO-d6)δppm 10.40-10.21(m,1H),8.29(s,1H),8.02(dd,J＝5.9,9.2Hz,1H),7.56-7.40(m,2H),7.17(s,1H),5.41-5.14(m,1H),4.44-4.23(m,2H),4.10(dd,J＝6.5,10.3Hz,1H),4.05-3.95(m,2H),3.65(br d,J＝12.3Hz,1H),3.56(br d,J＝10.3Hz,3H),3.16-3.04(m,2H),3.01(s,1H),2.89-2.77(m,1H),2.12(br s,1H),2.07-1.94(m,2H),1.90-1.72(m,3H),1.70-1.54(m,4H).The fourth step: the compound tert-butyl (1R,5S)-3-(6-cyano-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane- 8-Carboxylate (60% purity, 135mg, 0.10mmol) was added to trifluoroacetic acid/dichloromethane (volume ratio 4:1, 2.5mL), stirred at 20°C Mix for 2 hours. The reaction solution was concentrated under reduced pressure, the residue was added to acetonitrile (500uL), and triethylamine was added to adjust the pH to 8. The residue was purified by preparative HPLC to obtain a yellow solid compound 4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1 H-Pyrrolazin-7a(5H)-yl)methoxy)quinazoline-6-carbonitrile (9.11 mg, 15 umol, yield 14%). LCMS(ESI):[M+H] + ＝624.9； 1 H NMR(400MHz,DMSO-d 6 )δppm 10.40-10.21(m,1H),8.29(s,1H),8.02(dd,J＝5.9,9.2Hz,1H),7.56-7.40(m,2H),7.17(s,1H),5.41-5.14(m,1H),4.44-4.23(m,2H),4.10(dd,J＝6.5,10.3Hz,1H),4.05-3.95(m,2H),3.65(br d,J＝12.3Hz,1H),3.56(br d,J＝10.3Hz,3H),3.16-3.04(m,2H),3.01(s,1H),2.89-2.77(m,1H),2.12(br s,1H),2.07-1.94(m,2H),1.90-1.72(m,3H),1.70-1.54(m,4H).
以下实施例通过实施例47的合成路线方法进行制备：第二步中间体化合物叔丁基(1R,5S)-3-(6-氰基-8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三异丙基甲硅烷基)乙炔基)萘-1-基)-2-(2,2,2-三氟乙氧基)喹唑啉-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯与中间体A16-2反应，参照类似反应条件制备得到反式产物。经SFC分离(柱：DAICEL CHIRALPAK IG(250mm*30mm,10um)；流动相：A相为二氧化碳，B相为0.1％氨水/乙醇；B相保持45％；流速：80毫升/分钟)，得到目标化合物实施例48A～实施例48D。The following examples were prepared by the synthetic route method of Example 47: the second step intermediate compound tert-butyl (1R,5S)-3-(6-cyano-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalene-1-yl)-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane Alkane-8-carboxylate was reacted with intermediate A16-2, and the trans product was prepared by referring to similar reaction conditions. After separation by SFC (column: DAICEL CHIRALPAK IG (250mm*30mm, 10um); mobile phase: phase A is carbon dioxide, phase B is 0.1% ammonia water/ethanol; phase B is kept at 45%; flow rate: 80 ml/min), the target compounds Examples 48A to 48D were obtained.
实施例48A～48D：4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-2-(((1R,7a'R)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-吡咯嗪]-7a'(5'H)-基)甲氧基)-7-(R)-(8-乙炔基-7-氟-3-羟基萘-1-基)-8-氟喹唑啉-6-腈，4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-2-(((1R,7a'R)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-吡咯嗪]-7a'(5'H)-基)甲氧基)-7-(S)-(8-乙炔基-7-氟-3-羟基萘-1-基)-8-氟喹唑啉-6-腈，4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-吡咯嗪]-7a'(5'H)-基)甲氧基)-7-((R)-8-乙炔基-7-氟-3-羟基萘-1-基)-8-氟喹唑啉-6-腈，4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-吡咯嗪]-7a'(5'H)-基)甲氧基)-7-((S)-8-乙炔基-7-氟-3-羟基萘-1-基)-8-氟喹唑啉-6-腈
Examples 48A～48D: 4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(((1R,7a'R)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolazin]-7a'(5'H)-yl)methoxy)-7-(R)-(8-ethynyl-7- Fluoro-3-hydroxynaphthalen-1-yl)-8-fluoroquinazoline-6-carbonitrile, 4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(((1R,7a'R)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolazin]-7a'(5'H)-yl)methoxy)-7-(S )-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoroquinazoline-6-carbonitrile, 4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolazine]-7a'(5'H) -yl)methoxy)-7-((R)-8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoroquinazoline-6-carbonitrile, 4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrole Azine]-7a'(5'H)-yl)methoxy)-7-((S)-8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoroquinazoline-6-carbonitrile
实施例48A：异构体1，SFC分析(柱：Chiralpak IE 100*4.6mm 3um；流动相：A相为0.1％二乙胺/正庚烷，B相为异丙醇；梯度：A/B＝60/40，流速：1毫升/分钟)：RT＝4.236min,手性纯度：100％；1H NMR(400MHz,CD3OD)δppm 8.11(s,1H),7.78(br dd,J＝5.8,9.0Hz,1H),7.32-7.17(m,2H),7.05(d,J＝2.1Hz,1H),4.50(br d,J＝11.8Hz,1H),4.39(br d,J＝12.4Hz,1H),4.31-4.17(m,2H),3.69-3.49(m,4H),3.26(s,1H),3.17(br s,1H),3.10-3.00(m,1H),2.74(br d,J＝12.3Hz,1H),2.65-2.53(m,1H),2.18(br dd,J＝6.0,13.4Hz,1H),2.03(br dd,J＝6.6,11.9Hz,1H),1.92(br d,J＝13.5Hz,1H),1.83-1.61(m,7H),1.41-1.28(m,2H).Example 48A: Isomer 1, SFC analysis (column: Chiralpak IE 100*4.6mm 3um; mobile phase: phase A is 0.1% diethylamine/n-heptane, phase B is isopropanol; gradient: A/B=60/40, flow rate: 1 ml/min): RT=4.236min, chiral purity: 100%;1H NMR (400MHz, CD3OD)δppm 8.11(s,1H),7.78(br dd,J=5.8,9.0Hz,1H),7.32-7.17(m,2H),7.05(d,J=2.1Hz,1H),4.50(br d,J=11.8Hz,1H),4.39(br d,J=12.4Hz,1H),4.31 -4.17(m,2H),3.69-3.49(m,4H),3.26(s,1H),3.17(br s,1H),3.10-3.00(m,1H),2.74(br d,J＝12.3Hz,1H),2.65-2.53(m,1H),2.18(br dd,J＝6.0,13. 4Hz,1H),2.03(br d,J=6.6,11.9Hz,1H),1.92(br d,J=13.5Hz,1H),1.83-1.61(m,7H),1.41-1.28(m,2H).
实施例48B：异构体2，SFC分析(柱：Chiralpak IG-3(50mm*4.6mm)，3um；流动相：A相 为二氧化碳，B相为0.05％二乙胺/乙醇；梯度：B相在2分钟内从5％到40％，保持40％的B相1.2分钟，保持5％的B相0.8分钟，流速：4毫升/分钟)：RT＝1.942min,手性纯度：100％；LCMS(ESI):[M+H]+＝669.2；1H NMR(400MHz,CD3OD)δppm 8.23(s,1H),7.90(dd,J＝5.8,9.0Hz,1H),7.44-7.30(m,2H),7.17(d,J＝2.5Hz,1H),4.66-4.48(m,2H),4.40-4.31(m,2H),3.79-3.61(m,4H),3.40-3.36(m,1H),3.30(d,J＝6.8Hz,1H),3.20-3.13(m,1H),2.86(d,J＝12.0Hz,1H),2.76-2.67(m,1H),2.33-2.25(m,1H),2.20-2.11(m,1H),2.04(br d,J＝13.6Hz,1H),1.97-1.75(m,7H),1.52-1.37(m,2H).Example 48B: Isomer 2, SFC analysis (column: Chiralpak IG-3 (50mm*4.6mm), 3um; mobile phase: A phase为二氧化碳，B相为0.05％二乙胺/乙醇；梯度：B相在2分钟内从5％到40％，保持40％的B相1.2分钟，保持5％的B相0.8分钟，流速：4毫升/分钟)：RT＝1.942min,手性纯度：100％；LCMS(ESI):[M+H] + ＝669.2； 1 H NMR(400MHz,CD 3 OD)δppm 8.23(s,1H),7.90(dd,J＝5.8,9.0Hz,1H),7.44-7.30(m,2H),7.17(d,J＝2.5Hz,1H),4.66-4.48(m,2H),4.40-4.31(m,2H),3.79-3.61(m,4H),3.40-3.36(m,1H),3.30(d,J＝6.8Hz,1H),3.20-3.13(m,1H),2.86(d,J＝12.0Hz,1H),2.76-2.67(m,1H),2.33-2.25(m,1H),2.20-2.11(m,1H),2.04(br d,J＝13.6Hz,1H),1.97-1.75(m,7H),1.52-1.37(m,2H).
实施例48C：异构体3，SFC分析(柱：Chiralpak IG-3(50mm*4.6mm)，3um；流动相：A相为二氧化碳，B相为0.05％二乙胺/乙醇；梯度：B相在2分钟内从5％到40％，保持40％的B相1.2分钟，保持5％的B相0.8分钟，流速：4毫升/分钟)：RT＝2.343min,手性纯度＝97.12％；1H NMR(400MHz,CD3OD)δppm 8.23(s,1H),7.89(dd,J＝5.8,9.1Hz,1H),7.42-7.32(m,2H),7.17(d,J＝2.3Hz,1H),4.62-4.48(m,2H),4.36(s,2H),3.80-3.61(m,4H),3.37(s,1H),3.31-3.26(m,1H),3.20-3.12(m,1H),2.85(d,J＝12.2Hz,1H),2.76-2.65(m,1H),2.28(dd,J＝6.2,13.6Hz,1H),2.19-2.12(m,1H),2.03(d,J＝13.6Hz,1H),1.96-1.74(m,7H),1.50-1.37(m,2H).Example 48C: Isomer 3, SFC analysis (column: Chiralpak IG-3 (50mm*4.6mm), 3um; mobile phase: A phase is carbon dioxide, B phase is 0.05% diethylamine/ethanol; gradient: B phase from 5% to 40% within 2 minutes, keep 40% of B phase for 1.2 minutes, keep 5% of B phase for 0.8 minutes, flow rate: 4 ml/min): RT=2.343min, chiral pure degree = 97.12%;1H NMR (400MHz, CD3OD)δppm 8.23(s,1H),7.89(dd,J=5.8,9.1Hz,1H),7.42-7.32(m,2H),7.17(d,J=2.3Hz,1H),4.62-4.48(m,2H),4.36(s,2H),3.80-3.61(m,4H),3.37( s,1H),3.31-3.26(m,1H),3.20-3.12(m,1H),2.85(d,J=12.2Hz,1H),2.76-2.65(m,1H),2.28(dd,J=6.2,13.6Hz,1H),2.19-2.12(m,1H),2.03(d,J=13 .6Hz,1H),1.96-1.74(m,7H),1.50-1.37(m,2H).
实施例48D：异构体4，SFC分析(柱：Chiralpak IG-3(50mm*4.6mm)，3um；流动相：A相为二氧化碳，B相为0.05％二乙胺/乙醇；梯度：B相在2分钟内从5％到40％，保持40％的B相1.2分钟，保持5％的B相0.8分钟，流速：4毫升/分钟)：RT＝3.004min,手性纯度：98.43％；1H NMR(400MHz,CD3OD)δppm 8.11(s,1H),7.77(br dd,J＝5.9,8.9Hz,1H),7.32-7.18(m,2H),7.05(s,1H),4.48(br d,J＝12.8Hz,1H),4.38(br d,J＝12.4Hz,1H),4.23(q,J＝10.5Hz,2H),3.67-3.49(m,4H),3.26(s,1H),3.17(br d,J＝7.0Hz,1H),3.09-3.00(m,1H),2.73(br d,J＝12.3Hz,1H),2.59(br d,J＝6.4Hz,1H),2.17(br dd,J＝6.0,13.5Hz,1H),2.02(br dd,J＝5.8,10.5Hz,1H),1.91(br d,J＝13.5Hz,1H),1.84-1.62(m,7H),1.40-1.25(m,2H).Example 48D: Isomer 4, SFC analysis (column: Chiralpak IG-3 (50mm*4.6mm), 3um; mobile phase: phase A is carbon dioxide, phase B is 0.05% diethylamine/ethanol; gradient: phase B is from 5% to 40% in 2 minutes, keep 40% of B phase for 1.2 minutes, keep 5% of B phase for 0.8 minutes, flow rate: 4 ml/min): RT=3.004min, chiral pure Degree: 98.43%;1H NMR (400MHz, CD3OD)δppm 8.11(s,1H),7.77(br dd,J=5.9,8.9Hz,1H),7.32-7.18(m,2H),7.05(s,1H),4.48(br d,J=12.8Hz,1H),4.38(br d,J=12.4Hz,1H),4.23(q,J=10 .5Hz, 2H), 3.67-3.49(m, 4H), 3.26(s, 1H), 3.17(br d, J＝7.0Hz, 1H), 3.09-3.00(m, 1H), 2.73(br d, J＝12.3Hz, 1H), 2.59(br d, J＝6.4Hz, 1H), 2.17(br dd, J＝ 6.0,13.5Hz,1H),2.02(br dd,J=5.8,10.5Hz,1H),1.91(br d,J=13.5Hz,1H),1.84-1.62(m,7H),1.40-1.25(m,2H).
以下实施例通过实施例47的合成路线方法进行制备：第二步中间体化合物叔丁基(1R,5S)-3-(6-氰基-8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三异丙基甲硅烷基)乙炔基)萘-1-基)-2-(2,2,2-三氟乙氧基)喹唑啉-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯与中间体A16-1反应，参照类似反应条件制备得到顺式产物。经SFC分离(柱：DAICEL CHIRALPAK IG(250mm*30mm,10um)；流动相：A相为二氧化碳，B相为0.1％氨水/异丙醇；B相保持50％；流速：80毫升/分钟)，得到目标化合物实施例49A～实施例49D。The following examples were prepared by the synthetic route method of Example 47: the second step intermediate compound tert-butyl (1R,5S)-3-(6-cyano-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalene-1-yl)-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane The alkane-8-carboxylate was reacted with the intermediate A16-1, and the cis product was prepared by referring to similar reaction conditions. After SFC separation (column: DAICEL CHIRALPAK IG (250mm*30mm, 10um); mobile phase: phase A is carbon dioxide, phase B is 0.1% ammonia water/isopropanol; phase B is kept at 50%; flow rate: 80 ml/min), the target compounds Examples 49A to 49D were obtained.
实施例49A～49D:4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-2-(((1S,7a'R)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-吡咯嗪]-7a'(5'H)-基)甲氧基)-7-((R)-8-乙炔基-7-氟-3-羟基萘-1-基)-8-氟喹唑啉-6-腈，4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-2-(((1S,7a'R)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-吡咯嗪]-7a'(5'H)-基)甲氧基)-7-((S)-8-乙炔基-7-氟-3-羟基萘-1-基)-8-氟喹唑啉-6-腈,4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-2-(((1R,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-吡咯嗪]-7a'(5'H)-基)甲氧基)-7-((R)-8-乙炔基-7-氟-3-羟基萘-1-基)-8-氟喹唑啉-6-腈，4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-2-(((1R,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-吡咯嗪]-7a'(5'H)-基)甲氧基)-7-((S)-8-乙炔基-7-氟-3-羟基萘-1-基)-8-氟喹唑啉-6-腈
Examples 49A～49D: 4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(((1S,7a'R)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolazin]-7a'(5'H)-yl)methoxy)-7-((R)-8-ethynyl-7- Fluoro-3-hydroxynaphthalen-1-yl)-8-fluoroquinazoline-6-carbonitrile, 4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(((1S,7a'R)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolazin]-7a'(5'H)-yl)methoxy)-7-(( S)-8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoroquinazoline-6-carbonitrile, 4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(((1R,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolazine]-7a'(5'H) -yl)methoxy)-7-((R)-8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoroquinazoline-6-carbonitrile, 4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(((1R,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrole Azine]-7a'(5'H)-yl)methoxy)-7-((S)-8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoroquinazoline-6-carbonitrile
实施例49A：异构体1，SFC分析(柱：Chiralpak IC-3(100mm*4.6mm)，3um；流动相：A相为二氧化碳，B相为0.05％二乙胺/异丙醇；梯度：40％的B相，流速：2.8毫升/分钟)：RT＝2.414min,手性纯度：100％；1H NMR(400MHz,CD3OD)δppm 8.10(s,1H),7.76(dd,J＝5.7,9.2Hz,1H),7.27-7.16(m,2H),7.05(d,J＝2.5Hz,1H),4.52(br d,J＝11.6Hz,1H),4.37(br d,J＝12.5Hz,1H),4.17-4.07(m,2H),3.65(br d,J＝12.1Hz,1H),3.58-3.43(m,3H),3.26(s,1H),3.11(d,J＝10.8Hz,1H),3.01-2.93(m,1H),2.79-2.64(m,2H),2.19(d,J＝13.3Hz,1H),2.05-1.62(m,9H),1.37-1.30(m,2H).Example 49A: Isomer 1, SFC analysis (column: Chiralpak IC-3 (100mm*4.6mm), 3um; mobile phase: phase A is carbon dioxide, phase B is 0.05% diethylamine/isopropanol; gradient: 40% of phase B, flow rate: 2.8 ml/min): RT = 2.414min, chiral purity: 100%;1H NMR (400MHz, CD3OD)δppm 8.10(s,1H),7.76(dd,J=5.7,9.2Hz,1H),7.27-7.16(m,2H),7.05(d,J=2.5Hz,1H),4.52(br d,J=11.6Hz,1H),4.37(br d,J=12.5Hz,1H),4.17-4 .07(m,2H),3.65(br d,J=12.1Hz,1H),3.58-3.43(m,3H),3.26(s,1H),3.11(d,J=10.8Hz,1H),3.01-2.93(m,1H),2.79-2.64(m,2H),2.19(d,J=13.3Hz ,1H),2.05-1.62(m,9H),1.37-1.30(m,2H).
实施例49B：异构体2,SFC分析(柱：Chiralpak IC-3(100mm*4.6mm)，3um；流动相：A相为二氧化碳，B相为0.05％二乙胺/异丙醇；梯度：40％的B相，流速：2.8毫升/分钟)：RT＝3.344min,手性纯度：92.10％；1H NMR(400MHz,CD3OD)δppm 8.22(s,1H),7.93-7.85(m,1H),7.40-7.30(m,2H),7.17(d,J＝2.2Hz,1H),4.56(br d,J＝12.3Hz,2H),4.31-4.18(m,2H),3.78-3.62(m,4H),3.41-3.37(m,1H),3.24(d,J＝10.8Hz,1H),3.16-3.04(m,1H),2.94-2.78(m,2H),2.37-2.27(m,1H),2.09(ddd,J＝5.9,11.2,14.5Hz,2H),2.01-1.91(m,3H),1.87-1.77(m,4H),1.49-1.44(m,2H).Example 49B: Isomer 2, SFC analysis (column: Chiralpak IC-3 (100mm*4.6mm), 3um; mobile phase: phase A is carbon dioxide, phase B is 0.05% diethylamine/isopropanol; gradient: 40% of phase B, flow rate: 2.8 ml/min): RT = 3.344min, chiral purity: 92.10%;1H NMR (400MHz, CD3OD)δppm 8.22(s,1H),7.93-7.85(m,1H),7.40-7.30(m,2H),7.17(d,J=2.2Hz,1H),4.56(br d,J=12.3Hz,2H),4.31-4.18(m,2H),3.78-3.62(m,4H),3 .41-3.37(m,1H),3.24(d,J=10.8Hz,1H),3.16-3.04(m,1H),2.94-2.78(m,2H),2.37-2.27(m,1H),2.09(ddd,J=5.9,11.2,14.5Hz,2H),2.01-1.91(m, 3H),1.87-1.77(m,4H),1.49-1.44(m,2H).
实施例49C：异构体3，SFC分析(柱：Chiralpak IG-3(50mm*4.6mm)，3um；流动相：A相为二氧化碳，B相为0.05％二乙胺/异丙醇；梯度：保持40％的B相，流速：4毫升/分钟)：RT＝1.150min,手性纯度：91.48％；1H NMR(400MHz,CD3OD)δppm 8.28-8.18(m,1H),7.94-7.80(m,1H),7.42-7.28(m,2H),7.22-7.15(m,1H),4.64(br d,J＝12.5Hz,1H),4.49(br d,J＝12.3Hz,1H),4.27-4.19(m,2H),3.81-3.62(m,4H),3.38(s,1H),3.23(d,J＝10.8Hz,1H),3.14-3.05(m,1H),2.93-2.76(m,2H),2.31(br d,J＝13.3Hz,1H),2.18-2.04(m,2H),2.01-1.90(m,3H),1.88-1.73(m,4H),1.49-1.41(m,2H).Example 49C: Isomer 3, SFC analysis (column: Chiralpak IG-3 (50mm*4.6mm), 3um; mobile phase: phase A is carbon dioxide, phase B is 0.05% diethylamine/isopropanol; gradient: maintain 40% of phase B, flow rate: 4 ml/min): RT = 1.150min, chiral purity: 91.48%;1H NMR (400MHz, CD3OD)δppm 8.28-8.18(m,1H),7.94-7.80(m,1H),7.42-7.28(m,2H),7.22-7.15(m,1H),4.64(br d,J=12.5Hz,1H),4.49(br d,J=12.3Hz,1H),4.27-4.19 (m,2H),3.81-3.62(m,4H),3.38(s,1H),3.23(d,J=10.8Hz,1H),3.14-3.05(m,1H),2.93-2.76(m,2H),2.31(br d,J=13.3Hz,1H),2.18-2.04(m,2H),2 .01-1.90(m,3H),1.88-1.73(m,4H),1.49-1.41(m,2H).
实施例49D：异构体4，SFC分析(柱：Chiralpak IG-3(50mm*4.6mm)，3um；流动相：A相为二氧化碳，B相为0.05％二乙胺/异丙醇；梯度：保持40％的B相，流速：4毫升/分钟)：RT＝2.203min,手性纯度：98.67％；1H NMR(400MHz,CD3OD)δppm 8.10(s,1H),7.76(dd,J＝5.8,9.1Hz,1H),7.28-7.18(m,2H),7.05(d,J＝2.4Hz,1H),4.44(br d,J＝12.4Hz,2H),4.20-4.04(m,2H),3.65-3.44(m,4H),3.31-3.23(m,1H),3.12(d,J＝10.8Hz,1H),2.98(td,J＝5.6,10.8Hz,1H),2.80-2.64(m,2H),2.21(d,J＝13.4Hz,1H),1.99-1.61(m,9H),1.41-1.26(m,2H).Example 49D: Isomer 4, SFC analysis (column: Chiralpak IG-3 (50mm*4.6mm), 3um; mobile phase: phase A is carbon dioxide, phase B is 0.05% diethylamine/isopropanol; gradient: maintain 40% of phase B, flow rate: 4 ml/min): RT = 2.203min, chiral purity: 98.67%;1H NMR (400MHz, CD3OD)δppm 8.10(s,1H),7.76(dd,J=5.8,9.1Hz,1H),7.28-7.18(m,2H),7.05(d,J=2.4Hz,1H),4.44(br d,J=12.4Hz,2H),4.20-4.04(m,2H),3.65-3.44(m ,4H),3.31-3.23(m,1H),3.12(d,J=10.8Hz,1H),2.98(td,J=5.6,10.8Hz,1H),2.80-2.64(m,2H),2.21(d,J=13.4Hz,1H),1.99-1.61(m,9H),1.41-1.2 6(m,2H).
实施例50：4-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-6-(三氟甲基)喹唑啉-7-基)萘-2-醇
Example 50: 4-(4-((1R,5S)-3,8-Diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-6-(trifluoromethyl)quinazolin-7-yl)naphthalen-2-ol
第一步：化合物叔丁基(1R,5S)-3-(7-溴-8-氟-6-碘-2-(2,2,2-三氟乙氧基)喹唑啉-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(1.00g，1.51mmol)溶于N,N-二甲基甲酰胺(15mL)，氮气氛围中，20℃下加入2,2-二氟-2-(氟磺酰基)乙酸甲酯(2.03g，10.5mmol)和碘化亚铜(2.02g，10.5mmol)。反应在60℃下搅拌16小时。反应液过滤，减压浓缩。残留物用快速柱色谱纯化(硅胶，0-20％梯度的乙酸乙酯/石油醚)得到白色固体化合物叔丁基(1R,5S)-3-(7-溴-8-氟-2-(2,2,2-三氟乙氧基)-6-(三氟甲基)喹唑啉-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(0.80g，1.32mmol，收率88％)。LCMS(ESI):[M+H]+＝605.0.The first step: the compound tert-butyl(1R,5S)-3-(7-bromo-8-fluoro-6-iodo-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.00g, 1.51mmol) was dissolved in N,N-dimethylformamide (15mL), in a nitrogen atmosphere, 2,2-difluoro - Methyl 2-(fluorosulfonyl)acetate (2.03g, 10.5mmol) and cuprous iodide (2.02g, 10.5mmol). The reaction was stirred at 60°C for 16 hours. The reaction solution was filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 0-20% gradient of ethyl acetate/petroleum ether) to give white solid compound tert-butyl(1R,5S)-3-(7-bromo-8-fluoro-2-(2,2,2-trifluoroethoxy)-6-(trifluoromethyl)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (0.80 g, 1.32 mmol, yield 88%). LCMS (ESI): [M+H] + = 605.0.
第二步：在氮气环境下中，向叔丁基(1R,5S)-3-(7-溴-8-氟-2-(2,2,2-三氟乙氧基)-6-(三氟甲基)喹唑啉-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(200mg，0.33mmol)的四氢呋喃(3mL)溶液中加入4-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)萘-2-醇(107mg，0.40mmol)，磷酸钾(1.5M的水溶液，663uL，0.99mmol)，(2-二环己基膦-2,4,6-三异丙基-1,1-联苯)[2-(2-胺基-1,1-联苯]甲磺酸钯(28mg，0.03mmol)。并将混合物在60℃下搅拌2小时。将混合物真空浓缩。残余物通过快速柱色谱(硅胶，0-10％梯度的甲醇/二氯甲烷)纯化得到淡黄色固体化合物叔丁基(1R,5S)-3-(8-氟-7-(3-羟基萘-1-基)-2-(2,2,2-三氟乙氧基)-6-(三氟甲基)喹唑啉-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(190mg，0.29mmol，收率86％)。LCMS(ESI):[M+H]+＝667.2.Second step: To a solution of tert-butyl(1R,5S)-3-(7-bromo-8-fluoro-2-(2,2,2-trifluoroethoxy)-6-(trifluoromethyl)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (200 mg, 0.33 mmol) in THF (3 mL) was added 4-(4,4,5,5 -Tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalene-2-ol (107 mg, 0.40 mmol), potassium phosphate (1.5 M in water, 663 uL, 0.99 mmol), palladium (2-dicyclohexylphosphine-2,4,6-triisopropyl-1,1-biphenyl)[2-(2-amino-1,1-biphenyl]methanesulfonate (28 mg, 0.03 mmol). And the mixture was stirred at 60° C. for 2 hours. The mixture was concentrated in vacuo. The residue was purified by flash column chromatography (silica gel, 0-10% gradient of methanol/dichloromethane) to obtain light yellow solid compound tert-butyl (1R,5S)-3-(8-fluoro-7-(3-hydroxynaphthalene-1-yl)-2-(2,2,2-trifluoroethoxy)-6-(trifluoromethyl)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1] Octane-8-carboxylate (190 mg, 0.29 mmol, 86% yield). LCMS (ESI): [M+H]+=667.2.
第三步：将叔丁基(1R,5S)-3-(8-氟-7-(3-羟基萘-1-基)-2-(2,2,2-三氟乙氧基)-6-(三氟甲基)喹唑啉-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(170mg，0.26mmol)溶于二氯甲烷(3mL)降到0℃，慢慢往反应液中加入二异丙基乙胺(133uL，0.77mmol)和溴甲基甲醚(27uL，0.33mmol)，反应在25℃搅拌16小时。反应完用水(5mL)淬灭，然后用二氯甲烷(3mL*2)萃取，合并有机相减压浓缩。残留物用快速柱色谱纯化(硅胶，0-20％梯度的乙酸乙酯/石油醚)得到白色固体化合物叔丁基(1R,5S)-3-(8-氟-7-(3-(甲氧基甲氧基)萘-1-基)-2-(2,2,2-三氟乙氧基)-6-(三氟甲基)喹唑啉-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(170mg，0.24mmol，收率94％)。LCMS(ESI):[M+H]+＝710.8.Step 3: Dissolve tert-butyl(1R,5S)-3-(8-fluoro-7-(3-hydroxynaphthalene-1-yl)-2-(2,2,2-trifluoroethoxy)-6-(trifluoromethyl)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (170mg, 0.26mmol) in dichloromethane (3mL) to 0°C, and slowly pour into the reaction solution Diisopropylethylamine (133uL, 0.77mmol) and bromomethylmethyl ether (27uL, 0.33mmol) were added and the reaction was stirred at 25°C for 16 hours. The reaction was quenched with water (5 mL), then extracted with dichloromethane (3 mL*2), and the combined organic phases were concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 0-20% gradient of ethyl acetate/petroleum ether) to give the compound tert-butyl(1R,5S)-3-(8-fluoro-7-(3-(methoxymethoxy)naphthalen-1-yl)-2-(2,2,2-trifluoroethoxy)-6-(trifluoromethyl)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1 70mg, 0.24mmol, yield 94%). LCMS (ESI): [M+H] + = 710.8.
第四步：将((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲醇(40mg，0.25mmol)溶于四氢呋喃(1mL)降到0℃，慢慢往反应液中加入氢化钠(60％含量，13mg，0.32mmol)，反应在20℃搅拌1小时。然后向反应液中加入叔丁基(1R,5S)-3-(8-氟-7-(3-(甲氧基甲氧基)萘-1-基)-2-(2,2,2-三氟乙氧基)-6-(三氟甲基)喹唑啉-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(150mg，0.21mmol)的四氢呋喃(1mL)溶液。反应在20℃下搅拌16小时。反应液中加入乙酸(500uL)调节pH为5-6，反应液减压浓缩。残留物用快速柱色谱纯化(硅胶，0-10％梯度的甲醇/二氯甲烷)得到黄色油状化合物叔丁基(1R,5S)-3-(8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-7-(3-(甲氧基甲氧基)萘-1-基)-6-(三氟甲基) 喹唑啉-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(130mg，0.16mmol，收率80％)。LCMS(ESI):[M+H]+＝770.2.Step 4: Dissolve ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol (40mg, 0.25mmol) in tetrahydrofuran (1mL) and cool down to 0°C, slowly add sodium hydride (60% content, 13mg, 0.32mmol) to the reaction solution, and stir the reaction at 20°C for 1 hour. Then a solution of tert-butyl(1R,5S)-3-(8-fluoro-7-(3-(methoxymethoxy)naphthalen-1-yl)-2-(2,2,2-trifluoroethoxy)-6-(trifluoromethyl)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (150 mg, 0.21 mmol) in tetrahydrofuran (1 mL) was added to the reaction solution. The reaction was stirred at 20°C for 16 hours. Acetic acid (500 uL) was added to the reaction solution to adjust the pH to 5-6, and the reaction solution was concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 0-10% gradient of methanol/dichloromethane) to give tert-butyl(1R,5S)-3-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-7-(3-(methoxymethoxy)naphthalen-1-yl)-6-(trifluoromethyl) as a yellow oil Quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (130 mg, 0.16 mmol, yield 80%). LCMS (ESI): [M+H] + = 770.2.
第五步：化合物叔丁基(1R,5S)-3-(8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-7-(3-(甲氧基甲氧基)萘-1-基)-6-(三氟甲基)喹唑啉-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(160mg，0.21mmol)溶于二氯甲烷(2mL)，20℃下加入三氟乙酸(0.5mL)。反应在20℃下搅拌2小时。氮气下浓缩。残留物溶于四氢呋喃(2mL)，向溶液中加入三乙胺(400uL)调节pH为7-8，混合物减压浓缩。残留物用制备型HPLC纯化，得到白色固体化合物4-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛烷-3-基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-6-(三氟甲基)喹唑啉-7-基)萘-2-醇(1.03mg，1.64umol，收率0.77％)。LCMS(ESI):[M+H]+＝626.1.1H NMR(400MHz,CH3OD)δppm 8.24(s,1H),7.76(d,J＝7.7Hz,1H),7.53-7.37(m,1H),7.27(s,1H),7.19(br d,J＝3.6Hz,2H),7.05(s,1H),5.43-5.29(m,1H),4.58(m,2H),4.41-4.30(m,2H),3.77(m,4H),3.22-3.00(m,4H),2.40-2.17(m,3H),2.06(m,2H),1.91(m,5H).The fifth step: compound tert-butyl (1R,5S)-3-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-7-(3-(methoxymethoxy)naphthalene-1-yl)-6-(trifluoromethyl)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (16 0mg, 0.21mmol) was dissolved in dichloromethane (2mL), and trifluoroacetic acid (0.5mL) was added at 20°C. The reaction was stirred at 20°C for 2 hours. Concentrate under nitrogen. The residue was dissolved in tetrahydrofuran (2 mL), triethylamine (400 uL) was added to the solution to adjust the pH to 7-8, and the mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC to give white solid compound 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-6-(trifluoromethyl)quinazolin-7-yl)naphthalene-2-ol (1.03 mg, 1.64umol, yield 0.77%). LCMS(ESI):[M+H] + ＝626.1. 1 H NMR(400MHz,CH 3 OD)δppm 8.24(s,1H),7.76(d,J＝7.7Hz,1H),7.53-7.37(m,1H),7.27(s,1H),7.19(br d,J＝3.6Hz,2H),7.05(s,1H),5.43-5.29(m,1H),4.58(m,2H),4.41-4.30(m,2H),3.77(m,4H),3.22-3.00(m,4H),2.40-2.17(m,3H),2.06(m,2H),1.91(m,5H).
实施例51：4-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-6-(甲基磺酰基)喹唑啉-7-基)萘-2-醇
Example 51: 4-(4-((1R,5S)-3,8-Diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-6-(methylsulfonyl)quinazolin-7-yl)naphthalen-2-ol
实施例51的制备参考实施例50的合成路线，第一步向叔丁基(1R,5S)-3-(8-氟-6-碘-7-(3-(甲氧基甲氧基)萘-1-基)-2-(2,2,2-三氟乙氧基)喹唑啉-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯和碘化亚铜和甲基亚磺酸钠反应得到相应的中间体，然后经过类似反应，制备得到4-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-6-(甲基磺酰基)喹唑啉-7-基)萘-2-醇。LCMS(ESI):[M+H]+＝636.1；1H NMR(400MHz,CD3OD)δppm 8.70-8.62(m,1H),8.36-7.73(m,1H),7.45-7.33(m,1H),7.30-6.91(m,4H),5.40-5.19(m,1H),4.64-4.56(m,2H),4.35-4.20(m,2H),3.74-3.62(m,4H),3.27-3.16(m,3H),3.06-2.96(m,1H),2.68-2.39(m,3H),2.38-1.78(m,10H).The preparation of Example 51 refers to the synthetic route of Example 50, the first step is to react tert-butyl (1R,5S)-3-(8-fluoro-6-iodo-7-(3-(methoxymethoxy)naphthalene-1-yl)-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate with cuprous iodide and sodium methanesulfinate to obtain the corresponding intermediate, After similar reaction, 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-6-(methylsulfonyl)quinazolin-7-yl)naphthalene-2-ol was prepared. LCMS(ESI):[M+H] + ＝636.1； 1 H NMR(400MHz,CD 3 OD)δppm 8.70-8.62(m,1H),8.36-7.73(m,1H),7.45-7.33(m,1H),7.30-6.91(m,4H),5.40-5.19(m,1H),4.64-4.56(m,2H),4.35-4.20(m,2H),3.74-3.62(m,4H),3.27-3.16(m,3H),3.06-2.96(m,1H),2.68-2.39(m,3H),2.38-1.78(m,10H).
实施例52：(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-7-(3-羟基萘-1-基)喹唑啉-6-基)二甲基氧化膦
Example 52: (4-((1R,5S)-3,8-Diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-7-(3-hydroxynaphthalen-1-yl)quinazolin-6-yl)dimethylphosphine oxide
实施例52的制备参考实施例50的合成路线，第一步向叔丁基(1R,5S)-3-(8-氟-6-碘-7-(3-(甲氧基甲氧基)萘-1-基)-2-(2,2,2-三氟乙氧基)喹唑啉-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯与二甲基氧 化膦，二异丙基乙胺，三(二亚苄基丙酮)二钯，4,5-双二苯基膦-9,9-二甲基氧杂蒽反应得到相应的中间体，然后经过类似反应，制备得到(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-7-(3-羟基萘-1-基)喹唑啉-6-基)二甲基氧化膦。LCMS(ESI):[M+H]+＝634.2；1H NMR(400MHz,CD3OD)δppm 8.62(d,J＝14.1Hz,1H),7.79(d,J＝8.3Hz,1H),7.49-7.42(m,1H),7.34(d,J＝2.3Hz,1H),7.28-7.21(m,2H),7.15(d,J＝2.5Hz,1H),5.42-5.22(m,1H),4.65-4.58(m,2H),4.38-4.19(m,2H),3.77-3.65(m,4H),3.31-3.13(m,3H),3.08-2.98(m,1H),2.41-2.11(m,3H),2.08-1.96(m,2H),1.94-1.79(m,5H),1.50(d,J＝13.6Hz,3H),0.95(d,J＝13.6Hz,3H).The preparation of Example 52 refers to the synthetic route of Example 50, the first step is to tert-butyl (1R,5S)-3-(8-fluoro-6-iodo-7-(3-(methoxymethoxy)naphthalene-1-yl)-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate and dimethyloxy Phosphine, diisopropylethylamine, tris(dibenzylideneacetone)dipalladium, and 4,5-bisdiphenylphosphine-9,9-dimethylxanthene were reacted to obtain the corresponding intermediate, and then (4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazine-7a (5H)-yl)methoxy)-7-(3-hydroxynaphthalen-1-yl)quinazolin-6-yl)dimethylphosphine oxide. LCMS(ESI):[M+H] + ＝634.2； 1 H NMR(400MHz,CD 3 OD)δppm 8.62(d,J＝14.1Hz,1H),7.79(d,J＝8.3Hz,1H),7.49-7.42(m,1H),7.34(d,J＝2.3Hz,1H),7.28-7.21(m,2H),7.15(d,J＝2.5Hz,1H),5.42-5.22(m,1H),4.65-4.58(m,2H),4.38-4.19(m,2H),3.77-3.65(m,4H),3.31-3.13(m,3H),3.08-2.98(m,1H),2.41-2.11(m,3H),2.08-1.96(m,2H),1.94-1.79(m,5H),1.50(d,J＝13.6Hz,3H),0.95(d,J＝13.6Hz,3H).
实施例53：1-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-7-(3-羟基萘-1-基)喹唑啉-6-基)乙-1-酮
Example 53: 1-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-7-(3-hydroxynaphthalen-1-yl)quinazolin-6-yl)ethan-1-one
第一步：将化合物叔丁基(1R,5S)-3-(8-氟-6-碘-7-(3-(甲氧基甲氧基)萘-1-基)-2-(2,2,2-三氟乙氧基)喹唑啉-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(150mg，200umol)和三丁基(1-乙氧基乙烯基)锡烷(280mg，775umol)溶于二氧六环(2.00mL)，氮气下加入四(三苯基膦)钯(22.0mg，20umol)，反应在100℃搅拌16小时。反应液减压浓缩，残余物用快速柱色谱纯化(硅胶，0-30％梯度的乙酸乙酯/石油醚)得化合物叔丁基(1R,5S)-3-(6-(1-乙氧基乙烯基)-8-氟-7-(3-(甲氧基甲氧基)萘-1-基)-2-(2,2,2-三氟乙氧基)喹唑啉-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(75.0mg，112umol，收率56％)。LCMS(ESI):[M+H]+＝713.3.The first step: compound tert-butyl (1R,5S)-3-(8-fluoro-6-iodo-7-(3-(methoxymethoxy)naphthalene-1-yl)-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (150mg, 200umol) and tributyl(1-ethoxyvinyl)tin alkane (280mg , 775umol) was dissolved in dioxane (2.00mL), tetrakis(triphenylphosphine)palladium (22.0mg, 20umol) was added under nitrogen, and the reaction was stirred at 100°C for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by flash column chromatography (silica gel, 0-30% gradient ethyl acetate/petroleum ether) to obtain the compound tert-butyl (1R,5S)-3-(6-(1-ethoxyvinyl)-8-fluoro-7-(3-(methoxymethoxy)naphthalene-1-yl)-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane- 8-Carboxylate (75.0mg, 112umol, yield 56%). LCMS (ESI): [M+H] + = 713.3.
第二步：将化合物叔丁基(1R,5S)-3-(6-(1-乙氧基乙烯基)-8-氟-7-(3-(甲氧基甲氧基)萘-1-基)-2-(2,2,2-三氟乙氧基)喹唑啉-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(65.0mg，91umol)加入到四氢呋喃(0.60mL)中，加入((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲醇(21.0mg，136umol)和叔丁醇钠(26.0mg，274umol)，20℃搅拌16小时。反应液减压浓缩，残余物用快速柱色谱纯化(硅胶，0-10％梯度的甲醇/二氯甲烷)得叔丁基(1R,5S)-3-(6-(1-乙氧基乙烯基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-7-(3-(甲氧基甲氧基)萘-1-基)喹唑啉-4-基)-3,8-二氮杂双环[3.2.1]辛烷- 8-羧酸酯(75.0mg，90umol，收率99％)。LCMS(ESI):[M+H]+＝772.3.The second step: the compound tert-butyl (1R,5S)-3-(6-(1-ethoxyvinyl)-8-fluoro-7-(3-(methoxymethoxy)naphthalene-1-yl)-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (65.0mg, 91umol) was added to tetrahydrofuran (0.60mL ), add ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol (21.0mg, 136umol) and sodium tert-butoxide (26.0mg, 274umol), and stir at 20°C for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by flash column chromatography (silica gel, 0-10% gradient methanol/dichloromethane) to obtain tert-butyl(1R,5S)-3-(6-(1-ethoxyvinyl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-7-(3-(methoxymethoxy)naphthalene-1-yl)quinazolin-4- Base)-3,8-diazabicyclo[3.2.1]octane- 8-Carboxylate (75.0mg, 90umol, yield 99%). LCMS (ESI): [M+H] + = 772.3.
第三步：化合物叔丁基(1R,5S)-3-(6-(1-乙氧基乙烯基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-7-(3-(甲氧基甲氧基)萘-1-基)喹唑啉-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(65.0mg，84umol)加入到三氟乙酸/二氯甲烷(体积比为4:1，1.20mL)中，20℃搅拌2小时。反应液减压浓缩，残留物加入乙腈(500uL)，加入三乙胺调节pH到8，混合物用制备型HPLC纯化，得到白色固体化合物1-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-7-(3-羟基萘-1-基)喹唑啉-6-基)乙-1-酮(8.14mg，15umol，收率14％)。LCMS(ESI):[M+H]+＝600.6.1H NMR(400MHz,CD3OD)δppm 8.24(s,1H),7.77(br d,J＝8.3Hz,1H),7.43(br t,J＝7.4Hz,1H),7.35(br d,J＝8.4Hz,1H),7.30-7.19(m,2H),7.02(d,J＝2.0Hz,1H),5.46-5.23(m,1H),4.67-4.58(m,2H),4.39-4.23(m,2H),3.71(br s,4H),3.43-3.35(m,1H),3.31-3.22(m,2H),3.12-3.00(m,1H),2.46-2.13(m,3H),2.08-1.80(m,10H).The third step: compound tert-butyl (1R, 5S)-3-(6-(1-ethoxyvinyl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-7-(3-(methoxymethoxy)naphthalene-1-yl)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate ( 65.0mg, 84umol) was added into trifluoroacetic acid/dichloromethane (volume ratio 4:1, 1.20mL), and stirred at 20°C for 2 hours. The reaction solution was concentrated under reduced pressure, the residue was added to acetonitrile (500uL), and triethylamine was added to adjust the pH to 8. The mixture was purified by preparative HPLC to obtain a white solid compound 1-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-7- (3-Hydroxynaphthalen-1-yl)quinazolin-6-yl)ethan-1-one (8.14 mg, 15 umol, yield 14%). LCMS(ESI):[M+H] + ＝600.6. 1 H NMR(400MHz,CD 3 OD)δppm 8.24(s,1H),7.77(br d,J＝8.3Hz,1H),7.43(br t,J＝7.4Hz,1H),7.35(br d,J＝8.4Hz,1H),7.30-7.19(m,2H),7.02(d,J＝2.0Hz,1H),5.46-5.23(m,1H),4.67-4.58(m,2H),4.39-4.23(m,2H),3.71(br s,4H),3.43-3.35(m,1H),3.31-3.22(m,2H),3.12-3.00(m,1H),2.46-2.13(m,3H),2.08-1.80(m,10H).
以下实施例54～实施例65通过实施例53的合成路线方法进行制备：The following examples 54 to 65 were prepared by the synthetic route method of example 53:
实施例54：4-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-6-环丙基-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)喹唑啉-7-基)萘-2-醇
Example 54: 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-6-cyclopropyl-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinazolin-7-yl)naphthalen-2-ol
LCMS(ESI):[M+H]+＝598.5.1H NMR(400MHz,CD3OD)δppm 7.72(br d,J＝8.0Hz,1H),7.43-7.30(m,2H),7.27-7.11(m,3H),7.04(br d,J＝2.3Hz,1H),5.41-5.19(m,1H),4.71-4.38(m,3H),4.31-4.16(m,2H),3.61(br s,3H),3.20(br d,J＝15.6Hz,3H),3.00(br d,J＝4.8Hz,1H),2.48-1.80(m,10H),1.58-1.46(m,1H),0.79-0.51(m,4H).LCMS(ESI):[M+H]+=598.5.1H NMR (400MHz, CD3OD)δppm 7.72(br d,J=8.0Hz,1H),7.43-7.30(m,2H),7.27-7.11(m,3H),7.04(br d,J=2.3Hz,1H),5.41-5.19(m,1H),4.71-4.38(m,3H),4.31-4.16(m ,2H),3.61(br s,3H),3.20(br d,J=15.6Hz,3H),3.00(br d,J=4.8Hz,1H),2.48-1.80(m,10H),1.58-1.46(m,1H),0.79-0.51(m,4H).
实施例55：4-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-6-乙烯基喹唑啉-7-基)萘-2-醇
Example 55: 4-(4-((1R,5S)-3,8-Diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-6-vinylquinazolin-7-yl)naphthalen-2-ol
LCMS(ESI):[M+H]+＝583.9.1H NMR(400MHz,CD3OD)δppm 8.05(s,1H),7.74(d,J＝8.3Hz,1H),7.40(ddd,J＝8.2,6.2,1.8Hz,1H),7.28-7.14(m,3H),7.00-6.93(m,1H),6.23(dd,J＝17.6,11.0Hz,1H),5.69(d,J＝17.6Hz,1H),5.42-5.21(m,1H),5.07(d,J＝11.3Hz,1H),4.61-4.46(m,2H),4.34-4.16(m,2H),3.71-3.59(m,4H),3.27-3.17(m,3H),3.06-2.97(m,1H),2.39-2.11(m,3H),2.04-1.94(m,2H),1.86(m,5H).LCMS(ESI):[M+H]+=583.9.1H NMR (400MHz, CD3OD)δppm 8.05(s,1H),7.74(d,J=8.3Hz,1H),7.40(ddd,J=8.2,6.2,1.8Hz,1H),7.28-7.14(m,3H),7.00-6.93(m,1H),6.23(dd,J=17.6,11.0Hz,1H),5.6 9(d,J=17.6Hz,1H),5.42-5.21(m,1H),5.07(d,J=11.3Hz,1H),4.61-4.46(m,2H),4.34-4.16(m,2H),3.71-3.59(m,4H),3.27-3.17(m,3H),3.06-2.9 7(m,1H),2.39-2.11(m,3H),2.04-1.94(m,2H),1.86(m,5H).
实施例56：4-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-6-乙炔基-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)喹唑啉-7-基)萘-2-醇
Example 56: 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-6-ethynyl-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinazolin-7-yl)naphthalen-2-ol
LCMS(ESI):[M+H]+＝582.2；1H NMR(400MHz,CD3OD)δppm 8.04(s,1H),7.74(br d,J＝8.0Hz,1H),7.40(br t,J＝7.3Hz,1H),7.30-7.15(m,3H),7.07(br s,1H),5.43-5.20(m,1H),4.55(br s,2H),4.32-4.19(m,2H),3.63(br s,4H),3.27-3.15(m,4H),3.02(br d,J＝5.0Hz,1H),2.41-2.09(m,4H),2.00(br s,2H),1.84(br s,4H).LCMS(ESI):[M+H]+= 582.2;1H NMR (400MHz, CD3OD)δppm 8.04(s,1H),7.74(br d,J=8.0Hz,1H),7.40(br t,J=7.3Hz,1H),7.30-7.15(m,3H),7.07(br s,1H),5.43-5.20(m,1H),4.55(br s,2H),4.32-4 .19(m,2H),3.63(br s,4H),3.27-3.15(m,4H),3.02(br d,J＝5.0Hz,1H),2.41-2.09(m,4H),2.00(br s,2H),1.84(br s,4H).
实施例57：4-(6-氨基-4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)喹唑啉-7-基)萘-2-醇
Example 57: 4-(6-Amino-4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinazolin-7-yl)naphthalen-2-ol
实施例57的制备参考实施例50的合成路线，第一步向叔丁基(1R,5S)-3-(8-氟-6-碘-7-(3-(甲氧基甲氧基)萘-1-基)-2-(2,2,2-三氟乙氧基)喹唑啉-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯与二苯甲酮亚胺， 碳酸铯，三(二亚苄基丙酮)二钯，(±)-2,2-双(二苯膦基)-1,1-联萘反应得到相应的中间体，然后经过类似反应，制备得到4-(6-氨基-4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)喹唑啉-7-基)萘-2-醇。LCMS(ESI):[M+H]+＝573.6；1H NMR(400MHz,DMSO-d6)δppm 8.56(br s,1H),7.78(d,J＝8.5Hz,1H),7.45(t,J＝7.7Hz,1H),7.38-7.28(m,2H),7.26-7.13(m,2H),7.10(s,1H),5.56-5.30(m,1H),4.60-4.36(m,4H),3.99(br s,2H),3.74-3.50(m,5H),3.24(br s,1H),2.60-2.37(m,2H),2.28(br d,J＝8.3Hz,1H),2.23-2.11(m,4H),2.06(br d,J＝8.5Hz,3H).The preparation of Example 57 refers to the synthetic route of Example 50, the first step is to tert-butyl (1R,5S)-3-(8-fluoro-6-iodo-7-(3-(methoxymethoxy)naphthalene-1-yl)-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate and benzophenone imine, Cesium carbonate, tris(dibenzylideneacetone) dipalladium, (±)-2,2-bis(diphenylphosphino)-1,1-binaphthyl were reacted to obtain the corresponding intermediate, and then 4-(6-amino-4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazine -7a(5H-yl)methoxy)quinazolin-7-yl)naphthalen-2-ol. LCMS(ESI):[M+H] + ＝573.6； 1 H NMR(400MHz,DMSO-d 6 )δppm 8.56(br s,1H),7.78(d,J＝8.5Hz,1H),7.45(t,J＝7.7Hz,1H),7.38-7.28(m,2H),7.26-7.13(m,2H),7.10(s,1H),5.56-5.30(m,1H),4.60-4.36(m,4H),3.99(br s,2H),3.74-3.50(m,5H),3.24(br s,1H),2.60-2.37(m,2H),2.28(br d,J＝8.3Hz,1H),2.23-2.11(m,4H),2.06(br d,J＝8.5Hz,3H).
实施例58：4-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛烷-3-基)-6-(二甲氨基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)喹唑啉-7-基)萘-2-醇
Example 58: 4-(4-((1R,5S)-3,8-Diazabicyclo[3.2.1]octan-3-yl)-6-(dimethylamino)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinazolin-7-yl)naphthalen-2-ol
第一步：化合物叔丁基(1R,5S)-3-(6-氨基-8-氟-7-(3-(甲氧基甲氧基)萘-1-基)-2-(2,2,2-三氟乙氧基)喹唑啉-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(100mg，0.15mmol)溶于乙酸(5mL)，20℃下向反应液加入多聚甲醛(45.0mg，1.52mmol)和氰基硼氢化钠(29.0mg，0.46mmol)。反应在20℃下搅拌16小时。在0℃下将反应混合物倒入0.1M的氢氧化钠溶液(20mL)中，用二氯甲烷(10mL*2)萃取。将合并的有机相用无水硫酸钠干燥，过滤，减压浓缩。残留物用快速柱色谱纯化(硅胶，0-20％梯度的乙酸乙酯/石油醚)得到得到黄色固体化合物叔丁基(1R,5S)-3-(6-(二甲基氨基)-8-氟-7-(3-(甲氧基甲氧基)萘-1-基)-2-(2,2,2-三氟乙氧基)喹唑啉-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(80.0mg，0.12mmol，收率77％)。LCMS(ESI):[M+H]+＝686.2.The first step: the compound tert-butyl(1R,5S)-3-(6-amino-8-fluoro-7-(3-(methoxymethoxy)naphthalene-1-yl)-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (100mg, 0.15mmol) was dissolved in acetic acid (5mL), and polymer was added to the reaction solution at 20°C Formaldehyde (45.0 mg, 1.52 mmol) and sodium cyanoborohydride (29.0 mg, 0.46 mmol). The reaction was stirred at 20°C for 16 hours. The reaction mixture was poured into 0.1 M sodium hydroxide solution (20 mL) at 0° C., extracted with dichloromethane (10 mL*2). The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 0-20% gradient ethyl acetate/petroleum ether) to give the compound tert-butyl(1R,5S)-3-(6-(dimethylamino)-8-fluoro-7-(3-(methoxymethoxy)naphthalen-1-yl)-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate ( 80.0 mg, 0.12 mmol, yield 77%). LCMS (ESI): [M+H] + = 686.2.
第二步：将化合物叔丁基(1R,5S)-3-(6-(二甲基氨基)-8-氟-7-(3-(甲氧基甲氧基)萘-1-基)-2-(2,2,2-三氟乙氧基)喹唑啉-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(80.0mg，0.12mmol)和((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲醇(40mg，0.25mmol)溶于四氢呋喃(1.00mL)，在0℃下，慢慢往反应液中加入叔丁醇钠(27.9mg，0.29mmol)，反应在20℃搅拌16小时。反应液减压浓缩，残留物用快速柱色谱纯化(硅胶，0-10％梯度的甲醇/二氯甲烷)得到黄色油状化合物叔丁基(1R,5S)-3-(6-(二甲基氨基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-7-(3-(甲氧基甲氧基)萘-1-基)喹唑啉-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(纯度80％，75.0mg，0.08mmol，收率69％)。LCMS(ESI):[M+H]+＝745.3.The second step: compound tert-butyl(1R,5S)-3-(6-(dimethylamino)-8-fluoro-7-(3-(methoxymethoxy)naphthalene-1-yl)-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (80.0mg, 0.12mmol) and ((2R,7aS)-2- Fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol (40mg, 0.25mmol) was dissolved in tetrahydrofuran (1.00mL), and sodium tert-butoxide (27.9mg, 0.29mmol) was slowly added to the reaction solution at 0°C, and the reaction was stirred at 20°C for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by flash column chromatography (silica gel, 0-10% gradient methanol/dichloromethane) to obtain yellow oily compound tert-butyl(1R,5S)-3-(6-(dimethylamino)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-7-(3-(methoxymethoxy)naphthalene-1-yl)quinazoline-4 -yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (purity 80%, 75.0 mg, 0.08 mmol, yield 69%). LCMS (ESI): [M+H] + = 745.3.
第三步：将化合物叔丁基(1R,5S)-3-(6-(二甲基氨基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪- 7a(5H)-基)甲氧基)-7-(3-(甲氧基甲氧基)萘-1-基)喹唑啉-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(纯度80％，70.0mg，0.07mmol)溶于乙腈(1.00mL)，20℃下加入氯化氢(4M的二氧六环溶液，376uL，1.50mmol)。反应在20℃下搅拌2小时。反应液减压浓缩。残留物溶于三乙胺(400uL)的二甲亚砜溶液(2mL)，用制备型HPLC纯化，得到黄色固体化合物4-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛烷-3-基)-6-(二甲氨基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)喹唑啉-7-基)萘-2-醇(9.19mg，0.01mmol，收率17％)。LCMS(ESI):[M+H]+＝601.5.1H NMR(400MHz,CD3OD)δppm7.74(d,J＝8.1Hz,1H),7.44-7.37(m,2H),7.29-7.17(m,3H),7.12(d,J＝1.5Hz,1H),5.51-5.28(m,1H),4.54(br s,2H),4.47-4.32(m,2H),3.98-3.64(m,4H),3.53-3.37(m,3H),3.20-3.11(m,1H),2.51(s,6H),2.42-1.95(m,10H).The third step: the compound tert-butyl (1R,5S)-3-(6-(dimethylamino)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazine- 7a(5H)-yl)methoxy)-7-(3-(methoxymethoxy)naphthalene-1-yl)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (purity 80%, 70.0mg, 0.07mmol) was dissolved in acetonitrile (1.00mL), hydrogen chloride (4M dioxane solution, 376uL, 1.50 mmol). The reaction was stirred at 20°C for 2 hours. The reaction solution was concentrated under reduced pressure. The residue was dissolved in triethylamine (400 uL) in dimethyl sulfoxide (2 mL) and purified by preparative HPLC to give compound 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6-(dimethylamino)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl) as a yellow solid Methoxy)quinazolin-7-yl)naphthalen-2-ol (9.19 mg, 0.01 mmol, yield 17%). LCMS(ESI):[M+H] + ＝601.5. 1 H NMR(400MHz,CD 3 OD)δppm7.74(d,J＝8.1Hz,1H),7.44-7.37(m,2H),7.29-7.17(m,3H),7.12(d,J＝1.5Hz,1H),5.51-5.28(m,1H),4.54(br s,2H),4.47-4.32(m,2H),3.98-3.64(m,4H),3.53-3.37(m,3H),3.20-3.11(m,1H),2.51(s,6H),2.42-1.95(m,10H).
实施例59：4-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-6-(吡咯烷-1-基)喹唑啉-7-基)萘-2-醇
Example 59: 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-6-(pyrrolidin-1-yl)quinazolin-7-yl)naphthalen-2-ol
实施例59参考实施例58的合成路线,按照类似方法合成制备得到；LCMS(ESI):[M+H]+＝627.3；1H NMR(400MHz,CD3OD)δppm 7.74(br d,J＝8.0Hz,1H),7.45-7.36(m,2H),7.28-7.16(m,2H),7.08(s,1H),6.96(s,1H),5.48-5.23(m,1H),4.51(br t,J＝11.3Hz,2H),4.41-4.25(m,2H),3.83(br s,2H),3.67-3.57(m,2H),3.41(br d,J＝5.0Hz,3H),3.17-3.05(m,1H),2.87(br d,J＝6.5Hz,2H),2.73(br d,J＝5.8Hz,2H),2.45-2.21(m,3H),2.10-1.94(m,7H),1.66(br s,4H).Example 59 was synthesized and prepared according to a similar method with reference to the synthetic route of Example 58; LCMS (ESI): [M+H]+= 627.3;1H NMR (400MHz, CD3OD)δppm 7.74(br d,J=8.0Hz,1H),7.45-7.36(m,2H),7.28-7.16(m,2H),7.08(s,1H),6.96(s,1H),5.48-5.23(m,1H),4.51(br t,J=11.3Hz,2H),4.41 -4.25(m,2H),3.83(br s,2H),3.67-3.57(m,2H),3.41(br d,J=5.0Hz,3H),3.17-3.05(m,1H),2.87(br d,J=6.5Hz,2H),2.73(br d,J=5.8Hz,2H),2.45-2 .21(m,3H),2.10-1.94(m,7H),1.66(br s,4H).
实施例60：4-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-6-(1-甲基-1H-吡唑-4-基)喹唑啉-7-基)萘-2-醇
Example 60: 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-6-(1-methyl-1H-pyrazol-4-yl)quinazolin-7-yl)naphthalen-2-ol
LCMS(ESI):[M+H]+＝638.3；1H NMR(400MHz,CD3OD)δppm 7.80(s,1H),7.62(d,J＝8.3Hz,1H),7.27(t,J＝7.5Hz,1H),7.18-7.09(m,2H),7.08-6.97(m,2H),6.87(d,J＝2.3Hz,1H),6.79(s,1H), 5.36-5.09(m,1H),4.65-4.41(m,2H),4.23-4.07(m,2H),3.73-3.44(m,7H),3.19-3.03(m,3H),3.00-2.85(m,1H),2.44-2.12(m,2H),2.04(br d,J＝8.3Hz,1H),1.94-1.70(m,7H).LCMS (ESI): [M+H] + = 638.3; 1 H NMR (400MHz, CD 3 OD) δppm 7.80 (s, 1H), 7.62 (d, J = 8.3Hz, 1H), 7.27 (t, J = 7.5Hz, 1H), 7.18-7.09 (m, 2H), 7.08-6.97 (m, 2H), 6.87(d,J=2.3Hz,1H),6.79(s,1H), 5.36-5.09(m,1H),4.65-4.41(m,2H),4.23-4.07(m,2H),3.73-3.44(m,7H),3.19-3.03(m,3H),3.00-2.85(m,1H),2.44-2.12(m,2H),2.04(br d,J ＝8.3Hz,1H),1.94-1.70(m,7H).
实施例61：4-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-6-(1-甲基-1H-咪唑-2-基)喹唑啉-7-基)萘-2-醇
Example 61: 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-6-(1-methyl-1H-imidazol-2-yl)quinazolin-7-yl)naphthalen-2-ol
LCMS(ESI):[M+H]+＝638.2。1H NMR(400MHz,CD3OD)δppm 7.94(s,1H),7.67(d,J＝8.2Hz,1H),7.58-7.49(m,1H),7.37(t,J＝7.4Hz,1H),7.25-7.17(m,1H),7.13(d,J＝2.1Hz,1H),6.87(s,2H),6.78(s,1H),5.42-5.22(m,1H),4.66-4.54(m,2H),4.35-4.22(m,2H),3.69-3.56(m,4H),3.27-3.14(m,3H),3.08-2.98(m,1H),2.94(s,3H),2.42-2.10(m,3H),2.06-1.74(m,7H).LCMS (ESI): [M+H] + = 638.2. 1 H NMR(400MHz,CD 3 OD)δppm 7.94(s,1H),7.67(d,J＝8.2Hz,1H),7.58-7.49(m,1H),7.37(t,J＝7.4Hz,1H),7.25-7.17(m,1H),7.13(d,J＝2.1Hz,1H),6.87(s,2H),6.78(s,1H),5.42-5.22(m,1H),4.66-4.54(m,2H),4.35-4.22(m,2H),3.69-3.56(m,4H),3.27-3.14(m,3H),3.08-2.98(m,1H),2.94(s,3H),2.42-2.10(m,3H),2.06-1.74(m,7H).
实施例62：4-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-6-(氧杂环丁烷-3-基)喹唑啉-7-基)萘-2-醇
Example 62: 4-(4-((1R,5S)-3,8-Diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-6-(oxetan-3-yl)quinazolin-7-yl)naphthalen-2-ol
LCMS(ESI):[M+H]+＝614.1.1H NMR(400MHz,CD3OD)δppm 8.55(br s,1H),7.84-7.78(m,1H),7.76-7.71(m,1H),7.41(br t,J＝7.5Hz,1H),7.34(br d,J＝8.5Hz,1H),7.22(d,J＝2.4Hz,1H),7.21-7.16(m,1H),7.01(d,J＝2.1Hz,1H),5.49-5.34(m,1H),5.25-5.04(m,2H),4.65(br d,J＝11.9Hz,2H),4.43(br dd,J＝4.3,15.5Hz,2H),4.01-3.85(m,2H),3.78-3.70(m,4H),3.47(br d,J＝17.9Hz,4H),3.23-3.12(m,1H),2.54-2.24(m,3H),2.19-2.09(m,3H),1.99(br s,4H).LCMS(ESI):[M+H]+= 614.1.1H NMR (400MHz, CD3OD)δppm 8.55(br s,1H),7.84-7.78(m,1H),7.76-7.71(m,1H),7.41(br t,J=7.5Hz,1H),7.34(br d,J=8.5Hz,1H),7.22(d,J=2.4Hz,1H),7.21-7.16(m, 1H),7.01(d,J=2.1Hz,1H),5.49-5.34(m,1H),5.25-5.04(m,2H),4.65(br d,J=11.9Hz,2H),4.43(br dd,J=4.3,15.5Hz,2H),4.01-3.85(m,2H),3.78-3. 70(m,4H),3.47(br d,J＝17.9Hz,4H),3.23-3.12(m,1H),2.54-2.24(m,3H),2.19-2.09(m,3H),1.99(br s,4H).
实施例63：4-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-6-(3,6-二氢-2H-吡喃-4-基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)喹唑啉-7-基)萘-2-醇
Example 63: 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-6-(3,6-dihydro-2H-pyran-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)naphthalen-2-ol
LCMS(ESI):[M+H]+＝640.2.1H NMR(400MHz,CD3OD)δppm 7.77-7.66(m,2H),7.45-7.31(m,2H),7.26-7.15(m,2H),7.02(d,J＝2.4Hz,1H),5.71(br s,1H),5.45-5.23(m,1H),4.63-4.51(m,2H),4.35-4.20(m,2H),4.08-3.94(m,2H),3.71-3.60(m,4H),3.43-3.34(m,2H),3.29-3.15(m,3H),3.03(td,J＝9.4,5.8Hz,1H),2.42-2.13(m,3H),2.08-1.80(m,8H),1.66(br d,J＝17.1Hz,1H).LCMS(ESI):[M+H]+=640.2.1H NMR (400MHz, CD3OD)δppm 7.77-7.66(m,2H),7.45-7.31(m,2H),7.26-7.15(m,2H),7.02(d,J＝2.4Hz,1H),5.71(br s,1H),5.45-5.23(m,1H),4.63-4.51(m,2H),4.35 -4.20(m,2H),4.08-3.94(m,2H),3.71-3.60(m,4H),3.43-3.34(m,2H),3.29-3.15(m,3H),3.03(td,J＝9.4,5.8Hz,1H),2.42-2.13(m,3H),2.08-1.8 0(m,8H),1.66(br d,J＝17.1Hz,1H).
实施例64：4-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-6-(四氢-2H-吡喃-4-基)喹唑啉-7-基)萘-2-醇
Example 64: 4-(4-((1R,5S)-3,8-Diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-6-(tetrahydro-2H-pyran-4-yl)quinazolin-7-yl)naphthalen-2-ol
第一步：在20℃下，向叔丁基(1R,5S)-3-(6-(3,6-二氢-2H-吡喃-4-基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-7-(3-羟基萘-1-基)喹唑啉-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(100mg，0.14mmol)的乙酸乙酯(2.00mL)中加入湿钯碳(10％含量，7.19mg，0.01mmol)。将该溶液在15psi的氢气氛围下20℃搅拌16小时。反应液过滤，滤液减压浓缩得到黄色油状化合物叔丁基(1R,5S)-3-(8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-7-(3-羟基萘-1-基)-6-(四氢-2H-吡喃-4-基)喹唑啉-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(100mg，0.13mmol，收率99％)。LCMS(ESI):[M+H]+＝742.3.The first step: at 20°C, to tert-butyl (1R, 5S)-3-(6-(3,6-dihydro-2H-pyran-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-7-(3-hydroxynaphthalen-1-yl)quinazolin-4-yl)-3,8-diazabicyclo[3.2 .1] To ethyl acetate (2.00 mL) of octane-8-carboxylate (100 mg, 0.14 mmol) was added wet palladium on carbon (10% content, 7.19 mg, 0.01 mmol). The solution was stirred at 20° C. for 16 hours under a hydrogen atmosphere of 15 psi. The reaction liquid was filtered, and the filtrate was concentrated under reduced pressure to obtain a yellow oily compound tert-butyl (1R, 5S)-3-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-7-(3-hydroxynaphthalene-1-yl)-6-(tetrahydro-2H-pyran-4-yl)quinazolin-4-yl)-3,8-diazabicyclo[3.2 .1] Octane-8-carboxylate (100 mg, 0.13 mmol, 99% yield). LCMS (ESI): [M+H] + = 742.3.
第二步：在20℃下，向叔丁基(1R,5S)-3-(8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-7-(3-羟基萘-1-基)-6-(四氢-2H-吡喃-4-基)喹唑啉-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(100mg，0.13mmol)的乙腈(1.50mL)溶液中加入氯化氢(4M的二氧六环溶液，673uL，2.69mmol)。将该溶液在20℃搅拌1小时。溶液用三乙胺(200uL)淬灭并浓缩。残余物通过制备型HPLC纯化，得到白色固体化合物4-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-6-(四氢-2H-吡喃-4-基)喹唑啉-7-基)萘-2-醇(二甲酸盐，9.84mg，15.2umol，收率11％)。LCMS(ESI):[M+H]+＝642.3。1H NMR(400MHz,CD3OD)δppm 8.48(br s,2H),7.84-7.70(m,2H),7.43(ddd,J＝8.2,5.1,2.9Hz,1H),7.28(d,J＝2.4Hz,1H),7.22-7.12(m,2H),7.07-6.95(m,1H),5.59-5.36(m,1H),4.66(br d,J＝12.9Hz,2H),4.59-4.49(m,2H),4.08(br s,2H),3.87(br d,J＝9.9Hz,3H),3.84-3.75(m,2H),3.71-3.63(m,2H),3.20-3.09(m,1H),2.99(br t,J＝10.9Hz,1H),2.64-1.98(m,12H),1.86-1.69(m,3H),1.48(br d,J＝12.3Hz,1H). The second step: at 20°C, to tert-butyl (1R,5S)-3-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-7-(3-hydroxynaphthalen-1-yl)-6-(tetrahydro-2H-pyran-4-yl)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane To a solution of alkane-8-carboxylate (100 mg, 0.13 mmol) in acetonitrile (1.50 mL) was added hydrogen chloride (4M in dioxane, 673 uL, 2.69 mmol). The solution was stirred at 20°C for 1 hour. The solution was quenched with triethylamine (200 uL) and concentrated. The residue was purified by preparative HPLC to give the compound 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-6-(tetrahydro-2H-pyran-4-yl)quinazolin-7-yl)naphthalene-2-yl as a white solid Alcohol (diformate, 9.84mg, 15.2umol, yield 11%). LCMS (ESI): [M+H] + = 642.3. 1 H NMR(400MHz,CD 3 OD)δppm 8.48(br s,2H),7.84-7.70(m,2H),7.43(ddd,J＝8.2,5.1,2.9Hz,1H),7.28(d,J＝2.4Hz,1H),7.22-7.12(m,2H),7.07-6.95(m,1H),5.59-5.36(m,1H),4.66(br d,J＝12.9Hz,2H),4.59-4.49(m,2H),4.08(br s,2H),3.87(br d,J＝9.9Hz,3H),3.84-3.75(m,2H),3.71-3.63(m,2H),3.20-3.09(m,1H),2.99(br t,J＝10.9Hz,1H),2.64-1.98(m,12H),1.86-1.69(m,3H),1.48(br d,J＝12.3Hz,1H).
实施例65：1-(4-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-7-(3-羟基萘-1-基)喹唑啉-6-基)-3,6-二氢吡啶-1(2H)-基)乙-1-酮
Example 65: 1-(4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-7-(3-hydroxynaphthalen-1-yl)quinazolin-6-yl)-3,6-dihydropyridine-1(2 H)-yl)ethan-1-one
LCMS(ESI):[M+H]+＝681.3.1H NMR(400MHz,CD3OD)δppm 8.53(br s,1H),7.79-7.71(m,2H),7.42(t,J＝7.5Hz,1H),7.35(br t,J＝8.6Hz,1H),7.28-7.19(m,2H),7.06-7.02(m,1H),5.78-5.67(br s,1H),5.58-5.37(m,1H),4.76-4.65(m,2H),4.59-4.46(m,2H),4.01(br s,2H),3.98-3.79(m,4H),3.77-3.52(m,3H),3.32-3.00(m,3H),2.62-2.38(m,2H),2.31(m,1H),2.26-2.16(m,2H),2.04(m,5H),1.98-1.89(m,4H),1.85-1.68(m,1H).LCMS(ESI):[M+H]+=681.3.1H NMR (400MHz, CD3OD)δppm 8.53(br s,1H),7.79-7.71(m,2H),7.42(t,J=7.5Hz,1H),7.35(br t,J=8.6Hz,1H),7.28-7.19(m,2H),7.06-7.02(m,1H),5.78-5.67(br s,1H ),5.58-5.37(m,1H),4.76-4.65(m,2H),4.59-4.46(m,2H),4.01(br s,2H),3.98-3.79(m,4H),3.77-3.52(m,3H),3.32-3.00(m,3H),2.62-2.38(m, 2H),2.31(m,1H),2.26-2.16(m,2H),2.04(m,5H),1.98-1.89(m,4H),1.85-1.68(m,1H).
以下实施例66通过实施例64的合成路线方法进行制备：The following embodiment 66 is prepared by the synthetic route method of embodiment 64:
实施例66：1-(4-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-7-(3-羟基萘-1-基)喹唑啉-6-基)哌啶-1-基)乙-1-酮
Example 66: 1-(4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-7-(3-hydroxynaphthalen-1-yl)quinazolin-6-yl)piperidin-1-yl)ethan-1-one
LCMS(ESI):[M+H]+＝683.4.1H NMR(400MHz,CD3OD)δppm 7.78(d,J＝8.3Hz,1H),7.69(s,1H),7.49-7.35(m,1H),7.28(d,J＝2.2Hz,1H),7.21(s,2H),7.05(s,1H),5.43-5.24(m,1H),4.66-4.43(m,4H),4.35-4.19(m,2H),3.90-3.80(m,1H),3.75-3.62(m,4H),3.30-3.16(m,3H),3.04(dt,J＝5.6,9.3Hz,1H),2.84-2.48(m,2H),2.43-2.11(m,4H),2.06(d,J＝8.9Hz,3H),2.04-1.97(m,2H),1.96-1.82(m,6H),1.68-1.61(m,2H).LCMS(ESI):[M+H]+=683.4.1H NMR (400MHz, CD3OD)δppm 7.78(d,J=8.3Hz,1H),7.69(s,1H),7.49-7.35(m,1H),7.28(d,J=2.2Hz,1H),7.21(s,2H),7.05(s,1H),5.43-5.24(m,1H),4.66-4.43(m,4H ),4.35-4.19(m,2H),3.90-3.80(m,1H),3.75-3.62(m,4H),3.30-3.16(m,3H),3.04(dt,J=5.6,9.3Hz,1H),2.84-2.48(m,2H),2.43-2.11(m,4H),2. 06(d, J=8.9Hz, 3H), 2.04-1.97(m, 2H), 1.96-1.82(m, 6H), 1.68-1.61(m, 2H).
实施例67：4-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-6-硝基喹唑啉-7-基)萘-2-醇
Example 67: 4-(4-((1R,5S)-3,8-Diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-6-nitroquinazolin-7-yl)naphthalen-2-ol
第一步：将2-氨基-4-溴-3-氟苯甲酸(3.50g，14.96mmol)和尿素(8.98g，149.56mmol)的混合物在200℃下搅拌2小时。冷却到100℃，加入水(30mL)，搅拌1小时，过滤，固体产物再加入水(25mL)，在50℃下搅拌1小时，过滤，固体产物再加入水(25mL)，在25℃下搅拌12小时，过滤，固体真空干燥，得到粗品化合物7-溴-8-氟喹唑啉-2,4(1H,3H)-二酮(4.40g)，其为灰色固体。LCMS(ESI):[M+H]+＝258.8.Step 1: A mixture of 2-amino-4-bromo-3-fluorobenzoic acid (3.50 g, 14.96 mmol) and urea (8.98 g, 149.56 mmol) was stirred at 200° C. for 2 hours. Cool to 100°C, add water (30mL), stir for 1 hour, filter, add water (25mL) to the solid product, stir at 50°C for 1 hour, filter, add water (25mL) to the solid product, stir at 25°C for 12 hours, filter, and dry the solid in vacuum to obtain the crude compound 7-bromo-8-fluoroquinazoline-2,4(1H,3H)-dione (4.40g) as a gray solid. LCMS (ESI): [M+H] + = 258.8.
第二步：在0℃下，向7-溴-8-氟喹唑啉-2,4(1H,3H)-二酮(4.40g，14.96mmol)的浓硫酸溶液(35mL)中加入硝酸钾(3.43g，33.97mmol)。将该溶液在0℃搅拌1小时。混合物倒入水(35mL)中，过滤出固体，真空干燥，得到灰色固体化合物7-溴-8-氟-6-硝基喹唑啉-2,4(1H,3H)-二酮(3.50g，11.51mol，收率77％)。LCMS(ESI):[M+H]+＝303.9.1H NMR(400MHz,DMSO-d6)δppm 11.98(br s,1H),11.85(s,1H),8.34(s,1H).Second step: To a solution of 7-bromo-8-fluoroquinazoline-2,4(1H,3H)-dione (4.40 g, 14.96 mmol) in concentrated sulfuric acid (35 mL) was added potassium nitrate (3.43 g, 33.97 mmol) at 0°C. The solution was stirred at 0 °C for 1 hour. The mixture was poured into water (35 mL), the solid was filtered off, and dried in vacuo to obtain 7-bromo-8-fluoro-6-nitroquinazoline-2,4(1H,3H)-dione (3.50 g, 11.51 mol, yield 77%) as a gray solid. LCMS (ESI): [M+H] + =303.9. 1 H NMR (400MHz, DMSO-d 6 ) δppm 11.98(br s,1H), 11.85(s,1H), 8.34(s,1H).
第三步：在0℃下，向7-溴-8-氟-6-硝基喹唑啉-2,4(1H,3H)-二酮(1.50g，4.93mmol)和氧氯化磷(3.67mL，39.47mmol)的甲苯(22mL)溶液中，加入二异丙基乙胺(2.45mL，14.80mmol)。将混合物在氮气保护下100℃下搅拌3小时。混合物旋干，加入乙酸乙酯(30mL)，然后加入冰和冰水(30mL)，使用乙酸乙酯(20mL*3)萃取，合并的有机相用无水硫酸钠干燥，过滤，滤液旋干，得到粗品化合物7-溴-2,4-二氯-8-氟-6-硝基喹唑啉(1.55g)，其为灰色固体。LCMS(ESI):[M+H]+＝341.8.Step 3: To a solution of 7-bromo-8-fluoro-6-nitroquinazoline-2,4(1H,3H)-dione (1.50 g, 4.93 mmol) and phosphorus oxychloride (3.67 mL, 39.47 mmol) in toluene (22 mL) was added diisopropylethylamine (2.45 mL, 14.80 mmol) at 0°C. The mixture was stirred at 100° C. for 3 hours under nitrogen protection. The mixture was spin-dried, ethyl acetate (30 mL) was added, then ice and ice-water (30 mL) were added, extracted with ethyl acetate (20 mL*3), the combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried to obtain the crude compound 7-bromo-2,4-dichloro-8-fluoro-6-nitroquinazoline (1.55 g) as a gray solid. LCMS (ESI): [M+H] + = 341.8.
第四步：向7-溴-2,4-二氯-8-氟-6-硝基喹唑啉(1.55g，4.55mmol)和3,8-二氮杂双环[3.2.1]辛烷-8-羧酸叔丁酯(965mg，4.55mmol)的二氯甲烷(15mL)溶液中，加入三乙胺(1.84mL，13.20mmol)。将混合物在25℃下搅拌2小时。加入水(10mL)，使用二氯甲烷(15mL*3)萃取，合并的有机相用无水硫酸钠干燥，过滤，滤液旋干。残留物用快速柱色谱(硅胶，0-30％梯度的乙酸乙酯/石油醚)纯化，得到灰色固体化合物(1R,5S)-3-(7-溴-2-氯-8-氟-6-硝基喹唑啉-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸叔丁酯(590mg，1.14mmol，收率25％)。LCMS(ESI):[M+H]+＝517.7.Step 4: To a solution of 7-bromo-2,4-dichloro-8-fluoro-6-nitroquinazoline (1.55 g, 4.55 mmol) and tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (965 mg, 4.55 mmol) in dichloromethane (15 mL) was added triethylamine (1.84 mL, 13.20 mmol). The mixture was stirred at 25°C for 2 hours. Water (10 mL) was added, extracted with dichloromethane (15 mL*3), the combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried. The residue was purified by flash column chromatography (silica gel, 0-30% gradient of ethyl acetate/petroleum ether) to give gray solid compound (1R,5S)-3-(7-bromo-2-chloro-8-fluoro-6-nitroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (590 mg, 1.14 mmol, yield 25%). LCMS (ESI): [M+H] + = 517.7.
第五步：向(1R,5S)-3-(7-溴-2-氯-8-氟-6-硝基喹唑啉-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸叔丁酯(590mg，1.14mmol)的三氟乙醇(4.4mL)溶液中，加入二异丙基乙胺(944uL，5.71mmol)。将混合物在70℃下搅拌12小时，然后旋干。残留物用快速柱色谱(硅胶，0-30％梯度的乙酸乙酯/石 油醚)纯化，得到黄色固体化合物叔丁基(1R,5S)-3-(7-溴-8-氟-6-硝基-2-(2,2,2-三氟乙氧基)喹唑啉-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(500mg，0.86mmol，收率75％)。LCMS(ESI):[M+H]+＝581.7.Step 5: To a solution of tert-butyl (1R,5S)-3-(7-bromo-2-chloro-8-fluoro-6-nitroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (590 mg, 1.14 mmol) in trifluoroethanol (4.4 mL), diisopropylethylamine (944 uL, 5.71 mmol) was added. The mixture was stirred at 70 °C for 12 hours and then spin-dried. The residue was subjected to flash column chromatography (silica gel, 0-30% gradient ethyl acetate/silica oleyl ether) to obtain yellow solid compound tert-butyl(1R,5S)-3-(7-bromo-8-fluoro-6-nitro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (500mg, 0.86mmol, yield 75%). LCMS (ESI): [M+H] + = 581.7.
第六步：手套箱中，向叔丁基(1R,5S)-3-(7-溴-8-氟-6-硝基-2-(2,2,2-三氟乙氧基)喹唑啉-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(150mg，0.26mmol)和4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)萘-2-醇(90.8mg，0.34mmol)的二氧六环(3mL)溶液中，加入磷酸钾(1.5M的水溶液，517uL，0.78mmol)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)(18.8mg，0.03mmol)。将混合物在氮气保护下100℃搅拌12小时。过滤，滤液用水(3mL)稀释，使用乙酸乙酯(5mL*3)萃取，合并的有机相用无水硫酸钠干燥，过滤，滤液旋干。残留物用快速柱色谱(硅胶，0-30％梯度的乙酸乙酯/石油醚)纯化，得到棕色固体化合物叔丁基(1R,5S)-3-(8-氟-7-(3-羟基萘-1-基)-6-硝基-2-(2,2,2-三氟乙氧基)喹唑啉-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(110mg，1.21mmol，收率66％)。LCMS(ESI):[M+H]+＝644.1.Step 6: In the glove box, add tert-butyl (1R,5S)-3-(7-bromo-8-fluoro-6-nitro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (150mg, 0.26mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane To a solution of alk-2-yl)naphthalen-2-ol (90.8mg, 0.34mmol) in dioxane (3mL) was added potassium phosphate (1.5M in water, 517uL, 0.78mmol) and [n-butylbis(1-adamantyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium(II) methanesulfonate (18.8mg, 0.03mmol). The mixture was stirred at 100° C. for 12 hours under nitrogen protection. After filtration, the filtrate was diluted with water (3 mL), extracted with ethyl acetate (5 mL*3), the combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried. The residue was purified by flash column chromatography (silica gel, 0-30% gradient ethyl acetate/petroleum ether) to give brown solid compound tert-butyl(1R,5S)-3-(8-fluoro-7-(3-hydroxynaphthalen-1-yl)-6-nitro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (110 mg, 1.2 1 mmol, yield 66%). LCMS (ESI): [M+H] + = 644.1.
第七步：向叔丁基(1R,5S)-3-(8-氟-7-(3-羟基萘-1-基)-6-硝基-2-(2,2,2-三氟乙氧基)喹唑啉-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(100mg，0.16mmol)和((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲醇(49.5mg，0.31mmol)的四氢呋喃(2mL)溶液中，加入叔丁醇钠(22.4mg，0.23mmol)。将混合物在氮气保护下20℃搅拌4小时。加入水(5mL)稀释，使用乙酸乙酯(10mL*3)萃取，合并的有机相用无水硫酸钠干燥，过滤，滤液旋干，得到粗品化合物叔丁基(1R,5S)-3-(8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-7-(3-羟基萘-1-基)-6-硝基喹唑啉-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(150mg)，其为棕色油状液体。LCMS(ESI):[M+H]+＝703.4.Step 7: To tert-butyl(1R,5S)-3-(8-fluoro-7-(3-hydroxynaphthalen-1-yl)-6-nitro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (100mg, 0.16mmol) and ((2R,7aS)-2-fluorotetrahydro-1H-pyrrole To a solution of azin-7a(5H)-yl)methanol (49.5mg, 0.31mmol) in THF (2mL) was added sodium tert-butoxide (22.4mg, 0.23mmol). The mixture was stirred at 20°C for 4 hours under nitrogen protection. Diluted by adding water (5mL), extracted with ethyl acetate (10mL*3), the combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried to obtain the crude compound tert-butyl(1R,5S)-3-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-7-(3-hydroxynaphthalen-1-yl)-6-nitroquinazoline -4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (150 mg) as a brown oily liquid. LCMS (ESI): [M+H] + = 703.4.
第八步：在20℃下，向叔丁基(1R,5S)-3-(8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-7-(3-羟基萘-1-基)-6-硝基喹唑啉-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(145mg，0.14mmol)rongye的乙腈(2mL)溶液中加入氯化氢(4M的二氧六环溶液，722uL，2.89mmol)。将该溶液在20℃搅拌1小时。溶液用氮气吹干。残余物通过制备型HPLC纯化，得到黄色固体化合物4-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-6-硝基喹唑啉-7-基)萘-2-醇(甲酸盐，5.95mg，0.98umol，收率7％)。LCMS(ESI):[M+H]+＝603.1.1H NMR(400MHz,CD3OD)δppm 8.66(s,1H),8.53(br s,1H),7.77(d,J＝8.3Hz,1H),7.44(t,J＝7.5Hz,1H),7.36-7.25(m,2H),7.25-7.16(m,1H),7.02(d,J＝2.3Hz,1H),5.55-5.32(m,1H),4.72(br d,J＝12.0Hz,2H),4.53-4.38(m,2H),4.01-3.79(m,4H),3.50(br d,J＝12.5Hz,3H),3.26-3.16(m,1H),2.58-2.21(m,3H),2.20-2.09(m,2H),2.08-1.90(m,5H).The eighth step: tert-butyl (1R,5S)-3-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-7-(3-hydroxynaphthalene-1-yl)-6-nitroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (145mg , 0.14mmol) rongye in acetonitrile (2mL) was added hydrogen chloride (4M in dioxane, 722uL, 2.89mmol). The solution was stirred at 20°C for 1 hour. The solution was blown dry with nitrogen. The residue was purified by preparative HPLC to give compound 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-6-nitroquinazolin-7-yl)naphthalen-2-ol (formate salt, 5.95 mg, 0 .98umol, yield 7%). LCMS(ESI):[M+H] + ＝603.1. 1 H NMR(400MHz,CD 3 OD)δppm 8.66(s,1H),8.53(br s,1H),7.77(d,J＝8.3Hz,1H),7.44(t,J＝7.5Hz,1H),7.36-7.25(m,2H),7.25-7.16(m,1H),7.02(d,J＝2.3Hz,1H),5.55-5.32(m,1H),4.72(br d,J＝12.0Hz,2H),4.53-4.38(m,2H),4.01-3.79(m,4H),3.50(br d,J＝12.5Hz,3H),3.26-3.16(m,1H),2.58-2.21(m,3H),2.20-2.09(m,2H),2.08-1.90(m,5H).
实施例68：4-(6-氨基-4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-吡咯啉]-7a'(5'H)-基)甲氧基)-8-氟喹唑啉-7-基)-5-乙炔基-6-氟萘-2-醇
Example 68: 4-(6-amino-4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrroline]-7a'(5'H)-yl)methoxy)-8-fluoroquinazolin-7-yl)-5 -Ethynyl-6-fluoronaphthalen-2-ol
第一步：在手套箱中，向叔丁基(1R,5S)-3-(7-溴-6-((二苯基亚甲基)氨基)-8-氟-2-(2,2,2-三氟乙氧基)喹唑啉-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(500mg，0.70mmol)和((2-氟-6-(甲氧基甲氧基)-8-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)萘-1-基)乙炔基)三异丙基硅烷(466mg，0.91mmol)的1,4-二氧六环(10.0mL)溶液中加入磷酸钾(1.5M的水溶液，1.40mL，2.10mmol)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)(51mg，0.07mmol)。将混合物氮气保护下在100℃下搅拌2小时。加入水(10mL)，使用二氯甲烷(10mL)萃取3次，无水硫酸钠干燥，过滤旋干。残留物用快速柱色谱纯化(硅胶，0-30％梯度的乙酸乙酯/石油醚)。得到黄色固体化合物叔丁基(1R,5S)-3-(6-((二苯基亚甲基)氨基)-8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三异丙基甲硅烷基)乙炔基)萘-1-基)-2-(2,2,2-三氟乙氧基)喹唑啉-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(650mg，1.21mmol，收率91％)。LCMS(ESI):[M+H]+＝1020.7.The first step: In the glove box, add tert-butyl (1R,5S)-3-(7-bromo-6-((diphenylmethylene)amino)-8-fluoro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (500mg, 0.70mmol) and ((2-fluoro-6-(methoxymethoxy)-8-(4 ,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (466 mg, 0.91 mmol) in 1,4-dioxane (10.0 mL) was added potassium phosphate (1.5 M in water, 1.40 mL, 2.10 mmol) and methanesulfonic acid [n-butylbis(1-adamantyl)phosphine] (2-amino-1 , 1'-biphenyl-2-yl)palladium(II) (51 mg, 0.07 mmol). The mixture was stirred at 100° C. for 2 hours under nitrogen protection. Water (10 mL) was added, extracted three times with dichloromethane (10 mL), dried over anhydrous sodium sulfate, filtered and spin-dried. The residue was purified by flash column chromatography (silica gel, gradient 0-30% ethyl acetate/petroleum ether). The yellow solid compound tert-butyl(1R,5S)-3-(6-((diphenylmethylene)amino)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalene-1-yl)-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (6 50 mg, 1.21 mmol, yield 91%). LCMS (ESI): [M+H] + = 1020.7.
第二步：向叔丁基(1R,5S)-3-(6-((二苯基亚甲基)氨基)-8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三异丙基甲硅烷基)乙炔基)萘-1-基)-2-(2,2,2-三氟乙氧基)喹唑啉-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(150mg,0.15mmol)和((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-吡咯啉]-7a'(5'H)-基)甲醇(60mg,0.29mmol)的四氢呋喃(3.00mL)溶液中，加入叔丁醇钠(42.0mg，0.44mmol)。将混合物氮气保护下在60℃下搅拌12小时。反应液用水(3mL)稀释，用乙酸乙酯(10mL*3)萃取，合并的有机相用无水硫酸钠干燥，过滤，旋干。得到粗品化合物叔丁基(1R,5S)-3-(2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-吡咯啉]-7a'(5'H)-基)甲氧基)-6-((二苯基亚甲基)氨基)-8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三异丙基甲硅烷基)乙炔基)萘-1-基)喹唑啉-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(250mg)，其为黄色油状化合物。LCMS(ESI):[M+2H]2+/2＝562.7.The second step: to tert-butyl(1R,5S)-3-(6-((diphenylmethylene)amino)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalene-1-yl)-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (15 0 mg, 0.15 mmol) and ((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrroline]-7a'(5'H)-yl)methanol (60 mg, 0.29 mmol) in tetrahydrofuran (3.00 mL) was added sodium tert-butoxide (42.0 mg, 0.44 mmol). The mixture was stirred at 60° C. for 12 hours under nitrogen protection. The reaction solution was diluted with water (3 mL), extracted with ethyl acetate (10 mL*3), and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and spin-dried. The crude compound tert-butyl(1R,5S)-3-(2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrroline]-7a'(5'H)-yl)methoxy)-6-((diphenylmethylene)amino)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylmethyl Silyl)ethynyl)naphthalen-1-yl)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (250 mg) as a yellow oily compound. LCMS (ESI): [M+2H] 2+ /2=562.7.
第三步：向叔丁基(1R,5S)-3-(2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-吡咯啉]-7a'(5'H)-基)甲氧基)-6-((二苯基亚甲基)氨基)-8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三异丙基甲硅烷基)乙炔基)萘-1-基)喹唑啉-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(230mg，0.20mmol)的N,N-二甲基甲酰胺(4.6mL)溶液中加入氟化铯(249mg，1.64mmol)。将混合物氮气保护下在20℃下搅拌1小时。加入水(10mL)，使用乙酸乙酯(15mL*3)萃取，合并的有机相用无水硫酸钠干燥，过滤，滤液旋干。残留物用快速柱色谱纯化(硅胶，0-7％梯度的甲醇/二氯甲烷)，得到棕色固体化合物叔丁基(1R,5S)-3-(2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-吡咯啉]-7a'(5'H)-基)甲氧基)-6-((二苯基亚甲基)氨基)-7-(8-乙炔基-7-氟-3-(甲氧基甲氧基)萘-1-基)-8-氟喹唑啉-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯 (170mg，0.17mmol，收率86％)。LCMS(ESI):[M+H]+＝967.5.The third step: to tert-butyl(1R,5S)-3-(2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrroline]-7a'(5'H)-yl)methoxy)-6-((diphenylmethylene)amino)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl Alkyl)ethynyl)naphthalen-1-yl)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (230 mg, 0.20 mmol) in N,N-dimethylformamide (4.6 mL) was added cesium fluoride (249 mg, 1.64 mmol). The mixture was stirred at 20° C. for 1 hour under nitrogen protection. Water (10 mL) was added, extracted with ethyl acetate (15 mL*3), the combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried. The residue was purified by flash column chromatography (silica gel, 0-7% gradient of methanol/dichloromethane) to give brown solid compound tert-butyl(1R,5S)-3-(2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrroline]-7a'(5'H)-yl)methoxy)-6-((diphenylmethylene)amino)-7-(8- Ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (170 mg, 0.17 mmol, yield 86%). LCMS (ESI): [M+H] + = 967.5.
第四步：在0℃下，向叔丁基(1R,5S)-3-(2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-吡咯啉]-7a'(5'H)-基)甲氧基)-6-((二苯基亚甲基)氨基)-7-(8-乙炔基-7-氟-3-(甲氧基甲氧基)萘-1-基)-8-氟喹唑啉-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(45.0mg，0.05mmol)的乙腈(540uL)溶液中，加入氯化氢(4M的二氧六环溶液，270uL，1.08mmol)。将混合物氮气保护下在25℃下搅拌1小时。混合物用氮气吹干，加入乙腈(0.50mL)搅拌，混合物用离心机离心，分离掉液体，固体用制备型HPLC纯化，得到黄色固体化合物4-(6-氨基-4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-吡咯啉]-7a'(5'H)-基)甲氧基)-8-氟喹唑啉-7-基)-5-乙炔基-6-氟萘-2-醇(4.99mg，0.75umol，收率16％)。LCMS(ESI):[M+H]+＝659.2.1H NMR(400MHz,CD3OD)δppm 7.85(dd,J＝5.8,9.0Hz,1H),7.40-7.24(m,2H),7.11(d,J＝2.3Hz,1H),7.04(s,1H),4.66(br s,1H),4.47-4.35(m,2H),4.34-4.25(m,2H),3.67(br s,2H),3.51(br t,J＝13.9Hz,2H),3.20(br d,J＝3.0Hz,2H),2.87(br d,J＝12.0Hz,1H),2.79-2.62(m,1H),2.31(br dd,J＝5.4,13.0Hz,1H),2.17(br dd,J＝5.5,11.1Hz,1H),2.09-1.75(m,8H),1.57-1.36(m,2H).The fourth step: at 0°C, to tert-butyl (1R,5S)-3-(2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrroline]-7a'(5'H)-yl)methoxy)-6-((diphenylmethylene)amino)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalene-1 -yl)-8-fluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (45.0 mg, 0.05 mmol) in acetonitrile (540 uL) was added hydrogen chloride (4M in dioxane, 270 uL, 1.08 mmol). The mixture was stirred at 25 °C for 1 hour under nitrogen protection. The mixture was blown dry with nitrogen, added acetonitrile (0.50 mL) and stirred, the mixture was centrifuged with a centrifuge, the liquid was separated, and the solid was purified by preparative HPLC to obtain a yellow solid compound 4-(6-amino-4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1, 2'-pyrroline]-7a'(5'H)-yl)methoxy)-8-fluoroquinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (4.99mg, 0.75umol, yield 16%). LCMS(ESI):[M+H] + ＝659.2. 1 H NMR(400MHz,CD 3 OD)δppm 7.85(dd,J＝5.8,9.0Hz,1H),7.40-7.24(m,2H),7.11(d,J＝2.3Hz,1H),7.04(s,1H),4.66(br s,1H),4.47-4.35(m,2H),4.34-4.25(m,2H),3.67(br s,2H),3.51(br t,J＝13.9Hz,2H),3.20(br d,J＝3.0Hz,2H),2.87(br d,J＝12.0Hz,1H),2.79-2.62(m,1H),2.31(br dd,J＝5.4,13.0Hz,1H),2.17(br dd,J＝5.5,11.1Hz,1H),2.09-1.75(m,8H),1.57-1.36(m,2H).
实施例69：4-(6-氨基-4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-吡咯啉]-7a'(5'H)-基)甲氧基)-8-氟喹唑啉-7-基)-5,6-二氟萘-2-醇
Example 69: 4-(6-amino-4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrroline]-7a'(5'H)-yl)methoxy)-8-fluoroquinazolin-7-yl)-5 ,6-Difluoronaphthalen-2-ol
第一步：在手套箱中，向叔丁基(1R,5S)-3-(7-溴-6-((二苯基亚甲基)氨基)-8-氟-2-(2,2,2-三氟乙氧基)喹唑啉-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(112mg，0.16mmol)和2-(7,8-二氟-3-(甲氧基甲氧基)萘-1-基)-4,4,5,5-四甲基-1,3,2-二氧硼烷(50.0mg，0.14mmol)的二氧六环(2.10mL)溶液中，加入磷酸钾(1.5M的水溶液，286uL，0.43mmol)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)(10.0mg，0.014mmol)。将混合物氮气保护下在100℃下搅拌2小时。冷却至室温后加入水(2.00mL)稀释，用乙酸乙酯(10mL*3)萃取，合并的有机相用无水硫酸钠干燥，过滤，滤液旋干。残留物用快速柱色谱纯化(硅胶，0-30％梯度的四氢呋喃/石油醚)。得到黄色固体化合物叔丁基(1R,5S)-3-(7-(7,8-二氟-3-(甲氧基甲氧基)萘-1-基)-6-((二苯基亚甲基)氨基)-8-氟-2-(2,2,2-三氟乙氧基)喹唑啉-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(105mg，1.21mmol，收率86％)。LCMS(ESI):[M+H]+ ＝858.4.Step 1: In a glove box, add tert-butyl(1R,5S)-3-(7-bromo-6-((diphenylmethylene)amino)-8-fluoro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (112mg, 0.16mmol) and 2-(7,8-difluoro-3-(methoxymethoxy)naphthalene -1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (50.0 mg, 0.14 mmol) in dioxane (2.10 mL) was added potassium phosphate (1.5 M in water, 286 uL, 0.43 mmol) and [n-butylbis(1-adamantyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium(II) (10.0 mg, 0.014mmol). The mixture was stirred at 100° C. for 2 hours under nitrogen protection. After cooling to room temperature, it was diluted with water (2.00 mL), extracted with ethyl acetate (10 mL*3), the combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried. The residue was purified by flash column chromatography (silica gel, gradient 0-30% tetrahydrofuran/petroleum ether). The yellow solid compound tert-butyl(1R,5S)-3-(7-(7,8-difluoro-3-(methoxymethoxy)naphthalen-1-yl)-6-((diphenylmethylene)amino)-8-fluoro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (105 mg, 1.21 mmol, yield 8 6%). LCMS(ESI):[M+H] + =858.4.
第二步：将叔丁基(1R,5S)-3-(7-(7,8-二氟-3-(甲氧基甲氧基)萘-1-基)-6-((二苯基亚甲基)氨基)-8-氟-2-(2,2,2-三氟乙氧基)喹唑啉-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(100mg,0.12mmol)和((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-吡咯啉]-7a'(5'H)-基)甲醇(36.0mg,0.17mmol)溶于四氢呋喃(1mL)，加入叔丁醇钠(34.0mg，0.35mmol)。将混合物氮气保护下在60℃下搅拌5小时。加入水(3mL)，使用乙酸乙酯(10mL*3)萃取，合并的有机相用无水硫酸钠干燥，过滤，滤液旋干，得到粗品化合物叔丁基(1R,5S)-3-(7-(7,8-二氟-3-(甲氧基甲氧基)萘-1-基)-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-吡咯啉]-7a'(5'H)-基)甲氧基)-6-((二苯基亚甲基)氨基)-8-氟喹唑啉-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(170mg)，其为棕色油状液体。LCMS(ESI):[M+H]+＝961.5.The second step: tert-butyl (1R,5S)-3-(7-(7,8-difluoro-3-(methoxymethoxy)naphthalene-1-yl)-6-((diphenylmethylene)amino)-8-fluoro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (100mg, 0.12mmol) and ((1 S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrroline]-7a'(5'H)-yl)methanol (36.0 mg, 0.17 mmol) was dissolved in tetrahydrofuran (1 mL), and sodium tert-butoxide (34.0 mg, 0.35 mmol) was added. The mixture was stirred at 60° C. for 5 hours under nitrogen protection. Water (3 mL) was added, extracted with ethyl acetate (10 mL*3), the combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried to obtain the crude compound tert-butyl(1R,5S)-3-(7-(7,8-difluoro-3-(methoxymethoxy)naphthalene-1-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1, 2'-pyrroline]-7a'(5'H)-yl)methoxy)-6-((diphenylmethylene)amino)-8-fluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (170 mg) as a brown oily liquid. LCMS (ESI): [M+H] + =961.5.
第三步：在0℃下，向叔丁基(1R,5S)-3-(7-(7,8-二氟-3-(甲氧基甲氧基)萘-1-基)-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-吡咯啉]-7a'(5'H)-基)甲氧基)-6-((二苯基亚甲基)氨基)-8-氟喹唑啉-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(45.0mg，0.05mmol)的乙腈(200uL)溶液中，加入氯化氢(4M的二氧六环溶液，234uL，0.94mmol)。将混合物氮气保护下在25℃下搅拌1小时。混合物用氮气吹干，加入乙腈(0.5mL)搅拌，混合物用离心机离心，分离掉液体，固体用制备型HPLC纯化，得到黄色固体化合物4-(6-氨基-4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-吡咯啉]-7a'(5'H)-基)甲氧基)-8-氟喹唑啉-7-基)-5,6-二氟萘-2-醇(6.13mg，0.94umol，收率20％)。LCMS(ESI):[M+H]+＝653.2.1H NMR(400MHz,CD3OD)δppm 7.61(br dd,J＝4.5,8.8Hz,1H),7.46-7.34(m,1H),7.31(s,1H),7.12(br s,2H),4.44(br d,J＝12.3Hz,2H),4.39-4.27(m,2H),3.74(br s,2H),3.54(br d,J＝12.0Hz,2H),3.40-3.35(m,1H),3.23(br d,J＝5.3Hz,1H),2.90(br d,J＝12.3Hz,1H),2.83-2.66(m,1H),2.33(br dd,J＝6.0,13.4Hz,1H),2.24-2.13(m,1H),2.10-1.79(m,8H),1.57-1.35(m,2H).The third step: at 0°C, to tert-butyl (1R,5S)-3-(7-(7,8-difluoro-3-(methoxymethoxy)naphthalene-1-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrroline]-7a'(5'H)-yl)methoxy)-6-((diphenylmethylene)amino)- 8-Fluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (45.0 mg, 0.05 mmol) in acetonitrile (200 uL) was added hydrogen chloride (4M solution in dioxane, 234 uL, 0.94 mmol). The mixture was stirred at 25 °C for 1 hour under nitrogen protection. The mixture was blown dry with nitrogen, added acetonitrile (0.5mL) and stirred, the mixture was centrifuged to separate the liquid, and the solid was purified by preparative HPLC to obtain yellow solid compound 4-(6-amino-4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2 '-pyrroline]-7a'(5'H)-yl)methoxy)-8-fluoroquinazolin-7-yl)-5,6-difluoronaphthalen-2-ol (6.13mg, 0.94umol, yield 20%). LCMS(ESI):[M+H] + ＝653.2. 1 H NMR(400MHz,CD 3 OD)δppm 7.61(br dd,J＝4.5,8.8Hz,1H),7.46-7.34(m,1H),7.31(s,1H),7.12(br s,2H),4.44(br d,J＝12.3Hz,2H),4.39-4.27(m,2H),3.74(br s,2H),3.54(br d,J＝12.0Hz,2H),3.40-3.35(m,1H),3.23(br d,J＝5.3Hz,1H),2.90(br d,J＝12.3Hz,1H),2.83-2.66(m,1H),2.33(br dd,J＝6.0,13.4Hz,1H),2.24-2.13(m,1H),2.10-1.79(m,8H),1.57-1.35(m,2H).
实施例70：N-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-7-(7,8-二氟-3-羟基萘-1-基)-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-吡咯嗪]-7a'(5'H)-基)甲氧基)-8-氟喹唑啉-6-基)甲磺酰胺
Example 70: N-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-7-(7,8-difluoro-3-hydroxynaphthalen-1-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolazin]-7a'(5'H)-yl)methyl Oxy)-8-fluoroquinazolin-6-yl)methanesulfonamide
第一步：向叔丁基(1R,5S)-3-(7-(7,8-二氟-3-(甲氧基甲氧基)萘-1-基)-2-(((1S,7a'S)-2,2-二氟二氢- 1'H,3'H-螺[环丙烷-1,2'-吡咯嗪]-7a'(5'H)-基)甲氧基)-6-((二苯基亚甲基)氨基)-8-氟喹唑啉-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(90.0mg，0.09mmol)和乙酸钠(76.8mg，0.94mmol)的甲醇(1.44mL)和四氢呋喃(0.45mL)溶液中，加入盐酸羟胺(42.3mg，0.61mmol)。将混合物氮气保护下在20℃下搅拌16小时。加水(5mL)稀释，使用二氯甲烷(10mL*3)萃取，合并的有机相用无水硫酸钠干燥，过滤旋干，得到粗品化合物叔丁基(1R,5S)-3-(6-氨基-7-(7,8-二氟-3-(甲氧基甲氧基)萘-1-基)-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-吡咯嗪]-7a'(5'H)-基)甲氧基)-8-氟喹唑啉-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(90.0mg)，其为棕色油状液体。LCMS(ESI):[M+H]+＝797.5.The first step: to tert-butyl (1R,5S)-3-(7-(7,8-difluoro-3-(methoxymethoxy)naphthalene-1-yl)-2-(((1S,7a'S)-2,2-difluorodihydro- 1'H,3'H-spiro[cyclopropane-1,2'-pyrrolazine]-7a'(5'H)-yl)methoxy)-6-((diphenylmethylene)amino)-8-fluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (90.0 mg, 0.09 mmol) and sodium acetate (76.8 mg, 0.94 mmol) in methanol ( 1.44 mL) and THF (0.45 mL), was added hydroxylamine hydrochloride (42.3 mg, 0.61 mmol). The mixture was stirred at 20° C. for 16 hours under nitrogen protection. Diluted with water (5 mL), extracted with dichloromethane (10 mL*3), dried the combined organic phases with anhydrous sodium sulfate, filtered and spin-dried to obtain the crude product 1,2'-Pyrrolizine]-7a'(5'H)-yl)methoxy)-8-fluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (90.0 mg) as a brown oily liquid. LCMS (ESI): [M+H] + = 797.5.
第二步：向叔丁基(1R,5S)-3-(6-氨基-7-(7,8-二氟-3-(甲氧基甲氧基)萘-1-基)-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-吡咯嗪]-7a'(5'H)-基)甲氧基)-8-氟喹唑啉-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(40.0mg，0.05mmol)和三乙胺(112uL，0.80mmol)的二氯甲烷(1.6mL)溶液中，在0℃下加入甲磺酸酐(35.0mg，0.20mmol)。将混合物氮气保护下在20℃下搅拌1小时。旋干，加入氨气(7M的甲醇溶液，2.00mL，14.0mmol)，将混合物在25℃下搅拌4小时，旋干。得到粗品化合物叔丁基(1R,5S)-3-(7-(7,8-二氟-3-(甲氧基甲氧基)萘-1-基)-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-吡咯嗪]-7a'(5'H)-基)甲氧基)-8-氟-6-(甲磺酰基)喹唑啉-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(44.0mg)，其为棕色固体。LCMS(ESI):[M+2H]2+/2＝874.8.The second step: to tert-butyl(1R,5S)-3-(6-amino-7-(7,8-difluoro-3-(methoxymethoxy)naphthalene-1-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolazin]-7a'(5'H)-yl)methoxy)-8-fluoroquinazolin-4-yl)-3 , To a solution of 8-diazabicyclo[3.2.1]octane-8-carboxylate (40.0mg, 0.05mmol) and triethylamine (112uL, 0.80mmol) in dichloromethane (1.6mL), methanesulfonic anhydride (35.0mg, 0.20mmol) was added at 0°C. The mixture was stirred at 20° C. for 1 hour under nitrogen protection. After spinning to dryness, ammonia gas (7M solution in methanol, 2.00 mL, 14.0 mmol) was added, the mixture was stirred at 25° C. for 4 hours, and then spin-dried. The crude compound tert-butyl(1R,5S)-3-(7-(7,8-difluoro-3-(methoxymethoxy)naphthalen-1-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolazin]-7a'(5'H)-yl)methoxy)-8-fluoro-6-(methylsulfonyl)quinazoline- 4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (44.0 mg) as a brown solid. LCMS (ESI): [M+2H] 2+ /2=874.8.
第三步：向叔丁基(1R,5S)-3-(7-(7,8-二氟-3-(甲氧基甲氧基)萘-1-基)-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-吡咯嗪]-7a'(5'H)-基)甲氧基)-8-氟-6-(甲磺酰基)喹唑啉-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(40.0mg，0.05mmol)的乙腈(800uL)溶液中，在0℃下加入氯化氢(4M的二氧六环溶液，229uL，0.91mmol)。将混合物在20℃下搅拌1小时。混合物用氮气吹干。残留物用制备型HPLC纯化，得到黄色固体化合物N-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-7-(7,8-二氟-3-羟基萘-1-基)-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-吡咯嗪]-7a'(5'H)-基)甲氧基)-8-氟喹唑啉-6-基)甲磺酰胺(4.30mg，0.58umol，收率13％)。LCMS(ESI):[M+H]+＝731.2.1H NMR(400MHz,CD3OD)δppm 7.96(d,J＝1.3Hz,1H),7.60(br dd,J＝4.1,8.5Hz,1H),7.45-7.34(m,1H),7.31(s,1H),7.11(d,J＝2.1Hz,1H),4.58-4.42(m,2H),4.40-4.28(m,2H),3.69(br s,2H),3.59(br dd,J＝12.8,18.1Hz,2H),3.34(br s,1H),3.22-3.09(m,1H),2.85(d,J＝12.1Hz,1H),2.79-2.64(m,4H),2.30(br dd,J＝5.6,12.8Hz,1H),2.16(br dd,J＝5.3,10.9Hz,1H),2.05-1.77(m,8H),1.54-1.35(m,2H).The third step: to tert-butyl(1R,5S)-3-(7-(7,8-difluoro-3-(methoxymethoxy)naphthalene-1-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolazin]-7a'(5'H)-yl)methoxy)-8-fluoro-6-(methylsulfonyl)quinazoline-4 -yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (40.0mg, 0.05mmol) in acetonitrile (800uL) was added hydrogen chloride (4M solution in dioxane, 229uL, 0.91mmol) at 0°C. The mixture was stirred at 20°C for 1 hour. The mixture was blown dry with nitrogen. The residue was purified by preparative HPLC to give the yellow solid compound N-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-7-(7,8-difluoro-3-hydroxynaphthalen-1-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolazine]-7a'( 5'H)-yl)methoxy)-8-fluoroquinazolin-6-yl)methanesulfonamide (4.30 mg, 0.58 umol, yield 13%). LCMS(ESI):[M+H] + ＝731.2. 1 H NMR(400MHz,CD 3 OD)δppm 7.96(d,J＝1.3Hz,1H),7.60(br dd,J＝4.1,8.5Hz,1H),7.45-7.34(m,1H),7.31(s,1H),7.11(d,J＝2.1Hz,1H),4.58-4.42(m,2H),4.40-4.28(m,2H),3.69(br s,2H),3.59(br dd,J＝12.8,18.1Hz,2H),3.34(br s,1H),3.22-3.09(m,1H),2.85(d,J＝12.1Hz,1H),2.79-2.64(m,4H),2.30(br dd,J＝5.6,12.8Hz,1H),2.16(br dd,J＝5.3,10.9Hz,1H),2.05-1.77(m,8H),1.54-1.35(m,2H).
实施例71～实施例73参考实施例70的合成路线按照类似反应条件制备得到。Examples 71-73 were prepared with reference to the synthesis route of Example 70 according to similar reaction conditions.
实施例71：N-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-吡咯嗪]-7a'(5'H)-基)甲氧基)-7-(8-乙炔基-7-氟-3-羟基萘-1-基)-8-氟喹唑啉-6-基)甲磺酰胺
Example 71: N-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolazin]-7a'(5'H)-yl)methoxy)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene -1-yl)-8-fluoroquinazolin-6-yl)methanesulfonamide
LCMS(ESI):[M+H]+＝737.2.1H NMR(400MHz,MeOD)δppm 7.96(s,1H),7.87(dd,J＝5.8,9.2Hz,1H),7.40-7.26(m,2H),7.12(d,J＝2.5Hz,1H),4.63(br s,1H),4.51-4.42(m,2H),4.39-4.28(m,2H),3.70(br s,2H),3.63-3.51(m,2H),3.35-3.33(m,1H),3.23-3.12(m,1H),2.85(br d,J＝12.0Hz,1H),2.80(s,3H),2.76-2.64(m,1H),2.38-2.23(m,1H),2.21-2.11(m,1H),2.06-1.76(m,8H),1.52-1.38(m,2H).LCMS(ESI):[M+H]+=737.2.1H NMR(400MHz,MeOD)δppm 7.96(s,1H),7.87(dd,J＝5.8,9.2Hz,1H),7.40-7.26(m,2H),7.12(d,J＝2.5Hz,1H),4.63(br s,1H),4.51-4.42(m,2H),4.39-4.28 (m,2H),3.70(br s,2H),3.63-3.51(m,2H),3.35-3.33(m,1H),3.23-3.12(m,1H),2.85(br d,J＝12.0Hz,1H),2.80(s,3H),2.76-2.64(m,1H),2.38-2. 23(m,1H),2.21-2.11(m,1H),2.06-1.76(m,8H),1.52-1.38(m,2H).
实施例72：N-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-7-(7,8-二氟-3-羟基萘-1-基)-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-吡咯嗪]-7a'(5'H)-基)甲氧基)-8-氟喹唑啉-6-基)乙酰胺
Example 72: N-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-7-(7,8-difluoro-3-hydroxynaphthalen-1-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolazin]-7a'(5'H)-yl)methyl Oxy)-8-fluoroquinazolin-6-yl)acetamide
LCMS(ESI):[M+H]+＝695.4.1H NMR(400MHz,CD3OD)δppm 8.50(s,1H),8.27(s,1H),7.63(br dd,J＝4.4,8.7Hz,1H),7.47-7.37(m,1H),7.34(s,1H),7.07(d,J＝1.7Hz,1H),4.70(br d,J＝12.7Hz,1H),4.65-4.52(m,3H),4.13(br s,2H),3.93-3.73(m,2H),3.68(br dd,J＝6.2,12.2Hz,1H),3.52(br dd,J＝5.7,11.1Hz,1H),3.17(br d,J＝12.2Hz,1H),2.98(br d,J＝8.8Hz,1H),2.48(br dd,J＝5.0,13.9Hz,1H),2.37-2.25(m,1H),2.24-2.09(m,6H),2.08-1.94(m,2H),1.90(s,3H),1.69-1.54(m,2H).LCMS(ESI):[M+H]+=695.4.1H NMR (400MHz, CD3OD)δppm 8.50(s,1H),8.27(s,1H),7.63(br d,J=4.4,8.7Hz,1H),7.47-7.37(m,1H),7.34(s,1H),7.07(d,J=1.7Hz,1H),4.70(br d,J=12.7Hz,1H),4.6 5-4.52(m,3H),4.13(br s,2H),3.93-3.73(m,2H),3.68(br dd,J＝6.2,12.2Hz,1H),3.52(br dd,J＝5.7,11.1Hz,1H),3.17(br d,J＝12.2Hz,1H),2.98(br d,J ＝8.8Hz,1H),2.48(br dd,J＝5.0,13.9Hz,1H),2.37-2.25(m,1H),2.24-2.09(m,6H),2.08-1.94(m,2H),1.90(s,3H),1.69-1.54(m,2H).
实施例73：N-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-吡咯嗪]-7a'(5'H)-基)甲氧基)-7-(8-乙炔基-7-氟-3-羟基萘-1-基)-8-氟喹唑啉-6-基)乙酰胺
Example 73: N-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolazin]-7a'(5'H)-yl)methoxy)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene -1-yl)-8-fluoroquinazolin-6-yl)acetamide
LCMS(ESI):[M+H]+＝701.3.1H NMR(400MHz,CD3OD)δppm 8.48(s,1H),8.37(s,1H),7.88(dd,J＝5.7,9.1Hz,1H),7.42-7.26(m,2H),7.06(d,J＝2.4Hz,1H),4.67-4.59(m,2H),4.57-4.45(m,3H),4.05(br s,2H),3.79-3.59(m,2H),3.59-3.51(m,1H),3.40(br dd,J＝5.5,10.3Hz,1H),3.08(br d,J＝12.4Hz,1H),2.97-2.83(m,1H),2.47-2.34(m,1H),2.29-2.17(m,2H),2.16-1.99(m,6H),1.92(s,4H),1.64-1.46(m,2H).LCMS(ESI):[M+H]+=701.3.1H NMR (400MHz, CD3OD)δppm 8.48(s,1H),8.37(s,1H),7.88(dd,J=5.7,9.1Hz,1H),7.42-7.26(m,2H),7.06(d,J=2.4Hz,1H),4.67-4.59(m,2H),4.57-4.45(m,3H),4.05( br s,2H),3.79-3.59(m,2H),3.59-3.51(m,1H),3.40(br dd,J＝5.5,10.3Hz,1H),3.08(br d,J＝12.4Hz,1H),2.97-2.83(m,1H),2.47-2.34(m,1H),2.29- 2.17(m,2H),2.16-1.99(m,6H),1.92(s,4H),1.64-1.46(m,2H).
实施例74：1-(7-(3-氨基-7,8-二氟异喹啉-1-基)-4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)喹唑啉-6-基)乙-1-酮
Example 74: 1-(7-(3-Amino-7,8-difluoroisoquinolin-1-yl)-4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-6-yl)ethan-1-one
第一步：在氮气气氛下，向叔丁基(1R,5S)-3-(6-乙酰-7-溴-8-氟-2-(2,2,2-三氟乙氧基)喹唑啉-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(250mg，0.43mmol)的二氧六环(5mL)溶液中加入7,8-二氟-1-(三丁基甲锡烷基)异喹啉-3-胺(244mg，0.52mmol)，碘化亚铜(25mg，0.13mmol)，氯化锂(46mg，1.08mmol)和四(三苯基膦)钯(100mg，0.09mmol)。反应液在氮气气氛和120℃下搅拌16小时。混合物旋干，得到的粗产物通过快速柱色谱(硅胶，0-50％梯度乙酸乙酯/石油醚)纯化得到黄色固体化合物叔丁基(1R,5S)-3-(6-乙酰基-7-(3-氨基-7,8-二氟异喹啉-1-基)-8-氟-2-(2,2,2-三氟乙氧基)喹唑 啉-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(130mg，0.2mmol，收率46％)。LCMS(ESI):[M+H]+＝677.1.Step 1: To a solution of tert-butyl (1R,5S)-3-(6-acetyl-7-bromo-8-fluoro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (250 mg, 0.43 mmol) in dioxane (5 mL) was added 7,8-difluoro-1-(tributylmethyl Stannyl)isoquinolin-3-amine (244mg, 0.52mmol), cuprous iodide (25mg, 0.13mmol), lithium chloride (46mg, 1.08mmol) and tetrakis(triphenylphosphine)palladium (100mg, 0.09mmol). The reaction solution was stirred under nitrogen atmosphere at 120°C for 16 hours. The mixture was spin-dried, and the obtained crude product was purified by flash column chromatography (silica gel, 0-50% gradient ethyl acetate/petroleum ether) to obtain yellow solid compound tert-butyl(1R,5S)-3-(6-acetyl-7-(3-amino-7,8-difluoroisoquinolin-1-yl)-8-fluoro-2-(2,2,2-trifluoroethoxy)quinazole phen-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (130 mg, 0.2 mmol, yield 46%). LCMS (ESI): [M+H] + = 677.1.
第二步：向叔丁基(1R,5S)-3-(6-乙酰基-7-(3-氨基-7,8-二氟异喹啉-1-基)-8-氟-2-(2,2,2-三氟乙氧基)喹唑啉-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(80mg，0.12mmol)的四氢呋喃(800uL)溶液中加入4A分子筛(80mg)，叔丁醇钠(17mg，0.18mmol)和((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲醇(28mg，0.18mmol)。将反应在20℃搅拌2小时。混合物用水(2mL)稀释并用乙酸乙酯(2mL*3)萃取，合并的有机相用饱和食盐水(2mL)洗涤，无水硫酸镁干燥，过滤，滤液浓缩，残余物通过快速柱色谱(硅胶，0-10％梯度甲醇/二氯甲烷)纯化得到棕色固体化合物叔丁基(1R,5S)-3-(6-乙酰基-7-(3-氨基-7,8-二氟异喹啉-1-基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)喹唑啉-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(24.50mg，33umol，收率28％)。LCMS(ESI):[M+H]+＝736.1.The second step: add tert-butyl (1R,5S)-3-(6-acetyl-7-(3-amino-7,8-difluoroisoquinolin-1-yl)-8-fluoro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (80mg, 0.12mmol) in tetrahydrofuran (800uL) solution 4A molecular sieves (80 mg), sodium tert-butoxide (17 mg, 0.18 mmol) and ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol (28 mg, 0.18 mmol) were added. The reaction was stirred at 20 °C for 2 hours. The mixture was diluted with water (2 mL) and extracted with ethyl acetate (2 mL*3), the combined organic phases were washed with saturated brine (2 mL), dried over anhydrous magnesium sulfate, filtered, the filtrate was concentrated, and the residue was purified by flash column chromatography (silica gel, 0-10% gradient methanol/dichloromethane) to obtain brown solid compound tert-butyl (1R,5S)-3-(6-acetyl-7-(3-amino-7,8-difluoroisoquinolin-1-yl)-8-fluoro-2 -(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (24.50mg, 33umol, yield 28%). LCMS (ESI): [M+H] + = 736.1.
第三步：向叔丁基(1R,5S)-3-(6-乙酰基-7-(3-氨基-7,8-二氟异喹啉-1-基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)喹唑啉-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(24.50mg，33umol)的乙腈(500uL)溶液中加入氯化氢(4M的二氧六环溶液，166uL，0.67mmol)。将反应在20℃搅拌1小时。溶液浓缩后溶于乙腈(1mL)，用三乙胺淬灭中和至pH＝7并浓缩。残余物通过制备型HPLC纯化，得到黄色固体化合物1-(7-(3-氨基-7,8-二氟异喹啉-1-基)-4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)喹唑啉-6-基)乙-1-酮(甲酸盐，13.08mg，20.6umol，收率62％)。LCMS(ESI):[M+H]+＝636.3。1H NMR(400MHz,CD3OD)δppm 8.53(br s,1H),8.44(s,1H),7.53-7.44(m,2H),6.90(d,J＝2.3Hz,1H),5.56-5.41(m,1H),4.80-4.72(m,2H),4.59-4.50(m,2H),4.07(br s,2H),3.93(dt,J＝5.5,14.1Hz,2H),3.77-3.57(m,3H),3.32-3.26(m,1H),2.63-2.33(m,6H),2.25-2.03(m,7H).The third step: to tert-butyl (1R,5S)-3-(6-acetyl-7-(3-amino-7,8-difluoroisoquinolin-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (2 4.50 mg, 33 umol) in acetonitrile (500 uL) was added hydrogen chloride (4M in dioxane, 166 uL, 0.67 mmol). The reaction was stirred at 20 °C for 1 hour. The solution was concentrated and dissolved in acetonitrile (1 mL), quenched with triethylamine to pH=7 and concentrated. The residue was purified by preparative HPLC to give compound 1-(7-(3-amino-7,8-difluoroisoquinolin-1-yl)-4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinazolin-6-yl as a yellow solid ) Ethan-1-one (formate salt, 13.08mg, 20.6umol, yield 62%). LCMS (ESI): [M+H] + = 636.3. 1 H NMR(400MHz,CD 3 OD)δppm 8.53(br s,1H),8.44(s,1H),7.53-7.44(m,2H),6.90(d,J＝2.3Hz,1H),5.56-5.41(m,1H),4.80-4.72(m,2H),4.59-4.50(m,2H),4.07(br s,2H),3.93(dt,J＝5.5,14.1Hz,2H),3.77-3.57(m,3H),3.32-3.26(m,1H),2.63-2.33(m,6H),2.25-2.03(m,7H).
实施例75：1-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-7-(7,8-二氟-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)喹唑啉-6-基)乙-1-酮
Example 75: 1-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-7-(7,8-difluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinazolin-6-yl)ethan-1-one
第一步：在25℃下，化合物叔丁基(1S,5R)-3-[7-溴-8-氟-6-碘-2-(2,2,2-三氟乙氧基)喹唑啉-4-基]-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(1.00g，1.51mmol)溶于二氧六环(20.0mL)，加入三丁基(1-乙氧基乙烯基)锡烷(510mg，1.41mmol)，氮气氛围下加入四(三苯基膦)钯(170mg，0.15mmol)，100℃搅拌16小时。反应液冷却至室温，减压浓缩，残留物用快速柱色谱纯化(硅胶，0-30％梯度的乙酸乙酯/石油醚)得白色固体化合物叔丁基(1R,5S)-3-(7-溴-6-(1-乙氧基乙烯基)-8-氟-2-(2,2,2-三氟乙氧基)喹唑啉-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(680mg，1.12mmol，收率74％)。LCMS(ESI):[M+H]+＝605.0.The first step: at 25°C, the compound tert-butyl(1S,5R)-3-[7-bromo-8-fluoro-6-iodo-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.00g, 1.51mmol) was dissolved in dioxane (20.0mL), and tributyl(1-ethoxyvinyl) was added Stannane (510mg, 1.41mmol), tetrakis(triphenylphosphine)palladium (170mg, 0.15mmol) was added under nitrogen atmosphere, and stirred at 100°C for 16 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by flash column chromatography (silica gel, 0-30% gradient ethyl acetate/petroleum ether) to obtain white solid compound tert-butyl (1R,5S)-3-(7-bromo-6-(1-ethoxyvinyl)-8-fluoro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (680 mg, 1.12mmol, yield 74%). LCMS (ESI): [M+H] + = 605.0.
第二步：在25℃下，将化合物叔丁基(1R,5S)-3-(7-溴-6-(1-乙氧基乙烯基)-8-氟-2-(2,2,2-三氟乙氧基)喹唑啉-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(400mg，0.66mmol)和盐酸(2M的水溶液，1.65mL，3.30mmol)加入到四氢呋喃(8.00mL)中，反应体系20℃反应2小时。加入饱和碳酸氢钠调节pH到7，用乙酸乙酯(4mL*3)萃取。有机相减压浓缩，残留物用快速柱色谱纯化(硅胶，0-15％梯度的乙酸乙酯/石油醚)得白色固体化合物叔丁基(1R,5S)-3-(6-乙酰基-7-溴-8-氟-2-(2,2,2-三氟乙氧基)喹唑啉-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(220mg，0.38mmol，收率58％)。LCMS(ESI):[M+H]+＝579.2.The second step: at 25°C, the compound tert-butyl (1R,5S)-3-(7-bromo-6-(1-ethoxyvinyl)-8-fluoro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (400mg, 0.66mmol) and hydrochloric acid (2M aqueous solution, 1.65mL, 3.30 mmol) was added into tetrahydrofuran (8.00 mL), and the reaction system was reacted at 20° C. for 2 hours. Add saturated sodium bicarbonate to adjust the pH to 7, and extract with ethyl acetate (4 mL*3). The organic phase was concentrated under reduced pressure, and the residue was purified by flash column chromatography (silica gel, 0-15% gradient of ethyl acetate/petroleum ether) to obtain white solid compound tert-butyl (1R,5S)-3-(6-acetyl-7-bromo-8-fluoro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (220mg, 0.38mmol, Yield 58%). LCMS (ESI): [M+H] + = 579.2.
第三步：在25℃下，叔丁基(1R,5S)-3-(6-乙酰基-7-溴-8-氟-2-(2,2,2-三氟乙氧基)喹唑啉-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(90.0mg，0.16mmol)，2-(7,8-二氟-3-(甲氧基甲氧基)萘-1-基)-4,4,5,5-四甲基-1,3,2-二氧硼烷(81.9mg，0.23mmol)和碳酸钠(49.6mg，0.47mmol)加入到二氧六环(1.80mL)和水(360uL)中，氮气氛围下加入四(三苯基膦)钯(10.2mg，0.02mmol)，反应体系80℃反应2小时。冷却至室温，减压浓缩，残留物用快速柱色谱纯化(硅胶，0-30％梯度的乙酸乙酯/石油醚)得黄色固体化合物叔丁基(1R,5S)-3-(6-乙酰基-7-(7,8-二氟-3-(甲氧基甲氧基)萘-1-基)-8-氟-2-(2,2,2-三氟乙氧基)喹唑啉-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(60％纯度，140mg，0.12mmol，收率75％)。LCMS(ESI):[M+H]+＝721.4. The third step: at 25°C, tert-butyl (1R,5S)-3-(6-acetyl-7-bromo-8-fluoro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (90.0mg, 0.16mmol), 2-(7,8-difluoro-3-(methoxymethoxy)naphthalen-1-yl) -4,4,5,5-Tetramethyl-1,3,2-dioxaborane (81.9mg, 0.23mmol) and sodium carbonate (49.6mg, 0.47mmol) were added to dioxane (1.80mL) and water (360uL), tetrakis(triphenylphosphine)palladium (10.2mg, 0.02mmol) was added under nitrogen atmosphere, and the reaction system was reacted at 80°C for 2 hours. Cool to room temperature, concentrate under reduced pressure, and purify the residue by flash column chromatography (silica gel, 0-30% gradient of ethyl acetate/petroleum ether) to obtain yellow solid compound tert-butyl (1R,5S)-3-(6-acetyl-7-(7,8-difluoro-3-(methoxymethoxy)naphthalene-1-yl)-8-fluoro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2 .1] Octane-8-carboxylate (60% purity, 140 mg, 0.12 mmol, yield 75%). LCMS (ESI): [M+H] + = 721.4.
第四步：在25℃下，叔丁基(1R,5S)-3-(6-乙酰基-7-(7,8-二氟-3-(甲氧基甲氧基)萘-1-基)-8-氟-2-(2,2,2-三氟乙氧基)喹唑啉-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(60％纯度，83.0mg，0.07mmol)加入到四氢呋喃(200uL)中，加入((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲醇(12.1mg，0.08mmol)和叔丁醇钠(20.0mg，0.21mmol)，反应体系20℃反应2小时。加入水(1mL)，乙酸乙酯(1mL*3)萃取，有机相减压浓缩得粗品化合物叔丁基(1R,5S)-3-(6-乙酰基-7-(7,8-二氟-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)喹唑啉-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(50％纯度，100mg)，其为黄色油状液体。LCMS(ESI):[M+H]+＝780.4.The fourth step: at 25°C, tert-butyl (1R,5S)-3-(6-acetyl-7-(7,8-difluoro-3-(methoxymethoxy)naphthalene-1-yl)-8-fluoro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (60% purity, 83.0mg, 0.07 mmol) was added to tetrahydrofuran (200uL), and ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol (12.1mg, 0.08mmol) and sodium tert-butoxide (20.0mg, 0.21mmol) were added, and the reaction system was reacted at 20°C for 2 hours. Add water (1 mL), extract with ethyl acetate (1 mL*3), and concentrate the organic phase under reduced pressure to obtain the crude compound tert-butyl(1R,5S)-3-(6-acetyl-7-(7,8-difluoro-3-(methoxymethoxy)naphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinazolin-4-yl )-3,8-Diazabicyclo[3.2.1]octane-8-carboxylate (50% purity, 100 mg) as a yellow oily liquid. LCMS (ESI): [M+H] + = 780.4.
第五步：在25℃下，将叔丁基(1R,5S)-3-(6-乙酰基-7-(7,8-二氟-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)喹唑啉-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(50％纯度，90.0mg，0.06mmol)加入到乙腈(1.00mL)中，加入盐酸(4M的二氧六环溶液，216uL，0.86mmol)，反应体系20℃反应2小时。减压浓缩，残留物溶于乙腈(1mL)并用三乙胺调节pH到7-8。混合物通过制备型HPLC纯化，得到白色固体化合物1-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-7-(7,8-二氟-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)喹唑啉-6-基)乙-1-酮(甲酸盐，4.03mg，6.35umol，收率11％)。LCMS(ESI):[M+H]+＝635.9。1H NMR(400MHz,CD3OD)δppm 8.54(br s,1H),8.32(s,1H),7.61(br dd,J＝4.4,8.4Hz,1H),7.44-7.32(m,1H),7.28(br s,1H),6.93(s,1H),5.55-5.30(m,1H),4.76-4.62(m,2H),4.48(q,J＝11.5Hz,2H),4.07-3.77(m,4H),3.61-3.37(m,3H),3.27-3.19(m,1H),2.55-2.26(m,6H),2.18(br d,J＝6.1Hz,2H),2.02(m,5H).The fifth step: at 25°C, tert-butyl (1R,5S)-3-(6-acetyl-7-(7,8-difluoro-3-(methoxymethoxy)naphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1 ] Octane-8-carboxylate (50% purity, 90.0mg, 0.06mmol) was added to acetonitrile (1.00mL), hydrochloric acid (4M solution in dioxane, 216uL, 0.86mmol) was added, and the reaction system was reacted at 20°C for 2 hours. Concentrated under reduced pressure, the residue was dissolved in acetonitrile (1 mL) and adjusted to pH 7-8 with triethylamine. The mixture was purified by preparative HPLC to give compound 1-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-7-(7,8-difluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-6-yl)ethanol as a white solid 1-keto (formate salt, 4.03mg, 6.35umol, yield 11%). LCMS (ESI): [M+H] + = 635.9. 1 H NMR(400MHz,CD 3 OD)δppm 8.54(br s,1H),8.32(s,1H),7.61(br dd,J＝4.4,8.4Hz,1H),7.44-7.32(m,1H),7.28(br s,1H),6.93(s,1H),5.55-5.30(m,1H),4.76-4.62(m,2H),4.48(q,J＝11.5Hz,2H),4.07-3.77(m,4H),3.61-3.37(m,3H),3.27-3.19(m,1H),2.55-2.26(m,6H),2.18(br d,J＝6.1Hz,2H),2.02(m,5H).
实施例75A和实施例75B：1-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-7-((S)-7,8-二氟-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)喹唑啉-6-基)乙-1-酮和Example 75A and Example 75B: 1-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-7-((S)-7,8-difluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinazolin-6- base) ethyl-1-one and
1-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-7-((R)-7,8-二氟-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)喹唑啉-6-基)乙-1-酮
1-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-7-((R)-7,8-difluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinazolin-6-yl)ethan-1-one
实施例75经SFC分离(柱：DAICEL CHIRALPAK AD(250mm*30mm,10um)；流动相：A相为二氧化碳，B相为0.1％氨水/乙醇；梯度：B相保持40％；流速：80毫升/分钟)得到目标产物。Example 75 was separated by SFC (column: DAICEL CHIRALPAK AD (250mm*30mm, 10um); mobile phase: phase A was carbon dioxide, phase B was 0.1% ammonia water/ethanol; gradient: phase B was maintained at 40%; flow rate: 80 ml/min) to obtain the target product.
异构体1,实施例75A：LCMS(ESI):[M+H]+＝636.4；SFC分析(色谱柱:Chiralpak AD-3，50mm*4.6mm，3um；流动相：A相为二氧化碳，B相为0.05％二乙胺/乙醇；B相在2分钟内从5％到40％，保持40％的B相1.2分钟，保持5％的B相0.8分钟；流速：4毫升/分钟)：手性柱出峰位置为1.787min；1H NMR(400MHz,MeOD)δppm 8.33(s,1H),7.60(br dd,J＝4.2,8.3Hz,1H),7.41-7.34(m,1H),7.30-7.26(m,1H),6.92(d,J＝1.7Hz,1H),5.47-5.24(m,1H),4.57(br d,J＝6.0Hz,2H),4.40-4.29(m,2H),3.83-3.59 (m,4H),3.45-3.35(m,3H),3.10(br d,J＝5.0Hz,1H),2.43-2.13(m,6H),2.06(br dd,J＝6.8,10.9Hz,2H),1.98-1.85(m,5H).异构体1,实施例75A：LCMS(ESI):[M+H] + ＝636.4；SFC分析(色谱柱:Chiralpak AD-3，50mm*4.6mm，3um；流动相：A相为二氧化碳，B相为0.05％二乙胺/乙醇；B相在2分钟内从5％到40％，保持40％的B相1.2分钟，保持5％的B相0.8分钟；流速：4毫升/分钟)：手性柱出峰位置为1.787min； 1 H NMR(400MHz,MeOD)δppm 8.33(s,1H),7.60(br dd,J＝4.2,8.3Hz,1H),7.41-7.34(m,1H),7.30-7.26(m,1H),6.92(d,J＝1.7Hz,1H),5.47-5.24(m,1H),4.57(br d,J＝6.0Hz,2H),4.40-4.29(m,2H),3.83-3.59 (m,4H),3.45-3.35(m,3H),3.10(br d,J=5.0Hz,1H),2.43-2.13(m,6H),2.06(br dd,J=6.8,10.9Hz,2H),1.98-1.85(m,5H).
异构体2，实施例75B：LCMS(ESI):[M+H]+＝636.1；SFC分析(色谱柱:Chiralpak AD-3，50mm*4.6mm，3um；流动相：A相为二氧化碳，B相为0.05％二乙胺/乙醇；B相在2分钟内从5％到40％，保持40％的B相1.2分钟，保持5％的B相0.8分钟；流速：4毫升/分钟)：手性柱出峰位置为2.089min；1H NMR(400MHz,CD3OD)δppm 8.39-8.25(m,1H),7.61(br dd,J＝4.5,9.4Hz,1H),7.45-7.34(m,1H),7.28(s,1H),6.93(s,1H),5.50-5.26(m,1H),4.56(s,2H),4.45-4.30(m,2H),3.86-3.60(m,4H),3.55-3.40(m,3H),3.20-3.08(m,1H),2.53-2.17(m,6H),2.15-2.06(m,2H),1.94(br s,5H).Isomer 2, Example 75B: LCMS (ESI): [M+H]+=636.1; SFC analysis (chromatographic column: Chiralpak AD-3, 50mm*4.6mm, 3um; Mobile phase: A phase is carbon dioxide, B phase is 0.05% diethylamine/ethanol; B phase is from 5% to 40% in 2 minutes, keeps 40% of B phase for 1.2 minutes, keeps 5% of B phase for 0.8 minutes; flow rate: 4 ml/min): chiral column peak position is 2.089min;1H NMR (400MHz, CD3( m,2H),3.86-3.60(m,4H),3.55-3.40(m,3H),3.20-3.08(m,1H),2.53-2.17(m,6H),2.15-2.06(m,2H),1.94(br s,5H).
实施例76：1-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-7-(8-乙炔基-7-氟-3-羟基萘-1-基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)喹唑啉-6-基)乙-1-酮
Example 76: 1-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinazolin-6-yl)ethan-1-one
第一步：在25℃下，化合物叔丁基(1R,5S)-3-(6-乙酰基-7-溴-8-氟-2-(2,2,2-三氟乙氧基)喹唑啉-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(100mg，0.17mmol)溶于二氧六环(2.00mL)和水(400uL)，加入((2-氟-6-(甲氧基甲氧基)-8-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)萘-1-基)乙炔基)三异丙基硅烷(115mg，0.23mmol)和磷酸钾(110mg，0.52mmol)，氮气氛围下加入甲磺酸[正丁基二(1-金刚烷基)膦](2-氨基-1,1'-联苯-2-基)钯(II)(12.6mg，0.02mmol)，100℃搅拌2小时。反应液冷却至室温，减压浓缩，残留物用快速柱色谱纯化(硅胶，0-30％梯度的四氢呋喃/石油醚)得黄色油状化合物叔丁基(1R,5S)-3-(6-乙酰基-8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三异丙基甲硅烷基)乙炔基)萘-1-基)-2-(2,2,2-三氟乙氧基)喹唑啉-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(90.0mg，0.10mmol，收率 59％)。LCMS(ESI):[M+H]+＝883.5.The first step: at 25°C, the compound tert-butyl (1R,5S)-3-(6-acetyl-7-bromo-8-fluoro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (100mg, 0.17mmol) was dissolved in dioxane (2.00mL) and water (400uL), and added ( (2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalene-1-yl)ethynyl)triisopropylsilane (115mg, 0.23mmol) and potassium phosphate (110mg, 0.52mmol), methanesulfonic acid [n-butylbis(1-adamantyl)phosphine](2-amino-1,1' -Biphenyl-2-yl)palladium(II) (12.6mg, 0.02mmol), stirred at 100°C for 2 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by flash column chromatography (silica gel, 0-30% gradient tetrahydrofuran/petroleum ether) to obtain yellow oily compound tert-butyl(1R,5S)-3-(6-acetyl-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalene-1-yl)-2-(2,2,2-trifluoroethoxy)quinazoline-4 -yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (90.0mg, 0.10mmol, yield 59%). LCMS (ESI): [M+H] + = 883.5.
第二步：在25℃下，叔丁基(1R,5S)-3-(6-乙酰基-8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三异丙基甲硅烷基)乙炔基)萘-1-基)-2-(2,2,2-三氟乙氧基)喹唑啉-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(90.0mg，0.10mmol)加入到四氢呋喃(1.80mL)中，加入((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲醇(17.9mg，0.11mmol)和叔丁醇钠(29.4mg，0.31mmol)，反应体系20℃反应2小时。加入水(1mL)稀释，用乙酸乙酯(1mL*3)萃取，有机相减压浓缩得粗品化合物叔丁基(1R,5S)-3-(6-乙酰基-8-氟-7-(7-氟-3-(甲氧基甲氧基)-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)喹唑啉-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(90.0mg)，其为黄色油状液体。LCMS(ESI):[M+H]+＝942.5.The second step: at 25°C, tert-butyl (1R,5S)-3-(6-acetyl-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalene-1-yl)-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (90. 0mg, 0.10mmol) was added to tetrahydrofuran (1.80mL), ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol (17.9mg, 0.11mmol) and sodium tert-butoxide (29.4mg, 0.31mmol) were added, and the reaction system was reacted at 20°C for 2 hours.加入水(1mL)稀释，用乙酸乙酯(1mL*3)萃取，有机相减压浓缩得粗品化合物叔丁基(1R,5S)-3-(6-乙酰基-8-氟-7-(7-氟-3-(甲氧基甲氧基)-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)喹唑啉-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(90.0mg)，其为黄色油状液体。LCMS(ESI):[M+H] + ＝942.5.
第三步：在25℃下，叔丁基(1R,5S)-3-(6-乙酰基-8-氟-7-(7-氟-3-(甲氧基甲氧基)-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)喹唑啉-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(85.0mg，0.09mmol)加入到二甲基甲酰胺(1.80mL)中，加入氟化铯(41.1mg，0.27mmol)，反应体系20℃反应1小时。加入水(5mL)，乙酸乙酯(5mL*3)萃取，有机相减压浓缩得粗品化合物叔丁基(1R,5S)-3-(6-乙酰基-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-吡咯嗪-7a(5H)-基)甲氧基)喹唑啉-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(50％纯度，100mg)，其为黄色固体。LCMS(ESI):[M+H]+＝786.5.The third step: at 25°C, tert-butyl(1R,5S)-3-(6-acetyl-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalene-1-yl)-2-((((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3, Add 8-diazabicyclo[3.2.1]octane-8-carboxylate (85.0mg, 0.09mmol) to dimethylformamide (1.80mL), add cesium fluoride (41.1mg, 0.27mmol), and react at 20°C for 1 hour. Add water (5mL), extract with ethyl acetate (5mL*3), and concentrate the organic phase under reduced pressure to obtain the crude compound tert-butyl(1R,5S)-3-(6-acetyl Ethyl-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (50% purity, 100 mg) as a yellow solid LC. MS(ESI):[M+H]+=786.5.
第四步：在25℃下，叔丁基(1R,5S)-3-(6-乙酰基-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-吡咯嗪-7a(5H)-基)甲氧基)喹唑啉-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(50％纯度，95mg，0.06mmol)加入到乙腈(2.00mL)中，加入氯化氢(4M的二氧六环溶液，393uL，1.57mmol)，反应体系20℃反应2小时。减压浓缩，残留物溶于乙腈(1mL)并用三乙胺调节pH到7-8。混合物通过制备型HPLC纯化，得到白色固体化合物1-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-7-(8-乙炔基-7-氟-3-羟基萘-1-基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)喹唑啉-6-基)乙-1-酮(甲酸盐，3.65mg，5.68umol，收率9％)。LCMS(ESI):[M+H]+＝642.5.1H NMR(400MHz,CD3OD)δppm 8.54(br s,1H),8.25(s,1H),7.87(br dd,J＝6.0,8.9Hz,1H),7.50-7.22(m,2H),7.00-6.92(m,1H),5.53-5.29(m,1H),4.72-4.60(m,2H),4.49-4.34(m,2H),3.86(br s,3H),3.73(br dd,J＝7.0,12.6Hz,1H),3.60-3.39(m,4H),3.18(br s,1H),2.52-2.40(m,1H),2.36(br d,J＝8.9Hz,1H),2.25(br s,1H),2.20(s,3H),2.17-2.09(m,2H),1.98(br s,5H).The fourth step: at 25°C, tert-butyl (1R,5S)-3-(6-acetyl-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2 .1] octane-8-carboxylate (50% purity, 95mg, 0.06mmol) was added in acetonitrile (2.00mL), hydrogen chloride (4M solution in dioxane, 393uL, 1.57mmol) was added, and the reaction system was reacted at 20° C. for 2 hours. Concentrated under reduced pressure, the residue was dissolved in acetonitrile (1 mL) and adjusted to pH 7-8 with triethylamine. The mixture was purified by preparative HPLC to give the compound 1-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinazolin-6-yl as a white solid ) Ethan-1-one (formate salt, 3.65mg, 5.68umol, yield 9%). LCMS(ESI):[M+H] + ＝642.5. 1 H NMR(400MHz,CD 3 OD)δppm 8.54(br s,1H),8.25(s,1H),7.87(br dd,J＝6.0,8.9Hz,1H),7.50-7.22(m,2H),7.00-6.92(m,1H),5.53-5.29(m,1H),4.72-4.60(m,2H),4.49-4.34(m,2H),3.86(br s,3H),3.73(br dd,J＝7.0,12.6Hz,1H),3.60-3.39(m,4H),3.18(br s,1H),2.52-2.40(m,1H),2.36(br d,J＝8.9Hz,1H),2.25(br s,1H),2.20(s,3H),2.17-2.09(m,2H),1.98(br s,5H).
实施例76A和实施例76B 1-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-7-((S)-8-乙炔基-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)喹唑啉-6-基)乙-1-酮，和Example 76A and Example 76B 1-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-7-((S)-8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinazoline -6-yl) ethyl-1-one, and
1-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-7-((R)-8-乙炔基-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)喹唑啉-6-基)乙-1-酮
1-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-7-((R)-8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-6-yl)ethan-1-one
实施例76经SFC分离(柱：DAICEL CHIRALPAK AD(250mm*30mm,10um)；流动相：A相为二氧化碳，B相为0.1％氨水/乙醇；B相保持35％；流速：120毫升/分钟)，得到目标化合物。Example 76 was separated by SFC (column: DAICEL CHIRALPAK AD (250mm*30mm, 10um); mobile phase: phase A was carbon dioxide, phase B was 0.1% ammonia water/ethanol; phase B was kept at 35%; flow rate: 120 ml/min), and the target compound was obtained.
异构体1，实施例76A：LCMS(ESI):[M+H]+＝642.3；SFC分析(柱:Chiralpak AD-3，50mm*4.6mm，3um；流动相：A相为二氧化碳，B相为0.05％二乙胺/乙醇；梯度：B相在2分钟内从5％到40％，保持40％的B相1.2分钟，保持5％的B相0.8分钟；流速：4毫升/分钟)：手性柱出峰位置为1.696min；1H NMR(400MHz,MeOD)δppm 8.26(s,1H),7.89(dd,J＝5.9,9.2Hz,1H),7.38-7.31(m,2H),6.95(d,J＝2.3Hz,1H),5.61-5.43(m,1H),4.83(br d,J＝13.8Hz,1H),4.71(br d,J＝14.1Hz,1H),4.68-4.55(m,2H),4.21-4.12(m,2H),4.01(br d,J＝13.6Hz,1H),3.94-3.68(m,4H),3.41-3.35(m,2H),2.69-2.47(m,2H),2.41-2.34(m,1H),2.34-2.23(m,2H),2.20(s,3H),2.15-1.99(m,5H).Isomer 1, Example 76A: LCMS (ESI): [M+H]+=642.3; SFC analysis (column: Chiralpak AD-3, 50mm*4.6mm, 3um; Mobile phase: A phase is carbon dioxide, B phase is 0.05% diethylamine/ethanol; Gradient: B phase is from 5% to 40% in 2 minutes, keeps 40% B phase 1.2 minutes, keeps 5% B phase 0.8 minutes; Flow rate: 4 milliliters/minute): chiral column peak position is 1.696min;1H NMR (400MHz, MeOD) δppm 8.26(s, 1H), 7.89(dd, J＝5.9, 9.2Hz, 1H), 7.38-7.31(m, 2H), 6.95(d, J＝2.3Hz, 1H), 5.61-5.43(m, 1H), 4.83(br d, J＝13.8Hz, 1H), 4 .71(br d,J=14.1Hz,1H),4.68-4.55(m,2H),4.21-4.12(m,2H),4.01(br d,J=13.6Hz,1H),3.94-3.68(m,4H),3.41-3.35(m,2H),2.69-2.47(m,2H),2. 41-2.34(m,1H),2.34-2.23(m,2H),2.20(s,3H),2.15-1.99(m,5H).
异构体2，实施例76B：LCMS(ESI):[M+H]+＝642.4；SFC分析(柱:Chiralpak AD-3，50mm*4.6mm，3um；流动相：A相为二氧化碳，B相为0.05％二乙胺/乙醇；梯度：B相在2分钟内从5％到40％，保持40％的B相1.2分钟，保持5％的B相0.8分钟；流速：4毫升/分钟)：手性柱出峰位置为2.137min；1H NMR(400MHz,CD3OD)δppm 8.25(s,1H),7.85(dd,J＝5.8,9.0Hz,1H),7.34-7.30(m,2H),6.95(d,J＝2.3Hz,1H),5.40-5.22(m,1H),4.67-4.49(m,2H),4.31-4.21(m,2H),3.79-3.62(m,4H),3.33(br s,1H),3.31-3.16(m,3H),3.02(dt,J＝5.9,9.3Hz,1H),2.39-2.11(m,6H),2.06-1.79(m,7H).Isomer 2, Example 76B: LCMS (ESI): [M+H]+=642.4; SFC analysis (column: Chiralpak AD-3, 50mm*4.6mm, 3um; Mobile phase: A phase is carbon dioxide, B phase is 0.05% diethylamine/ethanol; Gradient: B phase is from 5% to 40% in 2 minutes, keeps 40% B phase 1.2 minutes, keeps 5% B phase 0.8 minutes; Flow rate: 4 milliliters/minute): chiral column peak position is 2.137min;1H NMR (400MHz, CD3OD)δppm 8.25(s,1H),7.85(dd,J=5.8,9.0Hz,1H),7.34-7.30(m,2H),6.95(d,J=2.3Hz,1H),5.40-5.22(m,1H),4.67-4.49(m,2H),4.31-4.21(m,2H), 3.79-3.62(m,4H),3.33(br s,1H),3.31-3.16(m,3H),3.02(dt,J＝5.9,9.3Hz,1H),2.39-2.11(m,6H),2.06-1.79(m,7H).
实施例77：4-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-吡咯嗪]-7a'(5'H)-基)甲氧基)-8-氟-6-乙烯基喹唑啉-7-基)-5,6-二氟萘-2-醇
Example 77: 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolazin]-7a'(5'H)-yl)methoxy)-8-fluoro-6-vinylquinazolin-7-yl)- 5,6-Difluoronaphthalen-2-ol
第一步：将化合物叔丁基(1R,5S)-3-(7-溴-8-氟-6-碘-2-(2,2,2-三氟乙氧基)喹唑啉-4-基)-3,8-二氮杂 双环[3.2.1]辛烷-8-羧酸酯(1.00g，1.51mmol)溶于四氢呋喃(10mL)中，20℃下加入三氟(乙烯基)硼酸钾(220mg，1.66mmol)和碳酸钠(1M的水溶液，4.54mL，4.54mmol)。氮气氛围下，向反应液中加入[1,1-双(二苯基膦)二茂铁]二氯化钯二氯甲烷(120mg，0.15mmol)。反应在60℃下搅拌5小时。反应液减压浓缩，残留物用快速柱色谱纯化(硅胶，0-30％梯度的乙酸乙酯/石油醚)得到淡黄色固体化合物叔丁基(1R,5S)-3-(7-溴-8-氟-2-(2,2,2-三氟乙氧基)-6-乙烯基喹唑啉-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(纯度85％，500mg，0.75mmol，收率50％)。LCMS(ESI):[M+H]+＝561.0.The first step: the compound tert-butyl (1R,5S)-3-(7-bromo-8-fluoro-6-iodo-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazepine Bicyclo[3.2.1]octane-8-carboxylate (1.00g, 1.51mmol) was dissolved in tetrahydrofuran (10mL), potassium trifluoro(vinyl)borate (220mg, 1.66mmol) and sodium carbonate (1M aqueous solution, 4.54mL, 4.54mmol) were added at 20°C. Under nitrogen atmosphere, [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane (120 mg, 0.15 mmol) was added to the reaction solution. The reaction was stirred at 60°C for 5 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by flash column chromatography (silica gel, 0-30% gradient ethyl acetate/petroleum ether) to obtain a light yellow solid compound tert-butyl (1R,5S)-3-(7-bromo-8-fluoro-2-(2,2,2-trifluoroethoxy)-6-vinylquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (purity 85%, 500mg, 0 .75mmol, yield 50%). LCMS (ESI): [M+H] + = 561.0.
第二步：在氮气环境下，向叔丁基(1R,5S)-3-(7-溴-8-氟-2-(2,2,2-三氟乙氧基)-6-乙烯基喹唑啉-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(纯度85％，352mg，0.53mmol)的四氢呋喃(5mL)溶液中加入2-(7,8-二氟-3-(甲氧基甲氧基)萘-1-基)-4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷(200mg，0.57mmol)，磷酸钾溶液(1.5M，856uL，1.71mmol)，[1,1-双(二叔丁基膦)二茂铁]二氯化钯(II)(37.0mg，0.06mmol)。并将混合物在20℃下搅拌16小时。加入水(5mL)，乙酸乙酯萃取(5mL*2)萃取，有机相用无水硫酸镁干燥，过滤，滤液减压浓缩。残余物通过快速硅胶色谱法(硅胶，0-65％梯度的乙酸乙酯/石油醚)纯化得到淡黄色固体化合物叔丁基(1R,5S)-3-(7-(7,8-二氟-3-(甲氧基甲氧基)萘-1-基)-8-氟-2-(2,2,2-三氟乙氧基)-6-乙烯基喹唑啉-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(230mg，0.32mmol，收率57％)。LCMS(ESI):[M+H]+＝704.8.The second step: under nitrogen atmosphere, 2-(7,8-di Fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (200 mg, 0.57 mmol), potassium phosphate solution (1.5 M, 856 uL, 1.71 mmol), [1,1-bis(di-tert-butylphosphino)ferrocene]palladium(II) dichloride (37.0 mg, 0.06 mmol). And the mixture was stirred at 20°C for 16 hours. Water (5 mL) was added, extracted with ethyl acetate (5 mL*2), the organic phase was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (silica gel, 0-65% gradient of ethyl acetate/petroleum ether) to give the compound tert-butyl(1R,5S)-3-(7-(7,8-difluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(2,2,2-trifluoroethoxy)-6-vinylquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane- 8-Carboxylate (230 mg, 0.32 mmol, yield 57%). LCMS (ESI): [M+H] + = 704.8.
第三步：将化合物叔丁基(1R,5S)-3-(7-(7,8-二氟-3-(甲氧基甲氧基)萘-1-基)-8-氟-2-(2,2,2-三氟乙氧基)-6-乙烯基喹唑啉-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(220mg，0.31mmol)和((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-吡咯啉]-7a'(5'H)-基)甲醇(95.0mg，0.47mmol)溶于四氢呋喃(3mL)，在0℃下，慢慢往反应液中加入叔丁醇钠(90.0mg，0.94mmol)，反应在60℃搅拌5小时。反应液减压浓缩，残留物用快速柱色谱纯化(硅胶，0-10％梯度的甲醇/二氯甲烷)得到黄色固体化合物叔丁基(1R,5S)-3-(7-(7,8-二氟-3-(甲氧基甲氧基)萘-1-基)-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-吡咯嗪]-7a'(5'H)-基)甲氧基)-8-氟-6-乙烯基喹唑啉-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(250mg，0.30mmol，收率99％)。LCMS(ESI):[M+H]+＝808.2.The third step: the compound tert-butyl (1R,5S)-3-(7-(7,8-difluoro-3-(methoxymethoxy)naphthalene-1-yl)-8-fluoro-2-(2,2,2-trifluoroethoxy)-6-vinylquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (220mg, 0.31mmol) and ((1S,7a'S )-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrroline]-7a'(5'H)-yl)methanol (95.0mg, 0.47mmol) was dissolved in tetrahydrofuran (3mL). At 0°C, sodium tert-butoxide (90.0mg, 0.94mmol) was slowly added to the reaction solution, and the reaction was stirred at 60°C for 5 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by flash column chromatography (silica gel, 0-10% gradient methanol/dichloromethane) to obtain yellow solid compound tert-butyl(1R,5S)-3-(7-(7,8-difluoro-3-(methoxymethoxy)naphthalene-1-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolazine]-7a '(5'H)-yl)methoxy)-8-fluoro-6-vinylquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (250 mg, 0.30 mmol, yield 99%). LCMS (ESI): [M+H] + = 808.2.
第四步：将化合物叔丁基(1R,5S)-3-(7-(7,8-二氟-3-(甲氧基甲氧基)萘-1-基)-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-吡咯嗪]-7a'(5'H)-基)甲氧基)-8-氟-6-乙烯基喹唑啉-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(240mg，0.30mmol)溶于乙腈(3mL)，0℃下加入氯化氢(4M的二氧六环溶液，1.49mL，5.96mmol)。反应在20℃下搅拌2小时。反应液减压浓缩。残留物溶于三乙胺(400uL)的二甲亚砜(2mL)溶液，反应液减压浓缩。残留物用制备型HPLC纯化，得到白色固体化合物4-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-吡咯嗪]-7a'(5'H)-基)甲氧基)-8-氟-6-乙烯基喹唑啉-7-基)-5,6-二氟萘-2-醇(20.87mg，0.02mmol，收率10％)。LCMS(ESI):[M+H]+＝664.2.1H NMR(400MHz,CD3OD)δppm 7.99(s,1H),7.59(br dd,J＝8.5,4.2Hz,1H),7.42-7.33(m,1H),7.29(s,1H),6.98(d,J＝2.0Hz,1H),6.32(dd,J＝17.4,11.0Hz,1H),5.69(d,J＝17.4Hz,1H),5.13(d,J＝11.1Hz,1H),4.64-4.50(m,2H),4.40-4.32(m,2H),3.77-3.64(m,4H),3.40-3.34(m,1H),3.24-3.16(m,1H),2.87(br d,J＝12.1Hz,1H),2.78-2.68(m,1H),2.31(br dd,J＝13.5,4.2Hz,1H),2.23-2.12(m,1H),2.04(br d,J＝13.4Hz,1H),1.96-1.86(m,6H),1.81(br dd,J＝11.9,7.4Hz,1H),1.53-1.37(m,2H). The fourth step: the compound tert-butyl(1R,5S)-3-(7-(7,8-difluoro-3-(methoxymethoxy)naphthalene-1-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolazin]-7a'(5'H)-yl)methoxy)-8-fluoro-6-vinylquinazolin-4-yl )-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (240mg, 0.30mmol) was dissolved in acetonitrile (3mL), and hydrogen chloride (4M solution in dioxane, 1.49mL, 5.96mmol) was added at 0°C. The reaction was stirred at 20°C for 2 hours. The reaction solution was concentrated under reduced pressure. The residue was dissolved in a solution of triethylamine (400 uL) in dimethyl sulfoxide (2 mL), and the reaction solution was concentrated under reduced pressure. The residue was purified by preparative HPLC to give the compound 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolazin]-7a'(5'H)-yl)methoxy)-8-fluoro-6-vinylquinol as a white solid Azolin-7-yl)-5,6-difluoronaphthalen-2-ol (20.87 mg, 0.02 mmol, yield 10%). LCMS(ESI):[M+H] + ＝664.2. 1 H NMR(400MHz,CD 3 OD)δppm 7.99(s,1H),7.59(br dd,J＝8.5,4.2Hz,1H),7.42-7.33(m,1H),7.29(s,1H),6.98(d,J＝2.0Hz,1H),6.32(dd,J＝17.4,11.0Hz,1H),5.69(d,J＝17.4Hz,1H),5.13(d,J＝11.1Hz,1H),4.64-4.50(m,2H),4.40-4.32(m,2H),3.77-3.64(m,4H),3.40-3.34(m,1H),3.24-3.16(m,1H),2.87(br d,J＝12.1Hz,1H),2.78-2.68(m,1H),2.31(br dd,J＝13.5,4.2Hz,1H),2.23-2.12(m,1H),2.04(br d,J＝13.4Hz,1H),1.96-1.86(m,6H),1.81(br dd,J＝11.9,7.4Hz,1H),1.53-1.37(m,2H).
实施例78：4-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-6-乙烯基喹唑啉-7-基)-5-乙炔基-6-氟萘-2-醇
Example 78: 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-6-vinylquinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol
实施例78的制备参考实施例76，采用类似的合成路线合成得到。LCMS(ESI):[M+H]+＝626.7.1H NMR(400MHz,MeOD-d4)δppm 7.92(s,1H),7.85(dd,J＝5.9,9.1Hz,1H),7.36-7.27(m,2H),7.00(d,J＝2.5Hz,1H),6.32-6.22(m,1H),5.66(d,J＝17.4Hz,1H),5.45-5.25(m,1H),5.15-5.07(m,1H),4.62-4.46(m,2H),4.36-4.19(m,2H),3.76-3.60(m,4H),3.41-3.34(m,1H),3.29-3.15(m,3H),3.10-3.00(m,1H),2.45-2.15(m,3H),2.07-1.86(m,7H).Preparation of Example 78 Referring to Example 76, it was synthesized using a similar synthetic route. LCMS(ESI):[M+H] + ＝626.7. 1 H NMR(400MHz,MeOD-d 4 )δppm 7.92(s,1H),7.85(dd,J＝5.9,9.1Hz,1H),7.36-7.27(m,2H),7.00(d,J＝2.5Hz,1H),6.32-6.22(m,1H),5.66(d,J＝17.4Hz,1H),5.45-5.25(m,1H),5.15-5.07(m,1H),4.62-4.46(m,2H),4.36-4.19(m,2H),3.76-3.60(m,4H),3.41-3.34(m,1H),3.29-3.15(m,3H),3.10-3.00(m,1H),2.45-2.15(m,3H),2.07-1.86(m,7H).
实施例79：4-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-6-乙炔基-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)喹唑啉-7-基)-5,6-二氟萘-2-醇
Example 79: 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-6-ethynyl-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinazolin-7-yl)-5,6-difluoronaphthalen-2-ol
实施例79的制备参考实施例75，采用类似的合成路线合成得到LCMS(ESI):[M+H]+＝618.7.1H NMR(400MHz,CD3OD-d4)δppm 7.98(s,1H),7.57(dd,J＝9.0,4.0Hz,1H),7.41-7.31(m,1H),7.26(s,1H),7.07(d,J＝2.3Hz,1H),5.41-5.21(m,1H),4.53(br t,J＝17.8Hz,2H),4.34-4.26(m,1H),4.26-4.19(m,1H),3.73-3.59(m,4H),3.30-3.15(m,4H),3.08-2.98(m,1H),2.41-1.79(m,10H).Preparation of Example 79 Referring to Example 75, a similar synthetic route was used to synthesize LCMS (ESI): [M+H]+=618.7.1H NMR (400MHz, CD3OD-d4)δppm 7.98(s,1H),7.57(dd,J=9.0,4.0Hz,1H),7.41-7.31(m,1H),7.26(s,1H),7.07(d,J=2.3Hz,1H),5.41-5.21(m,1H),4.53(br t,J=17.8Hz,2H),4 .34-4.26(m,1H),4.26-4.19(m,1H),3.73-3.59(m,4H),3.30-3.15(m,4H),3.08-2.98(m,1H),2.41-1.79(m,10H).
实施例80：1-(8-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-6-烯-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)-2-氟-6-羟基萘-1-基)乙-1-酮
Example 80: 1-(8-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-6-en-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-2-fluoro-6-hydroxynaphthalen-1-yl ) Ethan-1-one
第一步：化合物2,5-二氢-1H-吡咯-1-羧酸叔丁酯(145g，856mmol)溶于丙酮(580mL)和水(145mL)中，0℃和氮气保护下加入二水合锇酸钾(320mg，0.87mmol)和N-甲基吗啡啉氧化物(151g，1294mmol)，反应在20℃搅拌16小时。反应液在0℃下用饱和的硫代硫酸钠(2500mL)淬灭，1M盐调节pH为5，乙酸乙酯(2L*3)萃取，合并有机相，用饱和碳酸氢钠(1L)和饱和食盐水(1L)洗涤，硫酸钠干燥，过滤，减压浓缩得到黄色油状化合物3,4-二羟基吡咯烷-1-羧酸叔丁酯(120g，590mmol，收率69％)。1H NMR(400MHz,CDCl3)δppm 4.24(m,2H),3.58(m 2H),3.35(m,2H),1.47(s,9H).Step 1: Compound 2,5-dihydro-1H-pyrrole-1-carboxylic acid tert-butyl ester (145g, 856mmol) was dissolved in acetone (580mL) and water (145mL), and potassium osmate dihydrate (320mg, 0.87mmol) and N-methylmorpholine oxide (151g, 1294mmol) were added under nitrogen protection at 0°C, and the reaction was stirred at 20°C for 16 hours. The reaction solution was quenched with saturated sodium thiosulfate (2500 mL) at 0°C, adjusted to pH 5 with 1M salt, extracted with ethyl acetate (2 L*3), combined organic phases, washed with saturated sodium bicarbonate (1 L) and saturated brine (1 L), dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain yellow oily compound 3,4-dihydroxypyrrolidine-1-carboxylated tert-butyl ester (120 g, 590 mmol, yield 69%). 1 H NMR (400MHz, CDCl 3 ) δppm 4.24(m,2H),3.58(m 2H),3.35(m,2H),1.47(s,9H).
第二步：化合物3,4-二羟基吡咯烷-1-羧酸叔丁酯(115g，565mmol)溶于四氢呋喃(575mL)和水(230mL)中，0℃下加入高碘酸钠(157g，735mmol)，反应在20℃搅拌16小时。反应液在0℃下用亚硫酸钠(125g)的水(1L)溶液淬灭，乙酸乙酯(2L*3)萃取，合并有机相，用饱和碳酸氢钠(1L)和饱和食盐水(1L)洗涤，硫酸钠干燥，过滤，减压浓缩得到双(2-氧代乙基)氨基甲酸叔丁酯(108g，537umol，收率95％)。1H NMR(400MHz,CDCl3)δppm 9.59(s,1H),9.58(s,1H),4.11(s,2H),3.90(s,2H),1.38(s,9H).The second step: the compound 3,4-dihydroxypyrrolidine-1-carboxylic acid tert-butyl ester (115g, 565mmol) was dissolved in tetrahydrofuran (575mL) and water (230mL), sodium periodate (157g, 735mmol) was added at 0°C, and the reaction was stirred at 20°C for 16 hours. The reaction solution was quenched with a solution of sodium sulfite (125g) in water (1L) at 0°C, extracted with ethyl acetate (2L*3), combined the organic phases, washed with saturated sodium bicarbonate (1L) and saturated brine (1L), dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain tert-butyl bis(2-oxoethyl)carbamate (108g, 537umol, yield 95%). 1 H NMR (400MHz, CDCl 3 ) δppm 9.59(s,1H), 9.58(s,1H), 4.11(s,2H), 3.90(s,2H), 1.38(s,9H).
第三步：-70℃下，向乙烯基溴化镁(1M的四氢呋喃溶液，1250mL，1250mmol)中加入化合物双(2-氧代乙基)氨基甲酸叔丁酯(50.0g，248mmol)的四氢呋喃(108mL)溶液，反应在20℃搅拌16小时。将2个批次的该反应合并，在0℃下用饱和氯化铵(1500mL)淬灭，乙酸乙酯(2L* 3)萃取，合并有机相，用饱和碳酸氢钠(1L)和饱和食盐水(1L)洗涤，硫酸钠干燥，过滤，减压浓缩，残余物用快速柱色谱纯化(硅胶，0-30％梯度的乙酸乙酯/石油醚)得到黄色油状双(2-羟基丁-3-烯-1-基)氨基甲酸叔丁酯(32.0g，124mmol，收率25％)。1H NMR(400MHz,CDCl3)δppm 5.87-5.66(m,2H),5.37-5.19(m,2H),5.10(m,2H),4.52-4.09(m,2H),3.83-2.77(m,4H),1.43-1.36(m,9H).The third step: at -70°C, a tetrahydrofuran (108mL) solution of compound bis(2-oxoethyl)carbamate tert-butyl (50.0g, 248mmol) was added to vinylmagnesium bromide (1M solution in tetrahydrofuran, 1250mL, 1250mmol), and the reaction was stirred at 20°C for 16 hours. The 2 batches of this reaction were combined, quenched with saturated ammonium chloride (1500 mL) at 0 °C, ethyl acetate (2 L* 3) extraction, combined organic phases, washed with saturated sodium bicarbonate (1 L) and saturated brine (1 L), dried over sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by flash column chromatography (silica gel, 0-30% gradient ethyl acetate/petroleum ether) to obtain yellow oily bis(2-hydroxybut-3-en-1-yl)carbamate tert-butyl ester (32.0 g, 124 mmol, yield 25%). 1 H NMR (400MHz, CDCl 3 ) δppm 5.87-5.66(m,2H),5.37-5.19(m,2H),5.10(m,2H),4.52-4.09(m,2H),3.83-2.77(m,4H),1.43-1.36(m,9H).
第四步：将化合物双(2-羟基丁-3-烯-1-基)氨基甲酸叔丁酯(31.0g，120mmol)溶于二氯甲烷(320mL)，0℃下加入三氯乙腈(52.1g，361mmol)和1.8-二氮杂二环[5.4.0]十一烷-7-烯(9.00mL，60.2mmol)，反应在0℃搅拌1小时。反应液减压浓缩，残余物用快速柱色谱纯化(硅胶，6％梯度的乙酸乙酯/石油醚)得到黄色油状化合物((叔丁氧基羰基)氮杂二基)双(丁-3-烯-1,2-二基)双(2,2,2-三氯乙酰亚胺酯)(44.0g，80.6mmol，收率67％)。1H NMR(400MHz,CDCl3)δppm 8.30(s,2H),5.84-5.69(m,2H),5.64-5.50(m,2H),5.42-5.28(m,2H),5.26-5.14(m,2H),3.80-3.69(m,1H),3.65-3.50(m,2H),3.43-3.31(m,1H),1.42-1.39(m,9H).The fourth step: the compound tert-butyl bis(2-hydroxybut-3-en-1-yl)carbamate (31.0g, 120mmol) was dissolved in dichloromethane (320mL), trichloroacetonitrile (52.1g, 361mmol) and 1.8-diazabicyclo[5.4.0]undec-7-ene (9.00mL, 60.2mmol) were added at 0°C, and the reaction was stirred at 0°C for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was purified by flash column chromatography (silica gel, 6% gradient ethyl acetate/petroleum ether) to obtain a yellow oil compound ((tert-butoxycarbonyl)azadiyl)bis(but-3-ene-1,2-diyl)bis(2,2,2-trichloroacetimidate) (44.0 g, 80.6 mmol, yield 67%). 1 H NMR (400MHz, CDCl 3 ) δppm 8.30(s,2H),5.84-5.69(m,2H),5.64-5.50(m,2H),5.42-5.28(m,2H),5.26-5.14(m,2H),3.80-3.69(m,1H),3.65-3.50( m,2H),3.43-3.31(m,1H),1.42-1.39(m,9H).
第五步：将化合物2-苯基丙-2-胺(13.1g，96.7mmol)溶于二氯乙烷(100mL)，0℃和氮气保护下加入1,5-环辛二烯氯化铱二聚体(2.71g，4.03mmol)和((叔丁氧基羰基)氮杂二基)双(丁-3-烯-1,2-二基)双(2,2,2-三氯乙酰亚胺酯)(44g，80.6mmol)的二氯乙烷(350mL)溶液，反应在0℃搅拌2小时，然后升温到20℃搅拌16小时。反应液减压浓缩，残余物用快速柱色谱纯化(硅胶，0-3％梯度的乙酸乙酯/石油醚)得到黄色油状化合物(3S,5R)-4-(2-苯基丙-2-基)-3,5-二乙烯基哌嗪-1-羧酸叔丁酯(22.0g，61.7mmol，收率77％)。1H NMR(400MHz,CDCl3)δppm 7.56(dd,J＝1.0,8.3Hz,2H),7.32(t,J＝7.6Hz,2H),7.26-7.16(m,1H),6.05-5.92(m,2H),5.18-5.06(m,2H),5.01(d,J＝10.4Hz,2H),3.64-3.48(m,4H),3.35(br t,J＝13.8Hz,2H),1.49-1.45(m,15H).The fifth step: the compound 2-phenylpropan-2-amine (13.1g, 96.7mmol) was dissolved in dichloroethane (100mL), and 1,5-cyclooctadiene iridium chloride dimer (2.71g, 4.03mmol) and ((tert-butoxycarbonyl)azadiyl)bis(but-3-ene-1,2-diyl)bis(2,2,2-trichloroacetimidate) ( 44 g, 80.6 mmol) in dichloroethane (350 mL), the reaction was stirred at 0°C for 2 hours, then warmed to 20°C and stirred for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by flash column chromatography (silica gel, 0-3% gradient ethyl acetate/petroleum ether) to obtain yellow oily compound (3S,5R)-4-(2-phenylpropan-2-yl)-3,5-divinylpiperazine-1-carboxylic acid tert-butyl ester (22.0 g, 61.7 mmol, yield 77%). 1 H NMR (400MHz, CDCl 3 ) δppm 7.56(dd,J=1.0,8.3Hz,2H),7.32(t,J=7.6Hz,2H),7.26-7.16(m,1H),6.05-5.92(m,2H),5.18-5.06(m,2H),5.01(d,J=10.4 Hz,2H),3.64-3.48(m,4H),3.35(br t,J＝13.8Hz,2H),1.49-1.45(m,15H).
第六步：将化合物(3S,5R)-4-(2-苯基丙-2-基)-3,5-二乙烯基哌嗪-1-羧酸叔丁酯(22.0g，61.7mmol)溶于甲苯(510mL)，氮气下加入(1,3-双(2,4,6-三甲基苯基)-2-咪唑亚烷基)二氯(苯基亚甲基)(三环己基膦)钌(2.62g，3.09mmol)，反应在120℃搅拌16小时。反应液减压浓缩，残余物用快速柱色谱纯化(硅胶，0-4％梯度的乙酸乙酯/石油醚)得到白色固体化合物(1R,5S)-8-(2-苯基丙-2-基)-3,8-二氮杂双环[3.2.1]辛-6-烯-3-羧酸叔丁酯(12.0g，36.4mmol，收率59％)。LCMS(ESI):[M+H]+＝329.1；1H NMR(400MHz,CDCl3)δppm 7.51(br d,J＝7.9Hz,2H),7.29-7.21(m,2H),7.15(br d,J＝7.4Hz,1H),5.96-5.83(m,2H),3.62-3.49(m,2H),3.48-3.36(m,2H),3.02(ddd,J＝2.4,11.6,17.9Hz,2H),1.34(s,9H),1.18(d,J＝6.1Hz,6H).The sixth step: the compound (3S,5R)-4-(2-phenylpropan-2-yl)-3,5-divinylpiperazine-1-carboxylate tert-butyl ester (22.0g, 61.7mmol) was dissolved in toluene (510mL), and (1,3-bis(2,4,6-trimethylphenyl)-2-imidazolylene)dichloro(phenylmethylene)(tricyclohexylphosphine)ruthenium (2.62g, 3. 09 mmol), the reaction was stirred at 120 °C for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by flash column chromatography (silica gel, 0-4% gradient ethyl acetate/petroleum ether) to obtain (1R,5S)-8-(2-phenylpropan-2-yl)-3,8-diazabicyclo[3.2.1]oct-6-ene-3-carboxylic acid tert-butyl ester (12.0 g, 36.4 mmol, yield 59%) as a white solid. LCMS (ESI): [M+H] + = 329.1; 1 H NMR (400MHz, CDCl 3 ) δppm 7.51 (br d, J = 7.9Hz, 2H), 7.29-7.21 (m, 2H), 7.15 (br d, J = 7.4Hz, 1H), 5.96-5.83 (m, 2H), 3.62-3.49 (m,2H),3.48-3.36(m,2H),3.02(ddd,J=2.4,11.6,17.9Hz,2H),1.34(s,9H),1.18(d,J=6.1Hz,6H).
第七步：将化合物(1R,5S)-8-(2-苯基丙-2-基)-3,8-二氮杂双环[3.2.1]辛-6-烯-3-羧酸叔丁酯(600mg，1.83mmol)和2,6-二甲基吡啶(590mg，5.48mmol)溶于二氯甲烷(10mL)，0℃下加入三甲硅基三氟甲磺酸酯(810mg，3.65mmol)，反应在0℃搅拌1小时。在0℃下用饱和碳酸氢钠溶液(10mL)淬灭，混合物用乙酸乙酯(10mL*3)萃取，合并的有机相用饱和食盐水(10mL)洗涤，硫酸钠干燥，过滤，减压浓缩，残余物用快速柱色谱纯化(硅胶，0-10％梯度的甲醇/二氯甲烷)得到黄色油状化合物(1R,5S)-8-(2-苯基丙-2-基)-3,8-二氮杂双环[3.2.1]辛-6-烯(560mg，1.72mmol，收率94％)。LCMS(ESI):[M+H]+＝229.1；1H NMR(400MHz,CDCl3)δppm 7.59-7.50(m,2H),7.35(t,J＝7.6Hz,2H),7.29-7.22(m,1H),6.16(s,2H),3.68(s,2H),3.14(dd,J＝2.0,11.9Hz,2H),2.81(dd,J＝1.7,11.9Hz,2H),1.26(s,6H).Step 7: Dissolve the compound (1R,5S)-8-(2-phenylpropan-2-yl)-3,8-diazabicyclo[3.2.1]oct-6-ene-3-carboxylic acid tert-butyl ester (600mg, 1.83mmol) and 2,6-lutidine (590mg, 5.48mmol) in dichloromethane (10mL), and add trimethylsilyl trifluoromethanesulfonate (810mg, 3.65 mmol), and the reaction was stirred at 0 °C for 1 hour. Quenched with saturated sodium bicarbonate solution (10 mL) at 0°C, the mixture was extracted with ethyl acetate (10 mL*3), the combined organic phases were washed with saturated brine (10 mL), dried over sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by flash column chromatography (silica gel, 0-10% gradient of methanol/dichloromethane) to give compound (1R,5S)-8-(2-phenylpropan-2-yl)-3,8-diazabicyclo[3.2.1 ] Oct-6-ene (560 mg, 1.72 mmol, 94% yield). LCMS (ESI): [M+H] + = 229.1; 1 H NMR (400MHz, CDCl 3 ) δppm 7.59-7.50 (m, 2H), 7.35 (t, J = 7.6Hz, 2H), 7.29-7.22 (m, 1H), 6.16 (s, 2H), 3.68 (s, 2H), 3.14 (dd, J=2.0,11.9Hz,2H),2.81(dd,J=1.7,11.9Hz,2H),1.26(s,6H).
第八步：将化合物2,4,7-三氯-8-氟吡啶并[4,3-d]嘧啶(3.00g，11.88mmol)和三氟乙醇(1.43g， 14.26mmol)溶于甲苯(60mL)，0℃加入叔丁醇钠(1.14g，11.88mmol)，混合物0℃搅拌2小时。反应液通过硅藻土过滤，滤饼用乙酸乙酯(30mL*3)洗涤，滤液用饱和食盐水(50mL*2)洗涤，硫酸钠干燥，过滤，减压浓缩得到2,7-二氯-8-氟-4-(2,2,2-三氟乙氧基)吡啶并[4,3-d]嘧啶(纯度70％，3.76g，8.31mmol，收率70％)。LCMS(ESI):[M+H]+＝315.8.The eighth step: Compound 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (3.00g, 11.88mmol) and trifluoroethanol (1.43g, 14.26mmol) was dissolved in toluene (60mL), sodium tert-butoxide (1.14g, 11.88mmol) was added at 0°C, and the mixture was stirred at 0°C for 2 hours. The reaction solution was filtered through diatomaceous earth, the filter cake was washed with ethyl acetate (30mL*3), the filtrate was washed with saturated brine (50mL*2), dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain 2,7-dichloro-8-fluoro-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (purity 70%, 3.76g, 8.31mmol, yield 70%). LCMS (ESI): [M+H] + = 315.8.
第九步：将化合物((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲醇(0.710g，4.43mmol)，二异丙基乙胺(0.790mL，4.43mmol)和4A分子筛(1g)混合于甲基四氢呋喃(10mL)中，0℃加入2,7-二氯-8-氟-4-(2,2,2-三氟乙氧基)吡啶并[4,3-d]嘧啶(纯度70％，1.00g，2.21mmol)。反应体系升温到25℃反应1小时。将3个批次的反应混合，过滤，滤液减压浓缩，残余物用快速柱色谱纯化(硅胶，0-10％梯度的甲醇/二氯甲烷)得黄色油状化合物7-氯-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-4-(2,2,2-三氟乙氧基)吡啶并[4,3-d]嘧啶(纯度75％，3.00g，5.10mmol，收率77％)。LCMS(ESI):[M+H]+＝439.0.Step 9: Mix the compound ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol (0.710g, 4.43mmol), diisopropylethylamine (0.790mL, 4.43mmol) and 4A molecular sieve (1g) in methyl tetrahydrofuran (10mL), add 2,7-dichloro-8-fluoro-4-(2,2,2- Trifluoroethoxy)pyrido[4,3-d]pyrimidine (70% purity, 1.00 g, 2.21 mmol). The temperature of the reaction system was raised to 25° C. for 1 hour. The 3 batches of reactions were mixed, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by flash column chromatography (silica gel, 0-10% gradient of methanol/dichloromethane) to obtain a yellow oily compound 7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (purity 75%, 3.00 g, 5.10 mmol, yield 77%). LCMS (ESI): [M+H] + = 439.0.
第十步：向化合物7-氯-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-4-(2,2,2-三氟乙氧基)吡啶并[4,3-d]嘧啶(75％纯度，2.75g，4.69mmol)的二氧六环(60mL)溶液中，加入((2-氟-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)三异丙基硅烷(3.21g，6.27mmol)和碳酸铯(1.5M的水溶液，12.5mL，18.80mmol)，氮气氛围下加入氯[(正丁基二(1-金刚烷基)膦)-2-(2-氨基联苯)]钯(II)(419mg，0.63mmol)，反应液在80℃搅拌3小时。反应液减压浓缩，残余物用快速柱色谱纯化(硅胶，0-10％梯度的甲醇/二氯甲烷)，得到的粗品用快速柱色谱纯化(C18,0-60％梯度的乙腈/水(含1％甲酸))得黄色固体化合物8-氟-7-(7-氟-3-(甲氧基甲氧基)-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)-4-(2,2,2-三氟乙氧基)吡啶并[4,3-d]嘧啶(1.50g，1.90mmol，收率40％)。LCMS(ESI):[M+H]+＝789.3.1H NMR(400MHz,CDCl3)δppm 9.27(d,J＝2.3Hz,1H),7.82(dd,J＝5.6,8.9Hz,1H),7.55(d,J＝2.5Hz,1H),7.38-7.29(m,2H),5.57-5.38(m,1H),5.36-5.29(m,2H),5.27-5.17(m,1H),5.11-4.92(m,1H),4.87-4.51(m,2H),3.85(br s,2H),3.54(s,3H),3.49-3.33(m,1H),3.18(br s,1H),2.66-2.10(m,6H),0.91-0.82(m,18H),0.54(m,3H).Step 10: To compound 7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (75% purity, 2.75g, 4.69mmol) in dioxane (60mL), add ((2-fluoro-6-( Methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (3.21 g, 6.27 mmol) and cesium carbonate (1.5 M in water, 12.5 mL, 18.80 mmol), and chloro[(n-butylbis(1-adamantyl)phosphine)-2-(2-aminobiphenyl)]palladium was added under nitrogen atmosphere (II) (419mg, 0.63mmol), the reaction solution was stirred at 80°C for 3 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by flash column chromatography (silica gel, 0-10% gradient methanol/dichloromethane), and the obtained crude product was purified by flash column chromatography (C18, 0-60% gradient acetonitrile/water (containing 1% formic acid)) to obtain yellow solid compound 8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalene-1-yl)-2-(((2R,7aS )-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (1.50 g, 1.90 mmol, 40% yield). LCMS(ESI):[M+H] + ＝789.3. 1 H NMR(400MHz,CDCl 3 )δppm 9.27(d,J＝2.3Hz,1H),7.82(dd,J＝5.6,8.9Hz,1H),7.55(d,J＝2.5Hz,1H),7.38-7.29(m,2H),5.57-5.38(m,1H),5.36-5.29(m,2H),5.27-5.17(m,1H),5.11-4.92(m,1H),4.87-4.51(m,2H),3.85(br s,2H),3.54(s,3H),3.49-3.33(m,1H),3.18(br s,1H),2.66-2.10(m,6H),0.91-0.82(m,18H),0.54(m,3H).
第十一步：化合物8-氟-7-(7-氟-3-(甲氧基甲氧基)-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)-4-(2,2,2-三氟乙氧基)吡啶并[4,3-d]嘧啶(250mg，0.32mmol)溶于四氢呋喃(2.50mL)中，加入氢氧化钠(44.0mg，1.09mmol)的水(2.50mL)溶液，反应液在25℃搅拌16小时。向反应液加入乙酸(60uL)，二氯甲烷(5mL*3)萃取，有机相用饱和食盐水(5mL)洗涤，硫酸钠干燥，减压浓缩，残余物用快速柱色谱纯化(硅胶，0-10％梯度的甲醇/二氯甲烷)得黄色固体化合物8-氟-7-(7-氟-3-(甲氧基甲氧基)-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-醇(224mg，0.21mmol，收率67％)。LCMS(ESI):[M+H]+＝707.2.Step 11: Compound 8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalene-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (250mg, 0.3 2mmol) was dissolved in tetrahydrofuran (2.50mL), a solution of sodium hydroxide (44.0mg, 1.09mmol) in water (2.50mL) was added, and the reaction solution was stirred at 25°C for 16 hours. Acetic acid (60uL) was added to the reaction solution, dichloromethane (5mL*3) was extracted, the organic phase was washed with saturated brine (5mL), dried over sodium sulfate, concentrated under reduced pressure, and the residue was purified by flash column chromatography (silica gel, 0-10% gradient methanol/dichloromethane) to obtain the yellow solid compound 8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalene-1-yl)-2-(((2 R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-ol (224 mg, 0.21 mmol, 67% yield). LCMS (ESI): [M+H] + = 707.2.
第十二步：将化合物8-氟-7-(7-氟-3-(甲氧基甲氧基)-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-醇(230mg，0.33mmol)，(1R,5S)-8-(2-苯基丙-2-基)-3,8-二氮杂双环[3.2.1]辛-6-烯(223mg，0.98mmol)和二异丙基乙胺(566uL，3.25mmol)溶于二甲基乙酰胺(2.3mL)，0℃下加入苯并三唑-1-氧代-三(二甲氨基磷)六氟磷盐(287mg，0.65mmol)，反应在50℃搅拌2小时。在0℃下用饱和碳酸氢钠(10mL)淬灭，混合物用乙酸乙酯(10mL*3)萃取，合并的有机相用饱和食盐水(10mL)洗涤，硫酸钠干燥，过滤， 减压浓缩得到粗品化合物8-氟-7-(7-氟-3-((甲氧基甲氧基)-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)-4-((1R,5S)-8-(2-苯基丙-2-基)-3,8-二氮杂双环[3.2.1]辛-6-烯-3-基)吡啶并[4,3-d]嘧啶(300mg)，其为黄色油状液体。LCMS(ESI):[M+H]+＝916.9；The twelfth step: the compound 8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalene-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-ol (230mg, 0.33mmol), (1R,5 S)-8-(2-phenylprop-2-yl)-3,8-diazabicyclo[3.2.1]oct-6-ene (223mg, 0.98mmol) and diisopropylethylamine (566uL, 3.25mmol) were dissolved in dimethylacetamide (2.3mL), and benzotriazole-1-oxo-tris(dimethylaminophosphorus) hexafluorophosphonium salt (287mg, 0.65mmol) was added at 0°C, The reaction was stirred at 50°C for 2 hours. Quenched with saturated sodium bicarbonate (10 mL) at 0°C, the mixture was extracted with ethyl acetate (10 mL*3), the combined organic phases were washed with saturated brine (10 mL), dried over sodium sulfate, filtered, Concentration under reduced pressure gave the crude compound 8-fluoro-7-(7-fluoro-3-((methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalene-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4-((1R,5S)-8-(2-phenylpropan-2-yl)-3,8-diazabis Cyclo[3.2.1]oct-6-en-3-yl)pyrido[4,3-d]pyrimidine (300 mg) as a yellow oily liquid. LCMS (ESI): [M+H] + =916.9;
第十三步：化合物8-氟-7-(7-氟-3-((甲氧基甲氧基)-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)-4-((1R,5S)-8-(2-苯基丙-2-基)-3,8-二氮杂双环[3.2.1]辛-6-烯-3-基)吡啶并[4,3-d]嘧啶(300mg，0.33mmol)加入到N,N-二甲基甲酰胺(2mL)中，加入氟化铯(500mg，3.27mmol)，20℃搅拌1小时。反应液加入水(1500uL)稀释，用乙酸乙酯(3mL*3)萃取，有机相减压浓缩，残余物用快速柱色谱纯化(硅胶，0-10％梯度的甲醇/二氯甲烷)得到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-吡咯嗪-7a(5H)-基)甲氧基)-4-((1R,5S)-8-(2-苯基丙-2-基)-3,8-二氮杂双环[3.2.1]辛-6-烯-3-基)吡啶并[4,3-d]嘧啶(240mg，0.32mmol，收率96％)。LCMS(ESI):[M+H]+＝760.9.The thirteenth step: Compound 8-fluoro-7-(7-fluoro-3-((methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalene-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4-((1R,5S)-8-(2-phenylpropan-2-yl)-3,8-diazabicyclo[ 3.2.1] Oct-6-en-3-yl)pyrido[4,3-d]pyrimidine (300mg, 0.33mmol) was added to N,N-dimethylformamide (2mL), cesium fluoride (500mg, 3.27mmol) was added, and stirred at 20°C for 1 hour. The reaction solution was diluted with water (1500uL), extracted with ethyl acetate (3mL*3), the organic phase was concentrated under reduced pressure, and the residue was purified by flash column chromatography (silica gel , 0-10% gradient of methanol/dichloromethane) to give 7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4-((1R,5S)-8-(2-phenylpropan-2-yl)-3,8-diazabicyclo[3. 2.1] Oct-6-en-3-yl)pyrido[4,3-d]pyrimidine (240 mg, 0.32 mmol, yield 96%). LCMS (ESI): [M+H]+=760.9.
第十四步：化合物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-吡咯嗪-7a(5H)-基)甲氧基)-4-((1R,5S)-8-(2-苯基丙-2-基)-3,8-二氮杂双环[3.2.1]辛-6-烯-3-基)吡啶并[4,3-d]嘧啶(190mg，0.25mmol)加入到三氟乙酸(1.9mL)中，50℃搅拌1小时。反应液减压浓缩，残留物加入乙腈(500uL)，加入三乙胺调节pH到8，溶液用制备型HPLC纯化，得到红色固体化合物1-(8-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-6-烯-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)-2-氟-6-羟基萘-1-基)乙-1-酮(二甲酸盐，16.06mg，23umol，收率9％)。LCMS(ESI):[M+H]+＝617.2；1H NMR(400MHz,CD3OD)δppm 9.09(s,1H),8.46(br s,2H),8.00-7.91(m,1H),7.40-7.33(m,2H),7.30(s,1H),6.35(s,2H),5.63-5.46(m,1H),4.76-4.65(m,2H),4.65-4.55(m,2H),4.36(br s,2H),4.05-3.92(m,2H),3.88-3.68(m,3H),3.40(br dd,J＝4.5,10.0Hz,1H),2.72-2.48(m,2H),2.43-2.14(m,7H).Step 14: Compound 7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4-((1R,5S)-8-(2-phenylpropan-2-yl)-3,8-diazabicyclo[3.2.1]oct-6-ene- 3-yl)pyrido[4,3-d]pyrimidine (190mg, 0.25mmol) was added into trifluoroacetic acid (1.9mL), and stirred at 50°C for 1 hour. The reaction solution was concentrated under reduced pressure, the residue was added to acetonitrile (500uL), and triethylamine was added to adjust the pH to 8. The solution was purified by preparative HPLC to obtain a red solid compound 1-(8-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-6-en-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl )methoxy)pyrido[4,3-d]pyrimidin-7-yl)-2-fluoro-6-hydroxynaphthalen-1-yl)ethan-1-one (diformate salt, 16.06mg, 23umol, yield 9%). LCMS(ESI):[M+H] + ＝617.2； 1 H NMR(400MHz,CD 3 OD)δppm 9.09(s,1H),8.46(br s,2H),8.00-7.91(m,1H),7.40-7.33(m,2H),7.30(s,1H),6.35(s,2H),5.63-5.46(m,1H),4.76-4.65(m,2H),4.65-4.55(m,2H),4.36(br s,2H),4.05-3.92(m,2H),3.88-3.68(m,3H),3.40(br dd,J＝4.5,10.0Hz,1H),2.72-2.48(m,2H),2.43-2.14(m,7H).
实施例81：9-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基))-8-氟-2-(((2R,7aR)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲基)吡啶并[4,3-d]嘧啶-7-基)-2,3-二氢-1H-环戊[a]萘-7-醇
Example 81: 9-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl))-8-fluoro-2-(((2R,7aR)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methyl)pyrido[4,3-d]pyrimidin-7-yl)-2,3-dihydro-1H-cyclopenta[a]naphthalene-7- Alcohol
第一步:向4-氟-5-溴-1-茚酮(10.00g,43.22mmol)的三氟乙酸(10mL)溶液中加入三乙基硅烷(50.77g,432.22mmol),反应液加热至80℃搅拌16小时。反应液冷却至室温后，用饱和碳酸氢钠水溶液将pH调至7，乙酸乙酯(100mL X 3)萃取。合并有机相，无水硫酸钠干燥，浓缩得残余物。残余物快速柱色 谱(硅胶，0-4％梯度的乙酸乙酯/石油醚)得5-溴-4-氟-2,3-二氢-1H-茚化合物无色油状液体(8.00g,86％)；1H NMR(400MHz,CD3Cl)δppm 7.29(t,J＝8.0Hz,1H),6.87(d,J＝8.0Hz,1H),2.99-2.88(m,4H),2.16-2.09(m,2H).Step 1: Triethylsilane (50.77 g, 432.22 mmol) was added to a solution of 4-fluoro-5-bromo-1-indanone (10.00 g, 43.22 mmol) in trifluoroacetic acid (10 mL), and the reaction solution was heated to 80°C and stirred for 16 hours. After the reaction solution was cooled to room temperature, the pH was adjusted to 7 with saturated aqueous sodium bicarbonate solution, and extracted with ethyl acetate (100 mL X 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to obtain a residue. Residue Fast Column Chromatography Spectrum (silica gel, 0-4% gradient of ethyl acetate/petroleum ether) gave 5-bromo-4-fluoro-2,3-dihydro-1H-indene compound as a colorless oily liquid (8.00g, 86%); 1 H NMR (400MHz, CD 3 Cl) δppm 7.29 (t, J = 8.0Hz, 1H), 6.87 (d, J = 8.0Hz, 1H), 2.99-2.8 8(m,4H),2.16-2.09(m,2H).
第二步:氮气保护下，5-溴-4-氟-2,3-二氢-1H-茚(8.00g,37.20mmol)，呋喃(12.79g,186.00mmol)加到甲苯(50mL)中。反应液冷却至零下30℃。正丁基锂(1.6M,25.57mL)缓慢滴加至反应液。滴加完后，反应液升温至25℃搅拌18小时。反应液加入水(50mL),乙酸乙酯(50mL x 3)萃取，合并有机相，无水硫酸钠干燥，浓缩得残余物。残余物快速柱色谱(硅胶，0-9％梯度的乙酸乙酯/石油醚)得2,3,6,9-四氢-1H-6,9-环氧环戊并[a]萘化合物棕红色固体(5.30g,77％)。Step 2: Under nitrogen protection, 5-bromo-4-fluoro-2,3-dihydro-1H-indene (8.00g, 37.20mmol) and furan (12.79g, 186.00mmol) were added to toluene (50mL). The reaction solution was cooled to minus 30°C. n-Butyllithium (1.6M, 25.57mL) was slowly added dropwise to the reaction solution. After the dropwise addition, the temperature of the reaction solution was raised to 25° C. and stirred for 18 hours. Add water (50mL) to the reaction solution, extract with ethyl acetate (50mL x 3), combine the organic phases, dry over anhydrous sodium sulfate, and concentrate to obtain a residue. Flash column chromatography (silica gel, 0-9% gradient of ethyl acetate/petroleum ether) of the residue gave 2,3,6,9-tetrahydro-1H-6,9-epoxycyclopenta[a]naphthalene as a brown-red solid (5.30 g, 77%).
第三步:向2,3,6,9-四氢-1H-6,9-环氧环戊并[a]萘(5.30g,28.77mmol)的乙醇(20mL)溶液中加入浓盐酸(10mL,12M)。反应液加热至85℃搅拌2小时。反应液冷却至室温后，用氢氧化钠固体缓慢将pH调至6，乙酸乙酯(50mLx3)萃取，合并有机相，浓缩得残余物。残余物快速柱色谱(硅胶，0-9％梯度的乙酸乙酯/石油醚)得2,3-二氢-1H-环戊二[a]萘-9-醇化合物棕色固体(2.70g,51％)。Step 3: To a solution of 2,3,6,9-tetrahydro-1H-6,9-epoxycyclopenta[a]naphthalene (5.30 g, 28.77 mmol) in ethanol (20 mL) was added concentrated hydrochloric acid (10 mL, 12M). The reaction solution was heated to 85°C and stirred for 2 hours. After the reaction solution was cooled to room temperature, the pH was slowly adjusted to 6 with solid sodium hydroxide, extracted with ethyl acetate (50 mL×3), the organic phases were combined, and concentrated to obtain a residue. Flash column chromatography (silica gel, 0-9% gradient of ethyl acetate/petroleum ether) of the residue gave 2,3-dihydro-1H-cyclopentadi[a]naphthalene-9-ol as a brown solid (2.70 g, 51%).
第四步:向2,3-二氢-1H-环戊二[a]萘-9-醇(3.30g,17.91mmol)的二氯甲烷(20mL)溶液中加入N,N-二异丙基乙胺(5.90g,44.78mmol),反应液冷却至0℃。溴(甲氧基)甲烷(5.59g,44.78mmol)缓慢加至反应液，加完后，反应液0℃继续搅拌1小时。反应液倒入水(50mL)，乙酸乙酯(50mL x 3)萃取，合并有机相，无水硫酸钠干燥，浓缩得残余物。残余物快速柱色谱(硅胶，0-5％梯度的乙酸乙酯/石油醚)得9-(甲氧基甲氧基)-2,3-二氢-1H-环戊[a]萘化合物白色固体(2.70g,17.91mmol)。Step 4: Add N,N-diisopropylethylamine (5.90 g, 44.78 mmol) to a solution of 2,3-dihydro-1H-cyclopentadi[a]naphthalene-9-ol (3.30 g, 17.91 mmol) in dichloromethane (20 mL), and cool the reaction solution to 0°C. Bromo(methoxy)methane (5.59 g, 44.78 mmol) was slowly added to the reaction solution. After the addition was complete, the reaction solution was stirred at 0° C. for 1 hour. The reaction solution was poured into water (50 mL), extracted with ethyl acetate (50 mL x 3), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to obtain a residue. Flash column chromatography (silica gel, 0-5% gradient of ethyl acetate/petroleum ether) of the residue gave 9-(methoxymethoxy)-2,3-dihydro-1H-cyclopenta[a]naphthalene as a white solid (2.70 g, 17.91 mmol).
第五步:氮气保护下，9-(甲氧基甲氧基)-2,3-二氢-1H-环戊[a]萘(2.70g,11.83mmol),甲氧基(环辛二烯)合铱二聚体(380mg,0.591mmol),频哪醇硼烷(3.09g,23.65mmol),4,4'-二叔丁基-2,2'-二吡啶(393mg,1.42mmol)加到正己烷(6mL)中，加热至85℃反应16小时。反应冷却至室温后，倒入水(50mL)，乙酸乙酯(50mL x 3)萃取，合并有机相，浓缩得残留物。残余物快速柱色谱(硅胶，0-9％梯度的乙酸乙酯/石油醚)得2-(9-(甲氧基甲氧基)-2,3-二氢-1H-环戊[a]萘-7-基)-4,4,5,5-四甲基-1,3,2-二氧硼烷化合物棕色固体(1.80g,43％)。Step 5: Under nitrogen protection, 9-(methoxymethoxy)-2,3-dihydro-1H-cyclopenta[a]naphthalene (2.70g, 11.83mmol), methoxy(cyclooctadiene) iridium dimer (380mg, 0.591mmol), pinacol borane (3.09g, 23.65mmol), 4,4'-di-tert-butyl-2,2'-dipyridine (393mg , 1.42mmol) was added into n-hexane (6mL), and heated to 85°C for 16 hours. After the reaction was cooled to room temperature, it was poured into water (50 mL), extracted with ethyl acetate (50 mL x 3), the organic phases were combined, and concentrated to obtain a residue. Flash column chromatography (silica gel, 0-9% gradient of ethyl acetate/petroleum ether) of the residue gave 2-(9-(methoxymethoxy)-2,3-dihydro-1H-cyclopenta[a]naphthalene-7-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane as a brown solid (1.80 g, 43%).
第六步:向2-(9-(甲氧基甲氧基)-2,3-二氢-1H-环戊[a]萘-7-基)-4,4,5,5-四甲基-1,3,2-二氧硼烷(1.80g,5.08mmol)的四氢呋喃(5mL)溶液中加入乙酸(3.05g,50.81mmol),双氧水(925mg，50.81mmol，30％)。反应液25℃搅拌2小时。反应液倒入水(30mL)，用氢氧化钠固体将pH调至6，乙酸乙酯(30mL x 3)萃取，合并有机相，无水硫酸钠干燥，浓缩得粗品9-(甲氧基甲氧基)-2,3-二氢-1H-环戊二[a]萘-7-醇化合物棕色固体(1.20g,97％)。LCMS(ESI):[M+H]+＝245.1Step 6: Add acetic acid (3.05 g, 50.81 mmol), hydrogen peroxide (925 mg, 50.81 mmol, 3 0%). The reaction solution was stirred at 25°C for 2 hours. The reaction solution was poured into water (30 mL), the pH was adjusted to 6 with solid sodium hydroxide, extracted with ethyl acetate (30 mL x 3), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to give the crude 9-(methoxymethoxy)-2,3-dihydro-1H-cyclopentadi[a]naphthalene-7-ol compound as a brown solid (1.20 g, 97%). LCMS (ESI): [M+H] + = 245.1
第七步:向9-(甲氧基甲氧基)-2,3-二氢-1H-环戊二[a]萘-7-醇(1.20g,4.91mmol)的二氯甲烷(20mL)溶液中加入N,N-二异丙基乙胺(1.94g,14.74mmol)。反应液冷却至-40℃，乙酰氯(433mg,5.40mmol)缓慢滴加到反应液，滴加完后，反应液零下40℃继续搅拌30分钟。反应液倒入水(30mL)，乙酸乙酯(30mL x 3)萃取，有机相合并，无水硫酸钠干燥，浓缩得残余物。残余物快速柱色谱(硅胶，0-9％梯度的乙酸乙酯/石油醚)得9-(甲氧基甲氧基)-2,3-二氢-1H-环戊二[a]萘-7-乙酸酯化合物白色固体(1.30g,92％)。LCMS(ESI):[M+H]+＝287.1Step Seven: To a solution of 9-(methoxymethoxy)-2,3-dihydro-1H-cyclopentadi[a]naphthalene-7-ol (1.20 g, 4.91 mmol) in dichloromethane (20 mL) was added N,N-diisopropylethylamine (1.94 g, 14.74 mmol). The reaction solution was cooled to -40°C, and acetyl chloride (433mg, 5.40mmol) was slowly added dropwise to the reaction solution. After the dropwise addition, the reaction solution was stirred at minus 40°C for 30 minutes. The reaction solution was poured into water (30 mL), extracted with ethyl acetate (30 mL x 3), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to obtain a residue. Flash column chromatography (silica gel, 0-9% gradient of ethyl acetate/petroleum ether) of the residue gave 9-(methoxymethoxy)-2,3-dihydro-1H-cyclopentadi[a]naphthalene-7-acetate as a white solid (1.30 g, 92%). LCMS (ESI): [M+H] + = 287.1
第八步:9-(甲氧基甲氧基)-2,3-二氢-1H-环戊二[a]萘-7-乙酸酯(1.39g,4.85mmol)加到二氯甲烷(5mL)中，反应液冷却至-65℃。盐酸乙酸乙酯溶液(4M,20mL)缓慢滴加至反应液，滴加完后，-65℃继续搅拌30分钟，然后缓慢升温至0℃，继续搅拌30分钟。反应液直接浓缩得9-羟基-2,3-二氢-1H-环 戊[a]萘-7-乙酸酯化合物棕色固体(1.15g,97％)。LCMS(ESI):[M+H]+＝243.1Step 8: Add 9-(methoxymethoxy)-2,3-dihydro-1H-cyclopentadi[a]naphthalene-7-acetate (1.39g, 4.85mmol) into dichloromethane (5mL), and cool the reaction solution to -65°C. Ethyl acetate hydrochloride solution (4M, 20 mL) was slowly added dropwise to the reaction solution. After the dropwise addition, stirring was continued at -65°C for 30 minutes, and then the temperature was slowly raised to 0°C, and stirring was continued for 30 minutes. The reaction solution was concentrated directly to obtain 9-hydroxyl-2,3-dihydro-1H-cyclo Penta[a]naphthalene-7-acetate compound brown solid (1.15 g, 97%). LCMS (ESI): [M+H] + = 243.1
第九步:9-羟基-2,3-二氢-1H-环戊[a]萘-7-乙酸酯(1.15g,4.75mmol)加到二氯甲烷(10mL)中，反应液冷却至-65℃。N,N-二异丙基乙胺(1.88g,14.24mmol)缓慢加到反应液，反应液-65℃搅拌15分钟。三氟甲磺酸酐(1.60g,5.70mmol)缓慢滴加至反应液，反应液-65℃搅拌30分钟。反应液倒入水(30mL)，乙酸乙酯(30mL x 3)萃取，合并有机相，无水硫酸钠干燥，浓缩得残留物。残余物残余物快速柱色谱(硅胶，0-9％梯度的乙酸乙酯/石油醚)得9-((((三氟甲基)磺酰基)氧基)-2,3-二氢-1H-环戊二[a]萘-7-乙酸酯化合物白色固体(1.05g,59％)。Step 9: Add 9-hydroxy-2,3-dihydro-1H-cyclopenta[a]naphthalene-7-acetate (1.15g, 4.75mmol) into dichloromethane (10mL), and cool the reaction solution to -65°C. N,N-Diisopropylethylamine (1.88g, 14.24mmol) was slowly added to the reaction solution, and the reaction solution was stirred at -65°C for 15 minutes. Trifluoromethanesulfonic anhydride (1.60 g, 5.70 mmol) was slowly added dropwise to the reaction solution, and the reaction solution was stirred at -65°C for 30 minutes. The reaction solution was poured into water (30 mL), extracted with ethyl acetate (30 mL x 3), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to obtain a residue. The residue Flash column chromatography (silica gel, 0-9% gradient of ethyl acetate/petroleum ether) gave 9-((((trifluoromethyl)sulfonyl)oxy)-2,3-dihydro-1H-cyclopentadi[a]naphthalene-7-acetate as a white solid (1.05 g, 59%).
第十步:9-((((三氟甲基)磺酰基)氧基)-2,3-二氢-1H-环戊二[a]萘-7-乙酸酯(1.05g,2.81mmol)加到四氢呋喃(10mL)，水(3mL)溶液中，反应液冷却至0℃。氢氧化锂(0.10g,4.21mmol)加到反应液，反应液0℃继续搅拌30分钟。反应液用乙酸调pH至6，乙酸乙酯(20mL x 3)萃取，有机相饱和氯化钠水溶液(30mL x 3)洗，合并有机相，无水硫酸钠干燥，浓缩得粗品7-羟基-2,3-二氢-1H-环戊二[a]萘-9-基三氟甲磺酸酯化合物白色固体(0.90g,96％)。LCMS(ESI):[M+H]+＝333.1Step 10: 9-((((trifluoromethyl)sulfonyl)oxy)-2,3-dihydro-1H-cyclopentadi[a]naphthalene-7-acetate (1.05g, 2.81mmol) was added to tetrahydrofuran (10mL), water (3mL) solution, and the reaction solution was cooled to 0°C. Lithium hydroxide (0.10g, 4.21mmol) was added to the reaction solution, and the reaction solution was stirred at 0°C for 30 minutes. The reaction solution was adjusted with acetic acid pH to 6, extracted with ethyl acetate (20mL x 3), washed the organic phase with saturated aqueous sodium chloride solution (30mL x 3), combined the organic phases, dried over anhydrous sodium sulfate, concentrated to give the crude product 7-hydroxyl-2,3-dihydro-1H-cyclopentadi[a]naphthalene-9-yl trifluoromethanesulfonate compound as a white solid (0.90g, 96%). LCMS (ESI): [M+H]+=333.1
第十一步:7-羟基-2,3-二氢-1H-环戊二[a]萘-9-基三氟甲磺酸酯(900mg,2.71mmol)加到二氯甲烷(5mL)，反应液冷却至0℃。N,N-二异丙基乙胺(1.07g,8.12mmol)缓慢加至反应液。反应液0℃继续搅拌5分钟。溴(甲氧基)甲烷(508mg,4.06mmol)缓慢加至反应液，反应液0℃搅拌1小时。水(30mL)倒入反应液，乙酸乙酯(30mL x 3)萃取，合并有机相，无水硫酸钠干燥，浓缩得残余物。残余物快速柱色谱(硅胶，0-9％梯度的乙酸乙酯/石油醚)得7-(甲氧基甲氧基)-2,3-二氢-1H-环戊[a]萘-9-基三氟甲磺酸酯化合物(750mg,74％)。Step 11: Add 7-hydroxy-2,3-dihydro-1H-cyclopentadi[a]naphthalene-9-yl trifluoromethanesulfonate (900mg, 2.71mmol) to dichloromethane (5mL), and cool the reaction solution to 0°C. N,N-Diisopropylethylamine (1.07 g, 8.12 mmol) was slowly added to the reaction solution. The reaction solution was stirred at 0°C for 5 minutes. Bromo(methoxy)methane (508mg, 4.06mmol) was slowly added to the reaction solution, and the reaction solution was stirred at 0°C for 1 hour. Water (30 mL) was poured into the reaction solution, extracted with ethyl acetate (30 mL x 3), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to obtain a residue. Flash column chromatography (silica gel, 0-9% gradient of ethyl acetate/petroleum ether) of the residue gave 7-(methoxymethoxy)-2,3-dihydro-1H-cyclopenta[a]naphthalene-9-yl triflate (750 mg, 74%).
第十二步:氮气保护下，7-(甲氧基甲氧基)-2,3-二氢-1H-环戊[a]萘-9-基三氟甲磺酸酯(750mg,1.99mmol)，联硼酸频那醇酯(1.01g,3.98mmol)，[1,1'-双(二苯基膦)二茂铁]二氯化钯(151mg,0.20mmol)，乙酸钾(395mg,3.98mmol)加到N,N-二甲基甲酰胺(3mL)中，反应液加热至100℃搅拌4小时。反应液冷却至室温后抽滤，滤液倒入水(30mL)中，乙酸乙酯(30mL)萃取，饱和氯化钠水溶液(30mL x 3)洗，合并有机相，无水硫酸钠干燥，浓缩得残余物。残余物快速柱色谱(硅胶，0-9％梯度的乙酸乙酯/石油醚)得2-(7-(甲氧基甲氧基)-2,3-二氢-1H-环戊二[a]萘-9-基)-4,4,5,5-四甲基-1,3,2-二氧硼烷化合物白色固体(600mg,85％)。Step 12: Under nitrogen protection, 7-(methoxymethoxy)-2,3-dihydro-1H-cyclopenta[a]naphthalene-9-yl trifluoromethanesulfonate (750mg, 1.99mmol), biboronic acid pinacol ester (1.01g, 3.98mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (151mg, 0.20mmol), potassium acetate (395mg, 3 .98mmol) was added to N,N-dimethylformamide (3mL), and the reaction solution was heated to 100°C and stirred for 4 hours. The reaction solution was cooled to room temperature and suction filtered, the filtrate was poured into water (30mL), extracted with ethyl acetate (30mL), washed with saturated aqueous sodium chloride solution (30mL x 3), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to obtain a residue. Flash column chromatography (silica gel, 0-9% gradient of ethyl acetate/petroleum ether) of the residue gave 2-(7-(methoxymethoxy)-2,3-dihydro-1H-cyclopentadi[a]naphthalene-9-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane as a white solid (600mg, 85%).
第十三步:氮气保护下，2-(7-(甲氧基甲氧基)-2,3-二氢-1H-环戊二[a]萘-9-基)-4,4,5,5-四甲基-1,3,2-二氧硼烷(128mg,0.36mmol)，叔丁基(1R,5S)-3-(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-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(200mg,0.36mmol)，甲磺酸[正丁基二(1-金刚烷基)膦](2-氨基-1,1'-联苯-2-基)钯(II)(26mg,0.04mmol)，磷酸钾(157mg,0.72mmol)加到1,4-二氧六环(2mL)中，反应液加热到95℃搅拌18小时。反应液冷却至室温后，反应液抽滤，滤液制备薄层色谱(二氯甲烷/甲醇＝12/1)纯化得(1R,5S)-3-(8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-7-(7-(甲氧基甲氧基)-2,3-二氢-1H-环戊二[a]萘-9-基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯化合物白色固体(180mg,66％)。LCMS(ESI):[M+H]+＝743.3Step 13: Under nitrogen protection, 2-(7-(methoxymethoxy)-2,3-dihydro-1H-cyclopentadi[a]naphthalene-9-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (128mg, 0.36mmol), tert-butyl (1R,5S)-3-(7-chloro-8-fluoro-2-((((2R,7aS)-2-fluorotetrahydro-1 H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (200mg, 0.36mmol), [n-butylbis(1-adamantyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium(II) methanesulfonate (26mg, 0.04mmol), Potassium phosphate (157 mg, 0.72 mmol) was added to 1,4-dioxane (2 mL), and the reaction solution was heated to 95°C and stirred for 18 hours. After the reaction solution was cooled to room temperature, the reaction solution was filtered with suction, and the filtrate was purified by preparative thin-layer chromatography (dichloromethane/methanol=12/1) to obtain (1R,5S)-3-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazine-7a(5H) -yl)methoxy)-7-(7-(methoxymethoxy)-2,3-dihydro-1H-cyclopentadi[a]naphthalen-9-yl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate compound white solid (180 mg, 66%). LCMS (ESI): [M+H]+=743.3
第十四步:(1R,5S)-3-(8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-7-(7-(甲氧基甲氧基)-2,3-二氢-1H-环戊二[a]萘-9-基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(180mg,0.24mmol)加到盐酸乙酸乙酯(4M,4mL)，反应液0℃下搅拌1小时。反应液浓缩得残余物。残余物快速柱色谱(C18,5-35％乙腈/水，0.5％HCl)得9-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基))-8-氟-2- (((2R,7aR)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲基)吡啶并[4,3-d]嘧啶-7-基)-2,3-二氢-1H-环戊[a]萘-7-醇盐酸盐化合物淡黄色固体(49mg,34％)。LCMS(ESI):[M+H]+＝599.3；1H NMR(400MHz,DMSO)δppm11.61-11.50(m,1H),10.15-10.00(m,1H),9.8(s,1H),9.25(s,1H),7.65-7.55(m,1H),7.40-7.25(m,2H),7.10-7.00(m,1H),5.60-5.50(m,1H),4.79-4.65(m,5H),4.23-4.15(m,3H),4.00-3.75(m,4H),3.30-3.25(m,1H),2.90-2.75(m,2H),2.68-2.63(m,1H),2.50-2.41(m,2H),2.25-1.75(m,11H).The fourteenth step: (1R,5S)-3-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-7-(7-(methoxymethoxy)-2,3-dihydro-1H-cyclopentadi[a]naphthalene-9-yl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3. 2.1] Octane-8-carboxylate (180mg, 0.24mmol) was added to ethyl acetate hydrochloride (4M, 4mL), and the reaction solution was stirred at 0°C for 1 hour. The reaction solution was concentrated to obtain a residue. Flash column chromatography (C18, 5-35% acetonitrile/water, 0.5% HCl) of the residue gave 9-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl))-8-fluoro-2- (((2R,7aR)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methyl)pyrido[4,3-d]pyrimidin-7-yl)-2,3-dihydro-1H-cyclopenta[a]naphthalene-7-ol hydrochloride compound pale yellow solid (49 mg, 34%). LCMS(ESI):[M+H] + ＝599.3； 1 H NMR(400MHz,DMSO)δppm11.61-11.50(m,1H),10.15-10.00(m,1H),9.8(s,1H),9.25(s,1H),7.65-7.55(m,1H),7.40-7.25(m,2H),7.10-7.00(m,1H),5.60-5.50(m,1H),4.79-4.65(m,5H),4.23-4.15(m,3H),4.00-3.75(m,4H),3.30-3.25(m,1H),2.90-2.75(m,2H),2.68-2.63(m,1H),2.50-2.41(m,2H),2.25-1.75(m,11H).
实施例82：4-(10-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-6-氟-8-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)四唑并[1',5':1,2]吡啶并[4,3-d]嘧啶-5-基)-5-乙炔基-6-氟萘-2-醇
Example 82: 4-(10-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-6-fluoro-8-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)tetrazolo[1',5':1,2]pyrido[4,3-d]pyrimidin-5-yl)-5-ethyne yl-6-fluoronaphthalen-2-ol
第一步：向叔丁基(1R,5S)-3-(8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三异丙基甲硅烷基)乙炔基)萘-1-基)-2-(2,2,2-三氟乙氧基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(1.00g，1.19mmol)的二氯甲烷(3.00mL)溶液中加入间氯过氧苯甲酸(85％纯度，844mg，4.16mmol)，将混合物在20℃搅拌16小时。将溶液浓缩，残余物溶于乙酸乙酯(5mL)，用饱和碳酸钾溶液(5mL*3)洗涤，浓缩有机相，残余物用快速柱色谱(硅胶，0-71％梯度的乙酸乙酯/石油醚)纯化，得到黄色固体化合物4-((1R,5S)-8-(叔丁氧基羰基)-3,8-二氮杂双环[3.2.1]辛-3-基)-8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三异丙基甲硅烷基)乙炔基)萘-1-基)-2-(2,2,2-三氟乙氧基)吡啶并[4,3-d]嘧啶6-氧化物(420mg，0.49mmol，收率41％)。LCMS(ESI):[M+H]+＝858.3.The first step: to tert-butyl(1R,5S)-3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalene-1-yl)-2-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.00g , 1.19 mmol) in dichloromethane (3.00 mL) was added m-chloroperoxybenzoic acid (85% purity, 844 mg, 4.16 mmol), and the mixture was stirred at 20° C. for 16 hours. The solution was concentrated, the residue was dissolved in ethyl acetate (5 mL), washed with saturated potassium carbonate solution (5 mL*3), the organic phase was concentrated, and the residue was purified by flash column chromatography (silica gel, 0-71% gradient of ethyl acetate/petroleum ether) to obtain yellow solid compound 4-((1R,5S)-8-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-7-(7-fluoro-3- (Methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine 6-oxide (420 mg, 0.49 mmol, 41% yield). LCMS (ESI): [M+H] + = 858.3.
第二步：将化合物4-((1R,5S)-8-(叔丁氧基羰基)-3,8-二氮杂双环[3.2.1]辛-3-基)-8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三异丙基甲硅烷基)乙炔基)萘-1-基)-2-(2,2,2-三氟乙氧基)吡啶并[4,3-d]嘧啶6-氧化物 (200mg，0.23mmol)，叠氮磷酸二苯酯(1.92g，6.99mmol)和吡啶(225uL，2.80mmol)的混合物在110℃搅拌16小时。混合物用快速柱色谱(硅胶，0-50％梯度的乙酸乙酯/石油醚)纯化，得到黄色油状化合物叔丁基(1R,5S)-3-(6-氟-5-(7-氟-3-(甲氧基甲氧基)-8-((三异丙基甲硅烷基)乙炔基)萘-1-基)-8-(2,2,2-三氟乙氧基)四唑并[1',5':1,2]吡啶并[4,3-d]嘧啶-10-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(70％纯度，200mg，0.23mmol，收率68％)。LCMS(ESI):[M+H]+＝883.3.The second step: Compound 4-((1R,5S)-8-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalene-1-yl)-2-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine 6-oxide (200mg, 0.23mmol), a mixture of diphenylphosphoryl azide (1.92g, 6.99mmol) and pyridine (225uL, 2.80mmol) was stirred at 110°C for 16 hours. The mixture was purified by flash column chromatography (silica gel, 0-50% gradient ethyl acetate/petroleum ether) to give tert-butyl(1R,5S)-3-(6-fluoro-5-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalene-1-yl)-8-(2,2,2-trifluoroethoxy)tetrazolo[1′,5′:1,2]pyrido[4, 3-d]pyrimidin-10-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (70% purity, 200 mg, 0.23 mmol, yield 68%). LCMS (ESI): [M+H] + = 883.3.
第三步：向化合物叔丁基(1R,5S)-3-(6-氟-5-(7-氟-3-(甲氧基甲氧基)-8-((三异丙基甲硅烷基)乙炔基)萘-1-基)-8-(2,2,2-三氟乙氧基)四唑并[1',5':1,2]吡啶并[4,3-d]嘧啶-10-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(70％纯度，180mg，0.14mmol)和((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲醇(64.9mg，0.41mmol)的四氢呋喃(3.60mL)溶液中加入叔丁醇钠(60.0mg，0.61mmol)。混合物在20℃下搅拌16小时。加入水(4mL)稀释，用乙酸乙酯(4mL*3)萃取，浓缩有机相得到粗品化合物叔丁基(1R,5S)-3-(6-氟-5-(7-氟-3-(甲氧基甲氧基)-8-((三异丙基甲硅烷基)乙炔基)萘-1-基)-8-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)四唑并[1',5':1,2]吡啶并[4,3-d]嘧啶-10-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(125mg)，其为黄色固体。LCMS(ESI):[M+H]+＝942.4.The third step: to the compound tert-butyl(1R,5S)-3-(6-fluoro-5-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalene-1-yl)-8-(2,2,2-trifluoroethoxy)tetrazolo[1',5':1,2]pyrido[4,3-d]pyrimidin-10-yl)-3,8-diazabicyclo[3.2 .1] To a solution of octane-8-carboxylate (70% purity, 180 mg, 0.14 mmol) and ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol (64.9 mg, 0.41 mmol) in THF (3.60 mL) was added sodium tert-butoxide (60.0 mg, 0.61 mmol). The mixture was stirred at 20°C for 16 hours. Diluted by adding water (4mL), extracted with ethyl acetate (4mL*3), concentrated the organic phase to obtain the crude compound Oxy)tetrazolo[1',5':1,2]pyrido[4,3-d]pyrimidin-10-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (125 mg) as a yellow solid. LCMS (ESI): [M+H] + = 942.4.
第四步：向化合物叔丁基(1R,5S)-3-(6-氟-5-(7-氟-3-(甲氧基甲氧基)-8-((三异丙基甲硅烷基)乙炔基)萘-1-基)-8-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)四唑并[1',5':1,2]吡啶并[4,3-d]嘧啶-10-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(125mg，0.13mmol)的二甲基甲酰胺(2.00mL)溶液中加入氟化铯(202mg，1.33mmol)，反应液在20℃下搅拌1小时，然后用水(3mL)稀释，用乙酸乙酯(4mL*3)萃取。浓缩有机相，残余物用快速柱色谱(硅胶，0-10％梯度的甲醇/二氯甲烷)纯化，得到粗品化合物叔丁基(1R,5S)-3-(5-(8-乙炔基-7-氟-3-(甲氧基甲氧基)萘-1-基)-6-氟-8-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)四唑并[1',5':1,2]吡啶并[4,3-d]嘧啶-10-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(50.0mg)，其为黄色固体。LCMS(ESI):[M+H]+＝786.5.The fourth step: to the compound tert-butyl (1R,5S)-3-(6-fluoro-5-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalene-1-yl)-8-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)tetrazolo[1',5':1,2]pyrido[4,3 -d] Pyrimidin-10-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (125mg, 0.13mmol) in dimethylformamide (2.00mL) was added cesium fluoride (202mg, 1.33mmol), the reaction solution was stirred at 20°C for 1 hour, then diluted with water (3mL), extracted with ethyl acetate (4mL*3). The organic phase was concentrated and the residue was purified by flash column chromatography (silica gel, 0-10% gradient of methanol/dichloromethane) to give the crude compound tert-butyl(1R,5S)-3-(5-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yl)-6-fluoro-8-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)tetrazolo[ 1',5': 1,2]pyrido[4,3-d]pyrimidin-10-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (50.0 mg) as a yellow solid. LCMS (ESI): [M+H] + = 786.5.
第五步：向化合物叔丁基(1R,5S)-3-(5-(8-乙炔基-7-氟-3-(甲氧基甲氧基)萘-1-基)-6-氟-8-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)四唑并[1',5':1,2]吡啶并[4,3-d]嘧啶-10-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(45.0mg，0.03mmol)的乙腈(900uL)溶液中加入氯化氢(4M的二氧六环溶液，143uL，0.57mmol)，将溶液在20℃下搅拌1.5小时，浓缩，残余物溶于乙腈(2mL)并加入三乙胺将pH调节至8，溶液用制备型HPLC纯化，得到化合物4-(10-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-6-氟-8-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)四唑并[1',5':1,2]吡啶并[4,3-d]嘧啶-5-基)-5-乙炔基-6-氟萘-2-醇(2.10mg，3.27umol，收率11％)。LCMS(ESI):[M+H]+＝642.4.1H NMR(400MHz,CD3OD)δppm 7.98(dd,J＝5.6,9.2Hz,1H),7.55-7.50(m,2H),7.41(t,J＝8.9Hz,1H),5.42(br d,J＝4.0Hz,1H),4.69-4.53(m,2H),4.44-4.27(m,3H),3.82(br dd,J＝1.6,13.7Hz,2H),3.69(br dd,J＝5.6,13.2Hz,1H),3.57(br dd,J＝3.3,13.8Hz,1H),3.30-3.20(m,3H),3.10-3.03(m,1H),2.42-2.14(m,5H),2.08-1.88(m,5H).The fifth step: to the compound tert-butyl(1R,5S)-3-(5-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yl)-6-fluoro-8-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)tetrazolo[1',5':1,2]pyrido[4,3-d]pyrimidin-10-yl) -3,8-Diazabicyclo[3.2.1]octane-8-carboxylate (45.0mg, 0.03mmol) in acetonitrile (900uL) was added hydrogen chloride (4M solution in dioxane, 143uL, 0.57mmol), the solution was stirred at 20°C for 1.5 hours, concentrated, the residue was dissolved in acetonitrile (2mL) and triethylamine was added to adjust the pH to 8, and the solution was purified by preparative HPLC to obtain the compound 4-(10-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-6-fluoro-8-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)tetrazolo[1',5':1,2]pyrido[4,3-d]pyrimidin-5-yl)-5-ethynyl-6-fluoronaphthalene- 2-alcohol (2.10mg, 3.27umol, yield 11%). LCMS(ESI):[M+H] + ＝642.4. 1 H NMR(400MHz,CD 3 OD)δppm 7.98(dd,J＝5.6,9.2Hz,1H),7.55-7.50(m,2H),7.41(t,J＝8.9Hz,1H),5.42(br d,J＝4.0Hz,1H),4.69-4.53(m,2H),4.44-4.27(m,3H),3.82(br dd,J＝1.6,13.7Hz,2H),3.69(br dd,J＝5.6,13.2Hz,1H),3.57(br dd,J＝3.3,13.8Hz,1H),3.30-3.20(m,3H),3.10-3.03(m,1H),2.42-2.14(m,5H),2.08-1.88(m,5H).
实施例83：(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-7-(3-羟基萘-1-基)喹唑啉-6-基)(环丙基)甲酮甲酸盐
Example 83: (4-((1R,5S)-3,8-Diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-7-(3-hydroxynaphthalen-1-yl)quinazolin-6-yl)(cyclopropyl)methanone formate
实施例83通过实施例53的合成路线方法进行制备：LCMS(ESI):[M+H]+＝626.1。1H NMR(400MHz,CD3OD)δppm 8.53(br s,1H),8.11(s,1H),7.78(d,J＝8.1Hz,1H),7.50-7.38(m,2H),7.31-7.19(m,2H),7.07(d,J＝2.4Hz,1H),5.51-5.36(m,1H),4.70-4.40(m,4H),3.95-3.86(m,2H),3.83-3.75(m,2H),3.56-3.48(m,3H),3.24-3.18(m,1H),2.56-2.36(m,2H),2.32-2.24(m,1H),2.21-2.11(m,2H),2.05-1.96(m,5H),1.75-1.66(m,1H),0.98-0.87(m,1H),0.79-0.70(m,1H),0.64-0.55(m,1H),0.42-0.39(m,1H).Example 83 was prepared by the synthetic route method of Example 53: LCMS (ESI): [M+H] + =626.1. 1 H NMR(400MHz,CD 3 OD)δppm 8.53(br s,1H),8.11(s,1H),7.78(d,J＝8.1Hz,1H),7.50-7.38(m,2H),7.31-7.19(m,2H),7.07(d,J＝2.4Hz,1H),5.51-5.36(m,1H),4.70-4.40(m,4H),3.95-3.86(m,2H),3.83-3.75(m,2H),3.56-3.48(m,3H),3.24-3.18(m,1H),2.56-2.36(m,2H),2.32-2.24(m,1H),2.21-2.11(m,2H),2.05-1.96(m,5H),1.75-1.66(m,1H),0.98-0.87(m,1H),0.79-0.70(m,1H),0.64-0.55(m,1H),0.42-0.39(m,1H).
实施例84：(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-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)喹唑啉-6-基)(环己基)甲酮
Example 84: (4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrroline-7a(5H)-yl)methoxy)quinazolin-6-yl)(cyclohexyl)methanone
第一步：在-78℃下，向1.3M异丙基氯化镁氯化锂溶液(232uL,0.30mmol)的四氢呋喃(300 uL)溶液中加入氰化亚铜(13.5mg，0.15mmol)的四氢呋喃(300uL)溶液，溶液在-78℃下搅拌30分钟，然后在-78℃下加入叔丁基(1R,5S)-3-(7-溴-8-氟-6-碘-2-(2,2,2-三氟乙氧基)喹唑啉-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(100.0mg，0.15mmol)的四氢呋喃(300uL)溶液，撤除冷浴，搅拌30分钟，然后加入四氢呋喃(300uL)，搅拌40分钟，然后加入环己烷甲酰氯(26.6mg，0.18mmol)的四氢呋喃溶液(300uL)，搅拌15分钟。反应液倒入饱和氯化铵溶液(10mL)，使用乙酸乙酯(10mL*3)萃取，合并的有机相用无水硫酸钠干燥，过滤，滤液旋干。残留物用快速柱色谱纯化(硅胶，0-10％梯度的乙酸乙酯/石油醚)，得到无色液体化合物叔丁基(1R,5S)-3-(7-溴-6-(环己烷羰基)-8-氟-2-(2,2,2-三氟乙氧基)喹唑啉-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(34.0mg，0.05mmol，收率34％)。LCMS(ESI):[M+H]+＝647.2.Step 1: Add 1.3M isopropylmagnesium chloride lithium chloride solution (232uL, 0.30mmol) to tetrahydrofuran (300 uL) solution was added cuprous cyanide (13.5mg, 0.15mmol) in tetrahydrofuran (300uL), the solution was stirred at -78°C for 30 minutes, and then tert-butyl (1R,5S)-3-(7-bromo-8-fluoro-6-iodo-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2. 1] octane-8-carboxylate (100.0mg, 0.15mmol) in tetrahydrofuran (300uL) solution, remove the cooling bath, stir for 30 minutes, then add tetrahydrofuran (300uL), stir for 40 minutes, then add cyclohexanecarbonyl chloride (26.6mg, 0.18mmol) in tetrahydrofuran solution (300uL), stir for 15 minutes. The reaction solution was poured into saturated ammonium chloride solution (10 mL), extracted with ethyl acetate (10 mL*3), the combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried. The residue was purified by flash column chromatography (silica gel, 0-10% gradient ethyl acetate/petroleum ether) to give the compound tert-butyl(1R,5S)-3-(7-bromo-6-(cyclohexanecarbonyl)-8-fluoro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (34.0mg, 0.05mm ol, yield 34%). LCMS (ESI): [M+H] + = 647.2.
第二步：在手套箱中，向叔丁基(1R,5S)-3-(7-溴-6-(环己烷羰基)-8-氟-2-(2,2,2-三氟乙氧基)喹唑啉-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(100.0mg，0.15mmol)和((2-氟-6-(甲氧基甲氧基)-8-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)萘-1-基)乙炔基)三异丙基硅烷(103.2mg,0.20mmol)的1,4-二氧六环(2mL)溶液中，加入1.5M磷酸钾水溶液(309uL,0.46mmol)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)(11.3mg，0.02mmol)。将混合物在氮气保护下100℃下搅拌2小时。加入水(3mL)，使用乙酸乙酯(5mL*3)萃取，合并的有机相用无水硫酸钠干燥，过滤，滤液旋干。残留物用快速柱色谱纯化(硅胶，0-30％梯度的乙酸乙酯/石油醚)，得到棕色固体化合物叔丁基(1R,5S)-3-(6-(环己烷羰基)-8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三异丙基甲硅烷基)乙炔基)萘-1-基)-2-(2,2,2-三氟乙氧基)喹唑啉-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(100.0mg，0.04mmol，纯度40％，收率28％)。LCMS(ESI):[M+H]+＝951.6.The second step: In the glove box, add tert-butyl (1R,5S)-3-(7-bromo-6-(cyclohexanecarbonyl)-8-fluoro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (100.0mg, 0.15mmol) and ((2-fluoro-6-(methoxymethoxy)-8-(4 ,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalene-1-yl)ethynyl)triisopropylsilane (103.2mg, 0.20mmol) in 1,4-dioxane (2mL) solution, add 1.5M potassium phosphate aqueous solution (309uL, 0.46mmol) and methanesulfonic acid [n-butylbis(1-adamantyl)phosphine](2-amino-1,1 '-biphenyl-2-yl)palladium(II) (11.3 mg, 0.02 mmol). The mixture was stirred at 100° C. for 2 hours under nitrogen protection. Water (3 mL) was added, extracted with ethyl acetate (5 mL*3), the combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried. The residue was purified by flash column chromatography (silica gel, 0-30% gradient ethyl acetate/petroleum ether) to give brown solid compound tert-butyl(1R,5S)-3-(6-(cyclohexanecarbonyl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3 , 8-diazabicyclo[3.2.1]octane-8-carboxylate (100.0mg, 0.04mmol, purity 40%, yield 28%). LCMS (ESI): [M+H] + =951.6.
第三步：向叔丁基(1R,5S)-3-(6-(环己烷羰基)-8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三异丙基甲硅烷基)乙炔基)萘-1-基)-2-(2,2,2-三氟乙氧基)喹唑啉-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(100mg,0.10mmol)和((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲醇(33.5mg,0.21mmol)的四氢呋喃(2mL)溶液中，加入叔丁醇钠(15.2mg，0.16mmol)。将混合物氮气保护下在50℃搅拌3小时。加入水(5mL)，使用乙酸乙酯(10mL*3)萃取，合并的有机相用无水硫酸钠干燥，过滤，滤液旋干。得到粗品化合物叔丁基(1R,5S)-3-(6-(环己烷羰基)-8-氟-7-(7-氟-3-(甲氧基甲氧基)-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)喹唑啉-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(125mg)，其为棕色油状液体。LCMS(ESI):[M+2H]2+/2＝506.0.The third step: to tert-butyl(1R,5S)-3-(6-(cyclohexanecarbonyl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalene-1-yl)-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (100mg , 0.10mmol) and ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol (33.5mg, 0.21mmol) in tetrahydrofuran (2mL) was added sodium tert-butoxide (15.2mg, 0.16mmol). The mixture was stirred at 50° C. for 3 hours under nitrogen protection. Water (5 mL) was added, extracted with ethyl acetate (10 mL*3), the combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried. The crude compound tert-butyl(1R,5S)-3-(6-(cyclohexanecarbonyl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8 - Diazabicyclo[3.2.1]octane-8-carboxylate (125 mg) as a brown oily liquid. LCMS (ESI): [M+2H] 2+ /2=506.0.
第四步：向叔丁基(1R,5S)-3-(6-(环己烷羰基)-8-氟-7-(7-氟-3-(甲氧基甲氧基)-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)喹唑啉-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(120mg,0.12mmol)的N,N二甲基甲酰胺(2.4mL)溶液中，加入氟化铯(180.4mg，1.19mmol)。将混合物在25℃下搅拌1小时。加入水(7mL)稀释，使用乙酸乙酯(10mL*3)萃取，合并的有机相用无水硫酸钠干燥，过滤，滤液旋干。残留物用快速柱色谱纯化(硅胶，0-10％梯度的甲醇/二氯甲烷)，得到棕色油状化合物叔丁基(1R,5S)-3-(6-(环己烷羰基)-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-吡咯嗪-7a(5H)-基)甲氧基)喹唑啉-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(42mg，0.05mmol，收率41％)。LCMS(ESI):[M+H]+＝854.5.The fourth step: to tert-butyl (1R,5S)-3-(6-(cyclohexanecarbonyl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalene-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8 - To a solution of diazabicyclo[3.2.1]octane-8-carboxylate (120 mg, 0.12 mmol) in N,N dimethylformamide (2.4 mL) was added cesium fluoride (180.4 mg, 1.19 mmol). The mixture was stirred at 25°C for 1 hour. Add water (7 mL) to dilute and extract with ethyl acetate (10 mL*3). The combined organic phases are dried over anhydrous sodium sulfate, filtered, and the filtrate is spin-dried. The residue was purified by flash column chromatography (silica gel, 0-10% gradient of methanol/dichloromethane) to give the compound tert-butyl(1R,5S)-3-(6-(cyclohexanecarbonyl)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl) as a brown oil Methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (42 mg, 0.05 mmol, yield 41%). LCMS (ESI): [M+H] + = 854.5.
第五步：在20℃下，向叔丁叔丁基(1R,5S)-3-(6-(环己烷羰基)-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-吡咯嗪-7a(5H)-基)甲氧基)喹唑啉-4-基)-3,8-二氮杂双环[3.2.1] 辛烷-8-羧酸酯(42mg，0.05mmol)的乙腈(840uL)溶液中加入氯化氢(4M的二氧六环溶液，246uL，0.98mmol)。将该溶液在20℃搅拌1小时。溶液用氮气吹除HCl气并浓缩。混合物通过制备型HPLC纯化，得到白色固体化合物(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-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)喹唑啉-6-基)(环己基)甲酮(7.88mg，0.01mmol，收率23％)。LCMS(ESI):[M+H]+＝710.2。1H NMR(400MHz,CD3OD)δppm 7.99(s,1H),7.89(dd,J＝5.8,9.0Hz,1H),7.37(t,J＝8.9Hz,1H),7.33(d,J＝2.3Hz,1H),6.91(d,J＝2.3Hz,1H),5.43-5.28(m,1H),4.69-4.49(m,3H),4.40-4.26(m,2H),3.77-3.63(m,4H),3.36(br d,J＝5.3Hz,2H),3.13-3.06(m,1H),2.62-2.53(m,1H),2.47-2.26(m,2H),2.25-1.98(m,4H),1.92(br s,4H),1.72-1.59(m,2H),1.49(br s,2H),1.28-0.99(m,5H),0.95-0.86(m,1H),0.58(br d,J＝13.3Hz,1H).The fifth step: at 20°C, to tert-butyl-tert-butyl (1R,5S)-3-(6-(cyclohexanecarbonyl)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazepine Heterobicyclic [3.2.1] To a solution of octane-8-carboxylate (42 mg, 0.05 mmol) in acetonitrile (840 uL) was added hydrogen chloride (4M in dioxane, 246 uL, 0.98 mmol). The solution was stirred at 20°C for 1 hour. The solution was purged of HCl gas with nitrogen and concentrated. The mixture was purified by preparative HPLC to give the compound (4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolin-7a(5H)-yl)methoxy)quinazolin-6-yl) as a white solid ( Cyclohexyl)methanone (7.88 mg, 0.01 mmol, yield 23%). LCMS (ESI): [M+H] + = 710.2. 1 H NMR(400MHz,CD 3 OD)δppm 7.99(s,1H),7.89(dd,J＝5.8,9.0Hz,1H),7.37(t,J＝8.9Hz,1H),7.33(d,J＝2.3Hz,1H),6.91(d,J＝2.3Hz,1H),5.43-5.28(m,1H),4.69-4.49(m,3H),4.40-4.26(m,2H),3.77-3.63(m,4H),3.36(br d,J＝5.3Hz,2H),3.13-3.06(m,1H),2.62-2.53(m,1H),2.47-2.26(m,2H),2.25-1.98(m,4H),1.92(br s,4H),1.72-1.59(m,2H),1.49(br s,2H),1.28-0.99(m,5H),0.95-0.86(m,1H),0.58(br d,J＝13.3Hz,1H).
实施例85：1-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-7-(7,8-二氟-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)喹唑啉-6-基)乙-1-酮肟
Example 85: 1-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-7-(7,8-difluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinazolin-6-yl)ethan-1-one oxime
第一步：在25℃下，将化合物1-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-7-(7,8-二氟-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)喹唑啉-6-基)乙-1-酮(20.0mg，0.03mmol)，碳酸钠(6.67mg，0.06mmol)和盐酸羟胺(21.8mg，0.31mmol)溶于乙醇(200uL)，20℃搅拌2小时。反应液减压浓缩，残留物用制备型HPLC纯化，得到黄色固体化合物1-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-7-(7,8-二氟-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)喹唑啉-6-基)乙-1-酮肟(0.85mg，1.3umol，收率1％)。LCMS(ESI):[M+H]+＝651.2。1H NMR(400MHz,CD3OD)δppm 7.75-7.48(m,2H),7.48-7.27(m,2H),7.02-6.88(m,1H),5.62-5.38(m,1H),4.71-4.68(m,2H),4.03(br s,2H),3.84-3.60(m,7H),3.05(s,1H),2.62-2.48(m,2H),2.29(s,3H),2.08-1.99(m,5H),1.59(s,3H).The first step: at 25°C, the compound 1-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-7-(7,8-difluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-6-yl)eth-1- Ketone (20.0mg, 0.03mmol), sodium carbonate (6.67mg, 0.06mmol) and hydroxylamine hydrochloride (21.8mg, 0.31mmol) were dissolved in ethanol (200uL), and stirred at 20°C for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by preparative HPLC to obtain a yellow solid compound 1-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-7-(7,8-difluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinazoline- 6-yl)ethan-1-one oxime (0.85 mg, 1.3 umol, yield 1%). LCMS (ESI): [M+H] + = 651.2. 1 H NMR (400MHz, CD 3 OD) δppm 7.75-7.48(m,2H),7.48-7.27(m,2H),7.02-6.88(m,1H),5.62-5.38(m,1H),4.71-4.68(m,2H),4.03(br s,2H),3.84-3.6 0(m,7H),3.05(s,1H),2.62-2.48(m,2H),2.29(s,3H),2.08-1.99(m,5H),1.59(s,3H).
实施例86：1-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-7-(7,8-二氟-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)喹唑啉-6-基)乙烷-1-酮O-甲基肟
Example 86: 1-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-7-(7,8-difluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinazolin-6-yl)ethan-1-one O-methyl Oxime
实施例86使用与实施例85相同的操作方法，合成该化合物。1-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-7-(7,8-二氟-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)喹唑啉-6-基)乙烷-1-酮O-甲基肟(1.43mg，白色固体)。LCMS(ESI):[M+H]+＝665.3。1H NMR(400MHz,CD3OD)δppm 7.83(s,1H),7.67-7.54(m,1H),7.49-7.21(m,2H),6.97(d,J＝2.1Hz,1H),5.47-5.25(m,1H),4.71-4.62(m,2H),4.45-4.28(m,2H),3.86-3.61(m,7H),3.53-3.35(m,3H),3.12(br d,J＝6.0Hz,1H),2.45-2.17(m,3H),2.14-2.03(m,2H),1.94(br s,5H),1.64(s,3H).Example 86 Using the same operation method as in Example 85, this compound was synthesized. 1-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-7-(7,8-difluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-6-yl)ethane-1-one O-methyloxime (1.4 3 mg, white solid). LCMS (ESI): [M+H] + = 665.3. 1 H NMR(400MHz,CD 3 OD)δppm 7.83(s,1H),7.67-7.54(m,1H),7.49-7.21(m,2H),6.97(d,J＝2.1Hz,1H),5.47-5.25(m,1H),4.71-4.62(m,2H),4.45-4.28(m,2H),3.86-3.61(m,7H),3.53-3.35(m,3H),3.12(br d,J＝6.0Hz,1H),2.45-2.17(m,3H),2.14-2.03(m,2H),1.94(br s,5H),1.64(s,3H).
实施例87：4-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-6-硝基喹唑啉-7-基)萘-2-醇
Example 87: 4-(4-((1R,5S)-3,8-Diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-6-nitroquinazolin-7-yl)naphthalen-2-ol
第一步：在25℃下，向叔丁基(1R,5S)-3-(7-溴-8-氟-6-硝基-2-(2,2,2-三氟乙氧基)喹唑啉-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(1.60g，2.76mmol)和2-(7,8-二氟-3-(甲氧基甲氧基)萘-1-基)-4,4,5,5-四甲基-1,3,2-二氧硼烷(1.35g，3.86mmol)的二氧六环(32mL)溶液中，加入碳酸钠(1.3M的水溶液，6.36mL，0.78mmol)，氮气氛围下加入四(三苯基膦)钯(18.8mg，0.03mmol)。反应体系在氮气氛围下100℃搅拌16小时。冷却至室温，减压浓缩，残留物用快速柱色谱(硅胶，5-12％梯度的四氢呋喃/石油醚)纯化，得到浅黄色固体化合物叔丁基(1R,5S)-3-(7-(7,8-二氟-3-(甲氧基甲氧基)萘-1-基)-8-氟-6-硝基-2-(2,2,2-三氟乙氧基)喹唑啉-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(1.40g，1.93mmol，收率70％)。1H NMR(400MHz,CDCl3)δppm 8.63(s,1H),7.62-7.58(m,1H),7.51(s,1H),7.36-7.34(m,1H),7.10(d,J＝2.0Hz,1H),5.33-5.28(m,2H),4.92-4.88(m,2H),4.60-4.52(m,2H),4.47-4.44(m,2H),3.79-3.72(m,2H),3.54(s,3H),2.05-2.01(m,2H),1.84-1.80(m,2H),1.55(s,9H).The first step: tert-butyl (1R,5S)-3-(7-bromo-8-fluoro-6-nitro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.60g, 2.76mmol) and 2-(7,8-difluoro-3-(methoxymethoxy)naphthalene-1-yl) at 25°C - To a solution of 4,4,5,5-tetramethyl-1,3,2-dioxaborane (1.35g, 3.86mmol) in dioxane (32mL), sodium carbonate (1.3M aqueous solution, 6.36mL, 0.78mmol) was added, and tetrakis(triphenylphosphine)palladium (18.8mg, 0.03mmol) was added under nitrogen atmosphere. The reaction system was stirred at 100° C. for 16 hours under nitrogen atmosphere. Cooled to room temperature, concentrated under reduced pressure, and the residue was purified by flash column chromatography (silica gel, 5-12% gradient tetrahydrofuran/petroleum ether) to obtain light yellow solid compound tert-butyl(1R,5S)-3-(7-(7,8-difluoro-3-(methoxymethoxy)naphthalene-1-yl)-8-fluoro-6-nitro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3. 2.1] Octane-8-carboxylate (1.40 g, 1.93 mmol, 70% yield). 1 H NMR(400MHz,CDCl 3 )δppm 8.63(s,1H),7.62-7.58(m,1H),7.51(s,1H),7.36-7.34(m,1H),7.10(d,J＝2.0Hz,1H),5.33-5.28(m,2H),4.92-4.88(m,2H),4.60-4.52(m,2H),4.47-4.44(m,2H),3.79-3.72(m,2H),3.54(s,3H),2.05-2.01(m,2H),1.84-1.80(m,2H),1.55(s,9H).
第二步：在25℃下，向叔丁基(1R,5S)-3-(7-(7,8-二氟-3-(甲氧基甲氧基)萘-1-基)-8-氟-6-硝基-2-(2,2,2-三氟乙氧基)喹唑啉-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(700mg，0.97mmol)和((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲醇(176mg，1.10mmol)的四氢呋喃(14mL)溶液中，加入叔丁醇钠(279mg，2.90mmol)。反应体系25℃搅拌2小时。加入水(50mL)稀释，使用乙酸乙酯(20mL*3)萃取，合并的有机相用饱和食盐水(10mL)洗涤，无水硫酸钠干燥，过滤，滤液旋干，残留 物用快速柱色谱(硅胶，1-5％梯度的甲醇/二氯甲烷)纯化。产品再用制备型HPLC纯化得到浅黄色固体化合物叔丁基(1R,5S)-3-(7-(7,8-二氟-3-(甲氧基甲氧基)萘-1-基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a-基)甲氧基)-6-硝基喹唑啉-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(300mg，383umol，收率39％)。1H NMR(400MHz,CDCl3)δppm 8.62(s,1H),7.60-7.57(m,1H),7.50(s,1H),7.38-7.31(m,1H),7.11(s,1H),5.56-5.42(m,1H),5.33-5.28(m,2H),4.77(t,J＝7.8Hz,1H),4.77-4.54(m,5H),3.82-3.71(m,2H),3.65-3.55(m,2H),3.54(m,4H),3.27-3.24(m,1H),2.56-2.44(m,3H),2.26-2.25(m,3H),2.22-2.02(m,2H),1.80-1.74(m,2H),1.55(s,9H).The second step: at 25°C, tert-butyl (1R,5S)-3-(7-(7,8-difluoro-3-(methoxymethoxy)naphthalene-1-yl)-8-fluoro-6-nitro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (700mg, 0.97mmol) and ((2R ,7aS)-2-Fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol (176 mg, 1.10 mmol) in THF (14 mL) was added sodium tert-butoxide (279 mg, 2.90 mmol). The reaction system was stirred at 25°C for 2 hours. Add water (50mL) to dilute, use ethyl acetate (20mL*3) to extract, the combined organic phase is washed with saturated brine (10mL), dried over anhydrous sodium sulfate, filtered, and the filtrate is spin-dried to leave The material was purified by flash column chromatography (silica gel, 1-5% gradient of methanol/dichloromethane). The product was purified by preparative HPLC to obtain light yellow solid compound tert-butyl(1R,5S)-3-(7-(7,8-difluoro-3-(methoxymethoxy)naphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a-yl)methoxy)-6-nitroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octano Alkane-8-carboxylate (300mg, 383umol, yield 39%). 1 H NMR(400MHz,CDCl 3 )δppm 8.62(s,1H),7.60-7.57(m,1H),7.50(s,1H),7.38-7.31(m,1H),7.11(s,1H),5.56-5.42(m,1H),5.33-5.28(m,2H),4.77(t,J＝7.8Hz,1H),4.77-4.54(m,5H),3.82-3.71(m,2H),3.65-3.55(m,2H),3.54(m,4H),3.27-3.24(m,1H),2.56-2.44(m,3H),2.26-2.25(m,3H),2.22-2.02(m,2H),1.80-1.74(m,2H),1.55(s,9H).
第三步：在20℃下，向叔丁基(1R,5S)-3-(7-(7,8-二氟-3-(甲氧基甲氧基)萘-1-基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a-基)甲氧基)-6-硝基喹唑啉-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(200mg，0.26mmol)的乙腈(2mL)溶液中加入氯化氢(4M的二氧六环溶液，958uL，3.83mmol)。将该溶液在20℃搅拌2小时。溶液减压浓缩，溶于乙腈(3mL)，加入三乙胺调节pH至7-8，减压浓缩，残留物用制备型HPLC纯化，得到黄色固体化合物4-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛基-3-基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯啉-7a(5H)-基)甲氧基)-6-硝基喹唑啉-7-基)-5,6-二氟萘-2-醇(51mg，79.9umol，收率31％)。LCMS(ESI):[M+H]+＝639.2The third step: at 20°C, to tert-butyl (1R,5S)-3-(7-(7,8-difluoro-3-(methoxymethoxy)naphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a-yl)methoxy)-6-nitroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- To a solution of the carboxylate (200 mg, 0.26 mmol) in acetonitrile (2 mL) was added hydrogen chloride (4M in dioxane, 958 uL, 3.83 mmol). The solution was stirred at 20°C for 2 hours. The solution was concentrated under reduced pressure, dissolved in acetonitrile (3 mL), added triethylamine to adjust the pH to 7-8, concentrated under reduced pressure, and the residue was purified by preparative HPLC to obtain a yellow solid compound 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octyl-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrroline-7a(5H)-yl)methoxy)- 6-nitroquinazolin-7-yl)-5,6-difluoronaphthalen-2-ol (51 mg, 79.9 umol, yield 31%). LCMS (ESI): [M+H] + = 639.2
实施例87A和实施例87B：(S)-4-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-6-硝基喹唑啉-7-基)-5,6-二氟萘-2-醇，和Example 87A and Example 87B: (S)-4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-6-nitroquinazolin-7-yl)-5,6-difluoronaphthalen-2-ol, and
(R)-4-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-6-硝基喹唑啉-7-基)-5,6-二氟萘-2-醇
(R)-4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-6-nitroquinazolin-7-yl)-5,6-difluoronaphthalen-2-ol
实施例87经SFC分离(柱：DAICEL CHIRALPAK IG(250mm*30mm,10um)；流动相：A相为二氧化碳，B相为0.1％氨水/异丙醇；B相保持60％；流速：80毫升/分钟)，得到目标化合物。Example 87 was separated by SFC (column: DAICEL CHIRALPAK IG (250mm*30mm, 10um); mobile phase: phase A was carbon dioxide, phase B was 0.1% ammonia water/isopropanol; phase B was maintained at 60%; flow rate: 80 ml/min), and the target compound was obtained.
异构体1,实施例87A：LCMS(ESI):[M+H]+＝639.1；SFC分析(色谱柱:Chiralpak IG-3，50mm*4.6mm，3um；流动相：A相为二氧化碳，B相为0.05％二乙胺/异丙醇；梯度：保持40％的B相；流速：4毫升/分钟)：手性柱出峰位置为0.829min；1H NMR(400MHz,CD3OD)δppm 8.71(s,1H),7.63(dd,J＝4.3,8.8Hz,1H),7.48-7.34(m,1H),7.31(s,1H),7.01(d,J＝2.0Hz,1H),5.53-5.30(m,1H),4.78(br d,J＝13.6Hz,1H),4.69(br d,J＝12.3Hz,1H),4.56-4.43(m,2H),4.11-3.84(m,4H),3.60(s,1H),3.58(d,J＝3.5Hz,1H),3.56(s,1H),3.27-3.18(m,1H),2.46-1.95(m,10H).Isomer 1, Example 87A: LCMS (ESI): [M+H]+=639.1; SFC analysis (chromatographic column: Chiralpak IG-3, 50mm*4.6mm, 3um; mobile phase: phase A is carbon dioxide, phase B is 0.05% diethylamine/isopropanol; gradient: keep 40% of phase B; flow rate: 4 ml/min): chiral column peak position is 0.829min;1H NMR (400MHz, CD3OD)δppm 8.71(s,1H),7.63(dd,J=4.3,8.8Hz,1H),7.48-7.34(m,1H),7.31(s,1H),7.01(d,J=2.0Hz,1H),5.53-5.30(m,1H),4.78(br d,J=13.6Hz,1H), 4.69(br d,J=12.3Hz,1H),4.56-4.43(m,2H),4.11-3.84(m,4H),3.60(s,1H),3.58(d,J=3.5Hz,1H),3.56(s,1H),3.27-3.18(m,1H),2.46-1.95(m,10 H).
异构体2，实施例87B：LCMS(ESI):[M+H]+＝639.1；SFC分析(色谱柱:Chiralpak IG-3，50mm*4.6mm，3um；流动相：A相为二氧化碳，B相为0.05％二乙胺/异丙醇；梯度：保持40％的B相；流速：4毫升/分钟)：手性柱出峰位置为2.576min；1H NMR(400MHz,CD3OD)δppm 8.70(s,1H),7.61 (dd,J＝3.6,9.2Hz,1H),7.46-7.32(m,1H),7.33-7.21(m,1H),7.00(d,J＝2.3Hz,1H),5.41-5.17(m,1H),4.69-4.49(m,2H),4.35-4.20(m,2H),3.84-3.63(m,4H),3.30-3.14(m,3H),3.02(dt,J＝5.8,9.3Hz,1H),2.30-1.75(m,10H).Isomer 2, Example 87B: LCMS (ESI): [M+H] + =639.1; SFC analysis (chromatographic column: Chiralpak IG-3, 50mm*4.6mm, 3um; mobile phase: phase A is carbon dioxide, phase B is 0.05% diethylamine/isopropanol; gradient: maintain 40% of phase B; flow rate: 4 ml/min): the peak position of the chiral column is 2.576min; 1 H N MR(400MHz,CD 3 OD)δppm 8.70(s,1H),7.61 (dd,J=3.6,9.2Hz,1H),7.46-7.32(m,1H),7.33-7.21(m,1H),7.00(d,J=2.3Hz,1H),5.41-5.17(m,1H),4.69-4.49(m,2H),4.35-4.20(m,2H),3.84-3 .63(m,4H),3.30-3.14(m,3H),3.02(dt,J＝5.8,9.3Hz,1H),2.30-1.75(m,10H).
实施例88：4-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-6-硝基喹唑啉-7-基)-5-乙炔基-6-氟萘-2-醇
Example 88: 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-6-nitroquinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol
第一步：在氮气环境下，向叔丁基(1R,5S)-3-(7-溴-8-氟-6-硝基-2-(2,2,2-三氟乙氧基)喹唑啉-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(3.10g，5.34mmol)和(((2-氟-6-(甲氧基甲氧基)-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(3.56g，6.94mmol)的甲苯(124mL)和水(31mL)的混合溶液中，加入碳酸铯(5.22g，16.03mmol)，甲磺酰氧基(二金刚烷基-正丁基膦基)-2-氨基-1,1-联苯-2-基)钯(II)(0.78g，1.07mmol)。将混合物在100℃搅拌16小时。将残余物加水(150mL)稀释并用乙酸乙酯(150mL*3)萃取，合并的有机相用饱和食盐水(150mL)洗涤，无水硫酸镁干燥并过滤，滤液真空浓缩。残余物通过快速柱色谱(硅胶，0-10％梯度四氢呋喃/石油醚)纯化得到棕色固体化合物叔丁基(1R,5S)-3-(8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三异丙基甲硅烷基)乙炔基)萘-1-基)-6-硝基-2-(2,2,2-三氟乙氧基)喹唑啉-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(3.27g，3.69mmol，收率69％)。LCMS(ESI):[M+H]+＝886.1.The first step: under nitrogen atmosphere, tert-butyl (1R, 5S)-3-(7-bromo-8-fluoro-6-nitro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (3.10g, 5.34mmol) and (((2-fluoro-6-(methoxymethoxy)-8-(4,4,5 ,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalene-1-yl)ethynyl)triisopropylsilane (3.56g, 6.94mmol) in toluene (124mL) and water (31mL) mixed solution, add cesium carbonate (5.22g, 16.03mmol), methanesulfonyloxy (diamantyl-n-butylphosphino)-2-amino-1,1-biphenyl-2- base) palladium(II) (0.78 g, 1.07 mmol). The mixture was stirred at 100°C for 16 hours. The residue was diluted with water (150 mL) and extracted with ethyl acetate (150 mL*3). The combined organic phases were washed with saturated brine (150 mL), dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated in vacuo. The residue was purified by flash column chromatography (silica gel, 0-10% gradient THF/petroleum ether) to give brown solid compound tert-butyl(1R,5S)-3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-6-nitro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabis Cyclo[3.2.1]octane-8-carboxylate (3.27 g, 3.69 mmol, 69% yield). LCMS (ESI): [M+H] + = 886.1.
第二步：向叔丁基(1R,5S)-3-(8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三异丙基甲硅烷基)乙炔基)萘-1-基)-6-硝基-2-(2,2,2-三氟乙氧基)喹唑啉-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(500mg，0.56mmol)的四氢呋喃(10mL)溶液中加入4A分子筛(500mg)，叔丁醇钠(108mg，1.12mmol)和((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲醇(180mg，1.12mmol)。将反应在20℃搅拌2小时。混合物用水(10mL)稀释并用乙酸乙酯(10mL*3)萃取，并用饱和食盐水(20mL)洗涤，无水硫酸镁干燥。滤液浓缩，残余物通过快速柱色谱(硅胶，0-7％梯度甲醇/二氯甲烷)纯化得到棕色固体化合物叔丁基(1R,5S)-3-(8-氟-7-(7-氟-3-(甲氧基甲氧基)-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)-6-硝基喹唑啉-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(460mg，0.49mmol，收率87％)。LCMS(ESI):[M+H]+＝945.6.The second step: to tert-butyl(1R,5S)-3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalene-1-yl)-6-nitro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (500mg, 0.56 mmol) in THF (10 mL) were added 4A molecular sieves (500 mg), sodium tert-butoxide (108 mg, 1.12 mmol) and ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol (180 mg, 1.12 mmol). The reaction was stirred at 20 °C for 2 hours. The mixture was diluted with water (10 mL) and extracted with ethyl acetate (10 mL*3), washed with saturated brine (20 mL), and dried over anhydrous magnesium sulfate. The filtrate was concentrated and the residue was purified by flash column chromatography (silica gel, 0-7% methanol/dichloromethane gradient) to give brown solid compound tert-butyl(1R,5S)-3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalene-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl )methoxy)-6-nitroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (460 mg, 0.49 mmol, yield 87%). LCMS (ESI): [M+H] + = 945.6.
第三步：向叔丁基(1R,5S)-3-(8-氟-7-(7-氟-3-(甲氧基甲氧基)-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)-6-硝基喹唑啉-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(440mg，0.47mmol)的二甲基甲酰胺(5mL)溶液中加入氟化铯(566mg，3.7mmol)。将反应在20℃搅拌2小时。混合物用水(15mL)稀释并用乙酸乙酯(10mL*3)萃取，合并的有机相用饱和食盐水(20mL)洗涤，无水硫酸镁干燥，过滤，滤液浓缩，残余物通过快速柱色谱(硅胶，0-7％梯度甲醇/二氯甲烷)纯化得到棕色固体化合物叔丁基(1R,5S)-3-(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-吡咯嗪-7a(5H)-基)甲氧基)-6-硝基喹唑啉-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(330mg，0.42mmol，收率89％)。LCMS(ESI):[M+H]+＝789.2.The third step: to tert-butyl(1R,5S)-3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalene-1- To a solution of 2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-6-nitroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (440 mg, 0.47 mmol) in dimethylformamide (5 mL) was added cesium fluoride (566 mg, 3.7 mmol). The reaction was stirred at 20 °C for 2 hours. The mixture was diluted with water (15 mL) and extracted with ethyl acetate (10 mL*3), the combined organic phases were washed with saturated brine (20 mL), dried over anhydrous magnesium sulfate, filtered, the filtrate was concentrated, and the residue was purified by flash column chromatography (silica gel, 0-7% methanol/dichloromethane gradient) to obtain brown solid compound tert-butyl(1R,5S)-3-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yl)-8-fluoro -2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-6-nitroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (330 mg, 0.42 mmol, yield 89%). LCMS (ESI): [M+H] + = 789.2.
第四步：向叔丁基(1R,5S)-3-(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-吡咯嗪-7a(5H)-基)甲氧基)-6-硝基喹唑啉-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(330mg，0.42mmol)的乙腈(6.5mL)溶液中加入氯化氢(4M的二氧六环溶液，2mL，8mmol)。将反应在20℃搅拌1小时。真空旋干后溶于乙腈(5mL)并用三乙胺中和，然后减压浓缩。残余物通过制备型HPLC纯化，得到黄色固体化合物4-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-6-硝基喹唑啉-7-基)-5-乙炔基-6-氟萘-2-醇(118mg，0.18mmol，收率43％)。LCMS(ESI):[M+H]+＝645.1.The fourth step: to tert-butyl (1R,5S)-3-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrozin-7a(5H)-yl)methoxy)-6-nitroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane- To a solution of 8-carboxylate (330 mg, 0.42 mmol) in acetonitrile (6.5 mL) was added hydrogen chloride (4M in dioxane, 2 mL, 8 mmol). The reaction was stirred at 20 °C for 1 hour. After being spin-dried in vacuo, it was dissolved in acetonitrile (5 mL) and neutralized with triethylamine, then concentrated under reduced pressure. The residue was purified by preparative HPLC to give the yellow solid compound 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-6-nitroquinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol ( 118 mg, 0.18 mmol, yield 43%). LCMS (ESI): [M+H] + = 645.1.
实施例88A和实施例88B：(S)-4-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-6-硝基喹唑啉-7-基)-5-乙炔基-6-氟萘-2-醇，和Example 88A and Example 88B: (S)-4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-6-nitroquinazolin-7-yl)-5-ethynyl-6-fluoronaphthalene-2 -alcohol, and
(R)-4-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-6-硝基喹唑啉-7-基)-5-乙炔基-6-氟萘-2-醇
(R)-4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-6-nitroquinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol
实施例88经SFC分离(柱：DAICEL CHIRALPAK AD(250mm*30mm,10um)；流动相：A相为二氧化碳，B相为0.1％氨水/乙醇；B相保持50％；流速：80毫升/分钟)，得到目标化合物。Example 88 was separated by SFC (column: DAICEL CHIRALPAK AD (250mm*30mm, 10um); mobile phase: phase A was carbon dioxide, phase B was 0.1% ammonia water/ethanol; phase B was maintained at 50%; flow rate: 80 ml/min), and the target compound was obtained.
异构体1,实施例88A：LCMS(ESI):[M+H]+＝645.2；SFC分析(柱:ChiralPak AD-3，150*4.6mm，3um；流动相：A相为二氧化碳，B相为0.05％二乙胺/乙醇；梯度：保持40％的B相；流速：2.5毫升/分钟；)：手性柱出峰位置为1.865min；1H NMR(400MHz,CD3OD)δppm 8.69-8.65(m,1H),7.86(dd,J＝5.6,9.2Hz,1H),7.35-7.29(m,2H),7.00(d,J＝2.3Hz,1H),5.40-5.24(m,1H),4.67(br d,J＝12.5Hz,1H),4.52(br d,J＝12.5Hz,1H),4.36-4.21(m,2H),3.82(br d,J＝12.0Hz,1H),3.72-3.62(m,3H),3.36(s,1H),3.32-3.19(m,3H),3.04(dt,J＝5.6,9.5Hz,1H),2.40-2.12(m,3H),2.05-1.79(m,7H).Isomer 1, Example 88A: LCMS (ESI): [M+H]+=645.2; SFC analysis (column: ChiralPak AD-3, 150*4.6mm, 3um; Mobile phase: A phase is carbon dioxide, B phase is 0.05% diethylamine/ethanol; Gradient: maintain 40% B phase; Flow rate: 2.5 milliliters/minute;): chiral column peak position is 1.865min;1H NMR (400MHz, CD3OD)δppm 8.69-8.65(m,1H),7.86(dd,J=5.6,9.2Hz,1H),7.35-7.29(m,2H),7.00(d,J=2.3Hz,1H),5.40-5.24(m,1H),4.67(br d,J=12.5Hz,1H),4.52(br d,J=12.5Hz,1H),4.36-4.21(m,2H),3.82(br d,J=12.0Hz,1H),3.72-3.62(m,3H),3.36(s,1H),3.32-3.19(m,3H),3.04(dt,J=5.6,9.5Hz,1H),2.40- 2.12(m,3H),2.05-1.79(m,7H).
异构体2,实施例88B：LCMS(ESI):[M+H]+＝645.1；SFC分析(柱:ChiralPak AD-3，150*4.6mm，3um；流动相：A相为二氧化碳，B相为0.05％二乙胺/乙醇；梯度：保持40％的B相；流速： 2.5毫升/分钟；)：手性柱出峰位置为3.293min；1H NMR(400MHz,CD3OD)δppm 8.68-8.65(m,1H),7.86(dd,J＝5.8,9.3Hz,1H),7.35-7.30(m,2H),7.00(d,J＝2.5Hz,1H),5.40-5.24(m,1H),4.66(br d,J＝12.3Hz,1H),4.54(br d,J＝12.3Hz,1H),4.29(q,J＝10.5Hz,2H),3.80(br d,J＝12.0Hz,1H),3.71-3.65(m,3H),3.38-3.36(m,1H),3.32-3.19(m,3H),3.04(dt,J＝5.8,9.5Hz,1H),2.40-2.14(m,3H),2.04-1.80(m,7H).Isomer 2, Example 88B: LCMS (ESI): [M+H] + =645.1; SFC analysis (column: ChiralPak AD-3, 150*4.6mm, 3um; mobile phase: A phase is carbon dioxide, B phase is 0.05% diethylamine/ethanol; gradient: keep 40% of B phase; flow rate: 2.5毫升/分钟；)：手性柱出峰位置为3.293min； 1 H NMR(400MHz,CD 3 OD)δppm 8.68-8.65(m,1H),7.86(dd,J＝5.8,9.3Hz,1H),7.35-7.30(m,2H),7.00(d,J＝2.5Hz,1H),5.40-5.24(m,1H),4.66(br d,J＝12.3Hz,1H),4.54(br d,J＝12.3Hz,1H),4.29(q,J＝10.5Hz,2H),3.80(br d,J＝12.0Hz,1H),3.71-3.65(m,3H),3.38-3.36(m,1H),3.32-3.19(m,3H),3.04(dt,J＝5.8,9.5Hz,1H),2.40-2.14(m,3H),2.04-1.80(m,7H).
实施例89：4-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-2-(((1R,7a'R)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-吡咯嗪]-7a'(5'H)-基)甲氧基)-8-氟-6-硝基喹唑啉-7-基)-5,6-二氟萘-2-醇
Example 89: 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(((1R,7a'R)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolazin]-7a'(5'H)-yl)methoxy)-8-fluoro-6-nitroquinazolin-7-yl)- 5,6-Difluoronaphthalen-2-ol
实施例89采用与实施例87相同的方法，合成了该化合物4-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-2-(((1R,7a'R)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-吡咯嗪]-7a'(5'H)-基)甲氧基)-8-氟-6-硝基喹唑啉-7-基)-5,6-二氟萘-2-醇(甲酸盐，220mg，黄色固体)。LCMS(ESI):[M+H]+＝683.1。1H-NMR(400MHz,CD3OD)δppm 8.71(s,1H),8.46(s,1H),7.63(dd,J＝4.0,9.0Hz,1H),7.45-7.38(m,1H),7.31(s,1H),7.01(d,J＝2.1Hz,1H),4.78-4.69(m,2H),4.59-4.51(m,2H),4.07(br s,2H),4.00-3.83(m,2H),3.61(br dd,J＝6.3,12.1Hz,1H),3.51-3.42(m,1H),3.13(br d,J＝12.4Hz,1H),3.00-2.88(m,1H),2.44(br dd,J＝4.1,13.6Hz,1H),2.27(br dd,J＝5.9,11.7Hz,1H),2.19-1.90(m,8H),1.67-1.53(m,2H).Example 89 Using the same method as in Example 87, the compound 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(((1R,7a'R)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolazin]-7a'(5'H)-yl)methoxy)-8-fluoro- 6-nitroquinazolin-7-yl)-5,6-difluoronaphthalen-2-ol (formate salt, 220 mg, yellow solid). LCMS (ESI): [M+H] + = 683.1. 1 H-NMR(400MHz,CD 3 OD)δppm 8.71(s,1H),8.46(s,1H),7.63(dd,J＝4.0,9.0Hz,1H),7.45-7.38(m,1H),7.31(s,1H),7.01(d,J＝2.1Hz,1H),4.78-4.69(m,2H),4.59-4.51(m,2H),4.07(br s,2H),4.00-3.83(m,2H),3.61(br dd,J＝6.3,12.1Hz,1H),3.51-3.42(m,1H),3.13(br d,J＝12.4Hz,1H),3.00-2.88(m,1H),2.44(br dd,J＝4.1,13.6Hz,1H),2.27(br dd,J＝5.9,11.7Hz,1H),2.19-1.90(m,8H),1.67-1.53(m,2H).
实施例89AB和实施例89C和实施例89D：(S)-4-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-吡咯嗪]-7a'(5'H)-基)甲氧基)-8-氟-6-硝基喹唑啉-7-基)-5,6-二氟萘-2-醇，和Example 89AB and Example 89C and Example 89D: (S)-4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolazin]-7a'(5'H)-yl)methoxy)- 8-fluoro-6-nitroquinazolin-7-yl)-5,6-difluoronaphthalen-2-ol, and
(S)-4-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-2-(((1R,7a'R)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-吡咯嗪]-7a'(5'H)-基)甲氧基)-8-氟-6-硝基喹唑啉-7-基)-5,6-二氟萘-2-醇，和(S)-4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(((1R,7a'R)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolazin]-7a'(5'H)-yl)methoxy)-8-fluoro-6-nitroquinazolin-7-yl)-5, 6-difluoronaphthalen-2-ol, and
(R)-4-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-吡咯嗪]-7a'(5'H)-基)甲氧基)-8-氟-6-硝基喹唑啉-7-基)-5,6-二氟萘-2-醇，和(R)-4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolazin]-7a'(5'H)-yl)methoxy)-8-fluoro-6-nitroquinazolin-7-yl)-5, 6-difluoronaphth-2-ol, and
(R)-4-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-2-(((1R,7a'R)-2,2-二氟二氢-1'H,3'H-螺[环丙烷- 1,2'-吡咯嗪]-7a'(5'H)-基)甲氧基)-8-氟-6-硝基喹唑啉-7-基)-5,6-二氟萘-2-醇
(R)-4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(((1R,7a'R)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane- 1,2'-Pyrrolizine]-7a'(5'H)-yl)methoxy)-8-fluoro-6-nitroquinazolin-7-yl)-5,6-difluoronaphthalen-2-ol
实施例89经SFC分离(柱：DAICEL CHIRALPAK IG(250mm*30mm,10um)；流动相：A相为二氧化碳，B相为0.1％氨水/异丙醇；B相保持55％；流速：80毫升/分钟)，得到目标化合物。Example 89 was separated by SFC (column: DAICEL CHIRALPAK IG (250mm*30mm, 10um); mobile phase: phase A was carbon dioxide, phase B was 0.1% ammonia water/isopropanol; phase B was maintained at 55%; flow rate: 80 ml/min), and the target compound was obtained.
异构体1&2混合物，实施例89AB：LCMS(ESI):[M+H]+＝683.1；SFC分析(柱：Chiralpak AD-3 150*4.6mm，3um；流动相：A相为二氧化碳，B相为0.05％二乙胺/乙醇；梯度：保持40％的B相，流速：2.5毫升/分钟)：手性柱出峰位置为1.771min和2.830min；1H NMR(400MHz,CD3OD)δppm8.69(s,1H),7.60(dd,J＝3.7,9.2Hz,1H),7.38(q,J＝9.1Hz,1H),7.27(s,1H),6.99(d,J＝2.1Hz,1H),4.64(br d,J＝14.0Hz,1H),4.55(br d,J＝12.3Hz,1H),4.40-4.32(m,2H),3.80-3.62(m,4H),3.30-3.24(m,1H),3.17-3.12(m,1H),2.83(d,J＝12.3Hz,1H),2.73-2.65(m,1H),2.27(br dd,J＝5.3,13.4Hz,1H),2.13(br dd,J＝5.4,10.4Hz,1H),2.02(d,J＝13.4Hz,1H),1.96-1.75(m,7H),1.50-1.35(m,2H).Mixture of isomers 1 & 2, Example 89AB: LCMS (ESI): [M+H]+=683.1; SFC analysis (column: Chiralpak AD-3 150*4.6mm, 3um; mobile phase: phase A is carbon dioxide, phase B is 0.05% diethylamine/ethanol; gradient: keep 40% of phase B, flow rate: 2.5 ml/min): chiral column peak position is 1.771min and 2.830min;1H NMR (400MHz, CD3OD)δppm8.69(s,1H),7.60(dd,J=3.7,9.2Hz,1H),7.38(q,J=9.1Hz,1H),7.27(s,1H),6.99(d,J=2.1Hz,1H),4.64(br d,J=14.0Hz,1H),4.55(br d,J=12.3 Hz,1H),4.40-4.32(m,2H),3.80-3.62(m,4H),3.30-3.24(m,1H),3.17-3.12(m,1H),2.83(d,J＝12.3Hz,1H),2.73-2.65(m,1H),2.27(br dd,J＝5.3,13. 4Hz,1H),2.13(br dd,J＝5.4,10.4Hz,1H),2.02(d,J＝13.4Hz,1H),1.96-1.75(m,7H),1.50-1.35(m,2H).
异构体3，实施例89C：LCMS(ESI):[M+H]+＝683.1；SFC分析(柱：Chiralpak IG-3，100*4.6mm I.D.，3um；流动相：A相为二氧化碳，B相为0.05％二乙胺/异丙醇；梯度：保持40％的B相，流速：2.8毫升/分钟)：手性柱出峰位置为6.175min；1H NMR(400MHz,CD3OD)δppm 8.69(s,1H),7.60(dd,J＝3.7,9.3Hz,1H),7.45-7.31(m,1H),7.27(s,1H),6.99(d,J＝2.1Hz,1H),4.66-4.55(m,2H),4.40-4.31(m,2H),3.81-3.61(m,4H),3.27(br d,J＝6.9Hz,1H),3.18-3.12(m,1H),2.83(d,J＝12.1Hz,1H),2.75-2.64(m,1H),2.32-2.09(m,2H),2.02(br d,J＝13.5Hz,1H),1.96-1.72(m,7H),1.49-1.36(m,2H).Isomer 3, Example 89C: LCMS (ESI): [M+H]+=683.1; SFC analysis (column: Chiralpak IG-3, 100*4.6mm I.D., 3um; mobile phase: phase A is carbon dioxide, phase B is 0.05% diethylamine/isopropanol; gradient: keep 40% of phase B, flow rate: 2.8 ml/min): chiral column peak position is 6.175min;1H NMR (400MHz, CD3OD)δppm 8.69(s,1H),7.60(dd,J=3.7,9.3Hz,1H),7.45-7.31(m,1H),7.27(s,1H),6.99(d,J=2.1Hz,1H),4.66-4.55(m,2H),4.40-4.31(m,2H),3.81- 3.61(m,4H),3.27(br d,J=6.9Hz,1H),3.18-3.12(m,1H),2.83(d,J=12.1Hz,1H),2.75-2.64(m,1H),2.32-2.09(m,2H),2.02(br d,J=13.5Hz,1H),1.96 -1.72(m,7H),1.49-1.36(m,2H).
异构体4，实施例89D：LCMS(ESI):[M+H]+＝683.1；SFC分析(柱：Chiralpak IG-3，100*4.6mm I.D.，3um；流动相：A相为二氧化碳，B相为0.05％二乙胺/异丙醇；梯度：保持40％的B相，流速：2.8毫升/分钟)：手性柱出峰位置为9.134min；1H NMR(400MHz,CD3OD)δppm 8.69(s,1H),7.60(d, J＝9.0Hz,1H),7.38(q,J＝8.9Hz,1H),7.28(s,1H),6.99(d,J＝2.1Hz,1H),4.67(br d,J＝11.6Hz,1H),4.57(br d,J＝12.3Hz,1H),4.43-4.33(m,2H),3.85-3.67(m,4H),3.38-3.32(m,1H),3.23-3.15(m,1H),2.87(d,J＝12.1Hz,1H),2.79-2.66(m,1H),2.29(dd,J＝6.2,13.7Hz,1H),2.22-2.09(m,1H),2.03(br d,J＝13.5Hz,1H),1.98-1.75(m,7H),1.52-1.36(m,2H).Isomer 4, Example 89D: LCMS (ESI): [M+H] + =683.1; SFC analysis (column: Chiralpak IG-3, 100*4.6mm ID, 3um; mobile phase: phase A is carbon dioxide, phase B is 0.05% diethylamine/isopropanol; gradient: keep 40% of phase B, flow rate: 2.8 ml/min): the chiral column peak position is 9.134min; 1 H NMR (400MHz, CD3OD) δppm 8.69(s,1H),7.60(d, J=9.0Hz, 1H), 7.38(q, J=8.9Hz, 1H), 7.28(s, 1H), 6.99(d, J=2.1Hz, 1H), 4.67(br d, J=11.6Hz, 1H), 4.57(br d, J=12.3Hz, 1H), 4.43-4.33(m, 2H), 3.85-3.6 7(m,4H),3.38-3.32(m,1H),3.23-3.15(m,1H),2.87(d,J=12.1Hz,1H),2.79-2.66(m,1H),2.29(dd,J=6.2,13.7Hz,1H),2.22-2.09(m,1H),2.03(br d,J ＝13.5Hz,1H),1.98-1.75(m,7H),1.52-1.36(m,2H).
实施例90：4-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-2-(((1R,7a'R)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-吡咯嗪]-7a'(5'H)-基)甲氧基)-8-氟-6-硝基喹唑啉-7-基)-5-乙炔基-6-氟萘-2-醇
Example 90: 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(((1R,7a'R)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolazin]-7a'(5'H)-yl)methoxy)-8-fluoro-6-nitroquinazolin-7-yl)- 5-ethynyl-6-fluoronaphthalen-2-ol
实施例90采用与实施例88相同的方法，合成了该化合物4-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-2-(((1R,7a'R)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-吡咯嗪]-7a'(5'H)-基)甲氧基)-8-氟-6-硝基喹唑啉-7-基)-5-乙炔基-6-氟萘-2-醇(甲酸盐，328mg，黄色固体0.47mmol)。LCMS(ESI):[M+H]+＝689.1。1H NMR(400MHz,CD3OD)δppm 8.67(s,1H),8.47(s,1H),7.88(dd,J＝5.8,9.1Hz,1H),7.38-7.29(m,2H),7.01(d,J＝2.4Hz,1H),4.77-4.64(m,2H),4.59-4.49(m,2H),4.07(br s,2H),3.97(br d,J＝13.3Hz,1H),3.88-3.78(m,1H),3.65-3.54(m,1H),3.50-3.40(m,1H),3.39-3.35(m,1H),3.11(d,J＝12.3Hz,1H),2.97-2.88(m,1H),2.49-2.36(m,1H),2.32-2.20(m,1H),2.18-1.89(m,8H),1.66-1.52(m,2H).Example 90 Using the same method as in Example 88, the compound 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(((1R,7a'R)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolazin]-7a'(5'H)-yl)methoxy)-8-fluoro- 6-nitroquinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (formate salt, 328 mg, yellow solid 0.47 mmol). LCMS (ESI): [M+H] + = 689.1. 1 H NMR(400MHz,CD 3 OD)δppm 8.67(s,1H),8.47(s,1H),7.88(dd,J＝5.8,9.1Hz,1H),7.38-7.29(m,2H),7.01(d,J＝2.4Hz,1H),4.77-4.64(m,2H),4.59-4.49(m,2H),4.07(br s,2H),3.97(br d,J＝13.3Hz,1H),3.88-3.78(m,1H),3.65-3.54(m,1H),3.50-3.40(m,1H),3.39-3.35(m,1H),3.11(d,J＝12.3Hz,1H),2.97-2.88(m,1H),2.49-2.36(m,1H),2.32-2.20(m,1H),2.18-1.89(m,8H),1.66-1.52(m,2H).
实施例90A和实施例90B和实施例90C：(S)-4-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-吡咯嗪]-7a'(5'H)-基)甲氧基)-8-氟-6-硝基喹唑啉-7-基)-5-乙炔基-6-氟萘-2-醇，和Example 90A and Example 90B and Example 90C: (S)-4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolazin]-7a'(5'H)-yl)methoxy)- 8-fluoro-6-nitroquinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol, and
(S)-4-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-2-(((1R,7a'R)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-吡咯嗪]-7a'(5'H)-基)甲氧基)-8-氟-6-硝基喹唑啉-7-基)-5-乙炔基-6-氟萘-2-醇，和(S)-4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(((1R,7a'R)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolazin]-7a'(5'H)-yl)methoxy)-8-fluoro-6-nitroquinazolin-7-yl)-5- Ethynyl-6-fluoronaphthalen-2-ol, and
(R)-4-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-吡咯嗪]-7a'(5'H)-基)甲氧基)-8-氟-6-硝基喹唑啉-7-基)-5-乙炔基-6-氟萘-2-醇，和 (R)-4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolazin]-7a'(5'H)-yl)methoxy)-8-fluoro-6-nitroquinazolin-7-yl)-5- Ethynyl-6-fluoronaphthalen-2-ol, and
(R)-4-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-2-(((1R,7a'R)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-吡咯嗪]-7a'(5'H)-基)甲氧基)-8-氟-6-硝基喹唑啉-7-基)-5-乙炔基-6-氟萘-2-醇
(R)-4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(((1R,7a'R)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolazin]-7a'(5'H)-yl)methoxy)-8-fluoro-6-nitroquinazolin-7-yl)-5- Ethynyl-6-fluoronaphthalen-2-ol
实施例90经SFC分离(柱：DAICEL CHIRALPAK IG(250mm*30mm,10um)；流动相：A相为二氧化碳，B相为0.1％氨水/乙醇；B相保持55％；流速：80毫升/分钟)，得到目标化合物。Example 90 was separated by SFC (column: DAICEL CHIRALPAK IG (250mm*30mm, 10um); mobile phase: phase A was carbon dioxide, phase B was 0.1% ammonia water/ethanol; phase B was maintained at 55%; flow rate: 80 ml/min), and the target compound was obtained.
异构体1&2混合物，实施例90A：LCMS(ESI):[M+H]+＝689.2；SFC分析(柱：Chiralpak IG-3，100*4.6mm I.D.，3um；流动相：A相为二氧化碳，B相为0.05％二乙胺/乙醇；梯度：保持40％的B相，流速：2.8毫升/分钟)：手性柱出峰位置为1.381min和1.413min；1H NMR(400MHz,CD3OD)δppm 8.66(s,1H),7.85(dd,J＝5.8,9.1Hz,1H),7.35-7.25(m,2H),6.98(d,J＝2.3Hz,1H),4.65(br d,J＝12.9Hz,1H),4.51(br d,J＝12.4Hz,1H),4.39-4.30(m,2H),3.79(br d,J＝12.4Hz,1H),3.67(br s,3H),3.36-3.33(m,1H),3.29-3.24(m,1H),3.20-3.09(m,1H),2.83(d,J＝12.3Hz,1H),2.74-2.64(m,1H),2.26(td,J＝5.2,13.4Hz,1H),2.18-2.09(m,1H),2.01(br d,J＝13.6Hz,1H),1.94-1.75(m,7H),1.49-1.35(m,2H).Mixture of isomers 1 & 2, Example 90A: LCMS (ESI): [M+H]+=689.2; SFC analysis (column: Chiralpak IG-3, 100*4.6mm I.D., 3um; mobile phase: phase A is carbon dioxide, phase B is 0.05% diethylamine/ethanol; gradient: keep 40% of phase B, flow rate: 2.8 ml/min): chiral column peak position is 1.381min and 1.413min;1H NMR (400MHz, CD3OD)δppm 8.66(s,1H),7.85(dd,J=5.8,9.1Hz,1H),7.35-7.25(m,2H),6.98(d,J=2.3Hz,1H),4.65(br d,J=12.9Hz,1H),4.51(br d,J=12.4Hz,1H),4.39-4 .30(m,2H),3.79(br d,J=12.4Hz,1H),3.67(br s,3H),3.36-3.33(m,1H),3.29-3.24(m,1H),3.20-3.09(m,1H),2.83(d,J=12.3Hz,1H),2.74-2.64(m, 1H), 2.26(td, J＝5.2, 13.4Hz, 1H), 2.18-2.09(m, 1H), 2.01(br d, J＝13.6Hz, 1H), 1.94-1.75(m, 7H), 1.49-1.35(m, 2H).
异构体3，实施例90B：LCMS(ESI):[M+H]+＝689.2；SFC分析(柱：Chiralpak IG-3，100*4.6mm I.D.，3um；流动相：A相为二氧化碳，B相为0.05％二乙胺/乙醇；梯度：保持40％的B相，流速：2.8毫升/分钟)：手性柱出峰位置为2.974min；1H NMR(400MHz,CD3OD)δppm 8.66(s,1H),7.85(dd,J＝5.8,9.1Hz,1H),7.37-7.27(m,2H),6.98(d,J＝2.4Hz,1H),4.64(br d,J＝11.5Hz,1H),4.52(br d,J＝12.6Hz,1H),4.35(s,2H),3.79(br d,J＝12.0Hz,1H),3.71-3.63(m,3H),3.36-3.34(m,1H),3.30-3.24(m,1H),3.18-3.11(m,1H),2.83(d,J＝12.1Hz,1H),2.74-2.65(m,1H),2.30-2.10(m,2H),2.01(br d,J＝13.5Hz,1H),1.96-1.75(m,7H),1.50-1.35(m,2H). Isomer 3, Example 90B: LCMS (ESI): [M+H]+=689.2; SFC analysis (column: Chiralpak IG-3, 100*4.6mm I.D., 3um; mobile phase: phase A is carbon dioxide, phase B is 0.05% diethylamine/ethanol; gradient: keep 40% of phase B, flow rate: 2.8 ml/min): chiral column peak position is 2.974min;1H NMR (400MHz, CD3OD)δppm 8.66(s,1H),7.85(dd,J=5.8,9.1Hz,1H),7.37-7.27(m,2H),6.98(d,J=2.4Hz,1H),4.64(br d,J=11.5Hz,1H),4.52(br d,J=12.6Hz,1H),4.35(s ,2H),3.79(br d,J=12.0Hz,1H),3.71-3.63(m,3H),3.36-3.34(m,1H),3.30-3.24(m,1H),3.18-3.11(m,1H),2.83(d,J=12.1Hz,1H),2.74-2.65(m,1H ),2.30-2.10(m,2H),2.01(br d,J＝13.5Hz,1H),1.96-1.75(m,7H),1.50-1.35(m,2H).
异构体4，实施例90C：LCMS(ESI):[M+H]+＝689.2；SFC分析(柱：Chiralpak IG-3，100*4.6mm I.D.，3um；流动相：A相为二氧化碳，B相为0.05％二乙胺/乙醇；梯度：保持40％的B相，流速：2.8毫升/分钟)：手性柱出峰位置为6.670min；1H NMR(400MHz,CD3OD)δppm 8.66(s,1H),7.85(dd,J＝5.9,9.1Hz,1H),7.35-7.27(m,2H),6.98(d,J＝2.4Hz,1H),4.65(br d,J＝12.0Hz,1H),4.51(br d,J＝12.3Hz,1H),4.40-4.29(m,2H),3.79(br d,J＝12.4Hz,1H),3.71-3.61(m,3H),3.34(s,1H),3.27(d,J＝6.8Hz,1H),3.18-3.11(m,1H),2.83(d,J＝12.1Hz,1H),2.74-2.65(m,1H),2.27(dd,J＝6.3,13.4Hz,1H),2.21-2.08(m,1H),2.02(br d,J＝13.4Hz,1H),1.96-1.74(m,7H),1.50-1.35(m,2H).Isomer 4, Example 90C: LCMS (ESI): [M+H]+=689.2; SFC analysis (column: Chiralpak IG-3, 100*4.6mm I.D., 3um; mobile phase: phase A is carbon dioxide, phase B is 0.05% diethylamine/ethanol; gradient: keep 40% of phase B, flow rate: 2.8 ml/min): chiral column peak position is 6.670min;1H NMR (400MHz, CD3OD)δppm 8.66(s,1H),7.85(dd,J=5.9,9.1Hz,1H),7.35-7.27(m,2H),6.98(d,J=2.4Hz,1H),4.65(br d,J=12.0Hz,1H),4.51(br d,J=12.3Hz,1H),4.40-4 .29(m,2H),3.79(br d,J=12.4Hz,1H),3.71-3.61(m,3H),3.34(s,1H),3.27(d,J=6.8Hz,1H),3.18-3.11(m,1H),2.83(d,J=12.1Hz,1H),2.74-2.65(m, 1H), 2.27(dd, J＝6.3, 13.4Hz, 1H), 2.21-2.08(m, 1H), 2.02(br d, J＝13.4Hz, 1H), 1.96-1.74(m, 7H), 1.50-1.35(m, 2H).
实施例91：4-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-2-(((1R,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-吡咯嗪]-7a'(5'H)-基)甲氧基)-8-氟-6-硝基喹唑啉-7-基)-5,6-二氟萘-2-醇
Example 91: 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(((1R,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolazin]-7a'(5'H)-yl)methoxy)-8-fluoro-6-nitroquinazolin-7-yl)- 5,6-Difluoronaphthalen-2-ol
实施例91使用与实施例87相同的方法，合成了目标化合物4-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-2-(((1R,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-吡咯嗪]-7a'(5'H)-基)甲氧基)-8-氟-6-硝基喹唑啉-7-基)-5,6-二氟萘-2-醇。LCMS(ESI):[M+H]+＝683.1。1H NMR(400MHz,DMSO-d6)δppm 10.32(br s,1H),8.64(s,1H),7.74(dd,J＝4.6,8.9Hz,1H),7.61-7.53(m,1H),7.35(s,1H),7.07(s,1H),4.51-4.33(m,2H),4.10-3.96(m,2H),3.75-3.49(m,4H),3.03(d,J＝10.3Hz,1H),2.99-2.93(m,1H),2.77(br dd,J＝5.9,10.4Hz,1H),2.67(td,J＝6.5,9.6Hz,2H),2.13-2.08(m,1H),1.99-1.72(m,5H),1.68-1.58(m,4H),1.57-1.49(m,2H).Example 91 Using the same method as in Example 87, the target compound 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(((1R,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolazin]-7a'(5'H)-yl)methoxy)-8-fluoro- 6-nitroquinazolin-7-yl)-5,6-difluoronaphthalen-2-ol. LCMS (ESI): [M+H] + = 683.1. 1 H NMR(400MHz,DMSO-d6)δppm 10.32(br s,1H),8.64(s,1H),7.74(dd,J＝4.6,8.9Hz,1H),7.61-7.53(m,1H),7.35(s,1H),7.07(s,1H),4.51-4.33(m,2H),4.10-3.96(m,2H),3.75-3.49(m,4H),3.03(d,J＝10.3Hz,1H),2.99-2.93(m,1H),2.77(br dd,J＝5.9,10.4Hz,1H),2.67(td,J＝6.5,9.6Hz,2H),2.13-2.08(m,1H),1.99-1.72(m,5H),1.68-1.58(m,4H),1.57-1.49(m,2H).
实施例92：4-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-2-(((1S,7a'R)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-吡咯嗪]-7a'(5'H)-基)甲氧基)-8-氟-6-硝基喹唑啉-7-基)-5-乙炔基-6-氟萘-2-醇
Example 92: 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(((1S,7a'R)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolazin]-7a'(5'H)-yl)methoxy)-8-fluoro-6-nitroquinazolin-7-yl)- 5-ethynyl-6-fluoronaphthalen-2-ol
实施例92采用与实施例88相同的方法，合成了该化合物4-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-2-(((1S,7a'R)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-吡咯嗪]-7a'(5'H)-基)甲氧基)-8-氟-6-硝基喹唑啉-7-基)-5-乙炔基-6-氟萘-2-醇(52.95mg，黄色固体)。LCMS(ESI):[M+H]+＝689.1。1H NMR(400MHz,CD3OD)δppm 8.67(s,1H),8.47(br s,1H),7.88(dd,J＝5.7,9.3Hz,1H),7.38-7.30(m,2H),7.01(d,J＝2.3Hz,1H),4.77-4.64(m,2H),4.52-4.43(m,2H),4.10-3.92(m,3H),3.85(br dd,J＝6.5,13.6Hz,1H),3.58-3.46(m,1H),3.43-3.35(m,2H),3.23-3.07(m,2H),2.45(br d,J＝13.4Hz,1H),2.26-2.14(m,3H),2.13-1.95(m,6H),1.64-1.56(m,2H).Example 92 Using the same method as in Example 88, the compound 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(((1S,7a'R)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolazin]-7a'(5'H)-yl)methoxy)-8-fluoro- 6-nitroquinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (52.95 mg, yellow solid). LCMS (ESI): [M+H] + = 689.1. 1 H NMR(400MHz,CD 3 OD)δppm 8.67(s,1H),8.47(br s,1H),7.88(dd,J＝5.7,9.3Hz,1H),7.38-7.30(m,2H),7.01(d,J＝2.3Hz,1H),4.77-4.64(m,2H),4.52-4.43(m,2H),4.10-3.92(m,3H),3.85(br dd,J＝6.5,13.6Hz,1H),3.58-3.46(m,1H),3.43-3.35(m,2H),3.23-3.07(m,2H),2.45(br d,J＝13.4Hz,1H),2.26-2.14(m,3H),2.13-1.95(m,6H),1.64-1.56(m,2H).
实施例93：4-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-2,8-双((1-(吗啉代甲基)环丙基)甲氧基)-6-硝基喹唑啉-7-基)-5,6-二氟萘-2-醇Example 93: 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2,8-bis((1-(morpholinomethyl)cyclopropyl)methoxy)-6-nitroquinazolin-7-yl)-5,6-difluoronaphthalen-2-ol
实施例94：4-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-8-氟-2-((1-(吗啉甲基)环丙基)甲氧基)-6-硝基喹唑啉-7-基)-5,6-二氟萘-2-醇
Example 94: 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-((1-(morpholinylmethyl)cyclopropyl)methoxy)-6-nitroquinazolin-7-yl)-5,6-difluoronaphthalen-2-ol
第一步：在0℃下，向化合物叔丁基(1R,5S)-3-(7-(7,8-二氟-3-(甲氧基甲氧基)萘-1-基)-8-氟-6-硝基-2-(2,2,2-三氟乙氧基)喹唑啉-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(200mg，0.28mmol)和(1-(吗啉甲基)环丙基)甲醇(236mg，1.38mmol)的四氢呋喃(3mL)溶液中慢慢加入叔丁醇钠(106mg，1.11mmol)，反应在25℃搅拌2小时。反应液加入水(4mL)稀释，乙酸乙酯(3mL*2)萃取，有机相用无水硫酸镁干燥，过滤，减压浓缩。残余物通过快速硅胶色谱法(硅胶，0-30％梯度的四氢呋喃/石油醚)纯化得到黄色油状化合物叔丁基(1R,5S)-3-(7-(7,8-二氟-3-(甲氧基甲氧基)萘-1-基)-8-氟-2-((1-(吗啉甲基)环丙基)甲氧基)-6-硝基喹唑啉-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(75％purity，210.0mg，0.17mmol，收率62％)LCMS(ESI):[M+2H]2+/2＝398.0和化合物叔丁基(1R,5S)-3-(7-(7,8-二氟-3-(甲氧基甲氧基)萘-1-基)-2,8-双((1-(吗啉甲基)环丙基)甲氧基)-6-硝基喹唑啉-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(90.0mg，0.09mmol，收率35％)。LCMS(ESI):[M+2H]2+/2＝473.6.The first step: at 0 ℃, to compound tert-butyl (1R, 5S)-3-(7-(7,8-difluoro-3-(methoxymethoxy)naphthalene-1-yl)-8-fluoro-6-nitro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (200mg, 0.28mmol) and (1-( To a solution of morpholinemethyl)cyclopropyl)methanol (236mg, 1.38mmol) in THF (3mL) was slowly added sodium tert-butoxide (106mg, 1.11mmol), and the reaction was stirred at 25°C for 2 hours. The reaction solution was diluted with water (4 mL), extracted with ethyl acetate (3 mL*2), and the organic phase was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure.残余物通过快速硅胶色谱法(硅胶，0-30％梯度的四氢呋喃/石油醚)纯化得到黄色油状化合物叔丁基(1R,5S)-3-(7-(7,8-二氟-3-(甲氧基甲氧基)萘-1-基)-8-氟-2-((1-(吗啉甲基)环丙基)甲氧基)-6-硝基喹唑啉-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(75％purity，210.0mg，0.17mmol，收率62％)LCMS(ESI):[M+2H] 2+ /2＝398.0和化合物叔丁基(1R,5S)-3-(7-(7,8-二氟-3-(甲氧基甲氧基)萘-1-基)-2,8-双((1-(吗啉甲基)环丙基)甲氧基)-6-硝基喹唑啉-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(90.0mg，0.09mmol，收率35％)。 LCMS (ESI): [M+2H] 2+ /2=473.6.
第二步：在25℃下，向叔丁基(1R,5S)-3-(7-(7,8-二氟-3-(甲氧基甲氧基)萘-1-基)-8-氟-2-((1-(吗啉甲基)环丙基)甲氧基)-6-硝基喹唑啉-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(200mg，0.19mmol)的乙腈(2mL)溶液中加入氯化氢(4M的二氧六环溶液，943uL，3.77mmol)。将该溶液在20℃搅拌1小时。溶液用三乙胺(100uL)淬灭并浓缩。混合物通过制备型HPLC纯化，得到黄色固体化合物4-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-8-氟-2-((1-(吗啉甲基)环丙基)甲氧基)-6-硝基喹唑啉-7-基)-5,6-二氟萘-2-醇实施例94(甲酸盐，17.10mg，26.0umol，收率14％)。LCMS(ESI):[M+H]+＝650.9。1H NMR(400MHz,CD3OD)δppm 8.67(s,1H),8.43(br s,1H),7.61(dd,J＝9.4,4.0Hz,1H),7.45-7.35(m,1H),7.29(s,1H),6.99(d,J＝1.9Hz,1H),4.80-4.56(m,2H),4.49-4.41(m,2H),4.11(br s,2H),3.96-3.83(m,2H),3.68(br t,J＝4.2Hz,4H),2.67-2.54(m,6H),2.08(br s,4H),0.75(s,2H),0.56(s,2H).The second step: at 25°C, to tert-butyl (1R,5S)-3-(7-(7,8-difluoro-3-(methoxymethoxy)naphthalene-1-yl)-8-fluoro-2-((1-(morpholinylmethyl)cyclopropyl)methoxy)-6-nitroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (200mg, 0.19mmol) To a solution of acetonitrile (2 mL) was added hydrogen chloride (4M in dioxane, 943 uL, 3.77 mmol). The solution was stirred at 20°C for 1 hour. The solution was quenched with triethylamine (100 uL) and concentrated. The mixture was purified by preparative HPLC to give yellow solid compound 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-((1-(morpholinomethyl)cyclopropyl)methoxy)-6-nitroquinazolin-7-yl)-5,6-difluoronaphthalene-2-ol Example 94 (formate salt, 17.10mg, 26.0umol, yield 1 4%). LCMS (ESI): [M+H] + = 650.9. 1 H NMR(400MHz,CD 3 OD)δppm 8.67(s,1H),8.43(br s,1H),7.61(dd,J＝9.4,4.0Hz,1H),7.45-7.35(m,1H),7.29(s,1H),6.99(d,J＝1.9Hz,1H),4.80-4.56(m,2H),4.49-4.41(m,2H),4.11(br s,2H),3.96-3.83(m,2H),3.68(br t,J＝4.2Hz,4H),2.67-2.54(m,6H),2.08(br s,4H),0.75(s,2H),0.56(s,2H).
以化合物叔丁基(1R,5S)-3-(7-(7,8-二氟-3-(甲氧基甲氧基)萘-1-基)-2,8-双((1-(吗啉甲基)环丙基)甲氧基)-6-硝基喹唑啉-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯为原料，采用相同的方法，得到化合物 4-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-2,8-双((1-(吗啉代甲基)环丙基)甲氧基)-6-硝基喹唑啉-7-基)-5,6-二氟萘-2-醇实施例93(二甲酸盐，27.57mg，34.0umol，收率36％)。LCMS(ESI):[M+H]+＝801.9。1H NMR(400MHz,CD3OD)δppm 8.68(s,1H),8.44(br s,2H),7.65(br dd,J＝8.4,4.4Hz,1H),7.51-7.35(m,1H),7.28(s,1H),6.95(d,J＝2.1Hz,1H),4.77-4.44(m,6H),4.30(d,J＝10.9Hz,1H),4.14-3.77(m,9H),3.69(br t,J＝4.4Hz,4H),3.53(br d,J＝12.8Hz,2H),3.10(br d,J＝9.5Hz,1H),2.83(br d,J＝12.8Hz,1H),2.66-2.47(m,5H),2.29(br d,J＝12.6Hz,1H),2.15-1.82(m,4H),0.82-0.66(m,2H),0.64-0.43(m,4H),0.31--0.24(m,2H).Using the compound tert-butyl(1R,5S)-3-(7-(7,8-difluoro-3-(methoxymethoxy)naphthalene-1-yl)-2,8-bis((1-(morpholinemethyl)cyclopropyl)methoxy)-6-nitroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate as raw material, the same method was used to obtain the compound 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2,8-bis((1-(morpholinomethyl)cyclopropyl)methoxy)-6-nitroquinazolin-7-yl)-5,6-difluoronaphthalen-2-ol Example 93 (diformic acid salt, 27.57mg, 34.0umol, yield 36%). LCMS (ESI): [M+H] + = 801.9. 1 H NMR(400MHz,CD 3 OD)δppm 8.68(s,1H),8.44(br s,2H),7.65(br dd,J＝8.4,4.4Hz,1H),7.51-7.35(m,1H),7.28(s,1H),6.95(d,J＝2.1Hz,1H),4.77-4.44(m,6H),4.30(d,J＝10.9Hz,1H),4.14-3.77(m,9H),3.69(br t,J＝4.4Hz,4H),3.53(br d,J＝12.8Hz,2H),3.10(br d,J＝9.5Hz,1H),2.83(br d,J＝12.8Hz,1H),2.66-2.47(m,5H),2.29(br d,J＝12.6Hz,1H),2.15-1.82(m,4H),0.82-0.66(m,2H),0.64-0.43(m,4H),0.31--0.24(m,2H).
实施例94A和实施例94B：(S)-4-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-8-氟-2-((1-(吗啉甲基)环丙基)甲氧基)-6-硝基喹唑啉-7-基)-5,6-二氟萘-2-醇，和EXAMPLE 94A and EXAMPLE 94B: (S)-4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-((1-(morpholinylmethyl)cyclopropyl)methoxy)-6-nitroquinazolin-7-yl)-5,6-difluoronaphthalen-2-ol, and
(R)-4-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-8-氟-2-((1-(吗啉甲基)环丙基)甲氧基)-6-硝基喹唑啉-7-基)-5,6-二氟萘-2-醇
(R)-4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-((1-(morpholinylmethyl)cyclopropyl)methoxy)-6-nitroquinazolin-7-yl)-5,6-difluoronaphthalen-2-ol
实施例94经SFC分离(柱：DAICEL CHIRALPAK AD(250mm*30mm,10um)；流动相：A相为二氧化碳，B相为0.1％氨水/异丙醇；B相保持50％；流速：80毫升/分钟)，得到目标化合物。Example 94 was separated by SFC (column: DAICEL CHIRALPAK AD (250mm*30mm, 10um); mobile phase: phase A was carbon dioxide, phase B was 0.1% ammonia water/isopropanol; phase B was maintained at 50%; flow rate: 80 ml/min), and the target compound was obtained.
异构体1,实施例94A：LCMS(ESI):[M+H]+＝651.3；SFC分析(柱:Chiralpak AD-3,50*4.6mm,3um；流动相：A相为二氧化碳，B相为0.05％二乙胺/异丙醇；梯度：保持40％的B相；流速：4毫升/分钟)：手性柱出峰位置为0.435min；1H NMR(400MHz,CD3OD)δppm 8.69(d,J＝1.25Hz,1H),7.60(dd,J＝9.16,2.4Hz,1H),7.38(q,J＝8.9Hz,1H),7.27(s,1H),6.99(d,J＝2.5Hz,1H),4.74-4.51(m,4H),4.46-4.38(m,2H),3.77(br d,J＝12.8Hz,1H),3.70(br d,J＝10.5Hz,3H),3.63(t,J＝4.5Hz,4H),2.56-2.44(m,4H),1.93-1.78(m,4H),0.74-0.67(m,2H),0.53-0.46(m,2H).Isomer 1, Example 94A: LCMS (ESI): [M+H]+=651.3; SFC analysis (column: Chiralpak AD-3,50*4.6mm, 3um; mobile phase: phase A is carbon dioxide, phase B is 0.05% diethylamine/isopropanol; gradient: keep 40% of phase B; flow rate: 4 ml/min): chiral column peak position is 0.435min;1H NMR (400MHz, CD3( m,2H),3.77(br d,J=12.8Hz,1H),3.70(br d,J=10.5Hz,3H),3.63(t,J=4.5Hz,4H),2.56-2.44(m,4H),1.93-1.78(m,4H),0.74-0.67(m,2H),0.53-0.46 (m,2H).
异构体2，实施例94B：LCMS(ESI):[M+H]+＝651.3；SFC分析(柱:Chiralpak AD-3,50*4.6mm,3um；流动相：A相为二氧化碳，B相为0.05％二乙胺/异丙醇；梯度：保持40％的B相；流速：4毫升/分钟)：手性柱出峰位置为1.264min；1H NMR(400MHz,CD3OD)δppm 8.69(d,J＝1.3Hz,1H),7.61(d,J＝9.3Hz,1H),7.39(q,J＝9.0Hz,1H),7.28(s,1H),7.00(d,J＝2.3Hz,1H),4.77-4.53(m,4H),4.49-4.38(m,2H),3.87-3.70(m,4H),3.64(t,J＝4.6Hz,4H),2.61-2.47(m,4H),2.01-1.83(m,4H),0.77-0.67(m,2H),0.55-0.47(m,2H).Isomer 2, Example 94B: LCMS (ESI): [M+H]+=651.3; SFC analysis (column: Chiralpak AD-3,50*4.6mm, 3um; mobile phase: phase A is carbon dioxide, phase B is 0.05% diethylamine/isopropanol; gradient: keep 40% of phase B; flow rate: 4 ml/min): chiral column peak position is 1.264min;1H NMR (400MHz, CD3OD)δppm 8.69(d,J=1.3Hz,1H),7.61(d,J=9.3Hz,1H),7.39(q,J=9.0Hz,1H),7.28(s,1H),7.00(d,J=2.3Hz,1H),4.77-4.53(m,4H),4.49-4.38(m,2H), 3.87-3.70(m,4H),3.64(t,J＝4.6Hz,4H),2.61-2.47(m,4H),2.01-1.83(m,4H),0.77-0.67(m,2H),0.55-0.47(m,2H).
实施例95：4-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-8-氟-2-((1-(吗啉甲基)环丙基)甲氧基)-6-硝基喹唑啉-7-基)-5-乙炔基-6-氟萘-2-醇
Example 95: 4-(4-((1R,5S)-3,8-Diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-((1-(morpholinylmethyl)cyclopropyl)methoxy)-6-nitroquinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol
实施例95采用与实施例88相同的方法，合成了化合物4-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-8-氟-2-((1-(吗啉甲基)环丙基)甲氧基)-6-硝基喹唑啉-7-基)-5-乙炔基-6-氟萘-2-醇(甲酸盐，9mg，黄色固体)。LCMS(ESI):[M+H]+＝657.3。1H NMR(400MHz,CD3OD)δppm 8.65(s,1H),8.41(br s,1H),7.88(dd,J＝5.8,9.1Hz,1H),7.41-7.26(m,2H),7.00(d,J＝2.4Hz,1H),4.77(br d,J＝13.9Hz,1H),4.69(br d,J＝13.5Hz,1H),4.52-4.40(m,2H),4.21(br s,2H),4.00(br d,J＝13.5Hz,1H),3.89(br d,J＝13.4Hz,1H),3.75(br t,J＝4.4Hz,4H),3.39(s,1H),2.87-2.67(m,6H),2.21-2.01(m,4H),0.86-0.77(m,2H),0.69-0.58(m,2H).Example 95 Using the same method as in Example 88, the compound 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-((1-(morpholinomethyl)cyclopropyl)methoxy)-6-nitroquinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (formate salt, 9 mg, yellow solid) was synthesized. LCMS (ESI): [M+H] + = 657.3. 1 H NMR(400MHz,CD 3 OD)δppm 8.65(s,1H),8.41(br s,1H),7.88(dd,J＝5.8,9.1Hz,1H),7.41-7.26(m,2H),7.00(d,J＝2.4Hz,1H),4.77(br d,J＝13.9Hz,1H),4.69(br d,J＝13.5Hz,1H),4.52-4.40(m,2H),4.21(br s,2H),4.00(br d,J＝13.5Hz,1H),3.89(br d,J＝13.4Hz,1H),3.75(br t,J＝4.4Hz,4H),3.39(s,1H),2.87-2.67(m,6H),2.21-2.01(m,4H),0.86-0.77(m,2H),0.69-0.58(m,2H).
实施例96：4-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-2-((3,3-二氟二氢-1'H,3'H-螺[环丁烷-1,2'-吡咯嗪]-7a'(5'H)-基)甲氧基)-8-氟-6-硝基喹唑啉-7-基)-5,6-二氟萘-2-醇
Example 96: 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-((3,3-difluorodihydro-1'H,3'H-spiro[cyclobutane-1,2'-pyrrolazin]-7a'(5'H)-yl)methoxy)-8-fluoro-6-nitroquinazolin-7-yl)-5,6-difluoronaphthalene-2- Alcohol
第一步：在25℃和氮气保护下向2-亚甲基-5-氧代四氢-1H-吡咯嗪-7a(5H)-羧酸乙酯(15.0g， 71.69mmol)的二氧六环溶液(240mL)中分批加入锌粉(23.44g，358.45mmol)，随后缓慢滴加三氯乙酰氯(65.18g，358.45mmol)。滴加完毕将反应液在25℃下搅拌4个小时。将反应液通过硅藻土进行过滤并用乙酸乙酯(100mL*3)进行冲洗。滤液再用饱和碳酸氢钠溶液(300mL*2)进行洗涤，用无水硫酸钠干燥，过滤，滤液旋干，得到粗品化合物2,2-二氯-3,5'-二氧代二氢-1'H,3'H-螺[环丁烷-1,2'-吡咯嗪]-7a'(5'H)-甲酸乙酯(22.0g)，其为棕色油状液体。LCMS(ESI):[M+H]+＝320.2The first step: 2-methylene-5-oxotetrahydro-1H-pyrrolazine-7a(5H)-carboxylic acid ethyl ester (15.0g, 71.69mmol) in dioxane solution (240mL) was added portionwise with zinc powder (23.44g, 358.45mmol), followed by the slow dropwise addition of trichloroacetyl chloride (65.18g, 358.45mmol). After the dropwise addition, the reaction solution was stirred at 25° C. for 4 hours. The reaction solution was filtered through celite and rinsed with ethyl acetate (100 mL*3). The filtrate was washed with saturated sodium bicarbonate solution (300mL*2), dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried to obtain the crude compound 2,2-dichloro-3,5'-dioxodihydro-1'H,3'H-spiro[cyclobutane-1,2'-pyrrolazine]-7a'(5'H)-ethyl carboxylate (22.0g), which was a brown oily liquid. LCMS (ESI): [M+H] + = 320.2
第二步：在25℃和氮气保护下，向2,2-二氯-3,5'-二氧代二氢-1'H,3'H-螺[环丁烷-1,2'-吡咯嗪]-7a'(5'H)-甲酸乙酯(22.0g，68.71mmol)的乙酸(220mL)溶液中分批加入锌粉(23.44g，358.46mmol)。然后将反应液在50℃搅拌16小时。将反应液用乙酸乙酯(500mL)稀释后过滤，滤液用饱和碳酸氢钠溶液(500mL*2)洗涤，用无水硫酸钠干燥，过滤，滤液旋干得到粗品。将所得粗品用快速柱色谱(硅胶，0-30％梯度的乙酸乙酯/石油醚)纯化，得到黄色油状产品3,5'-二氧代二氢-1'H,3'H-螺[环丁烷-1,2'-吡咯嗪]-7a'(5'H)-甲酸乙酯(4.50g，17.91mmol，收率26％)。LCMS(ESI):[M+H]+＝252.2Step 2: Zinc powder (23.44 g, 358.46 mmol) was added in batches to a solution of ethyl 2,2-dichloro-3,5'-dioxodihydro-1'H,3'H-spiro[cyclobutane-1,2'-pyrrolazine]-7a'(5'H)-formate (22.0 g, 68.71 mmol) in acetic acid (220 mL) at 25°C under nitrogen protection. The reaction was then stirred at 50°C for 16 hours. The reaction solution was diluted with ethyl acetate (500 mL) and then filtered. The filtrate was washed with saturated sodium bicarbonate solution (500 mL*2), dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried to obtain a crude product. The obtained crude product was purified by flash column chromatography (silica gel, 0-30% gradient ethyl acetate/petroleum ether) to obtain yellow oil product 3,5'-dioxodihydro-1'H,3'H-spiro[cyclobutane-1,2'-pyrrolazine]-7a'(5'H)-ethyl carboxylate (4.50 g, 17.91 mmol, yield 26%). LCMS (ESI): [M+H] + = 252.2
第三步：在-70℃和氮气保护下，向3,5'-二氧代二氢-1'H,3'H-螺[环丁烷-1,2'-吡咯嗪]-7a'(5'H)-甲酸乙酯(3.30g，13.13mmol)的二氯甲烷(33mL)溶液中缓慢加入二乙氨基三氟化硫(4.20g，26.26mmol)。然后将反应液自然升至20℃并在20℃和氮气保护下搅拌16小时。将反应液用饱和碳酸氢钠溶液(30mL*2)洗涤，用无水硫酸钠干燥，过滤，滤液旋干得到粗品。将所得粗品用快速柱色谱(硅胶，0-30％梯度的乙酸乙酯/石油醚)纯化，得到黄色油状化合物3,3-二氟-5'-氧代二氢-1'H,3'H-螺[环丁烷-1,2'-吡咯嗪]-7a'(5'H)-甲酸乙酯(1.20g，4.39mmol，收率33％)。LCMS(ESI):[M+H]+＝274.1。1H NMR(400MHz,CDCl3)δppm 4.27-4.19(m,2H),3.87-3.80(m,1H),3.36-3.24(m,1H),2.83-2.72(m,1H),2.71-2.62(m,2H),2.61-2.51(m,4H),2.42(ddd,J＝1.3,9.2,16.6Hz,1H),2.13-2.02(m,1H),1.98-1.91(m,1H),1.30(t,J＝7.2Hz,3H).Step 3: Diethylaminosulfur trifluoride (4.20 g, 26.26 mmol) was slowly added to a solution of ethyl 3,5'-dioxodihydro-1'H,3'H-spiro[cyclobutane-1,2'-pyrrolazine]-7a'(5'H)-formate (3.30 g, 13.13 mmol) in dichloromethane (33 mL) at -70°C under nitrogen protection. Then the reaction solution was naturally raised to 20° C. and stirred at 20° C. under nitrogen protection for 16 hours. The reaction solution was washed with saturated sodium bicarbonate solution (30 mL*2), dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried to obtain a crude product. The resulting crude product was purified by flash column chromatography (silica gel, 0-30% gradient ethyl acetate/petroleum ether) to obtain yellow oily compound 3,3-difluoro-5'-oxodihydro-1'H,3'H-spiro[cyclobutane-1,2'-pyrrolazine]-7a'(5'H)-ethyl carboxylate (1.20 g, 4.39 mmol, yield 33%). LCMS (ESI): [M+H] + = 274.1. 1 H NMR (400MHz, CDCl 3 ) δppm 4.27-4.19(m,2H),3.87-3.80(m,1H),3.36-3.24(m,1H),2.83-2.72(m,1H),2.71-2.62(m,2H),2.61-2.51(m,4H),2.42( ddd,J=1.3,9.2,16.6Hz,1H),2.13-2.02(m,1H),1.98-1.91(m,1H),1.30(t,J=7.2Hz,3H).
第四步：将化合物3,3-二氟-5'-氧代二氢-1'H,3'H-螺[环丁烷-1,2'-吡咯嗪]-7a'(5'H)-甲酸乙酯(400mg，1.46mmol)溶于四氢呋喃(4mL)，0℃下加入四氢铝锂(333mg，8.78mmol)。反应在60℃下搅拌2小时。冷却后小心向反应液中加入水(333uL)，氢氧化钠(15％水溶液，333uL)，水(666uL)，无水硫酸镁(1g)，搅拌30分钟，反应液过滤，滤液减压浓缩得到无色油状粗品化合物(3,3-二氟二氢-1'H,3'H-螺[环丁烷-1,2'-吡咯嗪]-7a'(5'H)-基)甲醇(0.39g)。LCMS(ESI):[M+H]+＝218.1Step 4: The compound 3,3-difluoro-5'-oxodihydro-1'H,3'H-spiro[cyclobutane-1,2'-pyrrolazine]-7a'(5'H)-ethyl formate (400mg, 1.46mmol) was dissolved in tetrahydrofuran (4mL), and lithium aluminum tetrahydrogen (333mg, 8.78mmol) was added at 0°C. The reaction was stirred at 60°C for 2 hours. After cooling, water (333uL), sodium hydroxide (15% aqueous solution, 333uL), water (666uL), anhydrous magnesium sulfate (1g) were carefully added to the reaction solution, stirred for 30 minutes, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain a colorless oily crude compound (3,3-difluorodihydro-1'H,3'H-spiro[cyclobutane-1,2'-pyrrolazin]-7a'(5'H)-yl)methanol (0. 39g). LCMS (ESI): [M+H] + = 218.1
第五步：将化合物(3,3-二氟二氢-1'H,3'H-螺[环丁烷-1,2'-吡咯嗪]-7a'(5'H)-基)甲醇(390mg，1.79mmol)和二异丙基乙胺(1.5mL，8.98mmol)溶于二氯甲烷(4mL)中，0℃下加入苯甲酰氯(420uL，3.59mmol)，反应液在25℃搅拌16小时。反应液用水(15mL)稀释，二氯甲烷萃取(5mL*3)，有机相用饱和食盐水洗涤(5mL)，硫酸钠干燥，过滤，滤液减压浓缩，残余物用快速柱色谱纯化(硅胶，0-30％梯度的四氢呋喃/石油醚)得黄色油状化合物(3,3-二氟二氢-1'H,3'H-螺[环丁烷-1,2'-吡咯嗪]-7a'(5'H)-基)苯甲酸甲酯(360mg，1.11mmol，收率62％)。LCMS(ESI):[M+H]+＝322.1。1H NMR(400MHz,CDCl3)δppm 8.16-7.97(m,2H),7.68-7.32(m,3H),4.42-4.21(m,2H),3.59(d,J＝10.5Hz,1H),3.35(td,J＝6.7,11.2Hz,1H),2.95-2.75(m,3H),2.72-2.57(m,3H),2.31(d,J＝13.6Hz,1H),2.16-2.06(m,1H),2.05-1.94(m,3H),1.90-1.77(m,1H).Step 5: Dissolve the compound (3,3-difluorodihydro-1'H,3'H-spiro[cyclobutane-1,2'-pyrrolazin]-7a'(5'H)-yl)methanol (390mg, 1.79mmol) and diisopropylethylamine (1.5mL, 8.98mmol) in dichloromethane (4mL), add benzoyl chloride (420uL, 3.59mmol) at 0°C, and the reaction solution Stir at 25°C for 16 hours. The reaction solution was diluted with water (15 mL), extracted with dichloromethane (5 mL*3), the organic phase was washed with saturated brine (5 mL), dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 0-30% gradient tetrahydrofuran/petroleum ether) to obtain yellow oily compound (3,3-difluorodihydro-1'H,3'H-spiro[cyclobutane-1,2'-pyrrolazin]-7a'(5'H)-yl)benzene Methyl formate (360 mg, 1.11 mmol, 62% yield). LCMS (ESI): [M+H] + = 322.1. 1 H NMR(400MHz,CDCl 3 )δppm 8.16-7.97(m,2H),7.68-7.32(m,3H),4.42-4.21(m,2H),3.59(d,J＝10.5Hz,1H),3.35(td,J＝6.7,11.2Hz,1H),2.95-2.75(m,3H),2.72-2.57(m,3H),2.31(d,J＝13.6Hz,1H),2.16-2.06(m,1H),2.05-1.94(m,3H),1.90-1.77(m,1H).
第六步：化合物(3,3-二氟二氢-1'H,3'H-螺[环丁烷-1,2'-吡咯嗪]-7a'(5'H)-基)苯甲酸甲酯(250mg，0.78mmol)溶于四氢呋喃(3mL)中，加入氢氧化钠(93mg，2.33mmol)的水(3mL)溶液，反应液在25℃搅拌16小时。反应液用乙酸乙酯萃取(5mL*3)，有机相用饱和食盐水洗涤(5mL)，硫 酸钠干燥，过滤，滤液减压浓缩得黄色油状化合物(3,3-二氟二氢-1'H,3'H-螺[环丁烷-1,2'-吡咯嗪]-7a'(5'H)-基)甲醇(106mg，0.48mmol，收率62％)。LCMS(ESI):[M+H]+＝218.0。1H NMR(400MHz,CDCl3)δppm 3.36-3.22(m,2H),3.18(br d,J＝10.0Hz,1H),2.97(br s,1H),2.80(br d,J＝10.0Hz,2H),2.67-2.51(m,4H),2.13(br d,J＝13.3Hz,1H),1.98-1.73(m,4H),1.71-1.61(m,1H).Step 6: The compound (3,3-difluorodihydro-1'H,3'H-spiro[cyclobutane-1,2'-pyrrolazin]-7a'(5'H)-yl)methyl benzoate (250mg, 0.78mmol) was dissolved in tetrahydrofuran (3mL), a solution of sodium hydroxide (93mg, 2.33mmol) in water (3mL) was added, and the reaction solution was stirred at 25°C for 16 hours. The reaction solution was extracted with ethyl acetate (5mL*3), the organic phase was washed with saturated brine (5mL), sulfur NaCl was dried, filtered, and the filtrate was concentrated under reduced pressure to obtain yellow oily compound (3,3-difluorodihydro-1'H,3'H-spiro[cyclobutane-1,2'-pyrrolizin]-7a'(5'H)-yl)methanol (106mg, 0.48mmol, yield 62%). LCMS (ESI): [M+H] + = 218.0. 1 H NMR (400MHz, CDCl 3 ) δppm 3.36-3.22 (m, 2H), 3.18 (br d, J = 10.0Hz, 1H), 2.97 (br s, 1H), 2.80 (br d, J = 10.0Hz, 2H), 2.67-2.51 (m, 4H), 2.13 (br d, J = 13.3Hz, 1H),1.98-1.73(m,4H),1.71-1.61(m,1H).
第七步：将化合物叔丁基(1R,5S)-3-(7-(7,8-二氟-3-(甲氧基甲氧基)萘-1-基)-8-氟-6-硝基-2-(2,2,2-三氟乙氧基)喹唑啉-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(100mg，138umol)溶于四氢呋喃(2mL)中，加入(3,3-二氟二氢-1'H,3'H-螺[环丁烷-1,2'-吡咯嗪]-7a'(5'H)-基)甲醇(60mg，276umol)和叔丁醇钠(26mg，276umol)，20℃搅拌2小时。反应液减压浓缩得到粗品化合物叔丁基(1R,5S)-3-(7-(7,8-二氟-3-(甲氧基甲氧基)萘-1-基)-2-((3,3-二氟二氢-1'H,3'H)-螺[环丁烷-1,2'-吡咯啉]-7a'(5'H)-基)甲氧基)-8-氟-6-硝基喹唑啉-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(120mg)。LCMS(ESI):[M+H]+＝841.2。Step 7: Dissolve the compound tert-butyl(1R,5S)-3-(7-(7,8-difluoro-3-(methoxymethoxy)naphthalene-1-yl)-8-fluoro-6-nitro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (100mg, 138umol) in tetrahydrofuran (2mL) Add (3,3-difluorodihydro-1'H,3'H-spiro[cyclobutane-1,2'-pyrrolazin]-7a'(5'H)-yl)methanol (60mg, 276umol) and sodium tert-butoxide (26mg, 276umol), and stir at 20°C for 2 hours. The reaction solution was concentrated under reduced pressure to obtain the crude compound tert-butyl(1R,5S)-3-(7-(7,8-difluoro-3-(methoxymethoxy)naphthalen-1-yl)-2-((3,3-difluorodihydro-1'H,3'H)-spiro[cyclobutane-1,2'-pyrroline]-7a'(5'H)-yl)methoxy)-8-fluoro-6-nitroquinazolin-4-yl)-3,8- Diazabicyclo[3.2.1]octane-8-carboxylate (120 mg). LCMS (ESI): [M+H] + = 841.2.
第八步：将化合物叔丁基(1R,5S)-3-(7-(7,8-二氟-3-(甲氧基甲氧基)萘-1-基)-2-((3,3-二氟二氢-1'H,3'H)-螺[环丁烷-1,2'-吡咯啉]-7a'(5'H)-基)甲氧基)-8-氟-6-硝基喹唑啉-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(120mg，142umol)溶于乙腈(0.2mL)，加入氯化氢(4M的二氧六环，0.6mL，2.37mmol)，20℃搅拌2小时。反应液减压浓缩，残留物溶于乙腈(500uL)，加入三乙胺调节pH到8，混合物用制备型HPLC纯化，得到黄色固体化合物4-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-2-((3,3-二氟二氢-1'H,3'H-螺[环丁烷-1,2'-吡咯嗪]-7a'(5'H)-基)甲氧基)-8-氟-6-硝基喹唑啉-7-基)-5,6-二氟萘-2-醇(25mg，36umol，收率15％)。LCMS(ESI):[M+H]+＝697.1。1H NMR(400MHz,CD3OD)δppm8.71(s,1H),7.61(br d,J＝9.2Hz,1H),7.39(q,J＝8.7Hz,1H),7.29(s,1H),7.01(d,J＝2.2Hz,1H),4.68-4.49(m,2H),4.33-4.19(m,2H),3.82-3.64(m,4H),3.25(d,J＝10.5Hz,1H),3.16-3.05(m,1H),2.92-2.80(m,2H),2.76-2.56(m,4H),2.38(d,J＝13.3Hz,1H),2.09-1.78(m,9H).Step 8: Compound tert-butyl (1R,5S)-3-(7-(7,8-difluoro-3-(methoxymethoxy)naphthalen-1-yl)-2-((3,3-difluorodihydro-1'H,3'H)-spiro[cyclobutane-1,2'-pyrroline]-7a'(5'H)-yl)methoxy)-8-fluoro-6-nitroquinazolin-4-yl)-3,8-diazepine Bicyclo[3.2.1]octane-8-carboxylate (120mg, 142umol) was dissolved in acetonitrile (0.2mL), hydrogen chloride (4M dioxane, 0.6mL, 2.37mmol) was added, and stirred at 20°C for 2 hours. The reaction solution was concentrated under reduced pressure, the residue was dissolved in acetonitrile (500uL), and triethylamine was added to adjust the pH to 8. The mixture was purified by preparative HPLC to obtain a yellow solid compound 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-((3,3-difluorodihydro-1'H,3'H-spiro[cyclobutane-1,2'-pyrrolazine]-7a'(5'H )-yl)methoxy)-8-fluoro-6-nitroquinazolin-7-yl)-5,6-difluoronaphthalen-2-ol (25mg, 36umol, yield 15%). LCMS (ESI): [M+H] + = 697.1. 1 H NMR(400MHz,CD 3 OD)δppm8.71(s,1H),7.61(br d,J＝9.2Hz,1H),7.39(q,J＝8.7Hz,1H),7.29(s,1H),7.01(d,J＝2.2Hz,1H),4.68-4.49(m,2H),4.33-4.19(m,2H),3.82-3.64(m,4H),3.25(d,J＝10.5Hz,1H),3.16-3.05(m,1H),2.92-2.80(m,2H),2.76-2.56(m,4H),2.38(d,J＝13.3Hz,1H),2.09-1.78(m,9H).
实施例96B和实施例96C：4-((S)-4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-2-(((R)-3,3-二氟二氢-1'H,3'H-螺[环丁烷-1,2'-吡咯嗪]-7a'(5'H)-基)甲氧基)-8-氟-6-硝基喹唑啉-7-基)-5,6-二氟萘-2-醇，和Example 96B and Example 96C: 4-((S)-4-((1R,5S)-3,8-Diazabicyclo[3.2.1]oct-3-yl)-2-(((R)-3,3-difluorodihydro-1'H,3'H-spiro[cyclobutane-1,2'-pyrrolazin]-7a'(5'H)-yl)methoxy)-8-fluoro-6-nitroquinazoline- 7-yl)-5,6-difluoronaphthalen-2-ol, and
4-((S)-4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-2-(((S)-3,3-二氟二氢-1'H,3'H-螺[环丁烷-1,2'-吡咯嗪]-7a'(5'H)-基)甲氧基)-8-氟-6-硝基喹唑啉-7-基)-5,6-二氟萘-2-醇，和4-((S)-4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(((S)-3,3-difluorodihydro-1'H,3'H-spiro[cyclobutane-1,2'-pyrrolazin]-7a'(5'H)-yl)methoxy)-8-fluoro-6-nitroquinazolin-7-yl)-5,6-difluoronaphthalene -2-ol, and
4-((R)-4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-2-(((R)-3,3-二氟二氢-1'H,3'H-螺[环丁烷-1,2'-吡咯嗪]-7a'(5'H)-基)甲氧基)-8-氟-6-硝基喹唑啉-7-基)-5,6-二氟萘-2-醇，和4-((R)-4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(((R)-3,3-difluorodihydro-1'H,3'H-spiro[cyclobutane-1,2'-pyrrolazin]-7a'(5'H)-yl)methoxy)-8-fluoro-6-nitroquinazolin-7-yl)-5,6-difluoronaphthalene -2-ol, and
4-((R)-4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-2-(((S)-3,3-二氟二氢-1'H,3'H-螺[环丁烷-1,2'-吡咯嗪]-7a'(5'H)-基)甲氧基)-8-氟-6-硝基喹唑啉-7-基)-5,6-二氟萘-2-醇
4-((R)-4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(((S)-3,3-difluorodihydro-1'H,3'H-spiro[cyclobutane-1,2'-pyrrolazin]-7a'(5'H)-yl)methoxy)-8-fluoro-6-nitroquinazolin-7-yl)-5,6-difluoronaphthalene -2-ol
实施例96经SFC分离(柱：DAICEL CHIRALPAK AD(250mm*30mm,10um)；流动相：A相为二氧化碳，B相为0.1％氨水/异丙醇；B相保持55％；流速：80毫升/分钟)，得到目标化合物。Example 96 was separated by SFC (column: DAICEL CHIRALPAK AD (250mm*30mm, 10um); mobile phase: phase A was carbon dioxide, phase B was 0.1% ammonia water/isopropanol; phase B was maintained at 55%; flow rate: 80 ml/min), and the target compound was obtained.
异构体1&2混合物,实施例96A：LCMS(ESI):[M+H]+＝697.1；SFC分析(色谱柱:Chiralpak AD-3，50mm*4.6mm，3um；流动相：A相为二氧化碳，B相为0.05％二乙胺/异丙醇；梯度：保持B相在40％；流速：4毫升/分钟)：手性柱出峰位置为0.370min；1H NMR(400MHz,CD3OD)δppm 8.58(s,1H),7.52-7.45(m,1H),7.27(q,J＝8.8Hz,1H),7.17(s,1H),6.91-6.86(m,1H),4.55-4.50(m,1H),4.47-4.39(m,1H),4.24-4.05(m,2H),3.69-3.51(m,4H),3.16-3.08(m,1H),3.03-2.92(m,1H),2.81-2.68(m,2H),2.64-2.44(m,4H),2.25(br d,J＝13.4Hz,1H),1.95-1.83(m,3H),1.82-1.64(m,6H).Mixture of isomers 1 & 2, Example 96A: LCMS (ESI): [M+H]+=697.1; SFC analysis (chromatographic column: Chiralpak AD-3, 50mm*4.6mm, 3um; mobile phase: phase A is carbon dioxide, phase B is 0.05% diethylamine/isopropanol; gradient: keep phase B at 40%; flow rate: 4 ml/min): chiral column peak position is 0.370min;1H NMR (400MHz, CD3OD)δppm 8.58(s,1H),7.52-7.45(m,1H),7.27(q,J＝8.8Hz,1H),7.17(s,1H),6.91-6.86(m,1H),4.55-4.50(m,1H),4.47-4.39(m,1H),4.24-4.05(m 1 .82-1.64(m,6H).
异构体3,实施例96B：LCMS(ESI):[M+H]+＝697.1；SFC分析(色谱柱:Chiralpak AD-3，50mm*4.6mm，3um；流动相：A相为二氧化碳，B相为0.05％二乙胺/异丙醇；梯度：保持B相在40％；流速：4毫升/分钟)：手性柱出峰位置为0.739min；1H NMR(400MHz,CD3OD)δppm 8.68(s,1H),7.59(br d,J＝9.0Hz,1H),7.37(q,J＝8.9Hz,1H),7.27(br s,1H),6.99(s,1H),4.63(br d,J＝12.1Hz,1H),4.54(br d,J＝12.3Hz,1H),4.33-4.18(m,2H),3.82-3.62(m,4H),3.25-3.18(m,1H),3.12-3.03(m,1H),2.86(br d,J＝10.0Hz,2H),2.74-2.55(m,4H),2.35(br d,J＝13.1Hz,1H),2.05-1.95(m,3H),1.90-1.73(m,6H).Isomer 3, Example 96B: LCMS (ESI): [M+H]+=697.1; SFC analysis (chromatographic column: Chiralpak AD-3, 50mm*4.6mm, 3um; mobile phase: phase A is carbon dioxide, phase B is 0.05% diethylamine/isopropanol; gradient: keep phase B at 40%; flow rate: 4 ml/min): the chiral column peak position is 0.739min;1H NMR (400MHz, CD3OD)δppm 8.68(s,1H),7.59(br d,J=9.0Hz,1H),7.37(q,J=8.9Hz,1H),7.27(br s,1H),6.99(s,1H),4.63(br d,J=12.1Hz,1H),4.54(br d,J=12.3Hz,1H), 4.33-4.18(m,2H),3.82-3.62(m,4H),3.25-3.18(m,1H),3.12-3.03(m,1H),2.86(br d,J＝10.0Hz,2H),2.74-2.55(m,4H),2.35(br d,J＝13.1Hz,1H),2 .05-1.95(m,3H),1.90-1.73(m,6H).
异构体4,实施例96C：LCMS(ESI):[M+H]+＝697.1；SFC分析(色谱柱:Chiralpak AD-3，50mm*4.6mm，3um；流动相：A相为二氧化碳，B相为0.05％二乙胺/异丙醇；梯度：保持B相在40％；流速：4毫升/分钟)：手性柱出峰位置为1.893min；1H NMR(400MHz,CD3OD)δppm 8.69(s,1H),7.59(dd,J＝4.1,9.1Hz,1H),7.41-7.34(m,1H),7.27(s,1H),6.99(d,J＝2.1Hz,1H),4.58(br d,J＝12.0Hz,2H),4.31-4.17(m,2H),3.79-3.60(m,4H),3.24-3.17(m,1H),3.10-3.01(m,1H),2.87-2.76(m,2H),2.75- 2.55(m,4H),2.39-2.29(m,1H),2.06-1.96(m,3H),1.90-1.74(m,6H).异构体4,实施例96C：LCMS(ESI):[M+H] + ＝697.1；SFC分析(色谱柱:Chiralpak AD-3，50mm*4.6mm，3um；流动相：A相为二氧化碳，B相为0.05％二乙胺/异丙醇；梯度：保持B相在40％；流速：4毫升/分钟)：手性柱出峰位置为1.893min； 1 H NMR(400MHz,CD 3 OD)δppm 8.69(s,1H),7.59(dd,J＝4.1,9.1Hz,1H),7.41-7.34(m,1H),7.27(s,1H),6.99(d,J＝2.1Hz,1H),4.58(br d,J＝12.0Hz,2H),4.31-4.17(m,2H),3.79-3.60(m,4H),3.24-3.17(m,1H),3.10-3.01(m,1H),2.87-2.76(m,2H),2.75- 2.55(m,4H),2.39-2.29(m,1H),2.06-1.96(m,3H),1.90-1.74(m,6H).
实施例97：4-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-2-((3,3-二氟二氢-1'H,3'H-螺[环丁烷-1,2'-吡咯嗪]-7a'(5'H)-基)甲氧基)-8-氟-6-硝基喹唑啉-7-基)-5-乙炔基-6-氟萘-2-醇
Example 97: 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-((3,3-difluorodihydro-1'H,3'H-spiro[cyclobutane-1,2'-pyrrolazin]-7a'(5'H)-yl)methoxy)-8-fluoro-6-nitroquinazolin-7-yl)-5-ethynyl-6-fluoronaphthyl -2-ol
第一步：将化合物叔丁基(1R,5S)-3-(8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三异丙基甲硅烷基)乙炔基)萘-1-基)-6-硝基-2-(2,2,2-三氟乙氧基)喹唑啉-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(180mg，203umol)溶于四氢呋喃(2mL)中，加入(3,3-二氟二氢-1'H,3'H-螺[环丁烷-1,2'-吡咯嗪]-7a'(5'H)-基)甲醇(88mg，406umol)和叔丁醇钠(39mg，406umol)，20℃搅拌2小时。反应液用硅藻土过滤，滤液减压浓缩得到粗品化合物叔丁基(1R,5S)-3-(2-((3,3-二氟二氢-1'H,3'H-螺[环丁烷-1,2'-吡咯嗪]-7a'(5'H)-基)甲氧基)-8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三异丙基甲硅烷基)乙炔基)萘-1-基)-6-硝基喹唑啉-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(240mg)。LCMS(ESI):[M+H]+＝1003.3.The first step: compound tert-butyl(1R,5S)-3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalene-1-yl)-6-nitro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (180mg, 203 umol) was dissolved in tetrahydrofuran (2mL), and (3,3-difluorodihydro-1'H,3'H-spiro[cyclobutane-1,2'-pyrrolazin]-7a'(5'H)-yl)methanol (88mg, 406umol) and sodium tert-butoxide (39mg, 406umol) were added, and stirred at 20°C for 2 hours. The reaction solution was filtered with diatomaceous earth, and the filtrate was concentrated under reduced pressure to obtain the crude compound tert-butyl(1R,5S)-3-(2-((3,3-difluorodihydro-1'H,3'H-spiro[cyclobutane-1,2'-pyrrolazin]-7a'(5'H)-yl)methoxy)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalene-1 -yl)-6-nitroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (240 mg). LCMS (ESI): [M+H] + = 1003.3.
第二步：将化合物叔丁基(1R,5S)-3-(2-((3,3-二氟二氢-1'H,3'H-螺[环丁烷-1,2'-吡咯嗪]-7a'(5'H)-基)甲氧基)-8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三异丙基甲硅烷基)乙炔基)萘-1-基)-6-硝基喹唑啉-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(240mg，0.24mmol)和氟化铯(364mg，2.4mmol)的二甲基甲酰胺(2mL)溶液在25℃下搅拌2小时。反应液用水(5mL)稀释，乙酸乙酯(5mL*3)萃取，合并有机相，减压浓缩得到粗品化合物叔丁基(1R,5S)-3-(2-((3,3-二氟二氢-1'H,3'H-螺[环丁烷-1,2'-吡咯嗪]-7a'(5'H)-基)甲氧基)-7-(8-乙炔基-7-氟-3-(甲氧基甲氧基)萘-1-基)-8-氟-6-硝基喹唑啉-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(200mg)。LCMS(ESI):[M+H]+＝847.2.The second step: the compound tert-butyl (1R,5S)-3-(2-((3,3-difluorodihydro-1'H,3'H-spiro[cyclobutane-1,2'-pyrrolazin]-7a'(5'H)-yl)methoxy)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalene-1-yl)-6-nitroquinazoline- A solution of 4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (240 mg, 0.24 mmol) and cesium fluoride (364 mg, 2.4 mmol) in dimethylformamide (2 mL) was stirred at 25°C for 2 hours. The reaction solution was diluted with water (5mL), extracted with ethyl acetate (5mL*3), the organic phases were combined, and concentrated under reduced pressure to obtain the crude compound tert-butyl(1R,5S)-3-(2-((3,3-difluorodihydro-1'H,3'H-spiro[cyclobutane-1,2'-pyrrolazin]-7a'(5'H)-yl)methoxy)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalene-1 -yl)-8-fluoro-6-nitroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (200 mg). LCMS (ESI): [M+H] + = 847.2.
第三步：将化合物叔丁基(1R,5S)-3-(2-((3,3-二氟二氢-1'H,3'H-螺[环丁烷-1,2'-吡咯嗪]-7a'(5'H)-基)甲氧基)-7-(8-乙炔基-7-氟-3-(甲氧基甲氧基)萘-1-基)-8-氟-6-硝基喹唑啉-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(200mg，237umol)溶于乙腈(0.2mL)，加入氯化氢(4M的二氧六环溶液，0.6mL，2.37mmol)，20℃搅拌2小时。反应液减压浓缩，残留物溶于乙腈(500uL)，加入三乙胺调节pH到8，混合物用制备型HPLC纯化，得到黄色固体化合物4-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-2-((3,3-二氟二氢-1'H,3'H-螺[环丁烷-1,2'-吡咯嗪]-7a'(5'H)-基)甲氧基)-8-氟-6-硝基喹唑啉-7-基)-5-乙炔基-6-氟萘-2-醇(25mg，36umol，收率15％)。LCMS(ESI):[M+H]+＝703.3.1H NMR(400MHz,CD3OD) δppm 8.67(s,1H),7.86(dd,J＝5.9,9.1Hz,1H),7.37-7.26(m,2H),7.00(s,1H),4.69-4.49(m,2H),4.32-4.17(m,2H),3.86-3.75(m,1H),3.67(br s,3H),3.36(d,J＝6.0Hz,1H),3.21(d,J＝10.4Hz,1H),3.11-3.01(m,1H),2.89-2.77(m,2H),2.74-2.55(m,4H),2.36(br d,J＝14.1Hz,1H),2.09-1.80(m,9H).The third step: the compound tert-butyl(1R,5S)-3-(2-((3,3-difluorodihydro-1'H,3'H-spiro[cyclobutane-1,2'-pyrrolazin]-7a'(5'H)-yl)methoxy)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yl)-8-fluoro-6-nitroquinazolin-4-yl)-3,8-diaze Heterobicyclo[3.2.1]octane-8-carboxylate (200mg, 237umol) was dissolved in acetonitrile (0.2mL), hydrogen chloride (4M in dioxane, 0.6mL, 2.37mmol) was added, and stirred at 20°C for 2 hours. The reaction solution was concentrated under reduced pressure, the residue was dissolved in acetonitrile (500 uL), and triethylamine was added to adjust the pH to 8. The mixture was purified by preparative HPLC to obtain a yellow solid compound 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-((3,3-difluorodihydro-1'H,3'H-spiro[cyclobutane-1,2'-pyrrolazine]-7a'(5'H )-yl)methoxy)-8-fluoro-6-nitroquinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (25mg, 36umol, yield 15%). LCMS (ESI): [M+H] + = 703.3. 1 H NMR (400MHz, CD 3 OD) δppm 8.67(s,1H),7.86(dd,J＝5.9,9.1Hz,1H),7.37-7.26(m,2H),7.00(s,1H),4.69-4.49(m,2H),4.32-4.17(m,2H),3.86-3.75(m,1H),3.67(br s, 3H), 3.36(d, J=6.0Hz, 1H), 3.21(d, J=10.4Hz, 1H), 3.11-3.01(m, 1H), 2.89-2.77(m, 2H), 2.74-2.55(m, 4H), 2.36(br d, J=14.1Hz, 1H), 2.09-1.80(m, 9H ).
实施例97B和实施例97C：4-((S)-4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-2-(((R)-3,3-二氟二氢-1'H,3'H-螺[环丁烷)-1,2'-吡咯嗪]-7a'(5'H)-基)甲氧基)-8-氟-6-硝基喹唑啉-7-基)-5-乙炔基-6-氟萘-2-醇，或Example 97B and Example 97C: 4-((S)-4-((1R,5S)-3,8-Diazabicyclo[3.2.1]oct-3-yl)-2-(((R)-3,3-difluorodihydro-1'H,3'H-spiro[cyclobutane)-1,2'-pyrrolazin]-7a'(5'H)-yl)methoxy)-8-fluoro-6-nitroquinazoline -7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol, or
4-((S)-4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-2-(((S)-3,3-二氟二氢-1'H,3'H-螺[环丁烷)-1,2'-吡咯嗪]-7a'(5'H)-基)甲氧基)-8-氟-6-硝基喹唑啉-7-基)-5-乙炔基-6-氟萘-2-醇，或4-((S)-4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(((S)-3,3-difluorodihydro-1'H,3'H-spiro[cyclobutane)-1,2'-pyrrolazin]-7a'(5'H)-yl)methoxy)-8-fluoro-6-nitroquinazolin-7-yl)-5-ethynyl- 6-fluoronaphth-2-ol, or
4-((R)-4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-2-(((R)-3,3-二氟二氢-1'H,3'H-螺[环丁烷)-1,2'-吡咯嗪]-7a'(5'H)-基)甲氧基)-8-氟-6-硝基喹唑啉-7-基)-5-乙炔基-6-氟萘-2-醇，或4-((R)-4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(((R)-3,3-difluorodihydro-1'H,3'H-spiro[cyclobutane)-1,2'-pyrrolazin]-7a'(5'H)-yl)methoxy)-8-fluoro-6-nitroquinazolin-7-yl)-5-ethynyl- 6-fluoronaphth-2-ol, or
4-((R)-4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-2-(((S)-3,3-二氟二氢-1'H,3'H-螺[环丁烷)-1,2'-吡咯嗪]-7a'(5'H)-基)甲氧基)-8-氟-6-硝基喹唑啉-7-基)-5-乙炔基-6-氟萘-2-醇
4-((R)-4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(((S)-3,3-difluorodihydro-1'H,3'H-spiro[cyclobutane)-1,2'-pyrrolazin]-7a'(5'H)-yl)methoxy)-8-fluoro-6-nitroquinazolin-7-yl)-5-ethynyl- 6-Fluoronaphth-2-ol
实施例97经SFC分离(柱：DAICEL CHIRALPAK AD(250mm*30mm,10um)；流动相：A相为二氧化碳，B相为0.1％氨水/乙醇；B相保持50％；流速：80毫升/分钟)，得到目标化合物。Example 97 was separated by SFC (column: DAICEL CHIRALPAK AD (250mm*30mm, 10um); mobile phase: phase A was carbon dioxide, phase B was 0.1% ammonia water/ethanol; phase B was kept at 50%; flow rate: 80 ml/min), and the target compound was obtained.
异构体4,实施例97C：LCMS(ESI):[M+H]+＝703.1；SFC分析(色谱柱:Chiralpak AD-3，150mm*4.6mm，3um；流动相：A相为二氧化碳，B相为0.05％二乙胺/乙醇；梯度：B相保持在40％；流速：2.5毫升/分钟)：手性柱出峰位置为4.050min；1H NMR(400MHz,CD3OD)δppm 8.67(d,J＝1.1Hz,1H),7.86(dd,J＝5.8,9.1Hz,1H),7.39-7.28(m,2H),7.00(d,J＝2.3Hz,1H),4.66-4.50(m,2H),4.29-4.16(m,2H),3.84-3.75(m,1H),3.71-3.61(m,3H),3.37(s,1H),3.21(br d,J＝10.1Hz,1H),3.11-3.00(m,1H),2.88-2.79(m,2H),2.75-2.56(m,4H),2.35(d,J＝13.2Hz,1H),2.04-1.79(m,9H). Isomer 4, Example 97C: LCMS (ESI): [M+H]+=703.1; SFC analysis (chromatographic column: Chiralpak AD-3, 150mm*4.6mm, 3um; mobile phase: phase A is carbon dioxide, phase B is 0.05% diethylamine/ethanol; gradient: phase B remains at 40%; flow rate: 2.5 milliliters/minute): chiral column peak position is 4.050min;1H NMR (400MHz, CD3OD)δppm 8.67(d,J=1.1Hz,1H),7.86(dd,J=5.8,9.1Hz,1H),7.39-7.28(m,2H),7.00(d,J=2.3Hz,1H),4.66-4.50(m,2H),4.29-4.16(m,2H),3.84-3.75 (m,1H),3.71-3.61(m,3H),3.37(s,1H),3.21(br d,J=10.1Hz,1H),3.11-3.00(m,1H),2.88-2.79(m,2H),2.75-2.56(m,4H),2.35(d,J=13.2Hz,1H),2 .04-1.79(m,9H).
实施例98：4-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-2-((二氢-1'H,3'H-螺[氧杂环丁烷-3,2'-吡咯嗪]-7a'(5'H)-基)甲氧基)-8-氟-6-硝基喹唑啉-7-基)-5-乙炔基-6-氟萘-2-醇
Example 98: 4- (4- ((1R, 5s) -3,8-two-nitrogen miscellaneous dual ring [3.2.1] Xin-3-base) -2- ((dihydrous -1'h, 3'h-snail [oxygenytane-3, 2'pyrodiazine] -7A '(5'H)-base) -8-fluorobitoholine-7-base)-7-base)- 5-acetylene-6-fluorine-2-alcohol
实施例98参照实施例97类似合成路线制备得到的：LCMS(ESI):[M+H]+＝669.2；1H NMR(400MHz,CD3OD)δppm 8.67(s,1H),7.87(dd,J＝5.6,9.2Hz,1H),7.36-7.30(m,2H),7.00(s,1H),4.73(br d,J＝6.3Hz,2H),4.64(br d,J＝6.3Hz,2H),4.56-4.48(m,1H),4.23-4.12(m,2H),3.80(br d,J＝13.3Hz,1H),3.68(br s,3H),3.54(br d,J＝10.3Hz,1H),3.38-3.36(m,1H),3.08-3.01(m,1H),2.97(d,J＝10.3Hz,1H),2.78(td,J＝5.1,10.8Hz,1H),2.56(d,J＝13.3Hz,1H),2.11-1.91(m,4H),1.91-1.77(m,6H).Example 98 was prepared with reference to the similar synthetic route of Example 97: LCMS (ESI): [M+H]+= 669.2;1H NMR (400MHz, CD3OD)δppm 8.67(s,1H),7.87(dd,J=5.6,9.2Hz,1H),7.36-7.30(m,2H),7.00(s,1H),4.73(br d,J=6.3Hz,2H),4.64(br d,J=6.3Hz,2H),4.56-4.48(m,1H) ,4.23-4.12(m,2H),3.80(br d,J=13.3Hz,1H),3.68(br s,3H),3.54(br d,J=10.3Hz,1H),3.38-3.36(m,1H),3.08-3.01(m,1H),2.97(d,J=10.3Hz,1H), 2.78(td,J=5.1,10.8Hz,1H),2.56(d,J=13.3Hz,1H),2.11-1.91(m,4H),1.91-1.77(m,6H).
实施例99：4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-7-(8-乙炔基-7-氟萘-1-基)-8-氟-6-硝基-2-((四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)喹唑啉
Example 99: 4-((1R,5S)-3,8-Diazabicyclo[3.2.1]oct-3-yl)-7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-6-nitro-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinazoline
第一步：在氮气环境下，将叔丁基(1R,5S)-3-(7-溴-8-氟-6-硝基-2-(2,2,2-三氟乙氧基)喹唑啉-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(800mg，1.38mmol)和(((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(810mg，1.79mmol)加入到甲苯(32mL)和水(8mL)的混合溶液中，然后加入碳酸铯(1.35g，4.14mmol)，甲磺酰氧基(二金刚烷基-正丁基膦基)-2-氨基-1,1-联苯-2-基)钯(II)(200mg，0.28mmol)。将混合物在100℃搅拌16小时。将残余物用水(60mL)稀释并用乙酸乙酯(30mL*3)萃取，合并的有机相用盐水(60mL)洗涤，无水硫酸镁干燥并过滤，滤液真空浓缩。残余物通过快速柱色谱(硅胶，0-10％梯度四氢呋喃/石油醚)纯化得到棕色固体化合 物叔丁基(1R,5S)-3-(8-氟-7-(7-氟-8-((三异丙基甲硅烷基)乙炔基)萘-1-基)-6-硝基-2-(2,2,2-三氟乙氧基)喹唑啉-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(950mg，1.15mmol，收率83％)。LCMS(ESI):[M+H]+＝826.3.The first step: under nitrogen atmosphere, tert-butyl (1R,5S)-3-(7-bromo-8-fluoro-6-nitro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (800mg, 1.38mmol) and (((2-fluoro-8-(4,4,5,5-tetramethyl-1,3, 2-dioxaborolan-2-yl)naphthalene-1-yl)ethynyl)triisopropylsilane (810mg, 1.79mmol) was added to a mixed solution of toluene (32mL) and water (8mL), then cesium carbonate (1.35g, 4.14mmol), methanesulfonyloxy(diadamantyl-n-butylphosphino)-2-amino-1,1-biphenyl-2-yl)palladium (II) (200mg, 0.28 mmol). The mixture was stirred at 100°C for 16 hours. The residue was diluted with water (60 mL) and extracted with ethyl acetate (30 mL*3), the combined organic phases were washed with brine (60 mL), dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated in vacuo. The residue was purified by flash column chromatography (silica gel, 0-10% gradient tetrahydrofuran/petroleum ether) to give compound as a brown solid tert-Butyl(1R,5S)-3-(8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-6-nitro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (950mg, 1.15mmol, yield 83%). LCMS (ESI): [M+H] + = 826.3.
第二步：向叔丁基(1R,5S)-3-(8-氟-7-(7-氟-8-((三异丙基甲硅烷基)乙炔基)萘-1-基)-6-硝基-2-(2,2,2-三氟乙氧基)喹唑啉-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(400mg，0.48mmol)的四氢呋喃(8mL)溶液中加入4A分子筛(400mg)，叔丁醇钠(93mg，0.97mmol)和(四氢-1H-吡咯嗪-7a(5H)-基)甲醇(137mg，0.97mmol)。将反应在20℃搅拌2小时。混合物用水(15mL)稀释并用乙酸乙酯(15mL*3)萃取，合并的有机相用饱和食盐水(20mL)洗涤，无水硫酸镁干燥，过滤，滤液浓缩，残余物通过快速柱色谱(硅胶，0-6％梯度甲醇/二氯甲烷)纯化得到棕色固体化合物叔丁基(1R,5S)-3-(8-氟-7-(7-氟-8-((三异丙基甲硅烷基)乙炔基)萘-1-基)-6-硝基-2-((四氢-1H-吡咯啉-7a(5H)-基)甲氧基)喹唑啉-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(270mg，0.31mmol，收率65％)。LCMS(ESI):[M+H]+＝867.2.Second step: tetrahydrofuran ( 8 mL) solution was added 4A molecular sieves (400 mg), sodium tert-butoxide (93 mg, 0.97 mmol) and (tetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol (137 mg, 0.97 mmol). The reaction was stirred at 20 °C for 2 hours. The mixture was diluted with water (15mL) and extracted with ethyl acetate (15mL*3), the combined organic phase was washed with saturated brine (20mL), dried over anhydrous magnesium sulfate, filtered, the filtrate was concentrated, and the residue was purified by flash column chromatography (silica gel, 0-6% gradient methanol/dichloromethane) to obtain brown solid compound tert-butyl(1R,5S)-3-(8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalene-1- yl)-6-nitro-2-((tetrahydro-1H-pyrroline-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (270mg, 0.31mmol, yield 65%). LCMS (ESI): [M+H] + = 867.2.
第三步：向叔丁基(1R,5S)-3-(8-氟-7-(7-氟-8-((三异丙基甲硅烷基)乙炔基)萘-1-基)-6-硝基-2-((四氢-1H-吡咯啉-7a(5H)-基)甲氧基)喹唑啉-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(260mg，0.3mmol)的二甲基甲酰胺(3mL)溶液中加入氟化铯(364mg，2.4mmol)。将反应在20℃搅拌2小时。混合物用水(15mL)稀释并用乙酸乙酯(15mL*2)萃取，合并的有机相用饱和食盐水(20mL)洗涤，无水硫酸镁干燥，过滤，滤液浓缩，残余物通过快速柱色谱(硅胶，0-7％梯度甲醇/二氯甲烷)纯化得到棕色固体化合物叔丁基(1R,5S)-3-(7-(8-乙炔基-7-氟萘-1-基)-8-氟-6-硝基-2-((四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)喹唑啉-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(160mg，0.23mmol，收率77％)。LCMS(ESI):[M+H]+＝711.3.The third step: to tert-butyl (1R,5S)-3-(8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalene-1-yl)-6-nitro-2-((tetrahydro-1H-pyrroline-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (260mg, 0 .3 mmol) in dimethylformamide (3 mL) was added cesium fluoride (364 mg, 2.4 mmol). The reaction was stirred at 20 °C for 2 hours. The mixture was diluted with water (15 mL) and extracted with ethyl acetate (15 mL*2), the combined organic phases were washed with saturated brine (20 mL), dried over anhydrous magnesium sulfate, filtered, the filtrate was concentrated, and the residue was purified by flash column chromatography (silica gel, 0-7% methanol/dichloromethane gradient) to obtain brown solid compound tert-butyl (1R,5S)-3-(7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-6-nitro-2-( (Tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (160 mg, 0.23 mmol, yield 77%). LCMS (ESI): [M+H] + = 711.3.
第四步：向叔丁基(1R,5S)-3-(7-(8-乙炔基-7-氟萘-1-基)-8-氟-6-硝基-2-((四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)喹唑啉-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(155mg，0.22mmol)的乙腈(3mL)溶液中加入氯化氢(4M的二氧六环溶液，1mL，4mmol)。将反应在20℃搅拌1小时。真空旋干后溶于乙腈(2mL)，用三乙胺中和并浓缩。残余物通过制备型HPLC纯化，得到黄色固体化合物4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-7-(8-乙炔基-7-氟萘-1-基)-8-氟-6-硝基-2-((四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)喹唑啉(60mg，0.1mmol，收率45％)。LCMS(ESI):[M+H]+＝611.1.1H-NMR(400MHz,CD3OD)δppm 8.70(d,J＝1.3Hz,1H),8.17-8.04(m,2H),7.60(t,J＝7.8Hz,1H),7.49-7.37(m,2H),4.68(br d,J＝11.3Hz,1H),4.54(br d,J＝12.0Hz,1H),4.36-4.27(m,2H),3.82(br d,J＝11.5Hz,1H),3.72-3.63(m,3H),3.45(s,1H),3.21-3.09(m,2H),2.85-2.71(m,2H),2.11(td,J＝6.3,12.4Hz,2H),2.02-1.75(m,10H).Fourth step: Acetonitrile ( 3 mL) was added hydrogen chloride (4M in dioxane, 1 mL, 4 mmol). The reaction was stirred at 20 °C for 1 hour. After spinning in vacuo, it was dissolved in acetonitrile (2 mL), neutralized with triethylamine and concentrated. The residue was purified by preparative HPLC to give yellow solid compound 4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-6-nitro-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinazoline (60 mg, 0.1 mmol, yield 45%) . LCMS(ESI):[M+H] + ＝611.1. 1 H-NMR(400MHz,CD 3 OD)δppm 8.70(d,J＝1.3Hz,1H),8.17-8.04(m,2H),7.60(t,J＝7.8Hz,1H),7.49-7.37(m,2H),4.68(br d,J＝11.3Hz,1H),4.54(br d,J＝12.0Hz,1H),4.36-4.27(m,2H),3.82(br d,J＝11.5Hz,1H),3.72-3.63(m,3H),3.45(s,1H),3.21-3.09(m,2H),2.85-2.71(m,2H),2.11(td,J＝6.3,12.4Hz,2H),2.02-1.75(m,10H).
实施例100，实施例101参照实施例99的合成路线,第二步与不同的醇反应制备得到：Example 100 and Example 101 are prepared by referring to the synthetic route of Example 99, and reacting with different alcohols in the second step:
实施例100：4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛烷-3-基)-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)-6-硝基喹唑啉
Example 100: 4-((1R,5S)-3,8-Diazabicyclo[3.2.1]octan-3-yl)-7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-6-nitroquinazoline
LCMS(ESI):[M+H]+＝629.3。1H NMR(400MHz,CD3OD)δppm 8.69(d,J＝1.3Hz,1H),8.15-8.05(m,2H),7.60(t,J＝7.7Hz,1H),7.49-7.38(m,2H),5.39-5.23(m,1H),4.70-4.64(m,1H),4.57-4.49(m,1H),4.34-4.20(m,2H),3.81(br dd,J＝5.2,12.5Hz,1H),3.72-3.62(m,3H),3.43(d,J＝5.4Hz,1H),3.30-3.17(m,3H),3.02(dt,J＝5.4,9.4Hz,1H),2.41-2.12(m,3H),2.04-1.78(m,7H).LCMS (ESI): [M+H] + = 629.3. 1 H NMR(400MHz,CD 3 OD)δppm 8.69(d,J＝1.3Hz,1H),8.15-8.05(m,2H),7.60(t,J＝7.7Hz,1H),7.49-7.38(m,2H),5.39-5.23(m,1H),4.70-4.64(m,1H),4.57-4.49(m,1H),4.34-4.20(m,2H),3.81(br dd,J＝5.2,12.5Hz,1H),3.72-3.62(m,3H),3.43(d,J＝5.4Hz,1H),3.30-3.17(m,3H),3.02(dt,J＝5.4,9.4Hz,1H),2.41-2.12(m,3H),2.04-1.78(m,7H).
实施例101：反式-7a'-(((4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-7-(8-乙炔基-7-氟萘-1-基)-8-氟-6-硝基喹唑啉-2-基)氧基)甲基)-2,2-二氟四氢-1'H,3'H-螺[环丙烷-1,2'-吡咯嗪]
Example 101: trans-7a'-(((4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-6-nitroquinazolin-2-yl)oxy)methyl)-2,2-difluorotetrahydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolazine ]
LCMS(ESI):[M+H]+＝673.2。1H NMR(400MHz,CD3OD)δppm 8.71-8.68(m,1H),8.14-8.06(m,2H),7.60(t,J＝7.6Hz,1H),7.48-7.39(m,2H),4.67(br d,J＝13.1Hz,1H),4.53(br d,J＝12.8Hz,1H),4.41-4.32(m,2H),3.81(br d,J＝12.5Hz,1H),3.69(br s,3H),3.44(d,J＝2.1Hz,1H),3.32-3.26(m,1H),3.20-3.13(m,1H),2.85(d,J＝12.2Hz,1H),2.75-2.67(m,1H),2.28(ddd,J＝3.4,6.1,13.5Hz,1H),2.19-2.11(m,1H),2.03(br d,J＝13.3Hz,1H),1.95-1.77(m,7H),1.52-1.37(m,2H)LCMS (ESI): [M+H] + = 673.2. 1 H NMR(400MHz,CD 3 OD)δppm 8.71-8.68(m,1H),8.14-8.06(m,2H),7.60(t,J＝7.6Hz,1H),7.48-7.39(m,2H),4.67(br d,J＝13.1Hz,1H),4.53(br d,J＝12.8Hz,1H),4.41-4.32(m,2H),3.81(br d,J＝12.5Hz,1H),3.69(br s,3H),3.44(d,J＝2.1Hz,1H),3.32-3.26(m,1H),3.20-3.13(m,1H),2.85(d,J＝12.2Hz,1H),2.75-2.67(m,1H),2.28(ddd,J＝3.4,6.1,13.5Hz,1H),2.19-2.11(m,1H),2.03(br d,J＝13.3Hz,1H),1.95-1.77(m,7H),1.52-1.37(m,2H)
实施例101A:(1S,7a'S)-7a'-((((S)-4-((1R,5S)-3,8-二氮杂二环[3.2.1]辛-3-基)-7-(8-乙炔基-7-氟萘基-1-基)-8-氟-6-硝基喹唑啉-2-基)氧)甲基)-2,2-二氟四氢-1'H,3'H-螺旋[环丙烷-1,2'-吡咯嗪]、Example 101A: (1S,7a'S)-7a'-((((S)-4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-7-(8-ethynyl-7-fluoronaphthyl-1-yl)-8-fluoro-6-nitroquinazolin-2-yl)oxy)methyl)-2,2-difluorotetrahydro-1'H,3'H-helix [Cyclopropane-1,2'-pyrrolazine],
实施例101B：(1R,7a'R)-7a'-((((R)-4-((1R,5S)-3,8-二氮杂二环[3.2.1]辛-3-基)-7-(8-乙炔基-7-氟萘基-1-基)-8-氟-6-硝基喹唑啉-2-基)氧)甲基)-2,2-二氟四氢-1'H,3'H-螺旋[环丙烷-1,2'-吡咯嗪]、Example 101B: (1R,7a'R)-7a'-((((R)-4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-7-(8-ethynyl-7-fluoronaphthyl-1-yl)-8-fluoro-6-nitroquinazolin-2-yl)oxy)methyl)-2,2-difluorotetrahydro-1'H,3'H-helix [Cyclopropane-1,2'-pyrrolazine],
实施例101C:(1R,7a'R)-7a'-((((S)-4-((1R,5S)-3,8-二氮杂二环[3.2.1]辛-3-基)-7-(8-乙炔基-7-氟萘基-1-基)-8-氟-6-硝基喹唑啉-2-基)氧)甲基)-2,2-二氟四氢-1'H,3'H-螺旋[环丙烷-1,2'-吡咯嗪]和Example 101C: (1R,7a'R)-7a'-((((S)-4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-7-(8-ethynyl-7-fluoronaphthyl-1-yl)-8-fluoro-6-nitroquinazolin-2-yl)oxy)methyl)-2,2-difluorotetrahydro-1'H,3'H-helix [cyclopropane-1,2'-pyrrolazine] and
实施例101D:(1S,7a'S)-7a'-((((R)-4-((1R,5S)-3,8-二氮杂二环[3.2.1]辛-3-基)-7-(8-乙炔基-7-氟萘基-1-基)-8-氟-6-硝基喹唑啉-2-基)氧)甲基)-2,2-二氟四氢-1'H,3'H-螺旋[环丙烷-1,2'-吡咯嗪]
Example 101D: (1S,7a'S)-7a'-((((R)-4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-7-(8-ethynyl-7-fluoronaphthyl-1-yl)-8-fluoro-6-nitroquinazolin-2-yl)oxy)methyl)-2,2-difluorotetrahydro-1'H,3'H-helix [Cyclopropane-1,2'-pyrrolazine]
实施例101经SFC分离(柱：DAICEL CHIRALPAK IC(250mm*30mm,10um))；流动相：A相为二氧化碳，B相为0.1％氨水/异丙醇；B相保持60％；流速：80毫升/分钟)，得到异构体1和异构体2的混合物、异构体3和异构体4的混合物。Example 101 was separated by SFC (column: DAICEL CHIRALPAK IC (250mm*30mm, 10um)); mobile phase: phase A was carbon dioxide, phase B was 0.1% ammonia water/isopropanol; phase B was maintained at 60%; flow rate: 80 ml/min), and a mixture of isomer 1 and isomer 2, and a mixture of isomer 3 and isomer 4 were obtained.
异构体1和异构体2的混合物经SFC分离(柱：REGIS(S,S)WHELK-O1(250mm*25mm,10um))；流动相：A相为二氧化碳，B相为0.1％氨水/异丙醇；B相保持60％；流速：80毫升/分钟)，得到光学纯的实施例101A和实施例101B。The mixture of isomer 1 and isomer 2 was separated by SFC (column: REGIS (S, S) WHELK-O1 (250mm*25mm, 10um)); mobile phase: phase A was carbon dioxide, phase B was 0.1% ammonia water/isopropanol; phase B was kept at 60%; flow rate: 80 ml/min), and optically pure examples 101A and 101B were obtained.
异构体3和异构体4的混合物经SFC分离(柱：DAICEL CHIRALPAK IG(250mm*30mm,10um))；流动相：A相为二氧化碳，B相为0.1％氨水/乙醇；B相保持50％；流速：80毫升/分钟)，得到光学纯的实施例101C和实施例101D。The mixture of isomer 3 and isomer 4 was separated by SFC (column: DAICEL CHIRALPAK IG (250mm*30mm, 10um)); mobile phase: phase A was carbon dioxide, phase B was 0.1% ammonia water/ethanol; phase B was kept at 50%; flow rate: 80 ml/min), and optically pure examples 101C and 101D were obtained.
实施例101A：LCMS(ESI):[M+H]+＝673.4；SFC分析(柱:(S,S)Whelk-01 100×4.6mm I.D.,5.0um；流动相：A相为二氧化碳，B相为0.05％二乙胺/异丙醇；梯度：B相保持60％；流速：2.5毫升/分钟)：手性柱出峰位置为2.676min；1H NMR(400MHz,CD3OD)δppm 8.69(d,J＝1.4Hz,1H),8.17-8.03(m,2H),7.60(t,J＝7.7Hz,1H),7.50-7.37(m,2H),4.68(br d,J＝11.6Hz,1H),4.53(br d,J＝12.5Hz,1H),4.42-4.30(m,2H),3.82(br d,J＝12.3Hz,1H),3.73-3.61(m,3H),3.52-3.36(m,1H),3.31-3.27(m,1H),3.16(ddd,J＝3.9,5.8,9.9Hz,1H),2.84(d,J＝12.1Hz,1H),2.76-2.65(m,1H),2.29(dd,J＝6.3,13.5Hz,1H),2.19-2.10(m,1H),2.03(d,J＝13.5Hz,1H),1.98-1.75(m,7H),1.52-1.37(m,2H).Example 101A: LCMS (ESI): [M+H]+=673.4; SFC analysis (column: (S, S) Whelk-01 100 × 4.6mm I.D., 5.0um; mobile phase: phase A is carbon dioxide, phase B is 0.05% diethylamine/isopropanol; gradient: phase B maintains 60%; flow rate: 2.5 ml/min): the chiral column peak position is 2.676min;1H NMR (400MHz, CD3OD)δppm 8.69(d,J=1.4Hz,1H),8.17-8.03(m,2H),7.60(t,J=7.7Hz,1H),7.50-7.37(m,2H),4.68(br d,J=11.6Hz,1H),4.53(br d,J=12.5Hz,1H),4.42- 1 H),2.76-2.65(m,1H),2.29(dd,J=6.3,13.5Hz,1H),2.19-2.10(m,1H),2.03(d,J=13.5Hz,1H),1.98-1.75(m,7H),1.52-1.37(m,2H).
实施例101B：LCMS(ESI):[M+H]+＝673.6；SFC分析(柱:(S,S)Whelk-01 100×4.6mm I.D.,5.0um；流动相：A相为二氧化碳，B相为0.05％二乙胺/异丙醇；梯度：B相保持60％；流速：2.5毫升/分钟)：手性柱出峰位置为3.176min；1H NMR(400MHz,CD3OD)δppm 8.57(s,1H),8.04-7.93(m,2H),7.48(t,J＝7.6Hz,1H),7.37-7.26(m,2H),4.55(br d,J＝11.8Hz,1H),4.42(br d,J＝12.3Hz,1H),4.24(s,2H),3.69(br d,J＝12.4Hz,1H),3.56(br d,J＝10.9Hz,3H),3.33(s,1H),3.19-3.15(m,1H),3.08-3.01(m,1H),2.72(d,J＝12.1Hz,1H),2.63-2.54(m,1H),2.16(dd,J＝6.2,13.4Hz,1H),2.07-2.00(m,1H),1.94-1.88(m,1H),1.84-1.65(m,7H),1.38-1.25(m,2H). Example 101B: LCMS (ESI): [M+H]+=673.6; SFC analysis (column: (S, S) Whelk-01 100 × 4.6mm I.D., 5.0um; mobile phase: phase A is carbon dioxide, phase B is 0.05% diethylamine/isopropanol; gradient: phase B maintains 60%; flow rate: 2.5 ml/min): the chiral column peak position is 3.176min;1H NMR (400MHz, CD3OD)δppm 8.57(s,1H),8.04-7.93(m,2H),7.48(t,J=7.6Hz,1H),7.37-7.26(m,2H),4.55(br d,J=11.8Hz,1H),4.42(br d,J=12.3Hz,1H),4.24(s,2H),3 .69(br d,J=12.4Hz,1H),3.56(br d,J=10.9Hz,3H),3.33(s,1H),3.19-3.15(m,1H),3.08-3.01(m,1H),2.72(d,J=12.1Hz,1H),2.63-2.54(m,1H),2.16 (dd,J=6.2,13.4Hz,1H),2.07-2.00(m,1H),1.94-1.88(m,1H),1.84-1.65(m,7H),1.38-1.25(m,2H).
实施例101C：LCMS(ESI):[M+H]+＝673.4；SFC分析(柱:Chiralpak IG-3 50*4.6mm I.D.,3um；流动相：A相为二氧化碳，B相为0.05％二乙胺/乙醇；梯度：B相保持40％；流速：4毫升/分钟)：手性柱出峰位置为0.634min；1H NMR(400MHz,CD3OD)δppm 8.69(d,J＝1.4Hz,1H),8.16-8.03(m,2H),7.60(t,J＝7.7Hz,1H),7.48-7.37(m,2H),4.67(br d,J＝11.9Hz,1H),4.54(br d,J＝12.3Hz,1H),4.37(s,2H),3.81(br d,J＝11.3Hz,1H),3.68(br d,J＝10.8Hz,3H),3.44(s,1H),3.28(br d,J＝7.0Hz,1H),3.20-3.13(m,1H),2.85(d,J＝12.4Hz,1H),2.76-2.65(m,1H),2.28(dd,J＝6.2,13.6Hz,1H),2.19-2.11(m,1H),2.03(d,J＝13.5Hz,1H),1.97-1.77(m,7H),1.51-1.37(m,2H).Example 101C: LCMS (ESI): [M+H]+=673.4; SFC analysis (column: Chiralpak IG-3 50*4.6mm I.D., 3um; mobile phase: phase A is carbon dioxide, phase B is 0.05% diethylamine/ethanol; gradient: phase B maintains 40%; flow rate: 4 milliliters/minute): chiral column peak position is 0.634min;1H NMR (400MHz, CD3OD)δppm 8.69(d,J=1.4Hz,1H),8.16-8.03(m,2H),7.60(t,J=7.7Hz,1H),7.48-7.37(m,2H),4.67(br d,J=11.9Hz,1H),4.54(br d,J=12.3Hz,1H),4.37( s,2H),3.81(br d,J=11.3Hz,1H),3.68(br d,J=10.8Hz,3H),3.44(s,1H),3.28(br d,J=7.0Hz,1H),3.20-3.13(m,1H),2.85(d,J=12.4Hz,1H),2.76-2.65 (m,1H),2.28(dd,J=6.2,13.6Hz,1H),2.19-2.11(m,1H),2.03(d,J=13.5Hz,1H),1.97-1.77(m,7H),1.51-1.37(m,2H).
实施例101D：LCMS(ESI):[M+H]+＝673.4；SFC分析(柱:Chiralpak IG-3 50*4.6mm I.D.,3um；流动相：A相为二氧化碳，B相为0.05％二乙胺/乙醇；梯度：B相保持40％；流速：4毫升/分钟)：手性柱出峰位置为1.129min；1H NMR(400MHz,CD3OD)δppm 8.57(s,1H),8.03-7.92(m,2H),7.48(t,J＝7.7Hz,1H),7.36-7.27(m,2H),4.56(br d,J＝11.4Hz,1H),4.41(br d,J＝12.6Hz,1H),4.30-4.17(m,2H),3.69(br d,J＝12.6Hz,1H),3.60-3.51(m,3H),3.31(s,1H),3.19-3.14(m,1H),3.08-3.01(m,1H),2.73(d,J＝12.1Hz,1H),2.64-2.54(m,1H),2.16(dd,J＝6.3,13.5Hz,1H),2.07-1.98(m,1H),1.91(d,J＝13.5Hz,1H),1.85-1.64(m,7H),1.38-1.26(m,2H).Example 101D: LCMS (ESI): [M+H]+=673.4; SFC analysis (column: Chiralpak IG-3 50*4.6mm I.D., 3um; mobile phase: phase A is carbon dioxide, phase B is 0.05% diethylamine/ethanol; gradient: phase B maintains 40%; flow rate: 4 milliliters/minute): chiral column peak position is 1.129min;1H NMR (400MHz, CD3OD)δppm 8.57(s,1H),8.03-7.92(m,2H),7.48(t,J=7.7Hz,1H),7.36-7.27(m,2H),4.56(br d,J=11.4Hz,1H),4.41(br d,J=12.6Hz,1H),4.30-4.17(m, 2H),3.69(br d,J=12.6Hz,1H),3.60-3.51(m,3H),3.31(s,1H),3.19-3.14(m,1H),3.08-3.01(m,1H),2.73(d,J=12.1Hz,1H),2.64-2.54(m,1H),2.16 (dd,J=6.3,13.5Hz,1H),2.07-1.98(m,1H),1.91(d,J=13.5Hz,1H),1.85-1.64(m,7H),1.38-1.26(m,2H).
实施例102：4-(4-(1R,5S)-3,8-二氮杂二环[3.2.1]辛-3-基)-8-氟-2-(四氢-2H-吡喃-4-基)氧)吡啶[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-醇
Example 102: 4-(4-(1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(tetrahydro-2H-pyran-4-yl)oxy)pyridin[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol
LCMS(ESI):[M+H]+＝544.1。1H NMR(400MHz,CD3OD)δ＝9.02(br s,1H),8.53(br s,1H),7.86(dd,J＝5.7,8.9Hz,1H),7.43-7.26(m,2H),7.21(s,1H),5.45-5.34(m,1H),4.75-4.61(m,2H),4.09-3.93(m,4H),3.85(br d,J＝8.9Hz,2H),3.65(br t,J＝8.8Hz,2H),3.38(s,1H),2.14(br d,J＝10.6Hz,2H),2.08-1.91(m,4H),1.85(br dd,J＝3.4,8.6Hz,2H).LCMS (ESI): [M+H] + = 544.1. 1 H NMR(400MHz,CD 3 OD)δ＝9.02(br s,1H),8.53(br s,1H),7.86(dd,J＝5.7,8.9Hz,1H),7.43-7.26(m,2H),7.21(s,1H),5.45-5.34(m,1H),4.75-4.61(m,2H),4.09-3.93(m,4H),3.85(br d,J＝8.9Hz,2H),3.65(br t,J＝8.8Hz,2H),3.38(s,1H),2.14(br d,J＝10.6Hz,2H),2.08-1.91(m,4H),1.85(br dd,J＝3.4,8.6Hz,2H).
实施例103：1-(((4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-7-(8-乙炔基-7-氟-3-羟基萘-1-基)-8-氟吡啶[4,3-d]嘧啶-2-基)氧基)甲基)环丙烷-1-甲腈
Example 103: 1-(((4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyridin[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropane-1-carbonitrile
LCMS(ESI):[M+H]+＝539.5。1H NMR(400MHz,CD3OD)δppm 9.06(s,1H),8.52(s,1H),7.89(dd,J＝5.7,9.2Hz,1H),7.39-7.31(m,2H),7.23(d,J＝2.5Hz,1H),4.78-4.69(m,2H),4.57-4.52(m,2H),3.96(br s,2H),3.84(br d,J＝13.0Hz,2H),3.41-3.37(m,1H),2.05-1.96(m,4H),1.45-1.38(m,2H),1.33-1.28 (m,2H).LCMS (ESI): [M+H] + = 539.5. 1 H NMR(400MHz,CD 3 OD)δppm 9.06(s,1H),8.52(s,1H),7.89(dd,J＝5.7,9.2Hz,1H),7.39-7.31(m,2H),7.23(d,J＝2.5Hz,1H),4.78-4.69(m,2H),4.57-4.52(m,2H),3.96(br s,2H),3.84(br d,J＝13.0Hz,2H),3.41-3.37(m,1H),2.05-1.96(m,4H),1.45-1.38(m,2H),1.33-1.28 (m,2H).
实施例104：4-(4-(1R,5S)-3,8-二氮杂二环[3.2.1]辛-3-基)-8-氟-2-(2,2,2-三氟乙氧基)吡啶[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-醇
Example 104: 4-(4-(1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(2,2,2-trifluoroethoxy)pyridin[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol
LCMS(ESI):[M+H]+＝542.0。1H NMR(400MHz,CH3OD)δppm 9.07(s,1H),7.87(dd,J＝9.05,5.8Hz,1H),7.39-7.27(m,2H),7.22(d,J＝2.6Hz,1H),5.01(q,J＝8.9Hz,2H),4.71-4.57(m,2H),3.83-3.65(m,4H),3.38(s,1H),1.96-1.75(m,4H).LCMS (ESI): [M+H] + = 542.0. 1 H NMR (400MHz, CH 3 OD) δppm 9.07(s,1H),7.87(dd,J=9.05,5.8Hz,1H),7.39-7.27(m,2H),7.22(d,J=2.6Hz,1H),5.01(q,J=8.9Hz,2H),4.71-4.57(m,2H) ,3.83-3.65(m,4H),3.38(s,1H),1.96-1.75(m,4H).
实施例105：4-(4-(1R,5S)-3,8-二氮杂二环[3.2.1]辛-3-基)-8-氟-2-(四氢-2H-吡喃-4-基)甲氧基)吡啶[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-醇
Example 105: 4-(4-(1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(tetrahydro-2H-pyran-4-yl)methoxy)pyridin[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol
LCMS(ESI):[M+H]+＝558.1。1H NMR(400MHz,CH3OD)δppm 9.01(s,1H),7.86(dd,J＝9.0,5.8Hz,1H),7.41-7.27(m,2H),7.21(d,J＝2.1Hz,1H),4.75-4.59(m,2H),4.34(br d,J＝5.4Hz,2H),3.99(br dd,J＝10.8,3.7Hz,2H),3.93-3.71(m,4H),3.47(br t,J＝11.2Hz,2H),3.38(s,1H),2.23-2.05(m,1H),2.02-1.84(m,4H),1.79(br d,J＝12.5Hz,2H),1.55-1.40(m,2H).LCMS (ESI): [M+H] + = 558.1. 1 H NMR(400MHz,CH 3 OD)δppm 9.01(s,1H),7.86(dd,J＝9.0,5.8Hz,1H),7.41-7.27(m,2H),7.21(d,J＝2.1Hz,1H),4.75-4.59(m,2H),4.34(br d,J＝5.4Hz,2H),3.99(br dd,J＝10.8,3.7Hz,2H),3.93-3.71(m,4H),3.47(br t,J＝11.2Hz,2H),3.38(s,1H),2.23-2.05(m,1H),2.02-1.84(m,4H),1.79(br d,J＝12.5Hz,2H),1.55-1.40(m,2H).
实施例106：4-(2-((2-氧杂二环[2.2.2]辛-4-基)甲氧基)-4-((1R,5S)-3,8-二氮杂二环[3.2.1]辛-3-基)-8-氟吡啶[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-醇
Example 106: 4-(2-((2-oxabicyclo[2.2.2]oct-4-yl)methoxy)-4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoropyridin[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol
LCMS(ESI):[M+H]+＝584.3。1H NMR(400MHz,CD3OD)δppm 9.02(s,1H),7.91-7.84(m,1H),7.37(d,J＝2.4Hz,2H),7.24-7.21(m,1H),4.66-4.58(m,2H),4.18(d,J＝3.7Hz,2H),3.90(s,2H),3.83-3.80(m,1H),3.75(br s,4H),3.36-3.35(m,1H),2.11-2.04(m,2H),1.95-1.90(m,2H),1.88-1.81(m,4H), 1.77-1.69(m,4H).LCMS (ESI): [M+H] + = 584.3. 1 H NMR(400MHz,CD 3 OD)δppm 9.02(s,1H),7.91-7.84(m,1H),7.37(d,J＝2.4Hz,2H),7.24-7.21(m,1H),4.66-4.58(m,2H),4.18(d,J＝3.7Hz,2H),3.90(s,2H),3.83-3.80(m,1H),3.75(br s,4H),3.36-3.35(m,1H),2.11-2.04(m,2H),1.95-1.90(m,2H),1.88-1.81(m,4H), 1.77-1.69(m,4H).
实施例107：4-(2-((2-氧杂二环[2.1.1]己-1-基)甲氧基)-4-((1R,5S)-3,8-二氮杂二环[3.2.1]辛-3-基)-8-氟吡啶[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-醇
Example 107: 4-(2-((2-oxabicyclo[2.1.1]hex-1-yl)methoxy)-4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoropyridin[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol
LCMS(ESI):[M+H]+＝556.1。1H NMR(400MHz,CD3OD)δppm 9.04(s,1H),7.88(dd,J＝5.7,9.0Hz,1H),7.40-7.31(m,2H),7.23(d,J＝2.2Hz,1H),4.74(br d,J＝3.1Hz,2H),4.72-4.62(m,2H),3.93(br s,2H),3.88-3.77(m,4H),3.38(s,1H),3.00(br s,1H),2.06-1.91(m,6H),1.59(br d,J＝4.8Hz,2H).LCMS (ESI): [M+H] + = 556.1. 1 H NMR(400MHz,CD 3 OD)δppm 9.04(s,1H),7.88(dd,J＝5.7,9.0Hz,1H),7.40-7.31(m,2H),7.23(d,J＝2.2Hz,1H),4.74(br d,J＝3.1Hz,2H),4.72-4.62(m,2H),3.93(br s,2H),3.88-3.77(m,4H),3.38(s,1H),3.00(br s,1H),2.06-1.91(m,6H),1.59(br d,J＝4.8Hz,2H).
实施例108：4-(((4-((1R,5S)-3,8-二氮杂二环[3.2.1]辛-3-基)-7-(8-乙炔基-7-氟-3-羟基萘-1-基)-8-氟吡啶[4,3-d]嘧啶-2-基)氧基)甲基)四氢-2H-吡喃-4-腈
Example 108: 4-(((4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyridin[4,3-d]pyrimidin-2-yl)oxy)methyl)tetrahydro-2H-pyran-4-carbonitrile
LCMS(ESI):[M+H]+＝583.5。1H NMR(400MHz,CD3OD)δppm 9.06(s,1H),7.92-7.84(m,1H),7.34(s,2H),7.25-7.21(m,1H),4.60(s,4H),3.98(br d,J＝1.8Hz,2H),3.79-3.67(m,6H),3.35-3.35(m,1H),2.13-2.04(m,2H),1.86(br d,J＝15.6Hz,6H).LCMS (ESI): [M+H] + = 583.5. 1 H NMR (400MHz, CD 3 OD) δppm 9.06(s,1H),7.92-7.84(m,1H),7.34(s,2H),7.25-7.21(m,1H),4.60(s,4H),3.98(br d,J＝1.8Hz,2H),3.79-3.67(m,6H),3 .35-3.35(m,1H),2.13-2.04(m,2H),1.86(br d,J=15.6Hz,6H).
实施例109：4-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-8-氟-2-((4-(三氟甲基)四氢-2H-吡喃-4-基)甲氧基)吡啶并[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-醇
Example 109: 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-((4-(trifluoromethyl)tetrahydro-2H-pyran-4-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol
LCMS(ESI):[M+H]+＝626.2。1H NMR(400MHz,CD3OD)δppm 9.05(s,1H),7.88(dd,J＝5.8,9.1Hz,1H),7.40-7.29(m,2H),7.24(d,J＝2.5Hz,1H),4.86(br d,J＝3.3Hz,2H),4.71-4.60(m,2H),3.90(br d,J＝12.0Hz,2H),3.81-3.67(m,6H),3.42-3.36(m,1H),2.04-1.81(m,8H).LCMS (ESI): [M+H] + = 626.2. 1 H NMR (400MHz, CD 3 OD) δppm 9.05(s,1H),7.88(dd,J=5.8,9.1Hz,1H),7.40-7.29(m,2H),7.24(d,J=2.5Hz,1H),4.86(br d,J=3.3Hz,2H),4.71-4.60(m,2H) ,3.90(br d,J=12.0Hz,2H),3.81-3.67(m,6H),3.42-3.36(m,1H),2.04-1.81(m,8H).
实施例110：4-(4-((1R,5S)-3,8-二氮杂二环[3.2.1]辛-3-基)-8-氟-2-(反式-3-羟基环丁基)甲氧基)吡 啶[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-醇
Example 110: 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(trans-3-hydroxycyclobutyl)methoxy)pyridine Pyrid[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol
LCMS(ESI):[M+H]+＝544.1。1H NMR(400MHz,CD3OD)δppm 9.02(s,1H),7.87(dd,J＝5.7,9.2Hz,1H),7.38-7.31(m,2H),7.23(d,J＝2.2Hz,1H),4.69-4.59(m,2H),4.49(s,2H),4.48-4.39(m,1H),3.72(br d,J＝10.6Hz,4H),3.37-3.36(m,1H),2.78-2.67(m,1H),2.30(br d,J＝4.2Hz,2H),2.17(br s,2H),1.87(br d,J＝17.2Hz,4H).LCMS (ESI): [M+H] + = 544.1. 1 H NMR(400MHz,CD 3 OD)δppm 9.02(s,1H),7.87(dd,J＝5.7,9.2Hz,1H),7.38-7.31(m,2H),7.23(d,J＝2.2Hz,1H),4.69-4.59(m,2H),4.49(s,2H),4.48-4.39(m,1H),3.72(br d,J＝10.6Hz,4H),3.37-3.36(m,1H),2.78-2.67(m,1H),2.30(br d,J＝4.2Hz,2H),2.17(br s,2H),1.87(br d,J＝17.2Hz,4H).
实施例111：4-(2-((3-氧杂双环[3.1.0]己-6-基)甲氧基)-4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-8-氟吡啶[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-醇
Example 111: 4-(2-((3-oxabicyclo[3.1.0]hex-6-yl)methoxy)-4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoropyridin[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol
LCMS(ESI):[M+H]+＝556.3。1H NMR(400MHz,CD3OD)δppm 9.02(s,1H),7.88(dd,J＝5.8,9.1Hz,1H),7.40-7.29(m,2H),7.23(d,J＝2.4Hz,1H),4.72-4.59(m,3H),4.40(d,J＝7.4Hz,1H),4.07-4.00(m,1H),3.97-3.86(m,2H),3.84-3.69(m,5H),3.43-3.37(m,1H),1.99-1.76(m,6H),1.55-1.26(m,1H).LCMS (ESI): [M+H] + = 556.3. 1 H NMR(400MHz,CD 3 OD)δppm 9.02(s,1H),7.88(dd,J＝5.8,9.1Hz,1H),7.40-7.29(m,2H),7.23(d,J＝2.4Hz,1H),4.72-4.59(m,3H),4.40(d,J＝7.4Hz,1H),4.07-4.00(m,1H),3.97-3.86(m,2H),3.84-3.69(m,5H),3.43-3.37(m,1H),1.99-1.76(m,6H),1.55-1.26(m,1H).
实施例112：4-(4-((1R,5S)-3,8-二氮杂二环[3.2.1]辛-3-基)-8-氟-2-(顺式-3-羟基环丁基)甲氧基)吡啶[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-醇
Example 112: 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(cis-3-hydroxycyclobutyl)methoxy)pyridin[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol
LCMS(ESI):[M+H]+＝544.1。1H NMR(400MHz,CD3OD)δppm 9.02(s,1H),7.88(dd,J＝5.8,9.1Hz,1H),7.39-7.29(m,2H),7.23(d,J＝2.4Hz,1H),4.70-4.59(m,2H),4.49-4.41(m,2H),4.15(quin,J＝7.4Hz,1H),3.84-3.68(m,4H),3.39-3.35(m,1H),2.53-2.42(m,2H),2.37-2.24(m,1H),1.98-1.78(m,6H).LCMS (ESI): [M+H] + = 544.1. 1 H NMR(400MHz,CD 3 OD)δppm 9.02(s,1H),7.88(dd,J＝5.8,9.1Hz,1H),7.39-7.29(m,2H),7.23(d,J＝2.4Hz,1H),4.70-4.59(m,2H),4.49-4.41(m,2H),4.15(quin,J＝7.4Hz,1H),3.84-3.68(m,4H),3.39-3.35(m,1H),2.53-2.42(m,2H),2.37-2.24(m,1H),1.98-1.78(m,6H).
实施例113：4-(4-(1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-8-氟-2-(1-氮杂双环[2.2.2]辛-4-基甲氧基)吡啶并[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-醇
Example 113: 4-(4-(1R,5S)-3,8-Diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(1-azabicyclo[2.2.2]oct-4-ylmethoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol
LCMS(ESI):[M+H]+＝583.5.LCMS (ESI): [M+H] + = 583.5.
实施例114：4-(2-(双环[2.2.2]辛-1-基甲氧基)-4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-8-氟吡啶并[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-醇
Example 114: 4-(2-(Bicyclo[2.2.2]oct-1-ylmethoxy)-4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol
LCMS(ESI):[M+H]+＝582.5.LCMS (ESI): [M+H] + = 582.5.
实施例115：4-(4-(1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-8-氟-2-((4-甲氧基双环[2.2.2]辛-1-基)甲氧基)吡啶[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-醇
Example 115: 4-(4-(1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-((4-methoxybicyclo[2.2.2]oct-1-yl)methoxy)pyridin[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol
LCMS(ESI):[M+H]+＝612.6。1H NMR(400MHz,CD3OD)δppm 9.01(s,1H),7.88(dd,J＝5.7,9.2Hz,1H),7.40-7.29(m,2H),7.22(d,J＝2.5Hz,1H),4.67-4.55(m,2H),4.16-4.09(m,2H),3.77-3.66(m,4H),3.40-3.36(m,1H),3.21(s,3H),1.92-1.79(m,4H),1.78-1.70(m,12H).LCMS (ESI): [M+H] + = 612.6. 1 H NMR (400MHz, CD 3 OD) δppm 9.01(s,1H),7.88(dd,J=5.7,9.2Hz,1H),7.40-7.29(m,2H),7.22(d,J=2.5Hz,1H),4.67-4.55(m,2H),4.16-4.09(m,2H),3. 77-3.66(m,4H),3.40-3.36(m,1H),3.21(s,3H),1.92-1.79(m,4H),1.78-1.70(m,12H).
实施例116：1-(7-(8-乙炔基-7-氟萘-1-基)-8-氟-6-硝基-2-((四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)喹唑啉-4-基)-3-甲基哌啶-3-醇
Example 116: 1-(7-(8-Ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-6-nitro-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol
第一步：在氮气环境下，将1-(7-溴-8-氟-6-硝基-2-(2,2,2-三氟乙氧基)喹唑啉-4-基)-3-甲基哌啶-3-醇(550mg，1.14mmol)和(((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(670mg，1.48mmol)加入到甲苯(20mL)和水(5mL)的混合溶液中，然后加入碳酸铯(1.1g，3.4mmol)，甲磺酰氧基(二金刚烷基-正丁基膦基)-2-氨基-1,1-联苯-2-基)钯(II)(166mg，0.23mmol)。将混合物在100℃搅拌16小时。将反应液加水(60mL)稀释并用乙酸乙酯(30mL*3)萃取，合并的有机相用盐水(60mL)洗涤，无水硫酸镁干燥并过滤，滤液真空浓缩。残余物通过快速柱色谱(硅胶，0-15％梯度四氢呋喃/石油醚)纯化得到棕色固体化合物1-(8-氟-7-(7-氟-8-((三异丙基甲硅烷基)乙炔基)萘-1-基)-6-硝基-2-(2,2,2-三氟乙氧基)喹唑啉-4-基)-3-甲基哌啶-3-醇(565mg，0.78mmol，收率68％)。LCMS(ESI):[M+H]+＝729.3.The first step: under nitrogen atmosphere, mix 1-(7-bromo-8-fluoro-6-nitro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol (550mg, 1.14mmol) and (((2-fluoro-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalene-1-yl)ethynyl)tri Isopropylsilane (670 mg, 1.48 mmol) was added to a mixed solution of toluene (20 mL) and water (5 mL), and then cesium carbonate (1.1 g, 3.4 mmol), methanesulfonyloxy(diadamantyl-n-butylphosphino)-2-amino-1,1-biphenyl-2-yl)palladium(II) (166 mg, 0.23 mmol) were added. The mixture was stirred at 100°C for 16 hours. The reaction solution was diluted with water (60 mL) and extracted with ethyl acetate (30 mL*3), the combined organic phases were washed with brine (60 mL), dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated in vacuo. The residue was purified by flash column chromatography (silica gel, 0-15% gradient tetrahydrofuran/petroleum ether) to give brown solid compound 1-(8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalene-1-yl)-6-nitro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol (565mg, 0.78mmol, yield 68%) . LCMS (ESI): [M+H] + = 729.3.
第二步：向1-(8-氟-7-(7-氟-8-((三异丙基甲硅烷基)乙炔基)萘-1-基)-6-硝基-2-(2,2,2-三氟乙氧基)喹唑啉-4-基)-3-甲基哌啶-3-醇(400mg，0.55mmol)的四氢呋喃(8mL)溶液中加入4A分子筛(400mg)，叔丁醇钠(105mg，1.1mmol)和(四氢-1H-吡咯嗪-7a(5H)-基)甲醇(155mg，1.1mmol)。将反应在20℃搅拌2小时。混合物用水(15mL)稀释并用乙酸乙酯(15mL*3)萃取，合并的有机相用饱和食盐水(20mL)洗涤，无水硫酸镁干燥并过滤，滤液减压浓缩，残余物通过快速柱色谱(硅胶，0-10％梯度甲醇/二氯甲烷)纯化得到棕色固体化合物1-(8-氟-7-(7-氟-8-((三异丙基甲硅烷基)乙炔基)萘-1-基)-6-硝基-2-((四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)喹唑啉-4-基)-3-甲基哌啶-3-醇(254mg，0.33mmol，收率60％)。LCMS(ESI):[M+H]+＝770.2.Second step: To a solution of 1-(8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-6-nitro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol (400 mg, 0.55 mmol) in THF (8 mL) was added 4A molecular sieves (400 mg), sodium tert-butoxide (105 mg, 1.1 mmol) and (tetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol (155 mg, 1.1 mmol). The reaction was stirred at 20 °C for 2 hours. The mixture was diluted with water (15 mL) and extracted with ethyl acetate (15 mL*3), the combined organic phase was washed with saturated brine (20 mL), dried over anhydrous magnesium sulfate and filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by flash column chromatography (silica gel, 0-10% gradient methanol/dichloromethane) to obtain brown solid compound 1-(8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalene-1-yl)-6-nitro-2 -((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol (254 mg, 0.33 mmol, yield 60%). LCMS (ESI): [M+H] + = 770.2.
第三步：向1-(8-氟-7-(7-氟-8-((三异丙基甲硅烷基)乙炔基)萘-1-基)-6-硝基-2-((四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)喹唑啉-4-基)-3-甲基哌啶-3-醇(244mg，0.32mmol)的二甲基甲酰胺(3mL)溶液中加入氟化铯(385mg，2.53mmol)。将反应在20℃搅拌2小时。混合物用水(15mL)稀释并用乙酸乙酯(15mL*2)萃取，合并的有机相用饱和食盐水(20mL)洗涤，无水硫酸镁干燥并过滤，滤液浓缩，残余物通过快速柱色谱(硅胶，0-10％梯度甲醇/二氯甲烷)纯化得到棕色固体化合物1-(7-(8-乙炔基-7-氟萘-1-基)-8-氟-6-硝基-2-((四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)喹唑啉-4-基)-3-甲基哌啶-3-醇(140mg，0.23mmol，收率72％)。LCMS(ESI):[M+H]+＝614.1。1H NMR(400MHz,CD3OD)δppm8.88(s,1H),8.15-8.06(m,2H),7.61(t,J＝7.7Hz,1H),7.48-7.40(m,2H),4.56(br d,J＝13.6Hz,1H),4.39- 4.23(m,3H),3.70-3.51(m,2H),3.45-3.39(m,1H),3.27-3.17(m,2H),2.90-2.79(m,2H),2.20-2.09(m,2H),2.06-1.76(m,10H),1.30(s,3H).Step 3: To a solution of 1-(8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-6-nitro-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol (244 mg, 0.32 mmol) in dimethylformamide (3 mL) was added cesium fluoride (385 mg, 2.53 mmol). The reaction was stirred at 20 °C for 2 hours. The mixture was diluted with water (15 mL) and extracted with ethyl acetate (15 mL*2), the combined organic phase was washed with saturated brine (20 mL), dried over anhydrous magnesium sulfate and filtered, the filtrate was concentrated, and the residue was purified by flash column chromatography (silica gel, 0-10% gradient methanol/dichloromethane) to obtain brown solid compound 1-(7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-6-nitro-2-((tetrahydro-1H-pyrrolazine -7a(5H)-yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol (140 mg, 0.23 mmol, 72% yield). LCMS (ESI): [M+H] + = 614.1. 1 H NMR (400MHz, CD 3 OD) δppm8.88 (s, 1H), 8.15-8.06 (m, 2H), 7.61 (t, J = 7.7Hz, 1H), 7.48-7.40 (m, 2H), 4.56 (br d, J = 13.6Hz, 1H), 4.39- 4.23(m,3H),3.70-3.51(m,2H),3.45-3.39(m,1H),3.27-3.17(m,2H),2.90-2.79(m,2H),2.20-2.09(m,2H),2.06-1.76(m,10H),1.30(s,3H).
实施例116A:(R)-1-((R)-7-(8-乙炔基-7-氟萘-1-基)-8-氟-6-硝基-2-((四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)喹唑啉-4-基)-3-甲基哌啶-3-醇Example 116A: (R)-1-((R)-7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-6-nitro-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol
实施例116B:(R)-1-((S)-7-(8-乙炔基-7-氟萘-1-基)-8-氟-6-硝基-2-((四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)喹唑啉-4-基)-3-甲基哌啶-3-醇，
Example 116B: (R)-1-((S)-7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-6-nitro-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol,
实施例116经SFC分离(柱：DAICEL CHIRALCEL OD(250mm*30mm,10um)；流动相：A相为二氧化碳，B相为0.1％氨水/异丙醇；B相保持40％；流速：110毫升/分钟)，得到目标化合物。Example 116 was separated by SFC (column: DAICEL CHIRALCEL OD (250mm*30mm, 10um); mobile phase: phase A was carbon dioxide, phase B was 0.1% ammonia water/isopropanol; phase B was maintained at 40%; flow rate: 110 ml/min), and the target compound was obtained.
实施例116A：SFC分析(色谱柱:ChiralCel OD-3，150mm*4.6mm，3um；流动相：A相为二氧化碳，B相为0.05％二乙胺/异丙醇；保持40％的B相；流速：2.5毫升/分钟)：手性柱出峰位置为3.754min；LCMS(ESI):[M+H]+＝614.1。1H NMR(400MHz,CD3OD)δppm 8.80(d,J＝1.1Hz,1H),8.08-7.87(m,2H),7.49(t,J＝7.7Hz,1H),7.40-7.27(m,2H),4.53-4.39(m,3H),4.21(br d,J＝13.5Hz,1H),3.51-3.42(m,2H),3.41-3.34(m,2H),3.33-3.24(m,1H),3.03-2.94(m,2H),2.19-2.06(m,3H),2.05-1.84(m,6H),1.79-1.65(m,3H),1.19(s,3H).Example 116A: SFC analysis (chromatographic column: ChiralCel OD-3, 150mm*4.6mm, 3um; mobile phase: phase A is carbon dioxide, phase B is 0.05% diethylamine/isopropanol; maintain 40% of phase B; flow rate: 2.5 ml/min): the peak position of the chiral column is 3.754min; LCMS (ESI): [M+H] + =614.1. 1 H NMR(400MHz,CD 3 OD)δppm 8.80(d,J＝1.1Hz,1H),8.08-7.87(m,2H),7.49(t,J＝7.7Hz,1H),7.40-7.27(m,2H),4.53-4.39(m,3H),4.21(br d,J＝13.5Hz,1H),3.51-3.42(m,2H),3.41-3.34(m,2H),3.33-3.24(m,1H),3.03-2.94(m,2H),2.19-2.06(m,3H),2.05-1.84(m,6H),1.79-1.65(m,3H),1.19(s,3H).
实施例116B：SFC分析(色谱柱:ChiralCel OD-3，150mm*4.6mm，3um；流动相：A相为二氧化碳，B相为0.05％二乙胺/异丙醇；保持40％的B相；流速：2.5毫升/分钟)：手性柱出峰位置为3.131min；LCMS(ESI):[M+H]+＝614.1。1H NMR(400MHz,CD3OD)δppm 8.84(s,1H),8.10-7.91(m,2H),7.50(t,J＝7.7Hz,1H),7.40-7.24(m,2H),4.61-4.46(m,3H),4.21(br d,J＝13.4Hz,1H),3.65-3.51(m,3H),3.39-3.26(m,2H),3.20-3.13(m,2H),2.28-2.18(m,2H),2.15-1.95(m,7H),1.83-1.66(m,3H),1.22(s,3H).Example 116B: SFC analysis (chromatographic column: ChiralCel OD-3, 150mm*4.6mm, 3um; mobile phase: phase A is carbon dioxide, phase B is 0.05% diethylamine/isopropanol; maintain 40% of phase B; flow rate: 2.5 ml/min): the peak position of the chiral column is 3.131min; LCMS (ESI): [M+H] + =614.1. 1 H NMR(400MHz,CD 3 OD)δppm 8.84(s,1H),8.10-7.91(m,2H),7.50(t,J＝7.7Hz,1H),7.40-7.24(m,2H),4.61-4.46(m,3H),4.21(br d,J＝13.4Hz,1H),3.65-3.51(m,3H),3.39-3.26(m,2H),3.20-3.13(m,2H),2.28-2.18(m,2H),2.15-1.95(m,7H),1.83-1.66(m,3H),1.22(s,3H).
实施例117：1-(7-(8-乙基-7-氟萘-1-基)-8-氟-6-硝基-2-((四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)喹唑啉-4-基)-3-甲基哌啶-3-醇
Example 117: 1-(7-(8-Ethyl-7-fluoronaphthalen-1-yl)-8-fluoro-6-nitro-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol
第一步：向1-(7-(8-乙炔基-7-氟萘-1-基)-8-氟-6-硝基-2-((四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)喹唑啉-4-基)-3-甲基哌啶-3-醇(20mg，0.032mmol)的四氢呋喃(400uL)溶液中加入2-硝基苯磺酰肼(70.8mg，0.32mmol)和三乙胺(45.4uL，0.32mmol)。将反应在20℃搅拌16小时。混合物用水(2mL)稀释并用乙酸乙酯(2mL*2)萃取，合并的有机相用饱和食盐水(2mL)洗涤，无水硫酸镁 干燥，过滤，滤液浓缩，残余物通过制备型HPLC纯化得到黄色固体化合物1-(7-(8-乙基-7-氟萘-1-基)-8-氟-6-硝基-2-((四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)喹唑啉-4-基)-3-甲基哌啶-3-醇(7.00mg，11.3umol，35％)。LCMS(ESI):[M+H]+＝618.1。1H NMR(400MHz,CD3OD)δppm 9.10-8.84(m,1H),8.07-7.88(m,2H),7.54-7.36(m,2H),7.23(br s,1H),4.53(br s,1H),4.45-4.20(m,3H),3.83-3.54(m,1H),3.48(br s,1H),3.18(br s,1H),3.00-2.61(m,3H),2.48(br s,1H),2.30-1.68(m,13H),1.33(br d,J＝15.2Hz,3H),0.88(br s,3H).Step 1: Add 2-nitrobenzenesulfonylhydrazide (70.8 mg, 0.32mmol) and triethylamine (45.4uL, 0.32mmol). The reaction was stirred at 20°C for 16 hours. The mixture was diluted with water (2 mL) and extracted with ethyl acetate (2 mL*2), the combined organic phase was washed with saturated brine (2 mL), anhydrous magnesium sulfate Drying, filtration, concentration of the filtrate, and purification of the residue by preparative HPLC gave yellow solid compound 1-(7-(8-ethyl-7-fluoronaphthalen-1-yl)-8-fluoro-6-nitro-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol (7.00mg, 11.3umol, 35%). LCMS (ESI): [M+H] + = 618.1. 1 H NMR(400MHz,CD 3 OD)δppm 9.10-8.84(m,1H),8.07-7.88(m,2H),7.54-7.36(m,2H),7.23(br s,1H),4.53(br s,1H),4.45-4.20(m,3H),3.83-3.54(m,1H),3.48(br s,1H),3.18(br s,1H),3.00-2.61(m,3H),2.48(br s,1H),2.30-1.68(m,13H),1.33(br d,J＝15.2Hz,3H),0.88(br s,3H).
实施例118和实施例119，以及实施例127至实施例131参照实施例116的合成路线,第二步与不同的醇反应制备得到的：Example 118 and Example 119, and Example 127 to Example 131 are prepared by referring to the synthetic route of Example 116, and reacting with different alcohols in the second step:
实施例118：1-(7-(8-乙炔基-7-氟萘基-1-基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-6-硝基喹唑啉-4-基)-3-甲基哌啶-3-醇
Example 118: 1-(7-(8-Ethynyl-7-fluoronaphthyl-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-6-nitroquinazolin-4-yl)-3-methylpiperidin-3-ol
LCMS(ESI):[M+H]+＝632.2。1H NMR(400MHz,CD3OD)δppm 8.87(br s,1H),8.17-8.01(m,2H),7.59(t,J＝7.7Hz,1H),7.47-7.37(m,2H),5.45-5.23(m,1H),4.82-4.68(m,1H),4.66-4.15(m,6H),3.68-3.45(m,1H),3.50-3.37(m,2H),3.16-3.03(m,1H),2.47-2.13(m,4H),2.11-2.00(m,2H),1.99-1.72(m,4H),1.30(d,J＝7.6Hz,3H).LCMS (ESI): [M+H] + = 632.2. 1 H NMR(400MHz,CD 3 OD)δppm 8.87(br s,1H),8.17-8.01(m,2H),7.59(t,J＝7.7Hz,1H),7.47-7.37(m,2H),5.45-5.23(m,1H),4.82-4.68(m,1H),4.66-4.15(m,6H),3.68-3.45(m,1H),3.50-3.37(m,2H),3.16-3.03(m,1H),2.47-2.13(m,4H),2.11-2.00(m,2H),1.99-1.72(m,4H),1.30(d,J＝7.6Hz,3H).
实施例119：1-(2-((反式-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-吡咯嗪]-7a'(5'H)-基)甲氧基)-7-(8-乙炔基-7-氟萘-1-基)-8-氟-6-硝基喹唑啉-4-基)-3-甲基哌啶-3-醇
Example 119: 1-(2-((trans-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolazin]-7a'(5'H)-yl)methoxy)-7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-6-nitroquinazolin-4-yl)-3-methylpiperidin-3-ol
LCMS(ESI):[M+H]+＝676.2；1H NMR(400MHz,CD3OD)δppm 8.87(s,1H),8.14-8.05(m,2H),7.60(t,J＝7.7Hz,1H),7.48-7.39(m,2H),4.54(br d,J＝12.8Hz,1H),4.42-4.34(m,2H),4.28(br d,J＝13.2Hz,1H),3.64-3.53(m,2H),3.41(br t,J＝11.0Hz,1H),3.32-3.26(m,1H),3.20-3.12(m,1H),2.85(d,J＝12.1Hz,1H),2.75-2.66(m,1H),2.31-2.12(m,3H),2.04(br d,J＝13.9Hz,1H),1.95-1.74(m,6H),1.52-1.36(m,2H),1.30(s,3H).LCMS(ESI):[M+H]+= 676.2;1H NMR (400MHz, CD3OD)δppm 8.87(s,1H),8.14-8.05(m,2H),7.60(t,J=7.7Hz,1H),7.48-7.39(m,2H),4.54(br d,J=12.8Hz,1H),4.42-4.34(m,2H),4.28(br d,J=13.2Hz, 1H),3.64-3.53(m,2H),3.41(br t,J=11.0Hz,1H),3.32-3.26(m,1H),3.20-3.12(m,1H),2.85(d,J=12.1Hz,1H),2.75-2.66(m,1H),2.31-2.12(m,3H) ,2.04(br d,J＝13.9Hz,1H),1.95-1.74(m,6H),1.52-1.36(m,2H),1.30(s,3H).
实施例120：(3R)-1-(7-(8-乙炔基-7-氟萘-1-基)-8-氟-2-((2-亚甲基四氢-1H-吡咯嗪-7a(5H)-基)甲 氧基)-6-硝基喹唑啉-4-基)-3-甲基哌啶-3-醇
Example 120: (3R)-1-(7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-((2-methylenetetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol Oxy)-6-nitroquinazolin-4-yl)-3-methylpiperidin-3-ol
LCMS(ESI):[M+H]+＝626.1；1H NMR(400MHz,CD3OD)δppm 8.87(br d,J＝3.4Hz,1H),8.14-8.03(m,2H),7.59(t,J＝7.6Hz,1H),7.48-7.38(m,2H),5.06(br s,2H),4.58-4.18(m,4H),3.89(br d,J＝13.7Hz,1H),3.66-3.35(m,4H),2.85(br d,J＝13.3Hz,2H),2.56(br d,J＝16.0Hz,1H),2.26-1.69(m,9H),1.29(d,J＝7.6Hz,3H).LCMS(ESI):[M+H]+= 626.1;1H NMR (400MHz, CD3OD)δppm 8.87(br d,J=3.4Hz,1H),8.14-8.03(m,2H),7.59(t,J=7.6Hz,1H),7.48-7.38(m,2H),5.06(br s,2H),4.58-4.18(m,4H),3.89(br d,J=13.7Hz ,1H),3.66-3.35(m,4H),2.85(br d,J=13.3Hz,2H),2.56(br d,J=16.0Hz,1H),2.26-1.69(m,9H),1.29(d,J=7.6Hz,3H).
实施例120A：(R)-1-((R)-7-(8-乙基-7-氟萘-1-基)-8-氟-2-((S)-2-亚甲基四氢-1H-吡咯-7a(5H)-甲氧基)-6-硝基喹唑啉-4-基)-3-甲基哌啶-3-醇，Example 120A: (R)-1-((R)-7-(8-ethyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-((S)-2-methylenetetrahydro-1H-pyrrole-7a(5H)-methoxy)-6-nitroquinazolin-4-yl)-3-methylpiperidin-3-ol,
实施例120B:(R)-1-((S)-7-(8-乙基-7-氟萘-1-基)-8-氟-2-((S)-2-亚甲基四氢-1H-吡咯-7a(5H)-甲氧基)-6-硝基喹唑啉-4-基)-3-甲基哌啶-3-醇，Example 120B: (R)-1-((S)-7-(8-ethyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-((S)-2-methylenetetrahydro-1H-pyrrole-7a(5H)-methoxy)-6-nitroquinazolin-4-yl)-3-methylpiperidin-3-ol,
实施例120C:(R)-1-((R)-7-(8-乙基-7-氟萘-1-基)-8-氟-2-((R)-2-亚甲基四氢-1H-吡咯-7a(5H)-基)甲氧基)-6-硝基喹唑啉-4-基)-3-甲基哌啶-3-醇和Example 120C: (R)-1-((R)-7-(8-ethyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-((R)-2-methylenetetrahydro-1H-pyrrol-7a(5H)-yl)methoxy)-6-nitroquinazolin-4-yl)-3-methylpiperidin-3-ol and
实施例120D:(R)-1-((S)-7-(8-乙基-7-氟萘-1-基)-8-氟-2-((R)-2-甲基四氢-1H-吡咯-7a(5H)-基)甲氧基)-6-硝基喹唑啉-4-基)-3-甲基哌啶-3-醇
Example 120D: (R)-1-((S)-7-(8-ethyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-((R)-2-methyltetrahydro-1H-pyrrol-7a(5H)-yl)methoxy)-6-nitroquinazolin-4-yl)-3-methylpiperidin-3-ol
实施例120：经SFC分离(柱：Phenomenex-Cellulose-2(250mm*30mm,10um)；流动相：A相为二氧化碳，B相为0.1％氨水/乙醇；B相保持45％；流速：80毫升/分钟)，得到目标化合物。Example 120: Separation by SFC (column: Phenomenex-Cellulose-2 (250mm*30mm, 10um); mobile phase: phase A is carbon dioxide, phase B is 0.1% ammonia water/ethanol; phase B is maintained at 45%; flow rate: 80 ml/min), the target compound is obtained.
实施例120A：LCMS(ESI):[M+H]+＝626.1；SFC分析(柱:Cellulose-2 100*4.6mm I.D.,3um；流动相： A相为二氧化碳，B相为0.05％二乙胺/乙醇；梯度：保持50％的B相；流速：2.8毫升/分钟)：手性柱出峰位置为1.343min；1H NMR(400MHz,CD3OD)δ＝8.87(s,1H),8.15-8.01(m,2H),7.58(t,J＝7.7Hz,1H),7.50-7.36(m,2H),5.03(br s,2H),4.55-4.16(m,4H),3.83(br d,J＝14.2Hz,1H),3.69-3.56(m,1H),3.47-3.37(m,2H),3.27-3.18(m,1H),2.87-2.72(m,2H),2.52(br d,J＝15.3Hz,1H),2.28-2.12(m,2H),2.09-1.71(m,7H),1.30(s,3H).Example 120A: LCMS (ESI): [M+H] + =626.1; SFC analysis (column: Cellulose-2 100*4.6mm ID, 3um; mobile phase: A相为二氧化碳，B相为0.05％二乙胺/乙醇；梯度：保持50％的B相；流速：2.8毫升/分钟)：手性柱出峰位置为1.343min； 1 H NMR(400MHz,CD 3 OD)δ＝8.87(s,1H),8.15-8.01(m,2H),7.58(t,J＝7.7Hz,1H),7.50-7.36(m,2H),5.03(br s,2H),4.55-4.16(m,4H),3.83(br d,J＝14.2Hz,1H),3.69-3.56(m,1H),3.47-3.37(m,2H),3.27-3.18(m,1H),2.87-2.72(m,2H),2.52(br d,J＝15.3Hz,1H),2.28-2.12(m,2H),2.09-1.71(m,7H),1.30(s,3H).
实施例120B：LCMS(ESI):[M+H]+＝626.1；SFC分析(柱:Cellulose-2 100*4.6mm I.D.,3um；流动相：A相为二氧化碳，B相为0.05％二乙胺/乙醇；梯度：保持50％的B相；流速：2.8毫升/分钟)：手性柱出峰位置为1.527min；1H NMR(400MHz,CD3OD)δ＝8.89(s,1H),8.15-8.04(m,2H),7.59(t,J＝7.7Hz,1H),7.48-7.37(m,2H),5.22-5.11(m,2H),4.58-4.44(m,3H),4.27(br d,J＝13.5Hz,1H),4.10(br d,J＝13.8Hz,1H),3.73-3.59(m,2H),3.57-3.44(m,2H),3.09-2.91(m,2H),2.72-2.60(m,1H),2.36-1.74(m,9H),1.35-1.25(m,3H).Example 120B: LCMS (ESI): [M+H]+=626.1; SFC analysis (column: Cellulose-2 100*4.6mm I.D., 3um; mobile phase: phase A is carbon dioxide, phase B is 0.05% diethylamine/ethanol; gradient: keep 50% of phase B; flow rate: 2.8 ml/min): chiral column peak position is 1.527min;1H NMR (400MHz, CD3OD)δ=8.89(s,1H),8.15-8.04(m,2H),7.59(t,J=7.7Hz,1H),7.48-7.37(m,2H),5.22-5.11(m,2H),4.58-4.44(m,3H),4.27(br d,J=13.5Hz,1H),4.1 0(br d,J=13.8Hz,1H),3.73-3.59(m,2H),3.57-3.44(m,2H),3.09-2.91(m,2H),2.72-2.60(m,1H),2.36-1.74(m,9H),1.35-1.25(m,3H).
实施例120C：LCMS(ESI):[M+H]+＝626.1；SFC分析(柱:Cellulose-2 100*4.6mm I.D.,3um；流动相：A相为二氧化碳，B相为0.05％二乙胺/乙醇；梯度：保持50％的B相；流速：2.8毫升/分钟)：手性柱出峰位置为1.739min；1H NMR(400MHz,CD3OD)δ＝8.87(s,1H),8.14-8.01(m,2H),7.59(t,J＝7.7Hz,1H),7.48-7.37(m,2H),5.06(br s,2H),4.55(br d,J＝14.3Hz,1H),4.45-4.24(m,3H),3.89(br d,J＝14.1Hz,1H),3.63-3.34(m,4H),2.86(br d,J＝15.1Hz,2H),2.56(br d,J＝15.9Hz,1H),2.29-1.72(m,9H),1.29(s,3H).Example 120C: LCMS (ESI): [M+H]+=626.1; SFC analysis (column: Cellulose-2 100*4.6mm I.D., 3um; mobile phase: phase A is carbon dioxide, phase B is 0.05% diethylamine/ethanol; gradient: keep 50% of phase B; flow rate: 2.8 ml/min): chiral column peak position is 1.739min;1H NMR (400MHz, CD3OD)δ＝8.87(s,1H),8.14-8.01(m,2H),7.59(t,J＝7.7Hz,1H),7.48-7.37(m,2H),5.06(br s,2H),4.55(br d,J＝14.3Hz,1H),4.45-4.24(m,3H),3.89(br d,J=14.1Hz,1H),3.63-3.34(m,4H),2.86(br d,J=15.1Hz,2H),2.56(br d,J=15.9Hz,1H),2.29-1.72(m,9H),1.29(s,3H).
实施例120D：LCMS(ESI):[M+H]+＝626.2；SFC分析(柱:Cellulose-2 100*4.6mm I.D.,3um；流动相：A相为二氧化碳，B相为0.05％二乙胺/乙醇；梯度：保持50％的B相；流速：2.8毫升/分钟)：手性柱出峰位置为2.203min；1H NMR(400MHz,CD3OD)δ＝8.87(s,1H),8.15-8.00(m,2H),7.59(t,J＝7.7Hz,1H),7.48-7.35(m,2H),5.05(br s,2H),4.54(br d,J＝13.2Hz,1H),4.45-4.23(m,3H),3.94-3.83(m,1H),3.63-3.36(m,4H),3.16-3.12(m,1H),2.91-2.78(m,2H),2.55(br d,J＝15.8Hz,1H),2.29-2.12(m,2H),2.12-1.71(m,6H),1.29(s,3H).实施例120D：LCMS(ESI):[M+H] + ＝626.2；SFC分析(柱:Cellulose-2 100*4.6mm ID,3um；流动相：A相为二氧化碳，B相为0.05％二乙胺/乙醇；梯度：保持50％的B相；流速：2.8毫升/分钟)：手性柱出峰位置为2.203min； 1 H NMR(400MHz,CD 3 OD)δ＝8.87(s,1H),8.15-8.00(m,2H),7.59(t,J＝7.7Hz,1H),7.48-7.35(m,2H),5.05(br s,2H),4.54(br d,J＝13.2Hz,1H),4.45-4.23(m,3H),3.94-3.83(m,1H),3.63-3.36(m,4H),3.16-3.12(m,1H),2.91-2.78(m,2H),2.55(br d,J＝15.8Hz,1H),2.29-2.12(m,2H),2.12-1.71(m,6H),1.29(s,3H).
实施例121：(3R)-1-(7-(8-乙炔基-7-氟萘基-1-基)-8-氟-2-(-2-(氟亚甲基)四氢-1H-吡咯啉-7a(5H)-甲氧基)-6-硝基喹唑啉-4-基)-3-甲基哌啶-3-醇Example 121: (3R)-1-(7-(8-ethynyl-7-fluoronaphthyl-1-yl)-8-fluoro-2-(-2-(fluoromethylene)tetrahydro-1H-pyrroline-7a(5H)-methoxy)-6-nitroquinazolin-4-yl)-3-methylpiperidin-3-ol
实施例122：(3R)-1-(2-(2-(二氟亚甲基)四氢-1H-吡咯-7a(5H)-甲氧基)-7-(8-乙炔基-7-氟萘-1-基)-8-氟-6-硝基喹唑啉-4-基)-3-甲基哌啶-3-醇
Example 122: (3R)-1-(2-(2-(Difluoromethylene)tetrahydro-1H-pyrrole-7a(5H)-methoxy)-7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-6-nitroquinazolin-4-yl)-3-methylpiperidin-3-ol
第一步：在-50℃下，向叔丁醇钾(0.95g，8.52mmol)的N,N-二甲基甲酰胺(11mL)溶液中，加入2,5-二氧四氢-1H-吡咯嗪-7a(5H)-羧酸乙酯(1.0g，4.73mmol)和2-(二氟甲基磺酰)吡啶(0.82g，4.26mmol)的N,N-二甲基甲酰胺(5mL)溶液。将混合物氮气保护下缓慢升温至25℃，并在25℃下搅拌0.5小时。在冰浴下，加入饱和氯化铵溶液(5mL)和2M盐酸(9mL)，加入水(30mL)，使用乙酸乙酯(30mL*3)萃取，合并的有机相用无水硫酸钠干燥，过滤，滤液旋干。残留物用快速柱色谱纯化(硅胶，0-50％梯度的四氢呋喃/石油醚)，得到黄色油状化合物2-(二氟亚甲基)-5-氧四氢-1H-吡咯嗪-7a(5H)-羧酸乙酯(250mg，1.02mmol，收率22％)。LCMS(ESI):[M+H]+＝246.0。1H NMR(400MHz,CDCl3)δppm 4.36(br d,J＝14.7Hz,1H),4.23(q,J＝7.1Hz,2H),3.75(br d,J＝14.7Hz,1H),3.13(td,J＝1.3,15.4Hz,1H),2.90-2.73(m,1H),2.63(ddd,J＝2.0,9.2,13.2Hz,1H),2.55-2.34(m,2H),2.15(td,J＝10.1,13.2Hz,1H),1.29(t,J＝7.2Hz,3H).Step 1: To a solution of potassium tert-butoxide (0.95g, 8.52mmol) in N,N-dimethylformamide (11mL) at -50°C, add 2,5-dioxotetrahydro-1H-pyrrolazine-7a(5H)-carboxylic acid ethyl ester (1.0g, 4.73mmol) and 2-(difluoromethylsulfonyl)pyridine (0.82g, 4.26mmol) in N,N-dimethylformamide (5 mL) solution. The mixture was slowly warmed up to 25°C under nitrogen protection, and stirred at 25°C for 0.5 hours. Under ice-cooling, add saturated ammonium chloride solution (5 mL) and 2M hydrochloric acid (9 mL), add water (30 mL), use ethyl acetate (30 mL*3) to extract, the combined organic phases are dried with anhydrous sodium sulfate, filtered, and the filtrate is spin-dried. The residue was purified by flash column chromatography (silica gel, 0-50% gradient THF/petroleum ether) to give ethyl 2-(difluoromethylene)-5-oxotetrahydro-1H-pyrrolazine-7a(5H)-carboxylate (250 mg, 1.02 mmol, yield 22%) as a yellow oil. LCMS (ESI): [M+H] + = 246.0. 1 H NMR(400MHz,CDCl 3 )δppm 4.36(br d,J＝14.7Hz,1H),4.23(q,J＝7.1Hz,2H),3.75(br d,J＝14.7Hz,1H),3.13(td,J＝1.3,15.4Hz,1H),2.90-2.73(m,1H),2.63(ddd,J＝2.0,9.2,13.2Hz,1H),2.55-2.34(m,2H),2.15(td,J＝10.1,13.2Hz,1H),1.29(t,J＝7.2Hz,3H).
第二步：在0℃下，向四氢铝锂(15.5mg，0.41mmol)的四氢呋喃(1mL)溶液中加入2-(二氟亚甲基)-5-氧四氢-1H-吡咯嗪-7a(5H)-羧酸乙酯(100.0mg，0.41mmol)的四氢呋喃(1mL)溶液。将混合物在65℃下搅拌5小时，再加入四氢铝锂(7.7mg，0.20mmol)，在65℃下搅拌3小时。冷却到0℃，加入水(23uL)，15％氢氧化钠(23uL)，水(69uL)。用无水硫酸钠干燥，过滤，滤液旋干。得到黄色油状化合物(2-(二氟亚甲基)四氢-1H-吡咯啉-7a(5H)-基)甲醇和(2-(氟亚甲基)四氢-1H-吡咯啉-7a(5H)-基)甲醇的粗品混合物(74.0mg)。LCMS(ESI):[M+H]+＝190.1和172.1.Step 2: To a solution of lithium aluminum tetrahydride (15.5 mg, 0.41 mmol) in THF (1 mL) was added a solution of 2-(difluoromethylene)-5-oxotetrahydro-1H-pyrrolazine-7a(5H)-carboxylic acid ethyl ester (100.0 mg, 0.41 mmol) in THF (1 mL) at 0°C. The mixture was stirred at 65°C for 5 hours, then lithium aluminum hydride (7.7 mg, 0.20 mmol) was added, and stirred at 65°C for 3 hours. Cool to 0°C, add water (23uL), 15% sodium hydroxide (23uL), water (69uL). Dry over anhydrous sodium sulfate, filter, and spin the filtrate to dryness. A crude mixture of compounds (2-(difluoromethylene)tetrahydro-1H-pyrrolin-7a(5H)-yl)methanol and (2-(fluoromethylene)tetrahydro-1H-pyrrolin-7a(5H)-yl)methanol (74.0 mg) was obtained as a yellow oil. LCMS (ESI): [M+H] + = 190.1 and 172.1.
第三步：向(3R)-1-(7-(8-乙炔基-7-氟萘-1-基)-8-氟-6-硝基-2-(2,2,2-三氟乙氧基)喹唑啉-4-基)-3-甲基哌啶-3-醇(229.7mg，0.40mmol)以及(2-(二氟亚甲基)四氢-1H-吡咯啉-7a(5H)-基)甲醇和(2-(氟亚甲基)四氢-1H-吡咯啉-7a(5H)-基)甲醇混合物(69.0mg,0.36mmol)的四氢呋喃(2.3mL)溶液中，加入叔丁醇钠(70.1mg，0.73mmol)。将混合物氮气保护下在25℃下搅拌3小时。在0℃下加入水(6mL)稀释，使用乙酸乙酯(10mL*3)萃取，合并的有机相用无水硫酸钠干燥，过滤，滤液旋干。残余物通过制备型HPLC纯化两次，得到两个化合物：实施例121(3R)-1-(7-(8-乙炔基-7-氟萘基-1-基)- 8-氟-2-(-2-(氟亚甲基)四氢-1H-吡咯啉-7a(5H)-甲氧基)-6-硝基喹唑啉-4-基)-3-甲基哌啶-3-醇(23.97mg，0.04mmol，收率10％，黄色固体)。LCMS(ESI):[M+H]+＝644.3。1H NMR(400MHz,CD3OD)δppm8.90(br s,1H),8.18-8.00(m,2H),7.61(t,J＝7.7Hz,1H),7.51-7.36(m,2H),6.97-6.58(m,1H),4.60-4.39(m,3H),4.35-4.22(m,1H),4.13-3.92(m,1H),3.75-3.44(m,3H),3.43-3.35(m,2H),3.01-2.79(m,2H),2.77-2.52(m,1H),2.32-2.16(m,2H),2.14-1.93(m,3H),1.93-1.73(m,3H),1.31(d,J＝7.8Hz,3H).The third step: to (3R)-1-(7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-6-nitro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol (229.7mg, 0.40mmol) and (2-(difluoromethylene)tetrahydro-1H-pyrroline-7a(5H)-yl)methanol and (2-( To a solution of fluoromethylene)tetrahydro-1H-pyrrolin-7a(5H)-yl)methanol mixture (69.0mg, 0.36mmol) in tetrahydrofuran (2.3mL) was added sodium tert-butoxide (70.1mg, 0.73mmol). The mixture was stirred at 25 °C for 3 hours under nitrogen protection. Diluted with water (6 mL) at 0°C, extracted with ethyl acetate (10 mL*3), the combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried. The residue was purified twice by preparative HPLC to give two compounds: Example 121(3R)-1-(7-(8-ethynyl-7-fluoronaphthyl-1-yl)- 8-Fluoro-2-(-2-(fluoromethylene)tetrahydro-1H-pyrroline-7a(5H)-methoxy)-6-nitroquinazolin-4-yl)-3-methylpiperidin-3-ol (23.97mg, 0.04mmol, yield 10%, yellow solid). LCMS (ESI): [M+H] + = 644.3. 1 H NMR(400MHz,CD 3 OD)δppm8.90(br s,1H),8.18-8.00(m,2H),7.61(t,J＝7.7Hz,1H),7.51-7.36(m,2H),6.97-6.58(m,1H),4.60-4.39(m,3H),4.35-4.22(m,1H),4.13-3.92(m,1H),3.75-3.44(m,3H),3.43-3.35(m,2H),3.01-2.79(m,2H),2.77-2.52(m,1H),2.32-2.16(m,2H),2.14-1.93(m,3H),1.93-1.73(m,3H),1.31(d,J＝7.8Hz,3H).
实施例122(3R)-1-(2-(2-(二氟亚甲基)四氢-1H-吡咯-7a(5H)-甲氧基)-7-(8-乙炔基-7-氟萘-1-基)-8-氟-6-硝基喹唑啉-4-基)-3-甲基哌啶-3-醇(13.75mg，0.02mmol，收率6％，黄色固体)。LCMS(ESI):[M+H]+＝662.3。1H NMR(400MHz,CD3OD)δppm 8.88(d,J＝7.3Hz,1H),8.24-7.99(m,2H),7.60(t,J＝7.6Hz,1H),7.51-7.31(m,2H),4.59-4.45(m,1H),4.44-4.35(m,1H),4.35-4.18(m,2H),3.83(br d,J＝13.8Hz,1H),3.70-3.39(m,4H),3.23-3.13(m,1H),2.89-2.68(m,2H),2.54(br d,J＝15.8Hz,1H),2.30-2.09(m,2H),2.08-1.72(m,6H),1.31(d,J＝8.0Hz,3H).Example 122 (3R)-1-(2-(2-(difluoromethylene)tetrahydro-1H-pyrrole-7a(5H)-methoxy)-7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-6-nitroquinazolin-4-yl)-3-methylpiperidin-3-ol (13.75mg, 0.02mmol, yield 6%, yellow solid). LCMS (ESI): [M+H] + = 662.3. 1 H NMR(400MHz,CD 3 OD)δppm 8.88(d,J＝7.3Hz,1H),8.24-7.99(m,2H),7.60(t,J＝7.6Hz,1H),7.51-7.31(m,2H),4.59-4.45(m,1H),4.44-4.35(m,1H),4.35-4.18(m,2H),3.83(br d,J＝13.8Hz,1H),3.70-3.39(m,4H),3.23-3.13(m,1H),2.89-2.68(m,2H),2.54(br d,J＝15.8Hz,1H),2.30-2.09(m,2H),2.08-1.72(m,6H),1.31(d,J＝8.0Hz,3H).
实施例123：(3R)-1-(2-((2-亚环丙基四氢-1H-吡咯嗪-7a(5H)基)甲氧基)-7-(8-乙炔基-7-氟萘-1-基)-8-氟-6-硝基喹唑啉-4-基)-3-甲基哌啶-3-醇
Example 123: (3R)-1-(2-((2-Cyclopropylidenetetrahydro-1H-pyrrolazin-7a(5H)yl)methoxy)-7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-6-nitroquinazolin-4-yl)-3-methylpiperidin-3-ol
第一步：在25℃和氮气保护下，向环丙基三苯基溴化鏻(3.63g，9.47mmol)的四氢呋喃溶液(15mL)中分批加入钠氢(60％含量，378.73mg，9.47mmol)。将反应液在25℃下搅拌2个小时后，向反应液中依次缓慢加入2,5-二氧代四氢-1H-吡咯嗪-7a(5H)-甲酸乙酯(1.00g，4.73mmol)和三(3,6-二氧杂庚基)胺(153.13mg，473.45umol)。将反应液在25℃下搅拌10分钟后升温至62℃，并在62℃搅拌18小时。将反应混合物缓慢加入到饱和氯化铵(20mL)中进行淬灭，然后用乙酸乙酯 (10mL*3)萃取。合并的有机相用无水硫酸钠干燥，过滤，滤液旋干。粗品用快速柱色谱(硅胶，0-30％梯度的乙酸乙酯/石油醚)纯化，得到黄色油状化合物2-亚环丙基-5-氧代四氢-1H-吡咯嗪-7a(5H)-羧酸乙酯(0.10g，425.03umol，收率8％)。1H NMR(400MHz,CDCl3)δppm 4.43-4.31(m,1H),4.25-4.15(m,2H),3.85-3.75(m,1H),3.23-3.13(m,1H),2.85-2.75(m,1H),2.68-2.59(m,1H),2.56-2.42(m,2H),2.23-2.08(m,1H),1.30-1.21(m,3H),1.15-1.03(m,4H).Step 1: Add sodium hydrogen (60% content, 378.73mg, 9.47mmol) in portions to cyclopropyltriphenylphosphonium bromide (3.63g, 9.47mmol) in tetrahydrofuran (15mL) under nitrogen protection at 25°C. After the reaction solution was stirred at 25°C for 2 hours, 2,5-dioxotetrahydro-1H-pyrrolazine-7a(5H)-ethyl carboxylate (1.00g, 4.73mmol) and tris(3,6-dioxaheptyl)amine (153.13mg, 473.45umol) were slowly added to the reaction solution in sequence. The reaction solution was stirred at 25°C for 10 minutes, then heated up to 62°C, and stirred at 62°C for 18 hours. The reaction mixture was slowly added to saturated ammonium chloride (20 mL) to quench, then ethyl acetate (10mL*3) extraction. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried. The crude product was purified by flash column chromatography (silica gel, 0-30% gradient ethyl acetate/petroleum ether) to obtain ethyl 2-cyclopropylidene-5-oxotetrahydro-1H-pyrrolazine-7a(5H)-carboxylate (0.10 g, 425.03 umol, yield 8%) as a yellow oil. 1 H NMR (400MHz, CDCl 3 )δppm 4.43-4.31(m,1H),4.25-4.15(m,2H),3.85-3.75(m,1H),3.23-3.13(m,1H),2.85-2.75(m,1H),2.68-2.59(m,1H),2.56- 2.42(m,2H),2.23-2.08(m,1H),1.30-1.21(m,3H),1.15-1.03(m,4H).
第二步：在0℃的氮气氛围下，将四氢铝锂(83.9mg，2.21mmol)加入2-亚环丙基-5-氧代四氢-1H-吡咯嗪-7a(5H)-羧酸乙酯(130mg，0.55mmol)的四氢呋喃(5mL)溶液中。混合物在65℃下搅拌2小时。溶液冷却至室温后依次用水(84uL)、15％氢氧化钠溶液(84uL)、水(252uL)淬灭。悬浮液用无水硫酸钠干燥，在25℃搅拌0.5小时，然后过滤，滤液浓缩得到黄色油状化合物(2-亚环丙基四氢-1H-吡咯嗪-7a(5H)-基)甲醇(95.0mg，0.530mmol，收率96％)。LCMS(ESI):[M+H]+＝180.1Step 2: Add lithium aluminum tetrahydride (83.9 mg, 2.21 mmol) into a solution of ethyl 2-cyclopropylidene-5-oxotetrahydro-1H-pyrrolazine-7a(5H)-carboxylate (130 mg, 0.55 mmol) in tetrahydrofuran (5 mL) under a nitrogen atmosphere at 0°C. The mixture was stirred at 65°C for 2 hours. After the solution was cooled to room temperature, it was quenched with water (84 uL), 15% sodium hydroxide solution (84 uL), and water (252 uL) sequentially. The suspension was dried over anhydrous sodium sulfate, stirred at 25°C for 0.5 hours, then filtered, and the filtrate was concentrated to give yellow oily compound (2-cyclopropylidenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (95.0mg, 0.530mmol, yield 96%). LCMS (ESI): [M+H] + = 180.1
第三步：在25℃下，向(3R)-1-(8-氟-7-(7-氟-8-((三异丙基硅基)乙炔基)萘-1-基)-6-硝基-2-(2,2,2-三氟乙氧基)喹唑啉-4-基)-3-甲基哌啶-3-醇(200mg，0.27mmol)的四氢呋喃(2mL)溶液中加入叔丁醇钠(52.7mg，0.55mmol)和(2-亚环丙基四氢-1H-吡咯嗪-7a(5H)-基)甲醇(9.18mg，0.05mmol)。溶液在25℃搅拌2小时。混合物用水(5mL)稀释并用乙酸乙酯(5mL*3)萃取，合并的有机相干燥，过滤，滤液旋干。得到的粗品用快速柱色谱(硅胶，0-10％梯度的甲醇/二氯甲烷)纯化，得到棕色固体化合物(3R)-1-(2-(2-亚环丙基四氢-1H-吡咯嗪-7a(5H)-甲氧基)-8-氟-7-(7-氟-8-((三异丙基硅基)乙炔基)萘-1-基)-6-硝基喹唑啉-4-基)-3-甲基哌啶-3-醇(200mg，0.248mmol，收率90％)。LCMS(ESI):[M+H]+＝808.3.The third step: To (3R)-1-(8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-6-nitro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol (200 mg, 0.27 mmol) in THF (2 mL) was added sodium tert-butoxide (52.7 mg, 0.55 mmol) and (2-cyclopropylidenetetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol (9.18 mg, 0.05 mmol). The solution was stirred at 25°C for 2 hours. The mixture was diluted with water (5 mL) and extracted with ethyl acetate (5 mL*3), the combined organic phases were dried, filtered and the filtrate was spin-dried. The obtained crude product was purified by flash column chromatography (silica gel, 0-10% gradient of methanol/dichloromethane) to give brown solid compound (3R)-1-(2-(2-Cyclopropylidenetetrahydro-1H-pyrrolazine-7a(5H)-methoxy)-8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-6-nitroquinazolin-4-yl)-3-methylpiperidine- 3-alcohol (200 mg, 0.248 mmol, yield 90%). LCMS (ESI): [M+H] + = 808.3.
第四步：在25℃下，向氟化铯(141mg，0.93mmol)的二甲基甲酰胺(2mL)溶液中加入(3R)-1-(2-(2-亚环丙基四氢-1H-吡咯嗪-7a(5H)-甲氧基)-8-氟-7-(7-氟-8-((三异丙基硅基)乙炔基)萘-1-基)-6-硝基喹唑啉-4-基)-3-甲基哌啶-3-醇(150mg，0.19mmol)。溶液在25℃搅拌2小时。混合物用水(5mL)稀释，用乙酸乙酯(5mL*3)萃取，合并的有机相用无水硫酸钠干燥，过滤，滤液旋干。粗品经快速柱色谱(硅胶，0-10％梯度的甲醇/二氯甲烷)后，用制备型HPLC纯化得到黄色固体化合物(3R)-1-(2-((2-亚环丙基四氢-1H-吡咯嗪-7a(5H)基)甲氧基)-7-(8-乙炔基-7-氟萘-1-基)-8-氟-6-硝基喹唑啉-4-基)-3-甲基哌啶-3-醇(14.14mg，21.7umol，收率12％)。LCMS(ESI):[M+H]+＝652.4。1H NMR(400MHz,CD3OD)δppm 8.89(br s,1H),8.15-8.04(m,2H),7.59(t,J＝7.7Hz,1H),7.47-7.38(m,2H),4.60-4.44(m,3H),4.33-4.21(m,1H),4.09(br d,J＝13.9Hz,1H),3.73-3.54(m,2H),3.52(s,2H),2.98(br d,J＝12.8Hz,2H),2.76-2.65(m,1H),2.32-1.72(m,9H),1.30(d,J＝6.8Hz,3H),1.21-1.04(m,4H).Step 4: To a solution of cesium fluoride (141 mg, 0.93 mmol) in dimethylformamide (2 mL) was added (3R)-1-(2-(2-cyclopropylidenetetrahydro-1H-pyrrolazin-7a(5H)-methoxy)-8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-6-nitroquinazolin-4-yl) at 25°C -3-Methylpiperidin-3-ol (150 mg, 0.19 mmol). The solution was stirred at 25°C for 2 hours. The mixture was diluted with water (5 mL), extracted with ethyl acetate (5 mL*3), the combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried. The crude product was purified by preparative HPLC after flash column chromatography (silica gel, 0-10% gradient of methanol/dichloromethane) to give yellow solid compound (3R)-1-(2-((2-cyclopropylidenetetrahydro-1H-pyrrolazin-7a(5H)yl)methoxy)-7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-6-nitroquinazolin-4-yl)-3-methylpiperidin-3-ol ( 14.14mg, 21.7umol, yield 12%). LCMS (ESI): [M+H] + = 652.4. 1 H NMR(400MHz,CD 3 OD)δppm 8.89(br s,1H),8.15-8.04(m,2H),7.59(t,J＝7.7Hz,1H),7.47-7.38(m,2H),4.60-4.44(m,3H),4.33-4.21(m,1H),4.09(br d,J＝13.9Hz,1H),3.73-3.54(m,2H),3.52(s,2H),2.98(br d,J＝12.8Hz,2H),2.76-2.65(m,1H),2.32-1.72(m,9H),1.30(d,J＝6.8Hz,3H),1.21-1.04(m,4H).
实施例124：(3R)-1-(2-((2,6-二亚甲基四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-7-(8-乙炔基-7-氟萘-1-基)-8-氟-6-硝基喹唑啉-4-基)-3-甲基哌啶-3-醇
Example 124: (3R)-1-(2-((2,6-dimethylenetetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-6-nitroquinazolin-4-yl)-3-methylpiperidin-3-ol
第一步：将溴化甲基三苯基磷(20.g，56.0mmol)溶于四氢呋喃(75mL)中，温度降到0℃，氮气保护下加入叔丁醇钾(1M的四氢呋喃溶液，66.0mL，66.0mmol)，0℃搅拌0.5小时。将1-叔丁基2-甲基4-氧代吡咯烷-1,2-二甲酸酯(11.3g，46.4mmol)的四氢呋喃(150mL)溶液加入反应液中，反应液20℃搅拌16小时。反应液加入饱和氯化铵(100mL)淬灭，乙酸乙酯(100mL*3)萃取，合并有机相，用饱和食盐水(100mL)洗涤，硫酸钠干燥，过滤，减压浓缩，残余物通过快速柱色谱(硅胶，0-10％梯度乙酸乙酯/石油醚)纯化得到无色油状化合物1-叔丁基2-甲基4-亚甲基吡咯烷-1,2-二甲酸酯(5.80g，24.0mmol，收率50％)。LCMS(ESI):[M+H-56]+＝186.1。1H NMR(400MHz,CDCl3)δppm 5.02-4.87(m,2H),4.49-4.27(m,1H),4.00(br d,J＝15.0Hz,2H),3.71-3.61(m,3H),2.97-2.82(m,1H),2.62-2.50(m,1H),1.43-1.32(m,9H).Step 1: Dissolve methyltriphenylphosphine bromide (20.g, 56.0mmol) in tetrahydrofuran (75mL), lower the temperature to 0°C, add potassium tert-butoxide (1M solution in tetrahydrofuran, 66.0mL, 66.0mmol) under nitrogen protection, and stir at 0°C for 0.5 hours. A solution of 1-tert-butyl 2-methyl 4-oxopyrrolidine-1,2-dicarboxylate (11.3 g, 46.4 mmol) in tetrahydrofuran (150 mL) was added to the reaction solution, and the reaction solution was stirred at 20° C. for 16 hours. The reaction solution was quenched by adding saturated ammonium chloride (100 mL), extracted with ethyl acetate (100 mL*3), combined the organic phases, washed with saturated brine (100 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. Yield 50%). LCMS (ESI): [M+H-56] + = 186.1. 1 H NMR (400MHz, CDCl 3 )δppm 5.02-4.87(m,2H),4.49-4.27(m,1H),4.00(br d,J=15.0Hz,2H),3.71-3.61(m,3H),2.97-2.82(m,1H),2.62-2.50(m,1H),1 .43-1.32(m,9H).
第二步：化合物1-叔丁基2-甲基4-亚甲基吡咯烷-1,2-二甲酸酯(5.80g，24.0mmol)溶于四氢呋喃(75mL)中，温度降到-78℃，氮气下加入二(三甲基硅)氨基锂(1M的四氢呋喃溶液，48.0mL，48.0mmol)，-78℃搅拌1小时。3-氯-2-(氯甲基)丙-1-烯(7.51g，60.1mmol)加入反应液中，反应液20℃搅拌16小时。反应液加入水(100mL)淬灭，乙酸乙酯(100mL*3)萃取，合并有机相，用饱和食盐水(100mL)洗涤，硫酸钠干燥，过滤，减压浓缩，残余物通过快速柱色谱(硅胶，0-20％梯度乙酸乙酯/石油醚)纯化得到无色油状化合物1-叔丁基2-甲基2-[2-(氯甲基)丙-2-烯-1-基]-4-亚甲基吡咯烷-1,2-二甲酸酯(6.20g，20.6mmol，收率78％)。LCMS(ESI):[M-56+H]+＝274.1. Step 2: Compound 1-tert-butyl 2-methyl 4-methylenepyrrolidine-1,2-dicarboxylate (5.80g, 24.0mmol) was dissolved in tetrahydrofuran (75mL), the temperature dropped to -78°C, lithium bis(trimethylsilyl)amide (1M solution in tetrahydrofuran, 48.0mL, 48.0mmol) was added under nitrogen, and stirred at -78°C for 1 hour. 3-Chloro-2-(chloromethyl)prop-1-ene (7.51 g, 60.1 mmol) was added to the reaction solution, and the reaction solution was stirred at 20° C. for 16 hours. The reaction solution was quenched by adding water (100 mL), extracted with ethyl acetate (100 mL*3), combined the organic phases, washed with saturated brine (100 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 0-20% gradient ethyl acetate/petroleum ether) to obtain the colorless oily compound 1-tert-butyl 2-methyl 2-[2-(chloromethyl)prop-2-en-1-yl]-4-methylenepyrrolidin-1,2 - Dicarboxylate (6.20 g, 20.6 mmol, 78% yield). LCMS (ESI): [M-56+H] + = 274.1.
第三步：化合物1-叔丁基2-甲基2-[2-(氯甲基)丙-2-烯-1-基]-4-亚甲基吡咯烷-1,2-二甲酸酯(6.20g，20.6mmol)溶于二氯甲烷(68mL)，加入三氟乙酸(23mL，309mmol)，反应在20℃搅拌16小时。反应液减压浓缩，二氯甲烷(100mL)稀释，加入三乙胺调到碱性，减压浓缩，残余物通过快速柱色谱(硅胶，0-10％梯度的甲醇/二氯甲烷)纯化，得到黄色油状化合物2,6-二亚甲基四氢-1H-吡咯嗪-7a(5H)-羧酸甲酯(3.50g，17.9mmol，收率87％)。LCMS(ESI):[M+H]+＝194.1。1H NMR(400MHz,CDCl3)δppm 4.98-4.88(m,4H),3.83(br d,J＝15.0Hz,2H),3.70-3.67(m,3H),3.23(br dd,J＝1.8,15.0Hz,2H),2.95(dd,J＝1.1,16.6Hz,2H),2.54(dd,J＝1.8,16.6Hz,2H).Step 3: Compound 1-tert-butyl 2-methyl 2-[2-(chloromethyl)prop-2-en-1-yl]-4-methylenepyrrolidine-1,2-dicarboxylate (6.20g, 20.6mmol) was dissolved in dichloromethane (68mL), trifluoroacetic acid (23mL, 309mmol) was added, and the reaction was stirred at 20°C for 16 hours. The reaction solution was concentrated under reduced pressure, diluted with dichloromethane (100 mL), adjusted to basicity by adding triethylamine, concentrated under reduced pressure, and the residue was purified by flash column chromatography (silica gel, 0-10% gradient methanol/dichloromethane) to obtain yellow oily compound 2,6-dimethylenetetrahydro-1H-pyrrolazine-7a(5H)-methyl carboxylate (3.50 g, 17.9 mmol, yield 87%). LCMS (ESI): [M+H] + = 194.1. 1 H NMR (400MHz, CDCl 3 ) δppm 4.98-4.88 (m, 4H), 3.83 (br d, J = 15.0Hz, 2H), 3.70-3.67 (m, 3H), 3.23 (br dd, J = 1.8, 15.0Hz, 2H), 2.95 (dd, J = 1.1, 16.6Hz, 2H), 2 .54(dd,J=1.8,16.6Hz,2H).
第四步：将四氢铝锂(147mg，3.88mmol)溶于四氢呋喃(4mL)，0℃下加入2,6-二亚甲基四氢-1H-吡咯嗪-7a(5H)-羧酸甲酯(500mg，2.58mmol)，反应液在20℃搅拌2小时。向反应液加入水(147uL)，氢氧化钠(15％的水溶液，147uL)，水(147uL*3)淬灭，混合物过滤，滤液减压浓缩得到(2,6-二亚甲基四氢-1H-吡咯嗪-7a(5H)-基)甲醇(250mg，1.50mmol，收率58％)。LCMS(ESI):[M+H]+＝166.1。1H NMR(400MHz,CDCl3)δppm 4.92-4.80(m,4H),3.59(dd,J＝0.8,15.1Hz,2H),3.24-3.13(m,4H),2.50-2.41(m,2H),2.38-2.29(m,2H).Step 4: Dissolve lithium aluminum tetrahydride (147mg, 3.88mmol) in tetrahydrofuran (4mL), add 2,6-dimethyltetrahydro-1H-pyrrolazine-7a(5H)-methyl carboxylate (500mg, 2.58mmol) at 0°C, and stir the reaction solution at 20°C for 2 hours. Water (147uL), sodium hydroxide (15% aqueous solution, 147uL), quenched with water (147uL*3) were added to the reaction solution, the mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain (2,6-dimethylenetetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol (250mg, 1.50mmol, yield 58%). LCMS (ESI): [M+H] + = 166.1. 1 H NMR (400MHz, CDCl 3 ) δppm 4.92-4.80(m, 4H), 3.59(dd, J=0.8, 15.1Hz, 2H), 3.24-3.13(m, 4H), 2.50-2.41(m, 2H), 2.38-2.29(m, 2H).
第五步：将化合物(3R)-1-(8-氟-7-(7-氟-8-((三异丙基硅基)乙炔基)萘-1-基)-6-硝基-2-(2,2,2-三氟乙氧基)喹唑啉-4-基)-3-甲基哌啶-3-醇(100mg，0.14mmol)和(2,6-二亚甲基四氢-1H-吡咯嗪-7a(5H)-基)甲醇(45mg，0.27mmol)溶于四氢呋喃(2mL)中，加入叔丁醇钠(40mg，0.41mmol)，20℃搅拌16小时。反应液通过硅藻土过滤，滤液减压浓缩得粗品化合物(3R)-1-(2-((2,6-二亚甲基四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-8-氟-7-(7-氟-8-((三异丙基甲硅烷基)乙炔基)萘-1-基)-6-硝基喹唑啉-4-基)-3-甲基哌啶-3-醇(100mg)。LCMS(ESI):[M+H]+＝794.3.The fifth step: compound (3R)-1-(8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalene-1-yl)-6-nitro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol (100mg, 0.14mmol) and (2,6-dimethylenetetrahydro-1H-pyrrolazine-7a (5H) -yl)methanol (45mg, 0.27mmol) was dissolved in tetrahydrofuran (2mL), sodium tert-butoxide (40mg, 0.41mmol) was added, and stirred at 20°C for 16 hours. The reaction solution is filtered through diatomic soil, and the filtration solution is concentrated to the rough product (3R) -1- (2- ((2,6-two-dimensional methyl-1h-1H-picharine-7A (5H)-base) -8-fluorine-7- (7-fluorine-8- ((triopropyye metalite) acetyl) -6-nitigazolein -4-base) -3-metharine-3-alcohol (100 mg). LCMS (ESI): [M+H] + = 794.3.
第六步：化合物(3R)-1-(2-((2,6-二亚甲基四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-8-氟-7-(7-氟-8-((三异丙基甲硅烷基)乙炔基)萘-1-基)-6-硝基喹唑啉-4-基)-3-甲基哌啶-3-醇(100mg，0.12mmol)加入到N,N-二甲基甲酰胺(2.0mL)中，加入氟化铯(352mg，2.32mmol)，20℃搅拌1小时。反应液通过硅藻土过滤，滤液减压浓缩，残留物用制备型HPLC纯化得到(3R)-1-(2-((2,6-二亚甲基四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-7-(8-乙炔基-7-氟萘-1-基)-8-氟-6-硝基喹唑啉-4-基)-3-甲基哌啶-3-醇(8.10mg，12umol，收率10％)。LCMS(ESI):[M+H]+＝638.5；1H NMR(400MHz,CD3OD)δppm 8.78(d,J＝1.3Hz,1H),8.06-7.93(m,2H),7.51(t,J＝7.7Hz,1H),7.39-7.28(m,2H),4.97(br d,J＝6.5Hz,4H),4.44(br d,J＝13.1Hz,1H),4.37-4.27(m,2H),4.19(br d,J＝13.4Hz,1H),3.77(br d,J＝14.9Hz,2H),3.54-3.43(m,2H),3.39-3.28(m,3H),2.81-2.70(m,2H),2.54(br d,J＝16.5Hz,2H),2.17-2.02(m,1H),1.81-1.62(m,3H),1.21(s,3H).Step 6: Compound (3R)-1-(2-((2,6-dimethylenetetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalene-1-yl)-6-nitroquinazolin-4-yl)-3-methylpiperidin-3-ol (100mg, 0.12mmol) was added to N,N- To dimethylformamide (2.0 mL) was added cesium fluoride (352 mg, 2.32 mmol), and stirred at 20°C for 1 hour. The reaction solution was filtered through celite, the filtrate was concentrated under reduced pressure, and the residue was purified by preparative HPLC to obtain (3R)-1-(2-((2,6-dimethylenetetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-6-nitroquinazolin-4-yl)-3-methylpiperidin-3-ol (8.10mg, 12umol, Yield 10%). LCMS(ESI):[M+H] + ＝638.5； 1 H NMR(400MHz,CD 3 OD)δppm 8.78(d,J＝1.3Hz,1H),8.06-7.93(m,2H),7.51(t,J＝7.7Hz,1H),7.39-7.28(m,2H),4.97(br d,J＝6.5Hz,4H),4.44(br d,J＝13.1Hz,1H),4.37-4.27(m,2H),4.19(br d,J＝13.4Hz,1H),3.77(br d,J＝14.9Hz,2H),3.54-3.43(m,2H),3.39-3.28(m,3H),2.81-2.70(m,2H),2.54(br d,J＝16.5Hz,2H),2.17-2.02(m,1H),1.81-1.62(m,3H),1.21(s,3H).
实施例125：(3R)-1-(-(8-乙炔基-7-氟萘-1-基)-8-氟-(2-(((1aR,6aR)-4-亚甲基六氢环丙烷并[b]吡咯嗪-5a(3H)-基)甲氧基)-6-硝基喹唑啉-4-基)-3-甲基哌啶-3-醇
Example 125: (3R)-1-(-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-(2-(((1aR,6aR)-4-methylenehexahydrocyclopropano[b]pyrrolazin-5a(3H)-yl)methoxy)-6-nitroquinazolin-4-yl)-3-methylpiperidin-3-ol
第一步：氮气保护下，将化合物2-叔丁基3-乙基(1R,3R,5R)-2-氮杂双环[3.1.0]己烷-2,3-二羧酸酯(1.50g，5.87mmol)的四氢呋喃(30mL)溶液降到-78℃，加入二(三甲基硅)氨基锂(1M的四氢呋喃，10.0mL，10.0mmol)，-78℃搅拌1小时。3-氯-2-(氯甲基)丙-1-烯(1.84g，14.7mmol)加入反应液中，反应液20℃搅拌16小时。反应液加入水(100mL)淬灭，乙酸乙酯(50mL*3)萃取，合并的有机相用饱和食盐水(100mL)洗涤，硫酸钠干燥，过滤，滤液减压浓缩，残余物通过快速柱色谱(硅胶，0-10％梯度乙酸乙酯/石油醚)纯化，得到无色油状化合物2-叔丁基3-乙基(1R,3R,5R)-3-(2-(氯甲基)烯丙基)2-氮杂双环[3.1.0]己烷-2,3-二羧酸酯(1.20g，3.48mmol，收率59％)。LCMS(ESI):[M-56+H]+＝288.0。1H NMR(400MHz,CDCl3)δppm 5.36-5.27(m,1H),5.09-5.03(m,1H),4.20-4.09(m,1H),4.07-3.95(m,3H),3.32-3.05(m,2H),2.59-2.34(m,2H),2.12-2.03(m,1H),1.40-1.35(m,9H),1.26-1.18(m,3H),0.97(dq,J＝2.6,5.3Hz,1H),0.83-0.60(m,2H).The first step: under the protection of nitrogen, the tetrahydrofuran (30mL) solution of the compound 2-tert-butyl 3-ethyl (1R,3R,5R)-2-azabicyclo[3.1.0]hexane-2,3-dicarboxylate (1.50g, 5.87mmol) was lowered to -78°C, and lithium bis(trimethylsilyl)amide (1M tetrahydrofuran, 10.0mL, 10.0mmol) was added, and stirred at -78°C 1 hour. 3-Chloro-2-(chloromethyl)prop-1-ene (1.84 g, 14.7 mmol) was added to the reaction solution, and the reaction solution was stirred at 20° C. for 16 hours. The reaction solution was quenched by adding water (100 mL), extracted with ethyl acetate (50 mL*3), the combined organic phase was washed with saturated brine (100 mL), dried over sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by flash column chromatography (silica gel, 0-10% gradient ethyl acetate/petroleum ether) to obtain the colorless oily compound 2-tert-butyl 3-ethyl(1R,3R,5R)-3-(2-(chloromethyl)allyl)2-aza Bicyclo[3.1.0]hexane-2,3-dicarboxylate (1.20 g, 3.48 mmol, 59% yield). LCMS (ESI): [M-56+H] + = 288.0. 1 H NMR (400MHz, CDCl 3 ) δppm 5.36-5.27(m,1H),5.09-5.03(m,1H),4.20-4.09(m,1H),4.07-3.95(m,3H),3.32-3.05(m,2H),2.59-2.34(m,2H),2.12- 2.03(m,1H),1.40-1.35(m,9H),1.26-1.18(m,3H),0.97(dq,J=2.6,5.3Hz,1H),0.83-0.60(m,2H).
第二步：将化合物2-叔丁基3-乙基(1R,3R,5R)-3-(2-(氯甲基)烯丙基)2-氮杂双环[3.1.0]己烷-2,3-二羧酸酯(1.20g，3.48mmol)溶于二氯甲烷(17mL)，加入三氟乙酸(4mL，52mmol)，反应在20℃搅拌16小时。反应液减压浓缩，加入二氯甲烷(50mL)稀释，加入三乙胺调到pH>7，再次减压浓缩，得到粗品化合物(1R,5R)-3-(2-(氯甲基)烯丙基]-2-氮杂二环[3.1.0]己烷-3-羧酸乙酯(1.20g)，其为黄色油状液体。LCMS(ESI):[M+H]+＝244.1.The second step: the compound 2-tert-butyl 3-ethyl(1R,3R,5R)-3-(2-(chloromethyl)allyl)2-azabicyclo[3.1.0]hexane-2,3-dicarboxylate (1.20g, 3.48mmol) was dissolved in dichloromethane (17mL), trifluoroacetic acid (4mL, 52mmol) was added, and the reaction was stirred at 20°C for 16 hours. The reaction solution was concentrated under reduced pressure, diluted with dichloromethane (50 mL), adjusted to pH>7 by adding triethylamine, and concentrated under reduced pressure again to obtain the crude compound (1R,5R)-3-(2-(chloromethyl)allyl]-2-azabicyclo[3.1.0]hexane-3-carboxylic acid ethyl ester (1.20 g), which was a yellow oily liquid. LCMS (ESI): [M+H] + =244.1.
第三步：将化合物(1R,5R)-3-(2-(氯甲基)烯丙基]-2-氮杂二环[3.1.0]己烷-3-羧酸乙酯(1.20g，4.92mmol)溶于乙醇(12mL)，25℃下加入碘化钾(81.0mg，0.49mmol)和碳酸钾(2.00g，14.7mmol)。反应在25℃下搅拌16小时。反应液过滤，滤液减压浓缩，残留物用快速柱色谱纯化(硅胶，0-10％梯度的甲醇/二氯甲烷)得到黄色油状化合物(1aR,6aR)-4-亚甲基六氢环丙烷并[b]吡咯嗪-5a(3H)-羧酸乙酯(0.60g，两步收率：80％)。LCMS(ESI):[M+H]+＝208.2。1H NMR(400MHz,CDCl3)δppm 4.89- 4.77(m,2H),4.22-4.07(m,2H),3.96(br d,J＝4.3Hz,1H),3.27(dd,J＝1.9,14.3Hz,1H),2.73(br dd,J＝1.6,15.9Hz,1H),2.64(ddd,J＝2.8,5.2,7.5Hz,1H),2.59-2.47(m,2H),1.81(dd,J＝4.6,13.1Hz,1H),1.46-1.36(m,1H),1.20(t,J＝7.1Hz,3H),0.50-0.42(m,1H),0.20(ddd,J＝2.9,4.0,6.9Hz,1H).第三步：将化合物(1R,5R)-3-(2-(氯甲基)烯丙基]-2-氮杂二环[3.1.0]己烷-3-羧酸乙酯(1.20g，4.92mmol)溶于乙醇(12mL)，25℃下加入碘化钾(81.0mg，0.49mmol)和碳酸钾(2.00g，14.7mmol)。反应在25℃下搅拌16小时。反应液过滤，滤液减压浓缩，残留物用快速柱色谱纯化(硅胶，0-10％梯度的甲醇/二氯甲烷)得到黄色油状化合物(1aR,6aR)-4-亚甲基六氢环丙烷并[b]吡咯嗪-5a(3H)-羧酸乙酯(0.60g，两步收率：80％)。LCMS(ESI):[M+H] + ＝208.2。 1 H NMR(400MHz,CDCl 3 )δppm 4.89- 4.77(m,2H),4.22-4.07(m,2H),3.96(br d,J=4.3Hz,1H),3.27(dd,J=1.9,14.3Hz,1H),2.73(br dd,J=1.6,15.9Hz,1H),2.64(ddd,J=2.8,5.2,7.5Hz,1H), 2.59-2.47(m,2H),1.81(dd,J=4.6,13.1Hz,1H),1.46-1.36(m,1H),1.20(t,J=7.1Hz,3H),0.50-0.42(m,1H),0.20(ddd,J=2.9,4.0,6.9Hz,1H).
第四步：将四氢铝锂(220mg，5.79mmol)溶于四氢呋喃(6mL)，0℃下加入(1aR,6aR)-4-亚甲基六氢环丙烷并[b]吡咯嗪-5a(3H)-羧酸乙酯(600mg，2.89mmol)，反应液在20℃搅拌2小时。向反应液加入水(220uL)，氢氧化钠(15％的水溶液，220uL)，水(220uL*3)淬灭，过滤，滤液减压浓缩得到粗品化合物((1aR,6aR)-4-亚甲基六氢环丙烷并[b]吡咯嗪-5a(3H)-基)甲醇(300mg，1.81mmol，收率62％)。LCMS(ESI):[M+H]+＝166.2.Step 4: Dissolve lithium aluminum tetrahydride (220mg, 5.79mmol) in tetrahydrofuran (6mL), add (1aR,6aR)-4-methylenehexahydrocyclopropano[b]pyrrolazine-5a(3H)-ethyl carboxylate (600mg, 2.89mmol) at 0°C, and stir the reaction solution at 20°C for 2 hours. Water (220uL), sodium hydroxide (15% aqueous solution, 220uL), quenched with water (220uL*3) were added to the reaction solution, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude compound ((1aR,6aR)-4-methylenehexahydrocyclopropane[b]pyrrolazin-5a(3H)-yl)methanol (300mg, 1.81mmol, yield 62%). LCMS (ESI): [M+H] + = 166.2.
第五步：向化合物(3R)-1-(7-(8-乙炔基-7-氟萘-1-基)-8-氟-6-硝基-2-(2,2,2-三氟乙氧基)喹唑啉-4-基)-3-甲基哌啶-3-醇(100mg，0.17mmol)和((1aR,6aR)-4-亚甲基六氢环丙烷并[b]吡咯嗪-5a(3H)-基)甲醇(60mg，0.36mmol)的四氢呋喃(2mL)溶液中，加入叔丁醇钠(60mg，0.62mmol)，20℃搅拌16小时。反应液通过硅藻土过滤，滤液减压浓缩，残留物用制备型HPLC纯化得到化合物(3R)-1-(-(8-乙炔基-7-氟萘-1-基)-8-氟-(2-(((1aR,6aR)-4-亚甲基六氢环丙烷并[b]吡咯嗪-5a(3H)-基)甲氧基)-6-硝基喹唑啉-4-基)-3-甲基哌啶-3-醇(8.66mg，13umol，收率7％)。LCMS(ESI):[M+H]+＝638.5；1H NMR(400MHz,CD3OD)δppm 8.74(d,J＝1.4Hz,1H),8.05-7.92(m,2H),7.49(t,J＝7.7Hz,1H),7.37-7.28(m,2H),4.87(br s,2H),4.41(br d,J＝13.1Hz,1H),4.18-4.05(m,3H),3.71(br d,J＝14.4Hz,1H),3.54-3.43(m,3H),3.34-3.25(m,1H),2.71-2.65(m,1H),2.59(dt,J＝2.7,6.5Hz,1H),2.52(br d,J＝15.4Hz,1H),2.14-2.06(m,2H),1.99-1.90(m,2H),1.70(br dd,J＝3.7,13.9Hz,2H),1.60-1.54(m,1H),1.18(s,3H),0.71-0.63(m,1H),0.45-0.37(m,1H).The fifth step: To compound (3R)-1-(7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-6-nitro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol (100mg, 0.17mmol) and ((1aR,6aR)-4-methylenehexahydrocyclopropane[b]pyrrolazine-5a(3H) Sodium tert-butoxide (60 mg, 0.62 mmol) was added to a solution of methanol (60 mg, 0.36 mmol) in tetrahydrofuran (2 mL), and stirred at 20° C. for 16 hours.反应液通过硅藻土过滤，滤液减压浓缩，残留物用制备型HPLC纯化得到化合物(3R)-1-(-(8-乙炔基-7-氟萘-1-基)-8-氟-(2-(((1aR,6aR)-4-亚甲基六氢环丙烷并[b]吡咯嗪-5a(3H)-基)甲氧基)-6-硝基喹唑啉-4-基)-3-甲基哌啶-3-醇(8.66mg，13umol，收率7％)。LCMS(ESI):[M+H] + ＝638.5； 1 H NMR(400MHz,CD 3 OD)δppm 8.74(d,J＝1.4Hz,1H),8.05-7.92(m,2H),7.49(t,J＝7.7Hz,1H),7.37-7.28(m,2H),4.87(br s,2H),4.41(br d,J＝13.1Hz,1H),4.18-4.05(m,3H),3.71(br d,J＝14.4Hz,1H),3.54-3.43(m,3H),3.34-3.25(m,1H),2.71-2.65(m,1H),2.59(dt,J＝2.7,6.5Hz,1H),2.52(br d,J＝15.4Hz,1H),2.14-2.06(m,2H),1.99-1.90(m,2H),1.70(br dd,J＝3.7,13.9Hz,2H),1.60-1.54(m,1H),1.18(s,3H),0.71-0.63(m,1H),0.45-0.37(m,1H).
实施例126：(3R)-1-(2-((二氢-1'H,3'H-螺[环丙烷-1,2'-吡咯嗪]-7a'(5'H)-基)甲氧基)-7-(8-乙炔基-7-氟萘-1-基)-8-氟-6-硝基喹唑啉-4-基)-3-甲基哌啶-3-醇
Example 126: (3R)-1-(2-((Dihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolazin]-7a'(5'H)-yl)methoxy)-7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-6-nitroquinazolin-4-yl)-3-methylpiperidin-3-ol
LCMS(ESI):[M+H]+＝640.2；1H NMR(400MHz,CD3OD)δppm 8.89(s,1H),8.14-8.05(m,2H),7.59(t,J＝7.7Hz,1H),7.49-7.38(m,2H),4.58-4.46(m,3H),4.35-4.22(m,1H),3.71-3.45(m,2H),3.44-3.34(m,2H),3.23(br s,1H),3.10(br s,1H),3.00(br d,J＝6.2Hz,1H),2.31-1.72(m,10H),1.35-1.25(m,3H),0.78-0.69(m,2H),0.68-0.55(m,2H).LCMS(ESI):[M+H]+= 640.2;1H NMR (400MHz, CD3OD)δppm 8.89(s,1H),8.14-8.05(m,2H),7.59(t,J＝7.7Hz,1H),7.49-7.38(m,2H),4.58-4.46(m,3H),4.35-4.22(m,1H),3.71-3.45(m,2H),3.44-3 .34(m,2H),3.23(br s,1H),3.10(br s,1H),3.00(br d,J＝6.2Hz,1H),2.31-1.72(m,10H),1.35-1.25(m,3H),0.78-0.69(m,2H),0.68-0.55(m,2H).
实施例126A：(R)-1-((R)-2-(((S)-二氢-1'H,3'H-螺[环丙烷-1,2'-吡咯啉]-7a'(5'H)-基)甲氧基)-7-(8-乙炔基-7-氟萘-1-基)-8-氟-6-硝基喹唑啉-4-基)-3-甲基哌啶-3-醇 Example 126A: (R)-1-((R)-2-(((S)-dihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrroline]-7a'(5'H)-yl)methoxy)-7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-6-nitroquinazolin-4-yl)-3-methylpiperidin-3-ol
实施例126B:(R)-1-((S)-2-(((S)-二氢-1'H,3'H-螺[环丙烷-1,2'-吡咯啉]-7a'(5'H)-基)甲氧基)-7-(8-乙炔基-7-氟萘-1-基)-8-氟-6-硝基喹唑啉-4-基)-3-甲基哌啶-3-醇Example 126B: (R)-1-((S)-2-(((S)-dihydro-1 'H,3'H-spiro[cyclopropane-1,2'-pyrroline]-7a'(5'H)-yl)methoxy)-7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-6-nitroquinazolin-4-yl)-3-methylpiperidin-3-ol
实施例126C:(R)-1-((R)-2-(((R)-二氢-1'H,3'H-螺[环丙烷-1,2'-吡咯啉]-7a'(5'H)-基)甲氧基)-7-(8-乙炔基-7-氟萘-1-基)-8-氟-6-硝基喹唑啉-4-基)-3-甲基哌啶-3-醇Example 126C: (R)-1-((R)-2-(((R)-dihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrroline]-7a'(5'H)-yl)methoxy)-7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-6-nitroquinazolin-4-yl)-3-methylpiperidin-3-ol
实施例126D:(R)-1-((S)-2-(((R)-二氢-1'H,3'H-螺[环丙烷-1,2'-吡咯啉]-7a'(5'H)-基)甲氧基)-7-(8-乙炔基-7-氟萘-1-基)-8-氟-6-硝基喹唑啉-4-基)-3-甲基哌啶-3-醇
Example 126D: (R)-1-((S)-2-(((R)-dihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrroline]-7a'(5'H)-yl)methoxy)-7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-6-nitroquinazolin-4-yl)-3-methylpiperidin-3-ol
实施例126经过SFC分离(柱：DAICEL CHIRALPAK IC(250mm*30mm,10um)；流动相：A相为二氧化碳，B相为0.1％氨水/乙醇；B相保持60％；流速：80毫升/分钟)，得到异构体1和异构体2的混合物、光学纯的异构体3以及光学纯的异构体4三个组分。异构体1和异构体2的混合物经过SFC分离(柱：Phenomenex-Cellulose-2(250mm*30mm,10um)；流动相：A相为二氧化碳，B相为0.1％氨水/甲醇；B相保持50％；流速：80毫升/分钟)，得到光学纯的实施例126A实以及光学纯的实施例126B。Example 126 was separated by SFC (column: DAICEL CHIRALPAK IC (250mm*30mm, 10um); mobile phase: phase A was carbon dioxide, phase B was 0.1% ammonia water/ethanol; phase B was maintained at 60%; flow rate: 80 ml/min), and three components were obtained: a mixture of isomer 1 and isomer 2, optically pure isomer 3 and optically pure isomer 4. The mixture of isomer 1 and isomer 2 was separated by SFC (column: Phenomenex-Cellulose-2 (250mm*30mm, 10um); mobile phase: phase A was carbon dioxide, phase B was 0.1% ammonia water/methanol; phase B was maintained at 50%; flow rate: 80 ml/min), to obtain optically pure Example 126A and optically pure Example 126B.
实施例126A：LCMS(ESI):[M+H]+＝640.1；SFC分析(柱:Cellulose 2 100*4.6mm I.D.,3um；流动相：A相为二氧化碳，B相为0.05％二乙胺/甲醇；梯度：保持50％的B相；流速：2.8毫升/分钟)：手性柱出峰位置为3.304min；1H NMR(400MHz,CD3OD)δ＝8.89(d,J＝1.4Hz,1H),8.15-8.02(m,2H),7.59(t,J＝7.7Hz,1H),7.50-7.35(m,2H),4.62-4.48(m,3H),4.27(br d,J＝13.1Hz,1H),3.69-3.60(m,1H),3.52-3.33(m,4H),3.15(br d,J＝11.9Hz,1H),3.05(br d,J＝10.6Hz,1H),2.34-1.98(m,7H),1.93-1.72(m,3H),1.37-1.24(m,3H),0.82-0.59(m,4H).Example 126A: LCMS (ESI): [M+H]+=640.1; SFC analysis (column: Cellulose 2 100*4.6mm I.D., 3um; mobile phase: phase A is carbon dioxide, phase B is 0.05% diethylamine/methanol; gradient: keep 50% of phase B; flow rate: 2.8 ml/min): chiral column peak position is 3.304min;1H NMR (400MHz, CD3OD)δ＝8.89(d, J＝1.4Hz, 1H), 8.15-8.02(m, 2H), 7.59(t, J＝7.7Hz, 1H), 7.50-7.35(m, 2H), 4.62-4.48(m, 3H), 4.27(br d, J＝13.1Hz, 1H), 3.69-3.60(m, 1H),3.52-3.33(m,4H),3.15(br d,J=11.9Hz,1H),3.05(br d,J=10.6Hz,1H),2.34-1.98(m,7H),1.93-1.72(m,3H),1.37-1.24(m,3H),0.82-0.59(m,4 H).
实施例126B：LCMS(ESI):[M+H]+＝640.1；SFC分析(柱:Cellulose 2 100*4.6mm I.D.,3um；流动相：A相为二氧化碳，B相为0.05％二乙胺/甲醇；梯度：保持50％的B相；流速：2.8毫升/分钟)：手性柱出峰位置为4.369min；1H NMR(400MHz,CD3OD)δ＝8.89(s,1H),8.14-8.00(m,2H),7.59(t,J＝7.6Hz,1H),7.49-7.35(m,2H),4.64-4.50(m,3H),4.26(br d,J＝13.0Hz,1H),3.64(d,J＝13.4Hz,1H), 3.51-3.36(m,4H),3.13-3.01(m,2H),2.33-1.74(m,10H),1.36-1.21(m,3H),0.81-0.57(m,4H).实施例126B：LCMS(ESI):[M+H] + ＝640.1；SFC分析(柱:Cellulose 2 100*4.6mm ID,3um；流动相：A相为二氧化碳，B相为0.05％二乙胺/甲醇；梯度：保持50％的B相；流速：2.8毫升/分钟)：手性柱出峰位置为4.369min； 1 H NMR(400MHz,CD 3 OD)δ＝8.89(s,1H),8.14-8.00(m,2H),7.59(t,J＝7.6Hz,1H),7.49-7.35(m,2H),4.64-4.50(m,3H),4.26(br d,J＝13.0Hz,1H),3.64(d,J＝13.4Hz,1H), 3.51-3.36(m,4H),3.13-3.01(m,2H),2.33-1.74(m,10H),1.36-1.21(m,3H),0.81-0.57(m,4H).
实施例126C：LCMS(ESI):[M+H]+＝640.2；SFC分析(柱:Chiralpak IC-3 100*4.6mm I.D.,3um；流动相：A相为二氧化碳，B相为0.05％二乙胺/乙醇；梯度：保持50％的B相；流速：2.8毫升/分钟)：手性柱出峰位置为4.500min；1H NMR(400MHz,CD3OD)δ＝8.88(s,1H),8.15-8.03(m,2H),7.59(t,J＝7.6Hz,1H),7.48-7.36(m,2H),4.64-4.45(m,3H),4.30(br d,J＝13.4Hz,1H),3.64-3.51(m,2H),3.46-3.33(m,2H),3.15(br d,J＝9.1Hz,1H),3.09-2.92(m,2H),2.30-1.74(m,10H),1.29(s,3H),0.77-0.54(m,4H).Example 126C: LCMS (ESI): [M+H]+=640.2; SFC analysis (column: Chiralpak IC-3 100*4.6mm I.D., 3um; mobile phase: phase A is carbon dioxide, phase B is 0.05% diethylamine/ethanol; gradient: keep 50% of phase B; flow rate: 2.8 ml/min): chiral column peak position is 4.500min;1H NMR (400MHz, CD3OD)δ＝8.88(s,1H),8.15-8.03(m,2H),7.59(t,J＝7.6Hz,1H),7.48-7.36(m,2H),4.64-4.45(m,3H),4.30(br d,J＝13.4Hz,1H),3.64-3.51(m,2H),3.4 6-3.33(m,2H),3.15(br d,J＝9.1Hz,1H),3.09-2.92(m,2H),2.30-1.74(m,10H),1.29(s,3H),0.77-0.54(m,4H).
实施例126D：LCMS(ESI):[M+H]+＝640.2；SFC分析(柱:Chiralpak IC-3 100*4.6mm I.D.,3um；流动相：A相为二氧化碳，B相为0.05％二乙胺/乙醇；梯度：保持50％的B相；流速：2.8毫升/分钟)：手性柱出峰位置为5.555min；1H NMR(400MHz,CD3OD)δ＝8.87(s,1H),8.15-7.99(m,2H),7.59(t,J＝7.6Hz,1H),7.48-7.37(m,2H),4.59-4.43(m,3H),4.30(br d,J＝13.2Hz,1H),3.65-3.52(m,2H),3.39(br t,J＝13.3Hz,2H),3.15(br d,J＝10.9Hz,1H),3.08-2.88(m,2H),2.28-1.72(m,10H),1.40(s,3H),0.75-0.56(m,4H).Example 126D: LCMS (ESI): [M+H]+=640.2; SFC analysis (column: Chiralpak IC-3 100*4.6mm I.D., 3um; mobile phase: phase A is carbon dioxide, phase B is 0.05% diethylamine/ethanol; gradient: keep 50% of phase B; flow rate: 2.8 ml/min): chiral column peak position is 5.555min;1H NMR (400MHz, CD3OD)δ=8.87(s,1H),8.15-7.99(m,2H),7.59(t,J=7.6Hz,1H),7.48-7.37(m,2H),4.59-4.43(m,3H),4.30(br d,J=13.2Hz,1H),3.65-3.52(m,2H),3.3 9(br t,J=13.3Hz,2H),3.15(br d,J=10.9Hz,1H),3.08-2.88(m,2H),2.28-1.72(m,10H),1.40(s,3H),0.75-0.56(m,4H).
实施例127A：(R)-1-(7-((S)-8-乙炔基-7-氟萘-1-基)-8-氟-2-((1-(吗啉甲基)环丙基)甲氧基)-6-硝基喹唑啉-4-基)-3-甲基哌啶-3-醇的两个立体异构体Example 127A: Two stereoisomers of (R)-1-(7-((S)-8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-((1-(morpholinomethyl)cyclopropyl)methoxy)-6-nitroquinazolin-4-yl)-3-methylpiperidin-3-ol
实施例127B：(R)-1-(7-((R)-8-乙炔基-7-氟萘-1-基)-8-氟-2-((1-(吗啉甲基)环丙基)甲氧基)-6-硝基喹唑啉-4-基)-3-甲基哌啶-3-醇
Example 127B: (R)-1-(7-((R)-8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-((1-(morpholinomethyl)cyclopropyl)methoxy)-6-nitroquinazolin-4-yl)-3-methylpiperidin-3-ol
实施例127A(16.56mg，黄色固体)，HPLC分析(柱:Ultimate XB-C18,3um,3.0*50mm；流动相：A相为三氟乙酸/水(1.5mL/4L)，B相为三氟乙酸/乙腈(0.75mL/4L)；梯度：B相在1分钟内从1％到5％，在5分钟内从5％到100％，保持100％的B相2分钟，保持1％的B相2分钟；流速：1.2毫升/分钟)：出峰位置为3.586min；LCMS(ESI):[M+H]+＝644.3；1H NMR(400MHz,CD3OD)δppm8.89(d,J＝1.2Hz,1H),8.14-8.06(m,2H),7.60(t,J＝7.7Hz,1H),7.49-7.39(m,2H),4.49-4.41(m,3H),4.20(br d,J＝13.2Hz,1H),3.68-3.61(m,5H),3.52-3.40(m,2H),2.55-2.47(m,4H),2.44(d,J＝2.8Hz,2H),2.27-2.18(m,1H),1.88(br s,1H),1.85-1.78(m,2H),1.32(s,3H),0.75-0.68(m,2H),0.53-0.46(m,2H).Example 127A (16.56mg, yellow solid), HPLC analysis (column: Ultimate XB-C18, 3um, 3.0*50mm; mobile phase: phase A is trifluoroacetic acid/water (1.5mL/4L), phase B is trifluoroacetic acid/acetonitrile (0.75mL/4L); gradient: phase B is from 1% to 5% in 1 minute, from 5% to 100% in 5 minutes, hold 10 0% phase B for 2 minutes, keep 1% phase B for 2 minutes; flow rate: 1.2 ml/min): the peak position is 3.586min; LCMS (ESI): [M+H]+= 644.3;1H NMR (400MHz, CD3OD)δppm8.89(d,J=1.2Hz,1H),8.14-8.06(m,2H),7.60(t,J=7.7Hz,1H),7.49-7.39(m,2H),4.49-4.41(m,3H),4.20(br d,J=13.2Hz,1H),3.68-3.61(m ,5H),3.52-3.40(m,2H),2.55-2.47(m,4H),2.44(d,J＝2.8Hz,2H),2.27-2.18(m,1H),1.88(br s,1H),1.85-1.78(m,2H),1.32(s,3H),0.75-0.68(m, 2H),0.53-0.46(m,2H).
实施例127B(20.17mg，黄色固体)，HPLC分析(柱:Ultimate XB-C18,3um,3.0*50mm；流动相：A相为三氟乙酸/水(1.5mL/4L)，B相为三氟乙酸/乙腈(0.75mL/4L)；梯度：B相在1分钟内从1％到5％，在5分钟内从5％到100％，保持100％的B相2分钟，保持1％的B相2分钟；流速：1.2毫升/分钟)：出峰位置为3.607min；LCMS(ESI):[M+H]+＝644.2；1H NMR(400MHz,CD3OD)δppm8.86(d,J＝1.2Hz,1H),8.14-8.05(m,2H),7.60(t,J＝7.6Hz,1H),7.48-7.40(m,2H),4.54-4.40(m,3H),4.25(br d,J＝13.4Hz,1H),3.66(t,J＝4.5Hz,4H),3.61(d,J＝13.4Hz,1H),3.55(s,1H),3.42(br t,J＝10.9Hz,1H),2.60-2.47(m,4H),2.46-2.41(m,2H),2.30-2.16(m,1H),1.90-1.75(m,3H),1.30(s,3H),0.76- 0.69(m,2H),0.54-0.48(m,2H).实施例127B(20.17mg，黄色固体)，HPLC分析(柱:Ultimate XB-C18,3um,3.0*50mm；流动相：A相为三氟乙酸/水(1.5mL/4L)，B相为三氟乙酸/乙腈(0.75mL/4L)；梯度：B相在1分钟内从1％到5％，在5分钟内从5％到100％，保持100％的B相2分钟，保持1％的B相2分钟；流速：1.2毫升/分钟)：出峰位置为3.607min；LCMS(ESI):[M+H] + ＝644.2； 1 H NMR(400MHz,CD 3 OD)δppm8.86(d,J＝1.2Hz,1H),8.14-8.05(m,2H),7.60(t,J＝7.6Hz,1H),7.48-7.40(m,2H),4.54-4.40(m,3H),4.25(br d,J＝13.4Hz,1H),3.66(t,J＝4.5Hz,4H),3.61(d,J＝13.4Hz,1H),3.55(s,1H),3.42(br t,J＝10.9Hz,1H),2.60-2.47(m,4H),2.46-2.41(m,2H),2.30-2.16(m,1H),1.90-1.75(m,3H),1.30(s,3H),0.76- 0.69(m,2H),0.54-0.48(m,2H).
实施例128：(3R)-1-(7-(8-乙炔基-7-氟萘-1-基)-8-氟-2-((1-((4-甲基哌嗪-1-基)甲基)环丙基)甲氧基)-6-硝基喹唑啉-4-基)-3-甲基哌啶-3-醇
Example 128: (3R)-1-(7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-((1-((4-methylpiperazin-1-yl)methyl)cyclopropyl)methoxy)-6-nitroquinazolin-4-yl)-3-methylpiperidin-3-ol
LCMS(ESI):[M+H]+＝657.3。1H NMR(400MHz,CD3OD)δppm 8.88(d,J＝9.9Hz,1H),8.19-8.02(m,2H),7.61(t,J＝7.6Hz,1H),7.50-7.34(m,2H),4.76-4.20(m,5H),3.72-3.34(m,4H),2.78(br s,6H),2.53(br t,J＝6.1Hz,2H),2.48(br d,J＝2.4Hz,3H),2.22(br d,J＝10.8Hz,1H),1.92-1.70(m,3H),1.32(d,J＝8.1Hz,3H),0.75(s,2H),0.53(s,2H).LCMS (ESI): [M+H] + = 657.3. 1 H NMR(400MHz,CD 3 OD)δppm 8.88(d,J＝9.9Hz,1H),8.19-8.02(m,2H),7.61(t,J＝7.6Hz,1H),7.50-7.34(m,2H),4.76-4.20(m,5H),3.72-3.34(m,4H),2.78(br s,6H),2.53(br t,J＝6.1Hz,2H),2.48(br d,J＝2.4Hz,3H),2.22(br d,J＝10.8Hz,1H),1.92-1.70(m,3H),1.32(d,J＝8.1Hz,3H),0.75(s,2H),0.53(s,2H).
实施例129：(3R)-1-(7-(8-乙炔基-7-氟萘基-1-基)-8-氟-6-硝基-2-(((S)-1-(2,2,2-三氟乙基)吡咯烷-2-基)甲氧基)喹唑啉-4-基)-3-甲基哌啶-3-醇
Example 129: (3R)-1-(7-(8-ethynyl-7-fluoronaphthyl-1-yl)-8-fluoro-6-nitro-2-(((S)-1-(2,2,2-trifluoroethyl)pyrrolidin-2-yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol
LCMS(ESI):[M+H]+＝656.2；1H NMR(400MHz,CD3OD)δppm 8.89(d,J＝1.4Hz,1H),8.16-8.04(m,2H),7.60(t,J＝7.7Hz,1H),7.51-7.37(m,2H),4.57-4.44(m,2H),4.33-4.19(m,2H),3.78-3.59(m,2H),3.51-3.39(m,2H),3.31-3.13(m,3H),2.63-2.56(m,1H),2.29-2.17(m,1H),2.13-1.98(m,1H),1.93-1.74(m,6H),1.32(s,3H).LCMS(ESI):[M+H]+= 656.2;1H NMR (400MHz, CD3OD)δppm 8.89(d,J=1.4Hz,1H),8.16-8.04(m,2H),7.60(t,J=7.7Hz,1H),7.51-7.37(m,2H),4.57-4.44(m,2H),4.33-4.19(m,2H),3.78-3.59(m,2H) ,3.51-3.39(m,2H),3.31-3.13(m,3H),2.63-2.56(m,1H),2.29-2.17(m,1H),2.13-1.98(m,1H),1.93-1.74(m,6H),1.32(s,3H).
实施例130：(3R)-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)-6-硝基喹唑啉-4-基)-3-甲基哌啶-3-醇
Example 130: (3R)-1-(7-(8-Ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-6-nitroquinazolin-4-yl)-3-methylpiperidin-3-ol
LCMS(ESI):[M+H]+＝588.3。1H NMR(400MHz,CD3OD)δppm 8.92-8.85(m,1H),8.15-8.01(m,2H),7.60(t,J＝7.6Hz,1H),7.50-7.39(m,2H),4.68-4.48(m,3H),4.35-4.23(m,1H),3.67-3.37(m,3H), 3.30-3.21(m,1H),2.80-2.64(m,4H),2.29-2.14(m,2H),2.02-1.75(m,6H),1.36-1.26(m,3H).LCMS (ESI): [M+H] + = 588.3. 1 H NMR (400MHz, CD 3 OD) δppm 8.92-8.85(m,1H),8.15-8.01(m,2H),7.60(t,J=7.6Hz,1H),7.50-7.39(m,2H),4.68-4.48(m,3H),4.35-4.23(m,1H),3.6 7-3.37(m,3H), 3.30-3.21(m,1H),2.80-2.64(m,4H),2.29-2.14(m,2H),2.02-1.75(m,6H),1.36-1.26(m,3H).
实施例131A：(R)-1-(7-((S)-8-乙炔基-7-氟萘基-1-基)-8-氟-2-((3-(吗啉代甲基)氧杂环丁烷-3-基)甲氧基)-6-硝基喹唑啉-4-基)-3-甲基哌啶-3-醇Example 131A: (R)-1-(7-((S)-8-ethynyl-7-fluoronaphthyl-1-yl)-8-fluoro-2-((3-(morpholinomethyl)oxetan-3-yl)methoxy)-6-nitroquinazolin-4-yl)-3-methylpiperidin-3-ol
实施例131B：(R)-1-(7-((S)-8-乙炔基-7-氟萘基-1-基)-8-氟-2-((3-(吗啉代甲基)氧杂环丁烷-3-基)甲氧基)-6-硝基喹唑啉-4-基)-3-甲基哌啶-3-醇
Example 131B: (R)-1-(7-((S)-8-ethynyl-7-fluoronaphthyl-1-yl)-8-fluoro-2-((3-(morpholinomethyl)oxetan-3-yl)methoxy)-6-nitroquinazolin-4-yl)-3-methylpiperidin-3-ol
实施例131A(7.62mg，黄色固体)，HPLC分析(柱:Ultimate XB-C18,3um,3.0*50mm；流动相：A相为三氟乙酸/水(1.5mL/4L)，B相为三氟乙酸/乙腈(0.75mL/4L)；梯度：B相在1分钟内从1％到5％，在5分钟内从5％到100％，保持100％的B相2分钟，保持1％的B相2分钟；流速：1.2毫升/分钟)：出峰位置为3.539min；LCMS(ESI):[M+H]+＝660.2；1H NMR(400MHz,CD3OD)δppm 8.91(d,J＝1.3Hz,1H),8.11(dt,J＝6.6,9.7Hz,2H),7.60(t,J＝7.7Hz,1H),7.51-7.37(m,2H),4.86-4.82(m,1H),4.82-4.77(m,1H),4.64(dd,J＝4.2,6.2Hz,2H),4.60-4.56(m,2H),4.51(br d,J＝13.4Hz,1H),4.24(br d,J＝13.4Hz,1H),3.70-3.57(m,5H),3.54-3.41(m,2H),2.85(s,2H),2.51-2.34(m,4H),2.31-2.17(m,1H),1.95-1.76(m,3H),1.33(s,3H).Example 131A (7.62mg, yellow solid), HPLC analysis (column: Ultimate XB-C18, 3um, 3.0*50mm; mobile phase: phase A is trifluoroacetic acid/water (1.5mL/4L), phase B is trifluoroacetic acid/acetonitrile (0.75mL/4L); gradient: phase B is from 1% to 5% within 1 minute, from 5% to 100% within 5 minutes, and maintains 100% % of B phase for 2 minutes, keep 1% of B phase for 2 minutes; flow rate: 1.2 ml/min): the peak position is 3.539min; LCMS (ESI): [M+H]+= 660.2;1H NMR (400MHz, CD3OD)δppm 8.91(d,J=1.3Hz,1H),8.11(dt,J=6.6,9.7Hz,2H),7.60(t,J=7.7Hz,1H),7.51-7.37(m,2H),4.86-4.82(m,1H),4.82-4.77(m,1H),4.64(dd,J ＝4.2,6.2Hz,2H),4.60-4.56(m,2H),4.51(br d,J=13.4Hz,1H),4.24(br d,J=13.4Hz,1H),3.70-3.57(m,5H),3.54-3.41(m,2H),2.85(s,2H),2.51-2.3 4(m,4H),2.31-2.17(m,1H),1.95-1.76(m,3H),1.33(s,3H).
实施例131B(7.91mg，黄色固体)，HPLC分析(柱:Ultimate XB-C18,3um,3.0*50mm；流动相：A相为三氟乙酸/水(1.5mL/4L)，B相为三氟乙酸/乙腈(0.75mL/4L)；梯度：B相在1分钟内从1％到5％，在5分钟内从5％到100％，保持100％的B相2分钟，保持1％的B相2分钟；流速：1.2毫升/分钟)：出峰位置为3.565min；LCMS(ESI):[M+H]+＝660.3；1H NMR(400MHz,CD3OD)δppm 8.88(d,J＝1.3Hz,1H),8.19-7.99(m,2H),7.60(t,J＝7.7Hz,1H),7.49-7.36(m,2H),4.82(s,1H),4.66-4.54(m,5H),4.28(br d,J＝13.4Hz,1H),3.67-3.59(m,5H),3.56(s,1H),3.42(br t,J＝11.0Hz,1H),2.84(s,2H),2.50-2.32(m,4H),2.30-2.16(m,1H),1.95-1.68(m,3H),1.37-1.22(m,3H).Example 131B (7.91mg, yellow solid), HPLC analysis (column: Ultimate XB-C18, 3um, 3.0*50mm; mobile phase: phase A is trifluoroacetic acid/water (1.5mL/4L), phase B is trifluoroacetic acid/acetonitrile (0.75mL/4L); gradient: phase B is from 1% to 5% within 1 minute, from 5% to 100% within 5 minutes, and maintains 100% % of B phase for 2 minutes, keep 1% of B phase for 2 minutes; flow rate: 1.2 ml/min): the peak position is 3.565min; LCMS (ESI): [M+H]+= 660.3;1H NMR (400MHz, CD3OD)δppm 8.88(d,J=1.3Hz,1H),8.19-7.99(m,2H),7.60(t,J=7.7Hz,1H),7.49-7.36(m,2H),4.82(s,1H),4.66-4.54(m,5H),4.28(br d,J=13.4Hz,1H) ,3.67-3.59(m,5H),3.56(s,1H),3.42(br t,J＝11.0Hz,1H),2.84(s,2H),2.50-2.32(m,4H),2.30-2.16(m,1H),1.95-1.68(m,3H),1.37-1.22(m,3H) .
实施例132A:(R)-1-(2-((1-((4,4-二氟哌啶-1-基)甲基)环丙基)甲氧基)-7-((S)-8-乙炔基-7-氟萘-1-基)-8-氟-6-硝基喹唑啉-4-基)-3-甲基哌啶-3-醇Example 132A: (R)-1-(2-((1-((4,4-difluoropiperidin-1-yl)methyl)cyclopropyl)methoxy)-7-((S)-8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-6-nitroquinazolin-4-yl)-3-methylpiperidin-3-ol
和实施例132B:(R)-1-(2-((1-((4,4-二氟哌啶-1-基)甲基)环丙基)甲氧基)-7-((R)-8-乙炔基-7-氟萘-1-基)-8-氟-6-硝基喹唑啉-4-基)-3-甲基哌啶-3-醇
and Example 132B: (R)-1-(2-((1-((4,4-difluoropiperidin-1-yl)methyl)cyclopropyl)methoxy)-7-((R)-8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-6-nitroquinazolin-4-yl)-3-methylpiperidin-3-ol
实施例132A：LCMS(ESI):[M+H]+＝678.1。1H NMR(400MHz,CD3OD)δppm 8.94-8.83(m,1H),8.17-8.05(m,2H),7.60(t,J＝7.7Hz,1H),7.50-7.36(m,2H),4.54-4.15(m,4H),3.63(d,J＝13.4Hz,1H),3.51-3.39(m,2H),2.96-2.58(m,6H),2.22(d,J＝13.6Hz,1H),2.05(dt,J＝6.2,13.2Hz,4H),1.93-1.64(m,3H),1.32(s,3H),0.83-0.73(m,2H),0.58(s,2H).Example 132A: LCMS (ESI): [M+H] + = 678.1. 1 H NMR (400MHz, CD 3 OD) δppm 8.94-8.83 (m, 1H), 8.17-8.05 (m, 2H), 7.60 (t, J = 7.7Hz, 1H), 7.50-7.36 (m, 2H), 4.54-4.15 (m, 4H), 3.63 (d, J = 13.4Hz, 1H), ( s,2H).
实施例132B：SFC分析(色谱柱:ChiralCel OD-3，50mm*4.6mm，3um；流动相：A相为二氧化碳，B相为0.05％二乙胺/乙醇；2min从5％的B相升至40％的B相，保持40％的B相1.2min，然后保持5％的B相0.8min；流速：4毫升/分钟)：手性柱出峰位置为1.763min。LCMS(ESI):[M+H]+＝678.1。1H NMR(400MHz,CD3OD)δppm 8.85(s,1H),8.15-8.06(m,2H),7.60(t,J＝7.7Hz,1H),7.50-7.41(m,2H),4.53-4.22(m,4H),3.64-3.52(m,2H),3.44-3.37(m,1H),2.76-2.48(m,6H),2.23(d,J＝13.0Hz,1H),2.04-1.93(m,4H),1.90-1.74(m,3H),1.34-1.27(m,3H),0.75(s,2H),0.57-0.49(m,2H).Example 132B: SFC Analysis (color spectrum: chiralcel OD-3, 50mm*4.6mm, 3UM; flow phase: A phase: A phase is carbon dioxide, the B phase is 0.05 % ethomine/ethanol; 2min rises from 5 % to 40 % B phase, maintains a 40 % B phase 1.2min, and then maintains 5 % B. Phase 0.8min; flow rate: 4 ml/minute): The position of the hand column is 1.763min. LCMS (ESI): [M+H] + = 678.1. 1 H NMR(400MHz,CD 3 OD)δppm 8.85(s,1H),8.15-8.06(m,2H),7.60(t,J＝7.7Hz,1H),7.50-7.41(m,2H),4.53-4.22(m,4H),3.64-3.52(m,2H),3.44-3.37(m,1H),2.76-2.48(m,6H),2.23(d,J＝13.0Hz,1H),2.04-1.93(m,4H),1.90-1.74(m,3H),1.34-1.27(m,3H),0.75(s,2H),0.57-0.49(m,2H).
实施例133：(3R)-1-(7-(8-乙炔基-7-氟萘-1-基)-8-氟-6-硝基-2-((1-(哌啶-1-基)甲基)环丙基)甲氧基)喹唑啉-4-基)-3-甲基哌啶-3-醇甲酸盐
Example 133: (3R)-1-(7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-6-nitro-2-((1-(piperidin-1-yl)methyl)cyclopropyl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol formate
LCMS(ESI):[M+H]+＝642.2。1H NMR(400MHz,CD3OD)δppm 8.93-8.85(m,1H),8.56(s,1H),8.18-8.07(m,2H),7.62(t,J＝7.6Hz,1H),7.50-7.41(m,2H),4.60-4.46(m,3H),4.43-4.22(m,2H),3.65-3.52(m,2H),3.45-3.36(m,2H),3.21-2.83(m,4H),1.97-1.72(m,8H),1.62(br s,2H),1.33-1.29(m,3H),0.91(br s,2H),0.82-0.71(m,2H).LCMS (ESI): [M+H] + = 642.2. 1 H NMR(400MHz,CD 3 OD)δppm 8.93-8.85(m,1H),8.56(s,1H),8.18-8.07(m,2H),7.62(t,J＝7.6Hz,1H),7.50-7.41(m,2H),4.60-4.46(m,3H),4.43-4.22(m,2H),3.65-3.52(m,2H),3.45-3.36(m,2H),3.21-2.83(m,4H),1.97-1.72(m,8H),1.62(br s,2H),1.33-1.29(m,3H),0.91(br s,2H),0.82-0.71(m,2H).
实施例134：(3R)-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-6-硝基喹唑啉-4-基)-3-甲基哌啶-3-醇
Example 134: (3R)-1-(2-((1-(Dimethylamino)methyl)cyclopropyl)methoxy)-7-(8-ethyl-7-fluoronaphthalen-1-yl)-8-fluoro-6-nitroquinazolin-4-yl)-3-methylpiperidin-3-ol
LCMS(ESI):[M+H]+＝602.1。1H NMR(400MHz,CD3OD)δppm 8.93-8.87(m,1H),8.15-8.07(m, 2H),7.61(t,J＝7.8Hz,1H),7.49-7.40(m,2H),4.57-4.37(m,3H),4.32-4.20(m,1H),3.67-3.58(m,1H),3.50-3.37(m,2H),2.72(br s,2H),2.51(br s,6H),2.22(br d,J＝7.3Hz,1H),1.92-1.77(m,3H),1.34-1.29(m,3H),0.82(s,2H),0.64(br s,2H).LCMS (ESI): [M+H] + = 602.1. 1 H NMR (400MHz, CD 3 OD) δppm 8.93-8.87 (m, 1H), 8.15-8.07 (m, 2H), 7.61(t, J=7.8Hz, 1H), 7.49-7.40(m, 2H), 4.57-4.37(m, 3H), 4.32-4.20(m, 1H), 3.67-3.58(m, 1H), 3.50-3.37(m, 2H), 2.72(br s, 2H), 2.51(br s,6H),2.22(br d,J=7.3Hz,1H),1.92-1.77(m,3H),1.34-1.29(m,3H),0.82(s,2H),0.64(br s,2H).
实施例135：1-(7-(8-乙炔基-7-氟-3-羟基萘-1-基)-8-氟-2-((1-(吗啉甲基)环丙基)甲氧基)-6-硝基喹唑啉-4-基)-3-甲基哌啶-3-醇
Example 135: 1-(7-(8-Ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-((1-(morpholinylmethyl)cyclopropyl)methoxy)-6-nitroquinazolin-4-yl)-3-methylpiperidin-3-ol
第一步：在25℃下，向1-(7-溴-2-氯-8-氟-6-硝基喹唑啉-4-基)-3-甲基哌啶-3-醇(1.40g，3.34mmol)的三氟乙醇(15mL)溶液中加入二异丙基乙胺(2.33mL，13.35mmol)。将溶液在70℃搅拌3小时。将溶液浓缩并通过快速柱色谱(硅胶，0-30％梯度的乙酸乙酯/石油醚)纯化得到棕色油状化合物1-(7-溴-8-氟-6-硝基-2-(2,2,2-三氟乙氧基)喹唑啉-4-基)-3-甲基哌啶-3-醇(1.29g，2.67mmol，收率80％)。LCMS(ESI):[M+H]+＝485.1.Step 1: To a solution of 1-(7-bromo-2-chloro-8-fluoro-6-nitroquinazolin-4-yl)-3-methylpiperidin-3-ol (1.40 g, 3.34 mmol) in trifluoroethanol (15 mL) was added diisopropylethylamine (2.33 mL, 13.35 mmol) at 25°C. The solution was stirred at 70°C for 3 hours. The solution was concentrated and purified by flash column chromatography (silica gel, 0-30% gradient of ethyl acetate/petroleum ether) to give compound 1-(7-bromo-8-fluoro-6-nitro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol (1.29 g, 2.67 mmol, yield 80%) as a brown oil. LCMS (ESI): [M+H] + = 485.1.
第二步：在25℃和氮气氛围下，向1-(7-溴-8-氟-6-硝基-2-(2,2,2-三氟乙氧基)喹唑啉-4-基)-3-甲基哌啶-3-醇(0.50g，1.03mmol)和(((2-氟-6-(甲氧基甲氧基)-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(0.80g，1.55mmol)的甲苯(20mL)和水(5mL)溶液中加入碳酸铯(1.01g，3.10mmol)和甲磺酸(二金刚烷基-正丁基膦基)-2'-氨基-1,1'-联苯-2-基)钯(II)二氯甲烷(0.15g，0.21mmol)。将该溶液在100℃搅拌16小时。将溶液浓缩，残余物通过快速柱色谱(硅胶，0-30％梯度的四氢呋喃/石油醚)纯化得到棕色固体化合物1-(8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三异丙基甲硅烷基)乙炔基)萘-1-基)-6-硝基-2-(2,2,2-三氟乙氧基)喹唑啉-4-基)-3-甲基哌啶-3-醇(0.58g，0.62mmol，收率60％)。LCMS(ESI):[M+H]+＝789.1.The second step: 1-(7-bromo-8-fluoro-6-nitro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol (0.50g, 1.03mmol) and (((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2 To a solution of -yl)naphthalen-1-yl)ethynyl)triisopropylsilane (0.80 g, 1.55 mmol) in toluene (20 mL) and water (5 mL) was added cesium carbonate (1.01 g, 3.10 mmol) and methanesulfonic acid (diamantyl-n-butylphosphino)-2'-amino-1,1'-biphenyl-2-yl)palladium(II) dichloromethane (0.15 g, 0.21 mmol). The solution was stirred at 100°C for 16 hours. The solution was concentrated and the residue was purified by flash column chromatography (silica gel, 0-30% gradient THF/petroleum ether) to give the brown solid compound 1-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalene-1-yl)-6-nitro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol (0.58 g, 0.62 mmol, yield 60%). LCMS (ESI): [M+H] + = 789.1.
第三步：在25℃下，向1-(8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三异丙基甲硅烷基)乙炔基)萘-1-基)-6-硝基-2-(2,2,2-三氟乙氧基)喹唑啉-4-基)-3-甲基哌啶-3-醇(500mg，0.63mmol)和(1-(吗啉甲基)环丙基)甲醇(217mg，1.27mmol)的四氢呋喃(5mL)溶液中加入叔丁醇钠(122mg，1.27mmol)。将该溶液在25℃搅拌2小时。溶液用水(10mL)稀释并用乙酸乙酯(10mL*3)萃取。然后将有机层干燥并浓缩，粗品通过快速柱色谱(硅胶，0-10％梯度的甲醇/二氯甲烷)纯化，得到棕色油状化合物1-(8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三异丙基甲硅烷基)乙炔基)萘-1-基)-2-((1-(吗啉甲基)环丙基)甲氧基)-6-硝基喹唑啉-4-基)-3-甲基哌啶-3-醇(540mg，0.50mmol，收率88％)。LCMS(ESI):[M+H]+＝860.4. The third step: at 25°C, add 1-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalene-1-yl)-6-nitro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol (500mg, 0.63mmol) and (1-(morpholinemethyl)cyclopropyl)methanol (2 To a solution of 17 mg, 1.27 mmol) in tetrahydrofuran (5 mL) was added sodium tert-butoxide (122 mg, 1.27 mmol). The solution was stirred at 25°C for 2 hours. The solution was diluted with water (10 mL) and extracted with ethyl acetate (10 mL*3). The organic layer was then dried and concentrated, and the crude product was purified by flash column chromatography (silica gel, 0-10% gradient of methanol/dichloromethane) to give compound 1-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-((1-(morpholinylmethyl)cyclopropyl)methoxy)-6-nitroquinazolin-4-yl)-3-methylpiperidinium as a brown oil 3-ol (540 mg, 0.50 mmol, 88% yield). LCMS (ESI): [M+H] + = 860.4.
第四步：在25℃下，向1-(8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三异丙基甲硅烷基)乙炔基)萘-1-基)-2-((1-(吗啉甲基)环丙基)甲氧基)-6-硝基喹唑啉-4-基)-3-甲基哌啶-3-醇(500mg，0.58mmol)的二甲基甲酰胺(5mL)溶液中添加氟化铯(883mg，5.81mmol)。将该溶液在25℃搅拌2小时。溶液用水(10mL)稀释并乙酸乙酯(10mL*3)萃取。将合并的有机相干燥并浓缩。粗品通过快速柱色谱(硅胶，0-10％梯度的甲醇/二氯甲烷)纯化，得到黄色固体化合物1-(7-(8-乙炔基-7-氟-3-(甲氧基甲氧基)萘-1-基)-8-氟-2-((1-(吗啉甲基)环丙基)甲氧基)-6-硝基喹唑啉-4-基)-3-甲基哌啶-3-醇(280mg，0.34mmol，收率58％)。LCMS(ESI):[M+H]+＝704.2.Step 4: Add 1-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalene-1-yl)-2-((1-(morpholinemethyl)cyclopropyl)methoxy)-6-nitroquinazolin-4-yl)-3-methylpiperidin-3-ol (500mg, 0.58mmol) in dimethylformamide (5mL) at 25°C Cesium fluoride (883 mg, 5.81 mmol) was added. The solution was stirred at 25°C for 2 hours. The solution was diluted with water (10 mL) and extracted with ethyl acetate (10 mL*3). The combined organic phases were dried and concentrated. The crude product was purified by flash column chromatography (silica gel, 0-10% gradient of methanol/dichloromethane) to give yellow solid compound 1-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yl)-8-fluoro-2-((1-(morpholinylmethyl)cyclopropyl)methoxy)-6-nitroquinazolin-4-yl)-3-methylpiperidin-3-ol (280 mg, 0.34 mmol, yield 5 8%). LCMS (ESI): [M+H] + = 704.2.
第五步：在25℃下，向1-(7-(8-乙炔基-7-氟-3-(甲氧基甲氧基)萘-1-基)-8-氟-2-((1-(吗啉甲基)环丙基)甲氧基)-6-硝基喹唑啉-4-基)-3-甲基哌啶-3-醇(20mg，28.4umol)的乙腈(200uL)溶液中加入氯化氢(4M的二氧六环溶液，71uL，0.28mmol)。将该溶液在25℃搅拌1小时。将溶液浓缩，残余物分散到乙腈(1mL)中，加入三乙胺将其pH值调节至8。将溶液浓缩并通过制备型HPLC纯化得到黄色固体化合物1-(7-(8-乙炔基-7-氟-3-羟基萘-1-基)-8-氟-2-((1-(吗啉甲基)环丙基)甲氧基)-6-硝基喹唑啉-4-基)-3-甲基哌啶-3-醇(6.63mg，9.9umol，收率35％)。[M+H]+＝660.1。1H NMR(400MHz,CD3OD)δppm 8.84(d,J＝10.3Hz,1H),7.84(dd,J＝5.8,8.9Hz,1H),7.36-7.25(m,2H),7.00(dd,J＝2.4,10.6Hz,1H),4.51-4.37(m,3H),4.20(br dd,J＝13.5,19.9Hz,1H),3.68-3.56(m,5H),3.51-3.34(m,2H),2.62-2.37(m,6H),2.28-2.14(m,1H),1.92-1.72(m,3H),1.29(d,J＝8.1Hz,3H),0.75-0.67(m,2H),0.53-0.44(m,2H).Step 5: To a solution of 1-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yl)-8-fluoro-2-((1-(morpholinemethyl)cyclopropyl)methoxy)-6-nitroquinazolin-4-yl)-3-methylpiperidin-3-ol (20mg, 28.4umol) in acetonitrile (200uL) at 25°C was added hydrogen chloride (4M in dioxane solution, 71 uL, 0.28 mmol). The solution was stirred at 25°C for 1 hour. The solution was concentrated, the residue was dispersed in acetonitrile (1 mL), and its pH was adjusted to 8 by adding triethylamine. The solution was concentrated and purified by preparative HPLC to give yellow solid compound 1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-((1-(morpholinemethyl)cyclopropyl)methoxy)-6-nitroquinazolin-4-yl)-3-methylpiperidin-3-ol (6.63mg, 9.9umol, yield 35%). [M+H] + = 660.1. 1 H NMR(400MHz,CD 3 OD)δppm 8.84(d,J＝10.3Hz,1H),7.84(dd,J＝5.8,8.9Hz,1H),7.36-7.25(m,2H),7.00(dd,J＝2.4,10.6Hz,1H),4.51-4.37(m,3H),4.20(br dd,J＝13.5,19.9Hz,1H),3.68-3.56(m,5H),3.51-3.34(m,2H),2.62-2.37(m,6H),2.28-2.14(m,1H),1.92-1.72(m,3H),1.29(d,J＝8.1Hz,3H),0.75-0.67(m,2H),0.53-0.44(m,2H).
实施例136：1-(7-(8-乙基-7-氟-3-羟基萘-1-基)-8-氟-2-((1-(吗啉甲基)环丙基)甲氧基)-6-硝基喹唑啉-4-基)-3-甲基哌啶-3-醇
Example 136: 1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-((1-(morpholinylmethyl)cyclopropyl)methoxy)-6-nitroquinazolin-4-yl)-3-methylpiperidin-3-ol
第一步：在25℃和氮气氛围下，向1-(7-(8-乙炔基-7-氟-3-(甲氧基甲氧基)萘-1-基)-8-氟-2-((1-(吗啉甲基)环丙基)甲氧基)-6-硝基喹唑啉-4-基)-3-甲基哌啶-3-醇(30mg，0.04mmol)的四氢呋喃(100uL)溶液中加入2-硝基苯磺酰肼(47mg，0.21mmol)和三乙胺(30uL，0.21mmol)。将该溶液在25℃搅拌16小时。溶液加水(500uL)稀释并用乙酸乙酯(500uL*3)萃取，有机相干燥，过滤，滤液旋干得到棕色固体化合物1-(7-(8-乙基-7-氟-3-(甲氧基甲氧基)萘-1-基)-8-氟-2-((1-(吗啉甲基)环丙基)甲氧基)-6-硝基喹唑啉-4-基)-3-甲基哌啶-3-醇(30mg，38.1umol，收率89％)。LCMS(ESI):[M+H]+＝708.4.Step 1: Add 2-nitrobenzene to a solution of 1-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yl)-8-fluoro-2-((1-(morpholinemethyl)cyclopropyl)methoxy)-6-nitroquinazolin-4-yl)-3-methylpiperidin-3-ol (30mg, 0.04mmol) in tetrahydrofuran (100uL) at 25°C under nitrogen atmosphere Sulfonyl hydrazide (47 mg, 0.21 mmol) and triethylamine (30 uL, 0.21 mmol). The solution was stirred at 25°C for 16 hours. The solution was diluted with water (500uL) and extracted with ethyl acetate (500uL*3), the organic phase was dried, filtered, and the filtrate was spin-dried to obtain a brown solid compound 1-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yl)-8-fluoro-2-((1-(morpholinemethyl)cyclopropyl)methoxy)-6-nitroquinazolin-4-yl)-3-methylpiperidin-3-ol (30mg , 38.1umol, yield 89%). LCMS (ESI): [M+H] + = 708.4.
第二步：在25℃下，向1-(7-(8-乙基-7-氟-3-(甲氧基甲氧基)萘-1-基)-8-氟-2-((1-(吗啉甲基)环丙基)甲氧基)-6-硝基喹唑啉-4-基)-3-甲基哌啶-3-醇(30mg，0.04mmol)的乙腈(300uL)溶液中加入氯化氢(4M的二氧六环溶液，106uL，0.42mmol)。将溶液在25℃搅拌1小时。浓缩溶液，然后用二氯甲烷(1mL)稀释并加入三乙胺将其pH值调节至8。浓缩溶液并通过制备型HPLC纯化得到黄色固体化合物1-(7-(8-乙基-7-氟-3-羟基萘-1-基)-8-氟-2-((1-(吗啉甲基)环丙基)甲氧基)-6-硝基喹唑啉-4-基)-3-甲基哌啶-3-醇(4.95mg，7.1umol，收率17％)。LCMS(ESI):[M+H]+＝664.2。1H NMR(400MHz, CD3OD)δppm 8.93(d,J＝16.8Hz,1H),7.67(dd,J＝5.9,9.0Hz,1H),7.30-7.21(m,2H),6.85-6.78(m,1H),4.50-4.40(m,3H),4.28-4.16(m,1H),3.66(br t,J＝4.5Hz,4H),3.63-3.53(m,1H),3.51-3.40(m,1H),2.60(br s,5H),2.52(br s,2H),2.40(br s,1H),2.19(br d,J＝8.4Hz,1H),1.92-1.75(m,3H),1.32(d,J＝15.9Hz,3H),0.83(q,J＝7.4Hz,3H),0.73(s,2H),0.53(s,2H).Second step: To 1-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-((1-(morpholinemethyl)cyclopropyl)methoxy)-6-nitroquinazolin-4-yl)-3-methylpiperidin-3-ol (30mg, 0.04mmol) in acetonitrile (300uL) was added hydrogen chloride (4M in dioxane) at 25°C, 106 uL, 0.42 mmol). The solution was stirred at 25°C for 1 hour. The solution was concentrated, then diluted with dichloromethane (1 mL) and adjusted to pH 8 by the addition of triethylamine. The solution was concentrated and purified by preparative HPLC to give yellow solid compound 1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-((1-(morpholinemethyl)cyclopropyl)methoxy)-6-nitroquinazolin-4-yl)-3-methylpiperidin-3-ol (4.95mg, 7.1umol, yield 17%). LCMS (ESI): [M+H] + = 664.2. 1 H NMR (400MHz, CD 3 OD)δppm 8.93(d,J＝16.8Hz,1H),7.67(dd,J＝5.9,9.0Hz,1H),7.30-7.21(m,2H),6.85-6.78(m,1H),4.50-4.40(m,3H),4.28-4.16(m,1H),3.66(br t,J＝4.5Hz,4H),3.63-3.53(m,1H),3.51-3.40(m,1H),2.60(br s,5H),2.52(br s,2H),2.40(br s,1H),2.19(br d,J＝8.4Hz,1H),1.92-1.75(m,3H),1.32(d,J＝15.9Hz,3H),0.83(q,J＝7.4Hz,3H),0.73(s,2H),0.53(s,2H).
乙炔基)三异丙基硅烷(425mg，0.83mmol)的甲苯(12mL)和水(3mL)溶液中加入甲磺酸(二金刚烷基-正丁基膦基)-2'-氨基-1,1'-联苯-2-基)钯(II)二氯甲烷(81mg，0.11mmol)和碳酸铯(541mg，1.66mmol)。将该溶液在100℃搅拌16小时。将反应液旋干并通过快速柱色谱(硅胶，0-10％梯度的甲醇/二氯甲烷)纯化得到粗品化合物1-(8-氟-7-(7-氟-3-(甲氧基甲氧基)-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)-6-硝基喹唑啉-4-基)-3-甲基哌啶-3-醇(290mg)，其为棕色固体。[M+H]+＝848.4To a solution of ethynyl)triisopropylsilane (425 mg, 0.83 mmol) in toluene (12 mL) and water (3 mL) was added methanesulfonic acid (diamantyl-n-butylphosphino)-2'-amino-1,1'-biphenyl-2-yl)palladium(II) dichloromethane (81 mg, 0.11 mmol) and cesium carbonate (541 mg, 1.66 mmol). The solution was stirred at 100°C for 16 hours. The reaction solution was spin-dried and purified by flash column chromatography (silica gel, 0-10% gradient methanol/dichloromethane) to obtain the crude compound 1-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalene-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-6-nitro quinazolin-4-yl)-3-methylpiperidin-3-ol (290 mg) as a brown solid. [M+H] + ＝848.4
第六步：在25℃下，向1-(8-氟-7-(7-氟-3-(甲氧基甲氧基)-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)-6-硝基喹唑啉-4-基)-3-甲基哌啶-3-醇(430mg，0.51mmol)的二甲基甲酰胺(4300uL)溶液中加入氟化铯(771mg，5.07mmol)。将溶液在25℃搅拌2小时。反应液加水(8mL)稀释，用乙酸乙酯(4mL*3)萃取。合并的有机层用盐水(8mL)洗涤并用无水硫酸钠干燥，过滤，滤液减压浓缩，残余物通过快速柱色谱(硅胶，0-10％梯度的甲醇/二氯甲烷)纯化，得到棕色固体化合物1-(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-吡咯嗪-7a(5H)-基)甲氧基)-6-硝基喹唑啉-4-基)-3-甲基哌啶-3-醇(300mg，0.36mmol，收率72％)。[M+H]+＝692.3The sixth step: at 25°C, 1-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalene-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-6-nitroquinazolin-4-yl)-3-methylpiperidin-3-ol (430 mg, 0.51 mmol) in dimethylformamide (4300 uL) was added cesium fluoride (771 mg, 5.07 mmol). The solution was stirred at 25°C for 2 hours. The reaction solution was diluted with water (8 mL), and extracted with ethyl acetate (4 mL*3). The combined organic layers were washed with brine (8 mL) and dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by flash column chromatography (silica gel, 0-10% gradient of methanol/dichloromethane) to give compound 1-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazine-7a(5H )-yl)methoxy)-6-nitroquinazolin-4-yl)-3-methylpiperidin-3-ol (300 mg, 0.36 mmol, 72% yield). [M+H] + ＝692.3
第七步：在25℃下，向1-(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-吡咯嗪-7a(5H)-基)甲氧基)-6-硝基喹唑啉-4-基)-3-甲基哌啶-3-醇(30mg，43.37umol)的乙腈(300uL)溶液中加入氯化氢(4M的二氧六环溶液，109uL，0.436mmol)并搅拌2小时。将溶液旋干并加入二氯甲烷(1mL)稀释，用三乙胺调节pH至8。粗品经制备型HPLC纯化得到黄色固体化合物1-(7-(8-乙炔基-7-氟-3-羟基萘-1-基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-6-硝基喹唑啉-4-基)-3-甲基哌啶-3-醇(甲酸盐，5.66mg，8.57umol，收率20％)。[M+H]+＝648.1。1H NMR(400MHz,CD3OD)δppm 8.89(s,1H),8.51(s,1H),7.87(dd,J＝6.2,9.0Hz,1H),7.38-7.29(m,2H),7.02(dd,J＝2.3,8.9Hz,1H),5.54-5.33(m,1H),4.84-4.75(m,1H),4.56-4.44(m,2H),4.29(br dd,J＝13.3,19.7Hz,1H),3.70-3.40(m,6H),3.23(br s,1H),2.57-1.74(m,10H),1.32(d,J＝7.0Hz,3H).Step 7: Add 1-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-6-nitroquinazolin-4-yl)-3-methylpiperidin-3-ol (30mg, 43.37umol) in ethyl alcohol at 25°C To the nitrile (300uL) solution was added hydrogen chloride (4M in dioxane, 109uL, 0.436mmol) and stirred for 2 hours. The solution was spin-dried and diluted with dichloromethane (1 mL), and the pH was adjusted to 8 with triethylamine. The crude product was purified by preparative HPLC to obtain a yellow solid compound 1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-6-nitroquinazolin-4-yl)-3-methylpiperidin-3-ol (formate salt, 5.66mg, 8.57umol, yield rate 20%). [M+H] + = 648.1. 1 H NMR(400MHz,CD 3 OD)δppm 8.89(s,1H),8.51(s,1H),7.87(dd,J＝6.2,9.0Hz,1H),7.38-7.29(m,2H),7.02(dd,J＝2.3,8.9Hz,1H),5.54-5.33(m,1H),4.84-4.75(m,1H),4.56-4.44(m,2H),4.29(br dd,J＝13.3,19.7Hz,1H),3.70-3.40(m,6H),3.23(br s,1H),2.57-1.74(m,10H),1.32(d,J＝7.0Hz,3H).
实施例137：1-(7-(8-乙炔基-7-氟-3-羟基萘-1-基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-6-硝基喹唑啉-4-基)-3-甲基哌啶-3-醇
Example 137: 1-(7-(8-Ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-6-nitroquinazolin-4-yl)-3-methylpiperidin-3-ol
第一步：在0℃下，向7-溴-8-氟-1,3-二氢喹唑啉-2,4-二酮(18.00g，69.49mmol)的硫酸(150mL)溶液中分批加入硝酸钾(14.05g，138.98mmol)，将混合物在0℃搅拌1小时，小心倒入冰水(400mL)中，过滤，滤饼用水(100mL*3)洗涤并真空干燥得到棕色固体化合物7-溴-8-氟-6-硝基-1,3-二氢喹唑啉-2,4-二酮(21.50g，63.64mmol，收率92％)。LCMS(ESI):[M+H]+＝303.8Step 1: At 0°C, potassium nitrate (14.05g, 138.98mmol) was added in batches to a solution of 7-bromo-8-fluoro-1,3-dihydroquinazoline-2,4-dione (18.00g, 69.49mmol) in sulfuric acid (150mL), the mixture was stirred at 0°C for 1 hour, carefully poured into ice water (400mL), filtered, and the filter cake was washed with water (100mL*3) and dried in vacuo to obtain Brown solid compound 7-bromo-8-fluoro-6-nitro-1,3-dihydroquinazoline-2,4-dione (21.50 g, 63.64 mmol, yield 92%). LCMS (ESI): [M+H] + = 303.8
第二步：在0℃下，向7-溴-8-氟-6-硝基-1,3-二氢喹唑啉-2,4-二酮(2.00g，6.58mmol)和三氯氧磷(4.89mL，52.63mmol)的甲苯(30mL)溶液中加入二异丙基乙胺(3.45mL，19.74mmol)。将该溶液在110℃搅拌0.33小时，点板显示反应结束。溶液用乙酸乙酯(15mL)稀释，然后加入冰(30g)。混合物用乙酸乙酯(30mL*2)萃取。将合并的有机层用无水硫酸钠干燥，过滤并真空浓缩，得到棕色固体化合物7-溴-2,4-二氯-8-氟-6-硝基喹唑啉(2.00g，5.28mmol，收率80％)。1H NMR(400MHz,DMSO-d6)δppm 8.56(d,J＝2.0Hz,1H)Second step: To a solution of 7-bromo-8-fluoro-6-nitro-1,3-dihydroquinazoline-2,4-dione (2.00 g, 6.58 mmol) and phosphorus oxychloride (4.89 mL, 52.63 mmol) in toluene (30 mL) was added diisopropylethylamine (3.45 mL, 19.74 mmol) at 0°C. The solution was stirred at 110° C. for 0.33 hours, and blotted to show the reaction was complete. The solution was diluted with ethyl acetate (15 mL), then ice (30 g) was added. The mixture was extracted with ethyl acetate (30 mL*2). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford brown solid compound 7-bromo-2,4-dichloro-8-fluoro-6-nitroquinazoline (2.00 g, 5.28 mmol, yield 80%). 1 H NMR (400MHz, DMSO-d 6 ) δppm 8.56 (d, J=2.0Hz, 1H)
第三步：在-40℃下，向7-溴-2,4-二氯-8-氟-6-硝基喹唑啉(2.00g，5.87mmol)和3-甲基哌啶-3-醇(0.89g，5.87mmol)的二氯甲烷(20mL)溶液中加入二异丙基乙胺(2.30mL，12.91mmol)。将混合物在-40℃搅拌1小时。向混合物中加入水(20ml)，用二氯甲烷(20mL*3)萃取。合并的有机层用无水硫酸钠干燥，过滤并减压浓缩，得到棕色固体化合物1-(7-溴-2-氯-8-氟-6-硝基喹唑啉-4-基)-3-甲基哌啶-3-醇(2.28g，4.52mmol，收率77％)。LCMS(ESI):[M+H]+＝420.9Step 3: To a solution of 7-bromo-2,4-dichloro-8-fluoro-6-nitroquinazoline (2.00 g, 5.87 mmol) and 3-methylpiperidin-3-ol (0.89 g, 5.87 mmol) in dichloromethane (20 mL) was added diisopropylethylamine (2.30 mL, 12.91 mmol) at -40°C. The mixture was stirred at -40°C for 1 hour. Water (20ml) was added to the mixture, extracted with dichloromethane (20mL*3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give brown solid compound 1-(7-bromo-2-chloro-8-fluoro-6-nitroquinazolin-4-yl)-3-methylpiperidin-3-ol (2.28 g, 4.52 mmol, yield 77%). LCMS (ESI): [M+H] + = 420.9
第四步：在25℃下，向1-(7-溴-2-氯-8-氟-6-硝基喹唑啉-4-基)-3-甲基哌啶-3-醇(750mg，1.49mmol)和碳酸铯(971mg，2.98mmol)的二氧六环(8mL)悬浊液中，加入((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲醇(237mg，1.49mmol)。将溶液在100℃氮气氛围下在搅拌16小时，减压浓缩，残余物通过快速柱色谱(硅胶，0-10％梯度的甲醇/二氯甲烷)纯化，得到黄色固体化合物1-(7-溴-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-6-硝基喹唑啉-4-基)-3-甲基哌啶-3-醇(490mg，0.90mmol，收率61％)。LCMS(ESI):[M+H]+＝544.1 Step 4: To a suspension of 1-(7-bromo-2-chloro-8-fluoro-6-nitroquinazolin-4-yl)-3-methylpiperidin-3-ol (750mg, 1.49mmol) and cesium carbonate (971mg, 2.98mmol) in dioxane (8mL) at 25°C, add ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazine-7a(5H)- base) Methanol (237mg, 1.49mmol). The solution was stirred under a nitrogen atmosphere at 100°C for 16 hours, concentrated under reduced pressure, and the residue was purified by flash column chromatography (silica gel, 0-10% gradient of methanol/dichloromethane) to obtain a yellow solid compound 1-(7-bromo-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-6-nitroquinazolin-4-yl)-3-methylpiperidin-3-ol (490mg, 0.90mmol, yield 61%). LCMS (ESI): [M+H] + = 544.1
第五步：在25℃氮气氛围下，向1-(7-溴-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-6-硝基喹唑啉-4-基)-3-甲基哌啶-3-醇(300mg，0.55mmol)和(((2-氟-6-(甲氧基甲氧基)-8-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)萘-1-基)The fifth step: 1-(7-bromo-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-6-nitroquinazolin-4-yl)-3-methylpiperidin-3-ol (300mg, 0.55mmol) and (((2-fluoro-6-(methoxymethoxy)-8-(4,4 ,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalene-1-yl)
实施例138：1-(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)-6-硝基喹唑啉-4-基)-3-甲基哌啶-3-醇
Example 138: 1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-6-nitroquinazolin-4-yl)-3-methylpiperidin-3-ol
第一步：在-40℃下向7-溴-2,4-二氯-8-氟-6-硝基喹唑啉(2.00g，5.87mmol)和3-甲基哌啶-3-醇(0.89g，5.87mmol)的二氯甲烷(20mL)溶液中加入二异丙基乙胺(2.30mL，12.91mmol)。将混合物在-40℃搅拌1小时。向混合物中加入水(20ml)，用二氯甲烷(20mL*3)萃取。合并的有机层用无水硫酸钠干燥，过滤并减压浓缩，得到粗品化合物1-(7-溴-2-氯-8-氟-6-硝基喹唑啉-4-基)-3-甲基哌啶-3-醇(2.28g)，其为棕色固体。LCMS(ESI):[M+H]+＝420.9Step 1: To a solution of 7-bromo-2,4-dichloro-8-fluoro-6-nitroquinazoline (2.00 g, 5.87 mmol) and 3-methylpiperidin-3-ol (0.89 g, 5.87 mmol) in dichloromethane (20 mL) was added diisopropylethylamine (2.30 mL, 12.91 mmol) at -40°C. The mixture was stirred at -40°C for 1 hour. Water (20ml) was added to the mixture, extracted with dichloromethane (20mL*3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give crude compound 1-(7-bromo-2-chloro-8-fluoro-6-nitroquinazolin-4-yl)-3-methylpiperidin-3-ol (2.28 g) as a brown solid. LCMS (ESI): [M+H] + = 420.9
第二步：在25℃下向1-(7-溴-2-氯-8-氟-6-硝基喹唑啉-4-基)-3-甲基哌啶-3-醇(2.00g，4.77mmol)的三氟乙醇(20mL)溶液中加入二异丙基乙胺(3.33mL，19.06mmol)。将溶液在70℃搅拌3小时。将溶液旋干并通过快速柱色谱(硅胶，石油醚/乙酸乙酯＝0-40％)纯化得到黄色固体化合物1-(7-溴-8-氟-6-硝基-2-(2,2,2-三氟乙氧基)喹唑啉-4-基)-3-甲基哌啶-3-醇(1.82g，3.77mmol，收率79％)。LCMS(ESI):[M+H]+＝483.1Second step: To a solution of 1-(7-bromo-2-chloro-8-fluoro-6-nitroquinazolin-4-yl)-3-methylpiperidin-3-ol (2.00 g, 4.77 mmol) in trifluoroethanol (20 mL) was added diisopropylethylamine (3.33 mL, 19.06 mmol) at 25°C. The solution was stirred at 70°C for 3 hours. The solution was spin-dried and purified by flash column chromatography (silica gel, petroleum ether/ethyl acetate=0-40%) to obtain yellow solid compound 1-(7-bromo-8-fluoro-6-nitro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol (1.82g, 3.77mmol, yield 79%). LCMS (ESI): [M+H] + = 483.1
第三步：在25℃氮气氛围下向1-(7-溴-8-氟-6-硝基-2-(2,2,2-三氟乙氧基)喹唑啉-4-基)-3-甲基哌啶-3-醇(1.80g，3.32mmol)和1-乙基-2-氟-6-(甲氧基甲氧基)-8-(4,4,5,5-四甲基(1,3,2-二氧硼杂环戊烷-2-基))的甲苯(400uL)和水(100uL)溶液中加入甲磺酸(二金刚烷基-正丁基膦基)-2'-氨基-1,1'-联苯-2-基)钯(II)二氯甲烷(0.48g，0.66mmol)和碳酸铯(3.24g，9.96mmol)。将该溶液在100℃搅拌16小时。将反应液旋干并通过快速柱色谱(硅胶，石油醚/四氢呋喃＝0-30％)纯化得到棕色固体化合物1-(7-(8-乙基-7-氟-3-(甲氧基甲氧基)萘-1-基)-8-氟-6-硝基-2-(2,2,2-三氟乙氧基)喹唑啉-4-基)-3-甲基哌啶-3-醇(1.10g，1.58mmol，收率48％)。LCMS(ESI):[M+H]+＝637.3The third step: 1-(7-bromo-8-fluoro-6-nitro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol (1.80g, 3.32mmol) and 1-ethyl-2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl(1,3,2-dioxaborolane-2 - base)) in toluene (400uL) and water (100uL) solution was added methanesulfonic acid (diadamantyl-n-butylphosphino)-2'-amino-1,1'-biphenyl-2-yl) palladium (II) dichloromethane (0.48g, 0.66mmol) and cesium carbonate (3.24g, 9.96mmol). The solution was stirred at 100°C for 16 hours. The reaction solution was spin-dried and purified by flash column chromatography (silica gel, petroleum ether/THF=0-30%) to obtain brown solid compound 1-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yl)-8-fluoro-6-nitro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol (1.10g, 1.58mmol, yield 48 %). LCMS (ESI): [M+H] + = 637.3
第四步：在25℃下向1-(7-(8-乙基-7-氟-3-(甲氧基甲氧基)萘-1-基)-8-氟-6-硝基-2-(2,2,2-三氟乙氧基)喹唑啉-4-基)-3-甲基哌啶-3-醇(500mg，0.79mmol)和((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲醇(125mg，0.79mmol)的四氢呋喃(5mL)溶液中加入叔丁醇钠。将混合物在25℃下搅拌16小时。将混合物旋干并通过快速柱色谱纯化得到棕黄色固体化合物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-吡咯嗪-7a(5H)-基)甲氧基)-6-硝基喹唑啉-4-基)-3-甲基哌啶-3-醇(350mg，0.50mmol，收率64％)。LCMS(ESI):[M+H]+＝696.3 The fourth step: 1-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-6-nitro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol (500mg, 0.79mmol) and ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazine-7a (5 To a solution of H)-yl)methanol (125mg, 0.79mmol) in THF (5mL) was added sodium tert-butoxide. The mixture was stirred at 25°C for 16 hours. The mixture was spin-dried and purified by flash column chromatography to obtain tan solid compound 1-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-6-nitroquinazolin-4-yl)-3-methylpiperidin-3-ol (350mg, 0.50mm ol, yield 64%). LCMS (ESI): [M+H] + = 696.3
第五步：在25℃下，向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-吡咯嗪-7a(5H)-基)甲氧基)-6-硝基喹唑啉-4-基)-3-甲基哌啶-3-醇(350mg，0.50mmol)的乙腈(4mL)溶液中加入氯化氢(4M的二氧六环溶液，1.26mL,5.03mmol)并搅拌4小时。将溶液旋干并加入二氯甲烷(4mL)稀释，用三乙胺调节pH值至8。粗品经制备型HPLC纯化得到白色固体化合物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)-6-硝基喹唑啉-4-基)-3-甲基哌啶-3-醇(150mg，0.23mmol，收率46％)。LCMS(ESI):[M+H]+＝652.3。1H NMR(400MHz,CD3OD)δppm 9.00-8.91(m,1H),8.52(s,1H),7.68(dd,J＝5.8,9.1Hz,1H),7.31-7.22(m,2H),6.81(dd,J＝2.6,5.0Hz,1H),5.44(br s,1H),4.53-4.21(m,4H),3.67-3.48(m,2H),3.42(br s,3H),3.14(br s,1H),2.71-1.83(m,12H),1.30(s,3H),0.87-0.80(m,3H).Step 5: Add 1-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-6-nitroquinazolin-4-yl)-3-methylpiperidin-3-ol (350mg, 0.50mmol) in acetonitrile at 25°C (4 mL) was added hydrogen chloride (4M in dioxane, 1.26 mL, 5.03 mmol) and stirred for 4 hours. The solution was spin-dried and diluted with dichloromethane (4 mL), and the pH was adjusted to 8 with triethylamine. The crude product was purified by preparative HPLC to obtain the white solid compound 1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-6-nitroquinazolin-4-yl)-3-methylpiperidin-3-ol (150mg, 0.23mmol, yield 46%) . LCMS (ESI): [M+H] + = 652.3. 1 H NMR(400MHz,CD 3 OD)δppm 9.00-8.91(m,1H),8.52(s,1H),7.68(dd,J＝5.8,9.1Hz,1H),7.31-7.22(m,2H),6.81(dd,J＝2.6,5.0Hz,1H),5.44(br s,1H),4.53-4.21(m,4H),3.67-3.48(m,2H),3.42(br s,3H),3.14(br s,1H),2.71-1.83(m,12H),1.30(s,3H),0.87-0.80(m,3H).
实施例139：1-(7-(8-乙炔基-7-氟-3-羟基萘基)-8-氟-6-硝基-2-(2,2,2-三氟乙氧基)喹唑啉-4-基)-3-甲基哌啶-3-醇
Example 139: 1-(7-(8-Ethynyl-7-fluoro-3-hydroxynaphthyl)-8-fluoro-6-nitro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol
LCMS(ESI):[M+H]+＝589.5。1H NMR(400MHz,CD3OD)δppm 8.90(dd,J＝1.4,14.1Hz,1H),7.87(dd,J＝5.8,9.1Hz,1H),7.36-7.29(m,2H),7.03(dd,J＝2.4,9.9Hz,1H),5.06-4.97(m,2H),4.63-4.51(m,1H),4.30(br dd,J＝13.4,18.9Hz,1H),3.68-3.58(m,1H),3.51-3.36(m,2H),2.24(br d,J＝14.0Hz,1H),1.93-1.74(m,3H),1.32(d,J＝8.6Hz,3H).LCMS (ESI): [M+H] + = 589.5. 1 H NMR(400MHz,CD 3 OD)δppm 8.90(dd,J＝1.4,14.1Hz,1H),7.87(dd,J＝5.8,9.1Hz,1H),7.36-7.29(m,2H),7.03(dd,J＝2.4,9.9Hz,1H),5.06-4.97(m,2H),4.63-4.51(m,1H),4.30(br dd,J＝13.4,18.9Hz,1H),3.68-3.58(m,1H),3.51-3.36(m,2H),2.24(br d,J＝14.0Hz,1H),1.93-1.74(m,3H),1.32(d,J＝8.6Hz,3H).
实施例140A：(R)-1-(7-(S)-8-乙炔基-7-氟萘-1-基)-8-氟-2-(4-甲基四氢-2H-吡喃-4-基)甲氧基)-6-硝基喹唑啉-4-基)-3-甲基哌啶-3-醇Example 140A: (R)-1-(7-(S)-8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(4-methyltetrahydro-2H-pyran-4-yl)methoxy)-6-nitroquinazolin-4-yl)-3-methylpiperidin-3-ol
实施例140B：(R)-1-(7-(R)-8-乙炔基-7-氟萘-1-基)-8-氟-2-(4-甲基四氢-2H-吡喃-4-基)甲氧基)-6-硝基喹唑啉-4-基)-3-甲基哌啶-3-醇
Example 140B: (R)-1-(7-(R)-8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(4-methyltetrahydro-2H-pyran-4-yl)methoxy)-6-nitroquinazolin-4-yl)-3-methylpiperidin-3-ol
实施例140A：LCMS(ESI):[M+H]+＝603.1。1H NMR(400MHz,CD3OD)δppm 8.89(s,1H),8.23-8.02(m,2H),7.60(t,J＝7.7Hz,1H),7.54-7.30(m,2H),4.47(br d,J＝13.2Hz,1H),4.40-4.15(m,3H),3.85-3.58(m,5H),3.54-3.41(m,2H),2.31-2.16(m,1H),1.94-1.68(m,5H),1.48(br d,J＝13.9Hz,2H),1.32 (s,3H),1.21(s,3H).Example 140A: LCMS (ESI): [M+H] + = 603.1. 1 H NMR(400MHz,CD 3 OD)δppm 8.89(s,1H),8.23-8.02(m,2H),7.60(t,J＝7.7Hz,1H),7.54-7.30(m,2H),4.47(br d,J＝13.2Hz,1H),4.40-4.15(m,3H),3.85-3.58(m,5H),3.54-3.41(m,2H),2.31-2.16(m,1H),1.94-1.68(m,5H),1.48(br d,J＝13.9Hz,2H),1.32 (s,3H),1.21(s,3H).
实施例140B：LCMS(ESI):[M+H]+＝603.0。1H NMR(400MHz,CD3OD)δppm 8.86(s,1H),8.20-7.96(m,2H),7.59(t,J＝7.6Hz,1H),7.48-7.37(m,2H),4.51(br d,J＝13.6Hz,1H),4.34-4.21(m,3H),3.83-3.65(m,4H),3.63-3.53(m,2H),3.45-3.35(m,1H),2.30-2.16(m,1H),1.91-1.71(m,5H),1.47(br d,J＝13.9Hz,2H),1.30(s,3H),1.21(s,3H).Example 140B: LCMS (ESI): [M+H] + = 603.0. 1 H NMR(400MHz,CD 3 OD)δppm 8.86(s,1H),8.20-7.96(m,2H),7.59(t,J＝7.6Hz,1H),7.48-7.37(m,2H),4.51(br d,J＝13.6Hz,1H),4.34-4.21(m,3H),3.83-3.65(m,4H),3.63-3.53(m,2H),3.45-3.35(m,1H),2.30-2.16(m,1H),1.91-1.71(m,5H),1.47(br d,J＝13.9Hz,2H),1.30(s,3H),1.21(s,3H).
实施例141A：(R)-1-(7-(S)-8-乙炔基-7-氟萘-1-基)-8-氟-2-(4-羟甲基)双环[2.2.2]辛烷-1-基)氧基)-6-硝基喹唑啉-4-基)-3-甲基哌啶-3-醇Example 141A: (R)-1-(7-(S)-8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(4-hydroxymethyl)bicyclo[2.2.2]octan-1-yl)oxy)-6-nitroquinazolin-4-yl)-3-methylpiperidin-3-ol
实施例142B：(R)-1-(7-(R)-8-乙基-7-氟萘-1-基)-8-氟-2-(4-(羟甲基)双环[2.2.2]辛烷-1-基)氧基-6-硝基喹唑啉-4-基)-3-甲基哌啶-3-醇
Example 142B: (R)-1-(7-(R)-8-ethyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(4-(hydroxymethyl)bicyclo[2.2.2]octan-1-yl)oxy-6-nitroquinazolin-4-yl)-3-methylpiperidin-3-ol
实施例141A：LCMS(ESI):[M+H]+＝629.1。1H NMR(400MHz,CD3OD)δppm 8.88(s,1H),8.22-8.00(m,2H),7.60(t,J＝7.6Hz,1H),7.49-7.31(m,2H),4.45(br d,J＝13.0Hz,1H),4.24-4.05(m,3H),3.63(d,J＝13.2Hz,1H),3.52-3.39(m,2H),2.29-2.14(m,1H),1.92-1.63(m,15H),1.39-1.23(m,3H).Example 141A: LCMS (ESI): [M+H] + = 629.1. 1 H NMR (400MHz, CD 3 OD) δppm 8.88(s, 1H), 8.22-8.00(m, 2H), 7.60(t, J=7.6Hz, 1H), 7.49-7.31(m, 2H), 4.45(br d, J=13.0Hz, 1H), 4.24-4.05(m, 3H), 3.63 (d,J=13.2Hz,1H),3.52-3.39(m,2H),2.29-2.14(m,1H),1.92-1.63(m,15H),1.39-1.23(m,3H).
实施例142B：LCMS(ESI):[M+H]+＝629.1。1H NMR(400MHz,CD3OD)δppm 8.84(d,J＝0.9Hz,1H),8.16-7.99(m,2H),7.59(t,J＝7.7Hz,1H),7.52-7.33(m,2H),4.48(br d,J＝13.2Hz,1H),4.23(br d,J＝13.4Hz,1H),4.18-4.05(m,2H),3.64-3.50(m,2H),3.43-3.34(m,1H),2.30-2.15(m,1H),1.91-1.63(m,15H),1.36-1.24(m,3H).Example 142B: LCMS (ESI): [M+H] + = 629.1. 1 H NMR(400MHz,CD 3 OD)δppm 8.84(d,J＝0.9Hz,1H),8.16-7.99(m,2H),7.59(t,J＝7.7Hz,1H),7.52-7.33(m,2H),4.48(br d,J＝13.2Hz,1H),4.23(br d,J＝13.4Hz,1H),4.18-4.05(m,2H),3.64-3.50(m,2H),3.43-3.34(m,1H),2.30-2.15(m,1H),1.91-1.63(m,15H),1.36-1.24(m,3H).
实施例143A：(R)-1-(2-(双环[1.1.1]戊烷-1-基甲氧基)-7-((S)-8-乙炔基-7-氟萘-1-基)-8-氟-6-硝基喹唑啉-4-基)-3-甲基哌啶-3-醇Example 143A: (R)-1-(2-(bicyclo[1.1.1]pentan-1-ylmethoxy)-7-((S)-8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-6-nitroquinazolin-4-yl)-3-methylpiperidin-3-ol
实施例143B：(R)-1-(2-(双环[1.1.1]戊烷-1-基甲氧基)-7-((R)-8-乙炔基-7-氟萘-1-基)-8-氟-6-硝基喹唑啉-4-基)-3-甲基哌啶-3-醇
Example 143B: (R)-1-(2-(bicyclo[1.1.1]pentan-1-ylmethoxy)-7-((R)-8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-6-nitroquinazolin-4-yl)-3-methylpiperidin-3-ol
实施例143A:LCMS(ESI):[M+H]+＝571.1。1H NMR(400MHz,CD3OD)δppm 9.02-8.83(m,1H),8.18-8.02(m,2H),7.67-7.53(m,1H),7.52-7.29(m,2H),4.56-4.14(m,4H),3.75-3.38(m,3H),2.58-2.48(m,1H),2.30-2.16(m,1H),1.88(s,7H),1.85-1.76(m,2H),1.36-1.25(m,3H). Example 143A: LCMS (ESI): [M+H] + = 571.1. 1 H NMR (400MHz, CD 3 OD) δppm 9.02-8.83(m,1H),8.18-8.02(m,2H),7.67-7.53(m,1H),7.52-7.29(m,2H),4.56-4.14(m,4H),3.75-3.38(m,3H),2.58- 2.48(m,1H),2.30-2.16(m,1H),1.88(s,7H),1.85-1.76(m,2H),1.36-1.25(m,3H).
实施例143B:LCMS(ESI):[M+H]+＝571.1。1H NMR(400MHz,CD3OD)δppm 9.02-8.81(m,1H),8.24-7.99(m,2H),7.66-7.52(m,1H),7.48-7.30(m,2H),4.58-4.14(m,4H),3.66-3.36(m,3H),2.57-2.50(m,1H),2.27-2.13(m,1H),1.87(s,7H),1.83-1.73(m,2H),1.28(s,3H).Example 143B: LCMS (ESI): [M+H] + = 571.1. 1 H NMR (400MHz, CD 3 OD) δppm 9.02-8.81(m,1H),8.24-7.99(m,2H),7.66-7.52(m,1H),7.48-7.30(m,2H),4.58-4.14(m,4H),3.66-3.36(m,3H),2.57- 2.50(m,1H),2.27-2.13(m,1H),1.87(s,7H),1.83-1.73(m,2H),1.28(s,3H).
实施例144A：4-(((7-((S)-8-乙炔基-7-氟萘-1-基)-8-氟-4-((R)-3-羟基-3-甲基哌啶-1-基)-6-硝基喹唑啉-2-基)氧基)甲基)四氢-2H-吡喃-4-氰Example 144A: 4-(((7-((S)-8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-4-((R)-3-hydroxy-3-methylpiperidin-1-yl)-6-nitroquinazolin-2-yl)oxy)methyl)tetrahydro-2H-pyran-4-cyano
实施例144B：4-(((7-((R)-8-乙炔基-7-氟萘-1-基)-8-氟-4-((R)-3-羟基-3-甲基哌啶-1-基)-6-硝基喹唑啉-2-基)氧基)甲基)四氢-2H-吡喃-4-氰
Example 144B: 4-(((7-((R)-8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-4-((R)-3-hydroxy-3-methylpiperidin-1-yl)-6-nitroquinazolin-2-yl)oxy)methyl)tetrahydro-2H-pyran-4-cyano
实施例144A：LCMS(ESI):[M+H]+＝614.1。1H NMR(400MHz,CD3OD)δppm 9.06-8.75(m,1H),8.22-7.98(m,2H),7.60(t,J＝7.7Hz,1H),7.51-7.25(m,2H),4.68-4.50(m,3H),4.25(br d,J＝13.2Hz,1H),4.09-3.96(m,2H),3.81-3.58(m,3H),3.54-3.39(m,2H),2.31-1.75(m,8H),1.32(s,3H).Example 144A: LCMS (ESI): [M+H] + = 614.1. 1 H NMR (400MHz, CD 3 OD) δppm 9.06-8.75 (m, 1H), 8.22-7.98 (m, 2H), 7.60 (t, J = 7.7Hz, 1H), 7.51-7.25 (m, 2H), 4.68-4.50 (m, 3H), 4.25 (br d, J = 13.2Hz, 1H) ,4.09-3.96(m,2H),3.81-3.58(m,3H),3.54-3.39(m,2H),2.31-1.75(m,8H),1.32(s,3H).
实施例144B：LCMS(ESI):[M+H]+＝614.1。1H NMR(400MHz,CD3OD)δppm 8.88(d,J＝1.1Hz,1H),8.17-7.99(m,2H),7.64-7.55(m,1H),7.48-7.32(m,2H),4.64-4.49(m,3H),4.34-4.20(m,1H),4.08-3.95(m,2H),3.79-3.66(m,2H),3.63-3.51(m,2H),3.46-3.37(m,1H),2.33-1.71(m,8H),1.36-1.23(m,3H).Example 144B: LCMS (ESI): [M+H] + = 614.1. 1 H NMR(400MHz,CD 3 OD)δppm 8.88(d,J＝1.1Hz,1H),8.17-7.99(m,2H),7.64-7.55(m,1H),7.48-7.32(m,2H),4.64-4.49(m,3H),4.34-4.20(m,1H),4.08-3.95(m,2H),3.79-3.66(m,2H),3.63-3.51(m,2H),3.46-3.37(m,1H),2.33-1.71(m,8H),1.36-1.23(m,3H).
实施例145A：(R)-1-(7-(S)-8-乙炔基-7-氟萘-1-基)-8-氟-2-(3-甲基氧杂环丁烷-3-基)甲氧基)-6-硝基喹唑啉-4-基)-3-甲基哌啶-3-醇Example 145A: (R)-1-(7-(S)-8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(3-methyloxetan-3-yl)methoxy)-6-nitroquinazolin-4-yl)-3-methylpiperidin-3-ol
实施例145B：(R)-1-(7-(R)-8-乙炔基-7-氟萘-1-基)-8-氟-2-(3-甲基氧杂环丁烷-3-基)甲氧基)-6-硝基喹唑啉-4-基)-3-甲基哌啶-3-醇
Example 145B: (R)-1-(7-(R)-8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(3-methyloxetan-3-yl)methoxy)-6-nitroquinazolin-4-yl)-3-methylpiperidin-3-ol
实施例145A：LCMS(ESI):[M+H]+＝575.1。1H NMR(400MHz,CD3OD)δppm 8.90(d,J＝1.1Hz,1H),8.14-8.06(m,2H),7.60(t,J＝7.7Hz,1H),7.48-7.40(m,2H),4.70(dd,J＝3.1,5.9Hz,2H),4.65-4.50(m,3H),4.47(d,J＝5.9Hz,2H),4.24(br d,J＝13.2Hz,1H),3.64(d,J＝13.2Hz,1H),3.51-3.41(m,2H),2.29-2.16(m,1H),1.94-1.77(m,3H),1.47(s,3H),1.32(s,3H). Example 145A: LCMS (ESI): [M+H] + = 575.1. 1 H NMR(400MHz,CD 3 OD)δppm 8.90(d,J＝1.1Hz,1H),8.14-8.06(m,2H),7.60(t,J＝7.7Hz,1H),7.48-7.40(m,2H),4.70(dd,J＝3.1,5.9Hz,2H),4.65-4.50(m,3H),4.47(d,J＝5.9Hz,2H),4.24(br d,J＝13.2Hz,1H),3.64(d,J＝13.2Hz,1H),3.51-3.41(m,2H),2.29-2.16(m,1H),1.94-1.77(m,3H),1.47(s,3H),1.32(s,3H).
实施例145B：LCMS(ESI):[M+H]+＝575.1。1H NMR(400MHz,CD3OD)δppm 8.87(s,1H),8.25-7.98(m,2H),7.60(t,J＝7.7Hz,1H),7.50-7.39(m,2H),4.69(d,J＝5.9Hz,2H),4.59(s,2H),4.53(br d,J＝13.0Hz,1H),4.46(d,J＝5.9Hz,2H),4.27(br d,J＝13.4Hz,1H),3.65-3.52(m,2H),3.44-3.36(m,1H),2.30-2.16(m,1H),1.93-1.74(m,3H),1.47(s,3H),1.30(s,3H).Example 145B: LCMS (ESI): [M+H] + = 575.1. 1 H NMR(400MHz,CD 3 OD)δppm 8.87(s,1H),8.25-7.98(m,2H),7.60(t,J＝7.7Hz,1H),7.50-7.39(m,2H),4.69(d,J＝5.9Hz,2H),4.59(s,2H),4.53(br d,J＝13.0Hz,1H),4.46(d,J＝5.9Hz,2H),4.27(br d,J＝13.4Hz,1H),3.65-3.52(m,2H),3.44-3.36(m,1H),2.30-2.16(m,1H),1.93-1.74(m,3H),1.47(s,3H),1.30(s,3H).
实施例146A：(R)-1-(2-(4,4-二氟环己基)氧基)-7-((S)-8-乙炔基-7-氟萘基-1-基)-8-氟-6-硝基喹唑啉-4-基)-3-甲基哌啶-3-醇Example 146A: (R)-1-(2-(4,4-difluorocyclohexyl)oxy)-7-((S)-8-ethynyl-7-fluoronaphthyl-1-yl)-8-fluoro-6-nitroquinazolin-4-yl)-3-methylpiperidin-3-ol
实施例146B：(R)-1-(2-(4,4-二氟环己基)氧基)-7-((R)-8-乙炔基-7-氟萘基-1-基)-8-氟-6-硝基喹唑啉-4-基)-3-甲基哌啶-3-醇
Example 146B: (R)-1-(2-(4,4-difluorocyclohexyl)oxy)-7-((R)-8-ethynyl-7-fluoronaphthyl-1-yl)-8-fluoro-6-nitroquinazolin-4-yl)-3-methylpiperidin-3-ol
实施例146A：LCMS(ESI):[M+H]+＝609.1。1H NMR(400MHz,CD3OD)δppm 9.05-8.76(m,1H),8.21-7.98(m,2H),7.68-7.53(m,1H),7.49-7.35(m,2H),5.47-5.29(m,1H),4.56-4.43(m,1H),4.31-4.15(m,1H),3.69-3.59(m,1H),3.52-3.39(m,2H),2.32-1.75(m,12H),1.31(s,3H).Example 146A: LCMS (ESI): [M+H] + = 609.1. 1 H NMR (400MHz, CD 3 OD) δppm 9.05-8.76(m,1H),8.21-7.98(m,2H),7.68-7.53(m,1H),7.49-7.35(m,2H),5.47-5.29(m,1H),4.56-4.43(m,1H),4.31- 4.15(m,1H),3.69-3.59(m,1H),3.52-3.39(m,2H),2.32-1.75(m,12H),1.31(s,3H).
实施例146B：LCMS(ESI):[M+H]+＝609.1。1H NMR(400MHz,CD3OD)δppm 8.92-8.79(m,1H),8.17-8.04(m,2H),7.65-7.53(m,1H),7.49-7.39(m,2H),5.42-5.31(m,1H),4.58-4.44(m,1H),4.26(br d,J＝13.2Hz,1H),3.64-3.56(m,2H),3.44-3.35(m,1H),2.30-1.93(m,9H),1.91-1.72(m,3H),1.29(s,3H).Example 146B: LCMS (ESI): [M+H] + = 609.1. 1 H NMR(400MHz,CD 3 OD)δppm 8.92-8.79(m,1H),8.17-8.04(m,2H),7.65-7.53(m,1H),7.49-7.39(m,2H),5.42-5.31(m,1H),4.58-4.44(m,1H),4.26(br d,J＝13.2Hz,1H),3.64-3.56(m,2H),3.44-3.35(m,1H),2.30-1.93(m,9H),1.91-1.72(m,3H),1.29(s,3H).
实施例147A：(R)-1-(7-(S)-8-乙炔基-7-氟萘-1-基)-8-氟-2-(3-氟氧杂环丁烷-3-基)甲氧基)-6-硝基喹唑啉-4-基)-3-甲基哌啶-3-醇Example 147A: (R)-1-(7-(S)-8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(3-fluorooxetan-3-yl)methoxy)-6-nitroquinazolin-4-yl)-3-methylpiperidin-3-ol
实施例147B：(R)-1-(7-(R)-8-乙炔基-7-氟萘-1-基)-8-氟-2-(3-氟氧杂环丁烷-3-基)甲氧基)-6-硝基喹唑啉-4-基)-3-甲基哌啶-3-醇
Example 147B: (R)-1-(7-(R)-8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(3-fluorooxetan-3-yl)methoxy)-6-nitroquinazolin-4-yl)-3-methylpiperidin-3-ol
实施例147A：LCMS(ESI):[M+H]+＝579.0。1H NMR(400MHz,CD3OD)δppm 8.98-8.75(m,1H),8.26-7.95(m,2H),7.67-7.54(m,1H),7.52-7.35(m,2H),4.89-4.76(m,6H),4.58-4.46(m,1H),4.31-4.22(m,1H),3.69-3.57(m,1H),3.51-3.39(m,2H),2.37-2.11(m,1H),2.00-1.69(m,3H),1.41-1.22(m,3H).Example 147A: LCMS (ESI): [M+H] + = 579.0. 1 H NMR(400MHz,CD 3 OD)δppm 8.98-8.75(m,1H),8.26-7.95(m,2H),7.67-7.54(m,1H),7.52-7.35(m,2H),4.89-4.76(m,6H),4.58-4.46(m,1H),4.31-4.22(m,1H),3.69-3.57(m,1H),3.51-3.39(m,2H),2.37-2.11(m,1H),2.00-1.69(m,3H),1.41-1.22(m,3H).
实施例147B：LCMS(ESI):[M+H]+＝579.0。1H NMR(400MHz,CD3OD)δppm 8.93-8.84(m,1H),8.18-8.01(m,2H),7.65-7.53(m,1H),7.50-7.36(m,2H),4.90-4.74(m,6H),4.61-4.51(m,1H),4.36-4.22(m, 1H),3.66-3.51(m,2H),3.44-3.35(m,1H),2.29-2.11(m,1H),1.93-1.70(m,3H),1.34-1.23(m,3H).Example 147B: LCMS (ESI): [M+H] + = 579.0. 1 H NMR (400MHz, CD 3 OD) δppm 8.93-8.84(m,1H),8.18-8.01(m,2H),7.65-7.53(m,1H),7.50-7.36(m,2H),4.90-4.74(m,6H),4.61-4.51(m,1H),4.36- 4.22 (m, 1H),3.66-3.51(m,2H),3.44-3.35(m,1H),2.29-2.11(m,1H),1.93-1.70(m,3H),1.34-1.23(m,3H).
实施例148A：(R)-1-(7-(S)-8-乙炔基-7-氟萘-1-基)-8-氟-2-(2-甲氧基-2-甲基丙氧基)-6-硝基喹唑啉-4-基)-3-甲基哌啶-3-醇Example 148A: (R)-1-(7-(S)-8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(2-methoxy-2-methylpropoxy)-6-nitroquinazolin-4-yl)-3-methylpiperidin-3-ol
实施例148B：(R)-1-(7-(R)-8-乙炔基-7-氟萘-1-基)-8-氟-2-(2-甲氧基-2-甲基丙氧基)-6-硝基喹唑啉-4-基)-3-甲基哌啶-3-醇
Example 148B: (R)-1-(7-(R)-8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(2-methoxy-2-methylpropoxy)-6-nitroquinazolin-4-yl)-3-methylpiperidin-3-ol
实施例148A：LCMS(ESI):[M+H]+＝577.0。1H NMR(400MHz,CD3OD)δppm 9.08-8.80(m,1H),8.33-7.95(m,2H),7.72-7.58(m,1H),7.53-7.36(m,2H),4.54-4.33(m,3H),4.22(br d,J＝13.4Hz,1H),3.64(d,J＝13.2Hz,1H),3.52-3.41(m,2H),3.34-3.32(m,3H),2.36-2.12(m,1H),1.99-1.69(m,3H),1.47-1.21(m,9H).Example 148A: LCMS (ESI): [M+H] + = 577.0. 1 H NMR(400MHz,CD 3 OD)δppm 9.08-8.80(m,1H),8.33-7.95(m,2H),7.72-7.58(m,1H),7.53-7.36(m,2H),4.54-4.33(m,3H),4.22(br d,J＝13.4Hz,1H),3.64(d,J＝13.2Hz,1H),3.52-3.41(m,2H),3.34-3.32(m,3H),2.36-2.12(m,1H),1.99-1.69(m,3H),1.47-1.21(m,9H).
实施例148B：LCMS(ESI):[M+H]+＝577.1。1H NMR(400MHz,CD3OD)δppm 8.86(d,J＝1.3Hz,1H),8.17-7.97(m,2H),7.63-7.36(m,3H),4.56-4.15(m,4H),3.65-3.50(m,2H),3.44-3.35(m,1H),3.31(s,3H),2.37-2.10(m,1H),1.91-1.69(m,3H),1.42-1.16(m,9H).Example 148B: LCMS (ESI): [M+H] + = 577.1. 1 H NMR (400MHz, CD 3 OD) δppm 8.86 (d, J = 1.3Hz, 1H), 8.17-7.97 (m, 2H), 7.63-7.36 (m, 3H), 4.56-4.15 (m, 4H), 3.65-3.50 (m, 2H), 3.44-3.35 (m, 1H), 3.3 1(s,3H),2.37-2.10(m,1H),1.91-1.69(m,3H),1.42-1.16(m,9H).
实施例149，实施例152和实施例153参照实施例137的合成路线制备得到的：Example 149, Example 152 and Example 153 were prepared with reference to the synthetic route of Example 137:
实施例149：4-(7-(8-乙炔基-7-氟-3-羟基萘-1-基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-6-硝基喹唑啉-4-基)-6-甲基-1,4-氧氮杂环庚烷-6-醇
Example 149: 4-(7-(8-Ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-6-nitroquinazolin-4-yl)-6-methyl-1,4-oxazepan-6-ol
LCMS(ESI):[M+H]+＝664.5；1H NMR(400MHz,CD3OD)δppm 9.27-9.17(m,1H),7.75(dd,J＝5.8,9.1Hz,1H),7.25-7.15(m,2H),6.90(d,J＝2.3Hz,1H),5.31-5.09(m,1H),4.46-4.35(m,2H),4.26-4.08(m,3H),3.99-3.72(m,3H),3.66-3.55(m,2H),3.35-3.23(m,1H),3.20-3.06(m,3H),2.92(dt,J＝5.7,9.4Hz,1H),2.30-1.99(m,3H),1.95-1.75(m,3H),1.22(s,3H).LCMS(ESI):[M+H]+=664.5; 1H NMR (400MHz, CD3OD)δppm 9.27-9.17(m,1H),7.75(dd,J=5.8,9.1Hz,1H),7.25-7.15(m,2H),6.90(d,J=2.3Hz,1H),5.31-5.09(m,1H),4.46-4.35(m,2H),4.26-4.08(m ,3H),3.99-3.72(m,3H),3.66-3.55(m,2H),3.35-3.23(m,1H),3.20-3.06(m,3H),2.92(dt,J＝5.7,9.4Hz,1H),2.30-1.99(m,3H),1.95-1.75(m,3H) ,1.22(s,3H).
实施例150：4-(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)-6-硝基喹唑啉-4-基)-6-甲基-1,4-氧氮杂环庚烷-6-醇Example 150: 4-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-6-nitroquinazolin-4-yl)-6-methyl-1,4-oxazepan-6-ol
实施例151：4-(8-氟-7-(7-氟-3-羟基-8-乙烯基萘-1-基)-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-6-硝基喹唑啉-4-基)-6-甲基-1,4-氧氮杂环庚烷-6-醇
Example 151: 4-(8-fluoro-7-(7-fluoro-3-hydroxy-8-vinylnaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-6-nitroquinazolin-4-yl)-6-methyl-1,4-oxazepan-6-ol
实施例150和实施例151参照实施例136的合成路线制备得到的：Example 150 and Example 151 were prepared with reference to the synthetic route of Example 136:
实施例150：4-(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)-6-硝基喹唑啉-4-基)-6-甲基-1,4-氧氮杂环庚烷-6-醇(5.43mg，7umol，收率5％)为黄色固体，LCMS(ESI):[M+H]+＝668.5；1H NMR(400MHz,CD3OD)δppm 9.54-9.36(m,1H),7.69(dd,J＝5.9,9.0Hz,1H),7.32-7.21(m,2H),6.87-6.79(m,1H),5.41-5.21(m,1H),4.58-4.47(m,2H),4.38-4.17(m,3H),4.09-3.82(m,3H),3.72(s,2H),3.28-3.16(m,2H),3.08-2.99(m,1H),2.72-2.57(m,1H),2.45-2.31(m,2H),2.31-2.08(m,3H),2.05-1.86(m,3H),1.37-1.30(m,3H),0.89-0.77(m,3H).Example 150: 4-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-6-nitroquinazolin-4-yl)-6-methyl-1,4-oxazepan-6-ol (5.43mg, 7umol, yield 5%) As a yellow solid, LCMS (ESI): [M+H]+= 668.5;1H NMR (400MHz, CD3OD)δppm 9.54-9.36(m,1H),7.69(dd,J＝5.9,9.0Hz,1H),7.32-7.21(m,2H),6.87-6.79(m,1H),5.41-5.21(m,1H),4.58-4.47(m,2H),4.38-4.17(m,3 H),4.09-3.82(m,3H),3.72(s,2H),3.28-3.16(m,2H),3.08-2.99(m,1H),2.72-2.57(m,1H),2.45-2.31(m,2H),2.31-2.08(m,3H),2.05-1.86(m,3 H),1.37-1.30(m,3H),0.89-0.77(m,3H).
实施例151：4-(8-氟-7-(7-氟-3-羟基-8-乙烯基萘-1-基)-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-6-硝基喹唑啉-4-基)-6-甲基-1,4-氧氮杂环庚烷-6-醇(2.29mg，3umol，收率2％)为黄色固体，LCMS(ESI):[M+H]+＝666.5；1H NMR(400MHz,CD3OD)δppm 9.43-9.11(m,1H),7.82-7.59(m,1H),7.25-7.10(m,2H),6.90-6.76(m,1H),6.10-5.89(m,1H),5.41-4.86(m,3H),4.41(br dd,J＝4.9,14.5Hz,2H),4.28-4.05(m,3H),3.97-3.69(m,3H),3.60(s,2H),3.19-3.02(m,3H),2.98-2.85(m,1H),2.29-1.99(m,3H),1.94-1.73(m,3H),1.25-1.17(m,3H).Example 151: 4-(8-fluoro-7-(7-fluoro-3-hydroxy-8-vinylnaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-6-nitroquinazolin-4-yl)-6-methyl-1,4-oxazepan-6-ol (2.29mg, 3umol, yield 2%) As a yellow solid, LCMS (ESI): [M+H]+= 666.5;1H NMR (400MHz, CD3OD)δppm 9.43-9.11(m,1H),7.82-7.59(m,1H),7.25-7.10(m,2H),6.90-6.76(m,1H),6.10-5.89(m,1H),5.41-4.86(m,3H),4.41(br dd,J＝4.9,14.5 Hz,2H),4.28-4.05(m,3H),3.97-3.69(m,3H),3.60(s,2H),3.19-3.02(m,3H),2.98-2.85(m,1H),2.29-1.99(m,3H),1.94-1.73(m,3H),1.25-1.17( m,3H).
实施例152 6-(7-(8-乙炔基-7-氟-3-羟基萘-1-基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H))-基)甲氧基)-6-硝基喹唑啉-4-基)-6-氮杂螺[3.5]壬-2-醇
Example 152 6-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H))-yl)methoxy)-6-nitroquinazolin-4-yl)-6-azaspiro[3.5]nonan-2-ol
LCMS(ESI):[M+H]+＝674.3；1H NMR(400MHz,CD3OD)δppm 8.67(s,1H),7.87(br dd,J＝5.8,8.9Hz,1H),7.37-7.18(m,2H),7.01(s,1H),5.42-5.22(m,1H),4.66-4.58(m,1H),4.41-4.25(m,3H),4.07-3.86(m,4H),3.37(br d,J＝3.9Hz,1H),3.26(br s,1H),3.24-3.18(m,1H),3.04(br s,1H),2.44-2.35(m,2H),2.31-2.11(m,3H),2.08-1.94(m,3H),1.92-1.72(m,6H).LCMS(ESI):[M+H]+= 674.3;1H NMR (400MHz, CD3OD)δppm 8.67(s,1H),7.87(br dd,J＝5.8,8.9Hz,1H),7.37-7.18(m,2H),7.01(s,1H),5.42-5.22(m,1H),4.66-4.58(m,1H),4.41-4.25(m,3H),4.07- 3.86(m,4H),3.37(br d,J＝3.9Hz,1H),3.26(br s,1H),3.24-3.18(m,1H),3.04(br s,1H),2.44-2.35(m,2H),2.31-2.11(m,3H),2.08-1.94(m,3H),1. 92-1.72(m,6H).
实施例153：3-氯-5-(7-(8-乙炔基-7-氟-3-羟基萘-1-基)-8-氟-6-硝基2-((四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-喹唑啉-4-基)-N,N-二甲基-5,6,7,8-四氢-4H-吡唑并[1,5-a][1,4]二氮杂环庚烷-2-甲酰胺
Example 153: 3-Chloro-5-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-6-nitro2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-quinazolin-4-yl)-N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepane Alkane-2-carboxamides
LCMS(ESI):[M+H]+＝757.3；1H NMR(400MHz,CD3OD)δppm 8.65(s,1H),7.87(dd,J＝5.8,9.1Hz,1H),7.36-7.26(m,2H),7.00(d,J＝2.4Hz,1H),5.19(s,2H),4.52-4.48(m,2H),4.44-4.32(m,4H),3.42(s,1H),3.30-3.22(m,2H),3.14(d,J＝14.0Hz,6H),2.91-2.82(m,2H),2.54(br d,J＝4.4Hz,2H),2.17-2.08(m,2H),1.98(qt,J＝6.6,13.6Hz,4H),1.89-1.79(m,2H).LCMS(ESI):[M+H]+=757.3;1H NMR (400MHz, CD3OD)δppm 8.65(s,1H),7.87(dd,J=5.8,9.1Hz,1H),7.36-7.26(m,2H),7.00(d,J=2.4Hz,1H),5.19(s,2H),4.52-4.48(m,2H),4.44-4.32(m,4H),3.42( s,1H),3.30-3.22(m,2H),3.14(d,J=14.0Hz,6H),2.91-2.82(m,2H),2.54(br d,J=4.4Hz,2H),2.17-2.08(m,2H),1.98(qt,J=6.6,13.6Hz,4H),1.89-1 .79(m,2H).
实施例154：4-(7-(8-乙炔基-7-氟萘-1-基)-8-氟-6-硝基-2-((四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)喹唑啉-4-基)-1,4-氧氮杂环庚烷
Example 154: 4-(7-(8-Ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-6-nitro-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinazolin-4-yl)-1,4-oxazepane
第一步：在-40℃下，向7-溴-2,4-二氯-8-氟-6-硝基喹唑啉(500mg，1.47mmol)和1,4-氧氮杂环庚烷盐酸盐(141.3mg，1.03mmol)的二氯甲烷(10mL)溶液中，加入二异丙基乙基胺(1.5mL，8.43mmol)。将混合物在-40℃和氮气保护下搅拌1小时。加入水(20mL)，使用二氯甲烷(20mL*3)萃取，合并的有机相用无水硫酸钠干燥，过滤，旋干。残留物用快速柱色谱纯化(硅胶，0-25％梯度的乙酸乙酯/石油醚)，得到黄色固体化合物4-(7-溴-2-氯-8-氟-6-硝基喹唑啉-4-基)-1,4-氧氮杂环庚烷(330mg，0.81mmol，收率55％)。LCMS(ESI):[M+H]+＝407.1.Step 1: To a solution of 7-bromo-2,4-dichloro-8-fluoro-6-nitroquinazoline (500 mg, 1.47 mmol) and 1,4-oxazepane hydrochloride (141.3 mg, 1.03 mmol) in dichloromethane (10 mL) at -40°C, diisopropylethylamine (1.5 mL, 8.43 mmol) was added. The mixture was stirred at -40°C under nitrogen protection for 1 hour. Water (20 mL) was added, extracted with dichloromethane (20 mL*3), the combined organic phases were dried over anhydrous sodium sulfate, filtered, and spin-dried. The residue was purified by flash column chromatography (silica gel, 0-25% gradient ethyl acetate/petroleum ether) to give yellow solid compound 4-(7-bromo-2-chloro-8-fluoro-6-nitroquinazolin-4-yl)-1,4-oxazepane (330 mg, 0.81 mmol, yield 55%). LCMS (ESI): [M+H] + = 407.1.
第二步：向4-(7-溴-2-氯-8-氟-6-硝基喹唑啉-4-基)-1,4-氧氮杂环庚烷(330mg，0.81mmol)的三氟乙醇(3.3mL)溶液中，加入二异丙基乙基胺(568uL，3.25mmol)。将混合物在70℃和氮气保护下搅拌3小时，旋干。残留物用快速柱色谱纯化(硅胶，0-30％梯度的乙酸乙酯/石油醚)，得到黄色固体化合物4-(7-溴-8-氟-6-硝基-2-(2,2,2-三氟乙氧基)喹唑啉-4-基)-1,4-氧氮杂环庚烷(340mg，0.73mmol，收率89％)。LCMS(ESI):[M+H]+＝468.9.Second step: To a solution of 4-(7-bromo-2-chloro-8-fluoro-6-nitroquinazolin-4-yl)-1,4-oxazepane (330 mg, 0.81 mmol) in trifluoroethanol (3.3 mL) was added diisopropylethylamine (568 uL, 3.25 mmol). The mixture was stirred at 70° C. for 3 hours under nitrogen protection, and spin-dried. The residue was purified by flash column chromatography (silica gel, 0-30% gradient ethyl acetate/petroleum ether) to give yellow solid compound 4-(7-bromo-8-fluoro-6-nitro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-1,4-oxazepane (340 mg, 0.73 mmol, yield 89%). LCMS (ESI): [M+H] + = 468.9.
第三步：在手套箱中，向4-(7-溴-8-氟-6-硝基-2-(2,2,2-三氟乙氧基)喹唑啉-4-基)-1,4-氧氮杂环庚烷(120mg，0.26mmol)和((2-氟-6-(甲氧基甲氧基)-8-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)萘 -1-基)乙炔基)三异丙基硅烷(151mg，0.33mmol)的甲苯(4.8mL)和水(1.2mL)溶液中，加入碳酸铯(250mg，0.77mmol)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)(37.3mg，0.05mmol)。将混合物在100℃和氮气保护下搅拌16小时。加入水(5mL)稀释，使用乙酸乙酯(10mL*3)萃取，合并的有机相用无水硫酸钠干燥，过滤，旋干。残留物用快速柱色谱纯化(硅胶，0-15％梯度的四氢呋喃/石油醚)，得到棕色固体化合物4-(8-氟-7-(7-氟-8-((三异丙基甲硅烷基)乙炔基)萘-1-基)-6-硝基-2-(2,2,2-三氟乙氧基)喹唑啉-4-基)-1,4-氧氮杂环庚烷(150mg，0.21mmol，收率82％)。LCMS(ESI):[M+H]+＝715.3.Step 3: In a glove box, add 4-(7-bromo-8-fluoro-6-nitro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-1,4-oxazepane (120 mg, 0.26 mmol) and ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalene To a solution of -1-yl)ethynyl)triisopropylsilane (151 mg, 0.33 mmol) in toluene (4.8 mL) and water (1.2 mL) was added cesium carbonate (250 mg, 0.77 mmol) and [n-butylbis(1-adamantyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium(II) methanesulfonate (37.3 mg, 0.05 mmol). The mixture was stirred at 100°C under nitrogen protection for 16 hours. Add water (5 mL) to dilute and extract with ethyl acetate (10 mL*3). The combined organic phases are dried over anhydrous sodium sulfate, filtered and spin-dried. The residue was purified by flash column chromatography (silica gel, 0-15% gradient THF/petroleum ether) to give brown solid compound 4-(8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-6-nitro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-1,4-oxazepane (150 mg, 0.21 mmol, yield 8 2%). LCMS (ESI): [M+H] + = 715.3.
第四步：向4-(8-氟-7-(7-氟-8-((三异丙基甲硅烷基)乙炔基)萘-1-基)-6-硝基-2-(2,2,2-三氟乙氧基)喹唑啉-4-基)-1,4-氧氮杂环庚烷(140mg，0.20mmol)和(四氢-1H-吡咯嗪-7a(5H)-基)甲醇(55.0mg，0.39mmol)的四氢呋喃(2.8mL)溶液中，加入叔丁醇钠(37.6mg，0.39mmol)。将混合物在25℃和氮气保护下搅拌6小时。反应液冷却至0℃后加入水(3mL)稀释，使用乙酸乙酯(3mL*3)萃取，合并的有机相用无水硫酸钠干燥，过滤，旋干，得到粗品化合物4-(8-氟-7-(7-氟-8-((三异丙基甲硅烷基)乙炔基)萘-1-基)-6-硝基-2-((四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)喹唑啉-4-基)-1,4-氧氮杂环庚烷(240mg)，其为棕色油状液体。LCMS(ESI):[M+H]+＝756.4.Step 4: To 4-(8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalene-1-yl)-6-nitro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-1,4-oxazepane (140mg, 0.20mmol) and (tetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol (55.0mg, To a solution of 0.39 mmol) in tetrahydrofuran (2.8 mL), sodium tert-butoxide (37.6 mg, 0.39 mmol) was added. The mixture was stirred at 25°C under nitrogen protection for 6 hours. After the reaction solution was cooled to 0°C, it was diluted with water (3 mL), extracted with ethyl acetate (3 mL*3), the combined organic phase was dried over anhydrous sodium sulfate, filtered, and spin-dried to obtain the crude compound 4-(8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalene-1-yl)-6-nitro-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinazoline-4 -yl)-1,4-oxazepane (240 mg) as a brown oily liquid. LCMS (ESI): [M+H] + = 756.4.
第五步：向4-(8-氟-7-(7-氟-8-((三异丙基甲硅烷基)乙炔基)萘-1-基)-6-硝基-2-((四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)喹唑啉-4-基)-1,4-氧氮杂环庚烷(230.0mg，0.20mmol)的二甲基甲酰胺(4.6mL)溶液中加入氟化铯(192mg，3.04mmol)。将该溶液在25℃搅拌1小时。加入水(15mL)，使用乙酸乙酯(15mL*3)萃取，合并的有机相用无水硫酸钠干燥，过滤，旋干。残余物通过制备型HPLC纯化，得到黄色固体化合物4-(7-(8-乙炔基-7-氟萘-1-基)-8-氟-6-硝基-2-((四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)喹唑啉-4-基)-1,4-氧氮杂环庚烷(55.0mg，0.09mmol，收率30％)。LCMS(ESI):[M+H]+＝600.2。1H NMR(400MHz,DMSO-d6)δppm 8.74(s,1H),8.24(dd,J＝6.2,9.2Hz,1H),8.17(d,J＝7.3Hz,1H),7.70-7.56(m,2H),7.50(d,J＝6.8Hz,1H),4.24-4.15(m,3H),4.14-4.09(m,2H),4.07(s,2H),3.97(br t,J＝4.6Hz,2H),3.86-3.72(m,2H),2.98-2.90(m,2H),2.60-2.53(m,2H),2.14(br d,J＝4.0Hz,2H),1.95-1.85(m,2H),1.85-1.69(m,4H),1.58(td,J＝7.4,12.0Hz,2H).Step 5: To a solution of 4-(8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-6-nitro-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinazolin-4-yl)-1,4-oxazepane (230.0 mg, 0.20 mmol) in dimethylformamide (4.6 mL) was added fluorine Cesium chloride (192 mg, 3.04 mmol). The solution was stirred at 25°C for 1 hour. Water (15 mL) was added, extracted with ethyl acetate (15 mL*3), the combined organic phases were dried over anhydrous sodium sulfate, filtered, and spin-dried. The residue was purified by preparative HPLC to give yellow solid compound 4-(7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-6-nitro-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinazolin-4-yl)-1,4-oxazepane (55.0 mg, 0.09 mmol, yield 30%). LCMS (ESI): [M+H] + = 600.2. 1 H NMR(400MHz,DMSO-d 6 )δppm 8.74(s,1H),8.24(dd,J＝6.2,9.2Hz,1H),8.17(d,J＝7.3Hz,1H),7.70-7.56(m,2H),7.50(d,J＝6.8Hz,1H),4.24-4.15(m,3H),4.14-4.09(m,2H),4.07(s,2H),3.97(br t,J＝4.6Hz,2H),3.86-3.72(m,2H),2.98-2.90(m,2H),2.60-2.53(m,2H),2.14(br d,J＝4.0Hz,2H),1.95-1.85(m,2H),1.85-1.69(m,4H),1.58(td,J＝7.4,12.0Hz,2H).
实施例155：5-(7-(8-乙炔基-7-氟萘-1-基)-8-氟-6-硝基-2-((四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)喹唑啉-4-基)-N,N-二甲基-5,6,7,8-四氢-4H-吡唑并[1,5-a][1,4]二氮杂环庚烷-2-甲酰胺
Example 155: 5-(7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-6-nitro-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinazolin-4-yl)-N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepane-2-carboxamide
实施例155参照的合成路线制备得到的：LCMS(ESI):[M+H]+＝707.5；1H NMR(400MHz,CD3OD)δppm 8.80(s,1H),8.16-8.01(m,2H),7.59(t,J＝7.7Hz,1H),7.47-7.37(m,2H),6.88(s,1H),5.32-5.16(m,2H),4.60(br d,J＝4.4Hz,2H),4.48-4.33(m,2H),4.32-4.24(m,2H),3.48(s,1H),3.35(s,3H), 3.15-3.07(m,5H),2.80-2.68(m,2H),2.45(br d,J＝5.1Hz,2H),2.10-2.02(m,2H),1.98-1.85(m,4H),1.81-1.71(m,2H).实施例155参照的合成路线制备得到的：LCMS(ESI):[M+H] + ＝707.5； 1 H NMR(400MHz,CD 3 OD)δppm 8.80(s,1H),8.16-8.01(m,2H),7.59(t,J＝7.7Hz,1H),7.47-7.37(m,2H),6.88(s,1H),5.32-5.16(m,2H),4.60(br d,J＝4.4Hz,2H),4.48-4.33(m,2H),4.32-4.24(m,2H),3.48(s,1H),3.35(s,3H), 3.15-3.07(m,5H),2.80-2.68(m,2H),2.45(br d,J=5.1Hz,2H),2.10-2.02(m,2H),1.98-1.85(m,4H),1.81-1.71(m,2H).
实施例156：(3R)-1-(7-(7,8-二氟萘-1-基)-8-氟-6-硝基-2-((四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)喹唑啉-4-基)-3-甲基哌啶-3-醇
Example 156: (3R)-1-(7-(7,8-Difluoronaphthalen-1-yl)-8-fluoro-6-nitro-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol
第一步：把1-溴-2,3,4-三氟苯(10.0g，47.40mmol)和呋喃(20.4mL，284.39mmol)加入到甲苯(130mL)中，冷却至-15℃，氮气保护下，缓慢滴加正丁基锂(2M,28.4mL，56.8mmol)，将混合物在-15℃搅拌30分钟，然后升温至25℃并搅拌16小时。将反应混合物用水(100mL)淬灭并过滤。滤液用乙酸乙酯(50mL*3)萃取。合并的有机层用无水硫酸钠干燥，过滤并减压浓缩。残余物通过快速柱色谱(C18，0-65％梯度水/乙腈)纯化得到棕色油状化合物5,6-二氟-1,4-二氢-1,4-环氧萘(2.00g，11.10mmol，收率23％)。1H NMR(400MHz,CDCl3)δppm 7.12-7.03(m,2H),6.98-6.90(m,1H),6.84-6.73(m,1H),5.99(s,1H),5.73(s,1H).The first step: 1-bromo-2,3,4-trifluorobenzene (10.0g, 47.40mmol) and furan (20.4mL, 284.39mmol) were added to toluene (130mL), cooled to -15°C, under nitrogen protection, slowly added n-butyllithium (2M, 28.4mL, 56.8mmol), the mixture was stirred at -15°C for 30 minutes, then warmed to 25°C and stirred for 1 6 hours. The reaction mixture was quenched with water (100 mL) and filtered. The filtrate was extracted with ethyl acetate (50 mL*3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (C18, 0-65% gradient water/acetonitrile) to give brown oily compound 5,6-difluoro-1,4-dihydro-1,4-epoxynaphthalene (2.00 g, 11.10 mmol, yield 23%). 1 H NMR (400MHz, CDCl 3 ) δppm 7.12-7.03(m,2H),6.98-6.90(m,1H),6.84-6.73(m,1H),5.99(s,1H),5.73(s,1H).
第二步：向5,6-二氟-1,4-二氢-1,4-环氧萘(1.80g，9.99mmol)的乙醇(10.8mL)溶液中缓慢加入浓盐酸(10.2mL，122mmol)，将混合物在80℃搅拌16小时。真空去除溶剂，在残渣中加入饱和碳酸氢钠(直到pH>7)，加入乙酸乙酯(5mL*3)进行萃取，合并的有机层用无水硫酸镁干燥，过滤并减压浓缩得到黑色固体化合物7,8-二氟萘-1-醇(1.70g，9.39mmol，收率94％)。1H NMR(400MHz,CDCl3)δppm 7.64-7.56(m,1H),7.42-7.35(m,2H),7.02(br d,J＝6.2Hz,1H),6.76-6.54(m,1H)Second step: Concentrated hydrochloric acid (10.2 mL, 122 mmol) was slowly added to a solution of 5,6-difluoro-1,4-dihydro-1,4-epoxynaphthalene (1.80 g, 9.99 mmol) in ethanol (10.8 mL), and the mixture was stirred at 80° C. for 16 hours. The solvent was removed in vacuo, saturated sodium bicarbonate was added to the residue (until pH>7), ethyl acetate (5mL*3) was added for extraction, the combined organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to obtain a black solid compound 7,8-difluoronaphthalen-1-ol (1.70g, 9.39mmol, yield 94%). 1 H NMR (400MHz, CDCl 3 ) δppm 7.64-7.56(m,1H),7.42-7.35(m,2H),7.02(br d,J=6.2Hz,1H),6.76-6.54(m,1H)
第三步：将7,8-二氟萘-1-醇(500mg，2.78mmol)和二异丙基乙胺(1.38mL，8.33mmol)加入到二氯甲烷(5mL)中，然后在-40℃，缓慢滴加三氟甲磺酸酐(0.70mL，4.16mmol)，将混合物在 -40℃搅拌30分钟。真空去除溶剂，残余物通过快速柱色谱(硅胶，0-5％梯度乙酸乙酯/石油醚)纯化得到黄色油状化合物7,8-二氟萘-1-基三氟甲磺酸酯(610mg，1.95mmol，收率70％)。LCMS(ESI):[M+H]+＝313.0.The third step: 7,8-difluoronaphthalen-1-ol (500mg, 2.78mmol) and diisopropylethylamine (1.38mL, 8.33mmol) were added in dichloromethane (5mL), then at -40°C, trifluoromethanesulfonic anhydride (0.70mL, 4.16mmol) was slowly added dropwise, and the mixture was Stir at -40°C for 30 minutes. The solvent was removed in vacuo, and the residue was purified by flash column chromatography (silica gel, 0-5% ethyl acetate/petroleum ether gradient) to give compound 7,8-difluoronaphthalen-1-yl triflate (610 mg, 1.95 mmol, yield 70%) as a yellow oil. LCMS (ESI): [M+H] + = 313.0.
第四步：氮气保护下，将7,8-二氟萘-1-基三氟甲磺酸酯(500mg，1.60mmol)，双联嚬哪醇硼酸酯(813mg，3.20mmol)和醋酸钾(658mg，8.01mmol)加入到N,N-二甲基甲酰胺(5mL)中，然后加入[1,1-双(二苯基膦)二茂铁]二氯化钯二氯甲烷(117mg，0.16mmol)，将混合物在80℃搅拌16小时。反应液冷却至室温，减压浓缩并通过快速柱色谱(硅胶，0-5％梯度乙酸乙酯/石油醚)纯化得到白色固体化合物2-(7,8-二氟萘-1-基)-4,4,5,5-四甲基-1,3,2-二氧杂硼烷(400mg，1.38mmol，收率86％)。LCMS(ESI):[M+H]+＝291.1。1H NMR(400MHz,CDCl3)δppm 7.87(d,J＝7.9Hz,1H),7.74(d,J＝6.8Hz,1H),7.61(ddd,J＝1.6,4.8,9.0Hz,1H),7.49(dd,J＝6.9,8.2Hz,1H),7.40-7.30(m,1H),1.47(s,12H).The fourth step: under the protection of nitrogen, 7,8-difluoronaphthalen-1-yl trifluoromethanesulfonate (500mg, 1.60mmol), bis-diancol borate (813mg, 3.20mmol) and potassium acetate (658mg, 8.01mmol) were added to N,N-dimethylformamide (5mL), and then added [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane (11 7mg, 0.16mmol), and the mixture was stirred at 80°C for 16 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure and purified by flash column chromatography (silica gel, 0-5% gradient ethyl acetate/petroleum ether) to obtain white solid compound 2-(7,8-difluoronaphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (400mg, 1.38mmol, yield 86%). LCMS (ESI): [M+H] + = 291.1. 1 H NMR (400MHz, CDCl 3 ) δppm 7.87(d, J=7.9Hz, 1H), 7.74(d, J=6.8Hz, 1H), 7.61(ddd, J=1.6, 4.8,9.0Hz, 1H), 7.49(dd, J=6.9, 8.2Hz, 1H), 7.40-7.30(m, 1H), 1.47(s,12H).
第五步：将2-(7,8-二氟萘-1-基)-4,4,5,5-四甲基-1,3,2-二氧杂硼烷(135mg，0.46mmol)和(R)-1-(7-溴-8-氟-6-硝基-2-(2,2,2-三氟乙氧基)喹唑啉-4-基)-3-甲基哌啶-3-醇(150mg，0.31mmol)加入到二氧六环(3mL)中，在氮气保护下加入1.3M的碳酸钠水溶液(0.72mL，0.92mmol)和四(三苯基膦)钯(35.9mg，0.03mmol)，将混合物在100℃搅拌16小时。反应液冷却至室温，减压浓缩并通过快速柱色谱(硅胶，0-30％梯度四氢呋喃/石油醚)纯化得到棕色固体化合物(3R)-1-(7-(7,8-二氟萘-1-基)-8-氟-6-硝基-2-(2,2,2-三氟乙氧基)喹唑啉-4-基)-3-甲基哌啶-3-醇(150mg，0.26mmol，收率85％)。LCMS(ESI):[M+H]+＝567.1.Step 5: Combine 2-(7,8-difluoronaphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborinane (135mg, 0.46mmol) and (R)-1-(7-bromo-8-fluoro-6-nitro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol (150mg, 0.31mmol) Added to dioxane (3mL), added 1.3M aqueous sodium carbonate solution (0.72mL, 0.92mmol) and tetrakis(triphenylphosphine)palladium (35.9mg, 0.03mmol) under nitrogen protection, and stirred the mixture at 100°C for 16 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure and purified by flash column chromatography (silica gel, 0-30% gradient tetrahydrofuran/petroleum ether) to obtain brown solid compound (3R)-1-(7-(7,8-difluoronaphthalen-1-yl)-8-fluoro-6-nitro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol (150mg, 0.26mmol, yield 85%). LCMS (ESI): [M+H] + = 567.1.
第六步：把(3R)-1-(7-(7,8-二氟萘-1-基)-8-氟-6-硝基-2-(2,2,2-三氟乙氧基)喹唑啉-4-基)-3-甲基哌啶-3-醇(140mg，0.25mmol)和(四氢-1H-吡咯啉-7a(5H)-基)甲醇(69.8mg，0.49mmol)加入到四氢呋喃(2.80mL)溶液中，然后加入叔丁醇钠(47.5mg，0.49mmol)，在25℃搅拌6小时。反应液加入水(1mL)，用乙酸乙酯(1mL*3)萃取，有机相用无水硫酸镁干燥，过滤并减压浓缩，粗品用制备型HPLC纯化，得到黄色固体纯化化合物(3R)-1-(7-(7,8-二氟萘-1-基)-8-氟-6-硝基-2-((四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)喹唑啉-4-基)-3-甲基哌啶-3-醇(甲酸盐，21.3mg，0.25mmol，收率14％)。LCMS(ESI):[M+H]+＝608.2。1H NMR(400MHz,CD3OD)δppm 9.05-8.92(m,1H),8.56(s,1H),8.09(br d,J＝8.4Hz,1H),7.94-7.85(m,1H),7.67-7.59(m,1H),7.59-7.49(m,1H),7.46-7.40(m,1H),4.59-4.49(m,3H),4.30(br dd,J＝5.4,13.3Hz,1H),3.63(dd,J＝13.4,16.3Hz,1H),3.51-3.40(m,3H),3.14-3.02(m,2H),2.24(br dd,J＝6.5,12.2Hz,3H),2.15-2.04(m,4H),2.03-1.95(m,2H),1.93-1.77(m,3H),1.33(d,J＝8.6Hz,3H).Step 6: Add (3R)-1-(7-(7,8-difluoronaphthalen-1-yl)-8-fluoro-6-nitro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol (140mg, 0.25mmol) and (tetrahydro-1H-pyrroline-7a(5H)-yl)methanol (69.8mg, 0.49mmol) into Tetra Hydrofuran (2.80 mL) solution, then sodium tert-butoxide (47.5 mg, 0.49 mmol) was added, and stirred at 25°C for 6 hours. The reaction solution was added with water (1 mL), extracted with ethyl acetate (1 mL*3), the organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure, and the crude product was purified by preparative HPLC to obtain a yellow solid purified compound (3R)-1-(7-(7,8-difluoronaphthalen-1-yl)-8-fluoro-6-nitro-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3-methyl Piperidin-3-ol (formate salt, 21.3 mg, 0.25 mmol, yield 14%). LCMS (ESI): [M+H] + = 608.2. 1 H NMR(400MHz,CD 3 OD)δppm 9.05-8.92(m,1H),8.56(s,1H),8.09(br d,J＝8.4Hz,1H),7.94-7.85(m,1H),7.67-7.59(m,1H),7.59-7.49(m,1H),7.46-7.40(m,1H),4.59-4.49(m,3H),4.30(br dd,J＝5.4,13.3Hz,1H),3.63(dd,J＝13.4,16.3Hz,1H),3.51-3.40(m,3H),3.14-3.02(m,2H),2.24(br dd,J＝6.5,12.2Hz,3H),2.15-2.04(m,4H),2.03-1.95(m,2H),1.93-1.77(m,3H),1.33(d,J＝8.6Hz,3H).
效果实施例1：AlphaLISA化合物筛选实验Effect Example 1: AlphaLISA Compound Screening Experiment
实验方法：experimental method:
1.配制实验缓冲液(assay buffer)：1. Prepare the assay buffer:
缓冲液1的成分及终浓度：25mM HEPES pH7.5,10mM MgCl2,0.01％Triton X-100Components and final concentration of buffer 1: 25mM HEPES pH7.5, 10mM MgCl2, 0.01% Triton X-100
缓冲液2的成分及终浓度：25mM HEPES pH7.5,10mM MgCl2,0.01％Triton X-100,1mM DTTComponents and final concentration of buffer 2: 25mM HEPES pH7.5, 10mM MgCl2, 0.01% Triton X-100, 1mM DTT
2.实验设计及化合物准备：2. Experimental design and compound preparation:
1>用ECHO555自动化打板仪器准备化合物，测试浓度：化合物最高检测浓度为10uM或1uM， 3倍稀释，10个浓度，每个浓度2个重复，0.5％DMSO。1> Prepare the compound with ECHO555 automatic plate making instrument, test concentration: the highest detection concentration of the compound is 10uM or 1uM, 3-fold dilution, 10 concentrations, 2 replicates for each concentration, 0.5% DMSO.
2>高信号对照组(High control)：30个重复，0.5％DMSO，有KRAS蛋白参与反应，作为0％抑制2>High signal control group (High control): 30 repetitions, 0.5% DMSO, KRAS protein involved in the reaction, as 0% inhibition
3>低信号对照组(Low control)：30个重复，0.5％DMSO，无KRAS蛋白参与反应，作为100％抑制3> Low signal control group (Low control): 30 repetitions, 0.5% DMSO, no KRAS protein involved in the reaction, as 100% inhibition
3.实验步骤：3. Experimental steps:
a.KRAS-GDP蛋白实验步骤a. KRAS-GDP protein experimental steps
1>向测试板高信号对照组及化合物测试孔每孔加5μl用缓冲液1配好的KRAS溶液；向低信号对照组每孔加5μl缓冲液1，KRAS反应终浓度为(最初用40nM，优化后用5nM)5nM，室温孵育1h。1> Add 5 μl of KRAS solution prepared with buffer 1 to each well of the high-signal control group and compound test wells of the test plate; add 5 μl of buffer 1 to each well of the low-signal control group, the final concentration of KRAS reaction is (40nM initially, 5nM after optimization) 5nM, and incubate at room temperature for 1h.
2>向测试板每孔加5μl用缓冲液2配好的SOS1和GTP混合溶液，反应终浓度分别为(最初用250nM和625μM)50nM和125μM，室温孵育1h。2> Add 5 μl of the mixed solution of SOS1 and GTP prepared with buffer 2 to each well of the test plate, the final concentration of the reaction is 50 nM and 125 μM (initially 250 nM and 625 μM), and incubate at room temperature for 1 h.
3>向测试板每孔加5μl用缓冲液2配好的cRAF和AlphaLISA Nickel Acceptor beads混合溶液，反应终浓度分别为50nM和20μg/ml，室温孵育1h。3> Add 5 μl of the mixed solution of cRAF and AlphaLISA Nickel Acceptor beads prepared in buffer 2 to each well of the test plate, the final concentration of the reaction is 50nM and 20μg/ml respectively, and incubate at room temperature for 1h.
4>向测试板每孔加5μl用缓冲液2配好的AlphaScreen GSH Donor beads溶液，反应终浓度为20μg/ml，室温孵育1h。4> Add 5 μl of AlphaScreen GSH Donor beads solution prepared with buffer 2 to each well of the test plate, the final concentration of the reaction is 20 μg/ml, and incubate at room temperature for 1 hour.
5>用EnVision酶标仪读取测试板信号值，激发光波长680nm，发射光波长615nm。5> Read the signal value of the test plate with an EnVision microplate reader, the excitation light wavelength is 680nm, and the emission light wavelength is 615nm.
b.KRAS-GTP蛋白实验步骤b. KRAS-GTP protein experimental steps
1>将配好的蛋白溶液与SOS1-GTP混合溶液(浓度与GDP蛋白一致)按体积1:1混合后，室温预孵育1h。1> Mix the prepared protein solution with the SOS1-GTP mixed solution (the concentration is the same as the GDP protein) by volume 1:1, and pre-incubate at room temperature for 1 hour.
2>向测试板高信号对照组及化合物测试孔每孔加10μl步骤1混合溶液；向低信号对照组每孔加5μl缓冲液1与5μl SOS1和GTP混合溶液，室温孵育1h。2> Add 10 μl of the mixed solution of step 1 to each well of the high-signal control group and compound test wells of the test plate; add 5 μl of buffer 1 and 5 μl of the mixed solution of SOS1 and GTP to each well of the low-signal control group, and incubate at room temperature for 1 hour.
3>向测试板每孔加5μl用缓冲液2配好的cRAF和AlphaLISA Nickel Acceptor beads混合溶液，反应终浓度分别为50nM和20μg/ml，室温孵育1h。3> Add 5 μl of the mixed solution of cRAF and AlphaLISA Nickel Acceptor beads prepared in buffer 2 to each well of the test plate, the final concentration of the reaction is 50nM and 20μg/ml respectively, and incubate at room temperature for 1h.
4>向测试板每孔加5μl用缓冲液2配好的AlphaScreen GSH Donor beads溶液，反应终浓度为20μg/ml，室温孵育1h。4> Add 5 μl of AlphaScreen GSH Donor beads solution prepared with buffer 2 to each well of the test plate, the final concentration of the reaction is 20 μg/ml, and incubate at room temperature for 1 hour.
5>用EnVision酶标仪读取测试板信号值，激发光波长680nm，发射光波长615nm。5> Read the signal value of the test plate with an EnVision microplate reader, the excitation light wavelength is 680nm, and the emission light wavelength is 615nm.
c.KRAS-GCP蛋白实验步骤c.KRAS-GCP protein experimental steps
1>向测试板高信号对照组及化合物测试孔每孔加5μl用缓冲液1配好的KRAS溶液；向低信号对照组每孔加5μl缓冲液1，KRAS反应终浓度为5nM，室温孵育1h。1> Add 5 μl of KRAS solution prepared with buffer 1 to each well of the high-signal control group and compound test wells of the test plate; add 5 μl of buffer 1 to each well of the low-signal control group, the final concentration of KRAS reaction is 5 nM, and incubate at room temperature for 1 h.
2>向测试板每孔加5μl缓冲液2，室温孵育1h。2> Add 5 μl buffer 2 to each well of the test plate and incubate at room temperature for 1 hour.
3>向测试板每孔加5μl用缓冲液2配好的cRAF和AlphaLISA Nickel Acceptor beads混合溶液，反应终浓度分别为50nM和20μg/ml，室温孵育1h。3> Add 5 μl of the mixed solution of cRAF and AlphaLISA Nickel Acceptor beads prepared in buffer 2 to each well of the test plate, the final concentration of the reaction is 50nM and 20μg/ml respectively, and incubate at room temperature for 1h.
4>向测试板每孔加5μl用缓冲液2配好的AlphaScreen GSH Donor beads溶液，反应终浓度为20μg/ml，室温孵育1h。4> Add 5 μl of AlphaScreen GSH Donor beads solution prepared with buffer 2 to each well of the test plate, the final concentration of the reaction is 20 μg/ml, and incubate at room temperature for 1 hour.
5>用EnVision酶标仪读取测试板信号值，激发光波长680nm，发射光波长615nm。5> Read the signal value of the test plate with an EnVision microplate reader, the excitation light wavelength is 680nm, and the emission light wavelength is 615nm.
4.实验数据分析： 4. Experimental data analysis:
1>根据原始数据分别计算出高信号对照和低信号对照的平均值High control average和Low control average。1> Calculate the average High control average and Low control average of the high signal control and low signal control according to the original data.
2>计算化合物样品孔(Sample signal)的抑制率，计算公式如下：2> Calculate the inhibition rate of the compound sample hole (Sample signal), the calculation formula is as follows:
(High control average-Sample signal/High control average-Low control average)*100％(High control average-Sample signal/High control average-Low control average)*100%
3>利用Graphpad Prism软件中四参数拟合模式(log(inhibitor)vs.response--Variable slope(four parameters))对化合物及其不同浓度下对实验信号的抑制率做浓度响应曲线拟合，计算化合物的IC50值。3>Use the four-parameter fitting mode (log(inhibitor)vs.response--Variable slope(four parameters)) in the Graphpad Prism software to fit the concentration-response curve of the compound and its inhibitory rate to the experimental signal at different concentrations, and calculate the IC50 value of the compound.
实验材料：
Experimental Materials:
实验仪器：
laboratory apparatus:
实验结果：Experimental results:
本发明化合物对KRAS G12D的GDP，GTP，GCP蛋白的抑制效果见表1。See Table 1 for the inhibitory effects of the compounds of the present invention on KRAS G12D GDP, GTP, and GCP proteins.
表1




Table 1




NT:未测试NT: not tested
效果实施例2：ERK磷酸化细胞实验Effect example 2: ERK phosphorylation cell experiment
AGS_ERK蛋白磷酸化检测AGS_ERK protein phosphorylation detection
第一天：将AGS细胞接种于384孔细胞培养板中，于37℃，5％二氧化碳细胞培养箱中过夜培养。Day 1: AGS cells were seeded in 384-well cell culture plates and cultured overnight at 37°C in a 5% carbon dioxide incubator.
第二天：用Echo550将化合物加入板中，继续在37℃，5％二氧化碳细胞培养箱中培养3小时。最后细胞培养板经过多聚甲醛固定、甲醇渗透、封闭液封闭后，加入一抗混合液(rabbit anti pERK，mouse anti GAPDH)，于4℃孵育过夜。The next day: Add compounds to the plate with Echo550 and continue to incubate for 3 hours at 37°C in a 5% carbon dioxide cell incubator. Finally, after the cell culture plate was fixed with paraformaldehyde, permeated with methanol, and blocked with blocking solution, the primary antibody mixture (rabbit anti pERK, mouse anti GAPDH) was added and incubated overnight at 4°C.
第三天：弃掉一抗，加入二抗混合液(goat anti rabbit 800CW,goat anti mouse 680RD)，于室温避光孵育。最后用PBST清洗3次后，将细胞培养板倒扣离心1分钟。用Odyssey CLx读取荧光信号值。Day 3: Discard the primary antibody, add the secondary antibody mixture (goat anti rabbit 800CW, goat anti mouse 680RD), and incubate at room temperature in the dark. After the final wash with PBST 3 times, the cell culture plate was centrifuged upside down for 1 minute. Fluorescent signal values were read with Odyssey CLx.
根据以下公式计算ERK磷酸化：ERK phosphorylation was calculated according to the following formula:
相对表达量：(化合物的荧光信号比值–阳性对照平均值)/(阴性对照平均值-阳性对照平均值)Relative expression level: (the ratio of the fluorescence signal of the compound – the average value of the positive control)/(the average value of the negative control – the average value of the positive control)
阴性对照:DMSONegative control: DMSO
阳性对照:10μM ReferencePositive control: 10μM Reference
XLFit 5.0按参数公式拟合计算IC50值:XLFit 5.0 calculates the IC50 value according to the parameter formula fitting:
Y＝Bottom+(Top–Bottom)/(1+10^((Log IC50–X)×HillSlope))Y＝Bottom+(Top–Bottom)/(1+10^((Log IC50–X)×HillSlope))
X:化合物浓度log值X: log value of compound concentration
Y:复孔间p-ERK相对表达量的平均值Y: the average value of the relative expression of p-ERK among multiple wells
本发明化合物对AGS和AsPC-1细胞的pERK的抑制效果见表2。See Table 2 for the inhibitory effects of the compounds of the present invention on pERK in AGS and AsPC-1 cells.
表2






Table 2






NT:未测试NT: not tested
效果实施例3：细胞的3D增殖实验Effect example 3: 3D proliferation experiment of cells
AGS、AsPC-1细胞的3D增殖实验3D Proliferation Experiment of AGS and AsPC-1 Cells
利用纳升移液系统(LABCYTE,P-0200)将稀释好的待测化合物加入384孔低吸附细胞培养板中，铺入细胞后，将培养板放置于37℃，5％CO2恒温培养箱。化合物与细胞共孵育5天后，加入CellTiter-3D试剂，用Envision多功能酶标仪读取发光值(光信号和体系中ATP量成正比，而ATP的含量直接表征体系中的活细胞数)。最后使用XLFIT软件用非线性拟合公式得到化合物的IC50(半数抑制浓度)。Use the nanoliter pipetting system (LABCYTE, P-0200) to add the diluted compound to be tested into a 384-well low-adsorption cell culture plate. After spreading the cells, place the culture plate in a 37°C, 5% CO 2 constant temperature incubator. After the compound was co-incubated with the cells for 5 days, CellTiter- For 3D reagents, use the Envision multi-functional microplate reader to read the luminescence value (the light signal is directly proportional to the ATP amount in the system, and the ATP content directly represents the number of living cells in the system). Finally, use the XLFIT software to obtain the IC50 (half inhibitory concentration) of the compound with the nonlinear fitting formula.
Y＝Bottom+(Top-Bottom)/(1+10^((LogIC50-X)×HillSlope))Y＝Bottom+(Top-Bottom)/(1+10^((LogIC50-X)×HillSlope))
X:化合物浓度log值X: log value of compound concentration
Y:抑制率(％)Y: inhibition rate (%)
抑制率(％)＝100×(阴性对照平均值-化合物读值)/(阴性对照平均值-阳性对照平均值)Inhibition rate (%)=100×(negative control average value-compound reading value)/(negative control average value-positive control average value)
阴性对照:DMSONegative control: DMSO
阳性对照:Medium onlyPositive control: Medium only
本发明化合物对AGS和AsPC-1细胞的3D增殖抑制效果见表3。The 3D proliferation inhibitory effects of the compounds of the present invention on AGS and AsPC-1 cells are shown in Table 3.
表3


table 3


表4本发明化合物与已公布化合物的活性对比表

Table 4 Compounds of the present invention and the activity comparison table of published compounds

实验结论：本发明化合物比已知化合物具有更优活性。 Experimental conclusion: the compound of the present invention has better activity than known compounds.
实验例4.CD-I小鼠口服及静脉注射受试化合物的药代动力学研宄The pharmacokinetic research of experimental example 4.CD-1 mouse oral administration and intravenous injection test compound
实验目的：测试CD-I小鼠口服及静脉注射化合物的体内药代动力学Purpose of the experiment: To test the in vivo pharmacokinetics of oral and intravenous compounds in CD-I mice
实验步骤：Experimental steps:
受试化合物与5％DMSO/40％PEG400/55％Water水溶液混合，涡旋并超声，制备得到0.6mg/mL澄清溶液(静脉)或3mg/mL澄清溶液(口服)，微孔滤膜过滤后备用。选取6至8周龄的雄性CD小鼠，静脉注射给予候选化合物溶液，剂量约为3mg/kg。口服给予候选化合物溶液，剂量约为60mg/kg和100mpk。收集一定时间的全血，制备得到血浆，以LC-MSMS方法分析药物浓度，并用WinNonlin(PhoenixTM,version 8.3)软件计算药代参数。The test compound was mixed with 5% DMSO/40% PEG400/55% Water aqueous solution, vortexed and sonicated to prepare a 0.6 mg/mL clear solution (intravenous) or a 3 mg/mL clear solution (oral), which was filtered through a microporous membrane for use. Male CD mice aged 6 to 8 weeks were selected, and the candidate compound solution was administered intravenously at a dose of about 3 mg/kg. The candidate compound solution was administered orally at a dose of approximately 60 mg/kg and 100 mpk. Whole blood was collected for a certain period of time, and plasma was prepared. The drug concentration was analyzed by LC-MSMS, and the pharmacokinetic parameters were calculated by WinNonlin (Phoenix TM , version 8.3) software.
表5：静脉(IV)PK数据
Table 5: Intravenous (IV) PK Data
表6：口服(PO)PK数据
Table 6: Oral (PO) PK Data
实验结论：Experimental results:
本发明化合物具有良好的口服生物利用度。 The compounds of the present invention have good oral bioavailability.

Claims (19)

  1. 一种如式I-0所示的杂环类化合物、其药学上可接受的盐、其立体异构体或它们的溶剂合物：
    A heterocyclic compound as shown in formula I-0, its pharmaceutically acceptable salt, its stereoisomer or their solvate:
    其中，环K为芳环或杂芳环；Wherein, Ring K is an aromatic ring or a heteroaromatic ring;
    X1为N、NRX1’或CRX1；X2为N或CRX2； X1 is N, NR X1' or CR X1 ; X2 is N or CR X2 ;
    RX1和RX2各自独立地为H、CN、卤素、C1-C6烷基、被一个或多个卤素取代的C1-C6烷基、被一个或多个羟基取代C1-C6烷基、PO(C1-C6烷基)2、C3-C6环烷基、C3-C6环烯基、C2-C6烯基、C2-C6炔基、3～6元杂环烷基、3～6元杂环烯基、6-14元芳基、5～14元杂芳基、被一个或多个X1-1取代的3～6元杂环烷基、被一个或多个X1-2取代的5～14元杂芳基、NO2、被一个或多个X1-3取代的3～6元杂环烯基、ORa、SF5、C(＝O)X1-4、C(＝O)ORa、-NRaC(O)Ra、NX1-5X1-6或SO2X1-7；RX1and RX2Each independently is H, CN, halogen, C1-C6Alkyl, C substituted by one or more halogens1-C6Alkyl, substituted by one or more hydroxyl groups C1-C6Alkyl, PO(C1-C6alkyl)2、C3-C6Cycloalkyl, C3-C6Cycloalkenyl, C2-C6Alkenyl, C2-C6Alkynyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, 6-14 membered aryl, 5-14 membered heteroaryl, replaced by one or more X1-1Substituted 3-6 membered heterocycloalkyl, replaced by one or more X1-2Substituted 5-14 membered heteroaryl, NO2, by one or more X1-3Substituted 3-6 membered heterocycloalkenyl, ORa, SF5, C(=O)X1-4, C(=O)ORa, -NRaC(O)Ra、NX1-5x1-6or SO2x1-7;
    X1-1和X1-3各自独立地为(C＝O)-C1-C6烷基；X1-2独立地为C1-C6烷基；X1-4独立地为H、C3-C8环烷基、3～8元杂环烷基、C1-C6烷基、或被一个或多个卤素取代的C1-C6烷基；X1-5和X1-6各自独立地为H、C1-C6烷基、C3-C6环烷基、SO2-C1-C6烷基或(C＝O)-C1-C6烷基，或者X1-5和X1-6一起与与之相连的原子形成C3-C6脂碳环、C3-C6碳烯环、3～6元脂杂环或3～6元碳杂烯环；X1-7为ORa或C1-C6烷基；x1-1and x1-3Each independently is (C=O)-C1-C6Alkyl; X1-2independently for C1-C6Alkyl; X1-4independently H, C3-C8Cycloalkyl, 3-8 membered heterocycloalkyl, C1-C6Alkyl, or C substituted by one or more halogens1-C6Alkyl; X1-5and x1-6Each independently is H, C1-C6Alkyl, C3-C6Cycloalkyl, SO2-C1-C6Alkyl or (C=O)-C1-C6Alkyl, or X1-5and x1-6together with the atoms it is attached to form C3-C6Aliphatic ring, C3-C6Carbene ring, 3-6 membered aliphatic ring or 3-6 membered carbene ring; X1-7for ORaor C1-C6alkyl;
    X3为N或CRX3，RX3为H、卤素、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C6环烷基、C3-C6环烯基、3～6元杂环烷基、3～6元杂环烯基、卤代(C1-C6烷基)、ORa、羟基(C1-C6烷基)、氰基、硝基、-SO3Ra、-NRaRb、-C(O)Ra、-C(O)ORa、-C(O)NRaRb、-NRaC(O)Ra、5-14元杂芳基、6-14元芳基；X 3 is N or CR X3 , R X3 is H, halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkenyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, halogenated (C 1 -C 6 alkyl), OR a , hydroxyl (C 1 -C 6 alkyl), cyano, nitro, -SO 3 R a , -NR a R b , -C(O)R a , -C(O)OR a , -C(O)NR a R b , -NR a C(O)R a , 5-14 membered heteroaryl, 6-14 membered aryl;
    或者RX1与RX3和其相连的原子共同形成C5-C8环烯酮结构；Or R X1 and R X3 and the atoms connected to them jointly form a C 5 -C 8 cycloalkene structure;
    或者RX1’与RX3和其相连的原子共同形成5～8元杂芳环或被一个或多个羟基取代的5～8元杂芳环；Or R X1' and R X3 and the atoms connected to them together form a 5-8 membered heteroaryl ring or a 5-8 membered heteroaryl ring substituted by one or more hydroxyl groups;
    R1为C6～C14的芳基、被一个或多个R1-1取代的C6～C14的芳基、5～14元杂芳基或被一个或多个R1-2取代的5～14元杂芳基；R 1 is a C 6 -C 14 aryl group, a C 6 -C 14 aryl group substituted by one or more R 1-1 , a 5-14 membered heteroaryl group or a 5-14 membered heteroaryl group substituted by one or more R 1-2 ;
    R1-1和R1-2各自独立地为卤素、OH、CN、NO2、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C6环烷基、C3-C6环烯基、3～6元杂环烷基、3～6元杂环烯基、被一个或多个卤素取代的C1-C6烷基、被一个或多个羟基取代的C1-C6烷基、ORa、B(OH)2、O(C＝O)-C1-C10烷基、SO3Ra、NRaRb、CORa、CONRaRb、C(O)ORa、NRaCORa；R 1-1 and R 1-2 are each independently halogen, OH, CN, NO 2 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkenyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, C 1 -C 6 alkyl substituted by one or more halogens, C 1 - C 6 alkyl, OR a , B(OH) 2 , O(C=O)-C 1 -C 10 alkyl, SO 3 R a , NR a R b , COR a , CONR a R b , C(O)OR a , NR a COR a ;
    Ra和Rb各自独立地表示氢、C1-C6烷基或C3-C6环烷基；或者Ra、Rb一起与与之相连的原子形成C3-C6脂碳环、C3-C6碳烯环、3～6元脂杂环或3～6元碳杂烯环；R a and R b each independently represent hydrogen, C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl; or R a and R b together form a C 3 -C 6 aliphatic carbocyclic ring, a C 3 -C 6 carbene ring, a 3-6 membered aliphatic heterocyclic ring or a 3-6 membered carboalkene ring;
    或者，相邻的两个R1-1与其相连的原子一起形成C3-C8脂碳环或被一个或多个R1-3取代的C3-C8脂碳环，其余R1-1独立地为卤素、OH、CN、NO2、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C6环烷 基、C3-C6环烯基、3～6元杂环烷基、3～6元杂环烯基、被一个或多个卤素取代的C1-C6烷基、被一个或多个羟基取代的C1-C6烷基、ORa、B(OH)2、O(C＝O)-C1-C10烷基、SO3Ra、NRaRb、CORa、CONRaRb、C(O)ORa、NRaCORa；Alternatively, two adjacent R 1-1 and their connected atoms together form a C 3 -C 8 aliphatic carbon ring or a C 3 -C 8 aliphatic carbon ring substituted by one or more R 1-3 , and the remaining R 1-1 are independently halogen, OH, CN, NO 2 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkane C 3 -C 6 cycloalkenyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, C 1 -C 6 alkyl substituted by one or more halogens, C 1 -C 6 alkyl substituted by one or more hydroxyl groups, OR a , B(OH) 2 , O(C=O)-C 1 -C 10 alkyl, SO 3 R a , NR a R b , COR a , CONR a R b , C(O ) OR a , NR a COR a ;
    或者，相邻的两个R1-2与其相连的原子一起形成C3-C8脂碳环或被一个或多个R1-4取代的C3-C8脂碳环，其余R1-2独立地为卤素、OH、CN、NO2、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C6环烷基、C3-C6环烯基、3～6元杂环烷基、3～6元杂环烯基、被一个或多个卤素取代的C1-C6烷基、被一个或多个羟基取代的C1-C6烷基、ORa、B(OH)2、O(C＝O)-C1-C10烷基、SO3Ra、NRaRb、CORa、CONRaRb、C(O)ORa、NRaCORa；Or, adjacent two R1-2Together with its attached atoms form C3-C8Aliphatic carbocycle or by one or more R1-4Replaced C3-C8Aliphatic carbocycle, the rest R1-2independently halogen, OH, CN, NO2、C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, C3-C6Cycloalkyl, C3-C6Cycloalkenyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, C substituted by one or more halogens1-C6Alkyl, C substituted by one or more hydroxyl groups1-C6Alkyl, ORa, B(OH)2, O(C=O)-C1-C10Alkyl, SO3Ra、NRaRb、CORa、CONRaRb, C(O)ORa、NRaCORa;
    R1-3和R1-4独立地为卤素；R 1-3 and R 1-4 are independently halogen;
    或者X1为CRX1，其中，X1中的C原子与R1中的芳基或杂芳基中的C原子通过-O-(CH2)n1-*、*-NH-(CH2)n2-、-C≡C-(CH2)n3-C≡C-*或-(CH2)n4-O-(CH2)n5-*相连，其中，*端与X1中的C原子相连；Or X 1 is CR X1 , wherein, the C atom in X 1 is connected to the C atom in the aryl or heteroaryl group in R 1 through -O-(CH 2 ) n1 -*, *-NH-(CH 2 ) n2 -, -C≡C-(CH 2 ) n3 -C≡C-* or -(CH 2 ) n4 -O-(CH 2 ) n5 -*, wherein the * end is connected to the C atom in X 1 ;
    n1、n2、n3、n4和n5各自独立地为1、2、3、4、5或6；n1, n2, n3, n4 and n5 are each independently 1, 2, 3, 4, 5 or 6;
    R2为H、卤素、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C6环烷基、C3-C6环烯基、3～6元杂环烷基、3～6元杂环烯基、卤代(C1-C6烷基)、ORa、羟基(C1-C6烷基)、氰基、硝基、-SO3Ra、-NRaRb、-C(O)Ra、-C(O)ORa、-C(O)NRaRb、-NRaC(O)Ra、5-14元杂芳基、6-14元芳基；R 2 is H, halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkenyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, halogenated (C 1 -C 6 alkyl), OR a , hydroxyl (C 1 -C 6 alkyl), cyano, nitro, -SO 3 R a , -NR a R b , -C(O)R a , -C(O)OR a , -C(O)NR a R b , -NR a C(O)R a , 5-14 membered heteroaryl, 6-14 membered aryl;
    L2表示不存在、-O-(C1-C6亚烷基)或-NRa-(C1-C6亚烷基)；L 2 represents absence, -O-(C 1 -C 6 alkylene) or -NR a -(C 1 -C 6 alkylene);
    R3为 R3 is
    其中，R1'、R2'、R3'、R4'、R5'、R6'、R7'、R8'、R9'、R10'、R11'、R12'各自独立地表示氢、卤素、氰基、C1-C6烷基、C2-C6烯基、C2-C6炔基、卤代(C1-C6烷基)、羟基(C1-C6烷基)、C3-C6环烷基、C3-C6环烯基、3～6元杂环烷基、3～6元杂环烯基、-ORa、-SO3Ra、-NRaRb、-CO(C1-C6烷基)或-C(O)NRaRb；Among them, R1', R2', R3', R4', R5', R6', R7', R8', R9', R10', R11', R12'Each independently represents hydrogen, halogen, cyano, C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, halo(C1-C6Alkyl), hydroxyl (C1-C6Alkyl), C3-C6Cycloalkyl, C3-C6Cycloalkenyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, -ORa、-SO3Ra, -NRaRb, -CO(C1-C6Alkyl) or -C(O)NRaRb;
    或者R1'与R2'一起与与之相连的原子形成C3-C8脂碳环、C3-C8碳烯环、3-8元脂杂环、3-8元碳杂烯环、取代的C3-C8脂碳环、取代的C3-C8碳烯环、取代的3-8元脂杂环或取代的3-8元碳杂烯环；所述的取代是指任意地被1-2个选自卤素、氰基、C1-C6烷基、C2-C6烯基、C2-C6炔基、卤代(C1-C6烷基)、羟基(C1-C6烷基)、C3-C6环烷基、C3-C6环烯基、3～6元杂环烷基、3～6元杂环烯基、-ORa、-SO3Ra、-NRaRb、-C(O)Ra、-C(O)ORa、-C(O)NRaRb、-NRaC(O)Ra的取代基所取代；或者所述环中任意的CH2被C＝O所取代；or R1'with R2'together with the atoms it is attached to form C3-C8Aliphatic ring, C3-C8Carbene ring, 3-8 membered aliphatic ring, 3-8 membered carbene ring, substituted C3-C8Aliphatic ring, substituted C3-C8Carbene ring, substituted 3-8 membered aliphatic heterocyclic ring or substituted 3-8 membered carbene ring; said substitution refers to being randomly selected from 1-2 members selected from halogen, cyano, C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, halo(C1-C6Alkyl), hydroxyl (C1-C6Alkyl), C3-C6Cycloalkyl, C3-C6Cycloalkenyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, -ORa、-SO3Ra, -NRaRb, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, -NRaC(O)RaSubstituents; or any CH in the ring2replaced by C=O;
    或者R3'与R4'一起与与之相连的原子形成C3-C8脂碳环、C3-C8碳烯环、3-8元脂杂环、3-8元碳杂烯环、取代的C3-C8脂碳环、取代的C3-C8碳烯环、取代的3-8元脂杂环或取代的3-8元碳杂烯环；所述的取代是指任意地被1-2个选自卤素、氰基、C1-C6烷基、C2-C6烯基、C2-C6炔基、卤代(C1-C6烷基)、羟基(C1-C6烷基)、C3-C6环烷基、C3-C6环烯基、3～6元杂环烷基、3～6元杂环烯基、-ORa、-SO3Ra、-NRaRb、-C(O)Ra、-C(O)ORa、-C(O)NRaRb、-NRaC(O)Ra的取代基所取代；或者所述环中任意的CH2被C＝O所取代；or R3'with R4'together with the atoms it is attached to form C3-C8Aliphatic ring, C3-C8Carbene ring, 3-8 membered aliphatic ring, 3-8 membered carbene ring, substituted C3-C8Aliphatic ring, substituted C3-C8Carbene ring, substituted 3-8 membered aliphatic heterocyclic ring or substituted 3-8 membered carbene ring; said substitution refers to being randomly selected from 1-2 members selected from halogen, cyano, C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, halo(C1-C6Alkyl), hydroxyl (C1-C6Alkyl), C3-C6Cycloalkyl, C3-C6Cycloalkenyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, -ORa、-SO3Ra, -NRaRb, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, -NRaC(O)RaSubstituents; or any CH in the ring2replaced by C=O;
    或者R5'与R6'一起与与之相连的原子形成C3-C8脂碳环、C3-C8碳烯环、3-8元脂杂环、3-8元碳杂 烯环、取代的C3-C8脂碳环、取代的C3-C8碳烯环、取代的3-8元脂杂环或取代的3-8元碳杂烯环；所述的取代是指任意地被1-2个选自卤素、氰基、C1-C6烷基、C2-C6烯基、C2-C6炔基、卤代(C1-C6烷基)、羟基(C1-C6烷基)、C3-C6环烷基、C3-C6环烯基、3～6元杂环烷基、3～6元杂环烯基、-ORa、-SO3Ra、-NRaRb、-C(O)Ra、-C(O)ORa、-C(O)NRaRb、-NRaC(O)Ra的取代基所取代；或者所述环中任意的CH2被C＝O所取代；Or R 5' and R 6' together form C 3 -C 8 aliphatic carbon ring, C 3 -C 8 carbene ring, 3-8 membered aliphatic heterocyclic ring, 3-8 membered carbon heterocycle烯环、取代的C 3 -C 8脂碳环、取代的C 3 -C 8碳烯环、取代的3-8元脂杂环或取代的3-8元碳杂烯环；所述的取代是指任意地被1-2个选自卤素、氰基、C 1 -C 6烷基、C 2 -C 6烯基、C 2 -C 6炔基、卤代(C 1 -C 6烷基)、羟基(C 1 -C 6烷基)、C 3 -C 6环烷基、C 3 -C 6环烯基、3～6元杂环烷基、3～6元杂环烯基、-OR a 、-SO 3 R a 、-NR a R b 、-C(O)R a 、-C(O)OR a 、-C(O)NR a R b 、-NR a C(O)R a的取代基所取代；或者所述环中任意的CH 2被C＝O所取代；
    或者R7'与R8'一起与与之相连的原子形成C3-C8脂碳环、C3-C8碳烯环、3-8元脂杂环、3-8元碳杂烯环、取代的C3-C8脂碳环、取代的C3-C8碳烯环、取代的3-8元脂杂环或取代的3-8元碳杂烯环；所述的取代是指任意地被1-2个选自卤素、氰基、C1-C6烷基、C2-C6烯基、C2-C6炔基、卤代(C1-C6烷基)、羟基(C1-C6烷基)、C3-C6环烷基、C3-C6环烯基、3～6元杂环烷基、3～6元杂环烯基、-ORa、-SO3Ra、-NRaRb、-C(O)Ra、-C(O)ORa、-C(O)NRaRb、-NRaC(O)Ra的取代基所取代；或者所述环中任意的CH2被C＝O所取代；or R7'with R8'together with the atoms it is attached to form C3-C8Aliphatic ring, C3-C8Carbene ring, 3-8 membered aliphatic ring, 3-8 membered carbene ring, substituted C3-C8Aliphatic ring, substituted C3-C8Carbene ring, substituted 3-8 membered aliphatic heterocyclic ring or substituted 3-8 membered carbene ring; said substitution refers to being randomly selected from 1-2 members selected from halogen, cyano, C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, halo(C1-C6Alkyl), hydroxyl (C1-C6Alkyl), C3-C6Cycloalkyl, C3-C6Cycloalkenyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, -ORa、-SO3Ra, -NRaRb, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, -NRaC(O)Rasubstituted by substituents; or any CH in the ring2replaced by C=O;
    或者R9'与R10'一起与与之相连的原子形成C3-C8脂碳环、C3-C8碳烯环、3-8元脂杂环、3-8元碳杂烯环、取代的C3-C8脂碳环、取代的C3-C8碳烯环、取代的3-8元脂杂环或取代的3-8元碳杂烯环；所述的取代是指任意地被1-2个选自卤素、氰基、C1-C6烷基、C2-C6烯基、C2-C6炔基、卤代(C1-C6烷基)、羟基(C1-C6烷基)、C3-C6环烷基、C3-C6环烯基、3～6元杂环烷基、3～6元杂环烯基、-ORa、-SO3Ra、-NRaRb、-C(O)Ra、-C(O)ORa、-C(O)NRaRb、-NRaC(O)Ra的取代基所取代；或者所述环中任意的CH2被C＝O所取代；or R9'with R10'together with the atoms it is attached to form C3-C8Aliphatic ring, C3-C8Carbene ring, 3-8 membered aliphatic ring, 3-8 membered carbene ring, substituted C3-C8Aliphatic ring, substituted C3-C8Carbene ring, substituted 3-8 membered aliphatic heterocyclic ring or substituted 3-8 membered carbene ring; said substitution refers to being randomly selected from 1-2 members selected from halogen, cyano, C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, halo(C1-C6Alkyl), hydroxyl (C1-C6Alkyl), C3-C6Cycloalkyl, C3-C6Cycloalkenyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, -ORa、-SO3Ra, -NRaRb, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, -NRaC(O)RaSubstituents; or any CH in the ring2replaced by C=O;
    或者R11'与R12'一起与与之相连的原子形成C3-C8脂碳环、C3-C8碳烯环、3-8元脂杂环、3-8元碳杂烯环、取代的C3-C8脂碳环、取代的C3-C8碳烯环、取代的3-8元脂杂环或取代的3-8元碳杂烯环；所述的取代是指任意地被1-2个选自卤素、氰基、C1-C6烷基、C2-C6烯基、C2-C6炔基、卤代(C1-C6烷基)、羟基(C1-C6烷基)、C3-C6环烷基、C3-C6环烯基、3～6元杂环烷基、3～6元杂环烯基、-ORa、-SO3Ra、-NRaRb、-C(O)Ra、-C(O)ORa、-C(O)NRaRb、-NRaC(O)Ra的取代基所取代；或者所述环中任意的CH2被C＝O所取代；or R11'with R12'together with the atoms it is attached to form C3-C8Aliphatic ring, C3-C8Carbene ring, 3-8 membered aliphatic ring, 3-8 membered carbene ring, substituted C3-C8Aliphatic ring, substituted C3-C8Carbene ring, substituted 3-8 membered aliphatic heterocyclic ring or substituted 3-8 membered carbene ring; said substitution refers to being randomly selected from 1-2 members selected from halogen, cyano, C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, halo(C1-C6Alkyl), hydroxyl (C1-C6Alkyl), C3-C6Cycloalkyl, C3-C6Cycloalkenyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, -ORa、-SO3Ra, -NRaRb, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, -NRaC(O)Rasubstituted by substituents; or any CH in the ring2replaced by C=O;
    或者R2'、R3'一起与与之相连的原子形成C3-C8脂碳环、C3-C8碳烯环、3-8元脂杂环、3-8元碳杂烯环、取代的C3-C8脂碳环、取代的C3-C8碳烯环、取代的3-8元脂杂环或取代的3-8元碳杂烯环；所述的取代是指任意地被1-2个选自卤素、氰基、C1-C6烷基、C2-C6烯基、C2-C6炔基、卤代(C1-C6烷基)、羟基(C1-C6烷基)、C3-C6环烷基、C3-C6环烯基、3～6元杂环烷基、3～6元杂环烯基、-ORa、-SO3Ra、-NRaRb、-C(O)Ra、-C(O)ORa、-C(O)NRaRb、-NRaC(O)Ra的取代基所取代；或者所述环中任意的CH2被C＝O所取代；or R2', R3'together with the atoms it is attached to form C3-C8Aliphatic ring, C3-C8Carbene ring, 3-8 membered aliphatic ring, 3-8 membered carbene ring, substituted C3-C8Aliphatic ring, substituted C3-C8Carbene ring, substituted 3-8 membered aliphatic heterocyclic ring or substituted 3-8 membered carbene ring; said substitution refers to being randomly selected from 1-2 members selected from halogen, cyano, C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, halo(C1-C6Alkyl), hydroxyl (C1-C6Alkyl), C3-C6Cycloalkyl, C3-C6Cycloalkenyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, -ORa、-SO3Ra, -NRaRb, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, -NRaC(O)RaSubstituents; or any CH in the ring2replaced by C=O;
    或者R4'、R5'一起与与之相连的原子形成C3-C8脂碳环、C3-C8碳烯环、3-8元脂杂环、3-8元碳杂烯环、取代的C3-C8脂碳环、取代的C3-C8碳烯环、取代的3-8元脂杂环或取代的3-8元碳杂烯环；所述的取代是指任意地被1-2个选自卤素、氰基、C1-C6烷基、C2-C6烯基、C2-C6炔基、卤代(C1-C6烷基)、羟基(C1-C6烷基)、C3-C6环烷基、C3-C6环烯基、3～6元杂环烷基、3～6元杂环烯基、-ORa、-SO3Ra、-NRaRb、-C(O)Ra、-C(O)ORa、-C(O)NRaRb、-NRaC(O)Ra的取代基所取代；或者所述环中任意的CH2被C＝O所取代；or R4', R5'together with the atoms it is attached to form C3-C8Aliphatic ring, C3-C8Carbene ring, 3-8 membered aliphatic ring, 3-8 membered carbene ring, substituted C3-C8Aliphatic ring, substituted C3-C8Carbene ring, substituted 3-8 membered aliphatic heterocyclic ring or substituted 3-8 membered carbene ring; said substitution refers to being randomly selected from 1-2 members selected from halogen, cyano, C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, halo(C1-C6Alkyl), hydroxyl (C1-C6Alkyl), C3-C6Cycloalkyl, C3-C6Cycloalkenyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, -ORa、-SO3Ra, -NRaRb, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, -NRaC(O)RaSubstituents; or any CH in the ring2replaced by C=O;
    或者R8'、R9'一起与与之相连的原子形成C3-C8脂碳环、C3-C8碳烯环、3-8元脂杂环、3-8元碳杂烯环、取代的C3-C8脂碳环、取代的C3-C8碳烯环、取代的3-8元脂杂环或取代的3-8元碳杂烯环；所 述的取代是指任意地被1-2个选自卤素、氰基、C1-C6烷基、C2-C6烯基、C2-C6炔基、卤代(C1-C6烷基)、羟基(C1-C6烷基)、C3-C6环烷基、C3-C6环烯基、3～6元杂环烷基、3～6元杂环烯基、-ORa、-SO3Ra、-NRaRb、-C(O)Ra、-C(O)ORa、-C(O)NRaRb、-NRaC(O)Ra的取代基所取代；或者所述环中任意的CH2被C＝O所取代；Or R 8' and R 9' together with the atoms connected to it form a C 3 -C 8 aliphatic ring, a C 3 -C 8 carbene ring, a 3-8 membered aliphatic heterocycle, a 3-8 membered carbene ring, a substituted C 3 -C 8 aliphatic ring, a substituted C 3 -C 8 carbene ring, a substituted 3-8 membered aliphatic ring or a substituted 3-8 membered carbene ring; The above substitution refers to being randomly 1-2 selected from halogen, cyano, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, halogenated (C 1 -C 6 alkyl), hydroxyl (C 1 -C 6 alkyl), C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkenyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, -OR a , -SO 3 R a , -NR a R b , -C(O)R a , -C(O)OR a , -C(O)NR a R b , -NR a C(O)R a are substituted by substituents; or any CH 2 in the ring is replaced by C=O;
    或者R10'、R11'一起与与之相连的原子形成C3-C8脂碳环、C3-C8碳烯环、3-8元脂杂环、3-8元碳杂烯环、取代的C3-C8脂碳环、取代的C3-C8碳烯环、取代的3-8元脂杂环或取代的3-8元碳杂烯环；所述的取代是指任意地被1-2个选自卤素、氰基、C1-C6烷基、C2-C6烯基、C2-C6炔基、卤代(C1-C6烷基)、羟基(C1-C6烷基)、C3-C6环烷基、C3-C6环烯基、3～6元杂环烷基、3～6元杂环烯基、-ORa、-SO3Ra、-NRaRb、-C(O)Ra、-C(O)ORa、-C(O)NRaRb、-NRaC(O)Ra的取代基所取代；或者所述环中任意的CH2被C＝O所取代；or R10', R11'together with the atoms it is attached to form C3-C8Aliphatic ring, C3-C8Carbene ring, 3-8 membered aliphatic ring, 3-8 membered carbene ring, substituted C3-C8Aliphatic ring, substituted C3-C8Carbene ring, substituted 3-8 membered aliphatic heterocyclic ring or substituted 3-8 membered carbene ring; said substitution refers to being randomly selected from 1-2 members selected from halogen, cyano, C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, halo(C1-C6Alkyl), hydroxyl (C1-C6Alkyl), C3-C6Cycloalkyl, C3-C6Cycloalkenyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, -ORa、-SO3Ra, -NRaRb, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, -NRaC(O)Rasubstituted by substituents; or any CH in the ring2replaced by C=O;
    或者R3'与R4'一起与与之相连的原子形成C3-C8脂碳环、C3-C8碳烯环、3-8元脂杂环、3-8元碳杂烯环、取代的C3-C8脂碳环、取代的C3-C8碳烯环、取代的3-8元脂杂环或取代的3-8元碳杂烯环；所述的取代是指任意地被1-2个选自卤素、氰基、C1-C6烷基、C2-C6烯基、C2-C6炔基、卤代(C1-C6烷基)、羟基(C1-C6烷基)、C3-C6环烷基、C3-C6环烯基、3～6元杂环烷基、3～6元杂环烯基、-ORa、-SO3Ra、-NRaRb、-C(O)Ra、-C(O)ORa、-C(O)NRaRb、-NRaC(O)Ra的取代基所取代；或者所述环中任意的CH2被C＝O所取代；且R9'与R10'一起与与之相连的原子形成C3-C8脂碳环、C3-C8碳烯环、3-8元脂杂环、3-8元碳杂烯环、取代的C3-C8脂碳环、取代的C3-C8碳烯环、取代的3-8元脂杂环或取代的3-8元碳杂烯环；所述的取代是指任意地被1-2个选自卤素、氰基、C1-C6烷基、C2-C6烯基、C2-C6炔基、卤代(C1-C6烷基)、羟基(C1-C6烷基)、C3-C6环烷基、C3-C6环烯基、3～6元杂环烷基、3～6元杂环烯基、-ORa、-SO3Ra、-NRaRb、-C(O)Ra、-C(O)ORa、-C(O)NRaRb、-NRaC(O)Ra的取代基所取代；或者所述环中任意的CH2被C＝O所取代；or R3'with R4'together with the atoms it is attached to form C3-C8Aliphatic ring, C3-C8Carbene ring, 3-8 membered aliphatic ring, 3-8 membered carbene ring, substituted C3-C8Aliphatic ring, substituted C3-C8Carbene ring, substituted 3-8 membered aliphatic heterocyclic ring or substituted 3-8 membered carbene ring; said substitution refers to being randomly selected from 1-2 members selected from halogen, cyano, C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, halo(C1-C6Alkyl), hydroxyl (C1-C6Alkyl), C3-C6Cycloalkyl, C3-C6Cycloalkenyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, -ORa、-SO3Ra, -NRaRb, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, -NRaC(O)Rasubstituted by substituents; or any CH in the ring2is replaced by C=O; and R9'with R10'together with the atoms it is attached to form C3-C8Aliphatic ring, C3-C8Carbene ring, 3-8 membered aliphatic ring, 3-8 membered carbene ring, substituted C3-C8Aliphatic ring, substituted C3-C8Carbene ring, substituted 3-8 membered aliphatic heterocyclic ring or substituted 3-8 membered carbene ring; said substitution refers to being randomly selected from 1-2 members selected from halogen, cyano, C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, halo(C1-C6Alkyl), hydroxyl (C1-C6Alkyl), C3-C6Cycloalkyl, C3-C6Cycloalkenyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, -ORa、-SO3Ra, -NRaRb, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, -NRaC(O)Rasubstituted by substituents; or any CH in the ring2replaced by C=O;
    R4为L1-R5，L1表示不存在、CRaRb或NRa；R 4 is L 1 -R 5 , L 1 means absent, CR a R b or NR a ;
    R5为以下式(i)、式(ii)或式(iii)的中的任意一种环状结构：
     R is any ring structure in the following formula (i), formula (ii) or formula (iii):
    其中，W1表示CRW1RW2或NRW1；Among them, W 1 represents CR W1 R W2 or NR W1 ;
    其中，RW1、RW2各自独立地表示氢、卤素、氰基、硝基、C1-C6烷基、C2-C6烯基、C2-C6炔基、卤代(C1-C6烷基)、羟基(C1-C6烷基)、C3-C6环烷基、C3-C6环烯基、3～6元杂环烷基、3～6元杂环烯基、-ORa、-SO3Ra、-NRaRb、-C(O)Ra、-C(O)ORa、-C(O)NRaRb、-NRaC(O)Ra或-(C＝O)-O-C1-C6亚烷基O-(C＝O)-C1-C10烷基；或者RW1、RW2一起与与之相连的原子共同形成3～8元脂杂环；Among them, RW1, RW2Each independently represents hydrogen, halogen, cyano, nitro, C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, halo(C1-C6Alkyl), hydroxyl (C1-C6Alkyl), C3-C6Cycloalkyl, C3-C6Cycloalkenyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, -ORa、-SO3Ra, -NRaRb, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, -NRaC(O)Raor -(C=O)-O-C1-C6Alkylene O-(C=O)-C1-C10Alkyl; or RW1, RW2Together with the atoms connected to it together form a 3-8 membered aliphatic heterocyclic ring;
    其中，W2表示CH或N； Wherein, W 2 represents CH or N;
    其中，Y为亚甲基、亚乙基、C3亚烷基、C2-C3亚烯基、或 Wherein, Y is methylene, ethylene, C 3 alkylene, C 2 -C 3 alkenylene, or
    Rc和Rd与与其相连的原子共同形成C3-C6脂碳环或被一个或多个卤素取代的C3-C6脂碳环；或者Rd和Rd’和与之相连的原子一起形成C3-C6脂碳环或被一个或多个卤素取代的C3-C6脂碳环；R c and R d together with the atoms connected to them form a C 3 -C 6 aliphatic carbocycle or a C 3 -C 6 aliphatic carbocycle substituted by one or more halogens; or R d and R d' together with the atoms connected to them form a C 3 -C 6 aliphatic carbocycle or a C 3 -C 6 aliphatic carbocycle substituted by one or more halogens;
    其中，R1”、R2”、R3”、R4”、R5”、R6”、R7”、R8”各自独立地表示氢、卤素、氰基、硝基、C1-C6烷基、C2-C6烯基、C2-C6炔基、卤代(C1-C6烷基)、羟基(C1-C6烷基)、C3-C6环烷基、C3-C6环烯基、3～6元杂环烷基、3～6元杂环烯基、-ORa、-SO3Ra、-NRaRb、-C(O)Ra、-C(O)ORa、-C(O)NRaRb、-NRaC(O)Ra；Among them, R1", R2", R3", R4", R5", R6", R7", R8"Each independently represents hydrogen, halogen, cyano, nitro, C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, halo(C1-C6Alkyl), hydroxyl (C1-C6Alkyl), C3-C6Cycloalkyl, C3-C6Cycloalkenyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, -ORa、-SO3Ra, -NRaRb, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, -NRaC(O)Ra;
    或者R1”与R2”一起与与之相连的原子形成C3-C8脂碳环、C3-C8碳烯环、3-8元脂杂环、3-8元碳杂烯环、取代的C3-C8脂碳环、取代的C3-C8碳烯环、取代的3-8元脂杂环或取代的3-8元碳杂烯环；所述的取代是指任意地被1-2个选自卤素、氰基、C1-C6烷基、C2-C6烯基、C2-C6炔基、卤代(C1-C6烷基)、羟基(C1-C6烷基)、C3-C6环烷基、C3-C6环烯基、3～6元杂环烷基、3～6元杂环烯基、-ORa、-SO3Ra、-NRaRb、-C(O)Ra、-C(O)ORa、-C(O)NRaRb、-NRaC(O)Ra的取代基所取代；或者所述环中任意的CH2被C＝O所取代；or R1"with R2"together with the atoms it is attached to form C3-C8Aliphatic ring, C3-C8Carbene ring, 3-8 membered aliphatic ring, 3-8 membered carbene ring, substituted C3-C8Aliphatic ring, substituted C3-C8Carbene ring, substituted 3-8 membered aliphatic heterocyclic ring or substituted 3-8 membered carbene ring; said substitution refers to being randomly selected from 1-2 members selected from halogen, cyano, C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, halo(C1-C6Alkyl), hydroxyl (C1-C6Alkyl), C3-C6Cycloalkyl, C3-C6Cycloalkenyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, -ORa、-SO3Ra, -NRaRb, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, -NRaC(O)RaSubstituents; or any CH in the ring2replaced by C=O;
    或者R3”与R4”一起与与之相连的原子形成C3-C8脂碳环、C3-C8碳烯环、3-8元脂杂环、3-8元碳杂烯环、取代的C3-C8脂碳环、取代的C3-C8碳烯环、取代的3-8元脂杂环或取代的3-8元碳杂烯环；所述的取代是指任意地被1-2个选自卤素、氰基、C1-C6烷基、C2-C6烯基、C2-C6炔基、卤代(C1-C6烷基)、羟基(C1-C6烷基)、C3-C6环烷基、C3-C6环烯基、3～6元杂环烷基、3～6元杂环烯基、-ORa、-SO3Ra、-NRaRb、-C(O)Ra、-C(O)ORa、-C(O)NRaRb、-NRaC(O)Ra的取代基所取代；或者所述环中任意的CH2被C＝O所取代；or R3"with R4"together with the atoms it is attached to form C3-C8Aliphatic ring, C3-C8Carbene ring, 3-8 membered aliphatic ring, 3-8 membered carbene ring, substituted C3-C8Aliphatic ring, substituted C3-C8Carbene ring, substituted 3-8 membered aliphatic heterocyclic ring or substituted 3-8 membered carbene ring; said substitution refers to being randomly selected from 1-2 members selected from halogen, cyano, C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, halo(C1-C6Alkyl), hydroxyl (C1-C6Alkyl), C3-C6Cycloalkyl, C3-C6Cycloalkenyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, -ORa、-SO3Ra, -NRaRb, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, -NRaC(O)Rasubstituted by substituents; or any CH in the ring2replaced by C=O;
    或者R5”与R6”一起与与之相连的原子形成C3-C8脂碳环、C3-C8碳烯环、3-8元脂杂环、3-8元碳杂烯环、取代的C3-C8脂碳环、取代的C3-C8碳烯环、取代的3-8元脂杂环或取代的3-8元碳杂烯环；所述的取代是指任意地被1-2个选自卤素、氰基、C1-C6烷基、C2-C6烯基、C2-C6炔基、卤代(C1-C6烷基)、羟基(C1-C6烷基)、C3-C6环烷基、C3-C6环烯基、3～6元杂环烷基、3～6元杂环烯基、-ORa、-SO3Ra、-NRaRb、-C(O)Ra、-C(O)ORa、-C(O)NRaRb、-NRaC(O)Ra的取代基所取代；或者所述环中任意的CH2被C＝O所取代；or R5"with R6"together with the atoms it is attached to form C3-C8Aliphatic ring, C3-C8Carbene ring, 3-8 membered aliphatic ring, 3-8 membered carbene ring, substituted C3-C8Aliphatic ring, substituted C3-C8Carbene ring, substituted 3-8 membered aliphatic heterocyclic ring or substituted 3-8 membered carbene ring; said substitution refers to being randomly selected from 1-2 members selected from halogen, cyano, C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, halo(C1-C6Alkyl), hydroxyl (C1-C6Alkyl), C3-C6Cycloalkyl, C3-C6Cycloalkenyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, -ORa、-SO3Ra, -NRaRb, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, -NRaC(O)Rasubstituted by substituents; or any CH in the ring2replaced by C=O;
    或者R7”与R8”一起与与之相连的原子形成C3-C8脂碳环、C3-C8碳烯环、3-8元脂杂环、3-8元碳杂烯环、取代的C3-C8脂碳环、取代的C3-C8碳烯环、取代的3-8元脂杂环或取代的3-8元碳杂烯环；所述的取代是指任意地被1-2个选自卤素、氰基、C1-C6烷基、C2-C6烯基、C2-C6炔基、卤代(C1-C6烷基)、羟基(C1-C6烷基)、C3-C6环烷基、C3-C6环烯基、3～6元杂环烷基、3～6元杂环烯基、-ORa、-SO3Ra、-NRaRb、-C(O)Ra、-C(O)ORa、-C(O)NRaRb、-NRaC(O)Ra的取代基所取代；或者所述环中任意的CH2被C＝O所取代；or R7"with R8"together with the atoms it is attached to form C3-C8Aliphatic ring, C3-C8Carbene ring, 3-8 membered aliphatic ring, 3-8 membered carbene ring, substituted C3-C8Aliphatic ring, substituted C3-C8Carbene ring, substituted 3-8 membered aliphatic heterocyclic ring or substituted 3-8 membered carbene ring; said substitution refers to being randomly selected from 1-2 members selected from halogen, cyano, C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, halo(C1-C6Alkyl), hydroxyl (C1-C6Alkyl), C3-C6Cycloalkyl, C3-C6Cycloalkenyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, -ORa、-SO3Ra, -NRaRb, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, -NRaC(O)RaSubstituents; or any CH in the ring2replaced by C=O;
    或者R2”、R3”一起与与之相连的原子形成C3-C8脂碳环、C3-C8碳烯环、3-8元脂杂环、3-8元碳杂烯环、取代的C3-C8脂碳环、取代的C3-C8碳烯环、取代的3-8元脂杂环或取代的3-8元碳杂烯环；所述的取代是指任意地被1-2个选自卤素、氰基、C1-C6烷基、C2-C6烯基、C2-C6炔基、卤代(C1-C6烷基)、羟基(C1-C6烷基)、C3-C6环烷基、C3-C6环烯基、3～6元杂环烷基、3～6元杂环烯基、-ORa、-SO3Ra、-NRaRb、-C(O)Ra、-C(O)ORa、-C(O)NRaRb、-NRaC(O)Ra的取代基所取代；或者所述环中任意的CH2 被C＝O所取代；或者R 2” 、R 3”一起与与之相连的原子形成C 3 -C 8脂碳环、C 3 -C 8碳烯环、3-8元脂杂环、3-8元碳杂烯环、取代的C 3 -C 8脂碳环、取代的C 3 -C 8碳烯环、取代的3-8元脂杂环或取代的3-8元碳杂烯环；所述的取代是指任意地被1-2个选自卤素、氰基、C 1 -C 6烷基、C 2 -C 6烯基、C 2 -C 6炔基、卤代(C 1 -C 6烷基)、羟基(C 1 -C 6烷基)、C 3 -C 6环烷基、C 3 -C 6环烯基、3～6元杂环烷基、3～6元杂环烯基、-OR a 、-SO 3 R a 、-NR a R b 、-C(O)R a 、-C(O)OR a 、-C(O)NR a R b 、-NR a C(O)R a的取代基所取代；或者所述环中任意的CH 2 replaced by C=O;
    或者R4”、R5”一起与与之相连的原子形成C3-C8脂碳环、C3-C8碳烯环、3-8元脂杂环、3-8元碳杂烯环、取代的C3-C8脂碳环、取代的C3-C8碳烯环、取代的3-8元脂杂环或取代的3-8元碳杂烯环；所述的取代是指任意地被1-2个选自卤素、氰基、C1-C6烷基、C2-C6烯基、C2-C6炔基、卤代(C1-C6烷基)、羟基(C1-C6烷基)、C3-C6环烷基、C3-C6环烯基、3～6元杂环烷基、3～6元杂环烯基、-ORa、-SO3Ra、-NRaRb、-C(O)Ra、-C(O)ORa、-C(O)NRaRb、-NRaC(O)Ra的取代基所取代；或者所述环中任意的CH2被C＝O所取代；or R4", R5"together with the atoms it is attached to form C3-C8Aliphatic ring, C3-C8Carbene ring, 3-8 membered aliphatic ring, 3-8 membered carbene ring, substituted C3-C8Aliphatic ring, substituted C3-C8Carbene ring, substituted 3-8 membered aliphatic heterocyclic ring or substituted 3-8 membered carbene ring; said substitution refers to being randomly selected from 1-2 members selected from halogen, cyano, C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, halo(C1-C6Alkyl), hydroxyl (C1-C6Alkyl), C3-C6Cycloalkyl, C3-C6Cycloalkenyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, -ORa、-SO3Ra, -NRaRb, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, -NRaC(O)RaSubstituents; or any CH in the ring2replaced by C=O;
    或者R6”、R7”一起与与之相连的原子形成C3-C8脂碳环、C3-C8碳烯环、3-8元脂杂环、3-8元碳杂烯环、取代的C3-C8脂碳环、取代的C3-C8碳烯环、取代的3-8元脂杂环或取代的3-8元碳杂烯环；所述的取代是指任意地被1-2个选自卤素、氰基、C1-C6烷基、C2-C6烯基、C2-C6炔基、卤代(C1-C6烷基)、羟基(C1-C6烷基)、C3-C6环烷基、C3-C6环烯基、3～6元杂环烷基、3～6元杂环烯基、-ORa、-SO3Ra、-NRaRb、-C(O)Ra、-C(O)ORa、-C(O)NRaRb、-NRaC(O)Ra的取代基所取代；或者所述环中任意的CH2被C＝O所取代；or R6", R7"together with the atoms it is attached to form C3-C8Aliphatic ring, C3-C8Carbene ring, 3-8 membered aliphatic ring, 3-8 membered carbene ring, substituted C3-C8Aliphatic ring, substituted C3-C8Carbene ring, substituted 3-8 membered aliphatic heterocyclic ring or substituted 3-8 membered carbene ring; said substitution refers to being randomly selected from 1-2 members selected from halogen, cyano, C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, halo(C1-C6Alkyl), hydroxyl (C1-C6Alkyl), C3-C6Cycloalkyl, C3-C6Cycloalkenyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, -ORa、-SO3Ra, -NRaRb, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, -NRaC(O)Rasubstituted by substituents; or any CH in the ring2replaced by C=O;
    或者R3”与R4”一起与与之相连的原子形成C3-C8脂碳环、C3-C8碳烯环、3-8元脂杂环、3-8元碳杂烯环、取代的C3-C8脂碳环、取代的C3-C8碳烯环、取代的3-8元脂杂环或取代的3-8元碳杂烯环；所述的取代是指任意地被1-2个选自卤素、氰基、C1-C6烷基、C2-C6烯基、C2-C6炔基、卤代(C1-C6烷基)、羟基(C1-C6烷基)、C3-C6环烷基、C3-C6环烯基、3～6元杂环烷基、3～6元杂环烯基、-ORa、-SO3Ra、-NRaRb、-C(O)Ra、-C(O)ORa、-C(O)NRaRb、-NRaC(O)Ra的取代基所取代；或者所述环中任意的CH2被C＝O所取代；且R5”与R6”一起与与之相连的原子形成C3-C8脂碳环、C3-C8碳烯环、3-8元脂杂环、3-8元碳杂烯环、取代的C3-C8脂碳环、取代的C3-C8碳烯环、取代的3-8元脂杂环或取代的3-8元碳杂烯环；所述的取代是指任意地被1-2个选自卤素、氰基、C1-C6烷基、C2-C6烯基、C2-C6炔基、卤代(C1-C6烷基)、羟基(C1-C6烷基)、C3-C6环烷基、C3-C6环烯基、3～6元杂环烷基、3～6元杂环烯基、-ORa、-SO3Ra、-NRaRb、-C(O)Ra、-C(O)ORa、-C(O)NRaRb、-NRaC(O)Ra的取代基所取代；或者所述环中任意的CH2被C＝O所取代；or R3"with R4"together with the atoms it is attached to form C3-C8Aliphatic ring, C3-C8Carbene ring, 3-8 membered aliphatic ring, 3-8 membered carbene ring, substituted C3-C8Aliphatic ring, substituted C3-C8Carbene ring, substituted 3-8 membered aliphatic heterocyclic ring or substituted 3-8 membered carbene ring; said substitution refers to being randomly selected from 1-2 members selected from halogen, cyano, C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, halo(C1-C6Alkyl), hydroxyl (C1-C6Alkyl), C3-C6Cycloalkyl, C3-C6Cycloalkenyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, -ORa、-SO3Ra, -NRaRb, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, -NRaC(O)Rasubstituted by substituents; or any CH in the ring2is replaced by C=O; and R5"with R6"together with the atoms it is attached to form C3-C8Aliphatic ring, C3-C8Carbene ring, 3-8 membered aliphatic ring, 3-8 membered carbene ring, substituted C3-C8Aliphatic ring, substituted C3-C8Carbene ring, substituted 3-8 membered aliphatic heterocyclic ring or substituted 3-8 membered carbene ring; said substitution refers to being randomly selected from 1-2 members selected from halogen, cyano, C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, halo(C1-C6Alkyl), hydroxyl (C1-C6Alkyl), C3-C6Cycloalkyl, C3-C6Cycloalkenyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, -ORa、-SO3Ra, -NRaRb, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, -NRaC(O)Rasubstituted by substituents; or any CH in the ring2replaced by C=O;
    其满足下述至少一个条件：It meets at least one of the following conditions:
    条件1：R3中，R1'与R2'一起与与之相连的原子形成C3-C8脂碳环、C3-C8碳烯环、3-8元脂杂环、3-8元碳杂烯环、取代的C3-C8脂碳环、取代的C3-C8碳烯环、取代的3-8元脂杂环或取代的3-8元碳杂烯环所述的取代是指任意地被1-2个选自卤素、氰基、C1-C6烷基、C2-C6烯基、C2-C6炔基、卤代(C1-C6烷基)、羟基(C1-C6烷基)、C3-C6环烷基、C3-C6环烯基、3～6元杂环烷基、3～6元杂环烯基、-ORa、-SO3Ra、-NRaRb、-C(O)Ra、-C(O)ORa、-C(O)NRaRb、-NRaC(O)Ra的取代基所取代；或者所述环中任意的CH2被C＝O所取代；Condition 1: R3in, R1'with R2'together with the atoms it is attached to form C3-C8Aliphatic ring, C3-C8Carbene ring, 3-8 membered aliphatic ring, 3-8 membered carbene ring, substituted C3-C8Aliphatic ring, substituted C3-C8The substitution of carbene ring, substituted 3-8 membered aliphatic heterocyclic ring or substituted 3-8 membered carbene ring refers to being randomly selected from 1-2 members selected from halogen, cyano, C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, halo(C1-C6Alkyl), hydroxyl (C1-C6Alkyl), C3-C6Cycloalkyl, C3-C6Cycloalkenyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, -ORa、-SO3Ra, -NRaRb, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, -NRaC(O)RaSubstituents; or any CH in the ring2replaced by C=O;
    或者R3'与R4'一起与与之相连的原子形成C3-C8脂碳环、C3-C8碳烯环、3-8元脂杂环、3-8元碳杂烯环、取代的C3-C8脂碳环、取代的C3-C8碳烯环、取代的3-8元脂杂环或取代的3-8元碳杂烯环；所述的取代是指任意地被1-2个选自卤素、氰基、C1-C6烷基、C2-C6烯基、C2-C6炔基、卤代(C1-C6烷基)、羟基(C1-C6烷基)、C3-C6环烷基、C3-C6环烯基、3～6元杂环烷基、3～6元杂环烯基、-ORa、-SO3Ra、-NRaRb、-C(O)Ra、-C(O)ORa、-C(O)NRaRb、-NRaC(O)Ra的取代基所取代；或者所述环中任意的CH2被C＝O所取代； or R3'with R4'together with the atoms it is attached to form C3-C8Aliphatic ring, C3-C8Carbene ring, 3-8 membered aliphatic ring, 3-8 membered carbene ring, substituted C3-C8Aliphatic ring, substituted C3-C8Carbene ring, substituted 3-8 membered aliphatic heterocyclic ring or substituted 3-8 membered carbene ring; said substitution refers to being randomly selected from 1-2 members selected from halogen, cyano, C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, halo(C1-C6Alkyl), hydroxyl (C1-C6Alkyl), C3-C6Cycloalkyl, C3-C6Cycloalkenyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, -ORa、-SO3Ra, -NRaRb, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, -NRaC(O)Rasubstituted by substituents; or any CH in the ring2replaced by C=O;
    或者R5'与R6'一起与与之相连的原子形成C3-C8脂碳环、C3-C8碳烯环、3-8元脂杂环、3-8元碳杂烯环、取代的C3-C8脂碳环、取代的C3-C8碳烯环、取代的3-8元脂杂环或取代的3-8元碳杂烯环；所述的取代是指任意地被1-2个选自卤素、氰基、C1-C6烷基、C2-C6烯基、C2-C6炔基、卤代(C1-C6烷基)、羟基(C1-C6烷基)、C3-C6环烷基、C3-C6环烯基、3～6元杂环烷基、3～6元杂环烯基、-ORa、-SO3Ra、-NRaRb、-C(O)Ra、-C(O)ORa、-C(O)NRaRb、-NRaC(O)Ra的取代基所取代；或者所述环中任意的CH2被C＝O所取代；or R5'with R6'together with the atoms it is attached to form C3-C8Aliphatic ring, C3-C8Carbene ring, 3-8 membered aliphatic ring, 3-8 membered carbene ring, substituted C3-C8Aliphatic ring, substituted C3-C8Carbene ring, substituted 3-8 membered aliphatic heterocyclic ring or substituted 3-8 membered carbene ring; said substitution refers to being randomly selected from 1-2 members selected from halogen, cyano, C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, halo(C1-C6Alkyl), hydroxyl (C1-C6Alkyl), C3-C6Cycloalkyl, C3-C6Cycloalkenyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, -ORa、-SO3Ra, -NRaRb, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, -NRaC(O)Rasubstituted by substituents; or any CH in the ring2replaced by C=O;
    或者R7'与R8'一起与与之相连的原子形成C3-C8脂碳环、C3-C8碳烯环、3-8元脂杂环、3-8元碳杂烯环、取代的C3-C8脂碳环、取代的C3-C8碳烯环、取代的3-8元脂杂环或取代的3-8元碳杂烯环；所述的取代是指任意地被1-2个选自卤素、氰基、C1-C6烷基、C2-C6烯基、C2-C6炔基、卤代(C1-C6烷基)、羟基(C1-C6烷基)、C3-C6环烷基、C3-C6环烯基、3～6元杂环烷基、3～6元杂环烯基、-ORa、-SO3Ra、-NRaRb、-C(O)Ra、-C(O)ORa、-C(O)NRaRb、-NRaC(O)Ra的取代基所取代；或者所述环中任意的CH2被C＝O所取代；or R7'with R8'together with the atoms it is attached to form C3-C8Aliphatic ring, C3-C8Carbene ring, 3-8 membered aliphatic ring, 3-8 membered carbene ring, substituted C3-C8Aliphatic ring, substituted C3-C8Carbene ring, substituted 3-8 membered aliphatic heterocyclic ring or substituted 3-8 membered carbene ring; said substitution refers to being randomly selected from 1-2 members selected from halogen, cyano, C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, halo(C1-C6Alkyl), hydroxyl (C1-C6Alkyl), C3-C6Cycloalkyl, C3-C6Cycloalkenyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, -ORa、-SO3Ra, -NRaRb, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, -NRaC(O)RaSubstituents; or any CH in the ring2replaced by C=O;
    或者R9'与R10'一起与与之相连的原子形成C3-C8脂碳环、C3-C8碳烯环、3-8元脂杂环、3-8元碳杂烯环、取代的C3-C8脂碳环、取代的C3-C8碳烯环、取代的3-8元脂杂环或取代的3-8元碳杂烯环；所述的取代是指任意地被1-2个选自卤素、氰基、C1-C6烷基、C2-C6烯基、C2-C6炔基、卤代(C1-C6烷基)、羟基(C1-C6烷基)、C3-C6环烷基、C3-C6环烯基、3～6元杂环烷基、3～6元杂环烯基、-ORa、-SO3Ra、-NRaRb、-C(O)Ra、-C(O)ORa、-C(O)NRaRb、-NRaC(O)Ra的取代基所取代；或者所述环中任意的CH2被C＝O所取代；or R9'with R10'together with the atoms it is attached to form C3-C8Aliphatic ring, C3-C8Carbene ring, 3-8 membered aliphatic ring, 3-8 membered carbene ring, substituted C3-C8Aliphatic ring, substituted C3-C8Carbene ring, substituted 3-8 membered aliphatic heterocyclic ring or substituted 3-8 membered carbene ring; said substitution refers to being randomly selected from 1-2 members selected from halogen, cyano, C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, halo(C1-C6Alkyl), hydroxyl (C1-C6Alkyl), C3-C6Cycloalkyl, C3-C6Cycloalkenyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, -ORa、-SO3Ra, -NRaRb, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, -NRaC(O)Rasubstituted by substituents; or any CH in the ring2replaced by C=O;
    或者R11'与R12'一起与与之相连的原子形成C3-C8脂碳环、C3-C8碳烯环、3-8元脂杂环、3-8元碳杂烯环、取代的C3-C8脂碳环、取代的C3-C8碳烯环、取代的3-8元脂杂环或取代的3-8元碳杂烯环；所述的取代是指任意地被1-2个选自卤素、氰基、C1-C6烷基、C2-C6烯基、C2-C6炔基、卤代(C1-C6烷基)、羟基(C1-C6烷基)、C3-C6环烷基、C3-C6环烯基、3～6元杂环烷基、3～6元杂环烯基、-ORa、-SO3Ra、-NRaRb、-C(O)Ra、-C(O)ORa、-C(O)NRaRb、-NRaC(O)Ra的取代基所取代；或者所述环中任意的CH2被C＝O所取代；or R11'with R12'together with the atoms it is attached to form C3-C8Aliphatic ring, C3-C8Carbene ring, 3-8 membered aliphatic ring, 3-8 membered carbene ring, substituted C3-C8Aliphatic ring, substituted C3-C8Carbene ring, substituted 3-8 membered aliphatic heterocyclic ring or substituted 3-8 membered carbene ring; said substitution refers to being randomly selected from 1-2 members selected from halogen, cyano, C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, halo(C1-C6Alkyl), hydroxyl (C1-C6Alkyl), C3-C6Cycloalkyl, C3-C6Cycloalkenyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, -ORa、-SO3Ra, -NRaRb, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, -NRaC(O)Rasubstituted by substituents; or any CH in the ring2replaced by C=O;
    或者R2'、R3'一起与与之相连的原子形成C3-C8脂碳环、C3-C8碳烯环、3-8元脂杂环、3-8元碳杂烯环、取代的C3-C8脂碳环、取代的C3-C8碳烯环、取代的3-8元脂杂环或取代的3-8元碳杂烯环；所述的取代是指任意地被1-2个选自卤素、氰基、C1-C6烷基、C2-C6烯基、C2-C6炔基、卤代(C1-C6烷基)、羟基(C1-C6烷基)、C3-C6环烷基、C3-C6环烯基、3～6元杂环烷基、3～6元杂环烯基、-ORa、-SO3Ra、-NRaRb、-C(O)Ra、-C(O)ORa、-C(O)NRaRb、-NRaC(O)Ra的取代基所取代；或者所述环中任意的CH2被C＝O所取代；or R2', R3'together with the atoms it is attached to form C3-C8Aliphatic ring, C3-C8Carbene ring, 3-8 membered aliphatic ring, 3-8 membered carbene ring, substituted C3-C8Aliphatic ring, substituted C3-C8Carbene ring, substituted 3-8 membered aliphatic heterocyclic ring or substituted 3-8 membered carbene ring; said substitution refers to being randomly selected from 1-2 members selected from halogen, cyano, C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, halo(C1-C6Alkyl), hydroxyl (C1-C6Alkyl), C3-C6Cycloalkyl, C3-C6Cycloalkenyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, -ORa、-SO3Ra, -NRaRb, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, -NRaC(O)Rasubstituted by substituents; or any CH in the ring2replaced by C=O;
    或者R4'、R5'一起与与之相连的原子形成C3-C8脂碳环、C3-C8碳烯环、3-8元脂杂环、3-8元碳杂烯环、取代的C3-C8脂碳环、取代的C3-C8碳烯环、取代的3-8元脂杂环或取代的3-8元碳杂烯环；所述的取代是指任意地被1-2个选自卤素、氰基、C1-C6烷基、C2-C6烯基、C2-C6炔基、卤代(C1-C6烷基)、羟基(C1-C6烷基)、C3-C6环烷基、C3-C6环烯基、3～6元杂环烷基、3～6元杂环烯基、-ORa、-SO3Ra、-NRaRb、-C(O)Ra、-C(O)ORa、-C(O)NRaRb、-NRaC(O)Ra的取代基所取代；或者所述环中任意的CH2被C＝O所取代；or R4', R5'together with the atoms it is attached to form C3-C8Aliphatic ring, C3-C8Carbene ring, 3-8 membered aliphatic ring, 3-8 membered carbene ring, substituted C3-C8Aliphatic ring, substituted C3-C8Carbene ring, substituted 3-8 membered aliphatic heterocyclic ring or substituted 3-8 membered carbene ring; said substitution refers to being randomly selected from 1-2 members selected from halogen, cyano, C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, halo(C1-C6Alkyl), hydroxyl (C1-C6Alkyl), C3-C6Cycloalkyl, C3-C6Cycloalkenyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, -ORa、-SO3Ra, -NRaRb, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, -NRaC(O)Rasubstituted by substituents; or any CH in the ring2replaced by C=O;
    或者R8'、R9'一起与与之相连的原子形成C3-C8脂碳环、C3-C8碳烯环、3-8元脂杂环、3-8元碳杂 烯环、取代的C3-C8脂碳环、取代的C3-C8碳烯环、取代的3-8元脂杂环或取代的3-8元碳杂烯环；所述的取代是指任意地被1-2个选自卤素、氰基、C1-C6烷基、C2-C6烯基、C2-C6炔基、卤代(C1-C6烷基)、羟基(C1-C6烷基)、C3-C6环烷基、C3-C6环烯基、3～6元杂环烷基、3～6元杂环烯基、-ORa、-SO3Ra、-NRaRb、-C(O)Ra、-C(O)ORa、-C(O)NRaRb、-NRaC(O)Ra的取代基所取代；或者所述环中任意的CH2被C＝O所取代；Or R 8' and R 9' together with the atoms connected to it form a C 3 -C 8 aliphatic carbocyclic ring, a C 3 -C 8 carbene ring, a 3-8 membered aliphatic ring, a 3-8 membered carbocyclic烯环、取代的C 3 -C 8脂碳环、取代的C 3 -C 8碳烯环、取代的3-8元脂杂环或取代的3-8元碳杂烯环；所述的取代是指任意地被1-2个选自卤素、氰基、C 1 -C 6烷基、C 2 -C 6烯基、C 2 -C 6炔基、卤代(C 1 -C 6烷基)、羟基(C 1 -C 6烷基)、C 3 -C 6环烷基、C 3 -C 6环烯基、3～6元杂环烷基、3～6元杂环烯基、-OR a 、-SO 3 R a 、-NR a R b 、-C(O)R a 、-C(O)OR a 、-C(O)NR a R b 、-NR a C(O)R a的取代基所取代；或者所述环中任意的CH 2被C＝O所取代；
    或者R10'、R11'一起与与之相连的原子形成C3-C8脂碳环、C3-C8碳烯环、3-8元脂杂环、3-8元碳杂烯环、取代的C3-C8脂碳环、取代的C3-C8碳烯环、取代的3-8元脂杂环或取代的3-8元碳杂烯环；所述的取代是指任意地被1-2个选自卤素、氰基、C1-C6烷基、C2-C6烯基、C2-C6炔基、卤代(C1-C6烷基)、羟基(C1-C6烷基)、C3-C6环烷基、C3-C6环烯基、3～6元杂环烷基、3～6元杂环烯基、-ORa、-SO3Ra、-NRaRb、-C(O)Ra、-C(O)ORa、-C(O)NRaRb、-NRaC(O)Ra的取代基所取代；或者所述环中任意的CH2被C＝O所取代；or R10', R11'together with the atoms it is attached to form C3-C8Aliphatic ring, C3-C8Carbene ring, 3-8 membered aliphatic ring, 3-8 membered carbene ring, substituted C3-C8Aliphatic ring, substituted C3-C8Carbene ring, substituted 3-8 membered aliphatic heterocyclic ring or substituted 3-8 membered carbene ring; said substitution refers to being randomly selected from 1-2 members selected from halogen, cyano, C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, halo(C1-C6Alkyl), hydroxyl (C1-C6Alkyl), C3-C6Cycloalkyl, C3-C6Cycloalkenyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, -ORa、-SO3Ra, -NRaRb, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, -NRaC(O)RaSubstituents; or any CH in the ring2replaced by C=O;
    或者R3'与R4'一起与与之相连的原子形成C3-C8脂碳环、C3-C8碳烯环、3-8元脂杂环、3-8元碳杂烯环、取代的C3-C8脂碳环、取代的C3-C8碳烯环、取代的3-8元脂杂环或取代的3-8元碳杂烯环；所述的取代是指任意地被1-2个选自卤素、氰基、C1-C6烷基、C2-C6烯基、C2-C6炔基、卤代(C1-C6烷基)、羟基(C1-C6烷基)、C3-C6环烷基、C3-C6环烯基、3～6元杂环烷基、3～6元杂环烯基、-ORa、-SO3Ra、-NRaRb、-C(O)Ra、-C(O)ORa、-C(O)NRaRb、-NRaC(O)Ra的取代基所取代；或者所述环中任意的CH2被C＝O所取代；且R9'与R10'一起与与之相连的原子形成C3-C8脂碳环、C3-C8碳烯环、3-8元脂杂环、3-8元碳杂烯环、取代的C3-C8脂碳环、取代的C3-C8碳烯环、取代的3-8元脂杂环或取代的3-8元碳杂烯环；所述的取代是指任意地被1-2个选自卤素、氰基、C1-C6烷基、C2-C6烯基、C2-C6炔基、卤代(C1-C6烷基)、羟基(C1-C6烷基)、C3-C6环烷基、C3-C6环烯基、3～6元杂环烷基、3～6元杂环烯基、-ORa、-SO3Ra、-NRaRb、-C(O)Ra、-C(O)ORa、-C(O)NRaRb、-NRaC(O)Ra的取代基所取代；或者所述环中任意的CH2被C＝O所取代；or R3'with R4'together with the atoms it is attached to form C3-C8Aliphatic ring, C3-C8Carbene ring, 3-8 membered aliphatic ring, 3-8 membered carbene ring, substituted C3-C8Aliphatic ring, substituted C3-C8Carbene ring, substituted 3-8 membered aliphatic heterocyclic ring or substituted 3-8 membered carbene ring; said substitution refers to being randomly selected from 1-2 members selected from halogen, cyano, C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, halo(C1-C6Alkyl), hydroxyl (C1-C6Alkyl), C3-C6Cycloalkyl, C3-C6Cycloalkenyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, -ORa、-SO3Ra, -NRaRb, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, -NRaC(O)RaSubstituents; or any CH in the ring2is replaced by C=O; and R9'with R10'together with the atoms it is attached to form C3-C8Aliphatic ring, C3-C8Carbene ring, 3-8 membered aliphatic ring, 3-8 membered carbene ring, substituted C3-C8Aliphatic ring, substituted C3-C8Carbene ring, substituted 3-8 membered aliphatic heterocyclic ring or substituted 3-8 membered carbene ring; said substitution refers to being randomly selected from 1-2 members selected from halogen, cyano, C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, halo(C1-C6Alkyl), hydroxyl (C1-C6Alkyl), C3-C6Cycloalkyl, C3-C6Cycloalkenyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, -ORa、-SO3Ra, -NRaRb, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, -NRaC(O)RaSubstituents; or any CH in the ring2replaced by C=O;
    条件2：R5为以下式(i)、式(ii)或式(iii)的中的任意一种环状结构：
    Condition 2: R 5 is any ring structure in the following formula (i), formula (ii) or formula (iii):
    其中，式(ii)中，W2为N，W1为NRW1时，RW1不为H；Wherein, in formula (ii), W 2 is N, and when W 1 is NR W1 , R W1 is not H;
    式(iii)中，W2为N，W1为NRW1，RW1为H时，Y不为亚乙基；In formula (iii), W 2 is N, W 1 is NR W1 , and when R W1 is H, Y is not ethylene;
    条件3：X1为CRX1，RX1为C1-C6烷基、被一个或多个卤素取代的C1-C6烷基、PO(C1-C6烷基)2、C2-C6烯基、C2-C6炔基、被一个或多个X1-1取代的3～6元杂环烷基、6-14元芳基、5～14元杂芳基、被一个或多个X1-2取代的5～14元杂芳基、NO2、C3-C6环烷基、C3-C6环烯基、3～6元杂环烷基、3～6元杂环烯基、被一个或多个X1-3取代的3～6元杂环烯基、SF5、C(＝O)X1-4、C(＝O)ORa、-NRaC(O)Ra、NX1-5X1-6或SO2X1-7；或者，RX1与RX3和其相连的原子共同形成C5-C8环烯酮结构；Condition 3: X1for CRX1, RX1for C1-C6Alkyl, C substituted by one or more halogens1-C6Alkyl, PO(C1-C6alkyl)2、C2-C6Alkenyl, C2-C6Alkynyl, by one or more X1-1Substituted 3-6 membered heterocycloalkyl, 6-14-membered aryl, 5-14-membered heteroaryl, replaced by one or more X1-2Substituted 5-14 membered heteroaryl, NO2、C3-C6Cycloalkyl, C3-C6Cycloalkenyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, with one or more X1-3Substituted 3-6 membered heterocycloalkenyl, SF5, C(=O)X1-4, C(=O)ORa, -NRaC(O)Ra、NX1-5x1-6or SO2x1-7; or, RX1with RX3Together with its attached atoms form C5-C8Cycloenone structure;
    或者，X1为NRX1’，RX1’与RX3和其相连的原子共同形成5～8元杂芳环或被一个或多个羟基取代 的5～8元杂芳环；Alternatively, X 1 is NR X1' , and R X1' and R X3 together with the atoms connected to them form a 5- to 8-membered heteroaromatic ring or are substituted by one or more hydroxyl groups 5-8 membered heteroaromatic rings;
    或者，X1为CRX1，其中，X1中的C原子与R1中的芳基或杂芳基中的C原子通过-O-(CH2)n1-*、*-NH-(CH2)n2-、-C≡C-(CH2)n3-C≡C-*或-(CH2)n4-O-(CH2)n5-*相连，其中，*端与X1中的C原子相连；Alternatively, X 1 is CR X1 , wherein the C atom in X 1 is connected to the C atom in the aryl or heteroaryl group in R 1 through -O-(CH 2 ) n1 -*, *-NH-(CH 2 ) n2 -, -C≡C-(CH 2 ) n3 -C≡C-* or -(CH 2 ) n4 -O-(CH 2 ) n5 -*, wherein the * end is connected to the C atom in X 1 connected;
    条件4：R1为被一个或多个R1-1取代的C6～C14的芳基或被一个或多个R1-2取代的5～14元杂芳基；Condition 4: R 1 is a C 6 -C 14 aryl group substituted by one or more R 1-1 or a 5-14 membered heteroaryl group substituted by one or more R 1-2 ;
    当R1为被一个或多个R1-1取代的C6～C14的芳基时，相邻的两个R1-1与其相连的原子一起形成C3-C8脂碳环或被一个或多个R1-3取代的C3-C8脂碳环，其余R1-1独立地为卤素、OH、CN、NO2、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C6环烷基、C3-C6环烯基、3～6元杂环烷基、3～6元杂环烯基、被一个或多个卤素取代的C1-C6烷基、被一个或多个羟基取代的C1-C6烷基、ORa、B(OH)2、O(C＝O)-C1-C10烷基、SO3Ra、NRaRb、CORa、CONRaRb、C(O)ORa、NRaCORa；When R1for one or more R1-1Replaced C6~C14When the aryl group, two adjacent R1-1Together with its attached atoms form C3-C8Aliphatic carbocycle or by one or more R1-3Replaced C3-C8Aliphatic carbocycle, the rest R1-1independently halogen, OH, CN, NO2、C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, C3-C6Cycloalkyl, C3-C6Cycloalkenyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, C substituted by one or more halogens1-C6Alkyl, C substituted by one or more hydroxyl groups1-C6Alkyl, ORa, B(OH)2, O(C=O)-C1-C10Alkyl, SO3Ra、NRaRb、CORa、CONRaRb, C(O)ORa、NRaCORa;
    当R1为被一个或多个R1-2取代的5～14元杂芳基时，相邻的两个R1-2与其相连的原子一起形成C3-C8碳环或被一个或多个R1-4取代的C3-C8碳环，其余R1-2独立地为卤素、OH、CN、NO2、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C6环烷基、C3-C6环烯基、3～6元杂环烷基、3～6元杂环烯基、被一个或多个卤素取代的C1-C6烷基、被一个或多个羟基取代的C1-C6烷基、ORa、B(OH)2、O(C＝O)-C1-C10烷基、SO3Ra、NRaRb、CORa、CONRaRb、C(O)ORa、NRaCORa；When R1for one or more R1-2When a substituted 5- to 14-membered heteroaryl group, two adjacent R1-2Together with its attached atoms form C3-C8Carbocycle or by one or more R1-4Replaced C3-C8carbocycle, rest R1-2independently halogen, OH, CN, NO2、C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, C3-C6Cycloalkyl, C3-C6Cycloalkenyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, C substituted by one or more halogens1-C6Alkyl, C substituted by one or more hydroxyl groups1-C6Alkyl, ORa, B(OH)2, O(C=O)-C1-C10Alkyl, SO3Ra、NRaRb、CORa、CONRaRb, C(O)ORa、NRaCORa;
    R1-3和R1-4独立地为卤素；R 1-3 and R 1-4 are independently halogen;
    其中，所述的3～6元杂环烷基、3～6元杂环烯基、5～14元杂芳基、3～8元杂环烷基、3～6元脂杂环、3～6元碳杂烯环、5～8元杂芳环、3～8元脂杂环、3-8元碳杂烯环、3-8元脂杂环和3-8元碳杂烯环中的杂原子的种类各自独立地选自N、O和S中的一种、两种或三种；所述的3～6元杂环烷基、3～6元杂环烯基、3～8元杂环烷基、3～6元脂杂环、3～6元碳杂烯环、3～8元脂杂环、3-8元碳杂烯环、3-8元脂杂环和3-8元碳杂烯环中的杂原子的个数各自独立地为1个、2个或3个；所述5～14元杂芳基和5～8元杂芳环中杂原子的个数各自独立地为1个、2个、3个或4个。Wherein, the types of heteroatoms in the 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, 5-14-membered heteroaryl, 3-8-membered heterocycloalkyl, 3-6-membered aliphatic heterocycle, 3-6-membered carboalkene ring, 5-8-membered heteroaryl ring, 3-8-membered aliphatic heterocycle, 3-8-membered carbazaene ring, 3-8-membered aliphatic heterocycle and 3-8-membered carbazaene ring are each independently selected from one, two or three of N, O and S; The number of heteroatoms in ~6-membered heterocycloalkyl, 3-6-membered heterocycloalkenyl, 3-8-membered heterocycloalkyl, 3-6-membered aliphatic heterocycle, 3-6-membered carboalkene ring, 3-8-membered aliphatic heterocycle, 3-8-membered carboalkene ring, 3-8-membered aliphatic heterocycle, and 3-8-membered carboalkene ring is independently 1, 2 or 3; the number of heteroatoms in the 5-14-membered heteroaryl and 5-8-membered heteroaryl ring is each independently 1 , 2, 3 or 4.
  2. 如权利要求1所述的如式I-0所示的杂环类化合物、其药学上可接受的盐、其立体异构体或它们的溶剂合物，其特征在于，The heterocyclic compound represented by formula I-0, its pharmaceutically acceptable salt, its stereoisomer or their solvate according to claim 1, characterized in that,
    环K为芳环或杂芳环；Ring K is an aromatic ring or a heteroaryl ring;
    X1为N、NRX1’或CRX1，X 1 is N, NR X1' or CR X1 ,
    RX1为CN、卤素、C1-C6烷基、被一个或多个卤素取代的C1-C6烷基、PO(C1-C6烷基)2、C3-C6环烷基、C2-C6烯基、C2-C6炔基、3～6元杂环烷基、被一个或多个X1-1取代的3～6元杂环烷基、5～14元杂芳基、被一个或多个X1-2取代的5～14元杂芳基、NO2、3～6元杂环烯基、被一个或多个X1-3取代的3～6元杂环烯基、SF5、C(＝O)X1-4、NX1-5X1-6或SO2X1-7；RX1is CN, halogen, C1-C6Alkyl, C substituted by one or more halogens1-C6Alkyl, PO(C1-C6alkyl)2、C3-C6Cycloalkyl, C2-C6Alkenyl, C2-C6Alkynyl, 3-6 membered heterocycloalkyl, replaced by one or more X1-1Substituted 3-6 membered heterocycloalkyl, 5-14 membered heteroaryl, replaced by one or more X1-2Substituted 5-14 membered heteroaryl, NO2, 3-6 membered heterocycloalkenyl, replaced by one or more X1-3Substituted 3-6 membered heterocycloalkenyl, SF5, C(=O)X1-4、NX1-5x1-6or SO2x1-7;
    X1-1和X1-3各自独立地为(C＝O)-C1-C6烷基；X1-2独立地为C1-C6烷基；X1-4独立地为H、C3-C8环烷基、3～8元杂环烷基、C1-C6烷基、或被一个或多个卤素取代的C1-C6烷基；X1-5和X1-6各自独立地为H、C1-C6烷基、SO2-C1-C6烷基或(C＝O)-C1-C6烷基；X1-7为OH或C1-C6烷基；X 1-1 and X 1-3 are each independently (C=O)-C 1 -C 6 alkyl; X 1-2 are independently C 1 -C 6 alkyl; X 1-4 are independently H , C 3 -C 8 cycloalkyl, 3-8 membered heterocycloalkyl, C 1 -C 6 alkyl, or C 1 -C 6 alkyl substituted by one or more halogens; X 1-5 and X 1-6 are each independently H, C 1 -C 6 alkyl, SO 2 -C 1 -C 6 alkyl or (C=O)-C 1 -C 6 alkyl; X 1-7 is OH or C 1 -C 6 alkyl;
    X2为N或CRX2，RX2为CN；X 2 is N or CR X2 , R X2 is CN;
    X3为N或CRX3，RX3为H或C1-C6烷基；X 3 is N or CR X3 , R X3 is H or C 1 -C 6 alkyl;
    或者RX1与RX3和其相连的原子共同形成C5-C8环烯酮结构；Or R X1 and R X3 and the atoms connected to them together form a C 5 -C 8 cycloalkene structure;
    或者RX1’与RX3和其相连的原子共同形成5～8元杂芳环或被一个或多个羟基取代的5～8元杂芳环； Or R X1' and R X3 and the atoms connected to them together form a 5-8 membered heteroaryl ring or a 5-8 membered heteroaryl ring substituted by one or more hydroxyl groups;
    R1为C6～C14的芳基、被一个或多个R1-1取代的C6～C14的芳基、5～14元杂芳基或被一个或多个R1-2取代的5～14元杂芳基；R 1 is a C 6 -C 14 aryl group, a C 6 -C 14 aryl group substituted by one or more R 1-1 , a 5-14 membered heteroaryl group or a 5-14 membered heteroaryl group substituted by one or more R 1-2 ;
    R1-1和R1-2各自独立地为卤素、OH、NH2、CN、C1-C6烷基、(C＝O)C1-C6烷基、C2-C6炔基、被一个或多个卤素取代的C1-C6烷基、B(OH)2或O(C＝O)-C1-C10烷基，R 1-1 and R 1-2 are each independently halogen, OH, NH 2 , CN, C 1 -C 6 alkyl, (C=O)C 1 -C 6 alkyl, C 2 -C 6 alkynyl, C 1 -C 6 alkyl substituted by one or more halogens, B(OH) 2 or O(C=O ) -C 1 -C 10 alkyl,
    或者，相邻的两个R1-1与其相连的原子一起形成C3-C8脂碳环或被一个或多个R1-3取代的C3-C8脂碳环，其余R1-1独立地为卤素、OH、NH2、CN、C1-C6烷基、(C＝O)-C1-C6烷基、C2-C6炔基、被一个或多个卤素取代的C1-C6烷基、B(OH)2或O(C＝O)-C1-C10烷基；Alternatively, two adjacent R 1-1 and their connected atoms together form a C 3 -C 8 aliphatic carbon ring or a C 3 -C 8 aliphatic carbon ring substituted by one or more R 1-3 , and the remaining R 1-1 are independently halogen, OH, NH 2 , CN, C 1 -C 6 alkyl, (C=O)-C 1 -C 6 alkyl, C 2 -C 6 alkynyl, C 1 -C 6 alkyl substituted by one or more halogens, B(OH) 2 or O(C=O)-C 1 -C 10 alkyl;
    或者，相邻的两个R1-2与其相连的原子一起形成C3-C8脂碳环或被一个或多个R1-4取代的C3-C8脂碳环，其余R1-2独立地为卤素、OH、NH2、CN、C1-C6烷基、(C＝O)-C1-C6烷基、C2-C6炔基、被一个或多个卤素取代的C1-C6烷基、B(OH)2或O(C＝O)-C1-C10烷基；Alternatively, two adjacent R 1-2 and their connected atoms together form a C 3 -C 8 aliphatic carbon ring or a C 3 -C 8 aliphatic carbon ring substituted by one or more R 1-4 , and the remaining R 1-2 are independently halogen, OH, NH 2 , CN, C 1 -C 6 alkyl, (C=O)-C 1 -C 6 alkyl, C 2 -C 6 alkynyl, C 1 -C 6 alkyl substituted by one or more halogens, B(OH) 2 or O(C=O)-C 1 -C 10 alkyl;
    R1-3和R1-4独立地为卤素；R 1-3 and R 1-4 are independently halogen;
    或者X1为CRX1，其中，X1中的C原子与R1中的芳基或杂芳基中的C原子通过-O-(CH2)n1-*、*-NH-(CH2)n2-、-C≡C-(CH2)n3-C≡C-*或-(CH2)n4-O-(CH2)n5-*相连，其中，*端与X1中的C原子相连；Or X 1 is CR X1 , wherein, the C atom in X 1 is connected to the C atom in the aryl or heteroaryl group in R 1 through -O-(CH 2 ) n1 -*, *-NH-(CH 2 ) n2 -, -C≡C-(CH 2 ) n3 -C≡C-* or -(CH 2 ) n4 -O-(CH 2 ) n5 -*, wherein the * end is connected to the C atom in X 1 ;
    n1、n2、n3、n4和n5各自独立地为1、2、3、4、5或6；n1, n2, n3, n4 and n5 are each independently 1, 2, 3, 4, 5 or 6;
    R2为卤素、C1-C6烷基或C1-C6烷氧基；R 2 is halogen, C 1 -C 6 alkyl or C 1 -C 6 alkoxy;
    L2表示-O-(C1-C6亚烷基)；L 2 represents -O-(C 1 -C 6 alkylene);
    R3为以下的环状结构：
    R 3 is the following ring structure:
    其中，R1'、R2'、R3'、R4'、R5'、R6'、R7'、R8'、R9'、R10'、R11'、R12'各自独立地表示氢或卤素；Wherein, R 1' , R 2' , R 3' , R 4' , R 5' , R 6' , R 7' , R 8' , R 9' , R 10' , R 11' , R 12' each independently represent hydrogen or halogen;
    或者R3'与R4'一起与与之相连的原子形成C3-C8脂碳环、取代的C3-C8脂碳环或3-8元脂杂环，所述的取代是指任意地被1-2个卤素取代；Or R 3' and R 4' together form a C 3 -C 8 aliphatic carbocyclic ring, a substituted C 3 -C 8 aliphatic carbocyclic ring or a 3-8 membered aliphatic heterocyclic ring, and the substitution refers to being optionally substituted by 1-2 halogens;
    或者R9'与R10'一起与与之相连的原子形成C3-C8脂碳环、取代的C3-C8脂碳环或3-8元脂杂环，所述的取代是指任意地被1-2个卤素取代；Or R 9' and R 10' together form a C 3 -C 8 aliphatic carbocyclic ring, a substituted C 3 -C 8 aliphatic carbocyclic ring or a 3-8 membered aliphatic heterocyclic ring, and the substitution refers to being optionally substituted by 1-2 halogens;
    或者R3'与R4'一起与与之相连的原子形成C3-C8脂碳环、取代的C3-C8脂碳环或3-8元脂杂环，所述的取代是指任意地被1-2个卤素取代；且R9'与R10'一起与与之相连的原子形成C3-C8脂碳环、取代的C3-C8脂碳环或3-8元脂杂环，所述的取代是指任意地被1-2个卤素取代；Or R 3' and R 4' together form a C 3 -C 8 aliphatic carbocyclic ring, a substituted C 3 -C 8 aliphatic carbocyclic ring or a 3-8 membered aliphatic heterocyclic ring. Replaced by 1-2 halogens ;
    或者，R4'、R5'一起与与之相连的原子形成C3-C8脂碳环、取代的C3-C8脂碳环或3-8元脂杂环，所述的取代是指任意地被1-2个卤素取代；Alternatively, R 4' and R 5' together with the atoms connected to them form a C 3 -C 8 aliphatic carbocycle, a substituted C 3 -C 8 aliphatic carbocycle or a 3-8 membered aliphatic heterocycle, and the substitution refers to being optionally substituted by 1-2 halogens;
    或者，R8'、R9'一起与与之相连的原子形成C3-C8脂碳环、取代的C3-C8脂碳环或3-8元脂杂环，所述的取代是指任意地被1-2个卤素取代；Alternatively, R 8' and R 9' together with the atoms connected to them form a C 3 -C 8 aliphatic carbocycle, a substituted C 3 -C 8 aliphatic carbocycle or a 3-8 membered aliphatic heterocycle, and the substitution refers to being optionally substituted by 1-2 halogens;
    或者，R2'、R3'一起与与之相连的原子形成C3-C8脂碳环、取代的C3-C8脂碳环或3-8元脂杂环， 所述的取代是指任意地被1-2个卤素取代；Or, R 2' and R 3' together form a C 3 -C 8 aliphatic carbocyclic ring, a substituted C 3 -C 8 aliphatic carbocyclic ring or a 3-8 membered aliphatic heterocyclic ring with the atoms connected thereto, The substitution refers to being randomly substituted by 1-2 halogens;
    或者R10'、R11'一起与与之相连的原子形成C3-C8脂碳环、取代的C3-C8脂碳环或3-8元脂杂环，所述的取代是指任意地被1-2个卤素取代；Or R 10' and R 11' together with the atoms connected to them form a C 3 -C 8 aliphatic carbocyclic ring, a substituted C 3 -C 8 aliphatic carbocyclic ring or a 3-8 membered aliphatic heterocyclic ring, and the substitution refers to being optionally substituted by 1-2 halogens;
    R4为L1-R5，L1表示不存在或NRa，R 4 is L 1 -R 5 , L 1 means absent or NR a ,
    R5为以下式(i)、式(ii)或式(iii)的中的任意一种环状结构：
     R is any ring structure in the following formula (i), formula (ii) or formula (iii):
    其中，W1表示CRW1RW2或NRW1；Among them, W 1 represents CR W1 R W2 or NR W1 ;
    其中，RW1、RW2各自独立地表示氢、C1-C6烷基、3～6元杂环烷基、NRaRb、或(C＝O)-O-C1-C6亚烷基O-(C＝O)-C1-C10烷基；或者RW1、RW2一起与与之相连的原子共同形成3～8元脂杂环；Wherein, R W1 and R W2 each independently represent hydrogen, C 1 -C 6 alkyl, 3-6 membered heterocycloalkyl, NR a R b , or (C=O)-OC 1 -C 6 alkylene O-(C=O)-C 1 -C 10 alkyl; or R W1 , R W2 together form a 3-8 membered aliphatic heterocycle together with the atoms connected to it;
    Ra和Rb各自独立地表示氢或C1-C6烷基；R a and R b each independently represent hydrogen or C 1 -C 6 alkyl;
    其中，W2表示CH或N；Wherein, W 2 represents CH or N;
    其中，Y为亚甲基、亚乙基、C3亚烷基、C2-C3亚烯基、或 Wherein, Y is methylene, ethylene, C 3 alkylene, C 2 -C 3 alkenylene, or
    Rc和Rd与与其相连的原子共同形成C3-C6脂碳环或被一个或多个卤素取代的C3-C6脂碳环；或者Rd和Rd’和与之相连的原子一起形成C3-C6脂碳环或被一个或多个卤素取代的C3-C6脂碳环；R c and R d together with the atoms connected to them form a C 3 -C 6 aliphatic carbocycle or a C 3 -C 6 aliphatic carbocycle substituted by one or more halogens; or R d and R d' together with the atoms connected to them form a C 3 -C 6 aliphatic carbocycle or a C 3 -C 6 aliphatic carbocycle substituted by one or more halogens;
    其中，R1”、R2”、R3”、R4”、R5”、R6”、R7”、R8”各自独立地表示氢或C1-C6烷基；Wherein, R 1" , R 2" , R 3" , R 4" , R 5" , R 6" , R 7" , R 8" each independently represent hydrogen or C 1 -C 6 alkyl;
    或者，R2”、R3”一起与与之相连的原子形成C3-C8脂碳环、3～8元脂杂环或取代的3-8元脂杂环，所述的取代是指任意地被C1-C6烷基取代；或者环中任意的CH2被C＝O所取代；Alternatively, R 2" and R 3" together with the atoms connected to them form a C 3 -C 8 aliphatic carbocyclic ring, a 3-8 membered aliphatic heterocyclic ring or a substituted 3-8 membered aliphatic heterocyclic ring. The substitution refers to any substitution by a C 1 -C 6 alkyl group; or any CH 2 in the ring is substituted by C=O;
    或者，R3”与R4”一起与与之相连的原子形成C3-C8脂碳环、3～8元脂杂环或取代的3-8元脂杂环，所述的取代是指任意地被C1-C6烷基取代；或者环中任意的CH2被C＝O所取代；Alternatively, R 3" and R 4" together form a C 3 -C 8 aliphatic carbocyclic ring, a 3-8 membered aliphatic heterocyclic ring or a substituted 3-8 membered aliphatic heterocyclic ring, and the substitution refers to any substitution by a C 1 -C 6 alkyl group; or any CH 2 in the ring is substituted by C=O;
    或者，R4”、R5”一起与与之相连的原子形成C3-C8脂碳环、3～8元脂杂环或取代的3-8元脂杂环，所述的取代是指任意地被C1-C6烷基取代；或者环中任意的CH2被C＝O所取代；Alternatively, R 4" and R 5" together with the atoms connected to them form a C 3 -C 8 aliphatic carbocyclic ring, a 3-8 membered aliphatic heterocyclic ring or a substituted 3-8 membered aliphatic heterocyclic ring, and the substitution refers to being optionally substituted by a C 1 -C 6 alkyl group; or any CH 2 in the ring is substituted by C=O;
    或者，R5”与R6”一起与与之相连的原子形成C3-C8脂碳环、3～8元脂杂环或取代的3-8元脂杂环，所述的取代是指任意地被C1-C6烷基取代；或者环中任意的CH2被C＝O所取代；Alternatively, R 5" and R 6" together form a C 3 -C 8 aliphatic carbocyclic ring, a 3-8 membered aliphatic heterocyclic ring or a substituted 3-8 membered aliphatic heterocyclic ring with the atoms connected to it, and the substitution refers to being optionally substituted by a C 1 -C 6 alkyl group; or any CH 2 in the ring is substituted by C=O;
    或者，R6”、R7”一起与与之相连的原子形成C3-C8脂碳环、3～8元脂杂环或取代的3-8元脂杂环，所述的取代是指任意地被C1-C6烷基取代；或者环中任意的CH2被C＝O所取代；Or, R 6" and R 7" together with the atoms connected to them form a C 3 -C 8 aliphatic carbocyclic ring, a 3-8 membered aliphatic heterocyclic ring or a substituted 3-8 membered aliphatic heterocyclic ring, and the substitution refers to being optionally substituted by a C 1 -C 6 alkyl group; or any CH 2 in the ring is substituted by C=O;
    或者R3”与R4”一起与与之相连的原子形成C3-C8脂碳环、3～8元脂杂环或取代的3-8元脂杂环，所述的取代是指任意地被C1-C6烷基取代；或者环中任意的CH2被C＝O所取代；且R5”与R6”一起与与之相连的原子形成C3-C8脂碳环、3～8元脂杂环或取代的3-8元脂杂环，所述的取代是指任意地被C1-C6烷基取代；或者环中任意的CH2被C＝O所取代；Or R 3" and R 4" together with the atoms connected to it form a C 3 -C 8 aliphatic carbocyclic ring, a 3-8 membered aliphatic heterocyclic ring or a substituted 3-8 membered aliphatic heterocyclic ring. Aliphatic heterocycle, the substitution refers to any substitution by C 1 -C 6 alkyl ; or any CH 2 in the ring is replaced by C=O;
    其满足下述至少一个条件： It meets at least one of the following conditions:
    条件1：R3中，R3'与R4'一起与与之相连的原子形成C3-C8脂碳环、取代的C3-C8脂碳环或3-8元脂杂环，所述的取代是指任意地被1-2个卤素取代；Condition 1: In R 3 , R 3' and R 4' together form a C 3 -C 8 aliphatic carbocyclic ring, a substituted C 3 -C 8 aliphatic carbocyclic ring or a 3-8 membered aliphatic heterocyclic ring, and the substitution refers to being optionally substituted by 1-2 halogens;
    或者R9'与R10'一起与与之相连的原子形成C3-C8脂碳环、取代的C3-C8脂碳环或3-8元脂杂环，所述的取代是指任意地被1-2个卤素取代；Or R 9' and R 10' together form a C 3 -C 8 aliphatic carbocyclic ring, a substituted C 3 -C 8 aliphatic carbocyclic ring or a 3-8 membered aliphatic heterocyclic ring, and the substitution refers to being optionally substituted by 1-2 halogens;
    或者R3'与R4'一起与与之相连的原子形成C3-C8脂碳环、取代的C3-C8脂碳环或3-8元脂杂环，所述的取代是指任意地被1-2个卤素取代；且R9'与R10'一起与与之相连的原子形成C3-C8脂碳环、取代的C3-C8脂碳环或3-8元脂杂环，所述的取代是指任意地被1-2个卤素取代；Or R 3' and R 4' together form a C 3 -C 8 aliphatic carbocyclic ring, a substituted C 3 -C 8 aliphatic carbocyclic ring or a 3-8 membered aliphatic heterocyclic ring, the substitution refers to being optionally substituted by 1-2 halogens ; Replaced by 1-2 halogens;
    或者，R4'、R5'一起与与之相连的原子形成C3-C8脂碳环、取代的C3-C8脂碳环或3-8元脂杂环，所述的取代是指任意地被1-2个卤素取代；Alternatively, R 4' and R 5' together with the atoms connected to them form a C 3 -C 8 aliphatic carbocycle, a substituted C 3 -C 8 aliphatic carbocycle or a 3-8 membered aliphatic heterocycle, and the substitution refers to being optionally substituted by 1-2 halogens;
    或者，R2'、R3'一起与与之相连的原子形成C3-C8脂碳环、取代的C3-C8脂碳环或3-8元脂杂环，所述的取代是指任意地被1-2个卤素取代；Alternatively, R 2' and R 3' together with the atoms connected to them form a C 3 -C 8 aliphatic carbocycle, a substituted C 3 -C 8 aliphatic carbocycle or a 3-8 membered aliphatic heterocycle, and the substitution refers to being optionally substituted by 1-2 halogens;
    或者R10'、R11'一起与与之相连的原子形成C3-C8脂碳环、取代的C3-C8脂碳环或3-8元脂杂环，所述的取代是指任意地被1-2个卤素取代；Or R 10' and R 11' together with the atoms connected to them form a C 3 -C 8 aliphatic carbocyclic ring, a substituted C 3 -C 8 aliphatic carbocyclic ring or a 3-8 membered aliphatic heterocyclic ring, and the substitution refers to being optionally substituted by 1-2 halogens;
    条件2：R5为以下式(i)、式(ii)或式(iii)的中的任意一种环状结构：
    Condition 2: R 5 is any ring structure in the following formula (i), formula (ii) or formula (iii):
    其中，式(ii)中，W2为N，W1为NRW1时，RW1不为H；Wherein, in formula (ii), W 2 is N, and when W 1 is NR W1 , R W1 is not H;
    式(iii)中，W2为N，W1为NRW1，RW1为H时，Y不为亚乙基；In formula (iii), W 2 is N, W 1 is NR W1 , and when R W1 is H, Y is not ethylene;
    条件3：X1为CRX1，RX1为被一个或多个卤素取代的C1-C6烷基、PO(C1-C6烷基)2、C2-C6烯基、C2-C6炔基、NO2、C3-C6环烷基、3～6元杂环烷基、3～6元杂环烯基、被一个或多个X1-1取代的3～6元杂环烷基、被一个或多个X1-2取代的5～14元杂芳基、被一个或多个X1-3取代的3～6元杂环烯基、SF5、C(＝O)X1-4、NX1-5X1-6或SO2X1-7；或者，RX1与RX3和其相连的原子共同形成C5-C8环烯酮结构；Condition 3: X1for CRX1, RX1is C substituted by one or more halogens1-C6Alkyl, PO(C1-C6alkyl)2、C2-C6Alkenyl, C2-C6Alkynyl, NO2、C3-C6Cycloalkyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, with one or more X1-1Substituted 3-6 membered heterocycloalkyl, replaced by one or more X1-2Substituted 5- to 14-membered heteroaryl, replaced by one or more X1-3Substituted 3-6 membered heterocycloalkenyl, SF5, C(=O)X1-4、NX1-5x1-6or SO2x1-7; or, RX1with RX3Together with its attached atoms form C5-C8Cycloenone structure;
    或者，X1为NRX1’，RX1’与RX3和其相连的原子共同形成5～8元杂芳环或被一个或多个羟基取代的5～8元杂芳环；Alternatively, X 1 is NR X1' , and R X1' and R X3 together with the atoms connected to them form a 5-8 membered heteroaryl ring or a 5-8 membered heteroaryl ring substituted by one or more hydroxyl groups;
    或者，X1为CRX1，其中，X1中的C原子与R1中的芳基或杂芳基中的C原子通过-O-(CH2)n1-*、*-NH-(CH2)n2-、-C≡C-(CH2)n3-C≡C-*或-(CH2)n4-O-(CH2)n5-*相连，其中，*端与X1中的C原子相连；Alternatively, X 1 is CR X1 , wherein the C atom in X 1 is connected to the C atom in the aryl or heteroaryl group in R 1 through -O-(CH 2 ) n1 -*, *-NH-(CH 2 ) n2 -, -C≡C-(CH 2 ) n3 -C≡C-* or -(CH 2 ) n4 -O-(CH 2 ) n5 -*, wherein the * end is connected to the C atom in X 1 connected;
    条件4：R1为被一个或多个R1-1取代的C6～C14的芳基或被一个或多个R1-2取代的5～14元杂芳基；Condition 4: R 1 is a C 6 -C 14 aryl group substituted by one or more R 1-1 or a 5-14 membered heteroaryl group substituted by one or more R 1-2 ;
    当R1为被一个或多个R1-1取代的C6～C14的芳基时，相邻的两个R1-1与其相连的原子一起形成C3-C8脂碳环或被一个或多个R1-3取代的C3-C8脂碳环，其余R1-1独立地为卤素、OH、NH2、CN、C1-C6烷基、(C＝O)-C1-C6烷基、C2-C6炔基、被一个或多个卤素取代的C1-C6烷基、B(OH)2或O(C＝O)-C1-C10烷基；When R 1 is a C 6 -C 14 aryl group substituted by one or more R 1-1 , two adjacent R 1-1 and the atoms connected to them together form a C 3 -C 8 aliphatic carbon ring or a C 3 -C 8 aliphatic carbon ring substituted by one or more R 1-3 , and the remaining R 1-1 are independently halogen, OH, NH 2 , CN, C 1 -C 6 alkyl, (C=O)-C 1 -C 6 alkyl , C 2 -C 6 alkynyl, C 1 -C 6 alkyl substituted by one or more halogens, B(OH) 2 or O(C=O)-C 1 -C 10 alkyl;
    当R1为被一个或多个R1-2取代的5～14元杂芳基时，相邻的两个R1-2与其相连的原子一起形成C3-C8脂碳环或被一个或多个R1-4取代的C3-C8脂碳环，其余R1-2独立地为卤素、OH、NH2、CN、C1- C6烷基、(C＝O)-C1-C6烷基、C2-C6炔基、被一个或多个卤素取代的C1-C6烷基、B(OH)2或O(C＝O)-C1-C10烷基；When R 1 is a 5- to 14-membered heteroaryl group substituted by one or more R 1-2 , two adjacent R 1-2 and the atoms connected to it together form a C 3 -C 8 aliphatic carbon ring or a C 3 -C 8 aliphatic carbon ring substituted by one or more R 1-4 , and the remaining R 1-2 are independently halogen, OH, NH 2 , CN, C 1 - C 6 alkyl, (C=O)-C 1 -C 6 alkyl, C 2 -C 6 alkynyl, C 1 -C 6 alkyl substituted by one or more halogens, B(OH) 2 or O(C=O)-C 1 -C 10 alkyl;
    R1-3和R1-4独立地为卤素。R 1-3 and R 1-4 are independently halogen.
  3. 如权利要求1或2所述的如式I-0所示的杂环类化合物、其药学上可接受的盐、其立体异构体或它们的溶剂合物，其特征在于，其满足以下条件的一种或多种：The heterocyclic compound represented by formula I-0, its pharmaceutically acceptable salt, its stereoisomer or their solvate according to claim 1 or 2, is characterized in that it satisfies one or more of the following conditions:
    (1)当X1为CRX1时，X3为CRX3，RX3为H；RX1为CN、卤素、被一个或多个卤素取代的C1-C6烷基、PO(C1-C6烷基)2、C3-C6环烷基、C2-C6烯基、C2-C6炔基、3～6元杂环烷基、被一个或多个X1- 1取代的3～6元杂环烷基、被一个或多个X1-2取代的5～14元杂芳基、NO2、3～6元杂环烯基、被一个或多个X1-3取代的3～6元杂环烯基、C(＝O)X1-4、NX1-5X1-6或SO2X1-7；(1) When X1for CRX1when X3for CRX3, RX3for H; RX1is CN, halogen, C substituted by one or more halogens1-C6Alkyl, PO(C1-C6alkyl)2、C3-C6Cycloalkyl, C2-C6Alkenyl, C2-C6Alkynyl, 3-6 membered heterocycloalkyl, replaced by one or more X1- 1Substituted 3-6 membered heterocycloalkyl, replaced by one or more X1-2Substituted 5-14 membered heteroaryl, NO2, 3-6 membered heterocycloalkenyl, replaced by one or more X1-3Substituted 3-6 membered heterocycloalkenyl, C(=O)X1-4、NX1-5x1-6or SO2x1-7;
    或者，当X1为NRX1’时，X3为CRX3，RX1’与RX3和其相连的原子共同形成5～8元杂芳环；Or, when X 1 is NR X1' , X 3 is CR X3 , and R X1' , R X3 and the atoms connected to them together form a 5- to 8-membered heteroaromatic ring;
    或者，当X1为N时，X3为CRX3，RX3为H；Or, when X 1 is N, X 3 is CR X3 , and R X3 is H;
    (2)X1-4独立地为C1-C6烷基；(2) X 1-4 is independently C 1 -C 6 alkyl;
    (3)X1-7为C1-C6烷基；(3) X 1-7 is C 1 -C 6 alkyl;
    (4)R1为被一个或多个R1-1取代的C6～C14的芳基或被一个或多个R1-2取代的5～14元杂芳基；R1-1和R1-2各自独立地为卤素、OH、NH2、C1-C6烷基、(C＝O)-C1-C6烷基、C2-C6炔基、被一个或多个卤素取代的C1-C6烷基或B(OH)2；或者，相邻的两个R1-1与其相连的原子一起形成C3-C8脂碳环，其余R1-1独立地为卤素、OH、NH2、C1-C6烷基、(C＝O)-C1-C6烷基、C2-C6炔基、被一个或多个卤素取代的C1-C6烷基或B(OH)2；(4) R1for one or more R1-1Replaced C6~C14The aryl group or by one or more R1-2Substituted 5-14 membered heteroaryl; R1-1and R1-2each independently halogen, OH, NH2、C1-C6Alkyl, (C=O)-C1-C6Alkyl, C2-C6Alkynyl, C substituted by one or more halogen1-C6Alkyl or B(OH)2; or, adjacent two R1-1Together with its attached atoms form C3-C8Aliphatic carbocycle, the rest R1-1independently halogen, OH, NH2、C1-C6Alkyl, (C=O)-C1-C6Alkyl, C2-C6Alkynyl, C substituted by one or more halogen1-C6Alkyl or B(OH)2;
    或者，X1中的C原子与R1中的芳基或杂芳基中的C原子通过-O-(CH2)n1-*或-(CH2)n4-O-(CH2)n5-*相连，其中，*端与X1中的C原子相连；n1、n4和n5各自独立地为1、2、3、4、5或6；Alternatively, the C atom in X1 is connected to the C atom in the aryl or heteroaryl group in R1 through -O-( CH2 ) n1- * or -( CH2 ) n4 -O-( CH2 ) n5- *, wherein the * end is connected to the C atom in X1 ; n1, n4 and n5 are each independently 1, 2, 3, 4, 5 or 6;
    (5)R2为卤素；(5) R 2 is halogen;
    (6)R3为 (6) R 3 is
    其中X为卤素，环A、环B和环C与母体结构共用一个碳原子，环D和环E与母体结构共用两个原子和一根键；环A、环B和环C与母体结构共用一个碳原子，环D和环E与母体结构共用两个原子和一根键；环A、环B、环C、环D和环E各自独立地为3～8元脂杂环、C3-C8脂碳环或被一个或多个卤素取代的C3-C8脂碳环；Where X is halogen, ring A, ring B and ring C share one carbon atom with the parent structure, ring D and ring E share two atoms and one bond with the parent structure; ring A, ring B and ring C share one carbon atom with the parent structure, ring D and ring E share two atoms and one bond with the parent structure; ring A, ring B, ring C, ring D and ring E are each independently 3-8 membered aliphatic heterocyclic rings, C 3 -C 8 aliphatic carbocyclic rings, or C 3 -C substituted by one or more halogens 8 aliphatic carbon rings;
    较佳地，环A为3～8元脂杂环、C3-C8脂碳环或被1个或2个卤素取代的C3-C8脂碳环；环B和环C各自独立地为3～8元脂杂环；环D为3～8元脂杂环或C3-C8脂碳环；环E为C3-C8脂碳环；Preferably, ring A is a 3-8 membered aliphatic heterocycle, a C 3 -C 8 aliphatic carbocycle, or a C 3 -C 8 aliphatic carbocycle substituted by 1 or 2 halogens; ring B and ring C are each independently a 3-8 membered aliphatic heterocycle; ring D is a 3-8 membered aliphatic heterocycle or a C 3 -C 8 aliphatic carbocycle; ring E is a C 3 -C 8 aliphatic carbocycle;
    (7)R4为式(i)、式(ii)或式(iii)：
    (7) R 4 is formula (i), formula (ii) or formula (iii):
    其中，式(i)中，R1”、R2”、R7”和R8”各自独立地为氢；R3”与R4”一起与与之相连的原子形成C3-C8脂碳环、3-8元脂杂环或被一个或多个Ra取代的3～8元脂杂环；或者所述环中任意的CH2被C＝O所取代；Wherein, in formula (i), R 1" , R 2" , R 7" and R 8" are each independently hydrogen; R 3" and R 4" together form a C 3 -C 8 aliphatic carbocyclic ring, a 3-8 membered aliphatic heterocyclic ring, or a 3-8 membered aliphatic heterocyclic ring substituted by one or more R a ; or any CH 2 in the ring is substituted by C=O;
    或者，R5”与R6”一起与与之相连的原子形成C3-C8脂碳环、3-8元脂杂环或被一个或多个Ra取代的3～8元脂杂环；或者所述环中任意的CH2被C＝O所取代；Alternatively, R 5" and R 6" together form a C 3 -C 8 aliphatic carbocyclic ring, a 3-8 membered aliphatic heterocyclic ring or a 3-8 membered aliphatic heterocyclic ring substituted by one or more R a ; or any CH 2 in the ring is substituted by C=O;
    或者，R3”与R4”一起与与之相连的原子形成C3-C8脂碳环、3-8元脂杂环或被一个或多个Ra取代的3～8元脂杂环；或者所述环中任意的CH2被C＝O所取代；且R5”与R6”一起与与之相连的原子形成C3-C8脂碳环、3-8元脂杂环或被一个或多个Ra取代的3～8元脂杂环；或者所述环中任意的CH2被C＝O所取代；Ra独立地表示氢或C1-C6烷基；Or, R 3" and R 4" together form a C 3 -C 8 aliphatic carbocyclic ring, a 3-8 membered aliphatic heterocyclic ring, or a 3-8 membered aliphatic heterocyclic ring substituted by one or more R a ; or any CH 2 in the ring is substituted by C=O; and R 5" and R 6" together form a C 3 -C 8 aliphatic carbocyclic ring, a 3-8 membered aliphatic heterocyclic ring, or a 3-8 membered aliphatic heterocyclic ring substituted by one or more R a ; Or any CH 2 in the ring is replaced by C=O; R a independently represents hydrogen or C 1 -C 6 alkyl;
    其中，式(ii)中，W1表示CRW1RW2或NRW1；W2表示N；当W1为CRW1RW2时，RW1、RW2各自独立地表示H、3～8元杂环烷基或者RW1、RW2一起与与之相连的原子共同形成3～8元脂杂环；Wherein, in formula (ii), W 1 represents CR W1 R W2 or NR W1 ; W 2 represents N; when W 1 is CR W1 R W2 , R W1 and R W2 each independently represent H, a 3-8 membered heterocycloalkyl group or R W1 and R W2 form a 3-8 membered aliphatic heterocyclic ring together with the atoms connected to it;
    当W1为NRW1时，RW1为H，R1”、R2”、R3”、R4”、R7”和R8”各自独立地为氢或C1-C6烷基；When W 1 is NR W1 , R W1 is H, and R 1" , R 2" , R 3" , R 4" , R 7" and R 8" are each independently hydrogen or C 1 -C 6 alkyl;
    或者，R2”、R3”一起与与之相连的原子形成C3-C8脂碳环、3-8元脂杂环或被一个或多个Ra取代的3～8元脂杂环；或者所述环中任意的CH2被C＝O所取代；Alternatively, R 2" and R 3" together with the atoms connected to them form a C 3 -C 8 aliphatic carbocyclic ring, a 3-8 membered aliphatic heterocyclic ring or a 3-8 membered aliphatic heterocyclic ring substituted by one or more R a ; or any CH 2 in the ring is substituted by C=O;
    或者R6”、R7”一起与与之相连的原子形成C3-C8脂碳环、3-8元脂杂环或被一个或多个Ra取代的3～8元脂杂环；或者所述环中任意的CH2被C＝O所取代；Or R 6" and R 7" together with the atoms connected to them form a C 3 -C 8 aliphatic carbocyclic ring, a 3-8 membered aliphatic heterocyclic ring or a 3-8 membered aliphatic heterocyclic ring substituted by one or more R a ; or any CH 2 in the ring is substituted by C=O;
    或者R5”与R6”一起与与之相连的原子形成C3-C8脂碳环、3-8元脂杂环或被一个或多个Ra取代的3～8元脂杂环；或者所述环中任意的CH2被C＝O所取代；Or R 5" and R 6" together form a C 3 -C 8 aliphatic carbocyclic ring, a 3-8 membered aliphatic heterocyclic ring or a 3-8 membered aliphatic heterocyclic ring substituted by one or more R a ; or any CH 2 in the ring is substituted by C=O;
    或者R3”与R4”一起与与之相连的原子形成C3-C8脂碳环、3-8元脂杂环或被一个或多个Ra取代的3～8元脂杂环；或者所述环中任意的CH2被C＝O所取代；Or R 3" and R 4" together form a C 3 -C 8 aliphatic carbocyclic ring, a 3-8 membered aliphatic heterocyclic ring or a 3-8 membered aliphatic heterocyclic ring substituted by one or more R a ; or any CH 2 in the ring is substituted by C=O;
    Ra独立地表示氢或C1-C6烷基； R independently represents hydrogen or C 1 -C 6 alkyl;
    其中，式(iii)中，W1表示CRW1RW2或NRW1，RW1、RW2各自独立地表示氢、NRaRb、C1-C6烷基或(C＝O)-O-CH2-O-(C＝O)-C1-C10烷基，Ra和Rb各自独立地表示氢或C1-C6烷基；W2表示CH或N；R1”、R2”、R3”和R4”为氢；其中，Y为亚甲基、亚乙基、C3亚烷基、C2-C3亚烯基、或Rc和Rd与与其相连的原子共同形成C3-C6脂碳环或被一个或多个卤素取代的C3-C6脂碳环；或者Rd和Rd’和与之相连的原子一起形成C3-C6脂碳环或被一个或多个卤素取代的C3-C6脂碳环。Wherein, in formula (iii), W 1 represents CR W1 R W2 or NR W1 , R W1 , R W2 each independently represent hydrogen, NR a R b , C 1 -C 6 alkyl or (C=O)-O-CH 2 -O-(C=O)-C 1 -C 10 alkyl, R a and R b each independently represent hydrogen or C 1 -C 6 alkyl; W 2 represents CH or N; R 1 " , R 2" , R 3" and R 4" are hydrogen; wherein, Y is methylene, ethylene, C 3 alkylene, C 2 -C 3 alkenylene, or R c and R d and the atoms connected to them together form a C 3 -C 6 aliphatic carbocycle or a C 3 -C 6 aliphatic carbocycle substituted by one or more halogens; or R d and R d' together with the atoms connected to them form a C 3 -C 6 aliphatic carbocycle or a C 3 -C 6 aliphatic carbocycle substituted by one or more halogens.
  4. 如权利要求3所述的如式I-0所示的杂环类化合物、其药学上可接受的盐、其立体异构体或它 们的溶剂合物，其特征在于，R4为 其中，R4-1为H、C1-C6烷基或(C＝O)-O-CH2-O-(C＝O)-C1-C10烷基；R4-2为C1-C6烷基，R4-2的个数为一个或多个；R4-3和R4-4各自独立地为H或3～8元杂环烷基，或者R4-3和R4-4与其相连的碳原子共同形成3～8元脂杂环；环G、环I和环J与母体结构共用一个碳原子，环F和环H与母体结构共用两个原子和一根键，环F、环G、环H、环I和环J各自独立地为C3-C8脂碳环、3～8元脂杂环、5～8元内酰胺环或被一个或多个Re取代的3～8元脂杂环；Re为C1-C6烷基；The heterocyclic compound shown in formula I-0 as claimed in claim 3, its pharmaceutically acceptable salt, its stereoisomer or its their solvates, characterized in that R 4 is 其中，R 4-1为H、C 1 -C 6烷基或(C＝O)-O-CH 2 -O-(C＝O)-C 1 -C 10烷基；R 4-2为C 1 -C 6烷基，R 4-2的个数为一个或多个；R 4-3和R 4-4各自独立地为H或3～8元杂环烷基，或者R 4-3和R 4-4与其相连的碳原子共同形成3～8元脂杂环；环G、环I和环J与母体结构共用一个碳原子，环F和环H与母体结构共用两个原子和一根键，环F、环G、环H、环I和环J各自独立地为C 3 -C 8脂碳环、3～8元脂杂环、5～8元内酰胺环或被一个或多个R e取代的3～8元脂杂环；R e为C 1 -C 6烷基；
    较佳地，R4-1为H或C1-C6烷基；R4-2为C1-C6烷基，R4-2的个数为一个或多个；R4-3和R4-4各自独立地为H或3～6元杂环烷基，或者R4-3和R4-4与其相连的碳原子共同形成3～6元脂杂环；环G、环I和环J与母体结构共用一个碳原子，环F和环H与母体结构共用两个原子和一根键，环F和环G各自独立地为C3-C8脂碳环；环H为3～8元脂杂环或被一个或多个Re取代的3～8元脂杂环；环I和环J各自独立地为3～8元脂杂环和5～8元内酰胺环；Re为C1-C6烷基。Preferably, R4-1for H or C1-C6Alkyl; R4-2for C1-C6Alkyl, R4-2The number is one or more; R4-3and R4-4Each independently is H or 3-6 membered heterocycloalkyl, or R4-3and R4-4The carbon atoms connected to them together form a 3- to 6-membered aliphatic heterocyclic ring; ring G, ring I and ring J share one carbon atom with the parent structure, ring F and ring H share two atoms and a bond with the parent structure, ring F and ring G are each independently C3-C8Aliphatic carbon ring; Ring H is a 3-8 membered aliphatic heterocyclic ring or is surrounded by one or more ReSubstituted 3-8 membered aliphatic heterocyclic ring; ring I and ring J are each independently 3-8 membered aliphatic heterocyclic ring and 5-8 membered lactam ring; Refor C1-C6alkyl.
  5. 如权利要求1～4任一项所述的如式I-0所示的杂环类化合物、其药学上可接受的盐、其立体异构体或它们的溶剂合物，其特征在于，其满足以下条件的一种或多种：The heterocyclic compound represented by formula I-0, its pharmaceutically acceptable salt, its stereoisomer or their solvate according to any one of claims 1 to 4, characterized in that it satisfies one or more of the following conditions:
    (1)RX1中，所述的卤素独立地为F、Cl、Br或I，例如Cl；(1) In R X1 , the halogen is independently F, Cl, Br or I, such as Cl;
    (2)RX1中，所述的C1-C6烷基独立地为C1-C4烷基，例如甲基、乙基、正丙基、异丙基、正丁基、异丁基或叔丁基，优选为甲基；(2) In R X1 , the C 1 -C 6 alkyl is independently a C 1 -C 4 alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, preferably methyl;
    (3)RX1中，所述的C3-C6环烷基为环丙基、环丁基、环戊基或环己基，优选为环丙基； (3) In R X1 , the C 3 -C 6 cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, preferably cyclopropyl;
    (4)RX1中，所述的C2-C6烯基为C2-C4烯基，例如乙烯基；(4) In R X1 , the C 2 -C 6 alkenyl is C 2 -C 4 alkenyl, such as vinyl;
    (5)RX1中，所述的C2-C6炔基为C2-C4炔基，例如乙炔基；(5) In R X1 , the C 2 -C 6 alkynyl is C 2 -C 4 alkynyl, such as ethynyl;
    (6)RX1中，所述的3～6元杂环烷基中，杂原子的种类独立地选自N和O；(6) In R X1 , in the 3-6 membered heterocycloalkyl group, the type of heteroatom is independently selected from N and O;
    (7)RX1中，所述的3～6元杂环烷基中，杂原子的个数独立地为1个；(7) In R X1 , in the 3- to 6-membered heterocycloalkyl group, the number of heteroatoms is independently 1;
    (8)RX1中，所述的3～6元杂环烷基独立地为四氢吡咯基、氧杂环丁烷基、四氢吡喃基或哌啶基，更例如 (8) In R X1 , the 3-6 membered heterocycloalkyl is independently tetrahydropyrrolyl, oxetanyl, tetrahydropyranyl or piperidinyl, more for example
    (9)RX1中，所述的5～14元杂芳基中，杂原子的种类为N；(9) In R X1 , in the 5- to 14-membered heteroaryl group, the type of heteroatom is N;
    (10)RX1中，所述的5～14元杂芳基中，杂原子的个数为2个；(10) In R X1 , in the 5- to 14-membered heteroaryl group, the number of heteroatoms is 2;
    (11)RX1中，所述的5～14元杂芳基为5～6元杂芳基，例如吡唑基或咪唑基，更例如 (11) In R X1 , the 5-14 membered heteroaryl is a 5-6 membered heteroaryl, such as pyrazolyl or imidazolyl, more for example
    (12)RX1中，所述的3～6元杂环烯基中，杂原子的种类独立地选自N和O；(12) In R X1 , in the 3-6 membered heterocycloalkenyl group, the type of heteroatom is independently selected from N and O;
    (13)RX1中，所述的3～6元杂环烯基中，杂原子的个数独立地为1个；(13) In R X1 , in the 3- to 6-membered heterocycloalkenyl group, the number of heteroatoms is independently 1;
    (14)RX1中，所述的3～6元杂环烯基独立地为6元杂环烯基，例如含1个O原子的6元杂环烯基或含1个N原子的6元杂环烯基，更例如 (14) In R X1 , the 3- to 6-membered heterocycloalkenyl is independently a 6-membered heterocycloalkenyl, such as a 6-membered heterocycloalkenyl containing 1 O atom or a 6-membered heterocycloalkenyl containing 1 N atom, more for example
    (15)X1-1、X1-2、X1-3、X1-4、X1-5、X1-6和X1-7中，所述的C1-C6烷基独立地为C1-C4烷基，例如甲基、乙基、正丙基、异丙基、正丁基、异丁基或叔丁基，优选为甲基或乙基；(15) In X 1-1 , X 1-2 , X 1-3 , X 1-4 , X 1-5 , X 1-6 and X 1-7 , the C 1 -C 6 alkyl group is independently a C 1 -C 4 alkyl group, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, preferably methyl or ethyl;
    (16)X1-4中，所述的C3-C8环烷基为C3-C6环烷基，例如环丙基、环丁基、环戊基或环己基，优选为环丙基、环戊基或环己基；(16) In X 1-4 , the C 3 -C 8 cycloalkyl is C 3 -C 6 cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, preferably cyclopropyl, cyclopentyl or cyclohexyl;
    (17)X1-4中，所述的3～8元杂环烷基为3～6元杂环烷基，例如哌啶基、吗啉基或哌嗪基；(17) In X 1-4 , the 3-8 membered heterocycloalkyl group is a 3-6 membered heterocycloalkyl group, such as piperidinyl, morpholinyl or piperazinyl;
    (18)当RX1与RX3和其相连的原子共同形成C5-C8环烯酮结构时，所述的C5-C8环烯酮可为C5-C6环烯酮，例如环戊烯酮，此时，例如为 (18) When R X1 and R X3 and the atoms connected to them jointly form a C 5 -C 8 cycloalkene structure, the C 5 -C 8 cycloalkene can be a C 5 -C 6 cycloalkene, such as cyclopentenone, at this time, For example for
    (19)当RX1’与RX3和其相连的原子共同形成5～8元杂芳环或被一个或多个羟基取代的5～8元杂芳环时，所述的5～8元杂芳环中杂原子的种类独立地为N；(19) When R X1' , R X3 and the atoms connected to them jointly form a 5-8 membered heteroaromatic ring or a 5-8 membered heteroaromatic ring substituted by one or more hydroxyl groups, the type of heteroatom in the 5-8 membered heteroaromatic ring is independently N;
    (20)当RX1’与RX3和其相连的原子共同形成5～8元杂芳环或被一个或多个羟基取代的5～8元杂 芳环时，所述的5～8元杂芳环中杂原子的个数独立地为2个、3个或4个；(20) When R X1' and R X3 and the atoms connected to them together form a 5-8 membered heteroaromatic ring or a 5-8 membered heteroaromatic ring substituted by one or more hydroxyl groups In the case of an aromatic ring, the number of heteroatoms in the 5- to 8-membered heteroaromatic ring is independently 2, 3 or 4;
    (21)当RX1’与RX3和其相连的原子共同形成5～8元杂芳环时或被一个或多个羟基取代的5～8元杂芳环，所述的5～8元杂芳环独立地为5元杂芳环，例如吡唑环、三氮唑环、四氮唑环或恶二唑环，此时，例如为 (21) When R X1' and R X3 and their connected atoms jointly form a 5-8 membered heteroaromatic ring or a 5-8 membered heteroaromatic ring substituted by one or more hydroxyl groups, the 5-8 membered heteroaromatic ring is independently a 5-membered heteroaromatic ring, such as a pyrazole ring, a triazole ring, a tetrazole ring or an oxadiazole ring, at this time, For example for
    (22)R1中，所述的C6～C14的芳基独立地为苯基或萘基，例如 (22) In R 1 , the C 6 -C 14 aryl groups are independently phenyl or naphthyl, for example
    (23)R1中，所述的5～14元杂芳基中，杂原子的种类独立地为N；(23) In R1 , in the 5- to 14-membered heteroaryl group, the type of heteroatom is independently N;
    (24)R1中，所述的5～14元杂芳基中，杂原子的个数独立地为1个；(24) In R 1 , in the 5- to 14-membered heteroaryl group, the number of heteroatoms is independently 1;
    (25)R1中，所述的5～14元杂芳基独立地为5～12元杂芳基，例如吡啶基、喹啉基或异喹啉基，更例如 (25) In R 1 , the 5-14-membered heteroaryl group is independently a 5-12-membered heteroaryl group, such as pyridyl, quinolinyl or isoquinolyl, more for example
    (26)R1-1、R1-2、R1-3和R1-4中，所述的卤素独立地为F、Cl、Br或I，例如F或Cl；(26) In R 1-1 , R 1-2 , R 1-3 and R 1-4 , the halogens are independently F, Cl, Br or I, such as F or Cl;
    (27)R1-1和R1-2中，所述的C1-C6烷基独立地为C1-C4烷基，例如甲基、乙基、正丙基、异丙基、正丁基、异丁基或叔丁基，优选为甲基或乙基；(27) In R 1-1 and R 1-2 , the C 1 -C 6 alkyl is independently a C 1 -C 4 alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, preferably methyl or ethyl;
    (28)R1-1和R1-2中，所述的C1-C10烷基独立地为C1-C9烷基，例如正壬基；(28) In R 1-1 and R 1-2 , the C 1 -C 10 alkyl is independently a C 1 -C 9 alkyl, such as n-nonyl;
    (29)n1为2；(29) n1 is 2;
    (30)n2为6；(30) n2 is 6;
    (31)n3为4；(31) n3 is 4;
    (32)n4为1；(32) n4 is 1;
    (33)n5为1；(33) n5 is 1;
    (34)R2中，所述的卤素为F、Cl、Br或I，例如F(34) In R 2 , the halogen is F, Cl, Br or I, such as F
    (35)R2中，所述的C1-C6烷基为C1-C4烷基，例如甲基、乙基、正丙基、异丙基、正丁基、异 丁基或叔丁基；(35) In R 2 , the C 1 -C 6 alkyl is a C 1 -C 4 alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, iso Butyl or tert-butyl;
    (36)R2中，所述的C1-C6烷氧基为C1-C4烷氧基；例如甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基或叔丁氧基；(36) In R 2 , the C 1 -C 6 alkoxy group is a C 1 -C 4 alkoxy group; for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy or tert-butoxy;
    (37)L2中，所述的C1-C6亚烷基为C1-C3亚烷基，例如亚甲基、亚乙基或亚丙基，优选为亚甲基；(37) In L 2 , the C 1 -C 6 alkylene group is a C 1 -C 3 alkylene group, such as methylene, ethylene or propylene, preferably methylene;
    (38)R3定义中，所述的3～8元脂杂环中，杂原子的种类独立地为O；(38) In the definition of R3 , in the 3-8 membered aliphatic heterocyclic ring, the type of heteroatom is independently O;
    (39)R3定义中，所述的3～8元脂杂环中，杂原子的数目独立地为1个；(39) In the definition of R3 , in the 3-8 membered aliphatic heterocyclic ring, the number of heteroatoms is independently 1;
    (40)R3定义中，所述的3～8元脂杂环独立地为4～5元脂杂环，例如氧杂环丁烷或四氢呋喃环；(40) In the definition of R3 , the 3-8 membered aliphatic heterocycles are independently 4-5 membered aliphatic heterocycles, such as oxetane or tetrahydrofuran ring;
    (41)R3定义中，所述的C3-C8脂碳环独立地为C3-C6脂碳环，例如环丙烷、环丁烷、环戊烷或环己烷，优选为环丙烷；(41) In the definition of R 3 , the C 3 -C 8 aliphatic carbocycle is independently a C 3 -C 6 aliphatic carbocycle, such as cyclopropane, cyclobutane, cyclopentane or cyclohexane, preferably cyclopropane;
    (42)R3定义中，所述的卤素为F、Cl、Br或I，例如F；(42) In the definition of R3 , the halogen is F, Cl, Br or I, such as F;
    (43)R4-1和R4-2中，所述的C1-C6烷基为C1-C4烷基，例如甲基、乙基、正丙基、异丙基、正丁基、异丁基或叔丁基，优选为甲基；(43) In R 4-1 and R 4-2 , the C 1 -C 6 alkyl group is a C 1 -C 4 alkyl group, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, preferably methyl;
    (44)R4-1中，所述的C1-C10烷基为C1-C9烷基，例如正壬基或异丙基；(44) In R 4-1 , the C 1 -C 10 alkyl group is a C 1 -C 9 alkyl group, such as n-nonyl or isopropyl;
    (45)RW1、RW2、R4-3和R4-4中，所述的3～8元杂环烷基中，杂原子的种类独立地选自N和O；(45) In R W1 , R W2 , R 4-3 and R 4-4 , in the 3- to 8-membered heterocycloalkyl, the type of heteroatom is independently selected from N and O;
    (46)RW1、RW2、R4-3和R4-4中，所述的3～8元杂环烷基中，杂原子的种类个数独立地为1个或2个；(46) Among R W1 , R W2 , R 4-3 and R 4-4 , in the 3- to 8-membered heterocycloalkyl group, the number of heteroatoms is independently 1 or 2;
    (47)RW1、RW2、R4-3和R4-4中，所述的3～8元杂环烷基独立地为4～6元杂环烷基，例如四氢吡咯基、吗啉基或哌啶基，更例如 (47) Among R W1 , R W2 , R 4-3 and R 4-4 , the 3-8 membered heterocycloalkyl is independently 4-6 membered heterocycloalkyl, such as tetrahydropyrrolyl, morpholinyl or piperidinyl, more for example
    (48)当RW1和RW2与其相连的原子共同形成3～8元脂杂环或当R4-3和R4-4与其相连的碳原子共同形成3～8元脂杂环时，所述的3～8元脂杂环为4～5元脂杂环，例如N杂环丁烷，更例如 (48) When R W1 and R W2 form a 3-8 membered aliphatic heterocyclic ring together with their connected atoms or when R 4-3 and R 4-4 form a 3-8 membered aliphatic heterocyclic ring with their connected carbon atoms, the 3-8 membered aliphatic heterocyclic ring is a 4-5 membered aliphatic heterocyclic ring, such as N-heterocyclobutane, more for example
    (49)R4定义中，所述的C3-C8脂碳环独立地为C3-C6脂碳环，例如环丙烷、环丁烷、环戊烷或环己烷，优选为环丙烷、环丁烷或环己烷；(49) In the definition of R 4 , the C 3 -C 8 aliphatic carbocycle is independently a C 3 -C 6 aliphatic carbocycle, such as cyclopropane, cyclobutane, cyclopentane or cyclohexane, preferably cyclopropane, cyclobutane or cyclohexane;
    (50)R4定义中，所述的3～8元脂杂环独立地为4～5元脂杂环，例如四氢吡咯环或N杂环丁烷；(50) In the definition of R 4 , the 3-8 membered aliphatic heterocycles are independently 4-5 membered aliphatic heterocycles, such as tetrahydropyrrole ring or N-heterocyclobutane;
    (51)环F、环G、环H、环I和环J中，所述的5～8元内酰胺环独立地为5元内酰胺环；(51) In ring F, ring G, ring H, ring I and ring J, the 5- to 8-membered lactam rings are independently 5-membered lactam rings;
    (52)Re中，所述的C1-C6烷基为C1-C4烷基，例如甲基、乙基、正丙基、异丙基、正丁基、异丁基或叔丁基，优选为甲基；(52) In R e , the C 1 -C 6 alkyl group is a C 1 -C 4 alkyl group, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, preferably methyl;
    (53)X为F、Cl、Br或I，例如F或Br。(53) X is F, Cl, Br or I, eg F or Br.
  6. 如权利要求5所述的如式I-0所示的杂环类化合物、其药学上可接受的盐、其立体异构体或它们的溶剂合物，其特征在于，其满足以下条件的一种或多种：The heterocyclic compound represented by formula I-0, its pharmaceutically acceptable salt, its stereoisomer or their solvate according to claim 5, is characterized in that it satisfies one or more of the following conditions:
    (1)R3定义中，所述的3～8元脂杂环独立地为例如，环A、环B和环C中的3～8元脂杂环独立地为 (1) In the definition of R3 , the 3-8 membered aliphatic heterocycles are independently For example, the 3-8 membered aliphatic heterocyclic rings in Ring A, Ring B and Ring C are independently
    (2)R3定义中，所述的3～8元脂杂环独立地为例如环D和环E中，所述的3～8元脂杂环独立地为 (2) In the definition of R3 , the 3-8 membered aliphatic heterocycles are independently For example, in Ring D and Ring E, the 3-8 membered aliphatic heterocycles are independently
    (3)R3定义中，所述的C3-C8脂碳环独立地为例如环A、环B和环C中，所述的C3-C8脂碳环独立地为 (3) In the definition of R 3 , the C 3 -C 8 aliphatic carbocycle is independently For example, in Ring A, Ring B and Ring C, the C 3 -C 8 aliphatic carbocycles are independently
    (4)R3定义中，所述的C3-C8脂碳环独立地为例如环D和环E中的C3-C8脂碳环独立地为 (4) In the definition of R 3 , the C 3 -C 8 aliphatic carbocycle is independently For example, the C 3 -C 8 aliphatic carbocycles in ring D and ring E are independently
    (5)R4定义中，所述的C3-C8脂碳环可独立地为例如环F和环H中的C3-C8脂碳环独立地为 (5) In the definition of R 4 , the C 3 -C 8 aliphatic carbocyclic ring can be independently For example, the C 3 -C 8 aliphatic carbocyclic rings in ring F and ring H are independently
    (6)R4定义中，所述的C3-C8脂碳环可独立地为例如环G、环I和环J中的C3-C8脂碳环独立地为 (6) In the definition of R 4 , the C 3 -C 8 aliphatic carbocyclic ring can be independently For example, the C 3 -C 8 aliphatic carbocyclic rings in ring G, ring I and ring J are independently
    (7)R4定义中，所述的3～8元脂杂环可独立地为例如环F和环H中，所述的3～8元脂杂环独立地为 (7) In the definition of R 4 , the 3-8 membered aliphatic heterocycles can be independently For example, in Ring F and Ring H, the 3-8 membered aliphatic heterocycles are independently
    (8)R4定义中，所述的3～8元脂杂环可独立地为例如环G、环I和环J中，所述的3～8元脂杂环独立地为 (8) In the definition of R 4 , the 3-8 membered aliphatic heterocycles can be independently For example, among Ring G, Ring I and Ring J, the 3-8 membered aliphatic heterocycles are independently
    (9)环G、环I和环J中，所述的5～8元内酰胺环独立地为 (9) In ring G, ring I and ring J, the 5- to 8-membered lactam rings are independently
  7. 如权利要求1～6任一项所述的如式I-0所示的杂环类化合物、其药学上可接受的盐、其立体异构体或它们的溶剂合物，其特征在于，其满足以下条件的一种或多种：The heterocyclic compound represented by formula I-0, its pharmaceutically acceptable salt, its stereoisomer or their solvate according to any one of claims 1 to 6, characterized in that it satisfies one or more of the following conditions:
    (1)RX1为CN、Cl、CF3、NH2、N(CH3)2、NO2、NHSO2CH3、NHCOCH3、PO(CH3)2、SF5、C(＝O)H、C(＝O)CH3、C(＝O)CF3、C(＝O)CH2CH3、SO2CH3、SO3H、环丙基、乙烯基、乙炔基、四氢吡咯基、氧杂环丁烷基、四氢吡喃基、乙酰基取代的哌啶基、甲基取代的咪唑基、甲基取代的吡唑基、含1个O原子的6元杂环烯基、乙酰基取代的含1个N原子的6元杂环烯基、环丙基取代的羰基、环戊基取代的羰基或环己基取代的羰基，例如CN、Cl、CF3、NH2、N(CH3)2、NO2、NHSO2CH3、NHCOCH3、PO(CH3)2、SF5、C(＝O)H、C(＝O)CH3、C(＝O)CF3、C(＝O)CH2CH3、SO2CH3、SO3H、环丙基、乙烯基、乙炔基、 (1)RX1For CN, Cl, CF3, NH2, N(CH3)2, NO2, NHSO2CH3, NHCOCH3、PO(CH3)2, SF5, C(=O)H, C(=O)CH3, C(=O)CF3, C(=O)CH2CH3, SO2CH3, SO3H, cyclopropyl, vinyl, ethynyl, tetrahydropyrrolyl, oxetanyl, tetrahydropyranyl, acetyl-substituted piperidinyl, methyl-substituted imidazolyl, methyl-substituted pyrazolyl, 6-membered heterocycloalkenyl containing 1 O atom, 6-membered heterocycloalkenyl containing 1 N atom substituted by acetyl, cyclopropyl-substituted carbonyl, cyclopentyl-substituted carbonyl or cyclohexyl-substituted carbonyl, such as CN, Cl, CF3, NH2, N(CH3)2, NO2, NHSO2CH3, NHCOCH3、PO(CH3)2, SF5, C(=O)H, C(=O)CH3, C(=O)CF3, C(=O)CH2CH3, SO2CH3, SO3H, cyclopropyl, vinyl, ethynyl,
    (2)R1为一个或多个R1-1取代的萘基、一个或多个R1-1取代的苯基、被一个或多个R1-2取代的吡啶基、被一个或多个R1-2取代的喹啉基或被一个或多个R1-2取代的异喹啉基，例如
    (2) R is one or more R 1-1 substituted naphthyl, one or more R 1-1 substituted phenyl, one or more R 1-2 substituted pyridyl, one or more R 1-2 substituted quinolinyl or one or more R 1-2 substituted isoquinolinyl, for example
    (3)R2为F；(3) R2 is F;
    (4)当R3为 时，(4) When R 3 is hour,
    R4为
    R4 is
    (5)当R3为 时， (5) When R3 is hour,
    R4为 R4 is
  8. 如权利要求1～7任一项所述的如式I-0所示的杂环类化合物、其药学上可接受的盐、其立体异构体或它们的溶剂合物，其特征在于，The heterocyclic compound represented by formula I-0, its pharmaceutically acceptable salt, its stereoisomer or their solvate according to any one of claims 1 to 7, characterized in that,
    R4为 R4 is
    R4-3和R4-4各自独立地为H或3～8元杂环烷基，所述的3～8元杂环烷基较佳地为四氢吡咯基或 哌啶基，例如 R 4-3 and R 4-4 are each independently H or 3-8 membered heterocycloalkyl, and the 3-8 membered heterocycloalkyl is preferably tetrahydropyrrolyl or piperidinyl, such as
    环H为3～8元脂杂环或被一个或多个Re取代的3～8元脂杂环，较佳地为3～8元脂杂环，例如四氢吡咯环，更例如 Ring H is a 3-8 membered aliphatic heterocyclic ring or a 3-8 membered aliphatic heterocyclic ring substituted by one or more R e , preferably a 3-8 membered aliphatic heterocyclic ring, such as a tetrahydropyrrole ring, more for example
  9. 如权利要求1～7任一项所述的如式I-0所示的杂环类化合物、其药学上可接受的盐、其立体异构体或它们的溶剂合物，其特征在于，The heterocyclic compound represented by formula I-0, its pharmaceutically acceptable salt, its stereoisomer or their solvate according to any one of claims 1 to 7, characterized in that,
    X1为N； X1 is N;
    R3为 R3 is
    环A为3～8元脂杂环、C3-C8脂碳环或一个或多个卤素取代的C3-C8脂碳环，例如氧杂环丁烷、环丙烷、或F取代的环丙烷，更例如环D和环E各自独立地为为C3-C8脂碳环，例如环丙烷，更例如 Ring A is a 3-8 membered aliphatic heterocycle, a C 3 -C 8 aliphatic carbocycle or a C 3 -C 8 aliphatic carbocycle substituted by one or more halogens, such as oxetane, cyclopropane, or F-substituted cyclopropane, more for example Ring D and ring E are each independently a C 3 -C 8 aliphatic carbocyclic ring, such as cyclopropane, more for example
  10. 如权利要求1～7任一项所述的如式I-0所示的杂环类化合物、其药学上可接受的盐、其立体异构体或它们的溶剂合物，其特征在于，The heterocyclic compound represented by formula I-0, its pharmaceutically acceptable salt, its stereoisomer or their solvate according to any one of claims 1 to 7, characterized in that,
    X1为CRX1； X1 is CR X1 ;
    RX1为CN、NO2、卤素、被一个或多个卤素取代的C1-C6烷基、C3-C8环烷基、3～6元杂环烷基、3～6元杂环烯基、C2-C6烯基、C2-C6炔基、PO(C1-C6烷基)2、被一个或多个X1-1取代的3～6元杂环烷基、被一个或多个X1-2取代的5～14元杂芳基、被一个或多个X1-3取代的3～6元杂环烯基、C(＝O)X1- 4、NX1-5X1-6、或SO2X1-7；R X1 is CN, NO 2 , halogen, C 1 -C 6 alkyl substituted by one or more halogens, C 3 -C 8 cycloalkyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, PO(C 1 -C 6 alkyl) 2 , 3-6 membered heterocycloalkyl substituted by one or more X 1-1 , substituted by one or more X 1-2 5-14-membered heteroaryl, 3-6-membered heterocycloalkenyl substituted by one or more X 1-3 , C(=O)X 1-4 , NX 1-5 X 1-6 , or SO 2 X 1-7 ;
    所述的3～6元杂环烷基较佳地为氧杂环丁烷基或四氢吡咯基，例如 The 3-6 membered heterocycloalkyl is preferably oxetanyl or tetrahydropyrrolyl, for example
    所述的5～14元杂芳基较佳地为吡唑基，例如 The 5-14 membered heteroaryl is preferably pyrazolyl, for example
    R3为 R3 is
    环A较佳地为被一个或多个卤素取代的C3-C8脂碳环，例如被F取代的环丙烷，更例如 Ring A is preferably a C 3 -C 8 aliphatic carbocyclic ring substituted by one or more halogens, such as cyclopropane substituted by F, more for example
  11. 如权利要求1～7任一项所述的如式I-0所示的杂环类化合物、其药学上可接受的盐、其立体异构体或它们的溶剂合物，其特征在于，The heterocyclic compound represented by formula I-0, its pharmaceutically acceptable salt, its stereoisomer or their solvate according to any one of claims 1 to 7, characterized in that,
    R1为被一个或多个R1-1取代的C6～C14的芳基或被一个或多个R1-2取代的5～14元杂芳基；R 1 is a C 6 -C 14 aryl group substituted by one or more R 1-1 or a 5-14 membered heteroaryl group substituted by one or more R 1-2 ;
    当R1为被一个或多个R1-1取代的C6～C14的芳基时，相邻的两个R1-1与其相连的原子一起形成C3-C8脂碳环或被一个或多个R1-3取代的C3-C8脂碳环，其余R1-1独立地为卤素、OH、NH2、CN、C1-C6烷基、(C＝O)-C1-C6烷基、C2-C6炔基、被一个或多个卤素取代的C1-C6烷基、B(OH)2或O(C＝O)-C1-C10烷基；When R 1 is a C 6 -C 14 aryl group substituted by one or more R 1-1 , two adjacent R 1-1 and the atoms connected to them together form a C 3 -C 8 aliphatic carbon ring or a C 3 -C 8 aliphatic carbon ring substituted by one or more R 1-3 , and the remaining R 1-1 are independently halogen, OH, NH 2 , CN, C 1 -C 6 alkyl, (C=O)-C 1 -C 6 alkyl , C 2 -C 6 alkynyl, C 1 -C 6 alkyl substituted by one or more halogens, B(OH) 2 or O(C=O)-C 1 -C 10 alkyl;
    当R1为被一个或多个R1-2取代的5～14元杂芳基时，相邻的两个R1-2与其相连的原子一起形成C3-C8碳环或被一个或多个R1-4取代的C3-C8碳环，其余R1-2独立地为卤素、OH、NH2、CN、C1-C6烷基、(C＝O)-C1-C6烷基、C2-C6炔基、被一个或多个卤素取代的C1-C6烷基、B(OH)2或O(C＝O)-C1-C10烷基；When R 1 is a 5- to 14-membered heteroaryl group substituted by one or more R 1-2 , two adjacent R 1-2 and their connected atoms together form a C 3 -C 8 carbocycle or a C 3 -C 8 carbocycle substituted by one or more R 1-4 , and the remaining R 1-2 are independently halogen, OH, NH 2 , CN, C 1 -C 6 alkyl, (C=O)-C 1 -C 6 alkyl, C 2 -C 6 alkynyl, C 1 -C 6 alkyl substituted by one or more halogens, B(OH) 2 or O(C=O)-C 1 -C 10 alkyl;
    R1-3和R1-4独立地为卤素。R 1-3 and R 1-4 are independently halogen.
  12. 一种如下所示的杂环类化合物、其药学上可接受的盐、其立体异构体或它们的溶剂合物：














    A heterocyclic compound as shown below, its pharmaceutically acceptable salt, its stereoisomer or their solvate:














  13. 如权利要求12所述的杂环类化合物、其药学上可接受的盐、其立体异构体或它们的溶剂合物，其特征在于，所述杂环类化合物的药学上可接受的盐如下所示：


    The heterocyclic compound, its pharmaceutically acceptable salt, its stereoisomer or their solvate according to claim 12, wherein the pharmaceutically acceptable salt of the heterocyclic compound is as follows:


  14. 如下所示的杂环类化合物、其药学上可接受的盐、其立体异构体或它们的溶剂合物：The following heterocyclic compounds, their pharmaceutically acceptable salts, their stereoisomers or their solvates:
    在下述条件下保留时间为0.660min的化合物，其为中的一个立体异构体：色谱柱:Chiralpak AD-3，50mm*4.6mm，3um；流动相：A相为二氧化碳，B相为0.05％二乙胺/乙醇；梯度：保持50％的B相5分钟，流速：4毫升/分钟；The compound whose retention time is 0.660min under the following conditions is One stereoisomer in: Chromatographic column: Chiralpak AD-3, 50mm*4.6mm, 3um; Mobile phase: A phase is carbon dioxide, B phase is 0.05% diethylamine/ethanol; Gradient: keep 50% of B phase for 5 minutes, flow rate: 4 ml/min;
    在下述条件下保留时间为2.147min的化合物，其为中的一个 立体异构体：色谱柱:Chiralpak AD-3，50mm*4.6mm，3um；流动相：A相为二氧化碳，B相为0.05％二乙胺/乙醇；梯度：保持50％的B相5分钟，流速：4毫升/分钟；The compound whose retention time is 2.147min under the following conditions is one of the Stereoisomers: Chromatographic column: Chiralpak AD-3, 50mm*4.6mm, 3um; mobile phase: phase A is carbon dioxide, phase B is 0.05% diethylamine/ethanol; gradient: maintain 50% phase B for 5 minutes, flow rate: 4 ml/min;
    在下述条件下保留时间为2.311min的化合物，其为中的一个立体异构体：色谱柱:Chiralpak IG-3 100*4.6mm I.D.，3um；流动相：A相为二氧化碳，B相为0.05％二乙胺/乙醇；梯度：B相在4分钟内从5％到40％，保持40％的B相2.5分钟，保持5％的B相1.5分钟，流速：2.8毫升/分钟；The compound whose retention time is 2.311min under the following conditions is One stereoisomer in: Chromatographic column: Chiralpak IG-3 100*4.6mm ID, 3um; Mobile phase: A phase is carbon dioxide, B phase is 0.05% diethylamine/ethanol; Gradient: B phase from 5% to 40% in 4 minutes, keep 40% B phase for 2.5 minutes, keep 5% B phase for 1.5 minutes, flow rate: 2.8 ml/min;
    在下述条件下保留时间为3.397min的化合物，其为中的一个立体异构体：色谱柱:Chiralpak IG-3 100*4.6mm I.D.，3um；流动相：A相为二氧化碳，B相为0.05％二乙胺/乙醇；梯度：B相在4分钟内从5％到40％，保持40％的B相2.5分钟，保持5％的B相1.5分钟，流速：2.8毫升/分钟；The compound whose retention time is 3.397min under the following conditions is One stereoisomer in: Chromatographic column: Chiralpak IG-3 100*4.6mm ID, 3um; Mobile phase: A phase is carbon dioxide, B phase is 0.05% diethylamine/ethanol; Gradient: B phase from 5% to 40% in 4 minutes, keep 40% B phase for 2.5 minutes, keep 5% B phase for 1.5 minutes, flow rate: 2.8 ml/min;
    在下述条件下保留时间为4.236min的化合物，其为中的一个立体异构体：色谱柱:Chiralpak IE 100*4.6mm 3um；流动相：A相为0.1％二乙胺/正庚烷，B相为异丙醇；梯度：A/B＝60/40，流速：1毫升/分钟；The compound whose retention time is 4.236min under the following conditions is One stereoisomer in: Chromatographic column: Chiralpak IE 100*4.6mm 3um; Mobile phase: A phase is 0.1% diethylamine/n-heptane, B phase is isopropanol; Gradient: A/B=60/40, flow rate: 1 ml/min;
    在下述条件下保留时间为1.942min的化合物，其为中的一个立体异构体：色谱柱:Chiralpak IG-3，50mm*4.6mm，3um；流动相：A相为二氧化碳，B相为0.05％二乙 胺/乙醇；梯度：B相在2分钟内从5％到40％，保持40％的B相1.2分钟，保持5％的B相0.8分钟，流速：4毫升/分钟；The compound whose retention time is 1.942min under the following conditions is A stereoisomer in: Chromatographic column: Chiralpak IG-3, 50mm*4.6mm, 3um; Mobile phase: Phase A is carbon dioxide, phase B is 0.05% diethyl Amine/ethanol; Gradient: Phase B from 5% to 40% in 2 minutes, hold 40% of B for 1.2 minutes, hold 5% of B for 0.8 minutes, flow rate: 4 ml/min;
    在下述条件下保留时间为2.343min的化合物，其为中的一个立体异构体：色谱柱:Chiralpak IG-3，50mm*4.6mm，3um；流动相：A相为二氧化碳，B相为0.05％二乙胺/乙醇；梯度：B相在2分钟内从5％到40％，保持40％的B相1.2分钟，保持5％的B相0.8分钟，流速：4毫升/分钟；The compound whose retention time is 2.343min under the following conditions is One stereoisomer in: chromatographic column: Chiralpak IG-3, 50mm*4.6mm, 3um; mobile phase: phase A is carbon dioxide, phase B is 0.05% diethylamine/ethanol; gradient: phase B is from 5% to 40% in 2 minutes, keep 40% of B phase for 1.2 minutes, keep 5% of B phase for 0.8 minutes, flow rate: 4 ml/min;
    在下述条件下保留时间为3.004min的化合物，其为中的一个立体异构体：色谱柱:Chiralpak IG-3，50mm*4.6mm，3um；流动相：A相为二氧化碳，B相为0.05％二乙胺/乙醇；梯度：B相在2分钟内从5％到40％，保持40％的B相1.2分钟，保持5％的B相0.8分钟，流速：4毫升/分钟；The compound whose retention time is 3.004min under the following conditions is One stereoisomer in: Chromatographic column: Chiralpak IG-3, 50mm*4.6mm, 3um; Mobile phase: A phase is carbon dioxide, B phase is 0.05% diethylamine/ethanol; Gradient: B phase is from 5% to 40% in 2 minutes, keep 40% of B phase for 1.2 minutes, keep 5% of B phase for 0.8 minutes, flow rate: 4 ml/min;
    在下述条件下保留时间为2.414min的化合物，其为中的一个立体异构体：色谱柱:Chiralpak IC-3，100mm*4.6mm，3um；流动相：A相为二氧化碳，B相为0.05％二乙胺/异丙醇；梯度：40％的B相，流速：2.8毫升/分钟；The compound whose retention time is 2.414min under the following conditions is A stereoisomer in: Chromatographic column: Chiralpak IC-3, 100mm*4.6mm, 3um; Mobile phase: A phase is carbon dioxide, B phase is 0.05% diethylamine/isopropanol; Gradient: 40% B phase, flow rate: 2.8 ml/min;
    在下述条件下保留时间为3.344min的化合物，其为中的一个立体异构体：色谱柱:Chiralpak IC-3，100mm*4.6mm，3um；流动相：A相为二氧化碳，B相为0.05％二乙胺/异丙醇；梯度：40％的B相，流速：2.8毫升/分钟； The compound whose retention time is 3.344min under the following conditions is A stereoisomer in: Chromatographic column: Chiralpak IC-3, 100mm*4.6mm, 3um; Mobile phase: A phase is carbon dioxide, B phase is 0.05% diethylamine/isopropanol; Gradient: 40% B phase, flow rate: 2.8 ml/min;
    在下述条件下保留时间为1.150min的化合物，其为中的一个立体异构体：色谱柱:Chiralpak IG-3，50mm*4.6mm，3um；流动相：A相为二氧化碳，B相为0.05％二乙胺/异丙醇；梯度：保持40％的B相，流速：4毫升/分钟；The compound whose retention time is 1.150min under the following conditions is One stereoisomer in: Chromatographic column: Chiralpak IG-3, 50mm*4.6mm, 3um; Mobile phase: A phase is carbon dioxide, B phase is 0.05% diethylamine/isopropanol; Gradient: keep 40% of B phase, flow rate: 4 ml/min;
    在下述条件下保留时间为2.203min的化合物，其为中的一个立体异构体：色谱柱:Chiralpak IG-3，50mm*4.6mm，3um；流动相：A相为二氧化碳，B相为0.05％二乙胺/异丙醇；梯度：保持40％的B相，流速：4毫升/分钟；The compound whose retention time is 2.203min under the following conditions is One stereoisomer in: Chromatographic column: Chiralpak IG-3, 50mm*4.6mm, 3um; Mobile phase: A phase is carbon dioxide, B phase is 0.05% diethylamine/isopropanol; Gradient: keep 40% of B phase, flow rate: 4 ml/min;
    在下述条件下保留时间为1.696min的化合物，其为中的一个立体异构体：色谱柱:Chiralpak AD-3，50mm*4.6mm，3um；流动相：A相为二氧化碳，B相为0.05％二乙胺/乙醇；梯度：B相在2分钟内从5％到40％，保持40％的B相1.2分钟，保持5％的B相0.8分钟；流速：4毫升/分钟；The compound whose retention time is 1.696min under the following conditions is One stereoisomer in: Chromatographic column: Chiralpak AD-3, 50mm*4.6mm, 3um; Mobile phase: A phase is carbon dioxide, B phase is 0.05% diethylamine/ethanol; Gradient: B phase is from 5% to 40% in 2 minutes, keep 40% of B phase for 1.2 minutes, keep 5% of B phase for 0.8 minutes; flow rate: 4 ml/min;
    在下述条件下保留时间为2.137min的化合物，其为中的一个立体异构体：色谱柱:Chiralpak AD-3，50mm*4.6mm，3um；流动相：A相为二氧化碳，B相为0.05％二乙胺/乙醇；梯度：B相在2分钟内从5％到40％，保持40％的B相1.2分钟，保持5％的B相0.8 分钟；流速：4毫升/分钟；The compound whose retention time is 2.137min under the following conditions is One stereoisomer in: Chromatographic column: Chiralpak AD-3, 50mm*4.6mm, 3um; mobile phase: phase A is carbon dioxide, phase B is 0.05% diethylamine/ethanol; gradient: phase B is from 5% to 40% in 2 minutes, keep 40% of B phase for 1.2 minutes, keep 5% of B phase 0.8 minutes; flow rate: 4 ml/min;
    在下述条件下保留时间为1.787min的化合物，其为中的一个立体异构体：色谱柱:Chiralpak AD-3，50mm*4.6mm，3um；流动相：A相为二氧化碳，B相为0.05％二乙胺/乙醇；梯度：B相在2分钟内从5％到40％，保持40％的B相1.2分钟，保持5％的B相0.8分钟；流速：4毫升/分钟；The compound whose retention time is 1.787min under the following conditions is One stereoisomer in: Chromatographic column: Chiralpak AD-3, 50mm*4.6mm, 3um; mobile phase: phase A is carbon dioxide, phase B is 0.05% diethylamine/ethanol; gradient: phase B is from 5% to 40% in 2 minutes, keep 40% of B phase for 1.2 minutes, keep 5% of B phase for 0.8 minutes; flow rate: 4 ml/min;
    在下述条件下保留时间为2.089min的化合物，其为中的一个立体异构体：色谱柱:Chiralpak AD-3，50mm*4.6mm，3um；流动相：A相为二氧化碳，B相为0.05％二乙胺/乙醇；梯度：B相在2分钟内从5％到40％，保持40％的B相1.2分钟，保持5％的B相0.8分钟；流速：4毫升/分钟；The compound whose retention time is 2.089min under the following conditions is One stereoisomer in: Chromatographic column: Chiralpak AD-3, 50mm*4.6mm, 3um; mobile phase: phase A is carbon dioxide, phase B is 0.05% diethylamine/ethanol; gradient: phase B is from 5% to 40% in 2 minutes, keep 40% of B phase for 1.2 minutes, keep 5% of B phase for 0.8 minutes; flow rate: 4 ml/min;
    在下述条件下保留时间为0.797min的化合物，其为中的一个立体异构体：色谱柱:Chiralpak IG-3，50mm*4.6mm，3um；流动相：A相为二氧化碳，B相为0.05％二乙胺/异丙醇；梯度：保持40％的B相；流速：4毫升/分钟； The compound whose retention time is 0.797min under the following conditions is One stereoisomer in: Chromatographic column: Chiralpak IG-3, 50mm*4.6mm, 3um; Mobile phase: A phase is carbon dioxide, B phase is 0.05% diethylamine/isopropanol; Gradient: keep 40% of B phase; Flow rate: 4 ml/min;
    在下述条件下保留时间为2.514min的化合物，其为中的一个立体异构体：色谱柱:Chiralpak IG-3，50mm*4.6mm，3um；流动相：A相为二氧化碳，B相为0.05％二乙胺/异丙醇；梯度：保持40％的B相；流速：4毫升/分钟；The compound whose retention time is 2.514min under the following conditions is One stereoisomer in: Chromatographic column: Chiralpak IG-3, 50mm*4.6mm, 3um; Mobile phase: A phase is carbon dioxide, B phase is 0.05% diethylamine/isopropanol; Gradient: keep 40% of B phase; Flow rate: 4 ml/min;
    在下述条件下保留时间为1.943min的化合物，其为中的一个立体异构体：色谱柱:ChiralPak AD-3，150*4.6mm，3um；流动相：A相为二氧化碳，B相为0.05％二乙胺/乙醇；梯度：保持40％的B相；流速：2.5毫升/分钟；The compound whose retention time is 1.943min under the following conditions is One stereoisomer in: Chromatographic column: ChiralPak AD-3, 150*4.6mm, 3um; Mobile phase: A phase is carbon dioxide, B phase is 0.05% diethylamine/ethanol; Gradient: maintain 40% of B phase; Flow rate: 2.5 ml/min;
    在下述条件下保留时间为3.400min的化合物，其为中的一个立体异构体：色谱柱:ChiralPak AD-3，150*4.6mm，3um；流动相：A相为二氧化碳，B相为0.05％二乙胺/乙醇；梯度：保持40％的B相；流速：2.5毫升/分钟；The compound whose retention time is 3.400min under the following conditions is One stereoisomer in: Chromatographic column: ChiralPak AD-3, 150*4.6mm, 3um; Mobile phase: A phase is carbon dioxide, B phase is 0.05% diethylamine/ethanol; Gradient: maintain 40% of B phase; Flow rate: 2.5 ml/min;
    在下述条件下保留时间为1.729min和1.951min的化合物，其为 中的两个立体异构体混合物：色谱柱:Chiralpak IG-3，100*4.6mm I.D.，3um；流动相：A相为二氧化碳，B相为0.05％二乙胺/异丙醇；梯度：保持40％的B相，流速：2.8毫升/分钟；The compounds whose retention times are 1.729min and 1.951min under the following conditions are Two stereoisomer mixtures in: Chromatographic column: Chiralpak IG-3, 100*4.6mm ID, 3um; Mobile phase: A phase is carbon dioxide, B phase is 0.05% diethylamine/isopropanol; Gradient: keep 40% of B phase, flow rate: 2.8 ml/min;
    在下述条件下保留时间为6.088min的化合物，其为中的一个立体异构体混合物：色谱柱:Chiralpak IG-3 100*4.6mm I.D.，3um；流动相：A相为二氧化碳，B相为0.05％二乙胺/异丙醇；梯度：保持40％的B相，流速：2.8毫升/分钟；The compound whose retention time is 6.088min under the following conditions is A mixture of stereoisomers in: chromatographic column: Chiralpak IG-3 100*4.6mm ID, 3um; mobile phase: phase A is carbon dioxide, phase B is 0.05% diethylamine/isopropanol; gradient: maintain 40% phase B, flow rate: 2.8 ml/min;
    在下述条件下保留时间为8.998min的化合物，其为中的一个立体异构体混合物：色谱柱:Chiralpak IG-3 100*4.6mm I.D.，3um；流动相：A相为二氧化碳，B相为0.05％二乙胺/异丙醇；梯度：保持40％的B相，流速：2.8毫升/分钟；The compound whose retention time is 8.998min under the following conditions is A mixture of stereoisomers in: chromatographic column: Chiralpak IG-3 100*4.6mm ID, 3um; mobile phase: phase A is carbon dioxide, phase B is 0.05% diethylamine/isopropanol; gradient: maintain 40% phase B, flow rate: 2.8 ml/min;
    在下述条件下保留时间为1.374min的化合物，其为中的两个立体异构体混合物：色谱柱:Chiralpak IG-3，100*4.6mm I.D.，3um；流动相：A相为二氧化碳，B相为0.05％二乙胺/乙醇；梯度：保持40％的B相，流速：2.8毫升/分钟； The compound whose retention time is 1.374min under the following conditions is Two stereoisomer mixtures in: Chromatographic column: Chiralpak IG-3, 100*4.6mm ID, 3um; Mobile phase: A phase is carbon dioxide, B phase is 0.05% diethylamine/ethanol; Gradient: keep 40% of B phase, flow rate: 2.8 ml/min;
    在下述条件下保留时间为2.812min的化合物，其为中的一个立体异构体：色谱柱:Chiralpak IG-3，100*4.6mm I.D.，3um；流动相：A相为二氧化碳，B相为0.05％二乙胺/乙醇；梯度：保持40％的B相，流速：2.8毫升/分钟；The compound whose retention time is 2.812min under the following conditions is One stereoisomer in: Chromatographic column: Chiralpak IG-3, 100*4.6mm ID, 3um; Mobile phase: A phase is carbon dioxide, B phase is 0.05% diethylamine/ethanol; Gradient: keep 40% of B phase, flow rate: 2.8 ml/min;
    在下述条件下保留时间为6.215min的化合物，其为中的一个立体异构体：色谱柱:Chiralpak IG-3，100*4.6mm I.D.，3um；流动相：A相为二氧化碳，B相为0.05％二乙胺/乙醇；梯度：保持40％的B相，流速：2.8毫升/分钟；The compound whose retention time is 6.215min under the following conditions is One stereoisomer in: Chromatographic column: Chiralpak IG-3, 100*4.6mm ID, 3um; Mobile phase: A phase is carbon dioxide, B phase is 0.05% diethylamine/ethanol; Gradient: keep 40% of B phase, flow rate: 2.8 ml/min;
    在下述条件下保留时间为0.438min的化合物，其为中的一个立体异构体：色谱柱:Chiralpak AD-3,50*4.6mm,3um；流动相：A相为二氧化碳，B相为0.05％二乙胺/异丙醇；梯度：保持40％的B相；流速：4毫升/分钟；The compound whose retention time is 0.438min under the following conditions is One stereoisomer in: Chromatographic column: Chiralpak AD-3, 50*4.6mm, 3um; Mobile phase: A phase is carbon dioxide, B phase is 0.05% diethylamine/isopropanol; Gradient: maintain 40% of B phase; Flow rate: 4 ml/min;
    在下述条件下保留时间为1.251min的化合物，其为中的一个立体异构体：色谱柱:Chiralpak AD-3,50*4.6mm,3um；流动相：A相为二氧化碳，B相为0.05％二乙胺/异丙醇；梯度：保持40％的B相；流速：4毫升/分钟； The compound whose retention time is 1.251min under the following conditions is One stereoisomer in: Chromatographic column: Chiralpak AD-3, 50*4.6mm, 3um; Mobile phase: A phase is carbon dioxide, B phase is 0.05% diethylamine/isopropanol; Gradient: maintain 40% of B phase; Flow rate: 4 ml/min;
    在下述条件下保留时间为0.369min的化合物，其为中的两个立体异构体混合物：色谱柱:Chiralpak AD-3，50mm*4.6mm，3um；流动相：A相为二氧化碳，B相为0.05％二乙胺/异丙醇；梯度：保持B相在40％；流速：4毫升/分钟；The compound whose retention time is 0.369min under the following conditions is Two stereoisomer mixtures in: Chromatographic column: Chiralpak AD-3, 50mm*4.6mm, 3um; Mobile phase: A phase is carbon dioxide, B phase is 0.05% diethylamine/isopropanol; Gradient: keep B phase at 40%; Flow rate: 4 ml/min;
    在下述条件下保留时间为0.752min的化合物，其为中的一个立体异构体：色谱柱:Chiralpak AD-3，50mm*4.6mm，3um；流动相：A相为二氧化碳，B相为0.05％二乙胺/异丙醇；梯度：保持B相在40％；流速：4毫升/分钟；The compound whose retention time is 0.752min under the following conditions is One stereoisomer in: Chromatographic column: Chiralpak AD-3, 50mm*4.6mm, 3um; Mobile phase: A phase is carbon dioxide, B phase is 0.05% diethylamine/isopropanol; Gradient: keep B phase at 40%; Flow rate: 4 ml/min;
    在下述条件下保留时间为1.937min的化合物，其为中的一个立体异构体：色谱柱:Chiralpak AD-3，50mm*4.6mm，3um；流动相：A相为二氧化碳，B相为0.05％二乙胺/异丙醇；梯度：保持B相在40％；流速：4毫升/分钟；The compound whose retention time is 1.937min under the following conditions is One stereoisomer in: Chromatographic column: Chiralpak AD-3, 50mm*4.6mm, 3um; Mobile phase: A phase is carbon dioxide, B phase is 0.05% diethylamine/isopropanol; Gradient: keep B phase at 40%; Flow rate: 4 ml/min;
    在下述条件下保留时间为3.692min的化合物，其为中的一个立体异构体：色谱柱:Chiralpak AD-3，150mm*4.6mm，3um；流动相：A相为二氧化碳， B相为0.05％二乙胺/乙醇；梯度：B相保持在40％；流速：2.5毫升/分钟；The compound whose retention time is 3.692min under the following conditions is A stereoisomer in: Chromatographic column: Chiralpak AD-3, 150mm*4.6mm, 3um; Mobile phase: Phase A is carbon dioxide, Phase B is 0.05% diethylamine/ethanol; Gradient: Phase B is maintained at 40%; Flow rate: 2.5 ml/min;
    在下述条件下保留时间为3.586min的化合物，其为
    中的一个立体异构体：色谱柱:Ultimate XB-C18,3um,3.0*50mm；
    流动相：A相为三氟乙酸/水(1.5mL/4L)，B相为三氟乙酸/乙腈(0.75mL/4L)；梯度：B相在1分钟内从1％到5％，在5分钟内从5％到100％，保持100％的B相2分钟，保持1％的B相2分钟；流速：1.2毫升/分钟)：    The compound whose retention time is 3.586min under the following conditions is
    One stereoisomer in: Column: Ultimate XB-C18, 3um, 3.0*50mm;
    Mobile phase: phase A is trifluoroacetic acid/water (1.5mL/4L), phase B is trifluoroacetic acid/acetonitrile (0.75mL/4L); gradient: phase B from 1% to 5% in 1 minute, from 5% to 100% in 5 minutes, hold 100% of B for 2 minutes, hold 1% of B for 2 minutes; flow rate: 1.2 mL/min):
    在下述条件下保留时间为为3.607min的化合物，其为
    中的一个立体异构体：色谱柱:Ultimate XB-C18,3um,3.0*50mm；流
    动相：A相为三氟乙酸/水(1.5mL/4L)，B相为三氟乙酸/乙腈(0.75mL/4L)；梯度：B相在1分钟内从1％到5％，在5分钟内从5％到100％，保持100％的B相2分钟，保持1％的B相2分钟；流速：1.2毫升/分钟)；    The compound whose retention time is 3.607min under the following conditions is
    One stereoisomer in: Chromatographic column: Ultimate XB-C18, 3um, 3.0*50mm; Mobile phase: A phase is trifluoroacetic acid/water (1.5mL/4L), B phase is trifluoroacetic acid/acetonitrile (0.75mL/4L); Gradient: B phase from 1% to 5% in 1 minute, from 5% to 100% in 5 minutes, keep 100% of B phase for 2 minutes, keep 1% of B phase 2 minutes; flow rate: 1.2 ml/min);
    在下述条件下保留时间为3.539min的化合物，其为
    中的一个立体异构体：色谱柱:Ultimate XB-C18,3um,3.0*50mm；流
    动相：A相为三氟乙酸/水(1.5mL/4L)，B相为三氟乙酸/乙腈(0.75mL/4L)；梯度：B相在1分钟内从1％到5％，在5分钟内从5％到100％，保持100％的B相2分钟，保持1％的B相2分钟；流速：1.2毫升/分钟)；    The compound whose retention time is 3.539min under the following conditions is
    One stereoisomer in: Chromatographic column: Ultimate XB-C18, 3um, 3.0*50mm; Mobile phase: A phase is trifluoroacetic acid/water (1.5mL/4L), B phase is trifluoroacetic acid/acetonitrile (0.75mL/4L); Gradient: B phase from 1% to 5% in 1 minute, from 5% to 100% in 5 minutes, keep 100% of B phase for 2 minutes, keep 1% of B phase 2 minutes; flow rate: 1.2 ml/min);
    在下述条件下保留时间为为3.539min的化合物，其为
    中的一个立体异构体：色谱柱:Ultimate XB-C18,3um,3.0*50mm；流
    动相：A相为三氟乙酸/水(1.5mL/4L)，B相为三氟乙酸/乙腈(0.75mL/4L)；梯度：B相在1分钟内从1％到5％，在5分钟内从5％到100％，保持100％的B相2分钟，保持1％的B相2分钟；流速：1.2毫升/分钟)：出峰位置为3.565min；    Under the following conditions, the retention time is the compound of 3.539min, which is
    One stereoisomer in: Chromatographic column: Ultimate XB-C18, 3um, 3.0*50mm; Mobile phase: A phase is trifluoroacetic acid/water (1.5mL/4L), B phase is trifluoroacetic acid/acetonitrile (0.75mL/4L); Gradient: B phase from 1% to 5% in 1 minute, from 5% to 100% in 5 minutes, keep 100% of B phase for 2 minutes, keep 1% of B phase 2 minutes; flow rate: 1.2 ml/min): the peak position is 3.565 min;
    在下述条件下保留时间为3.754min的化合物，其为中的一个立体异构体：色谱柱:ChiralCel OD-3，150mm*4.6mm，3um；流动相：A相为二氧化碳，B相为0.05％二乙胺/异丙醇；保持40％的B相；流速：2.5毫升/分钟；The compound whose retention time is 3.754min under the following conditions is One stereoisomer in: Chromatographic column: ChiralCel OD-3, 150mm*4.6mm, 3um; Mobile phase: A phase is carbon dioxide, B phase is 0.05% diethylamine/isopropanol; keep 40% of B phase; flow rate: 2.5 ml/min;
    在下述条件下保留时间为3.131min的化合物，其为中的一个立体异构体：色谱柱:ChiralCel OD-3，150mm*4.6mm，3um；流动相：A相为二氧化碳，B相为0.05％二乙胺/异丙醇；保持40％的B相；流速：2.5毫升/分钟； The compound whose retention time is 3.131min under the following conditions is One stereoisomer in: Chromatographic column: ChiralCel OD-3, 150mm*4.6mm, 3um; Mobile phase: A phase is carbon dioxide, B phase is 0.05% diethylamine/isopropanol; keep 40% of B phase; flow rate: 2.5 ml/min;
    在下述条件下保留时间为1.653min的化合物，其为中的一个立体异构体：色谱柱:ChiralCel OD-3，50mm*4.6mm，3um；流动相：A相为二氧化碳，B相为0.05％二乙胺/乙醇；2min从5％的B相升至40％的B相，保持40％的B相1.2min，然后保持5％的B相0.8min；流速：4毫升/分钟；The compound whose retention time is 1.653min under the following conditions is One stereoisomer in: Chromatographic column: ChiralCel OD-3, 50mm*4.6mm, 3um; Mobile phase: A phase is carbon dioxide, B phase is 0.05% diethylamine/ethanol; 2min rises from 5% B phase to 40% B phase, maintains 40% B phase for 1.2min, then maintains 5% B phase for 0.8min; flow rate: 4 ml/min;
    在下述条件下保留时间为1.763min的化合物，其为中的一个立体异构体：色谱柱:ChiralCel OD-3，50mm*4.6mm，3um；流动相：A相为二氧化碳，B相为0.05％二乙胺/乙醇；2min从5％的B相升至40％的B相，保持40％的B相1.2min，然后保持5％的B相0.8min；流速：4毫升/分钟；The compound whose retention time is 1.763min under the following conditions is One stereoisomer in: Chromatographic column: ChiralCel OD-3, 50mm*4.6mm, 3um; Mobile phase: A phase is carbon dioxide, B phase is 0.05% diethylamine/ethanol; 2min rises from 5% B phase to 40% B phase, maintains 40% B phase for 1.2min, then maintains 5% B phase for 0.8min; flow rate: 4 ml/min;
    在下述条件下保留时间为1.343min的化合物，其为中的一个立体异构体：色谱柱:Cellulose-2 100*4.6mm I.D.,3um；流动相：A相为二氧化碳，B相为0.05％二乙胺/乙醇；梯度：保持50％的B相；流速：2.8毫升/分钟； The compound whose retention time is 1.343min under the following conditions is One stereoisomer in: Chromatographic column: Cellulose-2 100*4.6mm ID, 3um; Mobile phase: A phase is carbon dioxide, B phase is 0.05% diethylamine/ethanol; Gradient: maintain 50% of B phase; Flow rate: 2.8 ml/min;
    在下述条件下保留时间为1.527min的化合物，其为中的一个立体异构体：色谱柱:Cellulose-2 100*4.6mm I.D.,3um；流动相：A相为二氧化碳，B相为0.05％二乙胺/乙醇；梯度：保持50％的B相；流速：2.8毫升/分钟；The compound whose retention time is 1.527min under the following conditions is One stereoisomer in: Chromatographic column: Cellulose-2 100*4.6mm ID, 3um; Mobile phase: A phase is carbon dioxide, B phase is 0.05% diethylamine/ethanol; Gradient: maintain 50% of B phase; Flow rate: 2.8 ml/min;
    在下述条件下保留时间为1.739min的化合物，其为中的一个立体异构体：色谱柱:Cellulose-2 100*4.6mm I.D.,3um；流动相：A相为二氧化碳，B相为0.05％二乙胺/乙醇；梯度：保持50％的B相；流速：2.8毫升/分钟；The compound whose retention time is 1.739min under the following conditions is One stereoisomer in: Chromatographic column: Cellulose-2 100*4.6mm ID, 3um; Mobile phase: A phase is carbon dioxide, B phase is 0.05% diethylamine/ethanol; Gradient: maintain 50% of B phase; Flow rate: 2.8 ml/min;
    在下述条件下保留时间为2.203min的化合物，其为中的一个立体异构体：色谱柱:Cellulose-2 100*4.6mm I.D.,3um；流动相：A相为二氧化碳，B相为0.05％二乙胺/乙醇；梯度：保持50％的B相；流速：2.8毫升/分钟； The compound whose retention time is 2.203min under the following conditions is One stereoisomer in: Chromatographic column: Cellulose-2 100*4.6mm ID, 3um; Mobile phase: A phase is carbon dioxide, B phase is 0.05% diethylamine/ethanol; Gradient: maintain 50% of B phase; Flow rate: 2.8 ml/min;
    在下述条件下保留时间为3.304min的化合物，其为中的一个立体异构体：色谱柱:Cellulose 2 100*4.6mm I.D.,3um；流动相：A相为二氧化碳，B相为0.05％二乙胺/甲醇；梯度：保持50％的B相；流速：2.8毫升/分钟；The compound whose retention time is 3.304min under the following conditions is One stereoisomer in: Chromatographic column: Cellulose 2 100*4.6mm ID, 3um; Mobile phase: A phase is carbon dioxide, B phase is 0.05% diethylamine/methanol; Gradient: maintain 50% of B phase; Flow rate: 2.8 ml/min;
    在下述条件下保留时间为4.369min的化合物，其为中的一个立体异构体：色谱柱:Cellulose 2 100*4.6mm I.D.,3um；流动相：A相为二氧化碳，B相为0.05％二乙胺/甲醇；梯度：保持50％的B相；流速：2.8毫升/分钟；The compound whose retention time is 4.369min under the following conditions is One stereoisomer in: Chromatographic column: Cellulose 2 100*4.6mm ID, 3um; Mobile phase: A phase is carbon dioxide, B phase is 0.05% diethylamine/methanol; Gradient: maintain 50% of B phase; Flow rate: 2.8 ml/min;
    在下述条件下保留时间为4.500min的化合物，其为中的一个立体异构体：色谱柱:Chiralpak IC-3 100*4.6mm I.D.,3um；流动相：A相为二氧化碳，B相为0.05％二乙胺/乙醇；梯度：保持50％的B相；流速：2.8毫升/分钟； The compound whose retention time is 4.500min under the following conditions is One stereoisomer in: Chromatographic column: Chiralpak IC-3 100*4.6mm ID, 3um; Mobile phase: A phase is carbon dioxide, B phase is 0.05% diethylamine/ethanol; Gradient: maintain 50% of B phase; Flow rate: 2.8 ml/min;
    在下述条件下保留时间为5.555min的化合物，其为中的一个立体异构体：色谱柱:Chiralpak IC-3 100*4.6mm I.D.,3um；流动相：A相为二氧化碳，B相为0.05％二乙胺/乙醇；梯度：保持50％的B相；流速：2.8毫升/分钟；The compound whose retention time is 5.555min under the following conditions is One stereoisomer in: Chromatographic column: Chiralpak IC-3 100*4.6mm ID, 3um; Mobile phase: A phase is carbon dioxide, B phase is 0.05% diethylamine/ethanol; Gradient: maintain 50% of B phase; Flow rate: 2.8 ml/min;
    在下述条件下保留时间为2.676min的化合物，其为中的一个立体异构体：色谱柱:(S,S)Whelk-01 100×4.6mm I.D.,5.0um；流动相：A相为二氧化碳，B相为0.05％二乙胺/异丙醇；梯度：B相保持60％；流速：2.5毫升/分钟；The compound whose retention time is 2.676min under the following conditions is One stereoisomer in: Chromatographic column: (S, S) Whelk-01 100×4.6mm ID, 5.0um; Mobile phase: A phase is carbon dioxide, B phase is 0.05% diethylamine/isopropanol; Gradient: B phase maintains 60%; Flow rate: 2.5 ml/min;
    在下述条件下保留时间为3.176min的化合物，其为中的一个立体异构体：色谱柱:(S,S)Whelk-01 100×4.6mm I.D.,5.0um；流动相：A相为二氧化碳，B相为0.05％二乙胺/异丙醇；梯度：B相保持60％；流速：2.5毫升/分钟； The compound whose retention time is 3.176min under the following conditions is One stereoisomer in: Chromatographic column: (S, S) Whelk-01 100×4.6mm ID, 5.0um; Mobile phase: A phase is carbon dioxide, B phase is 0.05% diethylamine/isopropanol; Gradient: B phase maintains 60%; Flow rate: 2.5 ml/min;
    在下述条件下保留时间为0.634min的化合物，其为中的一个立体异构体：色谱柱:Chiralpak IG-3 50*4.6mm I.D.,3um；流动相：A相为二氧化碳，B相为0.05％二乙胺/乙醇；梯度：B相保持40％；流速：4毫升/分钟；The compound whose retention time is 0.634min under the following conditions is One stereoisomer in: Chromatographic column: Chiralpak IG-3 50*4.6mm ID, 3um; Mobile phase: A phase is carbon dioxide, B phase is 0.05% diethylamine/ethanol; Gradient: B phase maintains 40%; Flow rate: 4 ml/min;
    在下述条件下保留时间为1.129min的化合物，其为中的一个立体异构体：色谱柱::Chiralpak IG-3 50*4.6mm I.D.,3um；流动相：A相为二氧化碳，B相为0.05％二乙胺/乙醇；梯度：B相保持40％；流速：4毫升/分钟。The compound whose retention time is 1.129min under the following conditions is One stereoisomer in: Chromatographic column:: Chiralpak IG-3 50*4.6mm ID, 3um; mobile phase: phase A is carbon dioxide, phase B is 0.05% diethylamine/ethanol; gradient: phase B maintains 40%; flow rate: 4 ml/min.
  15. 如权利要求1～14任一项所述的如式I-0所示的杂环类化合物、其药学上可接受的盐、其立体异构体或它们的溶剂合物，其特征在于，所述的如式I-0所示的杂环类化合物为如式I-1所示的化合物，
    The heterocyclic compound represented by formula I-0, its pharmaceutically acceptable salt, its stereoisomer or their solvate according to any one of claims 1 to 14, characterized in that, said heterocyclic compound represented by formula I-0 is a compound represented by formula I-1,
    其中，R4为J为H或卤素；Among them, R4 is J is H or halogen;
    其为以下情况中的任一种：It is any of the following:
    其中，1)的改进点对应RX1；2)的改进点对应X1和X3成环；3)的改进点X1与R1结构成环；4)的改进点对应R1 Wherein, 1) the improved point corresponds to R X1 ; 2) the improved point corresponds to X 1 and X 3 form a ring; 3) the improved point X 1 and R 1 structure form a ring; 4) the improved point corresponds to R 1
    1)X1为CRX1，RX1为被一个或多个卤素取代的C1-C6烷基、PO(C1-C6烷基)2、C3-C6环烷基、C2-C6烯基、C2-C6炔基、3～6元杂环烷基、被一个或多个X1-1取代的3～6元杂环烷基、被一个或多个X1- 2取代的5～8元杂芳基、NO2、3～6元杂环烯基、被一个或多个X1-3取代的3～6元杂环烯基、SF5、C(＝O)X1-4、NX1-5X1-6或SO2X1-7；或者RX1与RX3和其相连的原子共同形成C5-C8环烯酮结构；其他取代基的定义均如权利要求1～14任一项所述；1)X1for CRX1, RX1is C substituted by one or more halogens1-C6Alkyl, PO(C1-C6alkyl)2、C3-C6Cycloalkyl, C2-C6Alkenyl, C2-C6Alkynyl, 3-6 membered heterocycloalkyl, replaced by one or more X1-1Substituted 3-6 membered heterocycloalkyl, replaced by one or more X1- 2Substituted 5-8 membered heteroaryl, NO2, 3-6 membered heterocycloalkenyl, replaced by one or more X1-3Substituted 3-6 membered heterocycloalkenyl, SF5, C(=O)X1-4、NX1-5x1-6or SO2x1-7; or RX1with RX3Together with its attached atoms form C5-C8Cycloalkene structure; the definitions of other substituents are as described in any one of claims 1 to 14;
    2)X1为NRX1’，RX1’与RX3和其相连的原子共同形成5～8元杂芳环或被一个或多个羟基取代的5～8元杂芳环；其他取代基的定义均如权利要求1～14任一项所述；2) X 1 is NR X1' , R X1' and R X3 and the atoms connected to them together form a 5-8 membered heteroaromatic ring or a 5-8 membered heteroaromatic ring substituted by one or more hydroxyl groups; the definitions of other substituents are as described in any one of claims 1-14;
    3)X1为CRX1，其中，X1中的C原子与R1中的芳基或杂芳基中的C原子通过-O-(CH2)n1-*、*-NH-(CH2)n2-、-C≡C-(CH2)n3-C≡C-*或-(CH2)n4-O-(CH2)n5-*相连，其中，*端与X1中的C原子相连；其他取代基的定义以及n1、n2、n3、n4和n5的定义均如如权利要求1～14任一项所述；3) X 1 is CR X1 , wherein, the C atom in X 1 is connected to the C atom in the aryl or heteroaryl group in R 1 through -O-(CH 2 ) n1 -*, *-NH-(CH 2 ) n2 -, -C≡C-(CH 2 ) n3 -C≡C-* or -(CH 2 ) n4 -O-(CH 2 ) n5 -*, where the * terminal is connected to C in X 1 The atoms are connected; the definitions of other substituents and the definitions of n1, n2, n3, n4 and n5 are as described in any one of claims 1 to 14;
    4)R1为被一个或多个R1-1取代的C6～C14的芳基或被一个或多个R1-2取代的5～14元杂芳基；4) R 1 is a C 6 -C 14 aryl group substituted by one or more R 1-1 or a 5-14 membered heteroaryl group substituted by one or more R 1-2 ;
    当R1为被一个或多个R1-1取代的C6～C14的芳基时，相邻的两个R1-1与其相连的原子一起形成C3-C8脂碳环或被一个或多个R1-3取代的C3-C8脂碳环，其余R1-1独立地为卤素、OH、NH2、CN、C1-C6烷基、(C＝O)-C1-C6烷基、C2-C6炔基、被一个或多个卤素取代的C1-C6烷基、B(OH)2或O(C＝O)-C1-C10烷基；When R 1 is a C 6 -C 14 aryl group substituted by one or more R 1-1 , two adjacent R 1-1 and the atoms connected to them together form a C 3 -C 8 aliphatic carbon ring or a C 3 -C 8 aliphatic carbon ring substituted by one or more R 1-3 , and the remaining R 1-1 are independently halogen, OH, NH 2 , CN, C 1 -C 6 alkyl, (C=O)-C 1 -C 6 alkyl , C 2 -C 6 alkynyl, C 1 -C 6 alkyl substituted by one or more halogens, B(OH) 2 or O(C=O)-C 1 -C 10 alkyl;
    当R1为被一个或多个R1-2取代的5～14元杂芳基时，相邻的两个R1-2与其相连的原子一起形成C3-C8脂碳环或被一个或多个R1-4取代的C3-C8脂碳环，其余R1-2独立地为卤素、OH、NH2、CN、C1-C6烷基、(C＝O)-C1-C6烷基、C2-C6炔基、被一个或多个卤素取代的C1-C6烷基、B(OH)2或O(C＝O)-C1-C10烷基；When R 1 is a 5- to 14-membered heteroaryl group substituted by one or more R 1-2 , two adjacent R 1-2 and their connected atoms together form a C 3 -C 8 aliphatic carbon ring or a C 3 -C 8 aliphatic carbon ring substituted by one or more R 1-4 , and the remaining R 1-2 are independently halogen, OH, NH 2 , CN, C 1 -C 6 alkyl, (C=O)-C 1 -C 6 alkyl, C 2 -C 6 alkynyl, C 1 -C 6 alkyl substituted by one or more halogens, B(OH) 2 or O(C=O)-C 1 -C 10 alkyl;
    R1-3和R1-4独立地为卤素；R 1-3 and R 1-4 are independently halogen;
    其余各取代基的定义均如权利要求1～14任一项所述。The definitions of all other substituents are as described in any one of claims 1-14.
  16. 如权利要求1～14任一项所述的如式I-0所示的杂环类化合物、其药学上可接受的盐、其立体异构体或它们的溶剂合物，其特征在于，所述的如式I-0所示的杂环类化合物为如式I-2所示的化合物，
    The heterocyclic compound represented by formula I-0, its pharmaceutically acceptable salt, its stereoisomer or their solvate according to any one of claims 1 to 14, characterized in that, said heterocyclic compound represented by formula I-0 is a compound represented by formula I-2,
    其为以下情况中的任一种：It is any of the following:
    其中，1)的改进点在于R3；2)的改进点在于R4 Wherein, 1) the improvement point lies in R 3 ; 2) the improvement point lies in R 4
    1)R3为 时；其中，环A、环B和环C与母体结构共用一个碳原子，环D和环E与母体结构共用两个原子和一根键；环A、环B、环C、环D和环E各自独立地为3～8元脂杂环、C3-C8脂碳环或被一个或多个卤素取代的C3-C8脂碳环；1) R3 is When; wherein, Ring A, Ring B and Ring C share one carbon atom with the parent structure, and Ring D and Ring E share two atoms and one bond with the parent structure; Ring A, Ring B, Ring C, Ring D and Ring E are each independently 3-8 membered aliphatic heterocyclic rings, C 3 -C 8 aliphatic carbocyclic rings, or C 3 -C 8 aliphatic carbocyclic rings substituted by one or more halogens;
    R4为 其中，R4-1为H、C1-C6烷基或(C＝O)-O-CH2-O-(C＝O)-C1-C10烷基；R4-2为C1-C6烷基，R4-2的个数为一个或多个；R4-3和R4-4各自独立地为H或3～8元杂环烷基，或者R4-3和R4-4与其相连的碳原子共同形成3～8元脂杂环；环G、环I和环J与母体结构共用一个碳原子，环F和环H与母体结构共用两个原子和一根键，环F、环G、环H、环I和环J各自独立地为C3-C8脂碳环、3～8元脂杂环、5～8元内酰胺环或被一个或多个Re取代的3～8元脂杂环；Re为C1-C6烷基； R4 is 其中，R 4-1为H、C 1 -C 6烷基或(C＝O)-O-CH 2 -O-(C＝O)-C 1 -C 10烷基；R 4-2为C 1 -C 6烷基，R 4-2的个数为一个或多个；R 4-3和R 4-4各自独立地为H或3～8元杂环烷基，或者R 4-3和R 4-4与其相连的碳原子共同形成3～8元脂杂环；环G、环I和环J与母体结构共用一个碳原子，环F和环H与母体结构共用两个原子和一根键，环F、环G、环H、环I和环J各自独立地为C 3 -C 8脂碳环、3～8元脂杂环、5～8元内酰胺环或被一个或多个R e取代的3～8元脂杂环；R e为C 1 -C 6烷基；
    其余各取代基的定义均如权利要求1～14任一项所述；The definitions of all other substituents are as described in any one of claims 1 to 14;
    2)R3为 时；其中X为卤素；环A、环B和环C与母体结构共用一个碳原子，环D和环E与母体结构共用两个原子和一根键；环A、环B、环C、环D和环E各自独立地为3～8元脂杂环、C3-C8脂碳环或被一个或多个卤素取代的C3-C8脂碳环； 2) R3 is when X is halogen; ring A, ring B and ring C share one carbon atom with the parent structure, ring D and ring E share two atoms and one bond with the parent structure; ring A, ring B, ring C, ring D and ring E are each independently 3-8 membered aliphatic heterocyclic rings, C 3 -C 8 aliphatic carbocyclic rings or C 3 -C 8 aliphatic carbocyclic rings substituted by one or more halogens;
    R4为 其中，X为卤素；R4-1为C1-C6烷基或(C＝O)-O-CH2-O-(C＝O)-C1-C10烷基；R4-3和R4-4各自独立地为H或3～8元杂环烷基，或者R4-3和R4-4与其相连的碳原子共同形成3～8元脂杂环；环G、环I和环J与母体结构共用一个碳原子，环F和环H与母体结构共用两个原子和一根键，环F、环G、环H、环I和环J各自独立地为C3-C8脂碳环、3～8元脂杂环、5～8元内酰胺环或被一个或多个Re取代的3～8元脂杂环；Re为C1-C6烷基； R4 is 其中，X为卤素；R 4-1为C 1 -C 6烷基或(C＝O)-O-CH 2 -O-(C＝O)-C 1 -C 10烷基；R 4-3和R 4-4各自独立地为H或3～8元杂环烷基，或者R 4-3和R 4-4与其相连的碳原子共同形成3～8元脂杂环；环G、环I和环J与母体结构共用一个碳原子，环F和环H与母体结构共用两个原子和一根键，环F、环G、环H、环I和环J各自独立地为C 3 -C 8脂碳环、3～8元脂杂环、5～8元内酰胺环或被一个或多个R e取代的3～8元脂杂环；R e为C 1 -C 6烷基；
    其余各取代基的定义均如权利要求1～14任一项所述。The definitions of all other substituents are as described in any one of claims 1-14.
  17. 一种药物组合物，其包括：A pharmaceutical composition comprising:
    (1)如权利要求1-16任一项所述的杂环类化合物、其药学上可接受的盐、其立体异构体或它们的溶剂合物，和(1) The heterocyclic compound according to any one of claims 1-16, its pharmaceutically acceptable salt, its stereoisomer or their solvate, and
    (2)药用辅料。(2) Pharmaceutical excipients.
  18. 物质A或如权利要求17所述的药物组合物在制备KRAS G12D抑制剂的应用，所述的物质A为如权利要求1-16任一项所述的杂环类化合物、其药学上可接受的盐、其立体异构体或它们的溶剂合物。The application of substance A or the pharmaceutical composition as claimed in claim 17 in the preparation of KRAS G12D inhibitor, said substance A is the heterocyclic compound as described in any one of claims 1-16, its pharmaceutically acceptable salt, its stereoisomer or their solvate.
  19. 物质A或如权利要求17所述的药物组合物在制备药物的应用，所述的物质A为如权利要求1-16任一项所述的杂环类化合物、其药学上可接受的盐、其立体异构体或它们的溶剂合物，所述药物用于治疗癌症，较佳地，所述癌症为结直肠癌，胃癌，胰腺癌，非小细胞肺癌，前列腺癌，乳腺癌。 The application of substance A or the pharmaceutical composition as claimed in claim 17 in the preparation of medicine, said substance A is the heterocyclic compound as claimed in any one of claims 1-16, its pharmaceutically acceptable salt, its stereoisomer or their solvate, said medicine is used for treating cancer, preferably, said cancer is colorectal cancer, gastric cancer, pancreatic cancer, non-small cell lung cancer, prostate cancer, breast cancer.
PCT/CN2023/072654 2022-01-21 2023-01-17 Heterocyclic compound, pharmaceutical composition and use thereof WO2023138583A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN202380017933.9A CN118556063A (en) 2022-01-21 2023-01-17 Heterocyclic compound, pharmaceutical composition and application thereof

Applications Claiming Priority (10)

Application Number Priority Date Filing Date Title
CN202210069864 2022-01-21
CN202210069864.3 2022-01-21
CN202210500130.6 2022-05-06
CN202210500130 2022-05-06
CN202210900237.X 2022-07-28
CN202210900237 2022-07-28
CN202211193916.4 2022-09-28
CN202211193916 2022-09-28
CN202310010142 2023-01-04
CN202310010142.5 2023-01-04

Publications (1)

Publication Number Publication Date
WO2023138583A1 true WO2023138583A1 (en) 2023-07-27

Family

ID=87347847

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2023/072654 WO2023138583A1 (en) 2022-01-21 2023-01-17 Heterocyclic compound, pharmaceutical composition and use thereof

Country Status (3)

Country Link
CN (1) CN118556063A (en)
TW (1) TWI841200B (en)
WO (1) WO2023138583A1 (en)

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2024054926A1 (en) * 2022-09-07 2024-03-14 Bristol-Myers Squibb Company Kras g12d inhibitors
WO2024051852A1 (en) * 2022-09-09 2024-03-14 上海翰森生物医药科技有限公司 Pyrimidine-containing polycyclic biological inhibitor, preparation method therefor, and use thereof
WO2024056063A1 (en) * 2022-09-16 2024-03-21 南京明德新药研发有限公司 Compound containing hexahydro-spiro [cyclopropane-1,2'-pyrrolizine]
WO2024061365A1 (en) * 2022-09-22 2024-03-28 成都奥睿药业有限公司 Pyrimidine fused ring compound, preparation method therefor, and use thereof
WO2024061333A1 (en) * 2022-09-21 2024-03-28 甘李药业股份有限公司 Kras mutant protein inhibitor, preparation method therefor, and use thereof
WO2024112654A1 (en) 2022-11-21 2024-05-30 Treeline Biosciences, Inc. Spirocyclic dihydropyranopyrimidine kras inhibitors
WO2024119277A1 (en) * 2022-12-08 2024-06-13 Risen (Suzhou) Pharma Tech Co., Ltd. Kras inhibitors and pharmaceutical uses thereof
WO2024149389A1 (en) * 2023-01-13 2024-07-18 苏州泽璟生物制药股份有限公司 Substituted bridge ring inhibitor, preparation method therefor, and application thereof
WO2024179546A1 (en) * 2023-03-01 2024-09-06 Ascentage Pharma (Suzhou) Co., Ltd. Kras inhibitors

Citations (35)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020146613A1 (en) * 2019-01-10 2020-07-16 Mirati Therapeutics, Inc. Kras g12c inhibitors
WO2021041671A1 (en) * 2019-08-29 2021-03-04 Mirati Therapeutics, Inc. Kras g12d inhibitors
WO2022002102A1 (en) * 2020-06-30 2022-01-06 InventisBio Co., Ltd. Quinazoline compounds, preparation methods and uses thereof
WO2022015375A1 (en) * 2020-07-16 2022-01-20 Mirati Therapeutics, Inc. Kras g12d inhibitors
WO2022042630A1 (en) * 2020-08-26 2022-03-03 InventisBio Co., Ltd. Heteroaryl compounds, preparation methods and uses thereof
WO2022061251A1 (en) * 2020-09-18 2022-03-24 Plexxikon Inc. Compounds and methods for kras modulation and indications therefor
WO2022068921A1 (en) * 2020-09-30 2022-04-07 上海医药集团股份有限公司 Quinazoline compound and application thereof
WO2022105859A1 (en) * 2020-11-20 2022-05-27 Jacobio Pharmaceuticals Co., Ltd. Kras g12d inhibitors
WO2022132200A1 (en) * 2020-12-15 2022-06-23 Mirati Therapeutics, Inc. Azaquinazoline pan-kras inhibitors
WO2022148422A1 (en) * 2021-01-08 2022-07-14 Beigene, Ltd. Bridged compounds as kras g12d inhibitor and degrader and the use thereof
WO2022171147A1 (en) * 2021-02-09 2022-08-18 南京明德新药研发有限公司 Pyrimidine aromatic ring compounds
WO2022173870A1 (en) * 2021-02-09 2022-08-18 Kumquat Biosciences Inc. Heterocyclic compounds and uses thereof
WO2022170999A1 (en) * 2021-02-09 2022-08-18 南京明德新药研发有限公司 Pyridine[4,3-d]pyrimidine compound
WO2022177917A2 (en) * 2021-02-16 2022-08-25 Theras, Inc. Compositions and methods for inhibition of ras
WO2022184178A1 (en) * 2021-03-05 2022-09-09 Jacobio Pharmaceuticals Co., Ltd. Kras g12d inhibitors
WO2022187528A1 (en) * 2021-03-05 2022-09-09 Nikang Therapeutics, Inc Quinazoline amine derivatives as kras inhibitors
WO2022192794A1 (en) * 2021-03-12 2022-09-15 Bristol-Myers Squibb Company Kras g12d inhibitors
WO2022194191A1 (en) * 2021-03-16 2022-09-22 Guangdong Newopp Biopharmaceuticals Co., Ltd. Heterocyclic compounds as inhibitors of kras g12d
CN115141215A (en) * 2021-03-30 2022-10-04 上海德琪医药科技有限公司 KRAS G12D protein inhibitors and uses thereof
WO2022214102A1 (en) * 2021-04-09 2022-10-13 杭州英创医药科技有限公司 Heterocyclic compound acting as kras g12d inhibitor
CN115197245A (en) * 2021-04-09 2022-10-18 上海拓界生物医药科技有限公司 Kras inhibitor and preparation method thereof
WO2022221739A1 (en) * 2021-04-16 2022-10-20 Merck Sharp & Dohme Corp. Small molecule inhibitors of kras g12d mutant
WO2022232332A1 (en) * 2021-04-29 2022-11-03 Amgen Inc. 2-aminobenzothiazole compounds and methods of use thereof
WO2022228568A1 (en) * 2021-04-30 2022-11-03 劲方医药科技(上海)有限公司 Pyridino- or pyrimido-cyclic compound, preparation method therefor and medical use thereof
WO2022232331A1 (en) * 2021-04-29 2022-11-03 Amgen Inc. Heterocyclic compounds and methods of use
WO2022228543A1 (en) * 2021-04-30 2022-11-03 江苏恒瑞医药股份有限公司 Bridged ring compound, preparation method therefor, and application thereof in medicine
CN115304623A (en) * 2021-04-30 2022-11-08 四川海思科制药有限公司 Pyrimido-cyclic derivative and application thereof in medicine
WO2022236578A1 (en) * 2021-05-10 2022-11-17 Nikang Therapeutics, Inc. Exocyclic amino quinazoline derivatives as kras inhibitors
WO2022248885A2 (en) * 2021-05-28 2022-12-01 Redx Pharma Plc. Compounds
WO2022247760A1 (en) * 2021-05-22 2022-12-01 上海科州药物研发有限公司 Heterocyclic compounds as kras inhibitor, and preparation therefor and use thereof in treatment
WO2022258974A1 (en) * 2021-06-10 2022-12-15 Redx Pharma Plc Quinazoline derivatives useful as ras inhibitiors
CN115490709A (en) * 2021-04-30 2022-12-20 四川海思科制药有限公司 KRASG12D inhibitor and application thereof in medicine
WO2022262686A1 (en) * 2021-06-13 2022-12-22 Jingrui Biopharma Co., Ltd. Kras g12d inhibitors
WO2023274324A1 (en) * 2021-06-30 2023-01-05 上海艾力斯医药科技股份有限公司 Nitrogen-containing heterocyclic compound, and preparation method therefor, intermediate thereof, and application thereof
WO2023280280A1 (en) * 2021-07-07 2023-01-12 微境生物医药科技(上海)有限公司 Fused-ring compound that acts as kras g12d inhibitor

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JO3556B1 (en) * 2014-09-18 2020-07-05 Araxes Pharma Llc Combination therapies for treatment of cancer
EP3458445B1 (en) * 2016-05-18 2021-02-17 Mirati Therapeutics, Inc. Kras g12c inhibitors
AU2018369759B2 (en) * 2017-11-15 2022-11-24 Array Biopharma Inc. KRas G12C inhibitors

Patent Citations (35)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020146613A1 (en) * 2019-01-10 2020-07-16 Mirati Therapeutics, Inc. Kras g12c inhibitors
WO2021041671A1 (en) * 2019-08-29 2021-03-04 Mirati Therapeutics, Inc. Kras g12d inhibitors
WO2022002102A1 (en) * 2020-06-30 2022-01-06 InventisBio Co., Ltd. Quinazoline compounds, preparation methods and uses thereof
WO2022015375A1 (en) * 2020-07-16 2022-01-20 Mirati Therapeutics, Inc. Kras g12d inhibitors
WO2022042630A1 (en) * 2020-08-26 2022-03-03 InventisBio Co., Ltd. Heteroaryl compounds, preparation methods and uses thereof
WO2022061251A1 (en) * 2020-09-18 2022-03-24 Plexxikon Inc. Compounds and methods for kras modulation and indications therefor
WO2022068921A1 (en) * 2020-09-30 2022-04-07 上海医药集团股份有限公司 Quinazoline compound and application thereof
WO2022105859A1 (en) * 2020-11-20 2022-05-27 Jacobio Pharmaceuticals Co., Ltd. Kras g12d inhibitors
WO2022132200A1 (en) * 2020-12-15 2022-06-23 Mirati Therapeutics, Inc. Azaquinazoline pan-kras inhibitors
WO2022148422A1 (en) * 2021-01-08 2022-07-14 Beigene, Ltd. Bridged compounds as kras g12d inhibitor and degrader and the use thereof
WO2022171147A1 (en) * 2021-02-09 2022-08-18 南京明德新药研发有限公司 Pyrimidine aromatic ring compounds
WO2022173870A1 (en) * 2021-02-09 2022-08-18 Kumquat Biosciences Inc. Heterocyclic compounds and uses thereof
WO2022170999A1 (en) * 2021-02-09 2022-08-18 南京明德新药研发有限公司 Pyridine[4,3-d]pyrimidine compound
WO2022177917A2 (en) * 2021-02-16 2022-08-25 Theras, Inc. Compositions and methods for inhibition of ras
WO2022184178A1 (en) * 2021-03-05 2022-09-09 Jacobio Pharmaceuticals Co., Ltd. Kras g12d inhibitors
WO2022187528A1 (en) * 2021-03-05 2022-09-09 Nikang Therapeutics, Inc Quinazoline amine derivatives as kras inhibitors
WO2022192794A1 (en) * 2021-03-12 2022-09-15 Bristol-Myers Squibb Company Kras g12d inhibitors
WO2022194191A1 (en) * 2021-03-16 2022-09-22 Guangdong Newopp Biopharmaceuticals Co., Ltd. Heterocyclic compounds as inhibitors of kras g12d
CN115141215A (en) * 2021-03-30 2022-10-04 上海德琪医药科技有限公司 KRAS G12D protein inhibitors and uses thereof
WO2022214102A1 (en) * 2021-04-09 2022-10-13 杭州英创医药科技有限公司 Heterocyclic compound acting as kras g12d inhibitor
CN115197245A (en) * 2021-04-09 2022-10-18 上海拓界生物医药科技有限公司 Kras inhibitor and preparation method thereof
WO2022221739A1 (en) * 2021-04-16 2022-10-20 Merck Sharp & Dohme Corp. Small molecule inhibitors of kras g12d mutant
WO2022232331A1 (en) * 2021-04-29 2022-11-03 Amgen Inc. Heterocyclic compounds and methods of use
WO2022232332A1 (en) * 2021-04-29 2022-11-03 Amgen Inc. 2-aminobenzothiazole compounds and methods of use thereof
WO2022228543A1 (en) * 2021-04-30 2022-11-03 江苏恒瑞医药股份有限公司 Bridged ring compound, preparation method therefor, and application thereof in medicine
WO2022228568A1 (en) * 2021-04-30 2022-11-03 劲方医药科技(上海)有限公司 Pyridino- or pyrimido-cyclic compound, preparation method therefor and medical use thereof
CN115304623A (en) * 2021-04-30 2022-11-08 四川海思科制药有限公司 Pyrimido-cyclic derivative and application thereof in medicine
CN115490709A (en) * 2021-04-30 2022-12-20 四川海思科制药有限公司 KRASG12D inhibitor and application thereof in medicine
WO2022236578A1 (en) * 2021-05-10 2022-11-17 Nikang Therapeutics, Inc. Exocyclic amino quinazoline derivatives as kras inhibitors
WO2022247760A1 (en) * 2021-05-22 2022-12-01 上海科州药物研发有限公司 Heterocyclic compounds as kras inhibitor, and preparation therefor and use thereof in treatment
WO2022248885A2 (en) * 2021-05-28 2022-12-01 Redx Pharma Plc. Compounds
WO2022258974A1 (en) * 2021-06-10 2022-12-15 Redx Pharma Plc Quinazoline derivatives useful as ras inhibitiors
WO2022262686A1 (en) * 2021-06-13 2022-12-22 Jingrui Biopharma Co., Ltd. Kras g12d inhibitors
WO2023274324A1 (en) * 2021-06-30 2023-01-05 上海艾力斯医药科技股份有限公司 Nitrogen-containing heterocyclic compound, and preparation method therefor, intermediate thereof, and application thereof
WO2023280280A1 (en) * 2021-07-07 2023-01-12 微境生物医药科技(上海)有限公司 Fused-ring compound that acts as kras g12d inhibitor

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
WANG XIAOLUN, ALLEN SHELLEY, BLAKE JAMES F., BOWCUT VICKIE, BRIERE DAVID M., CALINISAN ANDREW, DAHLKE JOSHUA R., FELL JAY B., FISC: "Identification of MRTX1133, a Noncovalent, Potent, and Selective KRAS G12D Inhibitor", JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY, US, vol. 65, no. 4, 24 February 2022 (2022-02-24), US , pages 3123 - 3133, XP055952002, ISSN: 0022-2623, DOI: 10.1021/acs.jmedchem.1c01688 *

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2024054926A1 (en) * 2022-09-07 2024-03-14 Bristol-Myers Squibb Company Kras g12d inhibitors
WO2024051852A1 (en) * 2022-09-09 2024-03-14 上海翰森生物医药科技有限公司 Pyrimidine-containing polycyclic biological inhibitor, preparation method therefor, and use thereof
WO2024056063A1 (en) * 2022-09-16 2024-03-21 南京明德新药研发有限公司 Compound containing hexahydro-spiro [cyclopropane-1,2'-pyrrolizine]
WO2024061333A1 (en) * 2022-09-21 2024-03-28 甘李药业股份有限公司 Kras mutant protein inhibitor, preparation method therefor, and use thereof
WO2024061365A1 (en) * 2022-09-22 2024-03-28 成都奥睿药业有限公司 Pyrimidine fused ring compound, preparation method therefor, and use thereof
WO2024112654A1 (en) 2022-11-21 2024-05-30 Treeline Biosciences, Inc. Spirocyclic dihydropyranopyrimidine kras inhibitors
WO2024119277A1 (en) * 2022-12-08 2024-06-13 Risen (Suzhou) Pharma Tech Co., Ltd. Kras inhibitors and pharmaceutical uses thereof
WO2024149389A1 (en) * 2023-01-13 2024-07-18 苏州泽璟生物制药股份有限公司 Substituted bridge ring inhibitor, preparation method therefor, and application thereof
WO2024179546A1 (en) * 2023-03-01 2024-09-06 Ascentage Pharma (Suzhou) Co., Ltd. Kras inhibitors

Also Published As

Publication number Publication date
TWI841200B (en) 2024-05-01
CN118556063A (en) 2024-08-27
TW202330536A (en) 2023-08-01

Similar Documents

Publication Publication Date Title
WO2023138583A1 (en) Heterocyclic compound, pharmaceutical composition and use thereof
TWI675833B (en) Biaryl inhibitors of bruton's tyrosine kinase
TWI680970B (en) Heteroaryl compounds useful as inhibitors of sumo activating enzyme
CN105732636B (en) Heteroaromatic compounds and their use in medicine
CN112166110A (en) SHP2 phosphatase inhibitors and methods of use thereof
EP4332105A1 (en) Pyridino- or pyrimido-cyclic compound, preparation method therefor and medical use thereof
CN111902415A (en) Pharmaceutical compounds
WO2020221239A1 (en) Oxaazaquinazoline-7(8h)-ketone compound, preparation method therfor and pharmaceutical application thereof
AU2018369759A1 (en) KRas G12C inhibitors
CA3228310A1 (en) Heterocyclic compounds and methods of use
CN107709322B (en) Tricyclic compounds as anticancer agents
TW202321242A (en) Heterocyclic compounds and methods of use
EP3681885B1 (en) Tetrahydro-imidazo quinoline compositions as cbp/p300 inhibitors
WO2023061294A1 (en) Nitrogen-containing heterocyclic derivative regulator, preparation method therefor and application thereof
CN108349996B (en) Tricyclic PI3K inhibitor compounds and methods of use thereof
TW201512173A (en) Alkynyl alcohols and methods of use
CN114269763A (en) Small molecule degradant for STAT3
WO2022134641A1 (en) Aromatic heterocyclic compound, pharmaceutical composition and use thereof
CN115867346A (en) Kinase inhibitors
CN113993872A (en) EGFR inhibitors for the treatment of cancer
CN117858872A (en) Heterocyclic EGFR inhibitors for the treatment of cancer
TW201516045A (en) Serine/threonine kinase inhibitors
CN111315750B (en) Pyridopyrimidines as mTORC1/2 dikinase inhibitors
WO2023116761A1 (en) Pyrimidine heterocyclic compound, preparation method therefor and use thereof in medicine
TW202300152A (en) Egfr inhibitors

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 23742898

Country of ref document: EP

Kind code of ref document: A1

WWE Wipo information: entry into national phase

Ref document number: 202380017933.9

Country of ref document: CN

NENP Non-entry into the national phase

Ref country code: DE