WO2022194245A1 - 嘧啶并环类化合物及其制法和用途 - Google Patents

嘧啶并环类化合物及其制法和用途 Download PDF

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Publication number
WO2022194245A1
WO2022194245A1 PCT/CN2022/081443 CN2022081443W WO2022194245A1 WO 2022194245 A1 WO2022194245 A1 WO 2022194245A1 CN 2022081443 W CN2022081443 W CN 2022081443W WO 2022194245 A1 WO2022194245 A1 WO 2022194245A1
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alkyl
haloalkyl
group
phenyl
halogen
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PCT/CN2022/081443
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English (en)
French (fr)
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蒋涛
周福生
张磊涛
蔡礼健
严峰
赵吉辰
兰炯
吕强
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劲方医药科技(上海)有限公司
浙江劲方药业有限公司
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Priority to JP2023557251A priority Critical patent/JP2024510022A/ja
Priority to EP22770598.5A priority patent/EP4310091A1/en
Priority to CA3211725A priority patent/CA3211725A1/en
Priority to CN202280021461.XA priority patent/CN117043167A/zh
Priority to AU2022235948A priority patent/AU2022235948A1/en
Priority to BR112023018785A priority patent/BR112023018785A2/pt
Priority to KR1020237035321A priority patent/KR20230157463A/ko
Publication of WO2022194245A1 publication Critical patent/WO2022194245A1/zh

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    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/22—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains four or more hetero rings
    • 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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • 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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/553—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one oxygen as ring hetero atoms, e.g. loxapine, staurosporine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the invention belongs to the field of medicine, in particular to a class of pyrimidocyclic compounds and a preparation method and uses thereof.
  • KRAS is a 21 kD member of the Ras family of GTPases proteins and is an essential component of cell signaling.
  • the role of KRAS in malignancies and its mutations in various tumor types eg, G12C mutation, G12D mutation, G12V mutation, etc.
  • KRAS G12C inhibitors of AMG and MIRATI have shown sufficient safety and efficacy.
  • KRAS inhibitors, especially the inhibition of activating KRAS mutants There is still ongoing interest and effort in the development of new agents, especially KRAS G12D.
  • the present invention provides a class of pyrimidocyclic compounds with novel structures, which will act as KRAS G12D inhibitors and have the advantages of high activity, good selectivity and low toxicity and side effects.
  • the first aspect of the present invention provides a compound that can be used as a KRAS G12D inhibitor or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof; the compound is of formula (I), formula (II- 1), a compound represented by formula (II-2) or formula (III).
  • the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof:
  • X is O or NR 11 ; wherein, R 11 is selected from H and C1-C6 alkyl;
  • Y is CR 12 R 13 , CR 14 R 15 CR 16 R 17 , C(O) or C(O)CR 18 R 19 ; wherein R 12 , R 13 , R 14 and R 15 are each independently selected from H, C1-C3 alkyl, C1-C3 deuterated alkyl and C1-C3 haloalkyl; R 16 , R 17 , R 18 , R 19 are each independently selected from H, C1-C3 alkyl and halogen;
  • W is N or CR 20 ; wherein, R 20 is H, C1-C6 alkyl, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, cycloalkyl, cycloalkyl-O-, heterocyclyl or Heterocyclyl-O-; wherein, the cycloalkyl group and the heterocyclyl group are each independently optionally substituted by halogen;
  • Ring A is selected from the group consisting of aryl, heteroaryl;
  • R 21 is H, C1-C6 alkyl, C1-C6 haloalkyl, C(O)C1-C6 alkyl or C(O) 2 C1-C6 alkyl;
  • R 22 is H, C1-C6 alkyl or C1 -C6 haloalkyl; or R 21 , R 22 and the nitrogen atom to which they are attached together form a 3- to 6-membered nitrogen-containing heterocyclic group, the 3- to 6-membered nitrogen-containing heterocyclic group is optionally replaced by 1 or 2 Substituted with a group selected from halogen, methyl, trifluoromethyl, methoxy, trifluoromethoxy;
  • R 23 , R 24 are each independently H, C1-C6 alkyl or C1-C6 haloalkyl; or R 23 , R 24 and the nitrogen atom to which they are attached together form a 3- to 6-membered nitrogen-containing heterocyclic group, the said The 3- to 6-membered nitrogen-containing heterocyclic group is optionally substituted with 1 or 2 groups selected from halogen, methyl, trifluoromethyl, methoxy, trifluoromethoxy;
  • R 25 is hydroxyl, cyano, heterocyclyl, NR 251 R 252 , C(O)NR 253 R 254 or SO 2 C1-C6 alkyl; wherein, R 251 , R 252 , R 253 , R 254 are each independently is H or C1-C6 alkyl; R 251 , R 252 and the nitrogen atom connected to them together form a 3- to 6-membered nitrogen-containing heterocyclic group, and the 3- to 6-membered nitrogen-containing heterocyclic group is optionally replaced by a Or 2 groups selected from halogen, methyl, trifluoromethyl, methoxy, trifluoromethoxy substituted; R 253 , R 254 and the nitrogen atoms connected to them together form a 3- to 6-membered nitrogen-containing hetero group cyclic group, the 3- to 6-membered nitrogen-containing heterocyclic group is optionally substituted with 1 or 2 groups selected from halogen, methyl, trifluoromethyl, methoxy, trifluorome
  • R 26 is C1-C6 alkyl, C1-C6 haloalkyl or NR 261 R 262 ; wherein, R 261 and R 262 are each independently H or C1-C6 alkyl; or R 261 , R 262 and the The nitrogen atoms together form a 3- to 6-membered nitrogen-containing heterocyclic group, which is optionally replaced by 1 or 2 atoms selected from halogen, methyl, trifluoromethyl, methoxy, group substitution of trifluoromethoxy;
  • R 27 , R 28 are each independently H, C1-C6 alkyl or C1-C6 haloalkyl; or R 27 , R 28 and the nitrogen atom to which they are attached together form a 3- to 6-membered nitrogen-containing heterocyclic group, the said The 3- to 6-membered nitrogen-containing heterocyclic group is optionally substituted with 1 or 2 groups selected from halogen, methyl, trifluoromethyl, methoxy, trifluoromethoxy;
  • R 29 , R 30 are each independently H, C1-C6 alkyl or C1-C6 haloalkyl; or R 29 , R 30 and the nitrogen atom to which they are attached together form a 3- to 6-membered nitrogen-containing heterocyclic group, the said The 3- to 6-membered nitrogen-containing heterocyclic group is optionally substituted with 1 or 2 groups selected from halogen, methyl, trifluoromethyl, methoxy, trifluoromethoxy;
  • n1 0, 1, 2 or 3;
  • R 2 is H, cyano, halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 deuterated alkoxy, NR 31 R 32 , C2-C4 alkynyl or CH 2 OR 33 ; wherein, R 31 , R 32 and R 33 are each independently hydrogen or C1-C6 alkyl;
  • R 3a , R 3b , R 3c are each independently hydrogen, halogen, hydroxy, cyano, C1-C3 alkyl, C1-C3 deuterated alkyl or C1-C3 haloalkyl;
  • L 1 is a bond, O or NR 34 ;
  • L 2 is a C1-C4 alkylene group or a heteroaryl group; wherein, 1 or 2 hydrogen atoms on any carbon atom of the C1-C4 alkylene group or on any same carbon atom are optionally each independently substituted by deuterium, C1-C6 alkyl or C1-C6 haloalkyl; or 2 hydrogen atoms on any one carbon atom of the C1-C4 alkylene are optionally simultaneously replaced by -(CH 2 ) m3 -, - (CH 2 ) m1 -O-(CH 2 ) m2 -, -(CH 2 ) m1 -N-(CH 2 ) m2 - is substituted to form a cyclic substituent; m3 is 1 or 2; each m1 is independently 0, 1, 2, or 3; each m2 is independently 0, 1, 2, or 3; and m1, m2 are not 0 at the same time;
  • Ring B is a 3- to 6-membered nitrogen-containing heterocyclic group
  • Ring C is a 3- to 6-membered nitrogen-containing heterocyclic group
  • R 4 is a substituent at any position on the ring B; n2 is 0, 1, 2 or 3;
  • R 5 is a substituent at any position on ring C; n3 is 0, 1, 2 or 3;
  • R 4 , R 5 are defined as follows:
  • each R 4 , each R 5 is independently halogen, hydroxy, C1-C3 hydroxyalkyl, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, cyano, - Phenyl, -Phenyl- SO2F , -O-Phenyl, -O-Phenyl- SO2F , -NHC(O)Phenyl, -NHC(O)Phenyl- SO2F , C1-C3 Alkyl-substituted pyrazolyl, aryl C1-C3 alkyl-, tert-butyldimethylsilyl CH 2 -, -N(R 34 ) 2 , (C1-C3 alkoxy)C1-C3 alkyl , (C1-C3 alkyl) C(O), oxo, (C1-C3 haloalkyl) C(O)-)-
  • R 4 is -CH 2 CH 2 - or -CH 2 CH 2 CH 2 - and together with the carbon atom to which it is attached forms cyclopropyl or cyclobutyl; the remaining R 4 and each R 5 are individually independently halogen, hydroxy, C1-C3 hydroxyalkyl, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, cyano, -phenyl, -phenyl-SO 2 F, -O -phenyl, -O-phenyl- SO2F , -NHC(O)phenyl, -NHC(O)phenyl- SO2F , C1-C3 alkyl substituted pyrazolyl, aryl C1-C3 alkane base-, tert-butyldimethylsilyl CH 2 -, -N(R 34 ) 2 , (C1-C3 alkoxy) C1-C3
  • R 5 is -CH 2 CH 2 - or -CH 2 CH 2 CH 2 - and together with the carbon atom to which it is attached forms cyclopropyl or cyclobutyl; the remaining R 5 and each R 4 are individually independently halogen, hydroxy, C1-C3 hydroxyalkyl, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, cyano, -phenyl, -phenyl-SO 2 F, -O -phenyl, -O-phenyl- SO2F , -NHC(O)phenyl, -NHC(O)phenyl- SO2F , C1-C3 alkyl substituted pyrazolyl, aryl C1-C3 alkane base-, tert-butyldimethylsilyl CH 2 -, -N(R 34 ) 2 , (C1-C3 alkoxy) C1-C3
  • R 4 is -CH 2 CH 2 - or -CH 2 CH 2 CH 2 - and together with the carbon atom attached to it constitutes cyclopropyl or cyclobutyl
  • 1 R 5 is -CH 2 CH 2 - or -CH 2 CH 2 CH 2 - and together with the carbon atoms attached to it form cyclopropyl or cyclobutyl
  • the remaining R 4 and the remaining R 5 are each independently halogen, hydroxy, C1-C3 hydroxyalkyl , C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, cyano, -phenyl, -phenyl-SO 2 F, -O-phenyl, -O-phenyl-SO 2 F , -NHC(O)phenyl, -NHC(O)phenyl-SO 2 F, C1-C3 alkyl substituted pyrazolyl, aryl C1-C3 alkyl
  • Each R 34 is independently hydrogen, C1-C3 alkyl or C1-C3 haloalkyl; or two R 34 and the nitrogen atom to which they are attached together form a 3- to 6-membered nitrogen-containing heterocyclic group, the 3- to The 6-membered nitrogen-containing heterocyclyl is optionally substituted with 1 or 2 groups selected from halogen, methyl, trifluoromethyl, methoxy, trifluoromethoxy.
  • the compound is of formula (I-1) or formula (I-2):
  • the present invention provides a compound represented by formula (II-1) or formula (II-2) or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof:
  • q 1 or 2;
  • X is O or NR 11 ; wherein, R 11 is selected from H and C1-C6 alkyl;
  • Y is CR 12 R 13 , CR 14 R 15 CR 16 R 17 , C(O) or C(O)CR 18 R 19 ; wherein R 12 , R 13 , R 14 and R 15 are each independently selected from H, C1-C3 alkyl, C1-C3 deuterated alkyl and C1-C3 haloalkyl; R 16 , R 17 , R 18 , R 19 are each independently selected from H, C1-C3 alkyl and halogen;
  • W is N or CR 20 ; wherein, R 20 is H, C1-C6 alkyl, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, cycloalkyl, cycloalkyl-O-, heterocyclyl or Heterocyclyl-O-; wherein, the cycloalkyl group and the heterocyclyl group are each independently optionally substituted by halogen;
  • Ring A is selected from the group consisting of aryl, heteroaryl;
  • R 21 is H, C1-C6 alkyl, C1-C6 haloalkyl, C(O)C1-C6 alkyl or C(O) 2 C1-C6 alkyl;
  • R 22 is H, C1-C6 alkyl or C1 -C6 haloalkyl; or R 21 , R 22 and the nitrogen atom to which they are attached together form a 3- to 6-membered nitrogen-containing heterocyclic group, the 3- to 6-membered nitrogen-containing heterocyclic group is optionally replaced by 1 or 2 Substituted with a group selected from halogen, methyl, trifluoromethyl, methoxy, trifluoromethoxy;
  • R 23 , R 24 are each independently H, C1-C6 alkyl or C1-C6 haloalkyl; or R 23 , R 24 and the nitrogen atom to which they are attached together form a 3- to 6-membered nitrogen-containing heterocyclic group, the said The 3- to 6-membered nitrogen-containing heterocyclic group is optionally substituted with 1 or 2 groups selected from halogen, methyl, trifluoromethyl, methoxy, trifluoromethoxy;
  • R 25 is hydroxyl, cyano, heterocyclyl, NR 251 R 252 , C(O)NR 253 R 254 or SO 2 C1-C6 alkyl; wherein, R 251 , R 252 , R 253 , R 254 are each independently is H or C1-C6 alkyl; R 251 , R 252 and the nitrogen atom connected to them together form a 3- to 6-membered nitrogen-containing heterocyclic group, and the 3- to 6-membered nitrogen-containing heterocyclic group is optionally replaced by a Or 2 groups selected from halogen, methyl, trifluoromethyl, methoxy, trifluoromethoxy substituted; R 253 , R 254 and the nitrogen atoms connected to them together form a 3- to 6-membered nitrogen-containing hetero group cyclic group, the 3- to 6-membered nitrogen-containing heterocyclic group is optionally substituted with 1 or 2 groups selected from halogen, methyl, trifluoromethyl, methoxy, trifluorome
  • R 26 is C1-C6 alkyl, C1-C6 haloalkyl or NR 261 R 262 ; wherein, R 261 and R 262 are each independently H or C1-C6 alkyl; or R 261 , R 262 and the The nitrogen atoms together form a 3- to 6-membered nitrogen-containing heterocyclic group, which is optionally replaced by 1 or 2 atoms selected from halogen, methyl, trifluoromethyl, methoxy, group substitution of trifluoromethoxy;
  • R 27 , R 28 are each independently H, C1-C6 alkyl or C1-C6 haloalkyl; or R 27 , R 28 and the nitrogen atom to which they are attached together form a 3- to 6-membered nitrogen-containing heterocyclic group, the said The 3- to 6-membered nitrogen-containing heterocyclic group is optionally substituted with 1 or 2 groups selected from halogen, methyl, trifluoromethyl, methoxy, trifluoromethoxy;
  • R 29 , R 30 are each independently H, C1-C6 alkyl or C1-C6 haloalkyl; or R 29 , R 30 and the nitrogen atom to which they are attached together form a 3- to 6-membered nitrogen-containing heterocyclic group, the said The 3- to 6-membered nitrogen-containing heterocyclic group is optionally substituted with 1 or 2 groups selected from halogen, methyl, trifluoromethyl, methoxy, trifluoromethoxy;
  • n1 0, 1, 2 or 3;
  • R 2 is H, cyano, halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 deuterated alkoxy, NR 31 R 32 , C2-C4 alkynyl or CH 2 OR 33 ; wherein, R 31 , R 32 and R 33 are each independently hydrogen or C1-C6 alkyl;
  • R is a substituent at any position on the bridged ring and is hydrogen, halogen, hydroxyl, cyano, C1-C3 alkyl, C1-C3 deuterated alkyl or C1-C3 haloalkyl;
  • L 3 is a bond, O or NR 34 ;
  • each L is independently a C1-C4 alkylene group or a heteroaryl group; wherein, one or two hydrogen atoms on any carbon atom of the C1-C4 alkylene group or on any same carbon atom Optionally each independently is substituted by deuterium, C1-C6 alkyl or C1-C6 haloalkyl; or 2 hydrogen atoms on any same carbon atom of the C1-C4 alkylene are optionally simultaneously replaced by -(CH 2 ) m3 -, -(CH 2 ) m1 -O-(CH 2 ) m2 -, -(CH 2 ) m1 -N-(CH 2 ) m2 - substituted to form a cyclic substituent; m3 is 1 or 2; Each m1 is independently 0, 1, 2, or 3; each m2 is independently 0, 1, 2, or 3; and m1, m2 are not 0 at the same time;
  • Each R is independently halogen , hydroxy, C1-C3 hydroxyalkyl, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, cyano, -phenyl, -phenyl-SO 2 F, -O-phenyl, -O-phenyl-SO 2 F, -NHC(O) phenyl, -NHC(O) phenyl-SO 2 F, C1-C3 alkyl substituted pyrazolyl, Aryl C1-C3 alkyl-, tert-butyldimethylsilyl CH 2 -, -N(R 34 ) 2 , (C1-C3 alkoxy) C1-C3 alkyl, (C1-C3 alkyl) C(O), oxo, (C1-C3 haloalkyl) C(O)-, -SO 2 F, (C1-C3 alkoxy) C1-
  • Each R 36 is independently halogen, hydroxy, HC(O)-, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, or -N(R 34 ) 2 ;
  • Each R 34 is independently hydrogen, C1-C3 alkyl or C1-C3 haloalkyl; or two R 34 and the nitrogen atom to which they are attached together form a 3- to 6-membered nitrogen-containing heterocyclic group, the 3- to The 6-membered nitrogen-containing heterocyclyl is optionally substituted with 1 or 2 groups selected from halogen, methyl, trifluoromethyl, methoxy, trifluoromethoxy.
  • the compound is represented by formula (II-1A), formula (II-1B), formula (II-2A), formula (II-2B):
  • X, Y, W, R 1 , R 2 , R 3 , R 6 , n1 , L 3 , q, and ring A each define the same formula (II-1) or formula (II-2).
  • the compound is of formula (II-1A1), formula (II-1A2), formula (II-1B1), formula (II-1B2), formula (II-1B1), or formula (II-1B2 ) as shown:
  • X, Y, W, R 1 , R 2 , R 3 , R 6 , n1 , L 3 , and ring A each define the same formula (II-1) or formula (II-2).
  • the present invention provides a compound of formula (III) or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof:
  • X is O or NR 11 ; wherein, R 11 is selected from H and C1-C6 alkyl;
  • Y is CR 12 R 13 , CR 14 R 15 CR 16 R 17 , C(O) or C(O)CR 18 R 19 ; wherein R 12 , R 13 , R 14 and R 15 are each independently selected from H, C1-C3 alkyl, C1-C3 deuterated alkyl and C1-C3 haloalkyl; R 16 , R 17 , R 18 , R 19 are each independently selected from H, C1-C3 alkyl and halogen;
  • W is N or CR 20 ; wherein, R 20 is H, C1-C6 alkyl, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, cycloalkyl, cycloalkyl-O-, heterocyclyl or Heterocyclyl-O-; wherein, the cycloalkyl group and the heterocyclyl group are each independently optionally substituted by halogen;
  • Ring A is selected from the group consisting of aryl, heteroaryl;
  • R 21 is H, C1-C6 alkyl, C1-C6 haloalkyl, C(O)C1-C6 alkyl or C(O) 2 C1-C6 alkyl;
  • R 22 is H, C1-C6 alkyl or C1 -C6 haloalkyl; or R 21 , R 22 and the nitrogen atom to which they are attached together form a 3- to 6-membered nitrogen-containing heterocyclic group, the 3- to 6-membered nitrogen-containing heterocyclic group is optionally replaced by 1 or 2 Substituted with a group selected from halogen, methyl, trifluoromethyl, methoxy, trifluoromethoxy;
  • R 23 , R 24 are each independently H, C1-C6 alkyl or C1-C6 haloalkyl; or R 23 , R 24 and the nitrogen atom to which they are attached together form a 3- to 6-membered nitrogen-containing heterocyclic group, the said The 3- to 6-membered nitrogen-containing heterocyclic group is optionally substituted with 1 or 2 groups selected from halogen, methyl, trifluoromethyl, methoxy, trifluoromethoxy;
  • R 25 is hydroxyl, cyano, heterocyclyl, NR 251 R 252 , C(O)NR 253 R 254 or SO 2 C1-C6 alkyl; wherein, R 251 , R 252 , R 253 , R 254 are each independently is H or C1-C6 alkyl; R 251 , R 252 and the nitrogen atom connected to them together form a 3- to 6-membered nitrogen-containing heterocyclic group, and the 3- to 6-membered nitrogen-containing heterocyclic group is optionally replaced by a Or 2 groups selected from halogen, methyl, trifluoromethyl, methoxy, trifluoromethoxy substituted; R 253 , R 254 and the nitrogen atoms connected to them together form a 3- to 6-membered nitrogen-containing hetero group cyclic group, the 3- to 6-membered nitrogen-containing heterocyclic group is optionally substituted with 1 or 2 groups selected from halogen, methyl, trifluoromethyl, methoxy, trifluorome
  • R 26 is C1-C6 alkyl, C1-C6 haloalkyl or NR 261 R 262 ; wherein, R 261 and R 262 are each independently H or C1-C6 alkyl; or R 261 , R 262 and the The nitrogen atoms together form a 3- to 6-membered nitrogen-containing heterocyclic group, which is optionally replaced by 1 or 2 atoms selected from halogen, methyl, trifluoromethyl, methoxy, group substitution of trifluoromethoxy;
  • R 27 , R 28 are each independently H, C1-C6 alkyl or C1-C6 haloalkyl; or R 27 , R 28 and the nitrogen atom to which they are attached together form a 3- to 6-membered nitrogen-containing heterocyclic group, the said The 3- to 6-membered nitrogen-containing heterocyclic group is optionally substituted with 1 or 2 groups selected from halogen, methyl, trifluoromethyl, methoxy, trifluoromethoxy;
  • R 29 , R 30 are each independently H, C1-C6 alkyl or C1-C6 haloalkyl; or R 29 , R 30 and the nitrogen atom to which they are attached together form a 3- to 6-membered nitrogen-containing heterocyclic group, the said The 3- to 6-membered nitrogen-containing heterocyclic group is optionally substituted with 1 or 2 groups selected from halogen, methyl, trifluoromethyl, methoxy, trifluoromethoxy;
  • n1 0, 1, 2 or 3;
  • R 3d , R 3e , R 3f are each independently hydrogen, halogen, hydroxy, cyano, C1-C3 alkyl, C1-C3 deuterated alkyl, or C1-C3 haloalkyl; or
  • R 3d is linked to R 3e to form -CHR 3d1 - or -CHR 3d2 CHR 3d3 -;
  • R 3f is hydrogen, halogen, hydroxyl, cyano, C1-C3 alkyl, C1-C3 deuterated alkyl or C1-C3 haloalkyl ;
  • R 3d1 , R 3d2 , R 3d3 are each independently hydrogen, halogen, hydroxy, cyano, C1-C3 alkyl, C1-C3 deuterated alkyl or C1-C3 haloalkyl; or
  • R 3d is linked to R 3f to form -CHR 3f1 - or -CHR 3f2 CHR 3f3 -;
  • R 3e is hydrogen, halogen, hydroxyl, cyano, C1-C3 alkyl, C1-C3 deuterated alkyl or C1-C3 haloalkyl ;
  • R 3f1 , R 3f2 , R 3f3 are each independently hydrogen, halogen, hydroxyl, cyano, C1-C3 alkyl, C1-C3 deuterated alkyl or C1-C3 haloalkyl;
  • L 3 is a bond, O or NR 34 ;
  • each L is independently a C1-C4 alkylene group or a heteroaryl group; wherein, one or two hydrogen atoms on any carbon atom of the C1-C4 alkylene group or on any same carbon atom Optionally each independently is substituted by deuterium, C1-C6 alkyl or C1-C6 haloalkyl; or 2 hydrogen atoms on any same carbon atom of the C1-C4 alkylene are optionally simultaneously replaced by -(CH 2 ) m3 -, -(CH 2 ) m1 -O-(CH 2 ) m2 -, -(CH 2 ) m1 -N-(CH 2 ) m2 - substituted to form a cyclic substituent; m3 is 1 or 2; Each m1 is independently 0, 1, 2, or 3; each m2 is independently 0, 1, 2, or 3; and m1, m2 are not 0 at the same time;
  • Each R is independently halogen , hydroxy, C1-C3 hydroxyalkyl, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, cyano, -phenyl, -phenyl-SO 2 F, -O-phenyl, -O-phenyl-SO 2 F, -NHC(O) phenyl, -NHC(O) phenyl-SO 2 F, C1-C3 alkyl substituted pyrazolyl, Aryl C1-C3 alkyl-, tert-butyldimethylsilyl CH 2 -, -N(R 34 ) 2 , (C1-C3 alkoxy) C1-C3 alkyl, (C1-C3 alkyl) C(O), oxo, (C1-C3 haloalkyl) C(O)-, -SO 2 F, (C1-C3 alkoxy) C1-
  • Each R 36 is independently halogen, hydroxy, HC(O)-, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, or -N(R 34 ) 2 ;
  • Each R 34 is independently hydrogen, C1-C3 alkyl or C1-C3 haloalkyl; or two R 34 and the nitrogen atom to which they are attached together form a 3- to 6-membered nitrogen-containing heterocyclic group, the 3- to The 6-membered nitrogen-containing heterocyclyl is optionally substituted with 1 or 2 groups selected from halogen, methyl, trifluoromethyl, methoxy, trifluoromethoxy.
  • the compound is of formula (III-1) or formula (III-2):
  • the compound is of formula (III-1a), formula (III-1b), formula (III-2a) or formula (III-2b):
  • q is 1 or 2;
  • R 3 is a substituent at any position on the bridged ring and is hydrogen, halogen, hydroxyl, cyano, C1-C3 alkyl, C1-C3 deuterated alkyl or C1-C3 halogenated alkyl group;
  • X, Y, W, ring A, R 1 , n1, L 3 , R 6 are as defined in formula (III).
  • the compound is of formula (III-1a1), formula (III-1a2), formula (III-1b1), formula (III-1b2), formula (III-1c1) or formula (III-1c2) ) as shown:
  • R 3 is a substituent at any position on the bridged ring and is hydrogen, halogen, hydroxyl, cyano, C1-C3 alkyl, C1-C3 deuterated alkyl or C1-C3 halogenated alkyl;
  • X, Y, W, ring A, R 1 , n1 , L 3 and R 6 are as defined in formula (III).
  • R3 is hydrogen
  • Y is -CH2- .
  • the cycloalkyl group is a C3-C20 cycloalkyl group.
  • the cycloalkyl is C3-C12 cycloalkyl (more preferably C3-C8 monocyclic cycloalkyl), C5-C20 spirocycloalkyl, C5-C20 fused cycloalkyl or C5-C20 bridged cycloalkane base.
  • the heterocyclyl group is a 3 to 20 membered heterocyclyl group.
  • the heterocyclyl is a monocyclic heterocyclyl (eg, a 3- to 8-membered monocyclic heterocyclyl), a 5- to 20-membered spiroheterocyclyl, a 5- to 20-membered fused heterocyclyl, and a 5- to 20-membered bridge Heterocyclyl.
  • the aryl group is a C6-C14 aryl group.
  • the aryl group is a monocyclic aryl group, a non-fused polycyclic aryl group and an aromatic fused polycyclic group.
  • the heteroaryl group is a 5- to 14-membered heteroaryl group.
  • the heteroaryl group is a monocyclic heteroaryl (eg, a 5- or 6-membered monocyclic heteroaryl), a fused bicyclic heteroaryl (eg, an 8- to 10-membered bicyclic heteroaryl) or a fused tricyclic Heteroaryl.
  • W is N or CR 20 ; wherein R 20 is hydrogen, fluoro, methyl, methoxy, or cyclopropoxy.
  • X is O.
  • Y is CH2 .
  • Y is selected from the group consisting of:
  • R 2 is fluoro, chloro, hydroxy, methoxy or cyano.
  • Ring A is phenyl, naphthyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrazolyl, imidazolyl, 1,2,3,4-tetrahydronaphthalene group, 2,3-dihydro-1H-indenyl, isoquinolinyl, indazolyl or benzo[d][1,3]dioxolane.
  • Ring A is selected from the group consisting of: And these groups can be attached to the rest of the molecule through any suitable ring atom.
  • R1 is a substituent at any position on Ring A; n1 is 0, 1, 2, or 3;
  • R 21 is H, C1-C3 alkyl, C1-C3 haloalkyl, C(O)C1-C3 alkyl or C(O) 2 C1-C3 alkyl;
  • R 22 is H, C1-C3 alkyl or C1 -C3 haloalkyl; or R 21 , R 22 and the nitrogen atom to which they are attached together form a 3- to 6-membered nitrogen-containing heterocyclic group, the 3- to 6-membered nitrogen-containing heterocyclic group is optionally replaced by 1 or 2 Substituted with a group selected from halogen, methyl, trifluoromethyl, methoxy, trifluoromethoxy;
  • R 23 , R 24 are each independently H, C1-C3 alkyl or C1-C3 haloalkyl; or R 23 , R 24 and the nitrogen atom to which they are attached together form a 3- to 6-membered nitrogen-containing heterocyclic group, the said The 3- to 6-membered nitrogen-containing heterocyclic group is optionally substituted with 1 or 2 groups selected from halogen, methyl, trifluoromethyl, methoxy, trifluoromethoxy;
  • R 25 is hydroxyl, cyano, heterocyclyl, NR 251 R 252 , C(O)NR 253 R 254 or SO 2 C1-C3 alkyl; wherein R 251 , R 252 , R 253 and R 254 are each independently is H or C1-C3 alkyl; R 251 , R 252 and the nitrogen atom connected to them together form a 3- to 6-membered nitrogen-containing heterocyclic group, and the 3- to 6-membered nitrogen-containing heterocyclic group is optionally replaced by a Or 2 groups selected from halogen, methyl, trifluoromethyl, methoxy, trifluoromethoxy substituted; R 253 , R 254 and the nitrogen atoms connected to them together form a 3- to 6-membered nitrogen-containing hetero group cyclic group, the 3- to 6-membered nitrogen-containing heterocyclic group is optionally substituted with 1 or 2 groups selected from halogen, methyl, trifluoromethyl, methoxy, trifluoromethoxy
  • R 26 is C1-C3 alkyl, C1-C3 haloalkyl or NR 261 R 262 ; wherein, R 261 and R 262 are each independently H or C1-C3 alkyl; or R 261 , R 262 and the The nitrogen atoms together form a 3- to 6-membered nitrogen-containing heterocyclic group, which is optionally replaced by 1 or 2 atoms selected from halogen, methyl, trifluoromethyl, methoxy, group substitution of trifluoromethoxy;
  • R 27 , R 28 are each independently H, C1-C3 alkyl or C1-C3 haloalkyl; or R 27 , R 28 and the nitrogen atom to which they are attached together form a 3- to 6-membered nitrogen-containing heterocyclic group, the said The 3- to 6-membered nitrogen-containing heterocyclic group is optionally substituted with 1 or 2 groups selected from halogen, methyl, trifluoromethyl, methoxy, trifluoromethoxy;
  • R 29 , R 30 are each independently H, C1-C3 alkyl or C1-C3 haloalkyl; or R 29 , R 30 and the nitrogen atom to which they are attached together form a 3- to 6-membered nitrogen-containing heterocyclic group, the said The 3- to 6-membered nitrogen-containing heterocyclic group is optionally substituted with 1 or 2 groups selected from halogen, methyl, trifluoromethyl, methoxy, trifluoromethoxy.
  • L 2 is methylene or ethylene or propylene; wherein, the methylene or ethylene or propylene is on any carbon atom or on any same carbon atom.
  • 1 or 2 hydrogen atoms are optionally substituted by deuterium or C1-C3 alkyl independently; or 2 hydrogen atoms on any same carbon atom of the methylene or ethylene or propylene are optionally is simultaneously substituted with -CH 2 - or -CH 2 CH 2 - to form cyclopropyl or cyclobutyl.
  • R 3a , R 3b , R 3c are each independently hydrogen, fluoro, methyl, or methoxy.
  • each of R 4 , R 5 , n2 and n3 is independently defined as in formula (I).
  • R3 is hydrogen, fluoro, methyl or methoxy.
  • R 3d , R 3e , R 3f are each independently hydrogen, fluoro, methyl, or methoxy; or
  • R 3d is connected with R 3e to form -CHR 3d1 -or -CHR 3d2 CHR 3d3 ;
  • R 3f is hydrogen, fluorine, methyl or methoxy;
  • R 3d1 , R 3d2 , R 3d3 are each independently hydrogen, fluorine, methyl or methoxy; or
  • R 3d is connected with R 3f to form -CHR 3f1 -or -CHR 3f2 CHR 3f3 ;
  • R 3e is hydrogen, fluorine, methyl or methoxy;
  • R 3f1 , R 3f2 , R 3f3 are each independently hydrogen, fluorine, methyl or methoxy.
  • L is methylene or ethylene or propylene; wherein, 1 on any carbon atom or on any same carbon atom on the methylene or ethylene or propylene
  • One or two hydrogen atoms are optionally each independently substituted by deuterium or C1-C3 alkyl; or two hydrogen atoms on any of the same carbon atoms of the methylene or ethylene or propylene are optionally Simultaneously substituted with -CH 2 - or -CH 2 CH 2 - to form cyclopropyl or cyclobutyl.
  • R 6 is hydrogen, -N(R 34 ) 2 , 3 to 8 membered monocyclic heterocyclyl, 5 to 20 membered spiroheterocyclyl, 5 to 20 membered fused heterocyclyl, 5 to 20 membered heterocyclyl Bridged heterocyclyl, C1-C6 alkyl, -L-3 to 8 membered monocyclic heterocyclyl, -L-5 to 20 membered spiro heterocyclyl, -L-5 to 20 membered fused heterocyclyl, - L-5 to 20-membered bridged heterocyclyl, -L-phenyl, -L-naphthyl, -L-5 to 14-membered heteroaryl, -L-C3-C12cycloalkyl, -L-C5-C20 Spirocycloalkyl, C5-C20 fused cycloalkyl, -L-C5-C20 bridged cycloalkyl,
  • R 6 is hydrogen or -N(R 34 ) 2 .
  • each R34 is independently hydrogen or C1-C3 alkyl; or one R34 is hydrogen and the other R34 is C1-C3 alkyl.
  • R34 is hydrogen, C1-C3 alkyl or C1-C3 cyanoalkyl.
  • C1-C6 alkyl is methyl, ethyl, isopropyl or isobutyl.
  • L is methylene or ethylene or propylene; wherein, 1 on any carbon atom or on any same carbon atom on the methylene or ethylene or propylene
  • One or two hydrogen atoms are optionally each independently substituted by deuterium or C1-C3 alkyl; or two hydrogen atoms on any of the same carbon atoms of the methylene or ethylene or propylene are optionally Simultaneously substituted with -CH 2 - or -CH 2 CH 2 - to form cyclopropyl or cyclobutyl.
  • each R is independently The definitions of R 4 , R 5 , L 2 , ring B, ring C, n2 and n3 are the same as those of each group in formula (I).
  • the heterocyclyl groups in R are each independently hexahydro -1H-pyrrolazinyl, hexahydro-3H-pyrrolazin-3-one, hexahydro-1H-pyrrolo[2, 1-c][1,4]oxazinyl, swaindolazinyl, hexahydropyrrolizine 4(1H)-oxide, azetidinyl, pyrrolidinyl, pyrrolidin-2-one, oxygen Heterobutyl, piperidinyl, 1-azabicyclo[2.2.1]heptyl, morpholinyl, oxa-5-azabicyclo[2.2.1]heptan-5-yl, thiopyranyl , 6-oxa-2-azaspiro[3.4]octyl, 7-oxa-2-azaspiro[3.5]nonyl, 2',3'-dihydrospiro[cyclopropan
  • R 6 is -L-heterocyclyl; the heterocyclyl is hexahydro-lH-pyrrolazinyl.
  • R6 is -L - heterocyclyl; the heterocyclyl is hexahydro-1H-pyrrolazinyl substituted with one R35 or two hydrogen atoms on the same carbon atom are -CH 2 CH 2 - or -CH 2 CH 2 CH 2 - substituted into cyclopropyl or cyclobutyl hexahydro-1H-pyrrolazinyl; wherein, R 35 is halogen, hydroxy, C1-C3 hydroxyalkyl, C1-C3 haloalkyl, C1-C3 alkyl, C1-C3 alkoxy, phenyl, pyrazolyl or -CH2OC (O)N( R34 ) 2 .
  • the halogen is fluorine
  • the heterocyclyl group is hexahydro-1H-pyrrolazinyl further substituted with two other R 35 ; the other two R 35 are each independently C1-C3 alkyl.
  • R6 is -L - heterocyclyl; the heterocyclyl is an azetidine substituted with one R35 or two hydrogen atoms on the same carbon atom are simultaneously replaced by -CH2 CH2- or -CH2CH2CH2 - substituted azetidine to become cyclopropyl or cyclobutyl ; said R35 is C1 - C3 alkyl.
  • R6 is -L - heterocyclyl; the heterocyclyl is pyrrolidinyl substituted with one R35 or two hydrogen atoms on the same carbon atom are simultaneously replaced by -CH2CH2 - or -CH 2 CH 2 CH 2 - substituted pyrrolidinyl to become cyclopropyl or cyclobutyl; wherein R 35 is hydroxyalkyl, haloalkyl, C1-C3 alkyl, alkoxy, aryl C1-C3 Alkyl, -phenyl, -O-phenyl and -NHC(O)phenyl; wherein, in the aryl group, the phenyl group, or the -O-phenyl group in the aryl C1-C3 alkyl group
  • the phenyl groups of the phenyl or -NHC(O)phenyl groups are each independently optionally substituted with one or more R 36 .
  • the phenyl of the phenyl, -O-phenyl or -NHC(O)phenyl is substituted with -SO2F .
  • R 6 is -L-heterocyclyl; the heterocyclyl is pyrrolidinyl substituted with two R 35 ; wherein one R 35 is C1-C3 alkyl and the other R 35 is C1-C3 alkoxy or halogen.
  • R6 is -L - heterocyclyl; the heterocyclyl is pyrrolidin-2-one substituted with one R35 or two hydrogen atoms on the same carbon atom are simultaneously replaced by -CH 2 CH 2 - or -CH 2 CH 2 CH 2 - substituted into cyclopropyl or cyclobutyl pyrrolidin-2-one; wherein R 35 is C1-C3 alkyl.
  • R6 is -L - heterocyclyl; the heterocyclyl is piperidinyl substituted with one R35 or two hydrogen atoms on the same carbon atom are simultaneously replaced by -CH2CH2 -or -CH 2 CH 2 CH 2 - substituted into cyclopropyl or cyclobutyl piperidinyl; wherein R 35 is acetyl, (C1-C3 alkoxy) C1-C3 alkoxy or -C( O) CH2Cl .
  • R 6 is -L-heterocyclyl; the heterocyclyl is morpholinyl or oxa-5-azabicyclo[2.2.1]heptan-5-yl.
  • R6 is -L - heteroaryl; the heteroaryl is optionally substituted with one or more R36 .
  • R 6 is -L-heteroaryl
  • L is methylene or ethylene or propylene
  • the heteroaryl group is pyridyl, pyrazolyl, imidazolyl, triazolyl, 4,5,6,7-tetrahydro-1H-indazolyl, benzimidazolyl, imidazo[1,2-a]pyridyl or pyrimidinyl; each of the above is optionally One or more R 36 substitutions.
  • R 6 is -L-heteroaryl
  • L is methylene or ethylene or propylene
  • 1 or 2 hydrogen atoms on the same or any same carbon atom are optionally each independently substituted by deuterium or C1-C3 alkyl; or the methylene or ethylene or propylene on any same carbon
  • the 2 hydrogen atoms on the atom are optionally simultaneously substituted with -CH 2 - or -CH 2 CH 2 - to form cyclopropyl or cyclobutyl
  • the heteroaryl group is pyridyl substituted with one R 36 ; wherein , R 36 is halogen, C1-C4 alkyl, -N(R 5 ) 2 or C1-C4 alkoxy.
  • R 6 is -L-heteroaryl
  • L is methylene or ethylene or propylene
  • R 36 is C1-C4 alkyl or -N(R 34 ) 2 .
  • R 6 is -L-heteroaryl
  • L is methylene or ethylene or propylene
  • the heteroaryl is imidazolyl substituted with one R 36 ; wherein , R 36 is C1-C4 alkyl, C1-C4 haloalkyl or C1-C4 hydroxyalkyl.
  • R 6 is -L-heteroaryl
  • L is methylene or ethylene or propylene
  • 1 or 2 hydrogen atoms on the same or any same carbon atom are optionally each independently substituted by deuterium or C1-C3 alkyl
  • the methylene or ethylene or propylene on any same carbon 2 hydrogen atoms on the atom are optionally simultaneously substituted with -CH 2 - or -CH 2 CH 2 - to form cyclopropyl or cyclobutyl
  • the heteroaryl group is triazolyl substituted with one R 36 ; wherein R 36 is C1-C4 alkyl.
  • R6 is -L - aryl; the aryl is optionally substituted with one or more R36 .
  • R6 is -L - cycloalkyl; said cycloalkyl is optionally substituted with one or more R35 or optionally both hydrogen atoms on the same carbon atom are simultaneously replaced by -CH 2CH2- or -CH2CH2CH2- is substituted as cyclopropyl or cyclobutyl ; each R 35 is as before.
  • R 6 is -LN(R 34 ) 2 ; wherein, L is a C1-C4 alkylene group; wherein, the C1-C4 alkylene group is on any carbon atom or on any same carbon atom
  • the 1 or 2 hydrogen atoms of the C1-C4 alkylene group are optionally substituted by deuterium or C1-C3 alkyl group independently; CH2- or -CH2CH2- is substituted to form cyclopropyl or cyclobutyl.
  • R 6 is -LN(R 34 ) 2 ; wherein L is methylene, ethylene or propylene; wherein any of the methylene, ethylene or propylene 1 or 2 hydrogen atoms on the carbon atom or on any same carbon atom are optionally each independently substituted by deuterium or C1-C3 alkyl; or the methylene, ethylene or propylene are any 2 hydrogen atoms on the same carbon atom are optionally simultaneously substituted by -CH 2 - or -CH 2 CH 2 - to form cyclopropyl or cyclobutyl ; each R is independently selected from C1-C3 alkyl .
  • L is ethylene or propylene.
  • R 6 is -L-C1-C6 haloalkyl; wherein, L is C1-C4 alkylene; wherein, the C1-C4 alkylene on any carbon atom or any same carbon atom 1 or 2 hydrogen atoms above are optionally substituted by deuterium or C1-C3 alkyl independently; or 2 hydrogen atoms on the same carbon atom of said C1-C4 alkylene are optionally simultaneously -CH2- or -CH2CH2- is substituted to form cyclopropyl or cyclobutyl.
  • R 6 is -L-OR 34 ; wherein, L is a C1-C4 alkylene group; wherein, the C1-C4 alkylene group is 1 on any carbon atom or on any same carbon atom
  • L is a C1-C4 alkylene group
  • the C1-C4 alkylene group is 1 on any carbon atom or on any same carbon atom
  • One or two hydrogen atoms are optionally each independently replaced by deuterium or C1-C3 alkyl; or two hydrogen atoms on any one carbon atom of the C1-C4 alkylene are optionally simultaneously replaced by -CH 2 -or -CH2CH2- to form cyclopropyl or cyclobutyl.
  • R 6 is -L-(CH 2 OR 34 )(CH 2 ) n OR 34 ; wherein L is a C1-C4 alkylene; wherein the C1-C4 alkylene is any carbon atom 1 or 2 hydrogen atoms on or on any same carbon atom are optionally each independently substituted by deuterium or C1-C3 alkyl; or 2 on any same carbon atom of the C1-C4 alkylene hydrogen atoms are optionally simultaneously substituted with -CH2- or -CH2CH2- to form cyclopropyl or cyclobutyl.
  • R 6 is -L-NR 34 C(O)-aryl; wherein, L is a C1-C4 alkylene group; wherein, the C1-C4 alkylene group is on any carbon atom or any 1 or 2 hydrogen atoms on the same carbon atom are optionally substituted by deuterium or C1-C3 alkyl independently; or any 2 hydrogen atoms on the same carbon atom of the C1-C4 alkylene are any Optionally simultaneously substituted with -CH2- or -CH2CH2- to form cyclopropyl or cyclobutyl .
  • R 6 is -L-heterocyclyl;
  • L is C1-C4 alkylene; wherein, the 2 hydrogen atoms on any of the same carbon atom of the C1-C4 alkylene are optionally each independently substituted by deuterium or C1-C6 alkyl; or 2 hydrogen atoms on the same carbon atom of said C1-C4 alkylene are optionally simultaneously substituted by -CH 2 - or -CH 2 CH 2 - to thereby Forms cyclopropyl or cyclobutyl.
  • L is methylene or ethylene or propylene; wherein the 2 hydrogen atoms on any one and the same carbon atom of the methylene or ethylene or propylene are optionally each independently substituted by deuterium or C1-C3 alkyl; or the 2 hydrogen atoms on any of the same carbon atom of the methylene or ethylene or propylene are optionally simultaneously replaced by -CH 2 - or -CH 2 CH2 -substituted to form cyclopropyl or cyclobutyl.
  • W is CR 20 ;
  • R 20 is cyclopropyl, cyclopropyl-O-, cyclobutyl, cyclobutyl-O-, cyclopentyl, cyclopentyl-O-, tetrahydrofuranyl, Tetrahydrofuran-O-; wherein, the cyclopropyl, cyclobutyl, cyclopentyl, and tetrahydrofuranyl groups are each independently substituted by halogen.
  • W is CR 20 ;
  • R 20 is hydrogen, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkyl-O-, 3- to 6-membered heterocyclyl, or 3 to 6-membered heterocyclyl-O-; wherein the C3-C6 cycloalkyl and the 3- to 6-membered heterocyclyl are each independently substituted with halogen.
  • R 20 is halo or C1-C3 alkyl.
  • R 20 is fluoro
  • R 20 is methyl
  • L 2 or L is methylene or ethylene or propylene; wherein, any 2 hydrogen atoms on the same carbon atom of the methylene or ethylene or propylene are any Optionally each independently is substituted by deuterium or C1-C3 alkyl; or 2 hydrogen atoms on any same carbon atom of the methylene or ethylene or propylene are optionally simultaneously replaced by -CH 2 - or -CH2CH2- is substituted to form cyclopropyl or cyclobutyl.
  • each R1 is independently halogen, hydroxy, ethynyl, methyl, methyl-O-, methyl-S-, trifluoromethyl group, trifluoromethyl-O-, amino, isopropyl, or cyclopropyl; the cyclopropyl is optionally substituted with halogen or methyl.
  • each R 8 is each independently halogen, hydroxy, ethynyl, methyl, methyl-O-, methyl-S-, trifluoromethyl group, trifluoromethyl-O-, amino, isopropyl, or cyclopropyl; the cyclopropyl is optionally substituted with halogen or methyl.
  • the -L3 - R6 is selected from the group consisting of:
  • R L1 and R L2 are each independently hydrogen, deuterium, C1-C6 alkyl or C1-C6 haloalkyl;
  • the -L3 - R6 is selected from the group consisting of:
  • R 61 is selected from the group consisting of:
  • R 61 is hexahydro-lH-pyrrolazinyl.
  • R 61 is hexahydro-1H-pyrrolazinyl substituted with one R 35 ; wherein R 35 is halo, hydroxy, C1-C3 hydroxyalkyl, C1-C3 haloalkyl, C1-C3 alkane group, C1-C3 alkoxy, phenyl, pyrazolyl or -CH 2 OC(O)N(R 34 ) 2 ; each R 34 is independently hydrogen, C1-C3 alkyl or C1-C3 haloalkane or two R 34 and the nitrogen atoms to which they are attached together form a 3- to 6-membered nitrogen-containing heterocyclic group, the 3- to 6-membered nitrogen-containing heterocyclic group is optionally replaced by 1 or 2 selected from halogen, Group substitution of methyl, trifluoromethyl, methoxy, trifluoromethoxy.
  • the compound is selected from the compounds in Table A.
  • the compound is selected from the compounds in Example 7 and Table B.
  • the compound is selected from the compounds in Examples 1 to 6, 8 to 12 and Table C.
  • the compound is selected from the compounds in Table (I):
  • the second aspect of the present invention provides a pharmaceutical composition, which comprises the compound described in the first aspect above or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof; and a pharmaceutically acceptable Carrier.
  • the term "pharmaceutically acceptable carrier” refers to any formulation or carrier medium representative of any formulation or carrier medium capable of delivering an effective amount of the active substance of the present invention, without interfering with the biological activity of the active substance, and without toxic side effects to the host or subject , including water, oil, vegetable and mineral, cream base, lotion base, ointment base, etc. These bases include suspending agents, tackifiers, penetration enhancers, and the like. Their formulations are well known to those skilled in the cosmetic or topical pharmaceutical field.
  • the pharmaceutical composition may be administered orally, by inhalation, rectally, nasally, bucally, topically, parenterally, such as subcutaneously, intravenously, intramuscularly , intraperitoneal, intrathecal, intraventricular, intrasternal and intracranial injection or infusion, or with the aid of an explanted reservoir.
  • parenterally such as subcutaneously, intravenously, intramuscularly , intraperitoneal, intrathecal, intraventricular, intrasternal and intracranial injection or infusion, or with the aid of an explanted reservoir.
  • oral, intraperitoneal or intravenous administration is preferred.
  • the compounds of the present invention may be formulated in any orally acceptable formulation, including but not limited to tablets, capsules, aqueous solutions or suspensions. Carriers for tablets typically include lactose and cornstarch, although lubricants such as magnesium stearate may also be added.
  • Diluents used in capsule formulations typically include lactose and dried cornstarch.
  • Aqueous suspensions are usually prepared by mixing the active ingredient with suitable emulsifying and suspending agents. If desired, some sweetening, flavoring or coloring agents may also be added to the above oral formulations.
  • the compounds of the present invention can be prepared into different topical formulations according to different affected surfaces or organs
  • the compounds of the present invention when administered topically to the eye, may be formulated as a micronized suspension or solution in the form of an isotonic, pH, sterile, isotonic carrier, with or without the addition of a preservative such as Benzyl alkoxide chloride.
  • the compounds can also be formulated in the form of an ointment such as petrolatum ointment.
  • the compounds of the present invention may be formulated in a suitable ointment, lotion or cream formulation wherein the active ingredient is suspended or dissolved in one or more carriers.
  • Carriers that can be used in ointment formulations include, but are not limited to: mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyethylene oxide, polypropylene oxide, emulsifying wax and water; carriers that can be used in lotions or creams include, but are not limited to: minerals Oil, sorbitan monostearate, Tween 60, cetyl ester wax, hexadecenaryl alcohol, 2-octyldodecanol, benzyl alcohol and water.
  • the compounds of the present invention may also be administered in the form of sterile injectable preparations, including sterile injectable aqueous or oily suspensions or sterile injectable solutions.
  • Useful vehicles and solvents include water, Ringer's solution and isotonic sodium chloride solution.
  • sterile fixed oils can also be employed as a solvent or suspending medium such as mono- or diglycerides.
  • Another aspect of the present invention provides the compound of the first aspect above or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof or the pharmaceutical composition of the second aspect above in the preparation of prophylaxis and/or treatment Use in medicine for a disease or condition; the disease or condition is a KRAS G12D-related disease or disorder.
  • KRAS G12D refers to a mutant form of a mammalian KRAS protein that contains an amino acid with aspartic acid in place of glycine at amino acid position 12.
  • the assignment of amino acid codons and residue positions for human KRAS is based on the amino acid sequence identified by UniProtKB/Swiss-Prot P01116:Variantp.Gly12Asp.
  • KRAS G12D inhibitor refers to a compound of the invention, as described herein, represented by Formula (I), Formula (II-1), Formula (II-1), or Formula (III). These compounds can negatively regulate or inhibit all or part of the enzymatic activity of KRAS G12D.
  • KRAS G12D-related disease or disorder refers to a disease or disorder associated with, mediated by, or having a KRAS G12D mutation.
  • a non-limiting example of a KRAS G12D-related disease or disorder is a KRAS G12D-related cancer.
  • Another aspect of the present invention provides a method for treating KRAS G12D-related cancer, the method comprising the step of: administering to a subject in need thereof a therapeutically effective amount of the compound of the first aspect of the present invention or a pharmaceutically acceptable form thereof salts, stereoisomers, solvates or prodrugs; or administer to a subject in need thereof a therapeutically effective amount of the pharmaceutical composition according to the second aspect of the invention.
  • the KRAS G12D-related cancer includes, but is not limited to, lung cancer, prostate cancer, breast cancer, brain cancer, skin cancer, cervical cancer, testicular cancer, and other tumors.
  • the KRAS G12D-related cancer includes, but is not limited to, astrocytic cancer, breast cancer, cervical cancer, colorectal cancer, endometrial cancer, esophageal cancer, gastric cancer, head and neck cancer, hepatocellular carcinoma, Throat cancer, lung cancer, oral cancer, ovarian cancer, prostate cancer, thyroid cancer, sarcoma, etc.
  • the KRAS G12D-related cancer includes, but is not limited to, cancers of the heart site, eg, sarcomas (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyomas, fibroids, lipomas and teratoma, etc.; lung cancer, for example, bronchial carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, Chondromatous hamartoma, mesothelioma; cancers of the gastrointestinal tract, e.g., esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (cancer, lymphoma, leioma
  • the KRAS G12D-related cancer is lung cancer.
  • the KRAS G12D-related cancer is selected from the group consisting of non-small cell lung cancer, small cell lung cancer, colorectal cancer, rectal cancer, or pancreatic cancer.
  • Another aspect of the invention provides a method for treating cancer in a subject in need thereof, the method comprising: (a) determining that the cancer is associated with a KRAS G12D mutation (eg, a KRAS G12D-associated cancer); and
  • the administration is by a method selected from the group consisting of parenteral, intraperitoneal, intradermal, intracardiac, intraventricular, intracranial, intraspinal, intraluminal, intrasynovial, intrathecal, intramuscular injection, vitreous Intratracheal, intravenous, intraarterial, oral, buccal, sublingual, transdermal, topical, intratracheal, rectal, subcutaneous and topical routes of administration.
  • Another aspect of the present invention provides a method for inhibiting the activity of KRAS G12D in a cell, the method comprising the step of: making the cell stereoisomeric with the compound of the first aspect of the present invention or a pharmaceutically acceptable salt, stereoisomer thereof body, solvate or prodrug; or the cell is contacted with the pharmaceutical composition of the second aspect of the present invention.
  • Another aspect of the present invention provides the compound of the first aspect above or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof or the pharmaceutical composition of the second aspect above in the preparation of a KRAS G12D inhibitor use in.
  • the term "subject” refers to an animal, particularly a mammal. People are preferred.
  • the term "effective amount” or “therapeutically effective amount” refers to a non-toxic but sufficient amount of a drug or agent to achieve the desired effect.
  • the amount of a given drug depends on factors such as the particular dosing regimen, the type of disease or condition and its severity, the subject in need of treatment or the uniqueness of the host (e.g. body weight), however, the dose to be administered may be known in the art depending on the particular surrounding circumstances, including, for example, the particular drug that has been employed, the route of administration, the condition being treated, and the subject or host being treated method is routinely determined.
  • the administered dose is typically in the range of 0.02-5000 mg/day, eg, about 1-1500 mg/day.
  • the desired dose may conveniently be presented as a single dose, or as divided doses administered simultaneously (or over a short period of time) or at appropriate intervals, eg, two, three, four or more divided doses per day. It will be understood by those skilled in the art that although the above dosage range is given, the specific effective amount can be appropriately adjusted according to the patient's condition and in conjunction with the physician's diagnosis.
  • the term "pharmaceutically acceptable salt” refers to a salt of a compound of the present invention that is pharmaceutically acceptable and possesses the pharmacological activity of the parent compound.
  • Such salts include: acid addition salts with inorganic acids or organic acids such as nitric acid, phosphoric acid, carbonic acid, etc.; organic acids such as propionic acid, caproic acid, cyclopentanoic acid, Glycolic acid, pyruvic acid, gluconic acid, stearic acid, muconic acid, etc.; or salts formed when acidic protons present on the parent compound are replaced by metal ions, such as alkali metal ions or alkaline earth metal ions; or with organic bases Formed coordination compounds, the organic bases such as ethanolamine and the like.
  • the pharmaceutically acceptable salts of the present invention can be synthesized from the acid or base containing parent compound by conventional chemical methods. Generally, such salts are prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of the appropriate base or acid in water or an organic solvent or a mixture of the two. Generally, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile are preferred.
  • the compounds provided herein also exist in prodrug forms. Prodrugs of the compounds described herein are readily chemically altered under physiological conditions to convert to the compounds of the present invention. Furthermore, prodrugs can be converted to the compounds of the present invention by chemical or biochemical methods in an in vivo environment.
  • solvate refers to a substance formed by combining a compound of the present invention with a pharmaceutically acceptable solvent.
  • Pharmaceutically acceptable solvents include acetic acid and the like.
  • Solvates include stoichiometric amounts and non-stoichiometric amounts of solvates. Certain compounds of the present invention may exist in unsolvated as well as solvated forms. In general, solvated and unsolvated forms are equivalent and are intended to be included within the scope of the present invention.
  • stereoisomer includes conformational isomers and configurational isomers, wherein configurational isomers mainly include cis-trans isomers and optical isomers.
  • the compounds described in the present invention may exist in stereoisomeric forms, and therefore all possible stereoisomeric forms are encompassed, including but not limited to cis-trans isomers, tautomers, enantiomers, non-isomers Enantiomers, atropisomers, etc.
  • the compounds of the present invention can also be in any combination or any mixture of the aforementioned stereoisomers, such as meso, racemate, atropisomer exist in the form of an equivalent mixture.
  • a single enantiomer, a single diastereomer or a mixture of the above, or a single atropisomer or a mixture thereof When the compounds of the present invention contain olefinic double bonds, unless otherwise specified, they include cis isomers and trans isomers, and any combination thereof.
  • Atropisomers of the present invention are stereoisomers based on axial or planar chirality resulting from restricted intramolecular rotation. And as a drug, a stereoisomer having excellent activity is preferable.
  • the compounds of the present invention have optical isomers derived from asymmetric carbons and the like, and if necessary, single isomers can be obtained by separation by methods known in the art, such as crystallization or chiral chromatography.
  • the isomer compounds obtained by resolution can arbitrarily designate the specific structure of each isomer.
  • C1-C6 alkyl refers to straight and branched chain aliphatic groups consisting of 1-6 carbon atoms. Preference is given to C1-C4 alkyl or C1-C3 alkyl. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, and hexyl.
  • C1-C6 haloalkyl means that one or more hydrogens in a C1-C6 alkyl group are replaced by halogen. wherein the alkyl moiety is as defined above. Preference is given to C1-C3 haloalkyl or C1-C4 haloalkyl. Examples of haloalkyl groups include, but are not limited to, trifluoromethyl, difluoromethyl, and monofluoromethyl.
  • C1-C6 deuterated alkyl refers to the substitution of one or more hydrogens in a C1-C6 alkyl group with a deuterium atom. wherein the alkyl moiety is as defined above. Preference is given to C1-C3 deuterated alkyl or C1-C4 deuterated alkyl.
  • haloalkyl groups include, but are not limited to, trifluoromethyl, difluoromethyl, and monofluoromethyl.
  • C1-C6 alkoxy refers to -O-C1-C6 alkyl. Preference is given to C1-C3 alkoxy or C1-C4 alkoxy. wherein the alkyl moiety is as defined above.
  • C1-C6 haloalkoxy refers to -O-C1-C6 haloalkyl. Preference is given to C1-C3 haloalkoxy or C1-C4 haloalkoxy. wherein the haloalkyl moiety is as defined above.
  • C1-C6 deuterated alkoxy refers to -O-C1-C6 deuterated alkyl. Preference is given to C1-C3 deuterated alkoxy or C1-C4 deuterated alkoxy. wherein the deuterated alkyl moiety is as defined above.
  • C1-C6 cyanoalkyl refers to -C1-C6 alkyl-cyano. Preference is given to C1-C3 cyanoalkyl or C1-C4 cyanoalkyl. wherein the alkyl moiety is as defined above.
  • C2-C6 alkynyl refers to straight and branched chain aliphatic chains consisting of 2-6 carbon atoms having 1 or 2 carbon-carbon triple bonds. Preference is given to C2-C4 alkynyl or C2-C3 alkynyl. Examples of alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, and the like.
  • C2-C6 alkenyl refers to straight and branched chain aliphatic chains consisting of 2-6 carbon atoms having 1 or 2 carbon-carbon double bonds. Preference is given to C2-C4 alkenyl or C2-C3 alkenyl. Examples of alkenyl groups include, but are not limited to, vinyl, propenyl, butenyl, and the like.
  • C1-C6 hydroxyalkyl refers to -C1-C6 alkyl-hydroxy (OH). Preference is given to C1-C3 hydroxyalkyl (ie -C1-C3 alkyl-hydroxy) or C1-C4 hydroxyalkyl (ie -C1-C4 alkyl-hydroxy). wherein the alkyl moiety is as defined above.
  • C2-C6 hydroxyalkynyl refers to -C2-C6 alkynyl-OH.
  • the alkynyl group is as defined above. Preference is given to C2-C4 hydroxyalkynyl or C2-C3 hydroxyalkynyl.
  • C2-C6 hydroxyalkenyl refers to -C2-C6 alkenyl-OH. wherein alkenyl is as defined above. Preference is given to C2-C4 hydroxyalkenyl or C2-C3 hydroxyalkenyl.
  • C1-C4 alkylene refers to a C1-C4 alkyl group, as defined above, that is positioned between and used to connect two other moieties of the molecule.
  • Typical alkylene groups include, but are not limited to, methylene, ethylene, propylene, and butylene.
  • cycloalkyl and “cycloalkyl ring” are used interchangeably and refer to saturated monocyclic or polycyclic cyclic hydrocarbon groups, including, for example, monocyclic cycloalkyls, spirocycloalkyls, fused cycloalkanes and bridged cycloalkyl groups.
  • the ring carbon atoms of the cycloalkyl group in the present invention can be optionally substituted with 1, 2 or 3 oxo groups to form a cyclic ketone structure.
  • C3-C20 cycloalkyl refers to cycloalkyl groups having 3 to 20 ring carbon atoms, including monocyclic cycloalkyls, spirocycloalkyls, fused cycloalkyls and bridged cycloalkyls.
  • it is C3-C12 cycloalkyl (more preferably C3-C8 monocyclic cycloalkyl), C5-C20 spirocycloalkyl, C5-C20 fused cycloalkyl or C5-C20 bridged cycloalkyl.
  • C3-C8 monocyclic cycloalkyl refers to a saturated monocyclic cyclic hydrocarbon group having 3 to 8 ring carbon atoms. Preferably it is C3-C6 monocyclic cycloalkyl or C4-C6 monocyclic cycloalkyl. More preferred is a C3, C4, C5 or C6 monocyclic cycloalkyl. Specific examples of monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like.
  • spirocycloalkyl and “spirocycloalkyl ring” refer to a polycyclic cyclic hydrocarbon group formed by two or more monocyclic rings sharing one carbon atom (referred to as a spiro atom). According to the number of spiro atoms shared between the rings, spirocycloalkyl groups are divided into mono-spirocycloalkyl groups, double-spirocycloalkyl groups and poly-spirocycloalkyl groups.
  • C5-C20 spirocycloalkyl refers to a polycyclic cyclic hydrocarbon group having 5 to 20 ring carbon atoms, wherein the monocyclic ring sharing spiro atoms is a C3-C8 monocyclic cycloalkyl ring.
  • Preferred is C6-C14 spirocycloalkyl. More preferred is C6-C14 monospirocycloalkyl. More preferred is C7-C11 spirocycloalkyl. More preferred is a 7- to 11-membered monospirocycloalkyl.
  • Specific examples of spirocycloalkyl include, but are not limited to:
  • spirocycloalkyl groups can be attached to the rest of the molecule through any one of the ring atoms.
  • fused cycloalkyl and “fused cycloalkyl ring” refer to a polycyclic cyclic hydrocarbon group in which two or more monocyclic rings are formed by sharing an adjacent pair of carbon atoms. According to the number of rings formed, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused cycloalkyl.
  • C5-C20 fused cycloalkyl refers to a polycyclic cyclic hydrocarbon group having 5 to 20 ring carbon atoms, wherein the monocyclic rings sharing adjacent pairs of carbon atoms are C3-C8 monocyclic cycloalkyl rings.
  • it is a C6-C14 fused cycloalkyl. More preferably, it is a C6-C14 di-fused cycloalkyl group. More preferred is C7-C10 fused cycloalkyl. More preferably, it is a C7-C10 di-fused cycloalkyl group.
  • Cycloalkyl ring is fused with C6 monocyclic cycloalkyl ring) double fused cycloalkyl.
  • fused cycloalkyl include, but are not limited to:
  • fused cycloalkyl groups can be attached to the rest of the molecule through any one of the ring atoms.
  • bridged cycloalkyl and “bridged cycloalkyl ring” refer to a polycyclic cyclic hydrocarbon group formed by sharing two non-directly attached carbon atoms between two or more monocyclic rings. According to the number of rings formed, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl groups.
  • C5-C20 bridged cycloalkyl refers to a polycyclic cyclic hydrocarbon group having 5 to 20 ring carbon atoms, wherein any two rings share two carbon atoms that are not directly connected. Preferably it is a C6-C14 bridged cycloalkyl. More preferred is a C7-C10 bridged cycloalkyl.
  • Specific examples of bridged cycloalkyl groups include, but are not limited to:
  • bridged cycloalkyl groups can be attached to the remainder of the molecule through any one of the ring atoms.
  • examples of cycloalkyl groups herein include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, bicyclo[1.1 .1] Amyl.
  • cycloalkoxy refers to -O-cycloalkyl, wherein cycloalkyl is as defined above.
  • heterocyclyl and “heterocyclyl ring” are used interchangeably and refer to saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon groups, including, for example, monocyclic heterocyclyl, spiroheterocyclyl , fused heterocyclyl and bridged heterocyclyl.
  • the ring carbon atoms of the heterocyclic group in the present invention can be optionally substituted with 1, 2 or 3 oxo groups to form a cyclic ketone, cyclic lactone or cyclic lactam structure.
  • m' is an integer from 0 to 2
  • the ring atom is a nitrogen atom, it may be substituted or unsubstituted (ie N or NR, R is hydrogen or other substituents already defined herein).
  • the 3- to 20-membered heterocyclyl groups of the present invention include monocyclic heterocyclyl groups (eg, 3- to 8-membered monocyclic heterocyclyl groups), 5- to 20-membered spiro heterocyclyl groups, 5- to 20-membered fused heterocyclyl groups, and 5- to 20-membered fused heterocyclyl groups. to 20-membered bridged heterocyclyl.
  • the 3- to 20-membered nitrogen-containing heterocyclic groups of the present invention include monocyclic heterocyclic groups (eg, 3- to 8-membered monocyclic nitrogen-containing heterocyclic groups), 5- to 20-membered nitrogen-containing spiro heterocyclic groups, 5- to 20-membered nitrogen-containing heterocyclic groups Nitrogen-containing fused heterocyclic groups and 5- to 20-membered nitrogen-containing bridged heterocyclic groups.
  • monocyclic heterocyclic groups eg, 3- to 8-membered monocyclic nitrogen-containing heterocyclic groups
  • 5- to 20-membered nitrogen-containing spiro heterocyclic groups e.g., 5- to 20-membered nitrogen-containing spiro heterocyclic groups
  • 5- to 20-membered nitrogen-containing heterocyclic groups Nitrogen-containing fused heterocyclic groups and 5- to 20-membered nitrogen-containing bridged heterocyclic groups.
  • a 4- to 6-membered monocyclic heterocyclyl group having 4 to 6 ring atoms, of which 1 or 2 are heteroatoms. More preferred is a 5- or 6-membered monocyclic heterocyclyl having 5 or 6 ring atoms, of which 1 or 2 are heteroatoms.
  • the heteroatom is a nitrogen atom
  • the nitrogen atom may be substituted or unsubstituted (ie, N or NR, R is hydrogen or other substituents already defined herein).
  • the heteroatom is a sulfur atom
  • the ring carbon atoms of the monocyclic heterocyclyl may be optionally substituted with 1, 2 or 3 oxo groups to form a cyclic ketone, cyclic lactone or cyclic lactam structure.
  • monocyclic heterocyclyl groups include, but are not limited to, aziridine, ethylene oxide, azetidine, azetidine-2-one, oxetane, oxetane-2 -one, oxazolidine, pyrrolidin-2-one, pyrrolidin-2,5-dione, 1,3-dioxolane, dihydrofuran-2(3H)-one, dihydrofuran-2, 5-dione, piperidin-2-one, piperidine-2,6-dione, tetrahydro-2H-pyran-2-one, imidazolidine, tetrahydrofuran, tetrahydrothiophene, tetrahydropyrrole, 1,3
  • Specific examples may be selected from 3- to 8-membered monocyclic heterocyclyl groups including, but not limited to, tetrahydropyrrolyl, oxazolidinyl, isoxazolidinyl, piperidinyl, piperazinyl, morpholinyl, thiophene phenoline, azetidine and the like.
  • spiroheterocyclyl and “spiroheterocyclyl ring” refer to a polycyclic heterocyclyl formed by two or more saturated or partially unsaturated monocyclic rings sharing a carbon atom (referred to as a spiro atom).
  • a cyclic group in which one or more (eg 1, 2 or 3) ring atoms are heteroatoms selected from nitrogen, oxygen or S( O) m ' (where m' is an integer from 0 to 2) and the remaining ring atoms for carbon.
  • the heteroatom is a nitrogen atom, the nitrogen atom may be substituted or unsubstituted (ie, N or NR, R is hydrogen or other substituents already defined herein).
  • Each single ring may contain one or more double bonds, but no ring has a fully conjugated pi electron system.
  • Spiroheterocyclyls are classified into mono-, bis-, or poly-spiroheterocyclyls according to the number of spiro atoms shared between the rings.
  • 5- to 20-membered spiroheterocyclyl refers to a spiroheterocyclyl having 5 to 20 ring atoms, wherein one of the monocycles sharing the spiro atoms is a 3- to 8-membered monocyclic heterocyclyl ring and the other
  • the monocycle is a 3- to 8-membered monocyclic heterocyclyl ring or a 3- to 8-membered monocyclic cycloalkyl ring.
  • 7 to 11 membered spiroheterocyclyl groups having 7 to 11 ring atoms, of which 1 or 2 are heteroatoms.
  • spiroheterocyclyl groups can be attached to the remainder of the molecule through any suitable ring atom.
  • the heteroatom is a nitrogen atom
  • the nitrogen atom may be substituted or unsubstituted (ie, N or NR, R is hydrogen or other substituents already defined herein).
  • Each single ring may contain one or more double bonds, but no ring has a fully conjugated pi electron system.
  • Shared pairs of adjacent ring atoms can be CC or NC. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic groups.
  • the term "5- to 20-membered fused heterocyclyl” refers to a fused heterocyclyl group having 5 to 20 ring atoms, wherein the monocycles sharing adjacent pairs of ring atoms are 3- to 8-membered monocyclic heterocyclyl rings.
  • More preferred is a 6- to 10-membered fused heterocyclic group having 6 to 10 ring atoms, of which 1 or 2 are heteroatoms. More preferred is an 8- to 10-membered fused heterocyclic group having 8 to 10 ring atoms, of which 1 or 2 are heteroatoms.
  • fused heterocyclic groups include, but are not limited to:
  • fused heterocyclyl groups can be attached to the remainder of the molecule through any suitable ring atom.
  • 5- to 20-membered bridged heterocyclyl refers to a saturated or partially unsaturated polycyclic heterocyclic group having 5 to 20 ring atoms, wherein any two rings share two non-directly connected ring atoms, each monocyclic Rings can contain one or more double bonds, but no ring has a fully conjugated pi electron system.
  • Preferred is a 6- to 14-membered bridged heterocyclyl group. More preferred is a 7- to 10-membered bridged heterocyclyl group.
  • Specific examples of bridged heterocyclyl groups include, but are not limited to:
  • bridged heterocyclyl groups can be attached to the remainder of the molecule through any suitable ring atom.
  • the above various types of heterocyclic groups may be optionally substituted, and when substituted, the substituents are preferably one or more of the substituent groups described in the present application.
  • heterocyclic group described in the present invention include, but are not limited to, epoxy group, azetidinyl group, tetrahydrofuranyl group, tetrahydropyranyl group, pyrrolidinyl group, pyrrolidone group, piperidinyl group, piperazine group base, imidazolyl, imidazopyridyl, thiazolyl, oxazolidinyl, oxazolidinedione, decahydroquinolinyl, piperidonyl, morpholinyl, azabicyclohexyl, azabicycloheptyl , azabicyclooctyl, azabicyclononyl, azabicyclodecyl, azaspiroheptyl, azaspirooctyl, azaspirononyl, azaspirodecyl, tetrahydrospiro Cyclo[
  • aryl refers to an all-carbon monocyclic ring, an all-carbon non-fused polycyclic ring (rings joined by covalent bonds to the rings, not fused), or an all-carbon fused polycyclic ring (ie, sharing adjacent carbon atoms)
  • a ring group
  • at least one ring in the group is aromatic, that is, has a conjugated ⁇ -electron system.
  • C6-C14 aryl refers to an aryl group having 6 to 14 ring atoms. Preferably it is a C6-C10 aryl group.
  • the C6-C14 aryl groups in the present invention include monocyclic aryl groups, non-fused polycyclic aryl groups and aromatic fused polycyclic groups, wherein examples of monocyclic aryl groups include phenyl groups, and examples of non-fused polycyclic aryl groups include bicyclic aryl groups Phenyl etc.
  • the aromatic condensed polycyclic ring may be a polycyclic group formed by condensing a single aryl ring and one or more single aryl rings, Non-limiting examples thereof include naphthyl, anthracenyl, and the like.
  • the aromatic condensed polycyclic ring when the C6-C14 aryl group is an aromatic condensed polycyclic ring, can also be a single aryl ring (such as phenyl) and one or more non-aromatic polycyclic rings A polycyclic group formed by ring fusion, wherein the ring connected to the parent structure is an aromatic ring or a non-aromatic ring.
  • the non-aromatic ring includes, but is not limited to, a 3- to 6-membered monocyclic heterocyclyl ring (preferably a 5- or 6-membered monocyclic heterocyclyl ring, the ring carbon atoms of the monocyclic heterocyclyl ring may be replaced by 1 to 2 oxo groups to form a cyclic lactam or cyclic lactone structure), a 3- to 6-membered monocyclic cycloalkyl ring (preferably a 5- or 6-membered monocyclic cycloalkyl ring, the Ring carbon atoms can be substituted with 1 or 2 oxo groups to form a cyclic ketone structure).
  • a 3- to 6-membered monocyclic heterocyclyl ring preferably a 5- or 6-membered monocyclic heterocyclyl ring, the ring carbon atoms of the monocyclic heterocyclyl ring may be replaced by 1 to 2 oxo groups to form a cyclic lactam or
  • the polycyclic group in which the above-mentioned single aryl ring is fused with one or more non-aromatic rings can be connected to other groups or parent structures through nitrogen atoms or carbon atoms, and the ring connected to the parent structure is a single aryl ring or a non-aromatic ring. ring.
  • the above-mentioned various aryl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the substituent groups described in this application.
  • aryl refers to a C6-C14 aromatic group comprising 1 to 3 aromatic rings. It may be optionally substituted with one or more R6 or one or more R7 .
  • the aryl group is a C6-C10 aryl group.
  • aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, fluorenyl, and dihydrobenzofuranyl.
  • Aryl also refers to bicyclic or tricyclic ring systems wherein one or both rings of the aryl group may be saturated or partially saturated, respectively. If the aryl group contains two saturated rings, the two saturated rings may be a fused ring system or a spiro ring system. Examples of aryl groups containing two saturated rings (and are spiro ring systems) include the following:
  • aromatic-C1-C6 alkyl or "aralkyl” is meant to include an aryl group covalently attached to an alkyl group.
  • aryl is as described above
  • alkyl is as described above, and any one or all of aryl or alkyl can be independently optionally substituted or unsubstituted.
  • An example of an aralkyl group is (C6-C10)aryl(C1-C6)alkyl-. Specifically, but not limited to, benzyl, phenethyl and naphthylmethyl.
  • An example of a substituted arC1-C6alkyl group is one in which the alkyl group is substituted with a hydroxyalkyl group.
  • heteroaryl refers to a monocyclic or fused polycyclic ring having ring atoms substituted with at least one heteroatom independently selected from nitrogen, oxygen, or sulfur (ie, sharing pairs of adjacent ring atoms, which may be is a CC or NC) group in which the nitrogen and sulfur atoms may be optionally oxidized and the nitrogen atom(s) may be optionally quaternized.
  • the heteroaryl group has 6, 10 or 14 pi electrons shared and at least one ring in the group is aromatic.
  • Preferred are 5 to 10 membered heteroaryl groups having 5 to 10 ring atoms of which 1, 2, 3 or 4 are heteroatoms.
  • the 5- to 14-membered heteroaryl groups of the present invention can be monocyclic heteroaryl groups (eg, 5- or 6-membered monocyclic heteroaryl groups), fused bicyclic heteroaryl groups (eg, 8- to 10-membered bicyclic heteroaryl groups) or fused Tricyclic heteroaryl.
  • monocyclic heteroaryl groups include, but are not limited to, thiophene, furan, thiazole, isothiazole, imidazole, oxazole, pyrrole, pyrazole, triazole, 1,2,3-triazole, 1,2,4-triazole azole, 1,2,5-triazole, 1,3,4-triazole, tetrazole, isoxazole, oxadiazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole , 1,2,5-oxadiazole, 1,3,4-oxadiazole, thiadiazole, pyridine, pyridazine, pyrimidine, pyrazine, etc.
  • the fused bicyclic heteroaryl group can be either a bicyclic group formed by condensing a single aryl ring (such as phenyl) with a monocyclic heteroaryl ring (preferably a 5- or 6-membered monocyclic heteroaryl ring).
  • a 9- or 10-membered bicyclic heteroaryl ring is a 9- or 10-membered bicyclic heteroaryl ring), or a monocyclic heteroaryl ring (preferably a 5- or 6-membered monocyclic heteroaryl ring) and a monocyclic heteroaryl ring (preferably a 5- or 6-membered monocyclic ring) ring heteroaryl ring) fused to form a bicyclic group.
  • the 2 ring atoms that are arbitrarily connected on the above-mentioned monocyclic heteroaryl ring, including CC, NC, NN, can be combined with the monocyclic cycloalkyl ring, monocyclic heterocyclyl ring, single aryl ring, 5 Or 6-membered monocyclic heteroaryl ring and other cycloalkyl, heterocyclyl, aryl or heteroaryl are fused to form a fused polycyclic ring.
  • the 2 ring atoms attached to the monocyclic heteroaryl ring forming a fused ring with other rings are preferably CC, including without limitation the following forms:
  • Non-limiting examples of 8- to 10-membered bicyclic heteroaryl groups include: benzo[d]isoxazole, 1H-indole, isoindole, 1H-benzo[d]imidazole, benzo[d]isothiazole, 1H-benzo[d][1,2,3]triazole, benzo[d]oxazole, benzo[d]thiazole, indazole, benzofuran, benzo[b]thiophene, quinoline, iso Quinoline, quinazoline, quinoxaline, cinnoline, pyrido[3,2-d]pyrimidine, pyrido[2,3-d]pyrimidine, pyrido[3,4-d]pyrimidine, pyrido[ 4,3-d]pyrimidine, 1,8-naphthyridine, 1,7-naphthyridine, 1,6-naphthyridine, 1,5-nap
  • bicyclic heteroaryl groups include, but are not limited to: These groups can be attached to the rest of the molecule through any suitable ring atom.
  • the ring attached to the parent structure can be a monocyclic heteroaryl ring or a benzene ring.
  • the fused bicyclic heteroaryl or fused tricyclic heteroaryl may be a monocyclic heteroaryl ring (preferably a 5- or 6-membered monocyclic heteroaryl ring) and a A polycyclic group formed by condensing multiple non-aromatic rings, wherein the ring connected to the parent structure is a monocyclic heteroaryl ring or a non-aromatic ring.
  • the non-aromatic ring includes, but is not limited to, a 3- to 6-membered monocyclic heterocyclyl ring (preferably a 5- or 6-membered monocyclic heterocyclyl ring, the ring carbon atoms of the monocyclic heterocyclyl ring may be replaced by 1 to 2 oxo group substitution to form a cyclic lactam or cyclic lactone structure), a 3- to 6-membered monocyclic cycloalkyl ring (preferably a 5- or 6-membered monocyclic cycloalkyl ring, the Ring carbon atoms can be substituted with 1 or 2 oxo groups to form a cyclic ketone structure) and the like.
  • a 3- to 6-membered monocyclic heterocyclyl ring preferably a 5- or 6-membered monocyclic heterocyclyl ring, the ring carbon atoms of the monocyclic heterocyclyl ring may be replaced by 1 to 2 oxo group substitution to form a cycl
  • the polycyclic group formed by condensing the above-mentioned monocyclic heteroaryl ring and one or more non-aromatic rings can be connected with other groups or parent structures through nitrogen atoms or carbon atoms, and the ring connected with the parent structure is a monocyclic heteroaromatic base ring or non-aromatic ring.
  • heteroaryl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the substituent groups described in the present application.
  • acetyl refers to -C(O) CH3 .
  • the compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments enumerated below, embodiments formed in combination with other chemical synthesis methods, and those well known to those skilled in the art equivalent replacement. Preferred embodiments include, but are not limited to, the embodiments of the present invention.
  • the synthesis method of intermediates or starting compounds is shown in a certain example in the preparation example section, and if the same intermediates or starting compounds are used in other examples, the preparation of the compounds will not be repeated.
  • Step 1 In a 1L single-necked bottle, add (S)-methyl 5-oxopyrrolidine-2-carboxylate (200 g, 1397 mmol) and dimethyl sulfate (134 mL). After the addition was completed, the system was reacted at 56° C. for 18 h, and the completion of the reaction was monitored by TLC. After cooling to room temperature, triethylamine (292 mL) was added dropwise, followed by stirring for 30 minutes. Add 400 mL of water, and extract with ethyl acetate (400 mL ⁇ 3).
  • ES-API: [M+1] + 245.1.
  • Step 4 In a 1L single-necked bottle, add the compound (1R,5S)-4-oxo-3,8-diazabicyclo[3.2.1]octane-2-carboxylic acid methyl ester (A1, 60.0 g, 325 mmol ), triethylamine (65.9 g, 651.5 mmol), dichloromethane (600 mL). Cool to 0°C and add di-tert-butyl dicarbonate (106.6 g, 488.6 mmol). After the addition was completed, the system was allowed to react at room temperature overnight, and LC-MS monitored the completion of the reaction. Water (1 L) was added and extracted with dichloromethane (1 L).
  • Step 5 In a 500mL three-necked flask, add the compound 8-(tert-butyl)2-methyl(1R,5S)-4-oxo-3,8-diazabicyclo[3.2.1]octane-2, 8-Dicarboxylate (A12, 20.0 g, 70.3 mmol), tetrahydrofuran (300 mL). Cool to 0 °C, add lithium aluminum tetrahydride (5.87 g, 154.7 mmol) in batches (the temperature is controlled below 5 °C). Join is complete. The system was reacted at room temperature overnight, and the reaction was completed by LC-MS monitoring.
  • 8-(tert-butyl)2-methyl(1R,5S)-4-oxo-3,8-diazabicyclo[3.2.1]octane-2, 8-Dicarboxylate A12, 20.0 g, 70.3 mmol
  • tetrahydrofuran 300 mL
  • Step 1 Dissolve (R)-5-oxopyrrolidine-2-carboxylic acid methyl ester (395.3 g, 2.762 mmol) in 3500 mL of dichloromethane, add trimethyloxonium tetrafluoroboric acid ( 612.697g, 4.142mol, 1.5eq), and the reaction was completed at 25°C for 24hr. The completion of the reaction was monitored by TLC.
  • Step 2 Add (R)-5-methoxy-3,4-dihydro-2H-pyrrole-2-carboxylate methyl ester (406.7g, 2.588mol) to methyl nitroacetate (308.133g, 2.588g) mol, 1eq). The reaction was carried out at 60°C for 48 hours, and the reaction was completed by nuclear magnetic monitoring.
  • Step 3 In a 5L autoclave, (R)-5-(2-methoxy-1-nitro-2-oxyethylene) pyrrolidine-2-carboxylic acid methyl ester (146.2g, 598.687mmol) Dissolve in methanol (1500 mL) and tetrahydrofuran (1500 mL), add Pd(OH) 2 /C (15.00 g, 20% purity), replace with hydrogen 3 times, 0.4 MPa, and react at 40° C. for 72 hr. Hydrogen was supplemented several times during the reaction. Cool down to room temperature.
  • Step 4 Dissolve the crude product (1S,5R)-4-oxo-3,8-diazabicyclo[3.2.1]octane-2-carboxylic acid methyl ester (A21, 10.00 g, 54.291 mmol) in water ( 50 mL) and tetrahydrofuran (50 mL), Na 2 CO 3 (5.754 g, 54.291 mmol) was added, (Boc) 2 O (11.849 g, 54.291 mmol) was added dropwise at 10° C., the dropping was completed, and the reaction was carried out at 20° C. for 12 hr. The reaction was complete as monitored by TLC.
  • Step 5 8-(tert-butyl)2-methyl(1S,5R)-4-oxo-3,8-diazabicyclo[3.2.1]octane-2,8-dicarboxylate (A22, 2.00 g, 7.035 mmol) was dissolved in tetrahydrofuran (20 mL), lithium aluminum tetrahydride (400.489 mg, 10.552 mmol, 1.5 eq) was added in batches at 0 °C, and the reaction was carried out at 20 °C for 12 hr. The reaction was complete as monitored by TLC.
  • Step 1 To triisopropyl((6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2- To the solution of N,N-dimethylformamide (5.0 mL) was added cesium fluoride (3.0 g, 20.24 mmol), and reacted at room temperature for 2 hours .
  • Step 2 To 2-(8-ethynyl-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxa To the methanol (10.0 mL) solution of borane (558 mg, crude product) was added palladium carbon (60 mg) with a mass fraction of 10%, replaced by hydrogen for 4 times, and reacted at room temperature for 2 hours under the protection of hydrogen.
  • Step 3 Dissolve 2,4,6-trichloronicotinic acid (5.0 g, 22.22 mmol) in dichloromethane (40.0 mL) at 0°C, and add oxalyl chloride (6.0 mL) dropwise to the above system , 8 drops of N,N-dimethylformamide were added, and the reaction system was stirred at room temperature for 1 hour. After 1 hour, the solvent was spin-dried under reduced pressure, a dry tetrahydrofuran (30.0 mL) solution was added, cooled to 0-5 °C, and the solution was added dropwise to a mixed solution of ammonia water (30.0 mL) and tetrahydrofuran (30.0 mL) at room temperature.
  • Step 4 In a 500 mL three-necked round bottom flask, (2,4-dimethoxyphenyl)methanamine (4.45 g, 26.66 mmol) was dissolved in dry dioxane (90.0 mL). The ice-water bath was cooled to 0 ⁇ 5°C, N,N-diisopropylethylamine (8.61g, 66.66mmol) was added under nitrogen protection, the reaction was carried out at this temperature for about 10 ⁇ 15 minutes, and 2,4,6-trichloro Nicotinamide (6.0 g, crude product) was dissolved in dry dioxane (20 mL) and added dropwise to the above solution. The reaction was continued for 5 hours at 50°C.
  • Step 5 Add 2,6-dichloro-4-((2,4-dimethoxybenzyl)amino)nicotinamide (3.723g, 10.47mmol) and dry tetrahydrofuran to a 500mL three-necked round bottom flask at room temperature (60 mL), cooled to 0-5° C. under an ice-water bath, sodium hydride (838 mg, 20.95 mmol) was added in portions, and the reaction was carried out at this temperature for 20 minutes.
  • N,N'-carbonyldiimidazole (5.09 g, 31.41 mmol) was added to dry tetrahydrofuran (30 mL), added dropwise to the above solution, the addition was completed, and the reaction was carried out at this temperature for 0.5 to 1 hour.
  • the reaction was monitored by LCMS, the reaction solution was poured into ice water (300 mL), the pH was adjusted to 7-8 with 6M aqueous hydrochloric acid under ice-water bath conditions, and 5,7-dichloro-1-(2,4-dimethoxy) was obtained by filtration.
  • benzyl)pyrido[4,3-d]pyrimidine-2,4(1H,3H)-dione (3.7 g, yield: 92.7%).
  • ES-API: [M+H] + 382.0/384.0.
  • Step 6 Add dry tetrahydrofuran (100 mL) to a 250 mL one-neck flask at room temperature, and then add (1R,5S)-2-(hydroxymethyl)-3,8-diazabicyclo[3.2.1]octane-8 - tert-butyl carboxylate (A1, 358.0 mg, 1.480 mmol), cooled to 0-5° C. in an ice-water bath, and sodium hydride (1.20 mg, 2.960 mmol) was added.
  • reaction was carried out under nitrogen protection for 10 to 20 minutes, and 5,7-dichloro-1-(2,4-dimethoxybenzyl)pyrido[4,3-d]pyrimidine-2,4(1H, 3H)-dione (565.0 mg, 1.480 mmol), and the reaction was continued for 20 to 30 minutes at 0 to 5 °C.
  • the reaction was monitored by LCMS, the reaction solution was poured into ice water (300 mL), the pH was adjusted to 7-8 with 6M aqueous hydrochloric acid, extracted with ethyl acetate (100 mL ⁇ 2), the ethyl acetate phases were combined and washed with saturated brine (100 mL ⁇ 1).
  • Step 7 Add dry N,N-dimethylformamide (20mL) and (1R,5S)-2-((((7-chloro-1-(2,4-dimethoxy) to a 250mL one-neck flask at room temperature ylbenzyl)-2,4-dioxa-1,2,3,4-tetrahydropyrido[4,3-d]pyrimidin-5-yl)oxy)methyl)-3,8-di Azabicyclo[3.2.1]octane-8-carboxylate tert-butyl ester (850 mg, 1.448 mmol).
  • Step 8 Add (6R,9S)-2-chloro-13-(3,4-dimethoxybenzyl)-12-oxo-5a,6,7,8,9 to trifluoroacetic acid (5 mL) ,10,12,13-Octahydro-5H-4-oxa-3,10a,11,13,14-pentaza-6,9-methylenenaphtho[1,8-ab]heptene- 14-Carboxylic acid tert-butyl ester (420 mg, 0.7380 mmol), stirred at 55°C for 1 hour.
  • Step 9 To (6R,9S)-2-chloro-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaza- Sodium carbonate was added to a mixed solution of 6,9-methylenenaphtho[1,8-ab]hepten-12(13H)-one (350 mg, 1.094 mmol) in tetrahydrofuran (5.0 mL) and water (5.0 mL) (350 mg, 3.282 mmol), cooled in an ice-water bath, added benzyloxycarbonyl succinimide (354 mg, 1.422 mmol), and reacted at room temperature for 3 hours.
  • Step ten at 0 °C, to (6R,9S)-2-chloro-12-oxa-5a,6,7,8,9,10,12,13-octahydro-5H-4-oxa- Benzyl 3,10a,11,13,14-pentaaza-6,9-methylenenaphtho[1,8-ab]heptene-14-carboxylate (460 mg, 1.013 mmol) in toluene (3.0 mL) ) solution was successively added phosphorus oxychloride (465 mg, 3.039 mmol) and N,N-diisopropylethylamine (392.0 mg, 3.039 mmol), and the reaction was carried out at 125° C.
  • Step 11 To (6R,9S)-2,12-dichloro-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14- A solution of benzyl pentaaza-6,9-methylenenaphtho[1,8-ab]heptene-14-carboxylate (200 mg, 0.4246 mmol) in N,N-dimethylformamide (3.0 mL) Potassium fluoride (500 mg, 8.492 mmol) was added to the mixture, and the reaction was carried out at 120° C. for 4 hours under nitrogen protection.
  • Step 12 (6R,9S)-2-chloro-12-fluoro-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14 -Pentaza-6,9-methylenenaphtho[1,8-ab]heptene-14-carboxylate benzyl ester (140 mg, 0.3076 mmol) was dissolved in tetrahydrofuran/water (2 mL/0.5 mL) and added 2-(8-ethyl-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (250mg , 0.7309 mmol), potassium phosphate (250 mg, 1.179 mmol) and [n-butylbis(1-adamantyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium methanesulf
  • Step thirteen under ice-water bath conditions, a solution of ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol (43.0 mg, 0.2714 mmol) in tetrahydrofuran (5.0 mL) was added Sodium hydride (22 mg, 0.5428 mmol) was added to the mixture, and the mixture was reacted at room temperature for 0.5 hours.
  • Step 1 Add dry tetrahydrofuran (100 mL) to a 250 mL one-neck flask at room temperature, and then add (1S,2S,5R)-2-(hydroxymethyl)-3,8-diazabicyclo[3.2.1]octane -8-Carboxylic acid tert-butyl ester (A2-1, 358.0 mg, 1.480 mmol) was cooled to 0-5° C. in an ice-water bath, and then sodium hydride (1, 20 mg, 2.960 mmol) was added.
  • Step 2 Add dry N,N-dimethylformamide (20mL) and tert-butyl (1S,2S,5R)-2-((((7-chloro-1-(2,) to a 250mL single-necked flask at room temperature. 4-Dimethoxybenzyl)-2,4-dioxa-1,2,3,4-tetrahydropyrido[4,3-d]pyrimidin-5-yl)oxy)methyl)- 3,8-Diazabicyclo[3.2.1]octane-8-carboxylate (850 mg, 1.448 mmol).
  • Step 3 To trifluoroacetic acid (5.0 mL) was added tert-butyl(5aS,6S,9R)-2-chloro-13-(2,4-dimethoxybenzyl)-12-oxo-5a,6 ,7,8,9,10,12,13-Octahydro-5H-4-oxa-3,10a,11,13,14-pentaza-6,9-methylenenaphtho[1,8 -ab]heptene-14-carboxylate (420 mg, 0.7380 mmol), stirred at 55°C for 1 hour.
  • Step 4 To (5aS,6S,9R)-2-chloro-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaza To a mixed solution of hetero-6,9-methylenenaphtho[1,8-ab]hepten-12(13H)-one (350 mg, 1.094 mmol) in tetrahydrofuran (5.0 mL) and water (5.0 mL) was added Sodium carbonate (350 mg, 3.282 mmol), the system was cooled with an ice-water bath, benzyloxycarbonyl succinimide (354 mg, 1.422 mmol) was added, and the reaction was carried out at room temperature for 3 hours.
  • dichloromethane 80 mL was added to the reaction solution, washed with saturated aqueous sodium bicarbonate solution (100 mL), saturated brine (80 mL), dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by flash silica gel column (ethyl acetate).
  • Step 5 At 0°C, to (5aS,6S,9R)-2-chloro-12-oxa-5a,6,7,8,9,10,12,13-octahydro-5H-4-oxygen Benzyl hetero-3,10a,11,13,14-pentaaza-6,9-methylenenaphtho[1,8-ab]heptene-14-carboxylate (460 mg, 1.013 mmol) in toluene ( 3.0 mL) solution was sequentially added phosphorus oxychloride (465 mg, 3.039 mmol) and N,N-diisopropylethylamine (392.0 mg, 3.039 mmol), and reacted at 125° C.
  • phosphorus oxychloride 465 mg, 3.039 mmol
  • N,N-diisopropylethylamine 392.0 mg, 3.039 mmol
  • Step 6 To (5aS,6S,9R)-2,12-dichloro-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14 -Pentaaza-6,9-methylenenaphtho[1,8-ab]heptene-14-carboxylate benzyl ester (200 mg, 0.4246 mmol) in N,N-dimethylformamide (3.0 mL) Potassium fluoride (500 mg, 8.492 mmol) was added to the solution, and the reaction was carried out at 120° C. for 4 hours under nitrogen protection.
  • Step 7 (5aS,6S,9R)-2-chloro-12-fluoro-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13, Benzyl 14-pentaaza-6,9-methylenenaphtho[1,8-ab]heptene-14-carboxylate (140 mg, 0.3076 mmol) was dissolved in tetrahydrofuran/water (2 mL/0.5 mL), Add 2-(8-ethyl-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (250 mg , 0.7309 mmol), potassium phosphate (250 mg, 1.179 mmol) and [n-butylbis(1-adamantyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium methanesulf
  • Step 8 Under ice-water bath conditions, to a solution of ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol (43.0 mg, 0.2714 mmol) in tetrahydrofuran (5.0 mL) Sodium hydride (22 mg, 0.5428 mmol) was added, and the mixture was reacted at room temperature for 0.5 hours.
  • Step 9 To (5aS,6S,9R)-2-(8-ethyl-3-(methoxymethoxy)naphthalen-1-yl)-12-(((2R,7aS)-2-fluoro Tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13, 14-Pentaaza-6,9-methylenenaphtho[1,8-ab]heptene-14-carboxylate benzyl ester (170mg, crude product) in methanol (10.0mL) solution was added with a mass fraction of 10% of palladium on carbon (500 mg), replaced with hydrogen 4 times, and reacted at room temperature for 2 hours under a hydrogen atmosphere to obtain (5aS,6S,9R)-2-(8-ethyl-3-(methoxymethoxy)naphthalene-1) -
  • Step ten (5aS,6S,9R)-2-(8-ethyl-3-(methoxymethoxy)naphthalen-1-yl)-12-(((2R,7aS)-2-fluoro Tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13, 14-Pentaaza-6,9-methylenenaphtho[1,8-ab]heptene (162 mg, crude product) was dissolved in acetonitrile (6.0 mL), and 4M hydrochloric acid/dioxane solution was added under ice bath (2.0 mL, 8.0 mmol), reacted under ice bath for 0.5 hours.
  • Example 3 Synthesis of 4-((6R,9S)-12-(3-(dimethylamino)azetidin-1-yl)-5a,6,7,8,9,10-hexahydro- 5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylenenaphtho[1,8-ab]hepten-2-yl)-5-ethylnaphthalene -2-ol (Z308)
  • Step 1 Add N,N-dimethylazetidine-3-amine hydrochloride (45.0mg, 0.332mmol) in dioxane (5.0mL) solution under ice-water bath condition - Diisopropylethylamine (430 mg, 3.322 mmol) and finally tert-butyl (6R,9S)-2-(8-ethyl-3-(methoxymethoxy)naphthalen-1-yl)- 12-Fluoro-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaza-6,9-methoxynaphtho[1 ,8-ab]heptene-14-carboxylate (100 mg, 0.1660 mmol).
  • the reaction was carried out at 110°C for 2 hours. After 2 hours, ice water (50 mL) was added to the system, extracted with dichloromethane (50 mL ⁇ 2), the dichloromethane phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was spin-dried under reduced pressure, and the mixture was evaporated to dryness under reduced pressure.
  • Step 2 tert-butyl(6R,9S)-12-(3-(dimethylamino)azetidin-1-yl)-2-(8-ethyl-3-(methoxymethoxy) base)naphthalen-1-yl)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-idene Methylnaphtho[1,8-ab]heptene-14-carboxylate (110 mg, 0.1612 mmol) was dissolved in acetonitrile (6.0 mL), and 4M hydrochloric acid/dioxane solution (2.0 mL, 8.0 mmol), reacted under ice bath for 0.5 hours.
  • acetonitrile 6.0 mL
  • 4M hydrochloric acid/dioxane solution 2.0 mL, 8.0 mmol
  • Step 1 To 2,4,6-trichloropyridine-3-carboxylic acid (200 mg, 0.883 mmol) and N,N-dimethylformamide (0.02 mL) in dichloromethane (5 mL) at 0°C 2-Chloro-2-oxoacetyl chloride (0.374 mL, 4.415 mmol) was slowly added to the mixture. The reaction was stirred at room temperature for 1 hour. The reaction was concentrated to give a yellow oily crude product 2,4,6-trichloropyridine-3-carbonyl chloride (216 mg, 0.882 mmol, yield: 99.87%), which was used directly in the next step.
  • Step 2 The reaction was stirred for 10 minutes at room temperature with aminocarbimidothiomethyl (6456.50 mg, 34.301 mmol) and sodium bicarbonate (7204.09 mg, 85.753 mmol) in tetrahydrofuran (40 mL) and water (70 mL). After cooling to 0°C, a solution of 2,4,6-trichloropyridine-3-carbonyl chloride (2100 mg, 8.575 mmol) in tetrahydrofuran (40 mL) was added dropwise. The reaction was stirred at 0°C for 30 minutes. It was then extracted with ethyl acetate.
  • Step 3 Under nitrogen protection, (2,4,6-trichloronicotinyl)carbamoylimidomethyl sulfate (2000mg, 6.698mmol) and N,N-diisopropylethylamine (2.775mL, 16.746mmol) ) was sealed in dioxane (25 mL) and heated at 100°C for 16 hours. The reaction was concentrated until the volume was ⁇ 5 mL. To the residue were added water (15 mL) and 2M aqueous hydrochloric acid (3 mL). After a precipitate formed, filter and wash the filter cake with water (10 mL).
  • Step 4 To a suspension of sodium hydride (427.29 mg, 10.682 mmol) in tetrahydrofuran (20 mL) was added tert-butyl (1S,2R,5R)-2-(hydroxymethyl)-3,8-di at 0°C Azabicyclo[3.2.1]octane-8-carboxylate (A2-2, 813.53 mg, 3.357 mmol) and stirred at this temperature for 10 minutes. 5,7-Dichloro-2-(methylthio)pyrido[4,3-d]pyrimidin-4(3H)-one (800 mg, crude) was added, and the mixture was heated and stirred at 60°C for 1 hour.
  • Step 5 To tert-butyl(1S,2R,5R)-2-((((7-chloro-4-hydroxy-2-(methylthio)pyrido[4,3-d]pyrimidin-5-yl] Oxy)methyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1400 mg, 2.992 mmol) and N,N-diisopropylethylamine (4.957 mL, 29.916 mmol) ) in dichloromethane (20 mL) was added propylphosphoric anhydride (50% in ethyl acetate) (11422.33 mg, 17.949 mmol) and stirred at room temperature for 3 hours.
  • propylphosphoric anhydride 50% in ethyl acetate
  • Step 6 To tert-butyl(5aR,6S,9R)-2-chloro-12-(methylthio)5a,6,7,8,9,10-hexahydro-5H-4- at 0°C Oxa-3,10a,11,13,14-pentaaza-6,9-methylenenaphtho[1,8-ab]heptene-14-carboxylate (550 mg, 1.222 mmol) in dichloro To a solution of methane (15 mL) was added m-chloroperoxybenzoic acid (322.61 mg, 1.589 mmol). Stir at room temperature for 1 hour. Quenched with saturated sodium sulfite and extracted with dichloromethane.
  • Step 7 Add ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol (239.16 g) to a solution of sodium hydride (45.07 mg, 1.878 mmol) in tetrahydrofuran at 0°C mg, 1.502 mmol). The reaction was stirred at room temperature for 10 minutes.
  • Step 8 To tert-butyl(5aR,6S,9R)-2-chloro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazine-7a(5H)-5a,6,7 ,8,9,10-Hexahydro-5H-4-oxa-3,10a,11,13,14-pentaza-6,9-methylenenaphtho[1,8-ab]heptene- 14-Carboxylic acid ester and triisopropyl ((6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2 -yl)naphthalen-1-yl)ethynyl)silane in dioxane (6 mL) and water (1.5 mL) was added potassium phosphate (147.55 mg, 0.695 mmol), [n-butylbis(1- methanesulfonic acid
  • Step 9 To tert-butyl(5aR,6S,9R)-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-2- (3-(Methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-5a,6,7,8,9,10-hexahydro-5H -4-oxa-3,10a,11,13,14-pentaaza-6,9-methylenenaphtho[1,8-ab]heptene-14-carboxylate (150 mg, 0.168 mmol) To a solution of N,N-dimethylformamide (3.0 mL) was added cesium fluoride (127.55 mg, 0.840 mmol).
  • Step ten To tert-butyl(5aR,6S,9R)-2-(8-ethynyl-3-(methoxymethoxy)naphthalen-1-yl)-12-(((2R,7aS)- 2-Fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11 , 13,14-Pentaaza-6,9-methylenenaphtho[1,8-ab]heptene-14-carboxylate (90 mg, 0.122 mmol) in methanol (5.0 mL) was added palladium on carbon (74.17 mg, 0.061 mmol), replaced with hydrogen and reacted for 1 hour at room temperature under a hydrogen atmosphere.
  • Example 5 Synthesis of 5-ethyl-4-((5aS,6S,9R)-1-fluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrozine-7a(5H) -yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaza-6,9-methylene Naphtho[1,8-ab]hepten-2-yl)naphthalen-2-ol (Z140-1)
  • Step 1 To a solution of 2,6-dichloro-5-fluoronicotinic acid (8.0 g, 38.095 mmol) in dry tetrahydrofuran (150 mL) was added dropwise methyllithium (47.6 mL, 76.19 mL) at -78°C over a period of hours mmol, 1.6M), and stirred at -20°C for 2 hours after the dropwise addition. After 2 hours, the system was lowered to -78 °C again, and 1,2-dibromo-1,1,2,2-tetrachloroethane (12.405 g, 38.095 mmol) in tetrahydrofuran (30 mL) was added dropwise within 30 minutes.
  • Step 2 Dissolve 4-bromo-2,6-dichloro-5-fluoronicotinic acid (6.0 g, 20.90 mmol) in thionyl chloride (40.0 mL) at room temperature, and then add 16 drops of N,N - Dimethylformamide was added to the above system, and the reaction system was stirred and reacted at 100°C for 1 hour. After 1 hour, the solvent was spin-dried under reduced pressure.
  • Step 3 Under nitrogen protection, methyl (4-bromo-2,6-dichloro-5-fluoronicotinoyl)carbamoyliminothioate (880mg, 2.45mmol) and N,N-diisopropyl Ethylamine (1.4 mL, 8.37 mmol) was sealed in dioxane (12 mL) and heated at 100°C for 16 hours. The reaction was concentrated until the volume was ⁇ 5 mL. To the residue were added water (15 mL) and 2M aqueous hydrochloric acid (3 mL). After a precipitate formed, filter and wash the filter cake with water (10 mL).
  • Step 4 To a suspension of sodium hydride (427.29 mg, 10.682 mmol) in tetrahydrofuran (20 mL) was added tert-butyl (1S,2S,5R)-2-(hydroxymethyl)-3,8-di at 0°C Azabicyclo[3.2.1]octane-8-carboxylate (A2-1, 813.53 mg, 3.357 mmol) and stirred at this temperature for 10 minutes. Add 5,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4(3H)-one (854 mg, 3.052 mmol) and stir with heating at 60°C for 1 h .
  • Step 5 To tert-butyl(1S,2S,5R)-2-((((7-chloro-8-fluoro-4-hydroxy-2-(methylthio)pyrido[4,3-d]pyrimidine- 5-yl)oxy)methyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1451 mg, 2.992 mmol) and N,N-diisopropylethylamine ( To a solution of 4.957 mL, 29.916 mmol) in dichloromethane (20 mL) was added propylphosphoric anhydride (50% in ethyl acetate) (11422.33 mg, 17.949 mmol) and stirred at room temperature for 3 hours.
  • Step 6 To tert-butyl(5aS,6S,9R)-2-chloro-1-fluoro-12-(methylthio)-5a,6,7,8,9,10-hexahydro at 0°C -5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylenenaphtho[1,8-ab]heptene-14-carboxylate (540 mg, 1.153 mmol) in dichloromethane (15 mL) was added m-chloroperoxybenzoic acid (322.61 mg, 1.589 mmol). Stir at room temperature for 1 hour.
  • Step 7 Add ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol (239.16 g) to a solution of sodium hydride (45.07 mg, 1.878 mmol) in tetrahydrofuran at 0°C mg, 1.502 mmol). The reaction was stirred at room temperature for 10 minutes.
  • Step 8 To tert-butyl(5aR,6S,9R)-2-chloro-1-fluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl )Methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylenenaphthalene and [1,8-ab]heptene-14-carboxylate (134.0 mg, 0.233 mmol) and triisopropyl ((6-(methoxymethoxy)-8-(4,4,5, 5-Tetramethyl-1,3,2-dioxaboran-2-yl)naphthalen-1-yl)ethynyl)silane (230.0 mg, 0.466 mmol) in dioxane (6 mL) and water (1.5 mL) was added potassium phosphate (147
  • Step 9 To tert-butyl(5aS,6S,9R)-1-fluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy )-2-(3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-5a,6,7,8,9,10- Hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylenenaphtho[1,8-ab]heptene-14-carboxylate (165mg , 0.181 mmol) in N,N-dimethylformamide (3.0 mL) solution was added cesium fluoride (127.55 mg, 0.840 mmol).
  • Step ten To tert-butyl(5aS,6S,9R)-2-(8-ethynyl-3-(methoxymethoxy)naphthalen-1-yl)-1-fluoro-12-(((2R ,7aS)-2-Fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3 , 10a,11,13,14-pentaaza-6,9-methylenenaphtho[1,8-ab]heptene-14-carboxylate (100 mg, 0.1324 mmol) in methanol (5.0 mL) Palladium on carbon (75.0 mg, 0.061 mmol) was added, hydrogen was replaced, and the reaction was carried out at room temperature for 1 hour under a hydrogen atmosphere.
  • the crude product was prepared by high performance liquid phase (ammonium bicarbonate method) to obtain 5-ethyl-4-((5aS,6S,9R)-1-fluoro-12-((((2R,7aS)-2-fluorotetrahydro -1H-Pyrrolizin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14- Pentaaza-6,9-methylenenaphtho[1,8-ab]hepten-2-yl)naphthalen-2-ol (5-ethyl-4-((5aS,6S,9R)-1- fluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa
  • Step 1 To tert-butyl(1S,2S,5R)-2-((((7-chloro-8-fluoro-(2-methylthio)-4-oxa-3,4-dihydropyridine[4 ,3-d]pyrimidin-5-yl)oxy)methyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (150.0 mg, 0.321 mmol) and triisopropyl yl((8-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)naphthalen-1-yl)ethynyl)silane (220.0 mg, 0.506 mmol) To the dioxane (6 mL) and water (1.5 mL) was added potassium phosphate (300 mg, 1.415 mmol), [n-butylbis(1-adamantyl)phosphine](2-amino-1,1 methanes
  • Step 2 Add tert-butyl(5aS,6S,9R)-1-fluoro-12-(methylthio)-2-(8-((triisopropylsilyl)ethynyl) at 0°C Naphthalen-1-yl)-5a,6,7,8,9,10-hexahydro-5H-4-oxo-3,10a,11,13,14-pentaza-6,9-methylene
  • m-chloroperoxybenzoic acid 67.12 mg, 0.389 mmol
  • Step 3 To a solution of ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol (100.0 mg, 0.628 mmol) in tetrahydrofuran (10.0 mL) at 0°C Sodium hydride (50.0 mg, 1.25 mmol) was added, and after stirring at this temperature for 10 minutes, tert-butyl (5aS,6S,9R)-1-fluoro-12-(methylsulfinyl)-2-(8 was added -((triisopropylsilyl)ethynyl)naphthalen-1-yl)-5a,6,7,8,9,10-hexahydro-5H-4-oxo-3,10a,11,13 , 14-Pentaaza-6,9-methylenenaphtho[1,8-ab]heptene-14-carboxylate (230.0 mg, 0.304 mmol) in te
  • the reaction was stirred at 0°C for 1 hour.
  • the reaction was quenched with saturated sodium bicarbonate solution and extracted with ethyl acetate.
  • the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated.
  • Step 4 To (5aS,6S,9R)-1-fluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-2 -(8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-5a,6,7,8,9,10-hexahydro-5H-4-oxo-3,10a, 11,13,14-Pentaaza-6,9-methylenenaphtho[1,8-ab]heptene-14-carboxylate tert-butyl ester (260 mg, crude) in N,N-dimethylmethane To the amide (5.0 mL) solution was added cesium fluoride (1000 mg, 6.583 mmol).
  • Step five (5aS,6S,9R)-2-(8-ethynylnaphthalen-1-yl)-1-fluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrroleazine-7a (5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxo-3,10a,11,13,14-pentaza-6,9 - methylenenaphtho[1,8-ab]heptene-14-carboxylate tert-butyl ester (120 mg, 0.173 mmol) and acetonitrile (5.0 mL) and 4M hydrochloric acid/dioxane solution (2.0 mL, 8.000 mmol) ) The reaction solution was reacted at 0°C for 1 hour.
  • the crude product was prepared by high performance liquid phase (ammonium bicarbonate method) to obtain (5aS,6S,9R)-2-(8-ethynylnaphthalen-1-yl)-1-fluoro-12-(((2R,7aS)- 2-Fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxo-3,10a,11 ,13,14-Pentaza-6,9-methylenenaphtho[1,8-ab]heptene((5aS,6S,9R)-2-(8-ethynylnaphthalen-1-yl)-1- fluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexa
  • Example 7 Synthesis of 4-((5aS,6S,9R)-3-chloro-13-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-ylmethoxy )-5a,6,7,8,9,10-hexahydro-5H-6,9-epiaminoaza[2',1':3,4][1,4]oxaza[5,6 ,7-De]quinazolin-2-yl)-5-ethylnaphthalen-2-ol (Z381)
  • Step 1 To a suspension of sodium hydrogen (60% in oil) (32 mg, 0.81 mmol) in tetrahydrofuran (10 mL) was added (1S,2S,5R)-2-(hydroxymethyl)-3 at 0°C , tert-butyl 8-diazacyclo[3.2.1]octane-8-carboxylate (A2-1, 131 mg, 0.54 mmol) and stirred at this temperature for 10 minutes. 7-Bromo-2,6-dichloro-5-fluoroquinazolin-4(3H)-one (170 mg, 0.54 mmol) was added and stirred with heating at 60°C for 1 hour.
  • Step 2 To tert-butyl(1S,2S,5R)-2-(((7-bromo-2,6-dichloro-4-oxo-3,4-dihydroquinazolin-5-yl)oxy yl)methyl)-3,8-diazacyclo[3.2.1]octane-8-carboxylate (110 mg, 0.21 mmol) and N,N-diisopropylethylamine (80 mg, 0.62 mmol) 1H-benzotriazol-1-yloxytripyrrolidinyl hexafluorophosphate (86 mg, 0.42 mmol) was added to the ultra-dry dichloromethane (10 mL) solution and stirred at room temperature for 16 hours.
  • Step 3 To tert-butyl(5aS,6S,9R)-2-bromo-3,13-dichloro-5a,6,7,8,9,10-hexahydro-5H-6,9-epiamino nitrogen Ultradry N,N of Hetero[2',1':3,4][1,4]oxaza[5,6,7-de]quinazoline-15-carboxylate (45 mg, 0.09 mmol) -((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol (29mg, 0.18mmol), potassium fluoride (51mg) to dimethylformamide (10mL) solution , 0.9mmol) and 4A molecular sieves.
  • the crude product was prepared by reverse phase (chromatographic column: Waters XBridge C18, mobile phase: water/acetonitrile (0.1% trifluoroacetic acid) (0-50%), flow rate: 50 mL/min, column temperature: 25°C) to obtain tert-butyl (5aS,6S,9R)-2-Bromo-3-chloro-13-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5a ,6,7,8,9,10-hexahydro-5H-6,9-epiaminoazepine[2',1':3,4][1,4]oxazepine[5,6,7- De]quinazoline-15-carboxylate (22 mg, yield: 38.4%).
  • ES-API: [M+H] + 638.2.
  • Step 4 tert-Butyl(5aS,6S,9R)-2-bromo-3-chloro-13-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl) methoxy)-5a,6,7,8,9,10-hexahydro-5H-6,9-epiaminoaza[2',1':3,4][1,4]oxaza[ 5,6,7-De]quinazoline-15-carboxylate (22 mg, 0.03 mmol) and 2-(8-ethyl-3-(methoxymethoxy)naphthalen-1-yl)-4 ,4,5,5-tetramethyl-1,3,2-dioxaborane (17 mg, 0.05 mmol) in tetrahydrofuran (6 mL) and water (1.0 mL) was added potassium phosphate (21 mg, 0.1 mmol), methyl phosphate Sulfonic acid [n-
  • Step 5 tert-Butyl(5aS,6S,9R)-3-chloro-2-(8-ethyl-3-(methoxymethoxy)naphthalen-1-yl)-13-(((2R, 7aS)-2-Fluorotetrahydro-1H-pyrroline-7a(5H)-ylmethoxy)-5a,6,7,8,9,10-hexahydro-5H-6,9-epiaminoazepine [2',1':3,4][1,4]oxazepine[5,6,7-de]quinazoline-15-carboxylate (10 mg, 0.013 mmol) and acetonitrile (2.0 mL) and 4M hydrochloric acid/dioxane solution (0.5mL, 2.000mmol) The reaction solution was reacted at 0 ° C for 1 hour.
  • Example 8 Synthesis of 5-ethynyl-6-fluoro-4-((5aS,6S,9R)-1-fluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazine- 7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxo-3,10a,11,13,14-pentaza-6, 9-Methylenenaphtho[1,8-ab]hepten-2-yl)naphthalen-2-ol (Z131-1)
  • Step 1 To a solution of ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol (100.0 mg, 0.628 mmol) in tetrahydrofuran (10.0 mL) at 0°C Sodium hydride (50.0 mg, 1.25 mmol) was added, and after stirring at this temperature for 10 minutes, tert-butyl (5aS, 6S, 9R)-1-fluoro-2-(7-fluoro-3-(methoxymethyl) was added Oxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-12-(methylsulfinyl)-5a,6,7,8,9,10-hexahydro -5H-4-oxo-3,10a,11,13,14-pentaaza-6,9-methylenenaphtho[1,8-ab]heptene-14-carboxylate
  • the reaction was stirred at 0°C for 1 hour.
  • the reaction was quenched with saturated sodium bicarbonate solution and extracted with ethyl acetate.
  • the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated.
  • Step 2 To tert-butyl(5aS,6S,9R)-1-fluoro-2-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)acetylene) yl)naphthalen-1-yl)-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5a,6,7,8, 9,10-Hexahydro-5H-4-oxo-3,10a,11,13,14-pentaza-6,9-methylenenaphtho[1,8-ab]heptene-14-carboxy To a solution of the acid ester (170 mg, 0.183 mmol) in N,N-dimethylformamide (5.0 mL) was added cesium fluoride (1000 mg, 6.583 mmol).
  • Step 3 (5aS,6S,9R)-2-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-1-fluoro-12-(((2R ,7aS)-2-Fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxo-3 , 10a,11,13,14-pentaza-6,9-methylenenaphtho[1,8-ab]heptene-14-carboxylate tert-butyl ester (200 mg, crude) and acetonitrile (10.0 mL) and 4M hydrochloric acid/dioxane solution (2.0 mL, 8.000 mmol) reaction solution at 0 °C for 1 hour.
  • the crude product was prepared by high performance liquid phase (ammonium bicarbonate method) to obtain 5-ethynyl-6-fluoro-4-((5aS,6S,9R)-1-fluoro-12-(((2R,7aS)-2 -Fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxo-3,10a,11, 13,14-Pentaaza-6,9-methylenenaphtho[1,8-ab]hepten-2-yl)naphthalen-2-ol (5-ethynyl-6-fluoro-4-((5aS ,6S,9R)-1-fluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10
  • Example 9 Synthesis of 5-ethyl-4-((5aS,6S,9R)-12-((1-methyl-1-azaspiro[4.4]nonan-6-yl)oxy)- 5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza[6,9]methylenenaphthalene[1,8-ab ]hepten-2-yl)naphthalen-2-ol (Z260-1)
  • Step 1 To triisopropyl((6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl) )naphthalen-1-yl)ethynyl)silane (500 mg, 1.012 mmol) in N,N-dimethylformamide (5.0 mL) solution was added cesium fluoride (3.0 g, 20.24 mmol), and the reaction was carried out at room temperature for 2 hours. After completion of the reaction, extract with ethyl acetate (100 mL ⁇ 2), combine the ethyl acetate phases and wash with saturated brine (100 mL ⁇ 3).
  • Step 2 To 2-(8-ethynyl-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxoboron To the methanol (10.0 mL) solution of alkane (558 mg, crude product) was added palladium carbon with a mass fraction of 10%, hydrogen was replaced 4 times and the reaction was carried out at room temperature for 2 hours under the protection of hydrogen.
  • Step 3 Dissolve 1-benzyl-1-azaspiro[4.4]nonan-6-one (1.5g, 6.5mmol) in methanol (10ml), add palladium-carbon catalyst (150mg), replace hydrogen 3 times at room temperature The reaction was carried out for 4 hours, filtered, washed with methanol, and concentrated to obtain 1-azaspiro[4.4]nonan-6-one (800 mg, yield: 88.5%).
  • ES-API: [M+H] + 140.1.
  • Step 4 Dissolve 1-azaspiro[4.4]nonan-6-one (800 mg, 5.7 mmol) in tetrahydrofuran (10 mL), add triethylamine (0.86 mg, 8.5 mmol) and di-tert-butyl dicarbonate at room temperature lipid (1.8 g, 8.5 mmol) and stirred at room temperature for 8 hours.
  • Step 5 Dissolve tert-butyl 6-oxo-1-azaspiro[4.4]nonane-1-carboxylate (900 mg, 3.7 mmol) in dry tetrahydrofuran (10 mL), add lithium aluminum hydride (11 mL) under ice bath , 11 mmol, 1 M tetrahydrofuran), stirred at 60 °C for 2 hours. Water (10 mL) was added, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated to give 1-methyl-1-azaspiro[4.4]nonan-6-ol (450 mg), which was directly used in the next step.
  • ES-API: [M+Na] + 156.1.
  • Step 6 To (1S,2S,5R)-2-(hydroxymethyl)-3,8-diazacyclo[3.2.1]octane-8-carboxylate tert-butyl ester (A2- To a solution of 1,242 mg, 1.0 mmol) in tetrahydrofuran (10 mL) was added sodium hydride (80 mg, 2.0 mmol). After 10-20 minutes of reaction under nitrogen protection, 5,7-dichloro-1-(2,4-dimethoxybenzyl)pyrido[4,3-d]pyrimidine-2,4( 1H, 3H)-dione (381 mg, 1.0 mmol), and react for another 20 to 30 minutes at 0 to 5 °C.
  • Step 7 Add dry N,N-dimethylformamide (15mL) and (1S,2S,5R)-2-((((7-chloro-1-(2,4-di) to a 250mL single-neck flask at room temperature Methoxybenzyl)-2,4-dioxa-1,2,3,4-tetrahydropyrido[4,3-d]pyrimidin-5-yl)oxy)methyl)-3,8 - tert-butyl diazabicyclo[3.2.1]octane-8-carboxylate (510 mg, 0.87 mmol).
  • Carter condensing agent (1.9 g, 4.35 mmol) was added, and after 5 minutes of reaction at room temperature, 1,8-diazabicyclo[5.4.0]undec-7-ene (661 mg, 4.35 mmol) was added dropwise. React at room temperature for 1 to 2 hours.
  • Step 8 To trifluoroacetic acid (5 mL) was added (5aS,6S,9R)-2-chloro-13-(2,4-dimethoxybenzyl)-12-oxo-5a,6,7, 8,9,10,12,13-Octahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylenenaphthalene[1,8-ab]heptane tert-Butyl ene-14-carboxylate (300 mg, 0.53 mmol), stirred at 55°C for 1 hour.
  • Step 9 To (5aS,6S,9R)-2-chloro-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaza Carbonic acid was added to a mixed solution of hetero-6,9-methylenenaphtho[1,8-ab]hepten-12(13H)-one (500 mg, crude product) in tetrahydrofuran (5.0 mL) and water (5.0 mL) Sodium (168 mg, 1.59 mmol), the system was cooled with an ice-water bath, benzyloxycarbonyl succinimide (171 mg, 0.68 mmol) was added, and the reaction was carried out at room temperature for 3 hours.
  • Step ten at 0 °C, to (5aS,6S,9R)-2-chloro-12-oxa-5a,6,7,8,9,10,12,13-octahydro-5H-4-oxygen Benzyl hetero-3,10a,11,13,14-pentaaza-6,9-methylenenaphthalene[1,8-ab]heptene-14-carboxylate (390 mg, 0.8 mmol) in toluene (5.0 mL) solution was sequentially added phosphorus oxychloride (365 mg, 2.4 mmol) and N,N-diisopropylethylamine (310 mg, 2.4 mmol), and the reaction was carried out at 105° C.
  • Step 11 To (5aS,6S,9R)-2,12-dichloro-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13, To a solution of benzyl 14-pentaaza-6,9-methylenenaphthalene[1,8-ab]heptene-14-carboxylate (50 mg, 0.1 mmol) in dimethyl sulfoxide (3.0 mL) was added fluoride Potassium (29 mg, 0.5 mmol), N,N-diisopropylethylenediamine (39 mg, 0.3 mmol), 1-methyl-1-azaspiro[4.4]nonan-6-ol (31 mg, 0.2 mmol) ) and 4A molecular sieve, react at 110°C for 4 hours under nitrogen protection.
  • fluoride Potassium 29 mg, 0.5 mmol
  • N,N-diisopropylethylenediamine 39 mg, 0.3
  • Step twelve (5aS,6S,9R)-2-chloro-12-((1-methyl-1-azaspiro[4.4]nonan-6-yl)oxy)-5a,6, 7,8,9,10-Hexahydro-5H-4-oxa-3,10a,11,13,14-pentaza-6,9-methylenenaphthalene[1,8-ab]heptene-
  • Benzyl 14-carboxylate 28 mg, 0.047 mmol
  • 2-(8-ethyl-3-(methoxymethoxy)naphthalen-1-yl) was added -4,4,5,5-Tetramethyl-1,3,2-dioxaborane (24 mg, 0.07 mmol)
  • potassium phosphate (30 mg, 0.14 mmol) and [n-butylbis(1- Adamantyl)phosphine](2-amino-1,1'-bi
  • Step fourteen (5aS,6S,9R)-2-(8-ethyl-3-(methoxymethoxy)naphthalene-1-yl)-12-((1-methyl-1-nitrogen) Heterospiro[4.4]nonan-6-yl)oxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxy-3,10a,11,13,14-pentaza Hetero-6,9-methylenenaphthalene[1,8-ab]heptene (17 mg, 0.027 mmol) was dissolved in acetonitrile (6.0 mL), 4M hydrochloric acid/dioxane solution (1.0 mL, 4.0 mmol), reacted under ice bath for 0.5 hours.
  • Step 1 To tert-butyl(1S,2S,5R)-2-((((7-chloro-8-fluoro-(2-methylthio)-4-oxa-3,4-dihydropyridine[4 ,3-d]pyrimidin-5-yl)oxy)methyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (200 mg, 0.427 mmol) and (5-methyl) 1H-indazol-4-yl)boronic acid (230.0 mg, 1.307 mmol) in tetrahydrofuran (10.0 mL) and water (2.0 mL) were added cesium carbonate (560 mg, 1.719 mmol), tetrakistriphenylphosphine palladium (100 mg) , 0.87 mmol), nitrogen was bubbled and the reaction was heated at 115 °C for 6 hours.
  • cesium carbonate 560 mg, 1.719 mmol
  • Step 2 Add tert-butyl(5aS,6S,9R)-1-fluoro-2-(5-methyl-1H-indazol-4-yl)-12-(methylthio)- 5a,6,7,8,9,10-hexahydro-5H-4-oxo-3,10a,11,13,14-pentaza-6,9-methylenenaphtho[1,8- ab] Heptene-14-carboxylate (180 mg, 0.319 mmol) in dichloromethane (15 mL) was added m-chloroperoxybenzoic acid (85 mg, 0.493 mmol). Stir at room temperature for 1 hour.
  • Step 3 To a solution of ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol (110.0 mg, 0.691 mmol) in tetrahydrofuran (10.0 mL) at 0°C Sodium hydride (55.0 mg, 1.382 mmol) was added, and after stirring at this temperature for 10 minutes, tert-butyl (5aS,6S,9R)-1-fluoro-2-(5-methyl-1H-indazole-4 was added) -yl)-12-(methylsulfinyl)-5a,6,7,8,9,10-hexahydro-5H-4-oxo-3,10a,11,13,14-pentaza- 6,9-Methylenenaphtho[1,8-ab]heptene-14-carboxylate (200 mg, crude) solution in tetrahydrofuran (5 mL).
  • the reaction was stirred at 0°C for 1 hour.
  • the reaction was quenched with saturated sodium bicarbonate solution and extracted with ethyl acetate.
  • the organic phase was dried with saturated brine, anhydrous sodium sulfate, filtered and concentrated.
  • Step 4 Add (5aS,6S,9R)-1-fluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy at 0°C yl)-2-(5-methyl-1H-indazol-4-yl)-5a,6,7,8,9,10-hexahydro-5H-4-oxo-3,10a,11,13 4M hydrochloric acid was added to a solution of tert-butyl ,14-pentaaza-6,9-methylenenaphtho[1,8-ab]heptene-14-carboxylate (200 mg, 0.296 mmol) in acetonitrile (5.0 mL) /dioxane solution (2.0 mL, 8.000 mmol) The reaction solution was reacted at 0°C for 1 hour.
  • Step 1 To tert-butyl(1S,2S,5R)-2-((((7-chloro-8-fluoro-(2-methylthio)-4-oxa-3,4-dihydropyridine[4 ,3-d]pyrimidin-5-yl)oxy)methyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (100 mg, 0.214 mmol) and ((2- Fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)naphthalen-1-yl)ethyne base) triisopropylsilane (200.0 mg, 0.390 mmol) in tetrahydrofuran (6 mL) and water (1.5 mL) was added potassium phosphate (200 mg, 0.943 mmol), [n-butylbis(1-adamantyl) methanesulf
  • Step 2 Add tert-butyl(5aS,6S,9R)-1-fluoro-2-(7-fluoro-3-(methoxymethoxy)-8-((triisopropyl) at 0°C Silyl)ethynyl)naphthalen-1-yl)-12-(methylthio)-5a,6,7,8,9,10-hexahydro-5H-4-oxo-3,10a,11, 13,14-Pentaaza-6,9-methylenenaphtho[1,8-ab]heptene-14-carboxylate (210 mg, crude) in dichloromethane (15 mL) was added m-chloroperoxide Oxybenzoic acid (55 mg, 0.320 mmol).
  • Step 3 Add sodium hydride (54.0 mg, 1.34 mmol) to a solution of (hexahydro-1H-pyrrolazin-3-yl)methanol (95.0 mg, 0.673 mmol) in tetrahydrofuran (10.0 mL) at 0° C. After stirring at temperature for 10 minutes, tert-butyl(5aS,6S,9R)-1-fluoro-2-(7-fluoro-3-(methoxymethoxy)-8-((triisopropyl) was added.
  • Step 4 To tert-butyl(5aS,6S,9R)-1-fluoro-2-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)acetylene) yl)naphthalen-1-yl)-12-((hexahydro-1H-pyrrolazin-3-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxo N,N- substituted-3,10a,11,13,14-pentaaza-6,9-methylenenaphtho[1,8-ab]heptene-14-carboxylate (300 mg, crude) To a solution of dimethylformamide (5.0 mL) was added cesium fluoride (1000 mg, 6.583 mmol).
  • Step 5 tert-Butyl(5aS,6S,9R)-2-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-1-fluoro-12-( (Hexahydro-1H-pyrrolazin-3-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxo-3,10a,11,13,14- Pentaaza-6,9-methoxynaphtho[1,8-ab]heptene-14-carboxylate (150 mg, 0.199 mmol) and acetonitrile (5.0 mL) and 4M hydrochloric acid/dioxane solution (2.0 mL, 8.000 mmol) The reaction solution was reacted at 0 °C for 1 hour.
  • Example 12 Synthesis of 1-(8-((5aS,6S,9R)-1-fluoro-12-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl) Methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxo-3,10a,11,13,14-pentaza-6,9-methylenenaphthalene[ 1,8-ab]hepten-2-yl)naphthalen-1-yl)propanol (Z385)
  • Step 1 Under nitrogen protection, add 1,8-dibromonaphthalene (4 g, 13.99 mmol) and tetrahydrofuran (40 mL) to the round-bottomed flask. It was cooled to -70°C, and a 2.5M solution of butyllithium in n-hexane (6.15 mL, 15.39 mmol) was added dropwise to the above solution. After the addition was complete, the reaction was stirred at -70°C for 30 minutes. To this was added dropwise a 3M solution of ethylene oxide in tetrahydrofuran (28 mL, 84 mmol). After the addition was complete, the reaction was warmed to 0°C and stirred for 1 hour.
  • Step 2 2-(8-Bromonaphthalen-1-yl)ethane-1-ol (1.4 g, 5.75 mmol) and dichloromethane (30 mL) were added to a round bottom flask. Under nitrogen protection, it was cooled to 0°C. With stirring, Dess-Martin oxidant (3.55 g, 8.36 mmol) was added to the above reaction solution. The reaction was stirred at 0°C for 1 hour. Saturated sodium thiosulfate solution (50 mL) and saturated aqueous sodium hydrogencarbonate solution (50 mL) were added to the above reaction solution, and the mixture was stirred at room temperature for 5 minutes. Extract with ethyl acetate (100 mL ⁇ 3).
  • Step 3 Under nitrogen protection, add 2-(8-bromonaphthalen-1-yl)acetaldehyde (1.8 g, 7.23 mmol) and tetrahydrofuran (40 mL) to the reaction flask, and cool to -30°C. With stirring, a 3M solution of methylmagnesium bromide in tetrahydrofuran (2.65 mL, 7.95 mmol) was added dropwise to the above reaction solution. The reaction was stirred at -20°C for 30 minutes. Remove ice bath. Saturated aqueous ammonium chloride solution (50 mL) was added to the reaction solution, followed by extraction with ethyl acetate (50 mL ⁇ 3).
  • Step 4 Add 1-(8-bromonaphthalen-1-yl)propan-2-ol (1.4g, 5.28mmol) and imidazole (0.719g, 10.56mmol) in anhydrous N,N-diol into the reaction flask.
  • methylformamide 15 mL
  • tert-butyldimethylsilyl chloride 1.03 g, 6.86 mmol.
  • Saturated aqueous ammonium chloride solution 100 mL was added to the reaction solution, followed by extraction with ethyl acetate (50 mL ⁇ 2). The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate.
  • Step 5 Add ((1-(8-bromonaphthalen-1-yl)propan-2-yl)oxy)(tert-butyl)dimethylsilane (1.8g, 4.74mmol) to the round-bottomed flask, Pinacol borate (2.41 g, 9.49 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride ((347 mg, 0.47 mmol), potassium acetate (1.40 g, 14.23 mmol) mmol) and 1,4-dioxane (30 mL). Under nitrogen protection, the system was heated and stirred in an oil bath at 95 °C for 12 hours.
  • Step 6 Add tert-butyldimethyl((1-(8-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)) to the round bottom flask Naphthalen-1-yl)propan-2-yl)oxy)silane (260 mg, 0.43 mmol), tert-butyl(5aS,6S,9R)-2-chloro-1-fluoro-12-(methylthio)- 5a,6,7,8,9,10-hexahydro-5H-4-oxo-3,10a,11,13,14-pentaaza-6,9-methylenenaphthalene[1,8-ab] Heptene-14-carboxylate (80 mg, 0.17 mmol), [n-butylbis(1-adamantyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium methanesulfonate (II) (12.4 mg
  • Step 7 Add tert-butyl(5aS,6S,9R)-2-(8-(2-((tert-butyldimethylsilyl)oxy)propyl)naphthalene-1-yl to the round bottom flask )-1-Fluoro-12-(methylthio)-5a,6,7,8,9,10-hexahydro-5H-4-oxo-3,10a,11,13,14-pentaza- 6,9-Methylenenaphthalene[1,8-ab]heptene-14-carboxylate (100 mg, 0.14 mmol) and dichloromethane (8 mL).
  • Step 8 To a round bottom flask was added sodium hydrogen (16 mg, 0.40 mmol) and tetrahydrofuran (5 mL). It was cooled to 0°C, and ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol (64 mg, 0.40 mmol) was added to the above reaction solution. The reaction was stirred at 0°C for 10 minutes.
  • Step 9 Add tert-butyl(5aS,6S,9R)-2-(8-(2-((tert-butyldimethylsilyl)oxy)propyl)naphthalene-1-yl to the round bottom flask )-1-fluoro-12-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10- Hexahydro-5H-4-oxy-3,10a,11,13,14-pentaaza-6,9-methylenenaphthalene[1,8-ab]heptene-14-carboxylate (20mg, 0.024 mmol), tetrabutylammonium fluoride (1 mL, 1 mmol, 1M solution in tetrahydrofuran), and tetrahydrofuran (1 mL).
  • Step 10 Add tert-butyl(5aS,6S,9R)-1-fluoro-12-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl to the round bottom flask Methoxy)-2-(8-(2-hydroxypropyl)naphthalen-1-yl)-5a,6,7,8,9,10-hexahydro-5H-4-oxy-3,10a, 11,13,14-Pentaaza-6,9-methylenenaphthalene[1,8-ab]heptene-14-carboxylate (16 mg, 0.022 mmol) and acetonitrile (1 mL).
  • the compounds of Table A, Table B or Table C are prepared by modifying some of the raw materials with reference to the preparation method of the above embodiment, respectively.
  • AGS is an endogenous human gastric adenocarcinoma cell line containing KRAS G12D mutation, cultured in F12K+10% FBS medium.
  • cells in the logarithmic growth phase were taken, digested with trypsin (containing EDTA), collected and counted, and seeded about 20,000 cells/well in a 96-well cell culture plate and cultured in 5% CO 2 Incubate overnight.
  • trypsin containing EDTA
  • Use DMSO to prepare 1000X compound 3.16 times gradient concentration stock solution, use the above medium to dilute 200 times to 5X compound stock solution, on the second day after cell seeding, add 5X compound stock solution to each cell culture well, the final concentration is 1X, DMSO content of 0.1%.
  • DMSO was used as experimental control. After adding the compound to continue culturing for 3 hours, remove the medium in the culture wells, add 50 ⁇ l of cell lysate (from Advance ERK phospho-T202/Y204kit, the same below) to each well, mix and incubate for 30 minutes, then transfer 16 ⁇ l of the mixture to white In a 96-well plate with an opaque bottom, another well was taken and 16 ⁇ l of cell lysate was added as a blank well.
  • cell lysate from Advance ERK phospho-T202/Y204kit, the same below
  • AsPC-1 is an endogenous human pancreatic cancer cell line containing KRAS G12D mutation, cultured in RPMI-1640 medium containing 10% FBS; AGS human gastric cancer cell line containing KRAS G12D mutation, cultured in FBS containing 10% FBS -12K medium. Cells in logarithmic growth phase were taken, digested with trypsin (containing EDTA), collected and counted, and seeded with 800 AsPC-1 cells/well or 400 AGS cells/well in 384-well spheroid plates, placed in 5 3D cell models were established overnight in % CO2 .
  • trypsin containing EDTA
  • DMSO DMSO to prepare 1000X compound 3.16-fold gradient concentration stock solution, dilute 100-fold with medium to 10X compound stock solution, add 10X compound stock solution to each cell culture well on the second day after cell seeding, the final concentration is 1X, DMSO content of 0.1%.
  • DMSO was used as the experimental control, and the medium was used as the blank control.
  • After adding the compound continue to culture the cells for 5 days, add 30 ⁇ l of CellTiter-Glo working solution to each well, mix and incubate for 30 minutes, and then transfer 40 ⁇ l of the mixture to a white bottom impermeable 384-well plate, and read it with a microplate reader.

Abstract

一种对KRAS基因突变具有抑制作用的嘧啶并环类化合物或其药学上可接受的盐、立体异构体、溶剂合物或前药，以及包含该化合物的药物组合物，及其在制备癌症药物中的应用。

Description

嘧啶并环类化合物及其制法和用途 技术领域
本发明属于医药领域，具体涉及一类嘧啶并环类化合物及其制法和用途。
背景技术
KRAS是GTP酶蛋白的Ras家族的21kD成员，并且是细胞信号传导所必需的组分。KRAS在恶性肿瘤中的作用以及在各种肿瘤类型中的突变(例如G12C突变、G12D突变、G12V突变等)已被公众获知，因此KRAS已成为制药业用于癌症治疗的非常有吸引力的靶点。抑制KRAS活性的化合物是本领域研究人员非常希望获得的且正在火热研究中。目前，本领域针对KRAS G12C已经有了突破性进展，例如AMG、MIRATI的KRAS G12C抑制剂已经显示足够的安全性和有效性，然而人们对开发KRAS的抑制剂，特别是激活KRAS突变体的抑制剂，特别是KRAS G12D，仍有持续的兴趣和努力。
发明内容
本发明提供了一类结构新颖的嘧啶并环类化合物，其将作为KRAS G12D抑制剂，具有活性高，选择性好且毒副作用低等优点。
本发明第一方面提供了一种可作为KRAS G12D抑制剂的化合物或其药学上可接受的盐、立体异构体、溶剂化物或前药；所述化合物为式(I)、式(II-1)、式(II-2)或式(III)所示的化合物。
在一实施方案中，本发明提供了一种式(I)所示的化合物或其药学上可接受的盐、立体异构体、溶剂化物或前药：
Figure PCTCN2022081443-appb-000001
式(I)中，
X为O或NR 11；其中，R 11选自H和C1-C6烷基；
Y为CR 12R 13、CR 14R 15CR 16R 17、C(O)或C(O)CR 18R 19；其中，R 12、R 13、R 14和R 15各自独立地选自H、C1-C3烷基、C1-C3氘代烷基和C1-C3卤代烷基；R 16、R 17、R 18、R 19各自独立地选自H、C1-C3烷基和卤素；
W为N或CR 20；其中，R 20为H、C1-C6烷基、卤素、C1-C6卤代烷基、C1-C6烷氧基、环烷基、环烷基-O-、杂环基或杂环基-O-；其中，所述环烷基、所述杂环基各自独立地任选地被卤素取代；
环A选自下组：芳基、杂芳基；
R 1为环A上任意位置的取代基；各个R 1各自独立地选自：C1-C6烷基、卤素、羟基、C1-C6烷氧基、C1-C6卤代烷基、C1-C6卤代烷氧基、氰基、NR 21R 22、C(O)NR 23R 24、CH 2R 25、N＝S(O)(C1-C6烷基) 2、S(O)C1-C6烷基、S(O) 2R 26、-S-C1-C6烷基、C2-C6烯基、C2-C6炔基、C2-C6羟基炔基、C1-C6 氰基烷基、***基、-S-C1-C6卤代烷基、C1-C6羟基烷基、-CH 2C(O)NR 27R 28、-C2-C6炔基NR 29R 30、C2-C6氘代炔基、(C1-C6烷氧基)C1-C6卤代烷基-或环烷基；其中，所述环烷基任选地被卤素或C1-C6烷基取代；其中，
R 21为H、C1-C6烷基、C1-C6卤代烷基、C(O)C1-C6烷基或C(O) 2C1-C6烷基；R 22为H、C1-C6烷基或C1-C6卤代烷基；或者R 21、R 22与和它们相连的氮原子共同构成3到6元含氮杂环基，所述3到6元含氮杂环基任选地被1个或2个选自卤素、甲基、三氟甲基、甲氧基、三氟甲氧基的基团取代；
R 23、R 24各自独立地为H、C1-C6烷基或C1-C6卤代烷基；或者R 23、R 24与和它们相连的氮原子共同构成3到6元含氮杂环基，所述3到6元含氮杂环基任选地被1个或2个选自卤素、甲基、三氟甲基、甲氧基、三氟甲氧基的基团取代；
R 25为羟基、氰基、杂环基、NR 251R 252、C(O)NR 253R 254或SO 2C1-C6烷基；其中，R 251、R 252、R 253、R 254各自独立地为H或C1-C6烷基；R 251、R 252与和它们相连的氮原子共同构成3到6元含氮杂环基，所述3到6元含氮杂环基任选地被1个或2个选自卤素、甲基、三氟甲基、甲氧基、三氟甲氧基的基团取代；R 253、R 254与和它们相连的氮原子共同构成3到6元含氮杂环基，所述3到6元含氮杂环基任选地被1个或2个选自卤素、甲基、三氟甲基、甲氧基、三氟甲氧基的基团取代；
R 26为C1-C6烷基、C1-C6卤代烷基或NR 261R 262；其中，R 261、R 262各自独立地为H或C1-C6烷基；或者R 261、R 262与和它们相连的氮原子共同构成3到6元含氮杂环基，所述3到6元含氮杂环基任选地被1个或2个选自卤素、甲基、三氟甲基、甲氧基、三氟甲氧基的基团取代；
R 27、R 28各自独立地为H、C1-C6烷基或C1-C6卤代烷基；或者R 27、R 28与和它们相连的氮原子共同构成3到6元含氮杂环基，所述3到6元含氮杂环基任选地被1个或2个选自卤素、甲基、三氟甲基、甲氧基、三氟甲氧基的基团取代；
R 29、R 30各自独立地为H、C1-C6烷基或C1-C6卤代烷基；或者R 29、R 30与和它们相连的氮原子共同构成3到6元含氮杂环基，所述3到6元含氮杂环基任选地被1个或2个选自卤素、甲基、三氟甲基、甲氧基、三氟甲氧基的基团取代；
n1是0、1、2或3；
R 2为H、氰基、卤素、C1-C6烷基、C1-C6烷氧基、C1-C6卤代烷基、C1-C6卤代烷氧基、C1-C6氘代烷氧基、NR 31R 32、C2-C4炔基或CH 2OR 33；其中，R 31、R 32、R 33各自独立地为氢或C1-C6烷基；
R 3a、R 3b、R 3c各自独立地为氢、卤素、羟基、氰基、C1-C3烷基、C1-C3氘代烷基或C1-C3卤代烷基；
L 1为一个键、O或NR 34；
L 2为C1-C4亚烷基或杂芳基；其中，所述C1-C4亚烷基任意碳原子上的或任意同一个碳原子上的1个或2个氢原子任选地各自独立地被氘、C1-C6烷基或C1-C6卤代烷基取代；或者所述C1-C4亚烷基任意同一个碳原子上的2个氢原子任选地同时被-(CH 2) m3-、-(CH 2) m1-O-(CH 2) m2-、-(CH 2) m1-N-(CH 2) m2-取代从而形成环状取代基；m3为1或2；各个m1各自独立地为0、1、2或3；各个m2各自独立地为0、1、2或3；且m1、m2不同时为0；
环B为3到6元含氮杂环基；
环C为3到6元含氮杂环基；
R 4为环B上任意位置的取代基；n2为0、1、2或3；
R 5为环C上任意位置的取代基；n3为0、1、2或3；
R 4、R 5定义如下：
(a)每个R 4、每个R 5各自独立地为卤素、羟基、C1-C3羟基烷基、C1-C3烷基、C1-C3卤代烷基、C1-C3烷氧基、氰基、-苯基、-苯基-SO 2F、-O-苯基、-O-苯基-SO 2F、-NHC(O)苯基、-NHC(O)苯基-SO 2F、C1-C3烷基取代的吡唑基、芳C1-C3烷基-、叔丁基二甲基甲硅烷基CH 2-、-N(R 34) 2、(C1-C3烷氧基)C1-C3烷基、(C1-C3烷基)C(O)、氧代、(C1-C3卤代烷基)C(O)-、-SO 2F、(C1-C3烷氧基)C1-C3烷氧基、-CH 2OC(O)N(R 34) 2、-CH 2NHC(O)OC1-C6烷基、-CH 2NHC(O)N(R 34) 2、-CH 2NHC(O)C1-C6烷基、-CH 2(吡唑基)、-CH 2NHSO 2C1-C6烷基、-CH 2OC(O)杂环基、-OC(O)N(R 34) 2、-OC(O)NH(C1-C3烷基)O(C1-C3烷基)、-OC(O)NH(C1-C3烷基)O(C1-C3烷基)苯基(C1-C3烷基)N(CH 3) 2、-OC(O)NH(C1-C3烷基)O(C1-C3烷基)苯基、-OC(O)杂环基或-CH 2杂环基；其中，-NHC(O)苯基或-OC(O)NH(C1-C3烷基)O(C1-C3烷基)苯基中的苯基任选地被-C(O)H或OH取代；-CH 2杂环基中的杂环基任选地被氧代取代；或者，
(b)1个R 4为-CH 2CH 2-或-CH 2CH 2CH 2-且与和它相连的碳原子共同构成环丙基或环丁基；其余R 4、每个R 5各自独立地为卤素、羟基、C1-C3羟基烷基、C1-C3烷基、C1-C3卤代烷基、C1-C3烷氧基、氰基、-苯基、-苯基-SO 2F、-O-苯基、-O-苯基-SO 2F、-NHC(O)苯基、-NHC(O)苯基-SO 2F、C1-C3烷基取代的吡唑基、芳C1-C3烷基-、叔丁基二甲基甲硅烷基CH 2-、-N(R 34) 2、(C1-C3烷氧基)C1-C3烷基、(C1-C3烷基)C(O)、氧代、(C1-C3卤代烷基)C(O)-、-SO 2F、(C1-C3烷氧基)C1-C3烷氧基、-CH 2OC(O)N(R 34) 2、-CH 2NHC(O)OC1-C6烷基、-CH 2NHC(O)N(R 34) 2、-CH 2NHC(O)C1-C6烷基、-CH 2(吡唑基)、-CH 2NHSO 2C1-C6烷基、-CH 2OC(O)杂环基、-OC(O)N(R 34) 2、-OC(O)NH(C1-C3烷基)O(C1-C3烷基)、-OC(O)NH(C1-C3烷基)O(C1-C3烷基)苯基(C1-C3烷基)N(CH 3) 2、-OC(O)NH(C1-C3烷基)O(C1-C3烷基)苯基、-OC(O)杂环基或-CH 2杂环基；其中，-NHC(O)苯基或-OC(O)NH(C1-C3烷基)O(C1-C3烷基)苯基中的苯基任选地被-C(O)H或OH取代；-CH 2杂环基中的杂环基任选地被氧代取代；或者
(c)1个R 5为-CH 2CH 2-或-CH 2CH 2CH 2-且与和它相连的碳原子共同构成环丙基或环丁基；其余R 5、每个R 4各自独立地为卤素、羟基、C1-C3羟基烷基、C1-C3烷基、C1-C3卤代烷基、C1-C3烷氧基、氰基、-苯基、-苯基-SO 2F、-O-苯基、-O-苯基-SO 2F、-NHC(O)苯基、-NHC(O)苯基-SO 2F、C1-C3烷基取代的吡唑基、芳C1-C3烷基-、叔丁基二甲基甲硅烷基CH 2-、-N(R 34) 2、(C1-C3烷氧基)C1-C3烷基、(C1-C3烷基)C(O)、氧代、(C1-C3卤代烷基)C(O)-、-SO 2F、(C1-C3烷氧基)C1-C3烷氧基、-CH 2OC(O)N(R 34) 2、-CH 2NHC(O)OC1-C6烷基、-CH 2NHC(O)N(R 34) 2、-CH 2NHC(O)C1-C6烷基、-CH 2(吡唑基)、-CH 2NHSO 2C1-C6烷基、-CH 2OC(O)杂环基、-OC(O)N(R 34) 2、-OC(O)NH(C1-C3烷基)O(C1-C3烷基)、-OC(O)NH(C1-C3烷基)O(C1-C3烷基)苯基(C1-C3烷基)N(CH 3) 2、-OC(O)NH(C1-C3烷基)O(C1-C3烷基)苯基、-OC(O)杂环基或-CH 2杂环基；其中，-NHC(O)苯基或-OC(O)NH(C1-C3烷基)O(C1-C3烷基)苯基中的苯基任选地被-C(O)H或OH取代；-CH 2杂环基中的杂环基任选地被氧代取代；或者
(d)1个R 4为-CH 2CH 2-或-CH 2CH 2CH 2-且与和它相连的碳原子共同构成环丙基或环丁基；1个R 5为-CH 2CH 2-或-CH 2CH 2CH 2-且与和它相连的碳原子共同构成环丙基或环丁基；其余R 4、其余R 5各自独立地为卤素、羟基、C1-C3羟基烷基、C1-C3烷基、C1-C3卤代烷基、C1-C3烷氧基、氰基、-苯基、-苯基-SO 2F、-O-苯基、-O-苯基-SO 2F、-NHC(O)苯基、-NHC(O)苯基-SO 2F、C1-C3烷基取代的吡唑基、芳C1-C3烷基-、叔丁基二甲基甲硅烷基CH 2-、-N(R 34) 2、(C1-C3烷氧基)C1-C3烷基、(C1-C3烷基)C(O)、氧代、(C1-C3卤代烷基)C(O)-、-SO 2F、(C1-C3烷氧基)C1-C3烷氧基、-CH 2OC(O)N(R 34) 2、-CH 2NHC(O)OC1-C6烷基、-CH 2NHC(O)N(R 34) 2、-CH 2NHC(O)C1-C6烷基、-CH 2(吡唑基)、-CH 2NHSO 2C1-C6烷基、-CH 2OC(O)杂环基、-OC(O)N(R 34) 2、-OC(O)NH(C1-C3烷基)O(C1-C3烷基)、-OC(O)NH(C1-C3烷基)O(C1-C3烷基)苯基(C1-C3烷基)N(CH 3) 2、-OC(O)NH(C1-C3烷基)O(C1-C3烷基)苯基、-OC(O)杂环基或-CH 2杂环基；其中，-NHC(O)苯基或-OC(O)NH(C1-C3烷基)O(C1-C3烷基)苯基 中的苯基任选地被-C(O)H或OH取代；-CH 2杂环基中的杂环基任选地被氧代取代；
每个R 34各自独立地为氢、C1-C3烷基或C1-C3卤代烷基；或者两个R 34与和它们相连的氮原子共同构成3到6元含氮杂环基，所述3到6元含氮杂环基任选地被1个或2个选自卤素、甲基、三氟甲基、甲氧基、三氟甲氧基的基团取代。
在一实施方案中，所述化合物如式(I-1)或式(I-2)所示：
Figure PCTCN2022081443-appb-000002
各式中，X、Y、W、R 1、R 2、R 3a、R 3b、R 3c、R 4、R 5、n1、n2、n3、L 1、L 2、环A、环B、环C各自定义同式(I)。
在一实施方案中，本发明提供了一种式(II-1)或式(II-2)所示的化合物或其药学上可接受的盐、立体异构体、溶剂化物或前药：
Figure PCTCN2022081443-appb-000003
式(II-1)或式(II-2)中，
q为1或2；
X为O或NR 11；其中，R 11选自H和C1-C6烷基；
Y为CR 12R 13、CR 14R 15CR 16R 17、C(O)或C(O)CR 18R 19；其中，R 12、R 13、R 14和R 15各自独立地选自H、C1-C3烷基、C1-C3氘代烷基和C1-C3卤代烷基；R 16、R 17、R 18、R 19各自独立地选自H、C1-C3烷基和卤素；
W为N或CR 20；其中，R 20为H、C1-C6烷基、卤素、C1-C6卤代烷基、C1-C6烷氧基、环烷基、环烷基-O-、杂环基或杂环基-O-；其中，所述环烷基、所述杂环基各自独立地任选地被卤素取代；
环A选自下组：芳基、杂芳基；
R 1为环A上任意位置的取代基；各个R 1各自独立地选自：C1-C6烷基、卤素、羟基、C1-C6烷氧基、C1-C6卤代烷基、C1-C6卤代烷氧基、氰基、NR 21R 22、C(O)NR 23R 24、CH 2R 25、N＝S(O)(C1-C6烷基) 2、S(O)C1-C6烷基、S(O) 2R 26、-S-C1-C6烷基、C2-C6烯基、C2-C6炔基、C2-C6羟基炔基、C1-C6氰基烷基、***基、-S-C1-C6卤代烷基、C1-C6羟基烷基、-CH 2C(O)NR 27R 28、-C2-C6炔基NR 29R 30、C2-C6氘代炔基、(C1-C6烷氧基)C1-C6卤代烷基-或环烷基；其中，所述环烷基任选地被卤素或C1-C6烷基取代；其中，
R 21为H、C1-C6烷基、C1-C6卤代烷基、C(O)C1-C6烷基或C(O) 2C1-C6烷基；R 22为H、C1-C6烷基或C1-C6卤代烷基；或者R 21、R 22与和它们相连的氮原子共同构成3到6元含氮杂环基，所述3到6元含氮杂环基任选地被1个或2个选自卤素、甲基、三氟甲基、甲氧基、三氟甲氧基的基团取代；
R 23、R 24各自独立地为H、C1-C6烷基或C1-C6卤代烷基；或者R 23、R 24与和它们相连的氮原子共同构成3到6元含氮杂环基，所述3到6元含氮杂环基任选地被1个或2个选自卤素、甲基、三氟甲基、甲氧基、三氟甲氧基的基团取代；
R 25为羟基、氰基、杂环基、NR 251R 252、C(O)NR 253R 254或SO 2C1-C6烷基；其中，R 251、R 252、R 253、R 254各自独立地为H或C1-C6烷基；R 251、R 252与和它们相连的氮原子共同构成3到6元含氮杂环基，所述3到6元含氮杂环基任选地被1个或2个选自卤素、甲基、三氟甲基、甲氧基、三氟甲氧基的基团取代；R 253、R 254与和它们相连的氮原子共同构成3到6元含氮杂环基，所述3到6元含氮杂环基任选地被1个或2个选自卤素、甲基、三氟甲基、甲氧基、三氟甲氧基的基团取代；
R 26为C1-C6烷基、C1-C6卤代烷基或NR 261R 262；其中，R 261、R 262各自独立地为H或C1-C6烷基；或者R 261、R 262与和它们相连的氮原子共同构成3到6元含氮杂环基，所述3到6元含氮杂环基任选地被1个或2个选自卤素、甲基、三氟甲基、甲氧基、三氟甲氧基的基团取代；
R 27、R 28各自独立地为H、C1-C6烷基或C1-C6卤代烷基；或者R 27、R 28与和它们相连的氮原子共同构成3到6元含氮杂环基，所述3到6元含氮杂环基任选地被1个或2个选自卤素、甲基、三氟甲基、甲氧基、三氟甲氧基的基团取代；
R 29、R 30各自独立地为H、C1-C6烷基或C1-C6卤代烷基；或者R 29、R 30与和它们相连的氮原子共同构成3到6元含氮杂环基，所述3到6元含氮杂环基任选地被1个或2个选自卤素、甲基、三氟甲基、甲氧基、三氟甲氧基的基团取代；
n1是0、1、2或3；
R 2为H、氰基、卤素、C1-C6烷基、C1-C6烷氧基、C1-C6卤代烷基、C1-C6卤代烷氧基、C1-C6氘代烷氧基、NR 31R 32、C2-C4炔基或CH 2OR 33；其中，R 31、R 32、R 33各自独立地为氢或C1-C6烷基；
R 3为桥环上任意位置的取代基且为氢、卤素、羟基、氰基、C1-C3烷基、C1-C3氘代烷基或C1-C3卤代烷基；
L 3为一个键、O或NR 34；
R 6是氢、-N(R 34) 2、杂环基、C1-C6烷基、-L-杂环基、-L-芳基、-L-杂芳基、-L-环烷基、-L-N(R 34) 2、-L-NHC(＝NH)NH 2、-L-C(O)N(R 34) 2、-L-C1-C6卤代烷基、-L-OR 34、-L-(CH 2OR 34)(CH 2) nOR 34、-L-NR 34C(O)-芳基、-L-COOH或-L-C(O)OC1-C6烷基；其中，所述杂环基、所述-L-NR 34C(O)-芳基中的芳基、所述-L-杂环基中的杂环基、所述-L-环烷基的环烷基各自可任选地被一个或多个R 35取代或者任选地同一个碳原子上的两个氢原子同时被-CH 2CH 2-或-CH 2CH 2CH 2-取代成为环丙基或环丁基；所述-L-芳基中的芳基、所述-L-杂芳基中的杂芳基各自可任选地被一个或多个R 36取代；
其中，每个L各自独立地为C1-C4亚烷基或杂芳基；其中，所述C1-C4亚烷基任意碳原子上的或任意同一个碳原子上的1个或2个氢原子任选地各自独立地被氘、C1-C6烷基或C1-C6卤代烷基取代；或者所述C1-C4亚烷基任意同一个碳原子上的2个氢原子任选地同时被-(CH 2) m3-、-(CH 2) m1-O-(CH 2) m2-、-(CH 2) m1-N-(CH 2) m2-取代从而形成环状取代基；m3为1或2；各个m1各自独立地为0、1、2或3；各个m2各自独立地为0、1、2或3；且m1、m2不同时为0；
每个R 35各自独立地为卤素、羟基、C1-C3羟基烷基、C1-C3烷基、C1-C3卤代烷基、C1-C3烷氧基、氰基、-苯基、-苯基-SO 2F、-O-苯基、-O-苯基-SO 2F、-NHC(O)苯基、-NHC(O)苯基-SO 2F、C1-C3烷基取代的吡唑基、芳C1-C3烷基-、叔丁基二甲基甲硅烷基CH 2-、-N(R 34) 2、(C1-C3烷氧基)C1-C3烷基、(C1-C3烷基)C(O)、氧代、(C1-C3卤代烷基)C(O)-、-SO 2F、(C1-C3烷氧基)C1-C3烷氧基、-CH 2OC(O)N(R 34) 2、-CH 2NHC(O)OC1-C6烷基、-CH 2NHC(O)N(R 34) 2、-CH 2NHC(O)C1-C6烷基、-CH 2(吡 唑基)、-CH 2NHSO 2C1-C6烷基、-CH 2OC(O)杂环基、-OC(O)N(R 34) 2、-OC(O)NH(C1-C3烷基)O(C1-C3烷基)、-OC(O)NH(C1-C3烷基)O(C1-C3烷基)苯基(C1-C3烷基)N(CH 3) 2、-OC(O)NH(C1-C3烷基)O(C1-C3烷基)苯基、-OC(O)杂环基(例如-OC(O)-3到6元杂环基)或-CH 2杂环基(例如-CH 2-3到6元杂环基)；其中，-NHC(O)苯基或-OC(O)NH(C1-C3烷基)O(C1-C3烷基)苯基中的苯基任选地被-C(O)H或OH取代；-CH 2杂环基中的杂环基任选地被氧代取代；
每个R 36各自独立地为卤素、羟基、HC(O)-、C1-C4烷基、C1-C4烷氧基、C1-C4卤代烷基、C1-C4羟基烷基或-N(R 34) 2；
每个R 34各自独立地为氢、C1-C3烷基或C1-C3卤代烷基；或者两个R 34与和它们相连的氮原子共同构成3到6元含氮杂环基，所述3到6元含氮杂环基任选地被1个或2个选自卤素、甲基、三氟甲基、甲氧基、三氟甲氧基的基团取代。
在一实施方案中，所述化合物如式(II-1A)、式(II-1B)、式(II-2A)、式(II-2B)所示：
Figure PCTCN2022081443-appb-000004
各式中，X、Y、W、R 1、R 2、R 3、R 6、n1、L 3、q、环A各自定义同式(II-1)或式(II-2)。
在一实施方案中，所述化合物如式(II-1A1)、式(II-1A2)、式(II-1B1)、式(II-1B2)、式(II-1B1)或式(II-1B2)所示：
Figure PCTCN2022081443-appb-000005
Figure PCTCN2022081443-appb-000006
各式中，X、Y、W、R 1、R 2、R 3、R 6、n1、L 3、环A各自定义同式(II-1)或式(II-2)。
在一实施方案中，本发明提供了一种式(III)所示的化合物或其药学上可接受的盐、立体异构体、溶剂化物或前药：
Figure PCTCN2022081443-appb-000007
式(III)中，
X为O或NR 11；其中，R 11选自H和C1-C6烷基；
Y为CR 12R 13、CR 14R 15CR 16R 17、C(O)或C(O)CR 18R 19；其中，R 12、R 13、R 14和R 15各自独立地选自H、C1-C3烷基、C1-C3氘代烷基和C1-C3卤代烷基；R 16、R 17、R 18、R 19各自独立地选自H、C1-C3烷基和卤素；
W为N或CR 20；其中，R 20为H、C1-C6烷基、卤素、C1-C6卤代烷基、C1-C6烷氧基、环烷基、环烷基-O-、杂环基或杂环基-O-；其中，所述环烷基、所述杂环基各自独立地任选地被卤素取代；
环A选自下组：芳基、杂芳基；
R 1为环A上任意位置的取代基；各个R 1各自独立地选自：C1-C6烷基、卤素、羟基、C1-C6烷氧基、C1-C6卤代烷基、C1-C6卤代烷氧基、氰基、NR 21R 22、C(O)NR 23R 24、CH 2R 25、N＝S(O)(C1-C6烷基) 2、S(O)C1-C6烷基、S(O) 2R 26、-S-C1-C6烷基、C2-C6烯基、C2-C6炔基、C2-C6羟基炔基、C1-C6氰基烷基、***基、-S-C1-C6卤代烷基、C1-C6羟基烷基、-CH 2C(O)NR 27R 28、-C2-C6炔基NR 29R 30、C2-C6氘代炔基、(C1-C6烷氧基)C1-C6卤代烷基-或环烷基；其中，所述环烷基任选地被卤素或C1-C6烷基取代；其中，
R 21为H、C1-C6烷基、C1-C6卤代烷基、C(O)C1-C6烷基或C(O) 2C1-C6烷基；R 22为H、C1-C6烷基或C1-C6卤代烷基；或者R 21、R 22与和它们相连的氮原子共同构成3到6元含氮杂环基，所述3到6元含氮杂环基任选地被1个或2个选自卤素、甲基、三氟甲基、甲氧基、三氟甲氧基的基团取代；
R 23、R 24各自独立地为H、C1-C6烷基或C1-C6卤代烷基；或者R 23、R 24与和它们相连的氮原子共同构成3到6元含氮杂环基，所述3到6元含氮杂环基任选地被1个或2个选自卤素、甲基、三氟甲基、甲氧基、三氟甲氧基的基团取代；
R 25为羟基、氰基、杂环基、NR 251R 252、C(O)NR 253R 254或SO 2C1-C6烷基；其中，R 251、R 252、R 253、R 254各自独立地为H或C1-C6烷基；R 251、R 252与和它们相连的氮原子共同构成3到6元含氮杂环基，所述3到6元含氮杂环基任选地被1个或2个选自卤素、甲基、三氟甲基、甲氧基、三氟甲氧基的基团取代；R 253、R 254与和它们相连的氮原子共同构成3到6元含氮杂环基，所述3到6元含氮杂环基任选地被1个或2个选自卤素、甲基、三氟甲基、甲氧基、三氟甲氧基的基团取代；
R 26为C1-C6烷基、C1-C6卤代烷基或NR 261R 262；其中，R 261、R 262各自独立地为H或C1-C6烷基；或者R 261、R 262与和它们相连的氮原子共同构成3到6元含氮杂环基，所述3到6元含氮杂环基任选地被1个或2个选自卤素、甲基、三氟甲基、甲氧基、三氟甲氧基的基团取代；
R 27、R 28各自独立地为H、C1-C6烷基或C1-C6卤代烷基；或者R 27、R 28与和它们相连的氮原子共同构成3到6元含氮杂环基，所述3到6元含氮杂环基任选地被1个或2个选自卤素、甲基、三氟甲基、甲氧基、三氟甲氧基的基团取代；
R 29、R 30各自独立地为H、C1-C6烷基或C1-C6卤代烷基；或者R 29、R 30与和它们相连的氮原子共同构成3到6元含氮杂环基，所述3到6元含氮杂环基任选地被1个或2个选自卤素、甲基、三氟甲基、甲氧基、三氟甲氧基的基团取代；
n1是0、1、2或3；
R 3d、R 3e、R 3f各自独立地为氢、卤素、羟基、氰基、C1-C3烷基、C1-C3氘代烷基或C1-C3卤代烷基；或者
R 3d与R 3e相连形成-CHR 3d1-或-CHR 3d2CHR 3d3-；R 3f为氢、卤素、羟基、氰基、C1-C3烷基、C1-C3氘代烷基或C1-C3卤代烷基；R 3d1、R 3d2、R 3d3各自独立地为氢、卤素、羟基、氰基、C1-C3烷基、C1-C3氘代烷基或C1-C3卤代烷基；或者
R 3d与R 3f相连形成-CHR 3f1-或-CHR 3f2CHR 3f3-；R 3e为氢、卤素、羟基、氰基、C1-C3烷基、C1-C3氘代烷基或C1-C3卤代烷基；R 3f1、R 3f2、R 3f3各自独立地为氢、卤素、羟基、氰基、C1-C3烷基、C1-C3氘代烷基或C1-C3卤代烷基；
L 3为一个键、O或NR 34；
R 6是氢、-N(R 34) 2、杂环基、C1-C6烷基、-L-杂环基、-L-芳基、-L-杂芳基、-L-环烷基、-L-N(R 34) 2、-L-NHC(＝NH)NH 2、-L-C(O)N(R 34) 2、-L-C1-C6卤代烷基、-L-OR 34、-L-(CH 2OR 34)(CH 2) nOR 34、-L-NR 34C(O)-芳基、-L-COOH或-L-C(O)OC1-C6烷基；其中，所述杂环基、所述-L-NR 34C(O)-芳基中的芳基、所述-L-杂环基中的杂环基、所述-L-环烷基的环烷基各自可任选地被一个或多个R 35取代或者任选地同一个碳原子上的两个氢原子同时被-CH 2CH 2-或-CH 2CH 2CH 2-取代成为环丙基或环丁基；所述-L-芳基中的芳基、所述-L-杂芳基中的杂芳基各自可任选地被一个或多个R 36取代；
其中，每个L各自独立地为C1-C4亚烷基或杂芳基；其中，所述C1-C4亚烷基任意碳原子上的或任意同一个碳原子上的1个或2个氢原子任选地各自独立地被氘、C1-C6烷基或C1-C6卤代烷基取代；或者所述C1-C4亚烷基任意同一个碳原子上的2个氢原子任选地同时被-(CH 2) m3-、-(CH 2) m1-O-(CH 2) m2-、-(CH 2) m1-N-(CH 2) m2-取代从而形成环状取代基；m3为1或2；各个m1各自独立地为0、1、2或3；各个m2各自独立地为0、1、2或3；且m1、m2不同时为0；
每个R 35各自独立地为卤素、羟基、C1-C3羟基烷基、C1-C3烷基、C1-C3卤代烷基、C1-C3烷氧基、氰基、-苯基、-苯基-SO 2F、-O-苯基、-O-苯基-SO 2F、-NHC(O)苯基、-NHC(O)苯基-SO 2F、C1-C3烷基取代的吡唑基、芳C1-C3烷基-、叔丁基二甲基甲硅烷基CH 2-、-N(R 34) 2、(C1-C3烷氧基)C1-C3烷基、(C1-C3烷基)C(O)、氧代、(C1-C3卤代烷基)C(O)-、-SO 2F、(C1-C3烷氧基)C1-C3烷氧基、-CH 2OC(O)N(R 34) 2、-CH 2NHC(O)OC1-C6烷基、-CH 2NHC(O)N(R 34) 2、-CH 2NHC(O)C1-C6烷基、-CH 2(吡唑基)、-CH 2NHSO 2C1-C6烷基、-CH 2OC(O)杂环基、-OC(O)N(R 34) 2、-OC(O)NH(C1-C3烷基)O(C1-C3烷基)、-OC(O)NH(C1-C3烷基)O(C1-C3烷基)苯基(C1-C3烷基)N(CH 3) 2、-OC(O)NH(C1-C3烷基)O(C1-C3烷基)苯基、-OC(O)杂环基(例如-OC(O)-3到6元杂环基)或-CH 2杂环基(例如-CH 2-3到6元杂环基)；其中，-NHC(O)苯基或-OC(O)NH(C1-C3烷基)O(C1-C3烷基)苯基中的苯基任选地被-C(O)H或OH取代； -CH 2杂环基中的杂环基任选地被氧代取代；
每个R 36各自独立地为卤素、羟基、HC(O)-、C1-C4烷基、C1-C4烷氧基、C1-C4卤代烷基、C1-C4羟基烷基或-N(R 34) 2；
每个R 34各自独立地为氢、C1-C3烷基或C1-C3卤代烷基；或者两个R 34与和它们相连的氮原子共同构成3到6元含氮杂环基，所述3到6元含氮杂环基任选地被1个或2个选自卤素、甲基、三氟甲基、甲氧基、三氟甲氧基的基团取代。
在一实施方案中，所述化合物如式(III-1)或式(III-2)所示：
Figure PCTCN2022081443-appb-000008
各式中，X、Y、W、R 1、R 3d、R 3e、R 3f、R 6、n1、L 3、环A各自定义同式(III)。
在一实施方案中，所述化合物如式(III-1a)、式(III-1b)、式(III-2a)或式(III-2b)所示：
Figure PCTCN2022081443-appb-000009
各式中，q为1或2；R 3为桥环上任意位置的取代基且为氢、卤素、羟基、氰基、C1-C3烷基、C1-C3氘代烷基或C1-C3卤代烷基；X、Y、W、环A、R 1、n1、L 3、R 6定义同式(III)。
在一实施方案中，所述化合物如式(III-1a1)、式(III-1a2)、式(III-1b1)、式(III-1b2)、式(III-1c1)或式(III-1c2)所示：
Figure PCTCN2022081443-appb-000010
Figure PCTCN2022081443-appb-000011
各式中，R 3为桥环上任意位置的取代基且为氢、卤素、羟基、氰基、C1-C3烷基、C1-C3氘代烷基或C1-C3卤代烷基；X、Y、W、环A、R 1、n1、L 3、R 6定义同式(III)。
在一实施方案中，各式中，R 3为氢。
在一实施方案中，各式中，Y为-CH 2-。
在一实施方案中，各式中，所述环烷基为C3-C20环烷基。优选地，所述环烷基为C3-C12环烷基(更优选C3-C8单环环烷基)、C5-C20螺环烷基、C5-C20稠环烷基或C5-C20桥环烷基。
在一实施方案中，各式中，所述杂环基为3到20元杂环基。优选地，所述杂环基为单环杂环基(例如3到8元单环杂环基)、5到20元螺杂环基、5到20元稠杂环基和5到20元桥杂环基。
在一实施方案中，各式中，所述芳基为C6-C14芳基。优选地，所述芳基为单环芳基、非稠合多环芳基和芳香稠合多环。
在一实施方案中，各式中，所述杂芳基为5到14元杂芳基。优选地，所述杂芳基为单环杂芳基(例如，5或6元单环杂芳基)、稠合双环杂芳基(例如8到10元双环杂芳基)或稠合三环杂芳基。
在一实施方案中，W为N或CR 20；其中，R 20为氢、氟、甲基、甲氧基或环丙氧基。
在一实施方案中，X为O。
在一实施方案中，Y为CH 2。
在一实施方案中，Y选自下组：
Figure PCTCN2022081443-appb-000012
在一实施方案中，R 2为氟、氯、羟基、甲氧基或氰基。
在一实施方案中，环A为苯基、萘基、吡啶基、嘧啶基、吡嗪基、哒嗪基、吡咯基、吡唑基、咪唑基、1,2,3,4-四氢化萘基、2,3-二氢-1H-茚基、异喹啉基、吲唑基或苯并[d][1,3]二氧戊环。
在一实施方案中，环A选自下组：
Figure PCTCN2022081443-appb-000013
Figure PCTCN2022081443-appb-000014
Figure PCTCN2022081443-appb-000015
且这些基团可通过任意一个合适的环原子与分子其余部分连接。
在一实施方案中，R 1为环A上任意位置的取代基；n1是0、1、2或3；
各个R 1各自独立地选自：C1-C3烷基、卤素、羟基、C1-C3烷氧基、C1-C3卤代烷基、C1-C3卤代烷氧基、氰基、NR 21R 22、C(O)NR 23R 24、CH 2R 25、N＝S(O)(C1-C3烷基) 2、S(O)C1-C3烷基、S(O) 2R 26、-S-C1-C3烷基、C2-C4烯基、C2-C4炔基、C2-C4羟基炔基、C1-C3氰基烷基、***基、-S-C1-C3卤代烷基、C1-C3羟基烷基、-CH 2C(O)NR 27R 28、-C2-C4炔基NR 29R 30、C2-C4氘代炔基、(C1-C3烷氧基)C1-C3卤代烷基-或环烷基；其中，所述环烷基任选地被卤素或C1-C3烷基取代；其中，
R 21为H、C1-C3烷基、C1-C3卤代烷基、C(O)C1-C3烷基或C(O) 2C1-C3烷基；R 22为H、C1-C3烷基或C1-C3卤代烷基；或者R 21、R 22与和它们相连的氮原子共同构成3到6元含氮杂环基，所述3到6元含氮杂环基任选地被1个或2个选自卤素、甲基、三氟甲基、甲氧基、三氟甲氧基的基团取代；
R 23、R 24各自独立地为H、C1-C3烷基或C1-C3卤代烷基；或者R 23、R 24与和它们相连的氮原子共同构成3到6元含氮杂环基，所述3到6元含氮杂环基任选地被1个或2个选自卤素、甲基、三氟甲基、甲氧基、三氟甲氧基的基团取代；
R 25为羟基、氰基、杂环基、NR 251R 252、C(O)NR 253R 254或SO 2C1-C3烷基；其中，R 251、R 252、R 253、R 254各自独立地为H或C1-C3烷基；R 251、R 252与和它们相连的氮原子共同构成3到6元含氮杂环基，所述3到6元含氮杂环基任选地被1个或2个选自卤素、甲基、三氟甲基、甲氧基、三氟甲氧基的基团取代；R 253、R 254与和它们相连的氮原子共同构成3到6元含氮杂环基，所述3到6元含氮杂环基任选地被1个或2个选自卤素、甲基、三氟甲基、甲氧基、三氟甲氧基的基团取代；
R 26为C1-C3烷基、C1-C3卤代烷基或NR 261R 262；其中，R 261、R 262各自独立地为H或C1-C3烷基；或者R 261、R 262与和它们相连的氮原子共同构成3到6元含氮杂环基，所述3到6元含氮杂环基任选地被1个或2个选自卤素、甲基、三氟甲基、甲氧基、三氟甲氧基的基团取代；
R 27、R 28各自独立地为H、C1-C3烷基或C1-C3卤代烷基；或者R 27、R 28与和它们相连的氮原子共同构成3到6元含氮杂环基，所述3到6元含氮杂环基任选地被1个或2个选自卤素、甲基、三氟甲基、甲氧基、三氟甲氧基的基团取代；
R 29、R 30各自独立地为H、C1-C3烷基或C1-C3卤代烷基；或者R 29、R 30与和它们相连的氮原子共同构成3到6元含氮杂环基，所述3到6元含氮杂环基任选地被1个或2个选自卤素、甲基、三氟甲基、甲氧基、三氟甲氧基的基团取代。
在一实施方案中，L 2是亚甲基或亚乙基或亚丙基；其中，所述亚甲基或亚乙基或亚丙基上任意碳原子上的或任意同一个碳原子上的1个或2个氢原子任选地各自独立地被氘或C1-C3烷基取代；或者所述亚甲基或亚乙基或亚丙基任意同一个碳原子上的2个氢原子任选地同时被-CH 2-或-CH 2CH 2-取代从而形成环丙基或环丁基。
在一实施方案中，R 3a、R 3b、R 3c各自独立地为氢、氟、甲基或甲氧基。
在一实施方案中，
Figure PCTCN2022081443-appb-000016
选自下组：
Figure PCTCN2022081443-appb-000017
各式中，每个R 4、R 5、n2、n3各自独立地定义同式(I)中的定义。
在一实施方案中，
Figure PCTCN2022081443-appb-000018
选自下组：
Figure PCTCN2022081443-appb-000019
在一实施方案中，R 3为氢、氟、甲基或甲氧基。
在一实施方案中，R 3d、R 3e、R 3f各自独立地为氢、氟、甲基或甲氧基；或者
R 3d与R 3e相连形成-CHR 3d1-或-CHR 3d2CHR 3d3；R 3f为氢、氟、甲基或甲氧基；R 3d1、R 3d2、R 3d3各自独立地为氢、氟、甲基或甲氧基；或者
R 3d与R 3f相连形成-CHR 3f1-或-CHR 3f2CHR 3f3；R 3e为氢、氟、甲基或甲氧基；R 3f1、R 3f2、R 3f3各自独立地为氢、氟、甲基或甲氧基。
在一实施方案中，L是亚甲基或亚乙基或亚丙基；其中，所述亚甲基或亚乙基或亚丙基上任意碳原子上的或任意同一个碳原子上的1个或2个氢原子任选地各自独立地被氘或C1-C3烷基取代；或者所述亚甲基或亚乙基或亚丙基任意同一个碳原子上的2个氢原子任选地同时被-CH 2-或-CH 2CH 2-取代从而形成环丙基或环丁基。
在一实施方案中，R 6是氢、-N(R 34) 2、3到20元杂环基、C1-C6烷基、-L-3到20元杂环基、-L-C6-C14芳基、-L-5到14元杂芳基、-L-C3-C20环烷基、-L-N(R 34) 2、-L-NHC(＝NH)NH 2、-L-C(O)N(R 34) 2、-L-C1-C6卤代烷基、-L-OR 34、-L-(CH 2OR 34)(CH 2) nOR 34、-L-NR 34C(O)-C6-C14芳基、-L-COOH或-L-C(O)OC1-C6烷基；其中，所述3到20元杂环基、所述-L-NR 34C(O)-C6-C14芳基中的C6-C14芳基、所述C3-C20环烷基可任选地被一个或多个R 35取代或者任选地同一个碳原子上的两个氢原子同时被-CH 2CH 2-或 -CH 2CH 2CH 2-取代成为环丙基或环丁基；-L-C6-C14芳基中的C6-C14芳基或-L-5到14元杂芳基中的5到14元杂芳基可任选地被一个或多个R 36取代；L、R 34、R 35、R 36各自定义同前。
在一实施方案中，R 6是氢、-N(R 34) 2、3到8元单环杂环基、5到20元螺杂环基、5到20元稠杂环基、5到20元桥杂环基、C1-C6烷基、-L-3到8元单环杂环基、-L-5到20元螺杂环基、-L-5到20元稠杂环基、-L-5到20元桥杂环基、-L-苯基、-L-萘基、-L-5到14元杂芳基、-L-C3-C12环烷基、-L-C5-C20螺环烷基、C5-C20稠环烷基、-L-C5-C20桥环烷基、-L-N(R 34) 2、-L-NHC(＝NH)NH 2、-L-C(O)N(R 34) 2、-L-C1-C6卤代烷基、-L-OR 34、-L-(CH 2OR 34)(CH 2) nOR 34、-L-NR 34C(O)-苯基、-L-NR 34C(O)-萘基、-L-COOH或-L-C(O)OC1-C6烷基；其中，所述3到8元单环杂环基、5到20元螺杂环基、5到20元稠杂环基、5到20元桥杂环基、C3-C12环烷基、C5-C20螺环烷基、C5-C20稠环烷基、C5-C20桥环烷基、所述-L-NR 34C(O)-苯基中的苯基、所述-L-NR 34C(O)-萘基中的萘基可任选地被一个或多个R 35取代或者任选地同一个碳原子上的两个氢原子同时被-CH 2CH 2-或-CH 2CH 2CH 2-取代成为环丙基或环丁基；-L-苯基中的苯基、-L-萘基中的萘基、-L-5到14元杂芳基中的5到14元杂芳基可任选地被一个或多个R 36取代；L、R 34、R 35、R 36各自定义同前。
在一实施方案中，R 6是氢或-N(R 34) 2。较佳地，各个R 34各自独立地是氢或C1-C3烷基；或者1个R 34是氢以及另1个R 34是C1-C3烷基。
在一实施方案中，R 34是氢、C1-C3烷基或C1-C3氰基烷基。
在一实施方案中，C1-C6烷基是甲基、乙基、异丙基或异丁基。
在一实施方案中，L是亚甲基或亚乙基或亚丙基；其中，所述亚甲基或亚乙基或亚丙基上任意碳原子上的或任意同一个碳原子上的1个或2个氢原子任选地各自独立地被氘或C1-C3烷基取代；或者所述亚甲基或亚乙基或亚丙基任意同一个碳原子上的2个氢原子任选地同时被-CH 2-或-CH 2CH 2-取代从而形成环丙基或环丁基。
在一实施方案中，每个R 6各自独立地为
Figure PCTCN2022081443-appb-000020
R 4、R 5、L 2、环B、环C、n2、n3定义同式(I)中各基团的定义。
在一实施方案中，R 6中的所述杂环基各自独立地为六氢-1H-吡咯嗪基、六氢-3H-吡咯嗪-3-酮、六氢-1H-吡咯并[2,1-c][1,4]噁嗪基、八氢吲哚嗪基、六氢吡咯嗪4(1H)-氧化物、氮杂环丁基、吡咯烷基、吡咯烷-2-酮、氧杂环丁基、哌啶基、1-氮杂二环[2.2.1]庚基、吗啉基、氧杂-5-氮杂二环[2.2.1]庚-5-基、噻喃基、6-氧杂-2-氮杂螺[3.4]辛基、7-氧杂-2-氮杂螺[3.5]壬基、2′,3′-二氢螺[环丙烷-1,1’-茚基]、(2S)-1-氮杂二环[2.2.1]庚-2-基或四氢呋喃基；上述每个基团各自独立地任选地被一个或多个R 35取代或者任选地同一个碳原子上的两个氢原子同时被-CH 2CH 2-或-CH 2CH 2CH 2-取代成为环丙基或环丁基。
在一实施方案中，R 6是-L-杂环基；所述杂环基是六氢-1H-吡咯嗪基。
在一实施方案中，R 6是-L-杂环基；所述杂环基是被一个R 35取代的六氢-1H-吡咯嗪基或者是同一个碳原子上的两个氢原子同时被-CH 2CH 2-或-CH 2CH 2CH 2-取代成为环丙基或环丁基的六氢-1H-吡咯嗪基；其中，R 35是卤素、羟基、C1-C3羟基烷基、C1-C3卤代烷基、C1-C3烷基、C1-C3烷氧基、苯基、吡唑基或-CH 2OC(O)N(R 34) 2。
在一实施方案中，所述卤素是氟。
在一实施方案中，所述杂环基是进一步被另外两个R 35取代的六氢-1H-吡咯嗪基；所述另外两个R 35各自独立地是C1-C3烷基。
在一实施方案中，R 6是-L-杂环基；所述杂环基是被一个R 35取代的氮杂环丁基或者是同一个碳原子上的两个氢原子同时被-CH 2CH 2-或-CH 2CH 2CH 2-取代成为环丙基或环丁基的氮杂环丁基；所述R 35是C1-C3烷基。
在一实施方案中，R 6是-L-杂环基；所述杂环基是被一个R 35取代的吡咯烷基或者是同一个碳原子上的两个氢原子同时被-CH 2CH 2-或-CH 2CH 2CH 2-取代成为环丙基或环丁基的吡咯烷基；其中，R 35是羟基烷基、卤代烷基、C1-C3烷基、烷氧基、芳C1-C3烷基、-苯基、-O-苯基和-NHC(O)苯基；其中，所述芳C1-C3烷基中的芳基、所述苯基、或所述-O-苯基中的苯基或-NHC(O)苯基中的苯基各自独立地任选地被一个或多个R 36取代。
在一实施方案中，所述苯基、-O-苯基或-NHC(O)苯基中的苯基被-SO 2F取代。
在一实施方案中，R 6是-L-杂环基；所述杂环基是被两个R 35取代的吡咯烷基；其中，一个R 35是C1-C3烷基，另一个R 35是C1-C3烷氧基或卤素。
在一实施方案中，R 6是-L-杂环基；所述杂环基是被一个R 35取代的吡咯烷-2-酮或者是同一个碳原子上的两个氢原子同时被-CH 2CH 2-或-CH 2CH 2CH 2-取代成为环丙基或环丁基的吡咯烷-2-酮；其中，R 35是C1-C3烷基。
在一实施方案中，R 6是-L-杂环基；所述杂环基是被一个R 35取代的哌啶基或者是同一个碳原子上的两个氢原子同时被-CH 2CH 2-或-CH 2CH 2CH 2-取代成为环丙基或环丁基的哌啶基；其中，R 35是乙酰基、(C1-C3烷氧基)C1-C3烷氧基或-C(O)CH 2Cl。
在一实施方案中，R 6是-L-杂环基；所述杂环基是吗啉基或氧杂-5-氮杂二环[2.2.1]庚-5-基。
在一实施方案中，R 6是-L-杂芳基；所述杂芳基任选地被一个或多个R 36取代。
在一实施方案中，R 6是-L-杂芳基；L是亚甲基或亚乙基或亚丙基；其中，所述亚甲基或亚乙基或亚丙基上任意碳原子上的或任意同一个碳原子上的1个或2个氢原子任选地各自独立地被氘或C1-C3烷基取代；或者所述亚甲基或亚乙基或亚丙基任意同一个碳原子上的2个氢原子任选地同时被-CH 2-或-CH 2CH 2-取代从而形成环丙基或环丁基；所述杂芳基是吡啶基、吡唑基、咪唑基、***基、4,5,6,7-四氢-1H-吲唑基、苯并咪唑基、咪唑并[1,2-a]吡啶基或嘧啶基；上述每个基团任选地被一个或多个R 36取代。
在一实施方案中，R 6是-L-杂芳基；L是亚甲基或亚乙基或亚丙基；其中，所述亚甲基或亚乙基或亚丙基上任意碳原子上的或任意同一个碳原子上的1个或2个氢原子任选地各自独立地被氘或C1-C3烷基取代；或者所述亚甲基或亚乙基或亚丙基任意同一个碳原子上的2个氢原子任选地同时被-CH 2-或-CH 2CH 2-取代从而形成环丙基或环丁基；所述杂芳基是被一个R 36取代的吡啶基；其中，R 36是卤素、C1-C4烷基、-N(R 5) 2或C1-C4烷氧基。
在一实施方案中，R 6是-L-杂芳基；L是亚甲基或亚乙基或亚丙基；其中，所述亚甲基或亚乙基或亚丙基上任意碳原子上的或任意同一个碳原子上的1个或2个氢原子任选地各自独立地被氘或C1-C3烷基取代；或者所述亚甲基或亚乙基或亚丙基任意同一个碳原子上的2个氢原子任选地同时被-CH 2-或-CH 2CH 2-取代从而形成环丙基或环丁基；所述杂芳基是被一个R 36取代的吡唑基；其中，R 36是C1-C4烷基或-N(R 34) 2。
在一实施方案中，R 6是-L-杂芳基；L是亚甲基或亚乙基或亚丙基；其中，所述亚甲基或亚乙基或亚丙基上任意碳原子上的或任意同一个碳原子上的1个或2个氢原子任选地各自独立地被氘或C1-C3烷基取代；或者所述亚甲基或亚乙基或亚丙基任意同一个碳原子上的2个氢原子任选地同时被-CH 2-或-CH 2CH 2-取代从而形成环丙基或环丁基；所述杂芳基是被一个R 36取代的咪唑基；其中，R 36是C1-C4 烷基、C1-C4卤代烷基或C1-C4羟基烷基。
在一实施方案中，R 6是-L-杂芳基；L是亚甲基或亚乙基或亚丙基；其中，所述亚甲基或亚乙基或亚丙基上任意碳原子上的或任意同一个碳原子上的1个或2个氢原子任选地各自独立地被氘或C1-C3烷基取代；或者所述亚甲基或亚乙基或亚丙基任意同一个碳原子上的2个氢原子任选地同时被-CH 2-或-CH 2CH 2-取代从而形成环丙基或环丁基；所述杂芳基是被一个R 36取代的***基；其中，R 36是C1-C4烷基。
在一实施方案中，R 6是-L-芳基；所述芳基任选地被一个或多个R 36取代。
在一实施方案中，R 6是-L-环烷基；所述环烷基任选地被一个或多个R 35取代或者任选地同一个碳原子上的两个氢原子同时被-CH 2CH 2-或-CH 2CH 2CH 2-取代成为环丙基或环丁基；各个R 35各自定义同前。
在一实施方案中，R 6是-L-N(R 34) 2；其中，L为C1-C4亚烷基；其中，所述C1-C4亚烷基任意碳原子上的或任意同一个碳原子上的1个或2个氢原子任选地各自独立地被氘或C1-C3烷基取代；或者所述C1-C4亚烷基任意同一个碳原子上的2个氢原子任选地同时被-CH 2-或-CH 2CH 2-取代从而形成环丙基或环丁基。
在一实施方案中，R 6是-L-N(R 34) 2；其中，L为亚甲基、亚乙基或亚丙基；其中，所述亚甲基、亚乙基或亚丙基上任意碳原子上的或任意同一个碳原子上的1个或2个氢原子任选地各自独立地被氘或C1-C3烷基取代；或者所述亚甲基、亚乙基或亚丙基任意同一个碳原子上的2个氢原子任选地同时被-CH 2-或-CH 2CH 2-取代从而形成环丙基或环丁基；每个R 34独立地选自C1-C3烷基。
在一实施方案中，R 6是-L-NC(＝NH)-NH 2；其中，L为C1-C4亚烷基；其中，所述C1-C4亚烷基任意碳原子上的或任意同一个碳原子上的1个或2个氢原子任选地各自独立地被氘或C1-C3烷基取代；或者所述C1-C4亚烷基任意同一个碳原子上的2个氢原子任选地同时被-CH 2-或-CH 2CH 2-取代从而形成环丙基或环丁基。
在一实施方案中，L是亚乙基或亚丙基。
在一实施方案中，R 6是-L-C1-C6卤代烷基；其中，L为C1-C4亚烷基；其中，所述C1-C4亚烷基任意碳原子上的或任意同一个碳原子上的1个或2个氢原子任选地各自独立地被氘或C1-C3烷基取代；或者所述C1-C4亚烷基任意同一个碳原子上的2个氢原子任选地同时被-CH 2-或-CH 2CH 2-取代从而形成环丙基或环丁基。
在一实施方案中，R 6是-L-OR 34；其中，L为C1-C4亚烷基；其中，所述C1-C4亚烷基任意碳原子上的或任意同一个碳原子上的1个或2个氢原子任选地各自独立地被氘或C1-C3烷基取代；或者所述C1-C4亚烷基任意同一个碳原子上的2个氢原子任选地同时被-CH 2-或-CH 2CH 2-取代从而形成环丙基或环丁基。
在一实施方案中，R 6是-L-(CH 2OR 34)(CH 2) nOR 34；其中，L为C1-C4亚烷基；其中，所述C1-C4亚烷基任意碳原子上的或任意同一个碳原子上的1个或2个氢原子任选地各自独立地被氘或C1-C3烷基取代；或者所述C1-C4亚烷基任意同一个碳原子上的2个氢原子任选地同时被-CH 2-或-CH 2CH 2-取代从而形成环丙基或环丁基。
在一实施方案中，R 6是-L-NR 34C(O)-芳基；其中，L为C1-C4亚烷基；其中，所述C1-C4亚烷基任意碳原子上的或任意同一个碳原子上的1个或2个氢原子任选地各自独立地被氘或C1-C3烷基取代；或者所述C1-C4亚烷基任意同一个碳原子上的2个氢原子任选地同时被-CH 2-或-CH 2CH 2-取代从而形成环丙基或环丁基。
在一实施方案中，R 6是-L-杂环基；L为C1-C4亚烷基；其中，所述C1-C4亚烷基任意同一个碳原子上的2个氢原子任选地各自独立地被氘或C1-C6烷基取代；或者所述C1-C4亚烷基任意同一个碳原子上的2个氢原子任选地同时被-CH 2-或-CH 2CH 2-取代从而形成环丙基或环丁基。
在一实施方案中，L是亚甲基或亚乙基或亚丙基；其中，所述亚甲基或亚乙基或亚丙基任意同一个碳原子上的2个氢原子任选地各自独立地被氘或C1-C3烷基取代；或者所述亚甲基或亚乙基或亚丙基任意同一个碳原子上的2个氢原子任选地同时被-CH 2-或-CH 2CH 2-取代从而形成环丙基或环丁基。
在一实施方案中，W为CR 20；R 20是环丙基、环丙基-O-、环丁基、环丁基-O-、环戊基、环戊基-O-、四氢呋喃基、四氢呋喃-O-；其中，所述环丙基、环丁基、环戊基、四氢呋喃基各自独立地被卤素取代。
在一实施方案中，W为CR 20；R 20是氢、卤素、C1-C6烷基、C3-C6环烷基、C3-C6环烷基-O-、3到6元杂环基或3到6元杂环基-O-；其中，所述C3-C6环烷基、所述3到6元杂环基各自独立地被卤素取代。
在一实施方案中，R 20是卤素或C1-C3烷基。
在一实施方案中，R 20是氟。
在一实施方案中，R 20是甲基。
在一实施方案中，L 2或L是亚甲基或亚乙基或亚丙基；其中，所述亚甲基或亚乙基或亚丙基任意同一个碳原子上的2个氢原子任选地各自独立地被氘或C1-C3烷基取代；或者所述亚甲基或亚乙基或亚丙基任意同一个碳原子上的2个氢原子任选地同时被-CH 2-或-CH 2CH 2-取代从而形成环丙基或环丁基。
在一实施方案中，
Figure PCTCN2022081443-appb-000021
是被一个、两个或三个R 1取代的苯基；其中，各个R 1各自独立地是卤素、羟基、乙炔基、甲基、甲基-O-、甲基-S-、三氟甲基、三氟甲基-O-、氨基、异丙基、或环丙基；所述环丙基任选地被卤素或甲基取代。
在一实施方案中，
Figure PCTCN2022081443-appb-000022
是被一个、两个或三个R 1取代的萘基；其中，各个R 1各自独立地是卤素、羟基、乙炔基、甲基、甲基-O-、甲基-S-、三氟甲基、三氟甲基-O-、氨基、异丙基、或环丙基；所述环丙基任选地被卤素或甲基取代。
在一实施方案中，
Figure PCTCN2022081443-appb-000023
是被一个、两个或三个R 1取代的萘基；其中，各个R 1各自独立地是卤素、羟基、乙炔基、甲基、乙基、二氟甲基或羟基取代的丙基。
在一实施方案中，
Figure PCTCN2022081443-appb-000024
是任选地被一个或多个R 1取代的杂芳基。
在一实施方案中，
Figure PCTCN2022081443-appb-000025
是被一个、两个或三个R 1取代的吡啶基；其中，各个R 8各自独立地是卤素、羟基、乙炔基、甲基、甲基-O-、甲基-S-、三氟甲基、三氟甲基-O-、氨基、异丙基、或环丙基；所述环丙基任选地被卤素或甲基取代。
在一实施方案中，
Figure PCTCN2022081443-appb-000026
是任选地被一个或多个R 1取代的异喹啉基、吲唑基或苯并[d][1,3]二氧戊环。
在一实施方案中，
Figure PCTCN2022081443-appb-000027
是被一个、两个或三个R 1取代的异喹啉基；其中，各个R 8各自独立地是卤素、羟基、乙炔基、甲基、甲基-O-、甲基-S-、三氟甲基、三氟甲基-O-、氨基、异丙基、或环丙基；所述环丙基任选地被卤素或甲基取代。
在一实施方案中，
Figure PCTCN2022081443-appb-000028
是被一个、两个或三个R 1取代的吲唑基；其中，各个R 8各自独立地是C1-C3烷基。
在一实施方案中，
Figure PCTCN2022081443-appb-000029
是被两个R 1基团取代的苯并[d][1,3]二氧戊环；其中，各个R 8各自独立地选自卤素。
在一实施方案中，
Figure PCTCN2022081443-appb-000030
选自下组：
Figure PCTCN2022081443-appb-000031
在一实施方案中，所述-L 3-R 6选自下组：
Figure PCTCN2022081443-appb-000032
Figure PCTCN2022081443-appb-000033
各式中，R L1、R L2各自独立地为氢、氘、C1-C6烷基或C1-C6卤代烷基；R 61是杂环基、芳基、杂芳基、环烷基、-N(R 34) 2、-NHC(＝NH)NH 2、-C(O)N(R 34) 2、-C1-C6卤代烷基、-OR 34、-(CH 2OR 34)(CH 2) nOR 34、-NR 34C(O)-芳基、-COOH或-C(O)OC1-C6烷基；其中，所述杂环基、所述-NR 34C(O)-芳基中的芳基、所述环烷基各自可任选地被一个或多个R 35取代或者任选地同一个碳原子上的两个氢原子同时被-CH 2CH 2-或-CH 2CH 2CH 2-取代成为环丙基或环丁基；所述芳基、所述杂芳基各自可任选地被一个或多个R 36取代；R 34、R 35、R 36各自定义同前。优选地，上述各式中，N-R 34中R 34为H。
在一实施方案中，所述-L 3-R 6选自下组：
Figure PCTCN2022081443-appb-000034
各式中，R 61是杂环基、芳基、杂芳基、环烷基、-N(R 34) 2、-NHC(＝NH)NH 2、-C(O)N(R 34) 2、-C1-C6卤代烷基、-OR 34、-(CH 2OR 34)(CH 2) nOR 34、-NR 34C(O)-芳基、-COOH或-C(O)OC1-C6烷基；其中，所述杂环基必需被一个或多个R 35取代或者任选地同一个碳原子上的两个氢原子同时被-CH 2CH 2-或-CH 2CH 2CH 2-取代成为环丙基或环丁基；所述-NR 34C(O)-芳基中的芳基、所述环烷基各自可任选地被一个或多个R 35取代或者任选地同一个碳原子上的两个氢原子同时被-CH 2CH 2-或-CH 2CH 2CH 2-取代成为环丙基或环丁基；所述芳基、所述杂芳基各自可任选地被一个或多个R 36取代；R 34、R 35、R 36定义同前各自定义同前。优选地，上述各式中，N-R 34中R 34为H。
在一实施方案中，R 61选自下组：
Figure PCTCN2022081443-appb-000035
在一实施方案中，R 61是六氢-1H-吡咯嗪基。
在一实施方案中，R 61是被一个R 35取代的六氢-1H-吡咯嗪基；其中，R 35是卤素、羟基、C1-C3羟基烷基、C1-C3卤代烷基、C1-C3烷基、C1-C3烷氧基、苯基、吡唑基或-CH 2OC(O)N(R 34) 2；每个R 34各自独立地为氢、C1-C3烷基或C1-C3卤代烷基；或者两个R 34与和它们相连的氮原子共同构成3到6元含氮杂环基，所述3到6元含氮杂环基任选地被1个或2个选自卤素、甲基、三氟甲基、甲氧基、三氟甲氧基的基团取代。
在一实施方案中，所述化合物选自表A中的化合物。
在一实施方案中，所述化合物选自实施例7和表B中的化合物。
在一实施方案中，所述化合物选自实施例1至6、8至12和表C中的化合物。
在一实施方案中，所述化合物选自表(I)中的化合物：
表(I)
Figure PCTCN2022081443-appb-000036
Figure PCTCN2022081443-appb-000037
本发明第二方面提供了一种药物组合物，所述药物组合物包括上述第一方面所述化合物或其药学上可接受的盐、立体异构体、溶剂化物或前药；以及药学可接受的载体。
如本文所用，术语“药学可接受的载体”是指能够递送本发明有效量活性物质、不干扰活性物质的生物活性并且对宿主或者受试者无毒副作用的任何制剂或载体介质代表性的载体，包括水、油、蔬菜和矿物质、膏基、洗剂基质、软膏基质等。这些基质包括悬浮剂、增粘剂、透皮促进剂等。它们的制剂为化妆品领域或局部药物领域的技术人员所周知。
在本发明的实施方案中，所述药物组合物可以以下的任意方式施用：口服，喷雾吸入，直肠用药，鼻腔用药，颊部用药，局部用药，非肠道用药，如皮下，静脉，肌内，腹膜内，鞘内，心室内，胸骨内和颅内注射或输入，或借助一种外植储器用药。其中优选口服、腹膜内或静脉内给药方式。当口服用药时，本发明的化合物可制成任意口服可接受的制剂形式，包括但不限于片剂、胶囊、水溶液或水悬浮液。片剂使用的载体一般包括乳糖和玉米淀粉，另外也可加入润滑剂如硬脂酸镁。胶囊制剂使用的稀释剂一般包括乳糖和干燥玉米淀粉。水悬浮液制剂则通常是将活性成分与适宜的乳化剂和悬浮剂混合使用。如果需要，以上口服制剂形式中还可加入一些甜味剂、芳香剂或着色剂。当局部用药时，特别是治疗局部外敷容易达到的患面或器官，如眼睛、皮肤或下肠道神经性疾病时，可根据不同的患面或器官将本发明化合物制成不同的局部用药制剂形式，当眼部局部施用时，本发明的化合物可配制成一种微粉化悬浮液或溶液的制剂形式，所使用载体为等渗的一定pH的无菌盐水，其中可加入也可不加防腐剂如氯化苄基烷醇盐。对于眼用，也可将化合物制成膏剂形式如凡士林膏。当皮肤局部施用时，本发明的化合物可制成适当的软膏、洗剂或霜剂制剂形式，其中将活性成分悬浮或溶解于一种或多种载体中。软膏制剂可使用的载体包括但不限于：矿物油，液体凡士林，白凡士林，丙二醇，聚氧化乙烯，聚氧化丙烯，乳化蜡和水；洗剂或霜剂可使用的载体包括但不限于：矿物油，脱水山梨糖醇单硬脂酸酯，吐温60，十六烷酯蜡，十六碳烯芳醇，2-辛基十二烷醇，苄醇和水。本发明的化合物还可以无菌注射制剂形式用药，包括无菌注射水或油悬浮液或无菌注射溶液。可使用的载体和溶剂包括水、林格氏溶液和等渗氯化钠溶液。此外灭菌的非挥发油也可用作溶剂或悬浮介质，如单甘油酯或二甘油酯。
本发明另一方面提供了上述第一方面所述化合物或其药学上可接受的盐、立体异构体、溶剂化物或前药或上述第二方面所述药物组合物在制备预防和/或治疗疾病或病症的药物中的用途；所述疾病或病症为KRAS G12D相关疾病或障碍。
如本文所用，“KRAS G12D”指的是哺乳动物KRAS蛋白的突变体形式，该突变体在12号氨基酸位上含有天冬氨酸取代甘氨酸的氨基酸。人类KRAS的氨基酸密码子和残基位置的分配基于UniProtKB/Swiss-Prot P01116:Variantp.Gly12Asp鉴定的氨基酸序列。
如本文所用，“KRAS G12D抑制剂”是指本发明的化合物，如本文所述，用式(I)、式(II-1)、式(II-1)或式(III)表示。这些化合物能够负向调控或抑制KRAS G12D的全部或部分酶活性。
如本文所用，“KRAS G12D相关疾病或障碍”是指与KRAS G12D突变相关，介导或具有KRAS G12D突变的疾病或障碍。KRAS G12D相关疾病或障碍的非限制性例子是KRAS G12D相关癌症。
本发明另一方面提供了一种治疗KRAS G12D相关癌症的方法，所述方法包括步骤：向需要的受试者施用治疗有效量的本发明第一方面所述的化合物或其药学上可接受的盐、立体异构体、溶剂化物或前药；或者向需要的受试者施用治疗有效量的发明第二方面所述的药物组合物。
在一实施方案中，所述KRAS G12D相关癌症包括但不限于肺癌、***癌、乳腺癌、脑癌、皮肤癌、***、睾丸癌等肿瘤。在一实施方案中，所述KRAS G12D相关癌症包括但不限于星形胶质细胞癌、乳腺癌、***、结直肠癌、子宫内膜癌、食管癌、胃癌、头颈癌、肝细胞癌、喉癌、肺癌、口腔癌、卵巢癌、***癌、甲状腺癌、肉瘤等。在一实施方案中，所述KRAS G12D相关癌症包括但不限于，心脏部位的癌症，例如，肉瘤(血管肉瘤、纤维肉瘤、横纹肌肉瘤、脂肪肉瘤)、粘液瘤、横纹肌瘤、纤维瘤、脂肪瘤和畸胎瘤等；肺部的癌症，例如，支气管癌(鳞状细胞、未分化小细胞、未分化大细胞、腺癌)、肺泡(细支气管)癌、支气管腺瘤、肉瘤、淋巴瘤、软骨瘤错构瘤、间皮瘤；胃肠道的癌症，例如，食道(鳞状细胞癌、腺癌、平滑肌肉瘤、淋巴瘤)、胃(癌、淋巴瘤、平滑肌肉瘤)、胰腺(导管腺癌、胰岛素瘤、胰高血糖素瘤、胃泌素瘤、类癌瘤、vipoma)、小肠(腺癌、类癌瘤)、卡波氏肉瘤、平滑肌瘤、血管瘤、脂肪瘤、神经纤维瘤、纤维瘤)、大肠(腺癌、管状腺瘤、绒毛状腺瘤、错构瘤、平滑肌瘤)；泌尿生殖道的癌症，例如，肾脏(腺癌、威尔姆氏瘤(肾母细胞瘤)、淋巴瘤、白血病)、膀胱和尿道(鳞状细胞癌、移行细胞癌、腺癌)、***(腺癌、肉瘤)、睾丸(***瘤、畸胎瘤、胚胎癌、畸胎瘤)、绒毛膜癌、肉瘤、***癌、纤维瘤、纤维腺瘤、腺瘤样肿瘤、脂肪瘤)；肝脏的癌症，例如，肝癌(肝细胞癌)、胆管癌、肝母细胞瘤、血管肉瘤、肝细胞腺瘤、血管瘤；胆道：胆囊癌、壶腹癌、胆管癌；骨部位的癌症，例如，成骨肉瘤(骨肉瘤)、纤维肉瘤、恶性纤维组织细胞瘤、软骨肉瘤、尤文氏肉瘤、恶性淋巴瘤(网状细胞肉瘤)、多发性骨髓瘤、恶性巨细胞瘤、脊索瘤、骨软骨瘤(骨软骨外软骨瘤)、良性软骨瘤、良性软骨瘤骨瘤和巨细胞瘤；神经***的癌症，例如，颅骨(骨瘤、血管瘤、肉芽肿、黄瘤、畸形骨炎)、脑膜(脑膜瘤、脑膜肉瘤、胶质瘤病)、脑(星形细胞瘤、成神经管细胞瘤、胶质瘤、室管膜瘤、生殖细胞瘤(松果体瘤)、胶质母细胞瘤、多形性胶质母细胞瘤、胶质母细胞瘤、先天性肿瘤)、脊髓神经纤维瘤、脑膜瘤、神经胶质瘤、肉瘤)；妇科癌症，例如，子宫(子宫内膜癌)、宫颈(***、癌前宫颈发育不良)、卵巢(卵巢癌(浆液性囊腺癌、粘液性囊腺癌、未分类癌)、颗粒-鞘膜细胞瘤、Sertoli-Leydig细胞瘤、无性细胞瘤、恶性畸胎瘤)、外阴(鳞状细胞癌、上皮内癌、腺癌、纤维肉瘤、黑色素瘤)、***(透明细胞癌、鳞状细胞癌、葡萄状肉瘤(胚胎横纹肌肉瘤)、输卵管(癌)；血液癌症，例如，血液(髓系白血病(急性)和慢性)、急性淋巴细胞白血病、慢性淋巴细胞白血病、骨髓增生性疾病、多发性骨髓瘤、骨髓增生异常综合征)、霍奇金病、非霍奇金淋巴瘤(恶性淋巴瘤)；皮肤部位的癌症，例如，恶性黑色素瘤、基底细胞癌、鳞状细胞癌、卡波西肉瘤、痣发育不良痣、脂肪瘤、血管瘤、皮 肤纤维瘤、瘢痕疙瘩、牛皮癣；和肾上腺部位的癌症，例如，神经母细胞瘤；等等。
在一实施方案中，所述KRAS G12D相关癌症是肺癌。
在一实施方案中，所述KRAS G12D相关癌症选自下组：非小细胞肺癌、小细胞肺癌、结肠直肠癌、直肠癌或胰腺癌。
本发明另一方面提供了一种用于治疗有此需要的受试者的癌症的方法，所述方法包括：(a)确定所述癌症与KRAS G12D突变相关(例如，KRAS G12D相关癌症)；和
(b)向所述受试者施用治疗有效量的本发明第一方面所述的化合物或其药学上可接受的盐、立体异构体、溶剂化物或前药；或者向所述受试者施用治疗有效量的本发明第二方面所述的药物组合物。
在一实施方案中，所述施用通过选自肠胃外、腹腔内、皮内、心内、心室内、颅内、脑脊髓内、内腔内、滑膜内、鞘内、肌内注射、玻璃体内注射、静脉内注射、动脉内注射、口服、颊、舌下、经皮、局部、气管内、直肠、皮下和局部给药的路线来完成。
本发明另一方面提供了一种抑制细胞中KRAS G12D活性的方法，所述方法包括步骤：使所述细胞与本发明第一方面所述的化合物或其药学上可接受的盐、立体异构体、溶剂化物或前药接触；或者使所述细胞与本发明第二方面所述的药物组合物接触。
本发明另一方面提供了上述第一方面所述化合物或其药学上可接受的盐、立体异构体、溶剂化物或前药或如上述第二方面所述药物组合物在制备KRAS G12D抑制剂中的用途。
如本文所用，术语“受试者”是指动物，特别是哺乳动物。优选人。
如本文所用，术语“有效量”或“治疗有效量”是指无毒的但能达到预期效果的药物或药剂的足够用量。在本发明的实施方式中，在根据本发明对患者进行治疗时，给定药物的量取决于诸多因素，如具体的给药方案、疾病或病症类型及其严重性、需要治疗的受治疗者或宿主的独特性(例如体重)，但是，根据特定的周围情况，包括例如已采用的具体药物、给药途径、治疗的病症、以及治疗的受治疗者或宿主，施用剂量可由本领域已知的方法常规决定。通常，就成人治疗使用的剂量而言，施用剂量典型地在0.02-5000mg/天，例如约1-1500mg/天的范围。该所需剂量可以方便地被表现为一剂、或同时给药的(或在短时间内)或在适当的间隔的分剂量，例如每天二、三、四剂或更多分剂。本领域技术人员可以理解的是，尽管给出了上述剂量范围，但具体的有效量可根据患者的情况并结合医师诊断而适当调节。
如本文所用，术语“药学上可接受的盐”是指在制药上可接受的并且具有母体化合物药理学活性的本发明化合物的盐。这类盐包括：与无机酸或与有机酸形成的酸加成的盐，所述的无机酸诸如硝酸，磷酸，碳酸等；所述的有机酸诸如丙酸，己酸，环戊丙酸，乙醇酸，丙酮酸，葡糖酸，硬脂酸，粘康酸等；或在母体化合物上存在的酸性质子被金属离子，例如碱金属离子或碱土金属离子取代时形成的盐；或与有机碱形成的配位化合物，所述的有机碱诸如乙醇胺等。本发明的药学上可接受的盐可由含有酸根或碱基的母体化合物通过常规化学方法合成。一般情况下，这样的盐的制备方法是：在水或有机溶剂或两者的混合物中，经由游离酸或碱形式的这些化合物与化学计量的适当的碱或酸反应来制备。一般地，优选醚、乙酸乙酯、乙醇、异丙醇或乙腈等非水介质。除了盐的形式，本发明所提供的化合物还存在前药形式。本文所描述的化合物的前药容易地在生理条件下发生化学变化从而转化成本发明的化合物。此外，前体药物可以在体内环境中通过化学或生化方法被转换到本发明的化合物。
如本文所用，术语“溶剂化物”是指本发明化合物与制药上可接受的溶剂结合形成的物质。制药上可接受的溶剂包括乙酸等。溶剂化物包括化学计算量的溶剂化物和非化学计算量的溶剂化物。本发明的某些化合物可以以非溶剂化形式或者溶剂化形式存在。一般而言，溶剂化形式与非溶剂化的形式相当，都包含在本发明的范围之内。
如本文所用，术语“立体异构体”包括构象异构体和构型异构体，其中构型异构体主要包括顺反异构体和旋光异构体。本发明所述化合物可以以立体异构体的形式存在，并因此涵盖所有可能的立体异构体形式，包括但不限于顺反异构体、互变异构体、对映异构体、非对映异构体、阻转异构体等，本发明所述化合物也可以以前述的立体异构体的任何组合或任何混合物，例如内消旋体、外消旋体、阻转异构体的等量混合物等形式存在。例如单一对映异构体，单一非对映异构体或以上的混合物，或单一阻转异构体或其混合物。当本发明所述的化合物含有烯烃双键时，除非特别说明，否则其包括顺式异构体和反式异构体，以及其任何组合。本发明的阻转异构体为基于分子内旋转受限制而产生的轴向或平面手性的立体异构体。且作为药物，具有优异活性的立体异构体是优选的。本发明化合物具有源于不对称碳等的光学异构体，必要时单一异构体可通过本领域已知的方法，例如结晶或手性色谱等方法进行拆分获得。通过拆分获得的异构体化合物可以任意指定各个异构体的具体结构。
如本文所用，术语“C1-C6烷基”是指由1-6个碳原子组成的直链和支链脂肪族。优选C1-C4烷基或C1-C3烷基。烷基的例子包括但不限于甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、戊基和己基。
如本文所用，术语“C1-C6卤代烷基”是指C1-C6烷基中的一个或多个氢被卤素取代。其中烷基部分定义如上所述。优选C1-C3卤代烷基或C1-C4卤代烷基。卤代烷基的例子包括但不限于三氟甲基、二氟甲基和单氟甲基。
如本文所用，术语“C1-C6氘代烷基”是指C1-C6烷基中的一个或多个氢被氘原子取代。其中烷基部分定义如上所述。优选C1-C3氘代烷基或C1-C4氘代烷基。卤代烷基的例子包括但不限于三氟甲基、二氟甲基和单氟甲基。
如本文所用，术语“C1-C6烷氧基”是指-O-C1-C6烷基。优选C1-C3烷氧基或C1-C4烷氧基。其中烷基部分定义如上所述。
如本文所用，术语“C1-C6卤代烷氧基”是指-O-C1-C6卤代烷基。优选C1-C3卤代烷氧基或C1-C4卤代烷氧基。其中卤代烷基部分定义如上所述。
如本文所用，术语“C1-C6氘代烷氧基”是指-O-C1-C6氘代烷基。优选C1-C3氘代烷氧基或C1-C4氘代烷氧基。其中氘代烷基部分定义如上所述。
如本文所用，术语“C1-C6氰基烷基”是指-C1-C6烷基-氰基。优选C1-C3氰基烷基或C1-C4氰基烷基。其中烷基部分定义如上所述。
如本文所用，术语“C2-C6炔基”是指由2-6个碳原子组成的具有1个或2个碳碳三键的直链和支链脂肪族。优选C2-C4炔基或C2-C3炔基。炔基的例子包括但不限于乙炔基、丙炔基、丁炔基等。
如本文所用，术语“C2-C6烯基”是指由2-6个碳原子组成的具有1个或2个碳碳双键的直链和支链脂肪族。优选C2-C4烯基或C2-C3烯基。烯基的例子包括但不限于乙烯基、丙烯基、丁烯基等。
如本文所用，术语“C1-C6羟基烷基”是指-C1-C6烷基-羟基(OH)。优选C1-C3羟基烷基(即-C1-C3烷基-羟基)或C1-C4羟基烷基(即-C1-C4烷基-羟基)。其中烷基部分定义如上所述。
如本文所用，术语“C2-C6羟基炔基”是指-C2-C6炔基-OH。其中炔基定义同前。优选C2-C4羟基炔基或C2-C3羟基炔基。
如本文所用，术语“C2-C6羟基烯基”是指-C2-C6烯基-OH。其中烯基定义同前。优选C2-C4羟基烯基或C2-C3羟基烯基。
如本文所用，术语“C1-C4亚烷基”是指上述定义的C1-C4烷基，是位于分子的其它两个部分之间且用于连接它们。典型的亚烷基包括但不限于亚甲基、亚乙基、亚丙基和亚丁基。
如本文所用，术语“环烷基”和“环烷基环”可互换使用，指饱和单环或多环的环状烃基，例如包括单环环烷基、螺环烷基、稠环烷基和桥环烷基。本发明中所述环烷基的环碳原子可任选地被1、2或3个氧代基取代形成环酮结构。例如，术语“C3-C20环烷基”指具有3到20个环碳原子的环烷基，包括单环环烷基、螺环烷基、稠环烷基和桥环烷基。优选为C3-C12环烷基(更优选C3-C8单环环烷基)、C5-C20螺环烷基、C5-C20稠环烷基或C5-C20桥环烷基。
术语“C3-C8单环环烷基”指具有3到8个环碳原子的饱和单环环状烃基。优选为C3-C6单环环烷基或C4-C6单环环烷基。更优选为C3、C4、C5或C6单环环烷基。单环环烷基的具体实例包括但不限于环丙基、环丁基、环戊基、环己基、环庚基、环辛基等。
如本文所用，术语“螺环烷基”和“螺环烷基环”指两个或两个以上的单环之间共用一个碳原子(称螺原子)形成的多环环状烃基。根据环与环之间共用螺原子的数目将螺环烷基分为单螺环烷基、双螺环烷基和多螺环烷基。术语“C5-C20螺环烷基”指具有5到20个环碳原子的多环环状烃基，其中共用螺原子的单环为C3-C8单环环烷基环。优选为C6-C14螺环烷基。更优选为C6-C14单螺环烷基。更优选为C7-C11螺环烷基。更优选为7到11元单螺环烷基。最优选为C7(C4单环环烷基环/C4单环环烷基环)、C8(C4单环环烷基环/C5单环环烷基环)、C9(C4单环环烷基环/C6单环环烷基环，C5单环环烷基环/C5单环环烷基环)、C10(C5单环环烷基环/C6单环环烷基环)或C11(C6单环环烷基环/C6单环环烷基环)单螺环烷基。螺环烷基的具体实例包括但不限于：
Figure PCTCN2022081443-appb-000038
这些螺环烷基可通过任意一个环原子与分子其余部分连接。
如本文所用，术语“稠环烷基”和“稠环烷基环”指两个或两个以上的单环通过共享毗邻的一对碳原子形成的多环环状烃基。根据形成环的数目可以分为双环、三环、四环或多环稠环烷基。术语“C5-C20稠环烷基”指具有5到20个环碳原子的多环环状烃基，其中共享毗邻碳原子对的单环为C3-C8单环环烷基环。优选为C6-C14稠环烷基。更优选为C6-C14双稠环烷基。更优选为C7-C10稠环烷基。更优选为C7-C10双稠环烷基。最优选为C8(C5单环环烷基环与C5单环环烷基环稠合)、C9(C5单环环烷基环与C6单环环烷基环稠合)或C10(C6单环环烷基环与C6单环环烷基环稠合)双稠环烷基。稠环烷基的具体实例包括但不限于：
Figure PCTCN2022081443-appb-000039
这些稠环烷基可通过任意一个环原子与分子其余部分连接。
如本文所用，术语“桥环烷基”和“桥环烷基环”指两个或两个以上的单环之间通过共用两个不直接连接的碳原子形成的多环环状烃基。根据形成环的数目可以分为双环、三环、四环或多环桥环烷基。术语“C5-C20桥环烷基”指具有5到20个环碳原子的多环环状烃基，其中任意两个环共用两个不直接连接的碳原子。优选为C6-C14桥环烷基。更优选为C7-C10桥环烷基。桥环烷基的具体实例包括但不限于：
Figure PCTCN2022081443-appb-000040
这些桥环烷基可通过任意一个环原子与分子其余部分连接。
例如，本文中的环烷基的例子包括但不限于环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环庚基、环辛基、双环[1.1.1]戊基。
如本文所用，术语“环烷氧基”是指-O-环烷基，其中环烷基定义如前所述。
如本文所用，术语“杂环基”和“杂环基环”可互换使用，指饱和或部分不饱和单环或多环的环状烃基， 例如包括单环杂环基、螺杂环基、稠杂环基和桥杂环基。本发明中所述杂环基的环碳原子可任选地被1、2或3个氧代基取代形成环酮、环内酯或环内酰胺结构。例如，术语“3到20元杂环基”指具有3到20个环原子的饱和或部分不饱和单环或多环的环状烃基，其中一个或多个(优选为1、2、3或4个)环原子为选自氮、氧或S(＝O) m'(其中m'是整数0到2)的杂原子，但不包括-O-O-、-O-S-或-S-S-的环部分，其余环原子为碳。其中当环原子为氮原子时，其可以是被取代的或未取代的(即N或NR，R为氢或本文已经定义过的其他取代基)。本发明所述的3到20元杂环基包括单环杂环基(例如3到8元单环杂环基)、5到20元螺杂环基、5到20元稠杂环基和5到20元桥杂环基。
如本文所用，术语“3到20元含氮杂环基”指至少含有1个氮原子的具有3到20个环原子的饱和或部分不饱和单环环状烃基；其中该基团通过所述氮原子与分子其它部分连接；且该基团还任选地含有另外的1个或2个选自氮、氧或S(＝O) m'(其中m'是整数0至2)的杂原子作为环原子。本发明所述的3到20元含氮杂环基包括单环杂环基(例如3到8元单环含氮杂环基)、5到20元含氮螺杂环基、5到20元含氮稠杂环基和5到20元含氮桥杂环基。
如本文所用，术语“3到8元单环杂环基”和“3到8元单环杂环基环”指具有3到8个环原子，其中1、2或3个环原子为选自氮、氧或S(＝O) m'(其中m'是整数0至2)的杂原子的饱和或部分不饱和单环环状烃基。优选为具有3到6个环原子，其中1或2个环原子为杂原子的3到6元单环杂环基。更优选为具有4到6个环原子，其中1或2个环原子为杂原子的4到6元单环杂环基。更优选为具有5或6个环原子，其中1或2个环原子为杂原子的5或6元单环杂环基。当杂原子为氮原子时，氮原子可以是被取代的或未取代的(即N或NR，R为氢或本文已经定义过的其他取代基)。当杂原子为硫原子时，硫原子可以为任选地被氧化(即S(＝O) m'，m'是整数0到2)。所述单环杂环基的环碳原子可任选地被1、2或3个氧代基取代形成环酮、环内酯或环内酰胺结构。单环杂环基的具体实例包括但不限于氮丙环、环氧乙烷、氮杂环丁烷、氮杂环丁烷-2-酮、氧杂环丁烷、氧杂环丁烷-2-酮、噁唑烷、吡咯烷-2-酮、吡咯烷-2,5-二酮、1,3-二氧戊环、二氢呋喃-2(3H)-酮、二氢呋喃-2,5-二酮、哌啶-2-酮、哌啶-2,6-二酮、四氢-2H-吡喃-2-酮、咪唑烷、四氢呋喃、四氢噻吩、四氢吡咯、1,3-二氧戊环-2-酮、噁唑烷-2-酮、咪唑烷-2-酮、哌啶、哌嗪、哌嗪-2-酮、吗啉、吗啉-3-酮、吗啉-2-酮、硫代吗啉-3-酮1,1-二氧化物、硫代吗啉、硫代吗啉-1,1-二氧化物、四氢吡喃、1,2-二氢氮杂环丁二烯、1,2-二氢氧杂环丁二烯、2,5-二氢-1H-吡咯、2,5-二氢呋喃、2,3-二氢呋喃、2,3-二氢-1H-吡咯、3,4-二氢-2H-吡喃、1,2,3,4-四氢吡啶、3,6-二氢-2H-吡喃、1,2,3,6-四氢吡啶、1,3-噁嗪烷、六氢嘧啶、1,4-二噁烷、四氢嘧啶-2(1H)-酮、1,4-二噁烷-2-酮、5,6-二氢-2H-吡喃-2-酮、5,6-二氢嘧啶-4(3H)-酮、3,4-二氢吡啶-2(1H)-酮、5,6-二氢吡啶-2(1H)-酮、5,6-二氢嘧啶-4(1H)-酮、嘧啶-4(3H)-酮、嘧啶-4(1H)-酮、4,5-二氢-1H-咪唑、2,3-二氢-1H-咪唑、2,3-二氢噁唑、1,3-二氧杂环戊烯、2,3-二氢噻吩、2,5-二氢噻吩、3,4-二氢-2H-1,4-噁嗪、3,4-二氢-2H-1,4-噻嗪1,1-二氧化物、1,2,3,4-四氢吡嗪、1,3-二氢-2H-吡咯-2-酮、1,5-二氢-2H-吡咯-2-酮、1H-吡咯-2,5-二酮、呋喃-2(3H)-酮、呋喃-2(5H)-酮、1,3-二氧杂环戊烯-2-酮、噁唑-2(3H)-酮、1,3-二氢-2H-咪唑-2-酮、呋喃-2,5-二酮、3,6-二氢吡啶-2(1H)-酮、吡啶-2,6-(1H，3H)-二酮、5,6-二氢-2H-吡喃-2-酮、3,6-二氢-2H-吡喃-2-酮、3,4-二氢-2H-1,3-噁嗪、3,6-二氢-2H-1,3-噁嗪、1,2,3,4-四氢嘧啶等。
如本文所用，术语“3到6元含氮杂环基”指至少含有1个氮原子作为环原子的具有3到6个环原子的饱和或部分不饱和单环环状烃基；其中该基团可以通过所述氮原子与分子其它部分连接，也可以通过该基团的其它环原子与分子的其它部分连接；且该基团还任选地含有另外的1个或2个选自氮、氧或S(＝O) m'(其中m'是整数0至2)的杂原子作为环原子。具体实例可选自3到8元单环杂环基，包括但不限于四氢吡咯基、噁唑烷基、异噁唑烷基、哌啶基、哌嗪基、吗啉基、硫代吗啉、氮杂环丁基等类 似基团。
如本文所用，术语“螺杂环基”和“螺杂环基环”指两个或两个以上的饱和或部分不饱和单环之间共用一个碳原子(称螺原子)形成的多环杂环基，其中一个或多个(如1、2或3个)环原子为选自氮、氧或S(＝O) m'(其中m'是整数0到2)的杂原子，其余环原子为碳。当杂原子为氮原子时，氮原子可以是被取代的或未取代的(即N或NR，R为氢或本文已经定义过的其他取代基)。每个单环中可以含有一个或多个双键，但没有一个环具有完全共轭的π电子***。根据环与环之间共用螺原子的数目将螺杂环基分为单螺杂环基、双螺杂环基或多螺杂环基。术语“5到20元螺杂环基”指具有5到20个环原子的螺杂环基，其中共用螺原子的单环中一个单环为3到8元单环杂环基环，另一个单环为3到8元单环杂环基环或3到8元单环环烷基环。优选为具有6到14个环原子，其中1或2个环原子为杂原子的6到14元螺杂环基。更优选为具有7到11个环原子，其中1或2个环原子为杂原子的7到11元螺杂环基。最优选为7元(4元单环杂环基环/4元单环杂环基环或4元单环杂环基环/4元单环环烷基或4元单环环烷基环/4元单环杂环基环)、8元(4元单环杂环基环/5元单环杂环基环)、9元(4元单环杂环基环/6元单环杂环基环，5元单环杂环基环/5元单环杂环基环)、10元(5元单环杂环基环/6元单环杂环基环)或11元(6元单环杂环基环/6元单环杂环基环)单螺杂环基。螺杂环基的具体实例包括但不限于：
Figure PCTCN2022081443-appb-000041
这些螺杂环基可通过任意一个合适的环原子与分子其余部分连接。
如本文所用，术语“5到20元含氮螺杂环基”指至少含有1个氮原子的具有5到20个环原子的螺杂环基；其中该基团通过所述氮原子与分子其它部分连接；且该基团还任选地含有另外的1个或2个或3个选自氮、氧或S(＝O) m'(其中m'是整数0至2)的杂原子作为环原子。
如本文所用，术语“稠杂环基”和“稠杂环基环”指两个或两个以上的饱和或部分不饱和单环通过共享毗邻的一对环原子形成的多环杂环基，其中一个或多个(如1、2或3个)环原子为选自氮、氧或S(＝O) m'(其中m'是整数0到2)的杂原子，其余环原子为碳。当杂原子为氮原子时，氮原子可以是被取代的或未取代的(即N或NR，R为氢或本文已经定义过的其他取代基)。每个单环中可以含有一个或多个双键，但没有一个环具有完全共轭的π电子***。共享的毗邻环原子对可以是C-C或N-C。根据组成环的数目可以分为双环、三环、四环或多环稠杂环基。术语“5到20元稠杂环基”指具有5到20个环原子的稠杂环基，其中共享毗邻环原子对的单环为3到8元单环杂环基环。优选为具有6到14个环原子，其中1 或2个环原子为杂原子的6到14元稠杂环基。更优选为具有6到10个环原子，其中1或2个环原子为杂原子的6到10元稠杂环基。更优选为具有8到10个环原子，其中1或2个环原子为杂原子的8到10元稠杂环基。最优选为8元(5元单环杂环基环与5元单环杂环基环稠合)、9元(5元单环杂环基环与6元单环杂环基环稠合)或10元(6元单环杂环基环与6元单环杂环基环稠合)双环稠杂环基。稠杂环基的具体实例包括但不限于：
Figure PCTCN2022081443-appb-000042
这些稠杂环基可通过任意一个合适的环原子与分子其余部分连接。
如本文所用，术语“5到20元含氮稠杂环基”指至少含有1个氮原子的具有5到20个环原子的稠杂环基；其中该基团通过所述氮原子与分子其它部分连接；且该基团还任选地含有另外的1个或2个或3个选自氮、氧或S(＝O) m'(其中m'是整数0至2)的杂原子作为环原子。
如本文所用，术语“桥杂环基”和“桥杂环基环”指两个或两个以上的饱和或部分不饱和单环通过共用两个不直接连接的环原子形成的多环杂环基，其中一个或多个(如1、2或3个)环原子为选自氮、氧或S(＝O) m'(其中m'是整数0到2)的杂原子，其余环原子为碳。根据形成环的数目可以分为双环、三环、四环或多环桥环烷基。术语“5到20元桥杂环基”指具有5到20个环原子的饱和或部分不饱和多环杂环基团，其中任意两个环共用两个不直接连接的环原子，每个单环中可以含有一个或多个双键，但没有一个环具有完全共轭的π电子***。优选为6到14元桥杂环基。更优选为7到10元桥杂环基。桥杂环基的具体实例包括但不限于：
Figure PCTCN2022081443-appb-000043
这些桥杂环基可通过任意一个合适的环原子与分子其余部分连接。
如本文所用，术语“5到20元含氮桥杂环基”指至少含有1个氮原子的具有5到20个环原子的桥杂环基；其中该基团通过所述氮原子与分子其它部分连接；且该基团还任选地含有另外的1个或2个或3个选自氮、氧或S(＝O) m'(其中m'是整数0至2)的杂原子作为环原子。
在本发明中，上述各类杂环基可以是任选取代的，当被取代时，取代基优选为一个或多个本申请中所记载的取代基团。
具体地，本发明所述的杂环基具体例子包含但不限于，环氧基、氮杂环丁基、四氢呋喃基、四氢吡喃基、吡咯烷基、吡咯烷酮基、哌啶基、哌嗪基、咪唑基、咪唑并吡啶基、噻唑基、噁唑烷基、噁唑烷二酮基、十氢喹啉基、哌啶酮基、***啉基、氮杂双环己基、氮杂双环庚基、氮杂双环辛基、氮杂双环壬基、氮杂双环癸基、氮杂螺环庚基、氮杂螺环辛基、氮杂螺环壬基、氮杂螺环癸基、四氢螺环[环丙烷-1,2'-吡咯嗪]基、六氢-1H-吡咯嗪基、六氢-1H-吡咯并[2,1-c][1,4]噁嗪基、八氢吲哚嗪基、氧杂螺环庚基、氧杂螺环辛基、氧杂螺环壬基、氧杂螺环癸基、双氮杂螺环壬基、氧杂双环己基、氧杂双环庚基、氧杂双环辛基、六氢咯嗪基4(1H)-氧化物。
如本文所用，术语“芳基”指全碳单环、全碳非稠合多环(环与环通过共价键连接，非稠合)或全碳稠合多环(也就是共享毗邻碳原子对的环)基团，基团中至少一个环为芳香性的，即具有共轭的π电子体系。 例如，术语“C6-C14芳基”是指具有6到14个环原子的芳基。优选为C6-C10芳基。本发明中C6-C14芳基包括单环芳基、非稠合多环芳基和芳香稠合多环，其中单环芳基的实例包括苯基，非稠合多环芳基的实例包括联苯基等。
本发明中，当C6-C14芳基为芳香稠合多环时，所述的芳香稠合多环可以为单芳基环与一个或多个单芳基环稠合形成的多环基团，其非限制性实例包括萘基，蒽基等。
在本发明的一些实施方案中，当C6-C14芳基为芳香稠合多环时，所述的芳香稠合多环也可以为单芳基环(如苯基)与一个或多个非芳香环稠合形成的多环基团，其中与母体结构连接的环为芳香环或非芳香环。所述非芳香环包括但不限于3到6元单环杂环基环(优选为5或6元单环杂环基环，所述单环杂环基环的环碳原子可被1到2个氧代基取代，形成环内酰胺或环内酯结构)，3到6元单环环烷基环(优选为5或6元单环环烷基环，所述单环环烷基环的环碳原子可被1或2个氧代基取代，形成环酮结构)。上述单芳基环与一个或多个非芳香环稠合的多环基团可通过氮原子或碳原子与其他基团或母体结构连接，与母体结构连接的环为单芳基环或非芳香环。
在本发明中，上述各类芳基可以是取代的或非取代的，当被取代时，取代基优选为一个或多个本申请中所记载的取代基团。
如本文所用，术语“芳基”是指包含1到3个芳香环组成的C6-C14芳香基团。它可以任选地被一个或多个R 6或一个或多个R 7取代。在一实施例中，芳基为C6-C10芳基。芳基的例子包括但不限于苯基、萘基、蒽基、芴基和二氢苯并呋喃基。“芳基”还指双环或三环体系，其中，所述芳基中的一个环或两个环分别可能是饱和的或部分饱和的。如果所述芳基包含两个饱和环，则这两个饱和环可能是稠环体系或螺环体系。包含两个饱和环(且为螺环体系)的芳基的示例包括如下：
Figure PCTCN2022081443-appb-000044
如本文所用，术语“芳C1-C6烷基”或“芳烷基”是指包括一个芳基与一个烷基共价连接。其中，芳基的定义如前所述，烷基的定义如前所述，芳基或烷基中的任何一个或全部可以独立地被选择性取代或未取代。一个芳烷基的例子是(C6-C10)芳基(C1-C6)烷基-。具体包括但不限于苄基、苯乙基和萘甲基。一个取代的芳C1-C6烷基的例子是其中烷基被羟基烷基取代。
如本文所用，术语“杂芳基”指环原子被至少一个独立选自氮、氧或硫的杂原子取代的单环或稠合多环(即共享毗邻环原子对，共享的毗邻环原子对可以是C-C或N-C)基团，其中氮和硫原子可任选地被氧化，氮原子可任选地被季铵化。所述杂芳基具有共享的6、10或14个π电子，基团中至少一个环是芳族的。例如，术语“5到14元杂芳基”指具有5到14个环原子，其中1、2、3或4个环原子为选自氮、氧或S(＝O) m'(其中m'是整数0到2)的杂原子的杂芳基。优选为具有5到10个环原子，其中1、2、3或4个环原子为杂原子的5到10元杂芳基。本发明中5到14元杂芳基可以为单环杂芳基(例如，5或6元单环杂芳基)、稠合双环杂芳基(例如8到10元双环杂芳基)或稠合三环杂芳基。
如本文所用，术语“5或6元单环杂芳基”指具有5或6个环原子，其中1、2或3个环原子为选自氮、氧或S(＝O) m'(其中m'是整数0到2)的杂原子的单环杂芳基。单环杂芳基的具体实例包括但不限于噻吩、呋喃、噻唑、异噻唑、咪唑、噁唑、吡咯、吡唑、***、1,2,3-***、1,2,4-***、1,2,5-***、1,3,4-***、四唑、异噁唑、噁二唑、1,2,3-噁二唑、1,2,4-噁二唑、1,2,5-噁二唑、1,3,4-噁二唑、噻二唑、吡啶、哒嗪、嘧啶、吡嗪等。
如本文所用，术语“8到10元双环杂芳基”指具有8到10个环原子，其中1、2、3、4或5个环原子为选自氮、氧或S(＝O) m'(其中m'是整数0到2)的杂原子的稠合双环杂芳基。所述稠合双环杂芳基既可以是单芳基环(如苯基)与单环杂芳基环(优选为5或6元单环杂芳基环)稠合形成的双环基团(优选为9 或10元双环杂芳基环)，也可以是单环杂芳基环(优选为5或6元单环杂芳基环)与单环杂芳基环(优选为5或6元单环杂芳基环)稠合形成的双环基团。
上述单环杂芳基环上任意相连的2个环原子，包括C-C、N-C、N-N均可与本发明所定义的单环环烷基环、单环杂环基环、单芳基环、5或6元单环杂芳基环等环烷基、杂环基、芳基或杂芳基稠合形成稠合多环。与其他环形成稠合环的单环杂芳基环上相连的2个环原子优选地为C-C，非限制性地包括如下形式：
Figure PCTCN2022081443-appb-000045
Figure PCTCN2022081443-appb-000046
上述基团中通过
Figure PCTCN2022081443-appb-000047
标记的环原子与分子其他部分连接。
8到10元双环杂芳基的非限制性实例包括：苯并[d]异噁唑、1H-吲哚、异吲哚、1H-苯并[d]咪唑、苯并[d]异噻唑、1H-苯并[d][1,2,3]***、苯并[d]噁唑、苯并[d]噻唑、吲唑、苯并呋喃、苯并[b]噻吩、喹啉、异喹啉、喹唑啉、喹喔啉、噌啉、吡啶并[3,2-d]嘧啶、吡啶并[2,3-d]嘧啶、吡啶并[3,4-d]嘧啶、吡啶并[4,3-d]嘧啶、1,8-萘啶、1,7-萘啶、1,6-萘啶、1,5-萘啶、吡唑并[1,5-a]嘧啶、咪唑并[1,2-b]哒嗪等。
双环杂芳基具体实例包括但不限于：
Figure PCTCN2022081443-appb-000048
Figure PCTCN2022081443-appb-000049
这些基团可通过任意一个合适的环原子与分子其余部分连接。与母体结构连接的环可以为单环杂芳基环或苯环。
在本发明的一些实施方案中，所述的稠合双环杂芳基或稠合三环杂芳基可以是单环杂芳基环(优选为5或6元单环杂芳基环)与一个或多个非芳香环稠合形成的多环基团，其中与母体结构连接的环为单环杂芳基环或非芳香环。所述非芳香环包括但不限于3到6元单环杂环基环(优选为5或6元单环杂环基环，所述单环杂环基环的环碳原子可被1到2个氧代基取代，形成环内酰胺或环内酯结构)，3到6元单环环烷基环(优选为5或6元单环环烷基环，所述单环环烷基环的环碳原子可被1或2个氧代基取代，形成环酮结构)等。上述单环杂芳基环与一个或多个非芳香环稠合形成的多环基团可通过氮原子或碳原子与其他基团或母体结构连接，与母体结构连接的环为单环杂芳基环或非芳香环。
在本发明中，上述各类杂芳基可以是取代的或非取代的，当被取代时，取代基优选为一个或多个本申请中所记载的取代基团。
如本文所用，术语“乙酰基”指的是-C(O)CH 3。
具体实施方式
本发明的化合物可以通过本领域技术人员所熟知的多种合成方法来制备，包括下面列举的具体实施方式、其与其他化学合成方法的结合所形成的实施方式以及本领域技术上人员所熟知的等同替换方 式。优选的实施方式包括但不限于本发明的实施例。本文中的中间体或起始化合物的合成方法部分单独以制备例展示部分展示在某一个实施例中，其余实施例若采用相同的中间体或起始化合物不再重复描述该化合物的制备。
下面通过实施例对本发明进行详细描述，但并不意味着对本发明任何不利限制。本文已经详细地描述了本发明，其中也公开了其具体实施例方式，对本领域的技术人员而言，在不脱离本发明精神和范围的情况下针对本发明具体实施方式进行各种变化和改进将是显而易见的。实施例中未注明具体条件者，按照常规条件或制造商建议的条件进行。所用试剂或仪器未注明生产厂商者，均为可以通过市购获得的常规产品。
以下实施例中所采用的制备HPLC，若无特殊说明，可采用如下条件：
制备HPLC(甲酸法)：柱型：Waters XBridge C18,190*250mm,5um；流动相体系:A:20 0.1％甲酸；B:制备级乙腈；流速:15ml/min；B％＝20％-100％；柱温:室温。
制备HPLC(碳酸氢铵法)：柱型：Waters XBridge C18,190*250mm,5um；流动相体系:A:0.1％碳酸氢铵水溶液；B:制备级乙腈；流速:15ml/min；B％＝20％-100％；柱温:室温。
制备例1合成(1R,5S)-2-(羟甲基)--3,8-二氮杂双环[3.2.1]辛烷-8-羧酸叔丁酯(A1)
Figure PCTCN2022081443-appb-000050
步骤一：1L单口瓶中，加入(S)-5-氧代吡咯烷-2-羧酸甲酯(200g,1397mmol)，硫酸二甲酯(134mL)。待加入完毕，体系56℃反应18h，TLC监控反应完成。冷却至室温，滴加三乙胺(292mL)，搅拌30分钟。加入400mL水，乙酸乙酯(400mLX3)萃取。有机相用饱和食盐水洗涤(400mL)，无水硫酸钠干燥，过滤，滤液旋干得到(S)-5-甲氧基-3,4-二氢-2H-吡咯-2-羧酸甲酯(150g,收率:68.4％)，黄色油状化合物。ES-API:[M+1] +＝158.1。
步骤二：1L单口瓶中，加入(S)-5-甲氧基-3,4-二氢-2H-吡咯-2-羧酸甲酯(150g,954.3mmol)，硝基乙酸甲酯(123.8g,1040.2mmol)。加入完毕，体系在60℃下反应40小时，核磁监控反应完成。柱层析纯化(DCM/EA＝50/1)得到(S,Z)-5-(2-甲氧基-1-硝基-2-氧亚乙基)吡咯烷-2-羧酸甲酯(80.0g，收率:34.2％)，黄色固体。ES-API:[M+1] +＝245.1。
步骤三：1L单口瓶中，加入(S,Z)-5-(2-甲氧基-1-硝基-2-氧亚乙基)吡咯烷-2-羧酸甲酯(20.0g,81.9mmol)，钯碳(2.0g)，甲醇(600mL)。加入完毕，氢气置换三次。体系在60℃下反应5天，LC-MS监控反应完成。重复投料4批次。过滤，滤液浓缩得到(1R,5S)-4-氧代-3,8-二氮杂双环[3.2.1]辛烷-2-羧酸甲酯(A11，60g,粗品)。ES-API:[M+1] +＝185.1
步骤四：1L单口瓶中，加入化合物(1R,5S)-4-氧代-3,8-二氮杂双环[3.2.1]辛烷-2-羧酸甲酯(A1，60.0g,325mmol)，三乙胺(65.9g,651.5mmol)，二氯甲烷(600mL)。冷却至0℃,加入二碳酸二叔丁酯(106.6g,488.6mmol)。加入完毕，体系在室温下反应过夜，LC-MS监控反应完成。加水(1L)，二氯甲烷(1L)萃取。有机相旋干，粗品经柱层析纯化(二氯己烷/甲醇＝20:1)得到8-(叔丁基)2-甲基(1R,5S)-4-氧代-3,8-二氮杂双环[3.2.1]辛烷-2,8-二羧酸酯(A12，70.0g，收率:75.8％)，黄色固体。ES-API:[M-Boc+1] +＝285.1。
步骤五：500mL三口瓶中，加入化合物8-(叔丁基)2-甲基(1R,5S)-4-氧代-3,8-二氮杂双环[3.2.1]辛 烷-2,8-二羧酸酯(A12，20.0g,70.3mmol)，四氢呋喃(300mL)。冷却至0℃,分批加入四氢锂铝(5.87g,154.7mmol)(温度控制在5℃以下)。加入完毕。体系在室温下反应过夜，LC-MS监控反应完成。冷却至0℃，加水淬灭反应，搅拌1h，过滤，二氯甲烷/甲醇(10:1)冲洗滤饼。滤液浓缩得到粗品。粗品经反相制备得到(1R,5S)-2-(羟甲基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸叔丁酯(A1，5.8g,收率:32.2％)，黄色固体。ES-API:[M-Boc+1] +＝243.2。
制备例2合成异构体(A1-1)和异构体(A1-2)
Figure PCTCN2022081443-appb-000051
参考文献Tetrahedron Letters,45(2004)1481–1483拆分方法将中间体A11拆分得到(1R,2R,5S)-4-氧代-3,8-二氮杂双环[3.2.1]辛烷-2-羧酸甲酯(A11-2)和(1R,2S,5S)-4-氧代-3,8-二氮杂双环[3.2.1]辛烷-2-羧酸甲酯(A11-1)。分别以两个异构体A11-1和A11-2为原料，参考制备例1的步骤四和步骤五分别合成得到(1R,2R,5S)-2-(羟甲基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸叔丁酯(A1-2)和(1R,2S,5S)-2-(羟甲基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸叔丁酯(A1-1)。A1-2的 1H NMR(400MHz,DMSO-d6):δ＝4.57(t,J＝5.6Hz,1H),3.94(br s,2H),3.17(br t,J＝5.6Hz,2H),2.72(br d,J＝10.4Hz,2H),2.51-2.57(m,1H),2.02-2.17(m,1H),1.45-1.83(m,4H),1.40(s,9H).ES-API:[M+1] +＝243.2。A1-1的 1H NMR(400MHz,CDCl 3):δ4.28-4.02(m,2H),3.53(d,J＝7.2Hz,2H),3.06-3.03(m,1H),2.75-2.43(m,4H),2.07-1.96(m,2H),1.86-1.76(m,2H),1.46(s,9H).ES-API:[M+1] +＝243.2。
制备例3合成异构体(A2-1)和异构体(A2-2)
Figure PCTCN2022081443-appb-000052
步骤一：将(R)-5-氧代吡咯烷-2-羧酸甲酯(395.3g,2.762mmol)，溶于3500mL二氯甲烷，5℃分批加入三甲基氧鎓四氟硼酸(612.697g,4.142mol,1.5eq)，加毕25℃反应24hr。TLC监控反应完成。将反应液缓慢倒入5000mL饱和碳酸钠水溶液中，pH在8～9，分液，水相用1500mL二氯甲烷萃取，合并有机相，饱和食盐水洗涤，无水硫酸镁干燥，过滤旋干得到(R)-5-甲氧基-3,4-二氢-2H-吡咯-2-羧酸甲酯(406.7g,2.588mol,收率:93.702％)淡黄色油状液体。ES-API:[M+1] +＝158.1。
步骤二：将(R)-5-甲氧基-3,4-二氢-2H-吡咯-2-羧酸甲酯(406.7g,2.588mol)加入到硝基乙酸甲酯(308.133g,2.588mol,1eq)中。60℃反应48hr，核磁监控反应完成。柱层析(石油醚:乙酸乙酯＝4:1～2:1) 得到250.0g黄色油状液体粗品，打浆纯化，过滤烘干得到(R)-5-(2-甲氧基-1-硝基-2-氧亚乙基)吡咯烷-2-羧酸甲酯(146.2g,598.687mmol,收率:23.136％)淡黄色固体。ES-API:[M+1] +＝245.1。
步骤三：5L高压釜中，将(R)-5-(2-甲氧基-1-硝基-2-氧亚乙基)吡咯烷-2-羧酸甲酯(146.2g,598.687mmol)溶于甲醇(1500mL)和四氢呋喃(1500mL)，加入Pd(OH) 2/C(15.00g,20％纯度)，氢气置换3次，0.4MPa,40℃反应72hr。反应过程中多次补充氢气。降至室温出釜。反应液过滤旋干得到(1S,5R)-4-氧代-3,8-二氮杂双环[3.2.1]辛烷-2-羧酸甲酯(A21，110.3g,粗品)黄色油状液体。ES-API:[M+1] +＝185.1。
步骤四：将粗品(1S,5R)-4-氧代-3,8-二氮杂双环[3.2.1]辛烷-2-羧酸甲酯(A21,10.00g,54.291mmol)溶水(50mL)和四氢呋喃(50mL)，加入Na 2CO 3(5.754g,54.291mmol)，10℃滴加(Boc) 2O(11.849g,54.291mmol)，滴毕，20℃反应12hr。TLC监测反应完全。反应液过滤，滤饼用50mL乙酸乙酯洗涤，分液，水相用50mL乙酸乙酯萃取，合并有机相，旋干柱层析(石油醚:乙酸乙酯＝2:1～1:1)得到8-(叔丁基)2-甲基(1S,5R)-4-氧代-3,8-二氮杂双环[3.2.1]辛烷-2,8-二羧酸酯(A22,3.61g,12.698mmol,收率：23.388％)白色固体。ES-API:[M-Boc+1] +＝285.1。
步骤五：将8-(叔丁基)2-甲基(1S,5R)-4-氧代-3,8-二氮杂双环[3.2.1]辛烷-2,8-二羧酸酯(A22，2.00g,7.035mmol)溶于四氢呋喃(20mL)，0℃分批加入四氢锂铝(400.489mg,10.552mmol,1.5eq)，加毕，20℃反应12hr。TLC监测反应完全。0℃，依次往反应液中滴加0.4mL水，0.4mL 15％的氢氧化钠溶液和1.2mL水，加毕，加入无水硫酸镁搅拌10min，过滤浓缩得到粗品。粗品经反相制备得到(1S,5R)-2-(羟甲基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸叔丁酯(A2，0.65g,收率:38％)，淡黄色固体。ES-API:[M-Boc+1] +＝243.2。
步骤六：将(1S,5R)-2-(羟甲基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸叔丁酯(A2，100mg)通过手性拆分[柱型:CHIRALPAK-AY,4.6*250mm,5um,流动相:己烷:EtOH(0.1％二乙胺)＝95:5(v/v),流速:1mL/min,柱温＝37℃，检测波长210nm]得到(1S,2S,5R)-2-(羟甲基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸叔丁酯(A2-1，58mg，峰2，保留时间10.391min)和(1S,2R,5R)-2-(羟甲基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸叔丁酯(A2-2，12mg，峰1，保留时间9.374min)。A2-1的 1H NMR(400MHz,DMSO-d6):δ4.57(br t,J＝5.2Hz,1H),3.94(br s,2H),3.18(br t,J＝5.2Hz,2H),2.73(br d,J＝10.4Hz,2H),2.52-2.59(m,1H),1.47-1.84(m,4H),1.40ppm(s,9H).ES-API:[M+1] +＝243.2。A2-2的 1H NMR(400MHz,CDCl 3):δ4.28-4.00(m,2H),3.54(d,J＝7.6Hz,2H),3.06-3.03(m,1H),2.76-2.43(m,4H),2.08-1.96(m,2H),1.87-1.77(m,2H),1.46(s,9H).ES-API:[M+1] +＝243.2。
实施例1 合成5-乙基-4-((6R,9S)-12-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-5a,6,7,8,9,10-六氢-5H-4-氧杂-3,10a,11,13,14-五氮杂-6,9-亚甲基萘并[1,8-ab]庚烯-2-基)萘-2-醇(Z1)
Figure PCTCN2022081443-appb-000053
步骤一：向三异丙基((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)硅烷(500mg,1.012mmol)的N,N-二甲基甲酰胺(5.0mL)溶液中加入氟化铯(3.0g,20.24mmol)，室温反应2小时。反应完毕后，乙酸乙酯萃取(100mLX2)，乙酸乙酯相合并用饱和食盐水洗(100mLX3)，无水硫酸钠干燥，过滤，旋干后得到2-(8-乙炔基-3-(甲氧基甲氧基)萘-1-基)-4,4,5,5-四甲基-1,3,2-二氧杂硼烷(558mg,粗品)。ES-API:[M+H] +＝339.3。
步骤二：向2-(8-乙炔基-3-(甲氧基甲氧基)萘-1-基)-4,4,5,5-四甲基-1,3,2-二氧杂硼烷(558mg,粗品)的甲醇(10.0mL)溶液中加入质量分数为10％的钯碳(60mg)，氢气置换4次，在氢气保护下室温反应2小时。反应完毕，过滤，减压旋干溶剂得到2-(8-乙基-3-(甲氧基甲氧基)萘-1-基)-4,4,5,5-四甲基-1,3,2-二氧杂硼烷(284mg,2步总收率:82％)。ES-API:[M+1] +＝343.3。
步骤三：在0℃条件下，将2,4,6-三氯烟酸(5.0g,22.22mmol)溶于二氯甲烷(40.0mL)中，将草酰氯(6.0mL)滴加入上述体系中，加入8滴N,N-二甲基甲酰胺，反应体系在室温下搅拌反应1小时。1小时 后，减压旋干溶剂，加入干燥四氢呋喃(30.0mL)溶液，冷却到0～5℃，将该溶液滴加到氨水(30.0mL)和四氢呋喃(30.0mL)的混合溶液中，室温下搅拌1小时。乙酸乙酯萃取(100mLX2)，乙酸乙酯相合并后用饱和食盐水洗(100mLX1)，无水硫酸钠干燥，过滤，旋干后得到2,4,6-三氯烟酰胺(6.0g,粗品)。ES-API:[M+H] +＝224.9/226.9。
步骤四：在500mL三口圆底烧瓶中，将(2,4-二甲氧基苯基)甲胺(4.45g,26.66mmol)溶解到干燥的二氧六环(90.0mL)中。冰水浴冷却到0～5℃，氮气保护下加入N,N-二异丙基乙胺(8.61g,66.66mmol)，该温度下反应约10～15分钟，将2,4,6-三氯烟酰胺(6.0g,粗品)溶解到干燥二氧六环(20mL)中滴加入上述溶液中。50℃下继续反应5小时。LCMS监测反应完毕，将反应液倒入冰水(400mL)中，乙酸乙酯萃取(200mLX1)，无水硫酸钠干燥，过滤，旋干，粗品经柱层析[石油醚:乙酸乙酯＝100:0～50:50,(v/v)]纯化得到2,6-二氯-4-((2,4-二甲氧基苄基)氨基)烟酰胺(4.16g,2步总收率:52％)。ES-API:[M+H] +＝356.1/358.1。
步骤五：室温条件下向500mL三口圆底烧瓶中加入2,6-二氯-4-((2,4-二甲氧基苄基)氨基)烟酰胺(3.723g,10.47mmol)和干燥四氢呋喃(60mL)，冰水浴下冷却到0～5℃，分批加入氢化钠(838mg,20.95mmol)，在该温度下反应20分钟。将N,N'-羰基二咪唑(5.09g,31.41mmol)加入到干燥四氢呋喃(30mL)中，滴加到上述溶液中，加毕，在该温度下反应0.5～1小时。LCMS监测反应完毕，反应液倾倒入冰水(300mL)中，冰水浴条件下用6M盐酸水溶液调pH至7～8，过滤得到5,7-二氯-1-(2,4-二甲氧基苄基)吡啶并[4,3-d]嘧啶-2,4(1H,3H)-二酮(3.7g,收率:92.7％)。ES-API:[M+H] +＝382.0/384.0。
步骤六：室温下向250mL单口烧瓶中加入干燥四氢呋喃(100mL)，再加入(1R,5S)-2-(羟甲基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸叔丁酯(A1，358.0mg,1.480mmol)，冰水浴冷却到0～5℃，加入氢化钠(1.20mg，2.960mmol)。氮气保护下反应10～20分钟，分批加入5,7-二氯-1-(2,4-二甲氧基苄基)吡啶并[4,3-d]嘧啶-2,4(1H,3H)-二酮(565.0mg,1.480mmol)，0～5℃条件下继续反应20～30分钟。LCMS监测反应完毕，反应液倒入冰水(300mL)中，用6M盐酸水溶液调pH至7～8，乙酸乙酯萃取(100mLX2)，乙酸乙酯相合并后用饱和食盐水洗(100mLX1)，无水硫酸钠干燥，过滤，旋干得到(1R,5S)-2-(((7-氯-1-(2,4-二甲氧基苄基)-2,4-二氧杂-1,2,3,4-四氢吡啶并[4,3-d]嘧啶-5-基)氧基)甲基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸叔丁酯(850mg,收率:97％)。ES-API:[M+H] +＝588.3。
步骤七：室温下向250mL单口烧瓶中加入干燥N,N-二甲基甲酰胺(20mL)和(1R,5S)-2-(((7-氯-1-(2,4-二甲氧基苄基)-2,4-二氧杂-1,2,3,4-四氢吡啶并[4,3-d]嘧啶-5-基)氧基)甲基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸叔丁酯(850mg,1.448mmol)。加入1-丙基磷酸酐(5.0g,7.856mmol)，室温反应5分钟，滴加入1,8-二氮杂二环[5.4.0]十一碳-7-烯(1.14g,7.488mmol)。室温反应1～2小时。反应完毕，向100mL冰水中缓慢滴加上述溶液，析出大量固体，过滤，减压旋干得到目标化合物(6R,9S)-2-氯-13-(3,4-二甲氧基苄基)-12-氧-5a,6,7,8,9,10,12,13-八氢-5H-4-氧杂-3,10a,11,13,14-五氮杂-6,9-亚甲基萘并[1,8-ab]庚烯-14-羧酸叔丁酯(620mg,收率:75.2％)。ES-API:[M+H] +＝570.3。
步骤八：向三氟乙酸(5mL)中加入(6R,9S)-2-氯-13-(3,4-二甲氧基苄基)-12-氧-5a,6,7,8,9,10,12,13-八氢-5H-4-氧杂-3,10a,11,13,14-五氮杂-6,9-亚甲基萘并[1,8-ab]庚烯-14-羧酸叔丁酯(420mg,0.7380mmol)，55℃下搅拌1小时。反应完毕，减压旋干溶剂，得到(6R,9S)-2-氯-5a,6,7,8,9,10-六氢-5H-4-氧杂-3,10a,11,13,14-五氮杂-6,9-甲氧萘并[1,8-ab]庚烯-12(13H)-酮(500mg,粗品)。ES-API:[M+H] +＝320.1。
步骤九：向(6R,9S)-2-氯-5a,6,7,8,9,10-六氢-5H-4-氧杂-3,10a,11,13,14-五氮杂-6,9-亚甲基萘并[1,8-ab]庚烯-12(13H)-酮(350mg,1.094mmol)的四氢呋喃(5.0mL)和水(5.0mL)的混合溶液中加入碳酸钠(350mg,3.282mmol)，冰水浴冷却，加入苯甲氧羰酰琥珀酰亚胺(354mg,1.422mmol)，室温下反应3小时。反应 完毕，向反应液中加入二氯甲烷(80mL)，饱和碳酸氢钠水溶液(100mL)和饱和食盐水(80mL)洗涤，无水硫酸钠干燥，浓缩，粗品用快速硅胶柱(乙酸乙酯/石油醚：0-50％)纯化得到(6R,9S)-2-氯-12-氧杂-5a,6,7,8,9,10,12,13-八氢-5H-4-氧杂-3,10a,11,13,14-五氮杂-6,9-亚甲基萘并[1,8-ab]庚烯-14-羧酸苄酯(460mg,收率93％)。ES-API:[M+H] +＝454.1。
步骤十：在0℃下，向(6R,9S)-2-氯-12-氧杂-5a,6,7,8,9,10,12,13-八氢-5H-4-氧杂-3,10a,11,13,14-五氮杂-6,9-亚甲基萘并[1,8-ab]庚烯-14-羧酸苄酯(460mg,1.013mmol)的甲苯(3.0mL)溶液中依次加入三氯氧磷(465mg,3.039mmol)和N,N-二异丙基乙胺(392.0mg,3.039mmol)，125℃下反应12小时。反应完毕，冷却到室温，减压旋干溶剂得到(6R,9S)-2,12-二氯-5a,6,7,8,9,10-六氢-5H-4-氧杂-3,10a,11,13,14-五氮杂-6,9-亚甲基萘并[1,8-ab]庚烯-14-羧酸苄酯(520mg,粗品)。ES-API:[M+H] +＝472.2。
步骤十一：向(6R,9S)-2,12-二氯-5a,6,7,8,9,10-六氢-5H-4-氧杂-3,10a,11,13,14-五氮杂-6,9-亚甲基萘并[1,8-ab]庚烯-14-羧酸苄酯(200mg,0.4246mmol)的N,N-二甲基甲酰胺(3.0mL)溶液中加入氟化钾(500mg,8.492mmol)，氮气保护下120℃反应4小时。反应完毕后，冷却到室温，乙酸乙酯萃取(50mLX2)，乙酸乙酯相合并后用饱和食盐水洗(50mLX4)，无水硫酸钠干燥，过滤，旋干后得到(6R,9S)-2-氯-12-氟-5a,6,7,8,9,10-六氢-5H-4-氧杂-3,10a,11,13,14-五氮杂-6,9-亚甲基萘并[1,8-ab]庚烯-14-羧酸苄酯(130mg,收率:67.4％)。ES-API:[M+H] +＝456.1。
步骤十二：将(6R,9S)-2-氯-12-氟-5a,6,7,8,9,10-六氢-5H-4-氧杂-3,10a,11,13,14-五氮杂-6,9-亚甲基萘并[1,8-ab]庚烯-14-羧酸苄酯(140mg,0.3076mmol)溶于四氢呋喃/水(2mL/0.5mL)中，加入2-(8-乙基-3-(甲氧基甲氧基)萘-1-基)-4,4,5,5-四甲基-1,3,2-二氧杂硼烷(250mg,0.7309mmol)，磷酸钾(250mg,1.179mmol)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)(40.0mg,0.05494mmol)，氮气置换4次，微波80℃反应1小时。反应液冷却至室温，乙酸乙酯(80mL)和水(60mL)萃取，有机相用无水硫酸钠干燥，过滤，滤液减压旋干，粗品用快速硅胶柱(乙酸乙酯/石油醚：0-70％)纯化得到产物(6R,9S)-2-(8-乙基-3-(甲氧基甲氧基)萘-1-基)-12-氟-5a,6,7,8,9,10-六氢-5H-4-氧杂-3,10a,11,13,14-五氮杂-6,9-亚甲基萘并[1,8-ab]庚烯-14-羧酸苄酯(144mg,收率:73％)。ES-API:[M/2+1] +＝636.3。
步骤十三：冰水浴条件下，向((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲醇(43.0mg,0.2714mmol)的四氢呋喃(5.0mL)溶液中加入氢化钠(22mg,0.5428mmol)，室温反应0.5小时。将(6R,9S)-2-(8-乙基-3-(甲氧基甲氧基)萘-1-基)-12-氟-5a,6,7,8,9,10-六氢-5H-4-氧杂-3,10a,11,13,14-五氮杂-6,9-亚甲基并[1,8-ab]庚烯-14-羧酸苄酯(145mg,0.1357mmol)加入到上述反应体系中，室温反应1～2小时。反应完毕，向体系中加入冰水(50mL)，二氯甲烷萃取(50mLX2)，合并二氯甲烷相，无水硫酸钠干燥，过滤，滤液减压旋干，粗品用快速硅胶柱(甲醇/二氯甲烷：0-10％)纯化得到(6R,9S)-2-(8-乙基-3-(甲氧基甲氧基)萘-1-基)-12-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-5a,6,7,8,9,10-六氢-5H-4-氧杂-3,10a,11,13,14-五氮杂-6,9-亚甲基萘并[1,8-ab]庚烯-14-羧酸苄酯(170mg,粗品)。ES-API:[M/2+1] +＝775.3。
步骤十四：向(6R,9S)-2-(8-乙基-3-(甲氧基甲氧基)萘-1-基)-12-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-5a,6,7,8,9,10-六氢-5H-4-氧杂-3,10a,11,13,14-五氮杂-6,9-亚甲基萘并[1,8-ab]庚烯-14-羧酸苄酯(170mg,粗品)的甲醇(10.0mL)溶液中加入质量分数为10％的钯碳(500mg)，氢气置换4次，氢气氛下室温反应2小时得到(6R,9S)-2-(8-乙基-3-(甲氧基甲氧基)萘-1-基)-12-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-5a,6,7,8,9,10-六氢-5H-4-氧杂-3,10a,11,13,14-五氮杂-6,9-亚甲基萘并[1,8-ab]庚烯(162mg,粗品)。ES-API:[M/2+1] +＝7641.3。
步骤十五：将(6R,9S)-2-(8-乙基-3-(甲氧基甲氧基)萘-1-基)-12-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-5a,6,7,8,9,10-六氢-5H-4-氧杂-3,10a,11,13,14-五氮杂-6,9-亚甲基萘并[1,8-ab]庚烯 (162mg,粗品)溶于乙腈(6.0mL)中，冰浴下加入4M盐酸/二氧六环溶液(2.0mL,8.0mmol)，冰浴下反应0.5小时。反应完毕后，减压旋干溶剂，加入二氯甲烷(20mL)，冰水浴条件下加入三乙胺(3.0mL)。搅拌10分钟，二氯甲烷(100mLX1)和水(50mLX1)萃取。有机相用无水硫酸钠干燥，过滤，滤液减压旋干，粗品用制备HPLC(甲酸法)得到5-乙基-4-((6R,9S)-12-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-5a,6,7,8,9,10-六氢-5H-4-氧杂-3,10a,11,13,14-五氮杂-6,9-亚甲基萘并[1,8-ab]庚烯-2-基)萘-2-醇(5-ethyl-4-((6R,9S)-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexah ydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalen-2-yl)naphthalen-2-ol)(Z1,甲酸盐,4.69mg,3步总收率:5％)。ES-API:[M+1] +＝597.3。 1H NMR(500MHz,CD 3OD)δ8.48(s,1H),7.58(d,J＝8.0Hz,1H),7.34(t,J＝8.0Hz,1H),7.25-6.91(m,4H),5.50-5.31(m,1H),5.11-4.97(m,1H),4.70-4.30(m,4H),4.20-4.10(m,1H),3.85-3.73(m,2H),3.65-3.40(m,3H),3.29-3.14(m,2H),2.56-1.75(m,12H),1.00-0.85(m,3H).
实施例2 合成5-乙基-4-((5aS,6S,9R)-12-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-5a,6,7,8,9,10-六氢-5H-4-氧杂-3,10a,11,13,14-五氮杂-6,9-亚甲基萘并[1,8-ab]庚烯-2-基)萘-2-醇(Z2)
Figure PCTCN2022081443-appb-000054
步骤一：室温下向250mL单口烧瓶中加入干燥四氢呋喃(100mL)，再加入(1S,2S,5R)-2-(羟甲基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸叔丁酯(A2-1，358.0mg,1.480mmol)，冰水浴冷却到0～5℃后加入氢化钠(1,20mg,2.960mmol)。氮气保护下反应10～20分钟后分批次加入5,7-二氯-1-(2,4-二甲氧基苄基)吡啶并[4,3-d]嘧啶-2,4(1H,3H)-二酮(565.0mg,1.480mmol)，0～5℃条件下再反应20～30分钟。LC-MS监测反应完毕，将反应液倾倒入冰水(300mL)中，冰水浴条件下用6M的盐酸水溶液调pH 7～8，乙酸乙酯萃取(100mLX2)，乙酸乙酯相合并后用饱和食盐水洗(100mLX1)。无水硫酸钠干燥，过滤，旋干得到叔丁 基(1S,2S,5R)-2-(((7-氯-1-(2,4-二甲氧基苄基)-2,4-二氧杂-1,2,3,4-四氢吡啶并[4,3-d]嘧啶-5-基)氧基)甲基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(850mg,收率:97％)。ES-API:[M+H] +＝588.3。
步骤二：室温下向250mL单口烧瓶中加入干燥N,N-二甲基甲酰胺(20mL)和叔丁基(1S,2S,5R)-2-(((7-氯-1-(2,4-二甲氧基苄基)-2,4-二氧杂-1,2,3,4-四氢吡啶并[4,3-d]嘧啶-5-基)氧基)甲基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(850mg,1.448mmol)。最后加入1-丙基磷酸酐(5.0g,7.856mmol)，室温反应5分钟后再滴加入1,8-二偶氮杂双螺环[5.4.0]十一-7-烯(1.14g,7.488mmol)。室温反应1～2小时。反应完毕后，向冰水中(100mL)缓慢滴加上述溶液，析出大量固体，过滤，滤饼减压旋干得到叔丁基(5aS,6S,9R)-2-氯-13-(3,4-二甲氧基苄基)-12-氧-5a,6,7,8,9,10,12,13-八氢-5H-4-氧杂-3,10a,11,13,14-五氮杂-6,9-亚甲基萘并[1,8-ab]庚烯-14-羧酸酯(620mg,收率:73％)。ES-API:[M+H] +＝570.3。
步骤三：向三氟乙酸(5.0mL)中加入叔丁基(5aS,6S,9R)-2-氯-13-(2,4-二甲氧基苄基)-12-氧-5a,6,7,8,9,10,12,13-八氢-5H-4-氧杂-3,10a,11,13,14-五氮杂-6,9-亚甲基萘并[1,8-ab]庚烯-14-羧酸酯(420mg,0.7380mmol)，55℃下搅拌1小时。反应完毕，减压旋干溶剂，得到(5aS,6S,9R)-2-氯-5a,6,7,8,9,10-六氢-5H-4-氧杂-3,10a,11,13,14-五氮杂-6,9-亚甲基萘并[1,8-ab]庚烯-12(13H)-酮(500mg,粗品)。ES-API:[M+H] +＝320.1。
步骤四：向(5aS,6S,9R)-2-氯-5a,6,7,8,9,10-六氢-5H-4-氧杂-3,10a,11,13,14-五氮杂-6,9-亚甲基萘并[1,8-ab]庚烯-12(13H)-酮(350mg,1.094mmol)的四氢呋喃(5.0mL)和水(5.0mL)的混合溶液中加入碳酸钠(350mg,3.282mmol)，体系用冰水浴冷却，加入苯甲氧羰酰琥珀酰亚胺(354mg,1.422mmol)，在室温下反应3小时。反应完毕，向反应液中加入二氯甲烷(80mL)，用饱和碳酸氢钠水溶液(100mL)，饱和食盐水(80mL)洗涤，无水硫酸钠干燥，浓缩，粗品用快速硅胶柱纯化(乙酸乙酯/石油醚：0-50％)得到(5aS,6S,9R)-2-氯-12-氧杂-5a,6,7,8,9,10,12,13-八氢-5H-4-氧杂-3,10a,11,13,14-五氮杂-6,9-亚甲基萘并[1,8-ab]庚烯-14-羧酸苄酯(460mg,收率:93％)。ES-API:[M+H] +＝454.1。
步骤五：在0℃下，向(5aS,6S,9R)-2-氯-12-氧杂-5a,6,7,8,9,10,12,13-八氢-5H-4-氧杂-3,10a,11,13,14-五氮杂-6,9-亚甲基萘并[1,8-ab]庚烯-14-羧酸苄酯(460mg,1.013mmol)的甲苯(3.0mL)溶液中依次加入三氯氧磷(465mg,3.039mmol)和N,N-二异丙基乙胺(392.0mg,3.039mmol)，125℃下反应12小时。反应完毕，冷却到室温，减压旋干溶剂得到(5aS,6S,9R)-2,12-二氯-5a,6,7,8,9,10-六氢-5H-4-氧杂-3,10a,11,13,14-五氮杂-6,9-亚甲基萘并[1,8-ab]庚烯-14-羧酸苄酯(520mg,粗品)。ES-API:[M+H] +＝472.2。
步骤六：向(5aS,6S,9R)-2,12-二氯-5a,6,7,8,9,10-六氢-5H-4-氧杂-3,10a,11,13,14-五氮杂-6,9-亚甲基萘并[1,8-ab]庚烯-14-羧酸苄酯(200mg,0.4246mmol)的N,N-二甲基甲酰胺(3.0mL)溶液中加入氟化钾(500mg,8.492mmol)，氮气保护下120℃反应4小时。反应完毕后，冷却到室温，用乙酸乙酯萃取(50mLX2)，乙酸乙酯相合并后用饱和食盐水洗(50mLX4)。乙酸乙酯相用无水硫酸钠干燥,过滤,旋干后得到(5aS,6S,9R)-2-氯-12-氟-5a,6,7,8,9,10-六氢-5H-4-氧杂-3,10a,11,13,14-五氮杂-6,9-亚甲基萘并[1,8-ab]庚烯-14-羧酸苄酯(130mg,收率:62％)。ES-API:[M+H] +＝456.1
步骤七：将(5aS,6S,9R)-2-氯-12-氟-5a,6,7,8,9,10-六氢-5H-4-氧杂-3,10a,11,13,14-五氮杂-6,9-亚甲基萘并[1,8-ab]庚烯-14-羧酸苄酯(140mg,0.3076mmol)溶于四氢呋喃/水(2mL/0.5mL)中，加入2-(8-乙基-3-(甲氧基甲氧基)萘-1-基)-4,4,5,5-四甲基-1,3,2-二氧硼烷(250mg,0.7309mmol)，磷酸钾(250mg,1.179mmol)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)(40.0mg,0.05494mmol)，置换氮气4次后微波80℃反应1小时。反应液冷却到室温，用乙酸乙酯(80mL)和水(60mL)萃取,有机相用无水硫酸钠干燥、过滤，滤液减压旋干，粗品用快速硅胶柱(乙酸乙酯/石油醚：0-70％)纯化得到 (5aS,6S,9R)-2-(8-乙基-3-(甲氧基甲氧基)萘-1-基)-12-氟-5a,6,7,8,9,10-六氢-5H-4-氧杂-3,10a,11,13,14-五氮杂-6,9-亚甲基萘并[1,8-ab]庚烯-14-羧酸苄酯(144mg,收率:73％)。ES-API:[M/2+1] +＝636.3。
步骤八：冰水浴条件下，向((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲醇(43.0mg，0.2714mmol)的四氢呋喃(5.0mL)溶液中加入氢化钠(22mg,0.5428mmol)，室温反应0.5小时。0.5小时后，将(5aS,6S,9R)-2-(8-乙基-3-(甲氧基甲氧基)萘-1-基)-12-氟-5a,6,7,8,9,10-六氢-5H-4-氧杂-3,10a,11,13,14-五氮杂-6,9-亚甲基萘并[1,8-ab]庚烯-14-羧酸苄酯(145mg,0.1357mmol)加入到上述反应体系中，室温反应1～2小时。反应完毕，向体系中加入冰水(50mL)，用二氯甲烷萃取(50mLX2)，合并二氯甲烷相，无水硫酸钠干燥，过滤，滤液减压旋干后用快速硅胶柱(甲醇/二氯甲烷：0-10％)纯化得到(5aS,6S,9R)-2-(8-乙基-3-(甲氧基甲氧基)萘-1-基)-12-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-5a，6,7,8,9,10-六氢-5H-4-氧杂-3,10a,11,13,14-五氮杂-6,9-亚甲基萘并[1,8-ab]庚烯-14-羧酸苄酯(170mg,粗品)。ES-API:[M/2+1] +＝775.3。
步骤九：向(5aS,6S,9R)-2-(8-乙基-3-(甲氧基甲氧基)萘-1-基)-12-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-5a,6,7,8,9,10-六氢-5H-4-氧杂-3,10a,11,13,14-五氮杂-6,9-亚甲基萘并[1,8-ab]庚烯-14-羧酸苄酯(170mg,粗品)的甲醇(10.0mL)溶液中加入质量分数为10％的钯碳(500mg)，置换氢气4次，氢气氛下室温反应2小时，得到(5aS,6S,9R)-2-(8-乙基-3-(甲氧基甲氧基)萘-1-基)-12-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-5a,6,7,8,9,10-六氢-5H-4-氧杂-3,10a,11,13,14-五氮杂-6,9-亚甲基萘并[1,8-ab]庚烯(162mg,粗品)。ES-API:[M/2+1] +＝7641.3。
步骤十：将(5aS,6S,9R)-2-(8-乙基-3-(甲氧基甲氧基)萘-1-基)-12-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-5a,6,7,8,9,10-六氢-5H-4-氧杂-3,10a,11,13,14-五氮杂-6,9-亚甲基萘并[1,8-ab]庚烯(162mg,粗品)溶于乙腈(6.0mL)中，冰浴下加入4M盐酸/二氧六环溶液(2.0mL,8.0mmol)，冰浴下反应0.5小时。反应完毕后，减压旋干溶剂后加入二氯甲烷(20mL)，冰水浴条件下加入三乙胺(3.0mL)。搅拌10分钟后，加入二氯甲烷(100mLX1)和水(50mLX1)萃取。二氯甲烷相用无水硫酸钠干燥、过滤，滤液减压旋干,粗品用高效液相制备(碳酸氢铵法)得到5-乙基-4-((5aS,6S,9R)-12-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-5a,6,7,8,9,10-六氢-5H-4-氧杂-3,10a,11,13,14-五氮杂-6,9-亚甲基萘并[1,8-ab]庚烯-2-基)萘-2-醇(5-ethyl-4-((5aS,6S,9R)-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalen-2-yl)naphthalen-2-ol)(Z2，4.65mg,3步收率:2.73％)。ES-API:[M+1] +＝597.3。 1H NMR(500MHz,CD 3OD)δ7.57(d,J＝8.2Hz,1H),7.32(t,J＝7.5Hz,1H),7.27-7.09(m,3H),7.06-6.90(m,1H),5.43-5.18(m,1H),5.01(dd,J＝31.4,13.5Hz,1H),4.58(d,J＝11.5Hz,1H),4.53-4.38(m,1H),4.25(d,J＝10.4Hz,1H),4.19(d,J＝10.4Hz,1H),4.16-4.04(m,1H),3.71(s,1H),3.63(s,1H),3.27-3.17(m,4H),3.01(td,J＝9.6,5.5Hz,1H),2.55-2.08(m,5H),2.05-1.71(m,7H),0.97(t,J＝7.5Hz,1H),0.90(t,J＝7.4Hz,2H).
实施例3：合成4-((6R,9S)-12-(3-(二甲氨基)氮杂环丁烷-1-基)-5a,6,7,8,9,10-六氢-5H-4-氧杂-3,10a,11,13,14-五氮杂-6,9-亚甲基萘并[1,8-ab]庚烯-2-基)-5-乙基萘-2-醇(Z308)
Figure PCTCN2022081443-appb-000055
步骤一：冰水浴条件下，向N,N-二甲基氮杂环丁烷-3-胺盐酸盐(45.0mg，0.332mmol)的二氧六环 (5.0mL)溶液中加入N,N-二异丙基乙胺(430mg,3.322mmol)，最后加入叔丁基(6R,9S)-2-(8-乙基-3-(甲氧基甲氧基)萘-1-基)-12-氟-5a,6,7,8,9,10-六氢-5H-4-氧杂-3,10a,11,13,14-五氮杂-6,9-甲氧萘并[1,8-ab]庚烯-14-羧酸酯(100mg,0.1660mmol)。110℃反应2小时。2小时后，向体系中加入冰水(50mL)，用二氯甲烷萃取(50mLX2)，合并二氯甲烷相，无水硫酸钠干燥，过滤，滤液减压旋干，用快速硅胶柱(甲醇/二氯甲烷：0-10％)纯化得到叔丁基(6R,9S)-12-(3-(二甲氨基)氮杂环丁烷-1-基)-2-(8-乙基-3-(甲氧基甲氧基)萘-1-基)-5a,6,7,8,9,10-六氢-5H-4-氧杂-3,10a,11,13,14-五氮杂-6,9-亚甲基萘并[1,8-ab]庚烯-14-羧酸酯(110mg,收率:97％)。ES-API:[M+1] +＝682.3。
步骤二：将叔丁基(6R,9S)-12-(3-(二甲氨基)氮杂环丁烷-1-基)-2-(8-乙基-3-(甲氧基甲氧基)萘-1-基)-5a,6,7,8,9,10-六氢-5H-4-氧杂-3,10a,11,13,14-五氮杂-6,9-亚甲基萘并[1,8-ab]庚烯-14-羧酸酯(110mg,0.1612mmol)溶于乙腈(6.0mL)中，冰浴下加入4M盐酸/二氧六环溶液(2.0mL,8.0mmol)，冰浴下反应0.5小时。反应完毕后，减压旋干溶剂后加入二氯甲烷(20mL)，冰水浴条件下加入三乙胺(3.0mL)。搅拌10分钟后加入二氯甲烷(100mL)和水(50mL)萃取一次。将二氯甲烷相用无水硫酸钠干燥、过滤，滤液减压旋干得到粗品用高效液相制备(碳酸氢铵法)得到4-((6R,9S)-12-(3-(二甲氨基)氮杂环丁烷-1-基)-5a,6,7,8,9,10-六氢-5H-4-氧杂-3,10a,11,13,14-五氮杂-6,9-亚甲基萘并[1,8-ab]庚烯-2-基)-5-乙基萘-2-醇(4-((6R,9S)-12-(3-(dimethylamino)azetidin-1-yl)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalen-2-yl)-5-ethylnaphthalen-2-ol)(Z308,14.92mg,收率:16.8％)。ES-API:[M+1] +＝538.3。
实施例4：合成5-乙基-4-((5aR,6S,9R)-12-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-5a,6,7,8,9,10-六氢-5H-4-氧杂-3,10a,11,13,14-五氮杂-6,9-亚甲基萘并[1,8-ab]庚烯-2-基)萘-2-醇(Z170)
Figure PCTCN2022081443-appb-000056
步骤一：在0℃下，向2,4,6-三氯吡啶-3-羧酸(200mg,0.883mmol)和N,N-二甲基甲酰胺(0.02mL)的二氯甲烷(5mL)混合物中缓慢加入2-氯-2-氧代乙酰氯(0.374mL,4.415mmol)。反应室温搅拌1小时。反应浓缩得到黄色油状粗品2,4,6-三氯吡啶-3-碳酰氯(216mg,0.882mmol,收率:99.87％)，直接用于下一步。
步骤二：在室温下氨基甲亚氨基硫代甲酯(6456.50mg,34.301mmol)和碳酸氢钠(7204.09mg，85.753mmol)在四氢呋喃(40mL)和水(70mL)中搅拌反应10分钟。冷却至0℃，滴加2,4,6-三氯吡啶-3-碳酰氯(2100mg，8.575mmol)的四氢呋喃(40mL)溶液。在0℃下搅拌反应30分钟。然后用乙酸乙酯萃取。有机层用盐水洗涤，经无水硫酸钠干燥，过滤并浓缩，得到呈黄色固体状的(2,4,6-三氯烟酰基)氨基甲亚氨基硫酸甲酯(2500mg,8.373mmol,收率:97.64％)。ES-API:[M+1] +＝297.3。
步骤三：在氮气保护下，(2,4,6-三氯烟酰基)氨基甲亚氨基硫酸甲酯(2000mg,6.698mmol)和N,N-二异丙基乙胺(2.775mL，16.746mmol)在二氧六环(25mL)中密封并加热100℃反应16小时。将反应浓缩直至体积为～5mL。向残余物中加入水(15mL)和2M盐酸水溶液(3mL)。形成沉淀后，过滤并用水(10mL)洗涤滤饼。滤饼减压干燥得到黄色固体的5,7-二氯-2-(甲硫基)吡啶并[4,3-d]嘧啶-4(3H)-酮(1300mg,粗品)。ES-API:[M+H] +＝262.0。
步骤四：在0℃下向氢化钠(427.29mg,10.682mmol)的四氢呋喃(20mL)悬浮液中加入叔丁基(1S,2R,5R)-2-(羟甲基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(A2-2，813.53mg,3.357mmol)并在该温度下搅拌10分钟。加入5,7-二氯-2-(甲硫基)吡啶并[4,3-d]嘧啶-4(3H)-酮(800mg，粗品)，并在60℃下加热搅拌1小时。完全反应后用水淬灭并用二氯甲烷/甲醇(10:1,25mLX3)萃取。有机层用无水硫酸钠干燥，过滤并浓缩得到叔丁基(1S,2R,5R)-2-(((7-氯-4-羟基-2-(甲硫基)吡啶并[4,3-d]嘧啶-5-基]氧基)甲基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(1400mg，2.992mmol，收率:98.02％)，黄色固体。ES-API:[M+H] +＝468.1。
步骤五：向叔丁基(1S,2R,5R)-2-(((7-氯-4-羟基-2-(甲硫基)吡啶并[4,3-d]嘧啶-5-基]氧基)甲基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(1400mg，2.992mmol)和N,N-二异丙乙胺(4.957mL，29.916mmol)的二氯甲烷(20mL)溶液中加入丙基磷酸酐(50％in乙酸乙酯)(11422.33mg,17.949mmol)并在室温下搅拌3小时。用水淬灭并用二氯甲烷萃取。有机层用无水硫酸钠干燥，过滤并浓缩。将所得固体悬浮在乙腈中并在室温搅拌10分钟。过滤并收集滤饼，得到叔丁基(5aR,6S,9R)-2-氯-12-(甲硫基)5a,6,7,8,9,10-六氢-5H-4-氧杂-3,10a,11,13,14-五氮杂-6,9-亚甲基萘并[1,8-ab]庚烯-14-羧酸酯(600mg,1.333mmol,收率:44.57％)，白色固体。ES-API:[M+H] +＝450.1。
步骤六：在0℃下，向叔丁基(5aR,6S,9R)-2-氯-12-(甲硫基)5a,6,7,8,9,10-六氢-5H-4-氧杂-3,10a,11,13,14-五氮杂-6,9-亚甲基萘并[1,8-ab]庚烯-14-羧酸酯(550mg,1.222mmol)的二氯甲烷(15mL)溶液中加入间氯过氧苯甲酸(322.61mg,1.589mmol)。室温搅拌1小时。用饱和亚硫酸钠淬灭并用二氯甲烷萃取。有机层用无水硫酸钠干燥并浓缩得到粗品，将其通过快速硅胶柱(0-10％甲醇/二氯甲烷)纯化得到叔丁基(5aR,6S,9R)-2-氯-12-(甲基亚磺酰基)-5a,6,7,8,9,10-六氢-5H-4-氧杂-3,10a,11,13,14-五氮杂-6,9-亚甲基萘并[1,8-ab]庚烯-14-羧酸酯(470mg,1.009mmol,收率:82.52％)，白色固体。ES-API:[M+H] +＝466.1。
步骤七：0℃下，向氢化钠(45.07mg,1.878mmol)的四氢呋喃溶液中加入((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲醇(239.16mg,1.502mmol)。室温搅拌反应10分钟。冷却至0℃，加入叔丁基(5aR,6S,9R)-2-氯-12-(甲基亚磺酰基)-5a,6,7,8,9,10-六氢-5H-4-氧杂-3,10a,11,13,14-五氮杂-6,9-亚甲基萘并[1,8-ab]庚烯-14-羧酸酯(350mg,0.751mmol)四氢呋喃溶液(5mL)。0℃下搅拌反应1小时。用饱和碳 酸氢钠溶液淬灭反应并用乙酸乙酯萃取。有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩。粗品经快速硅胶柱(0-5％甲醇/二氯甲烷)纯化得到叔丁基(5aR,6S,9R)-2-氯-12-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-5a,6,7,8,9,10-六氢-5H-4-氧杂-3,10a,11,13,14-五氮杂-6,9-亚甲基萘并[1,8-ab]庚烯-14-羧酸酯(130mg,0.232mmol,收率：30.85％)，黄色固体。ES-API:[M+H] +＝561.2。
步骤八：向叔丁基(5aR,6S,9R)-2-氯-12-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-5a,6,7,8,9,10-六氢-5H-4-氧杂-3,10a,11,13,14-五氮杂-6,9-亚甲基萘并[1,8-ab]庚烯-14-羧酸酯和三异丙基((6-(甲氧基甲氧基)-8-(4,4,5,5-四甲基-1,3,2-二氧硼烷-2-基)萘-1-基)乙炔基)硅烷的二氧六环(6mL)和水(1.5mL)中加入磷酸钾(147.55mg,0.695mmol)，甲磺酸[正丁基二(1-金刚烷基)膦](2-氨基-1,1'-联苯-2-基)钯(II)(1.95mg,0.003mmol)，氮气鼓泡并在80℃下微波反应40分钟。反应完毕，用水淬灭反应，乙酸乙酯(30mLX2)和饱和食盐水(30mL)萃取。合并乙酸乙酯相，无水硫酸钠干燥，过滤，滤液减压浓缩。粗品经快速硅胶柱(0-4％甲醇/二氯甲烷)纯化得到叔丁基(5aR,6S,9R)-12-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-2-(3-(甲氧基甲氧基)-8-((三异丙基甲硅烷基)乙炔基)萘-1-基)-5a,6,7,8,9,10-六氢-5H-4-氧杂-3,10a,11,13,14-五氮杂-6,9-亚甲基萘并[1,8-ab]庚烯-14-羧酸酯(160mg,0.179mmol,收率:77.31％)，黄色固体。ES-API:[M+H] +＝893.5。
步骤九：向叔丁基(5aR,6S,9R)-12-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-2-(3-(甲氧基甲氧基)-8-((三异丙基甲硅烷基)乙炔基)萘-1-基)-5a,6,7,8,9,10-六氢-5H-4-氧杂-3,10a,11,13,14-五氮杂-6,9-亚甲基萘并[1,8-ab]庚烯-14-羧酸酯(150mg,0.168mmol)的N,N-二甲基甲酰胺(3.0mL)溶液中加入氟化铯(127.55mg,0.840mmol).室温下搅拌反应0.5小时。反应完毕。用水淬灭，乙酸乙酯萃取。有机相饱和食盐水洗，无水硫酸钠干燥，过滤、浓缩得到叔丁基(5aR,6S,9R)-2-(8-乙炔基-3-(甲氧基甲氧基)萘-1-基)-12-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-5a,6,7,8,9,10-六氢-5H-4-氧杂-3,10a,11,13,14-五氮杂-6,9-亚甲基萘并[1,8-ab]庚烯-14-羧酸酯(120mg,0.163mmol,收率:96.97％)，黄色油。ES-API:[M+H] +＝737.3。
步骤十：向叔丁基(5aR,6S,9R)-2-(8-乙炔基-3-(甲氧基甲氧基)萘-1-基)-12-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-5a,6,7,8,9,10-六氢-5H-4-氧杂-3,10a,11,13,14-五氮杂-6,9-亚甲基萘并[1,8-ab]庚烯-14-羧酸酯(90mg,0.122mmol)的甲醇(5.0mL)溶液中加入钯碳(74.17mg,0.061mmol)，置换氢气并在氢气氛下室温反应1小时。过滤，浓缩。粗品经快速硅胶柱(0-3％甲醇/二氯甲烷)纯化得到叔丁基(5aR,6S,9R)-2-(8-乙基-3-(甲氧基甲氧基)萘-1-基)-12-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-5a,6,7,8,9,10-六氢-5H-4-氧杂-3,10a,11,13,14-五氮杂-6,9-亚甲基萘并[1,8-ab]庚烯-14-羧酸酯(30mg,0.040mmol,收率:33.15％)，黄色固体.ES-API:[M+H] +＝741.4。
步骤十一：叔丁基(5aR,6S,9R)-2-(8-乙基-3-(甲氧基甲氧基)萘-1-基)-12-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-5a,6,7,8,9,10-六氢-5H-4-氧杂-3,10a,11,13,14-五氮杂-6,9-亚甲基萘并[1,8-ab]庚烯-14-羧酸酯(30mg,0.040mmol)和乙腈(2.0mL)和4M盐酸/二氧六环溶液(0.500mL,2.000mmol)反应液在0℃下反应1小时。浓缩，粗品用高效液相(碳酸氢铵法)制备得到5-乙基-4-((5aR,6S,9R)-12-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-5a,6,7,8,9,10-六氢-5H-4-氧杂-3,10a,11,13,14-五氮杂-6,9-亚甲基萘并[1,8-ab]庚烯-2-基)萘-2-醇(5-ethyl-4-((5aR,6S,9R)-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalen-2-yl)naphthalen-2-ol)(Z170,10.7mg,收率:45％)，白色固体。ES-API:[M+1] +＝597.3。 1HNMR(500MHz,CD 3OD):7.57(d,J＝8.0Hz,1H),7.35-7.31(m,1H),7.20-7.13(m,2H),7.05-6.92(m,1H),6.86-6.85(m,1H),5.33-5.22(m,1H),4.80-4.77(m,1H),4.57-4.46(m,2H),4.28-4.20(m,2H),3.88-3.84(m, 1H),3.78-3.77(m,1H),3.74-3.67(m,1H),3.51-3.44(m,1H),3.30-3.18(m,3H),3.02-2.97(m,1H),2.52-2.01(m,5H),1.98-1.84(m,7H),0.95(t,J＝7.5Hz,3H).
实施例5：合成5-乙基-4-((5aS,6S,9R)-1-氟-12-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-5a,6,7,8,9,10-六氢-5H-4-氧杂-3,10a,11,13,14-五氮杂-6,9-亚甲基萘并[1,8-ab]庚烯-2-基)萘-2-醇(Z140-1)
Figure PCTCN2022081443-appb-000057
步骤一：在-78℃条件下,于小时内向2,6-二氯-5-氟烟酸(8.0g,38.095mmol)的干燥四氢呋喃(150mL)溶液中滴加入甲基锂(47.6mL,76.19mmol,1.6M)，滴加完毕后在-20℃下搅拌2小时。2小时后，再次将体系降至-78℃，在30分钟内滴加完1,2-二溴-1,1,2,2-四氯乙烷(12.405g,38.095mmol)的四氢呋喃(30mL)溶液，加毕，0℃下反应1.5小时。反应完毕，将反应液倒入冰水(500mL)中，用氯仿(100mLX1)洗，水相用盐酸(3M)调pH＝3左右，将水相减压旋干，粗品用柱层析纯化[DCM:MeOH＝100:0～90:10,(v/v)]得到4-溴-2,6-二氯-5-氟烟酸(7.6g,收率:88％)。ES-API:[M+H] +＝287.9。
步骤二：在室温条件下,将4-溴-2,6-二氯-5-氟烟酸(6.0g,20.90mmol)溶于氯化亚砜(40.0mL),再将16滴N,N-二甲基甲酰胺加入上述体系中，该反应体系在100℃下搅拌反应1小时。1小时后，减压旋干溶剂。在0℃下将粗品加入到四氢呋喃(100mL)和饱和碳酸氢钠(100mL)混合溶剂中，最后加入氨基甲亚氨基硫代甲酯(12.91g，68.607mmol)，在该温度下搅拌反应30分钟。然后用乙酸乙酯(200mL)萃取反应。有机层用盐水洗涤，经无水硫酸钠干燥，过滤并浓缩，得到呈黄色固体状的甲基(4-溴-2,6-二氯-5-氟烟酰基)氨基甲亚氨基硫代酸酯(2.23g，收率:29.8％)。ES-API:[M+1] +＝359.5。
步骤三：在氮气保护下，甲基(4-溴-2,6-二氯-5-氟烟酰基)氨基甲亚氨基硫代酸酯(880mg，2.45mmol)和N，N-二异丙基乙胺(1.4mL，8.37mmol)在二氧六环(12mL)中密封并加热100℃反应16小时。将反 应浓缩直至体积为～5mL。向残余物中加入水(15mL)和2M盐酸水溶液(3mL)。形成沉淀后，过滤并用水(10mL)洗涤滤饼。滤饼减压干燥得到黄色固体的5,7-二氯-8-氟-2-(甲硫基)吡啶并[4,3-d]嘧啶-4(3H)-酮(350mg,收率:51％)。ES-API:[M+H] +＝280.0。
步骤四：在0℃下向氢化钠(427.29mg,10.682mmol)的四氢呋喃(20mL)悬浮液中加入叔丁基(1S,2S,5R)-2-(羟甲基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(A2-1，813.53mg,3.357mmol)并在该温度下搅拌10分钟。加入5,7-二氯-8-氟-2-(甲硫基)吡啶并[4,3-d]嘧啶-4(3H)-酮(854mg,3.052mmol)并在60℃下加热搅拌1h。完全反应后用水淬灭并用二氯甲烷/甲醇(10:1,25mLX3)萃取。有机层用无水硫酸钠干燥，过滤并浓缩得到叔丁基(1S,2S,5R)-2-(((7-氯-8-氟-4-羟基-2-(甲硫基)吡啶并[4,3-d]嘧啶-5-基)氧基)甲基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(1451mg，2.992mmol，收率：98.02％)，为黄色固体。ES-API:[M+H] +＝486.1。
步骤五：向叔丁基(1S,2S,5R)-2-(((7-氯-8-氟-4-羟基-2-(甲硫基)吡啶并[4,3-d]嘧啶-5-基)氧基)甲基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(1451mg，2.992mmol)和N，N-二异丙基乙胺(4.957mL，29.916mmol)的二氯甲烷(20mL)溶液中加入丙基磷酸酐(50％in乙酸乙酯)(11422.33mg,17.949mmol)并在室温下搅拌3小时。用水淬灭并用二氯甲烷萃取。有机层用无水硫酸钠干燥，过滤并浓缩。将所得固体悬浮在乙腈中并在室温搅拌10分钟。过滤并收集滤饼，得到叔丁基(5aS,6S,9R)-2-氯-1-氟-12-(甲硫基)-5a,6,7,8,9,10-六氢-5H-4-氧杂-3,10a,11,13,14-五氮杂-6,9-亚甲基萘并[1,8-ab]庚烯-14-羧酸酯(623mg,收率：45.0％)，为白色固体。ES-API:[M+H] +＝468.1。
步骤六：在0℃下，向叔丁基(5aS,6S,9R)-2-氯-1-氟-12-(甲硫基)-5a,6,7,8,9,10-六氢-5H-4-氧杂-3,10a,11,13,14-五氮杂-6,9-亚甲基萘并[1,8-ab]庚烯-14-羧酸酯(540mg,1.153mmol)的二氯甲烷(15mL)溶液中加入间氯过氧苯甲酸(322.61mg,1.589mmol)。室温搅拌1小时。用饱和亚硫酸钠淬灭并用二氯甲烷(100mLX2)萃取。有机层用无水硫酸钠干燥并浓缩得到粗品，通过快速硅胶柱(0-10％甲醇/二氯甲烷)纯化得到(5aS,6S,9R)-2-氯-1-氟-12-(甲基亚磺酰基)-5a,6,7,8,9,10-六氢-5H-4-氧杂-3,10a,11,13,14-五氮杂-6,9-亚甲基萘并[1,8-ab]庚烯-14-羧酸叔丁酯(452mg,收率:81.0％)，白色固体。ES-API:[M+H] +＝484.1。
步骤七：0℃下，向氢化钠(45.07mg,1.878mmol)的四氢呋喃溶液中加入((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲醇(239.16mg,1.502mmol)。室温搅拌反应10分钟。冷却至0℃，加入(5aS,6S,9R)-2-氯-1-氟-12-(甲基亚磺酰基)-5a,6,7,8,9,10-六氢-5H-4-氧杂-3,10a,11,13,14-五氮杂-6,9-亚甲基萘并[1,8-ab]庚烯-14-羧酸叔丁酯(363.5mg,0.751mmol)四氢呋喃溶液(5mL)。0℃下搅拌反应1小时。用饱和碳酸氢钠溶液淬灭反应并用乙酸乙酯萃取。有机相用饱和食盐水水，无水硫酸钠干燥，过滤，浓缩。粗品经快速柱层析(0-5％甲醇/二氯甲烷)纯化得到叔丁基(5aR,6S,9R)-2-氯-1-氟-12-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-5a,6,7,8,9,10-六氢-5H-4-氧杂-3,10a,11,13,14-五氮杂-6,9-亚甲基萘并[1,8-ab]庚烯-14-羧酸酯(134mg,收率30.85％)，黄色固体。ES-API:[M+H] +＝579.2。
步骤八：向叔丁基(5aR,6S,9R)-2-氯-1-氟-12-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-5a,6,7,8,9,10-六氢-5H-4-氧杂-3,10a,11,13,14-五氮杂-6,9-亚甲基萘并[1,8-ab]庚烯-14-羧酸酯(134.0mg,0.233mmol)和三异丙基((6-(甲氧基甲氧基)-8-(4,4,5,5-四甲基-1,3,2-二氧硼烷-2-基)萘-1-基)乙炔基)硅烷(230.0mg,0.466mmol)的二氧六环(6mL)和水(1.5mL)中加入磷酸钾(147.55mg,0.695mmol)，甲磺酸[正丁基二(1-金刚烷基)膦](2-氨基-1,1'-联苯-2-基)钯(II)(1.95mg,0.003mmol)，N 2鼓泡并在80℃下微波反应40分钟。反应完毕，乙酸乙酯(30mLX2)和饱和食盐水(30mL)萃取。合并乙酸乙酯相，无水硫酸钠干燥，过滤，滤液减压浓缩。粗品经快速硅胶柱(0-4％甲醇/二氯甲烷)纯化得到叔丁基 (5aS,6S,9R)-1-氟-12-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-2-(3-(甲氧基甲氧基)-8-((三异丙基甲硅烷基)乙炔基)萘-1-基)-5a,6,7,8,9,10-六氢-5H-4-氧杂-3,10a,11,13,14-五氮杂-6,9-亚甲基萘并[1,8-ab]庚烯-14-羧酸酯(164mg,收率:77.33％)，黄色固体。ES-API:[M+H] +＝911.5。
步骤九：向叔丁基(5aS,6S,9R)-1-氟-12-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-2-(3-(甲氧基甲氧基)-8-((三异丙基甲硅烷基)乙炔基)萘-1-基)-5a,6,7,8,9,10-六氢-5H-4-氧杂-3,10a,11,13,14-五氮杂-6,9-亚甲基萘并[1,8-ab]庚烯-14-羧酸酯(165mg,0.181mmol)的N,N-二甲基甲酰胺(3.0mL)溶液中加入氟化铯(127.55mg,0.840mmol).室温下搅拌反应0.5小时。反应完毕。用水淬灭，乙酸乙酯萃取。有机相饱和食盐水洗，无水硫酸钠干燥，过滤、浓缩得到叔丁基(5aS,6S,9R)-2-(8-乙炔基-3-(甲氧基甲氧基)萘-1-基)-1-氟-12-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-5a,6,7,8,9,10-六氢-5H-4-氧杂-3,10a,11,13,14-五氮杂-6,9-亚甲基萘并[1,8-ab]庚烯-14-羧酸酯(150mg,粗品)，黄色油。ES-API:[M+H] +＝755.3。
步骤十：向叔丁基(5aS,6S,9R)-2-(8-乙炔基-3-(甲氧基甲氧基)萘-1-基)-1-氟-12-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-5a,6,7,8,9,10-六氢-5H-4-氧杂-3,10a,11,13,14-五氮杂-6,9-亚甲基萘并[1,8-ab]庚烯-14-羧酸酯(100mg,0.1324mmol)的甲醇(5.0mL)溶液中加入钯碳(75.0mg,0.061mmol)，置换氢气并在氢气氛下室温反应1小时。过滤，浓缩。粗品经快速硅胶柱(0-3％甲醇/二氯甲烷)纯化得到叔丁基(5aS,6S,9R)-2-(8-乙基-3-(甲氧基甲氧基)萘-1-基)-1-氟-12-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-5a,6,7,8,9,10-六氢-5H-4-氧杂-3,10a,11,13,14-五氮杂-6,9-亚甲基萘并[1,8-ab]庚烯-14-羧酸酯(70mg,收率:70％)，黄色固体.ES-API:[M+H] +＝759.4。
步骤十一：叔丁基(5aS,6S,9R)-2-(8-乙基-3-(甲氧基甲氧基)萘-1-基)-1-氟-12-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-5a,6,7,8,9,10-六氢-5H-4-氧杂-3,10a,11,13,14-五氮杂-6,9-亚甲基萘并[1,8-ab]庚烯-14-羧酸酯(80mg,0.105mmol)和乙腈(2.0mL)和4M盐酸/二氧六环溶液(0.500mL,2.000mmol)反应液在0℃下反应1小时。浓缩，粗品用高效液相制备(碳酸氢铵法)得到5-乙基-4-((5aS,6S,9R)-1-氟-12-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-5a,6,7,8,9,10-六氢-5H-4-氧杂-3,10a,11,13,14-五氮杂-6,9-亚甲基萘并[1,8-ab]庚烯-2-基)萘-2-醇(5-ethyl-4-((5aS,6S,9R)-1-fluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalen-2-yl)naphthalen-2-ol)(Z140-1,9.65mg,收率:14.9％)，黄色固体。ES-API:[M+1] +＝615.3。
实施例6：合成(5aS,6S,9R)-2-(8-乙炔萘-1-基)-1-氟-12-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-5a,6,7,8,9,10-六氢-5H-4-氧代-3,10a,11,13,14-五氮杂-6,9-亚甲基萘并[1,8-ab]庚烯(Z350)
Figure PCTCN2022081443-appb-000058
步骤一：向叔丁基(1S,2S,5R)-2-(((7-氯-8-氟-(2-甲硫基)-4-氧杂-3,4-二氢吡啶[4,3-d]嘧啶-5-基)氧基) 甲基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(150.0mg,0.321mmol)和三异丙基((8-(4,4,5,5-四甲基-1,3,2-二氧硼烷-2-基)萘-1-基)乙炔基)硅烷(220.0mg,0.506mmol)的二氧六环(6mL)和水(1.5mL)中加入磷酸钾(300mg,1.415mmol)，甲磺酸[正丁基二(1-金刚烷基)膦](2-氨基-1,1'-联苯-2-基)钯(II)(100mg,0.137mmol)，氮气鼓泡并在80℃下微波反应40分钟。反应完毕，乙酸乙酯(30mLX2)和饱和食盐水(30mL)萃取。合并乙酸乙酯相，无水硫酸钠干燥，过滤，滤液减压浓缩。粗品经柱层析(甲醇/二氯甲烷＝0-4％)纯化得到叔丁基(5aS,6S,9R)-1-氟-12-(甲硫基)-2-(8-((三异丙基甲硅烷基)乙炔基)萘-1-基)-5a,6,7,8,9,10-六氢-5H-4-氧代-3,10a,11,13,14-五氮杂-6,9-亚甲基萘并[1,8-ab]庚烯-14-羧酸酯(272mg,粗品)，黄色固体。ES-API:[M+H] +＝800.4。
步骤二：在0℃下，向叔丁基(5aS,6S,9R)-1-氟-12-(甲硫基)-2-(8-((三异丙基甲硅烷基)乙炔基)萘-1-基)-5a,6,7,8,9,10-六氢-5H-4-氧代-3,10a,11,13,14-五氮杂-6,9-亚甲基萘并[1,8-ab]庚烯-14-羧酸酯(272mg,粗品)的二氯甲烷(15mL)溶液中加入间氯过氧苯甲酸(67.12mg,0.389mmol)。室温搅拌1小时。用饱和亚硫酸钠淬灭并用二氯甲烷(100mLX2)萃取。有机层用无水硫酸钠干燥并浓缩，得到粗品通过硅胶柱层析(甲醇/二氯甲烷＝0-10％)纯化得到叔丁基(5aS,6S,9R)-1-氟-12-(甲基亚磺酰基)-2-(8-((三异丙基甲硅烷基)乙炔基)萘-1-基)-5a,6,7,8,9,10-六氢-5H-4-氧代-3,10a,11,13,14-五氮杂-6,9-亚甲基萘并[1,8-ab]庚烯-14-羧酸酯(230mg,2步总收率:93.8％)，白色固体。ES-API:[M+H] +＝756.3。
步骤三：0℃下，向含有((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲醇(100.0mg,0.628mmol)的四氢呋喃(10.0mL)溶液中加入氢化钠(50.0mg,1.25mmol)，该温度下搅拌10分钟后，再加入叔丁基(5aS,6S,9R)-1-氟-12-(甲基亚磺酰基)-2-(8-((三异丙基甲硅烷基)乙炔基)萘-1-基)-5a,6,7,8,9,10-六氢-5H-4-氧代-3,10a,11,13,14-五氮杂-6,9-亚甲基萘并[1,8-ab]庚烯-14-羧酸酯(230.0mg,0.304mmol)四氢呋喃溶液(5mL)。0℃下搅拌反应1小时。用饱和碳酸氢钠溶液淬灭反应并用乙酸乙酯萃取。有机相用饱和食盐水洗，无水硫酸钠干燥，过滤，浓缩。粗品经硅胶柱层析(甲醇/二氯甲烷＝0-5％)纯化得到(5aS,6S,9R)-1-氟-12-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-2-(8-((三异丙基甲硅烷基)乙炔基)萘-1-基)-5a,6,7,8,9,10-六氢-5H-4-氧代-3,10a,11,13,14-五氮杂-6,9-亚甲基萘并[1,8-ab]庚烯-14-羧酸叔丁酯(260mg,粗品)，黄色固体。ES-API:[M+H] +＝851.5。
步骤四：向(5aS,6S,9R)-1-氟-12-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-2-(8-((三异丙基甲硅烷基)乙炔基)萘-1-基)-5a,6,7,8,9,10-六氢-5H-4-氧代-3,10a,11,13,14-五氮杂-6,9-亚甲基萘并[1,8-ab]庚烯-14-羧酸叔丁酯(260mg,粗品)的N,N-二甲基甲酰胺(5.0mL)溶液中加入氟化铯(1000mg,6.583mmol)。室温下搅拌反应0.5小时。反应完毕。用水淬灭反应，乙酸乙酯萃取。有机相饱和食盐水洗，无水硫酸钠干燥，过滤，浓缩得到(5aS,6S,9R)-2-(8-乙炔萘-1-基)-1-氟-12-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-5a,6,7,8,9,10-六氢-5H-4-氧代-3,10a,11,13,14-五氮杂-6,9-亚甲基萘并[1,8-ab]庚烯-14-羧酸叔丁酯(120mg,2步总收率:57％)，黄色油。ES-API:[M+H] +＝695.3。
步骤五：(5aS,6S,9R)-2-(8-乙炔萘-1-基)-1-氟-12-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-5a,6,7,8,9,10-六氢-5H-4-氧代-3,10a,11,13,14-五氮杂-6,9-亚甲基萘并[1,8-ab]庚烯-14-羧酸叔丁酯(120mg,0.173mmol)和乙腈(5.0mL)和4M盐酸/二氧六环溶液(2.0mL,8.000mmol)反应液在0℃下反应1小时。浓缩，粗品用高效液相制备(碳酸氢铵法)得到(5aS,6S,9R)-2-(8-乙炔萘-1-基)-1-氟-12-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-5a,6,7,8,9,10-六氢-5H-4-氧代-3,10a,11,13,14-五氮杂-6,9-亚甲基萘并[1,8-ab]庚烯((5aS,6S,9R)-2-(8-ethynylnaphthalen-1-yl)-1-fluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanon aphtho[1,8-ab]heptalene)(Z350,34mg,收率:33％)，黄色固体。ES-API:[M+1] +＝595.3。 1H NMR(500MHz, CD 3OD)δ8.07(d,J＝8.2Hz,1H),8.03(dd,J＝7.8,3.6Hz,1H),7.73(ddd,J＝13.6,7.2,1.2Hz,1H),7.67-7.47(m,3H),5.30(d,J＝54.1Hz,1H),5.05(ddd,J＝13.5,6.6,2.2Hz,1H),4.59(ddd,J＝13.2,8.9,2.0Hz,1H),4.44(ddd,J＝13.2,7.4,5.9Hz,1H),4.28(t,J＝10.1Hz,1H),4.21(dd,J＝10.5,5.4Hz,1H),4.12(d,J＝6.2Hz,1H),3.72(s,1H),3.63(d,J＝5.2Hz,1H),3.27-3.16(m,4H),3.02(td,J＝9.8,5.9Hz,1H),2.29-2.21(m,1H),2.16-2.10(m,1H),1.99(dq,J＝13.5,6.7Hz,2H),1.95-1.75(m,5H)。
实施例7：合成4-((5aS,6S,9R)-3-氯-13-((2R,7aS)-2-氟四氢-1H-吡咯里嗪-7a(5H)-基甲氧基)-5a,6,7,8,9,10-六氢-5H-6,9-表氨基氮杂[2',1':3,4][1,4]氧氮杂[5,6,7-脱]喹唑啉-2-基)-5-乙基萘-2-醇(Z381)
Figure PCTCN2022081443-appb-000059
步骤一：在0℃下向钠氢(60％分散在油中)(32mg,0.81mmol)的四氢呋喃(10mL)悬浮液中加入(1S,2S,5R)-2-(羟甲基)-3,8-二氮杂环[3.2.1]辛烷-8-羧酸叔丁酯(A2-1，131mg,0.54mmol)并在该温度下搅拌10分钟。加入7-溴-2,6-二氯-5-氟喹唑啉-4(3H)-酮(170mg,0.54mmol)并在60℃下加热搅拌1小时。完全反应后用水淬灭反应并用二氯甲烷/甲醇(10:1,25mLX 3)萃取。有机层用无水硫酸钠干燥，旋干，得到叔丁基(1S,2S,5R)-2-(((7-溴-2,6-二氯-4-氧-3,4-二氢喹唑啉-5-基)氧基)甲基)-3,8-二氮杂环[3.2.1]辛烷-8-羧酸酯(150mg,收率:51.0％)。ES-API:[M+H] +＝533.2。
步骤二：向叔丁基(1S,2S,5R)-2-(((7-溴-2,6-二氯-4-氧-3,4-二氢喹唑啉-5-基)氧基)甲基)-3,8-二氮杂环[3.2.1]辛烷-8-羧酸酯(110mg,0.21mmol)和N,N-二异丙基乙胺(80mg,0.62mmol)的超干二氯甲烷(10mL)溶液中加入1H-苯并***-1-基氧三吡咯烷基六氟磷酸盐(86mg,0.42mmol)并在室温下搅拌16个小时。用水淬灭反应并用二氯甲烷(25mLX 3)萃取，饱和食盐水(10mL)洗。有机层用无水硫酸钠干燥，过滤并浓缩。得到的粗品用反相制备(色谱柱:Waters XBridge C18，流动相：水/乙腈(0.1％三氟乙酸)0-80％，流速：50mL/min，柱温：25℃)得叔丁基(5aS,6S,9R)-2-溴-3,13-二氯-5a,6,7,8,9,10-六氢-5H-6,9-表氨基氮杂[2',1':3,4][1,4]氧氮杂[5,6,7-脱]喹唑啉-15-羧酸盐(64mg,收率:60.3％)。ES-API:[M+H] +＝515.1。
步骤三：向叔丁基(5aS,6S,9R)-2-溴-3,13-二氯-5a,6,7,8,9,10-六氢-5H-6,9-表氨基氮杂[2',1':3,4][1,4]氧氮杂[5,6,7-脱]喹唑啉-15-羧酸盐(45mg,0.09mmol)的超干N,N-二甲基甲酰胺(10mL)溶液中加入((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲醇(29mg,0.18mmol)，氟化钾(51mg,0.9mmol)和4A分子筛。氮气保护下，120℃搅拌16小时。反应结束后用水淬灭并用二氯甲烷(25mLX 3)萃取，饱和食盐水(10mL)洗。有机层用无水硫酸钠干燥，过滤并浓缩。得到粗品用反相制备(色谱柱：Waters XBridge C18，流动相：水/乙腈(0.1％三氟乙酸)(0-50％)，流速：50mL/min，柱温：25℃)得叔丁基(5aS,6S,9R)-2-溴-3-氯-13-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-5a,6,7,8,9,10-六氢-5H-6,9-表氨基氮杂[2',1':3,4][1,4]氧氮杂[5,6,7-脱]喹唑啉-15-羧酸盐(22mg,收率:38.4％)。ES-API:[M+H] +＝638.2。
步骤四：叔丁基(5aS,6S,9R)-2-溴-3-氯-13-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧 基)-5a,6,7,8,9,10-六氢-5H-6,9-表氨基氮杂[2',1':3,4][1,4]氧氮杂[5,6,7-脱]喹唑啉-15-羧酸盐(22mg,0.03mmol)和2-(8-乙基-3-(甲氧基甲氧基)萘-1-基)-4,4,5,5-四甲基-1,3,2-二氧硼烷(17mg,0.05mmol)的四氢呋喃(6mL)和水(1.0mL)中加入磷酸钾(21mg,0.1mmol)，甲磺酸[正丁基二(1-金刚烷基)膦](2-氨基-1,1'-联苯-2-基)钯(II)(15mg)，氮气保护下，在60℃下反应2小时。反应完毕，乙酸乙酯(30mLX2)和饱和食盐水(10mL)萃取。合并乙酸乙酯相，无水硫酸钠干燥，过滤，滤液减压浓缩。得到粗品用薄层层析纯化(甲醇/二氯甲烷＝1:15)得到叔丁基(5aS,6S,9R)-3-氯-2-(8-乙基-3-(甲氧基甲氧基)萘-1-基)-13-(((2R,7aS)-2-氟四氢-1H-吡咯啉-7a(5H)-基甲氧基)-5a,6,7,8,9,10-六氢-5H-6,9-表氨基氮杂[2',1':3,4][1,4]氧氮杂[5,6,7-脱]喹唑啉-15-羧酸盐(10mg,收率:43％)。ES-API:[M+H] +＝774.1。
步骤五：叔丁基(5aS,6S,9R)-3-氯-2-(8-乙基-3-(甲氧基甲氧基)萘-1-基)-13-(((2R,7aS)-2-氟四氢-1H-吡咯啉-7a(5H)-基甲氧基)-5a,6,7,8,9,10-六氢-5H-6,9-表氨基氮杂[2',1':3,4][1,4]氧氮杂[5,6,7-脱]喹唑啉-15-羧酸盐(10mg,0.013mmol)和乙腈(2.0mL)和4M盐酸/二氧六环溶液(0.5mL,2.000mmol)反应液在0℃下反应1小时。反应液浓缩，得到的粗品用高效液相制备(甲酸法)得到4-((5aS,6S,9R)-3-氯-13-((2R,7aS)-2-氟四氢-1H-吡咯里嗪-7a(5H)-基甲氧基)-5a,6,7,8,9,10-六氢-5H-6,9-表氨基氮杂[2',1':3,4][1,4]氧氮杂[5,6,7-脱]喹唑啉-2-基)-5-乙基萘-2-醇(4-((5aS,6S,9R)-3-chloro-13-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-6,9-epiminoazepino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazolin-2-yl)-5-ethylnaphthalen-2-ol)(Z381,甲酸盐，5.0mg,收率:61.1％)，黄色固体。ES-API:[M+1] +＝630.3。 1H NMR(400MHz,CD 3OD)δ8.51(s,2H),7.59(d,J＝8.1Hz,1H),7.37-7.27(m,1H),7.24-7.07(m,2H),6.97(d,J＝2.7Hz,1H),6.79(dd,J＝12.2,2.6Hz,1H),5.44(d,J＝52.4Hz,1H),5.09(dd,J＝29.8,11.5Hz,3H),4.66-4.44(m,1H),4.24-4.08(m,1H),3.92-3.57(m,5H),3.29-3.22(m,2H),2.63-2.31(m,5H),2.27-2.13(m,2H),1.99(dd,J＝30.6,18.8Hz,5H),0.91(dt,J＝14.5,7.4Hz,3H).
实施例8：合成5-乙炔基-6-氟-4-((5aS,6S,9R)-1-氟-12-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-5a,6,7,8,9,10-六氢-5H-4-氧代-3,10a,11,13,14-五氮杂-6,9-亚甲基萘并[1,8-ab]庚烯-2-基)萘-2-醇(Z131-1)
Figure PCTCN2022081443-appb-000060
步骤一：0℃下，向含有((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲醇(100.0mg,0.628mmol)的四氢呋喃(10.0mL)溶液中加入氢化钠(50.0mg,1.25mmol)，该温度下搅拌10分钟后，再加入叔丁基(5aS,6S,9R)-1-氟-2-(7-氟-3-(甲氧基甲氧基)-8-((三异丙基甲硅烷基)乙炔基)萘-1-基)-12-(甲基亚磺酰基)-5a,6,7,8,9,10-六氢-5H-4-氧代-3,10a,11,13,14-五氮杂-6,9-亚甲基萘并[1,8-ab]庚烯-14-羧酸酯(210.0mg,0.252mmol)四氢呋喃溶液(5mL)。0℃下搅拌反应1小时。用饱和碳酸氢钠溶液淬灭反应并用 乙酸乙酯萃取。有机相用饱和食盐水洗，无水硫酸钠干燥，过滤，浓缩。粗品经硅胶柱层析(0-5％甲醇/二氯甲烷)纯化得到叔丁基(5aS,6S,9R)-1-氟-2-(7-氟-3-(甲氧基甲氧基)-8-((三异丙基甲硅烷基)乙炔基)萘-1-基)-12-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-5a,6,7,8,9,10-六氢-5H-4-氧代-3,10a,11,13,14-五氮杂-6,9-亚甲基萘并[1,8-ab]庚烯-14-羧酸酯(170.0mg,收率:72.6％)，黄色固体。ES-API:[M+H] +＝929.3。
步骤二：向叔丁基(5aS,6S,9R)-1-氟-2-(7-氟-3-(甲氧基甲氧基)-8-((三异丙基甲硅烷基)乙炔基)萘-1-基)-12-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-5a,6,7,8,9,10-六氢-5H-4-氧代-3,10a,11,13,14-五氮杂-6,9-亚甲基萘并[1,8-ab]庚烯-14-羧酸酯(170mg,0.183mmol)的N,N-二甲基甲酰胺(5.0mL)溶液中加入氟化铯(1000mg,6.583mmol)。室温下搅拌反应0.5小时。反应完毕。用水淬灭反应，乙酸乙酯萃取。有机相饱和食盐水洗，无水硫酸钠干燥，过滤，浓缩得到(5aS,6S,9R)-2-(8-乙炔基-7-氟-3-(甲氧基甲氧基)萘-1-基)-1-氟-12-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-5a,6,7,8,9,10-六氢-5H-4-氧代-3,10a,11,13,14-五氮杂-6,9-亚甲基萘并[1,8-ab]庚烯-14-羧酸叔丁酯(200mg,粗品)，黄色油。ES-API:[M+H] +＝773.3。
步骤三：(5aS,6S,9R)-2-(8-乙炔基-7-氟-3-(甲氧基甲氧基)萘-1-基)-1-氟-12-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-5a,6,7,8,9,10-六氢-5H-4-氧代-3,10a,11,13,14-五氮杂-6,9-亚甲基萘并[1,8-ab]庚烯-14-羧酸叔丁酯(200mg,粗品)和乙腈(10.0mL)和4M盐酸/二氧六环溶液(2.0mL,8.000mmol)反应液在0℃下反应1小时。浓缩，粗品用高效液相制备(碳酸氢铵法)得到5-乙炔基-6-氟-4-((5aS,6S,9R)-1-氟-12-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-5a,6,7,8,9,10-六氢-5H-4-氧代-3,10a,11,13,14-五氮杂-6,9-亚甲基萘并[1,8-ab]庚烯-2-基)萘-2-醇(5-ethynyl-6-fluoro-4-((5aS,6S,9R)-1-fluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalen-2-yl)naphthalen-2-ol)(Z131-1,8.95mg,2步总收率:7.8％)，黄色固体。ES-API:[M+1] +＝629.3。
实施例9：合成5-乙基-4-((5aS,6S,9R)-12-((1-甲基-1-氮杂螺环[4.4]壬烷-6-基)氧基)-5a,6,7,8,9,10-六氢-5H-4-氧杂-3,10a,11,13,14-五氮杂[6,9]亚甲基萘[1,8-ab]庚烯-2-基)萘-2-醇(Z260-1)
Figure PCTCN2022081443-appb-000061
Figure PCTCN2022081443-appb-000062
步骤一：向三异丙基((6-(甲氧基甲氧基)-8-(4,4,5,5-四甲基-1,3,2-二氧硼烷-2-基)萘-1-基)乙炔基)硅烷(500mg,1.012mmol)的N,N-二甲基甲酰胺(5.0mL)溶液中加入氟化铯(3.0g,20.24mmol)，室温反应2小时。反应完毕后，用乙酸乙酯萃取(100mLX2)，乙酸乙酯相合并后用饱和食盐水洗(100mLX3)。乙酸乙酯相用无水硫酸钠干燥，过滤，旋干后得到2-(8-乙炔基-3-(甲氧基甲氧基)萘-1-基)-4,4,5,5-四甲基-1,3,2-二氧硼烷(558mg,粗品)。ES-API:[M+H] +＝339.3。
步骤二：向2-(8-乙炔基-3-(甲氧基甲氧基)萘-1-基)-4,4,5,5-四甲基-1,3,2-二氧硼烷(558mg,粗品)的甲醇(10.0mL)溶液中加入质量分数为10％的钯碳，氢气置换4次并在氢气保护下室温反应2小时。反应完毕后，过滤，减压旋干溶剂得到2-(8-乙基-3-(甲氧基甲氧基)萘-1-基)-4,4,5,5-四甲基-1,3,2-二氧硼烷(284mg,2步总收率:82％)。ES-API:[M+1] +＝343.3。
步骤三：将1-苄基-1-氮杂螺环[4.4]壬-6-酮(1.5g,6.5mmol)溶于甲醇(10ml)，加入钯碳催化剂(150mg)，置换氢气3次常温反应4小时，过滤，甲醇洗涤，浓缩得1-氮杂螺环[4.4]壬-6-酮(800mg,收率:88.5％)。ES-API:[M+H] +＝140.1。
步骤四：将1-氮杂螺环[4.4]壬-6-酮(800mg,5.7mmol)溶于四氢呋喃(10mL)，常温下加入三乙胺(0.86mg,8.5mmol)和二碳酸二叔丁脂(1.8g,8.5mmol)，室温搅拌8小时。LCMS监测反应完全，加入水(10ml)，乙酸乙酯萃取，无水硫酸钠干燥，浓缩，得到粗品经硅胶柱层析纯化(乙酸乙酯/石油醚＝0～80％)得6-氧代-1-氮杂螺环[4.4]壬烷-1-羧酸叔丁酯(900mg,收率:66％)。ES-API:[M+H] +＝240.1。
步骤五：6-氧代-1-氮杂螺环[4.4]壬烷-1-羧酸叔丁酯(900mg,3.7mmol)溶于干燥四氢呋喃(10mL)， 冰浴下加入氢化锂铝(11ml,11mmol,1M四氢呋喃)，60℃搅拌2小时。加入水(10mL)，乙酸乙酯萃取，无水硫酸钠干燥，浓缩得1-甲基-1-氮杂螺环[4.4]壬-6-醇(450mg)，直接用于下一步。ES-API:[M+Na] +＝156.1。
步骤六：在0℃下向(1S,2S,5R)-2-(羟甲基)-3,8-二氮杂环[3.2.1]辛烷-8-羧酸叔丁酯(A2-1，242mg,1.0mmol)的四氢呋喃(10mL)溶液中加入氢化钠(80mg,2.0mmol)。氮气保护下反应10～20分钟后，分批次加入5,7-二氯-1-(2,4-二甲氧基苄基)吡啶并[4,3-d]嘧啶-2,4(1H,3H)-二酮(381mg,1.0mmol)，0～5℃条件下再反应20～30分钟。LCMS监测反应完毕，将反应液倾倒入约冰水(300mL)中，冰水浴条件下用6M的盐酸水溶液调pH至7～8，用乙酸乙酯萃取(100mLX2)，有机相合并后用饱和食盐水(100mLX1)洗。有机相用无水硫酸钠干燥，过滤，旋干得到目标化合物(1S,2S,5R)-2-(((7-氯-1-(2,4-二甲氧基苄基)-2,4-二氧杂-1,2,3,4-四氢吡啶并[4,3-d]嘧啶-5-基)氧基)甲基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸叔丁酯(560mg,收率:87％)。ES-API:[M+H] +＝588.2。
步骤七：室温下向250mL单口烧瓶中加入干燥N,N-二甲基甲酰胺(15mL)和(1S,2S,5R)-2-(((7-氯-1-(2,4-二甲氧基苄基)-2,4-二氧杂-1,2,3,4-四氢吡啶并[4,3-d]嘧啶-5-基)氧基)甲基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸叔丁酯(510mg,0.87mmol)。最后加入卡特缩合剂(1.9g,4.35mmol)，室温反应5分钟后，再滴加1,8-二氮杂二环[5.4.0]十一碳-7-烯(661mg,4.35mmol)。室温反应1～2小时。反应完毕后，向冰水(100mL)中缓慢滴加上述溶液，析出大量固体，过滤，滤饼减压旋干后经柱层析纯化(石油醚/乙酸乙酯＝1/1)得到(5aS,6S,9R)-2-氯-13-(2,4-二甲氧基苄基)-12-氧-5a,6,7,8,9,10,12,13-八氢-5H-4-氧杂-3,10a,11,13,14-五氮杂-6,9-亚甲基萘[1,8-ab]庚烯-14-羧酸叔丁酯(300mg,收率:61％)。ES-API:[M+H] +＝568.2。
步骤八：向三氟乙酸(5mL)中中加入(5aS,6S,9R)-2-氯-13-(2,4-二甲氧基苄基)-12-氧-5a,6,7,8,9,10,12,13-八氢-5H-4-氧杂-3,10a,11,13,14-五氮杂-6,9-亚甲基萘[1,8-ab]庚烯-14-羧酸叔丁酯(300mg,0.53mmol)，55℃下搅拌1小时。反应完毕，减压旋干溶剂，得到化合物(5aS,6S,9R)-2-氯-5a,6,7,8,9,10-六氢-5H-4-氧杂-3,10a,11,13,14-五氮杂-6,9-亚甲基萘并[1,8-ab]庚烯-12(13H)-酮(500mg,粗品)。ES-API:[M+H] +＝320.1。
步骤九：向(5aS,6S,9R)-2-氯-5a,6,7,8,9,10-六氢-5H-4-氧杂-3,10a,11,13,14-五氮杂-6,9-亚甲基萘并[1,8-ab]庚烯-12(13H)-酮(500mg,粗品)的四氢呋喃(5.0mL)和水(5.0mL)的混合溶液中加入碳酸钠(168mg,1.59mmol)，体系用冰水浴冷却，加入苯甲氧羰酰琥珀酰亚胺(171mg,0.68mmol)，在室温下反应3小时。反应完毕，向反应液中加入二氯甲烷(80mL)，用饱和碳酸氢钠水溶液(100mL)洗涤，饱和食盐水(80mL)洗涤，无水硫酸钠干燥后浓缩，得到粗品用硅胶柱层析纯化(乙酸乙酯/石油醚：0-50％)得到目标产物(5aS,6S,9R)-2-氯-12-氧杂-5a,6,7,8,9,10,12,13-八氢-5H-4-氧杂-3,10a,11,13,14-五氮杂-6,9-亚甲基萘[1,8-ab]庚烯-14-羧酸苄酯(396mg,收率:93％)。ES-API:[M+H] +＝454.1。
步骤十：在0℃下，向(5aS,6S,9R)-2-氯-12-氧杂-5a,6,7,8,9,10,12,13-八氢-5H-4-氧杂-3,10a,11,13,14-五氮杂-6,9-亚甲基萘[1,8-ab]庚烯-14-羧酸苄酯(390mg,0.8mmol)的甲苯(5.0mL)溶液中依次加入三氯氧磷(365mg,2.4mmol)和N,N-二异丙基乙胺(310mg,2.4mmol)，在105℃下反应12小时。反应完毕，冷却到室温，减压旋干溶剂后粗品经高效液相制备(碳酸氢铵法)得到(5aS,6S,9R)-2,12-二氯-5a,6,7,8,9,10-六氢-5H-4-氧杂-3,10a,11,13,14-五氮杂-6,9-亚甲基萘[1,8-ab]庚烯-14-羧酸苄酯(70mg,收率:17％)。ES-API:[M+H] +＝472.1。
步骤十一：向(5aS,6S,9R)-2,12-二氯-5a,6,7,8,9,10-六氢-5H-4-氧杂-3,10a,11,13,14-五氮杂-6,9-亚甲基萘[1,8-ab]庚烯-14-羧酸苄酯(50mg,0.1mmol)的二甲亚砜(3.0mL)溶液中加入氟化钾(29mg,0.5mmol)， N,N-二异丙基乙二胺(39mg,0.3mmol)，1-甲基-1-氮杂螺环[4.4]壬-6-醇(31mg,0.2mmol)和4A分子筛，氮气保护下110℃反应4小时。反应完毕后，冷却到室温，用乙酸乙酯萃取(50mLX2)，乙酸乙酯相合并后用饱和食盐水洗(50mLX4)。乙酸乙酯相用无水硫酸钠干燥，过滤，旋干后粗品经硅胶柱层析(石油醚/乙酸乙酯＝2:1)纯化得到(5aS,6S,9R)-2-氯-12-((1-甲基-1-氮杂螺环[4.4]壬烷-6-基)氧基)-5a,6,7,8,9,10-六氢-5H-4-氧杂-3,10a,11,13,14-五氮杂-6,9-亚甲基萘[1,8-ab]庚烯-14-羧酸苄酯(28mg,收率:44％)。ES-API:[M+H] +＝591.2。
步骤十二：将(5aS,6S,9R)-2-氯-12-((1-甲基-1-氮杂螺环[4.4]壬烷-6-基)氧基)-5a，6,7,8,9,10-六氢-5H-4-氧杂-3,10a,11,13,14-五氮杂-6,9-亚甲基萘[1,8-ab]庚烯-14-羧酸苄酯(28mg,0.047mmol)溶于四氢呋喃/水(2mL/0.5mL)中，加入2-(8-乙基-3-(甲氧基甲氧基)萘-1-基)-4,4,5,5-四甲基-1,3,2-二氧硼烷(24mg,0.07mmol)，磷酸钾(30mg,0.14mmol)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)(10mg,0.014mmol)，氮气置换4次后60℃反应1小时。反应液冷却到室温，用乙酸乙酯(80mL)和水(60mL)萃取，有机相用无水硫酸钠干燥，过滤，滤液减压旋干，得到粗品用硅胶柱层析纯化(乙酸乙酯/石油醚：0-70％)得到(5aS,6S,9R)-2-(8-乙基-3-(甲氧基甲氧基)萘-1-基)-12-((1-甲基-1-氮杂螺[4.4]壬-6-基)氧基)-5a,6,7,8,9,10-六氢-5H-4-氧基-3,10a,11,13,14-五氮杂-6,9-亚甲基萘[1,8-ab]庚烯-14-羧酸苄酯(26mg,收率:73％)。ES-API:[M+H] +＝771.4。
步骤十三：向(5aS,6S,9R)-2-(8-乙基-3-(甲氧基甲氧基)萘-1-基)-12-((1-甲基-1-氮杂螺[4.4]壬-6-基)氧基)-5a,6,7,8,9,10-六氢-5H-4-氧基-3,10a,11,13,14-五氮杂-6,9-亚甲基萘[1,8-ab]庚烯-14-羧酸苄酯(26mg,0.034mmol)的甲醇(10.0mL)溶液中加入质量分数为10％的钯碳(50mg)，氢气置换4次并在氢气氛下室温反应2小时。过滤得到粗品目标化合物(5aS,6S,9R)-2-(8-乙基-3-(甲氧基甲氧基)萘-1-基)-12-((1-甲基-1-氮杂螺环[4.4]壬-6-基)氧基)-5a,6,7,8,9,10-六氢-5H-4-氧基-3,10a,11,13,14-五氮杂-6,9-亚甲基萘[1,8-ab]庚烯(17mg,收率:80％)。ES-API:[M+H] +＝637.3。
步骤十四：将(5aS,6S,9R)-2-(8-乙基-3-(甲氧基甲氧基)萘-1-基)-12-((1-甲基-1-氮杂螺环[4.4]壬-6-基)氧基)-5a,6,7,8,9,10-六氢-5H-4-氧基-3,10a,11,13,14-五氮杂-6,9-亚甲基萘[1,8-ab]庚烯(17mg,0.027mmol)溶于乙腈(6.0mL)中，冰浴下加入4M盐酸/二氧六环溶液(1.0mL,4.0mmol)，冰浴下反应0.5小时。反应完毕后，减压旋干溶剂后加入二氯甲烷(20mL)，冰水浴条件下加入三乙胺(3.0mL)。搅拌10分钟后加入二氯甲烷(100mLX1)和水(50mLX1)萃取。二氯甲烷相用无水硫酸钠干燥，过滤，滤液减压旋干，得到粗品用高效液相制备(甲酸法)得到5-乙基-4-((5aS,6S,9R)-12-((1-甲基-1-氮杂螺环[4.4]壬烷-6-基)氧基)-5a,6,7,8,9,10-六氢-5H-4-氧杂-3,10a,11,13,14-五氮杂[6,9]亚甲基萘[1,8-ab]庚烯-2-基)萘-2-醇(5-ethyl-4-((5aS,6S,9R)-12-((1-methyl-1-azaspiro[4.4]nonan-6-yl)oxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza[6,9]methanonaphtho[1,8-ab]heptalen-2-yl)naphthalen-2-ol)(Z260-1,甲酸盐，1.6mg,收率:10％)。ES-API:[M+H] +＝593.3。
实施例10：合成(5aS,6S,9R)-1-氟-12-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-2-(5-甲基-1H-吲唑-4-基)-5a,6,7,8,9,10-六氢-5H-4-氧代-3,10a,11,13,14-五氮杂-6,9-亚甲基萘并[1,8-ab]庚烯(Z382)
Figure PCTCN2022081443-appb-000063
步骤一：向叔丁基(1S,2S,5R)-2-(((7-氯-8-氟-(2-甲硫基)-4-氧杂-3,4-二氢吡啶[4,3-d]嘧啶-5-基)氧基)甲基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(200mg,0.427mmol)和(5-甲基-1H-吲唑-4-基)硼酸(230.0mg,1.307mmol)的四氢呋喃(10.0mL)和水(2.0mL)中加入碳酸铯(560mg,1.719mmol)，四三苯基膦钯(100mg,0.87mmol)，氮气鼓泡并在115℃下加热反应6小时。反应完毕，乙酸乙酯(30mLX2)和饱和食盐水(30mL)萃取。合并乙酸乙酯相，无水硫酸钠干燥，过滤，滤液减压浓缩。粗品经硅胶柱层析(甲醇/二氯甲烷＝0-4％)纯化得到叔丁基(5aS,6S,9R)-1-氟-2-(5-甲基-1H-吲唑-4-基)-12-(甲硫基)-5a,6,7,8,9,10-六氢-5H-4-氧代-3,10a,11,13,14-五氮杂-6,9-亚甲基萘并[1,8-ab]庚烯-14-羧酸酯(400mg,粗品)，黄色固体。ES-API:[M+H] +＝564.4。
步骤二：在0℃下，向叔丁基(5aS,6S,9R)-1-氟-2-(5-甲基-1H-吲唑-4-基)-12-(甲硫基)-5a,6,7,8,9,10-六氢-5H-4-氧代-3,10a,11,13,14-五氮杂-6,9-亚甲基萘并[1,8-ab]庚烯-14-羧酸酯(180mg,0.319mmol)的二氯甲烷(15mL)溶液中加入间氯过氧苯甲酸(85mg,0.493mmol)。室温搅拌1小时。用饱和亚硫酸钠淬灭反应并用二氯甲烷(100mLX2)萃取。有机层用无水硫酸钠干燥并浓缩，得到粗品通过硅胶柱层析(甲醇/二氯甲烷＝0-10％)纯化得到向叔丁基(5aS,6S,9R)-1-氟-2-(5-甲基-1H-吲唑-4-基)-12-(甲基亚磺酰基)-5a,6,7,8,9,10-六氢-5H-4-氧代-3,10a,11,13,14-五氮杂-6,9-亚甲基萘并[1,8-ab]庚烯-14-羧酸酯(200mg,粗品)，为白色固体。ES-API:[M+H] +＝580.3。
步骤三：0℃下，向含有((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲醇(110.0mg,0.691mmol)的四氢呋喃(10.0mL)溶液中加入氢化钠(55.0mg,1.382mmol)，该温度下搅拌10分钟后，再加入叔丁基(5aS,6S,9R)-1-氟-2-(5-甲基-1H-吲唑-4-基)-12-(甲基亚磺酰基)-5a,6,7,8,9,10-六氢-5H-4-氧代-3,10a,11,13,14-五氮杂-6,9-亚甲基萘并[1,8-ab]庚烯-14-羧酸酯(200mg,粗品)四氢呋喃溶液(5mL)。0℃下搅拌反应1小时。用饱和碳酸氢钠溶液淬灭反应并用乙酸乙酯萃取。有机相用饱和食盐水水，无水硫酸钠干燥，过滤，浓缩。得到粗品经硅胶柱层析(甲醇/二氯甲烷＝0-5％)纯化得到(5aS,6S,9R)-1-氟-12-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-2-(5-甲基-1H-吲唑-4-基)-5a,6,7,8,9,10-六氢-5H-4-氧代-3,10a,11,13,14-五氮杂-6,9-亚甲基萘并[1,8-ab]庚烯-14-羧酸叔丁酯(220mg,3步总收率:94.5％)，黄色固体。ES-API:[M+H] +＝675.3。
步骤四：0℃下，向(5aS,6S,9R)-1-氟-12-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-2-(5-甲基-1H-吲唑-4-基)-5a,6,7,8,9,10-六氢-5H-4-氧代-3,10a,11,13,14-五氮杂-6,9-亚甲基萘并[1,8-ab]庚烯-14-羧酸叔丁酯(200mg,0.296mmol)的乙腈(5.0mL)溶液中加入4M盐酸/二氧六环溶液(2.0mL,8.000mmol)反应液在0℃下反应1小时。浓缩，粗品用高效液相制备(碳酸氢铵法)得到(5aS,6S,9R)-1-氟-12-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-2-(5-甲基-1H-吲唑-4-基)-5a,6,7,8,9,10-六氢 -5H-4-氧代-3,10a,11,13,14-五氮杂-6,9-亚甲基萘并[1,8-ab]庚烯((5aS,6S,9R)-1-fluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-(5-methyl-1H-indazol-4-yl)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalene)(Z382,30mg,收率:17.6％)，黄色固体。ES-API:[M+1] +＝575.3。 1H NMR(500MHz,CD 3OD)δ8.39(s,2H),7.74(d,J＝27.1Hz,1H),7.59(d,J＝8.6Hz,1H),7.40(dd,J＝8.6,3.2Hz,1H),5.52(d,J＝52.0Hz,1H),5.20(t,J＝12.5Hz,1H),4.82-4.48(m,4H),4.33(d,J＝5.9Hz,1H),4.20-3.67(m,4H),3.37(dd,J＝23.7,13.9Hz,2H),2.73-1.87(m,12H)。
实施例11：合成5-乙炔基-6-氟-4-((5aS,6S,9R)-1-氟-12-((六氢-1H-吡咯嗪-3-基)甲氧基)-5a,6,7,8,9,10-六氢-5H-4-氧代-3,10a,11,13,14-五氮杂-6,9-亚甲基萘并[1,8-ab]庚烯-2-基)萘-2-醇(Z383)
Figure PCTCN2022081443-appb-000064
步骤一：向叔丁基(1S,2S,5R)-2-(((7-氯-8-氟-(2-甲硫基)-4-氧杂-3,4-二氢吡啶[4,3-d]嘧啶-5-基)氧基)甲基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸酯(100mg,0.214mmol)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(200.0mg,0.390mmol)的四氢呋喃(6mL)和水(1.5mL)中加入磷酸钾(200mg,0.943mmol)，甲磺酸[正丁基二(1-金刚烷基)膦](2-氨基-1,1'-联苯-2-基)钯(II)(50mg,0.069mmol)，氮气鼓泡并在80℃下微波反应40分钟。反应完毕，乙酸乙酯(30mLX2)和饱和食盐水(30mL)萃取。合并乙酸乙酯相，无水硫酸钠干燥，过滤，滤液减压浓缩。得到粗品经硅胶柱层析(甲醇/二氯甲烷＝0-4％)纯化得到叔丁基(5aS,6S,9R)-1-氟-2-(7-氟-3-(甲氧基甲氧基)-8-((三异丙基甲硅烷基)乙炔基)萘-1-基)-12-(甲硫基)-5a,6,7,8,9,10-六氢-5H-4-氧代-3,10a,11,13,14-五氮杂-6,9-亚甲基萘并[1,8-ab]庚烯-14-羧酸酯(210mg,粗品)，黄色固体。ES-API:[M+H] +＝818.3。
步骤二：在0℃下，向叔丁基(5aS,6S,9R)-1-氟-2-(7-氟-3-(甲氧基甲氧基)-8-((三异丙基甲硅烷基)乙炔基)萘-1-基)-12-(甲硫基)-5a,6,7,8,9,10-六氢-5H-4-氧代-3,10a,11,13,14-五氮杂-6,9-亚甲基萘并[1,8-ab]庚烯-14-羧酸酯(210mg,粗品)的二氯甲烷(15mL)溶液中加入间氯过氧苯甲酸(55mg,0.320mmol)。室温搅拌1小时。用饱和亚硫酸钠淬灭反应并用二氯甲烷(100mLX2)萃取。有机层用无水硫酸钠干燥并浓缩，得到粗品通过硅胶柱层析(甲醇/二氯甲烷＝0-10％)纯化得到叔丁基(5aS,6S,9R)-1-氟-2-(7-氟-3-(甲氧基甲氧基)-8-((三异丙基甲硅烷基)乙炔基)萘-1-基)-12-(甲基亚磺酰基)-5a,6,7,8,9,10-六氢-5H-4-氧代-3,10a,11,13,14-五氮杂-6,9-亚甲基萘并[1,8-ab]庚烯-14-羧酸酯(210mg,粗品)，白色固体。ES-API:[M+H] +＝834.4。
步骤三：0℃下，向含有(六氢-1H-吡咯嗪-3-基)甲醇(95.0mg,0.673mmol)的四氢呋喃(10.0mL)溶液中加入氢化钠(54.0mg,1.34mmol)，该温度下搅拌10分钟后，再加入叔丁基(5aS,6S,9R)-1-氟-2-(7-氟-3-(甲氧基甲氧基)-8-((三异丙基甲硅烷基)乙炔基)萘-1-基)-12-(甲基亚磺酰基)-5a,6,7,8,9,10-六氢-5H-4- 氧代-3,10a,11,13,14-五氮杂-6,9-亚甲基萘并[1,8-ab]庚烯-14-羧酸酯(270.0mg,0.324mmol)四氢呋喃溶液(5mL)。0℃下搅拌反应1小时。用饱和碳酸氢钠溶液淬灭反应并用乙酸乙酯萃取。有机相用饱和食盐水水，无水硫酸钠干燥，过滤，浓缩。得到粗品经硅胶柱层析(甲醇/二氯甲烷＝0-5％)纯化得到叔丁基(5aS,6S,9R)-1-氟-2-(7-氟-3-(甲氧基甲氧基)-8-((三异丙基甲硅烷基)乙炔基)萘-1-基)-12-((六氢-1H-吡咯嗪-3-基)甲氧基)-5a,6,7,8,9,10-六氢-5H-4-氧代-3,10a,11,13,14-五氮杂-6,9-亚甲基萘并[1,8-ab]庚烯-14-羧酸酯(300mg,粗品)，黄色固体。ES-API:[M+H] +＝911.5。
步骤四：向叔丁基(5aS,6S,9R)-1-氟-2-(7-氟-3-(甲氧基甲氧基)-8-((三异丙基甲硅烷基)乙炔基)萘-1-基)-12-((六氢-1H-吡咯嗪-3-基)甲氧基)-5a,6,7,8,9,10-六氢-5H-4-氧代-3,10a,11,13,14-五氮杂-6,9-亚甲基萘并[1,8-ab]庚烯-14-羧酸酯(300mg,粗品)的N,N-二甲基甲酰胺(5.0mL)溶液中加入氟化铯(1000mg,6.583mmol)。室温下搅拌反应0.5小时。反应完毕。用水淬灭反应，乙酸乙酯萃取。有机相饱和食盐水洗，无水硫酸钠干燥，过滤，浓缩得到叔丁基(5aS,6S,9R)-2-(8-乙炔基-7-氟-3-(甲氧基甲氧基)萘-1-基)-1-氟-12-((六氢-1H-吡咯嗪-3-基)甲氧基)-5a,6,7,8,9,10-六氢-5H-4-氧代-3,10a,11,13,14-五氮杂-6,9-亚甲基萘并[1,8-ab]庚烯-14-羧酸酯(150mg,3步总收率:60.3％)，黄色油。ES-API:[M+H] +＝755.3。
步骤五：叔丁基(5aS,6S,9R)-2-(8-乙炔基-7-氟-3-(甲氧基甲氧基)萘-1-基)-1-氟-12-((六氢-1H-吡咯嗪-3-基)甲氧基)-5a,6,7,8,9,10-六氢-5H-4-氧代-3,10a,11,13,14-五氮杂-6,9-甲氧萘并[1,8-ab]庚烯-14-羧酸酯(150mg,0.199mmol)和乙腈(5.0mL)和4M盐酸/二氧六环溶液(2.0mL,8.000mmol)反应液在0℃下反应1小时。浓缩，粗品用高效液相制备(甲酸法)得到5-乙炔基-6-氟-4-((5aS,6S,9R)-1-氟-12-((六氢-1H-吡咯嗪-3-基)甲氧基)-5a,6,7,8,9,10-六氢-5H-4-氧代-3,10a,11,13,14-五氮杂-6,9-亚甲基萘并[1,8-ab]庚烯-2-基)萘-2-醇(5-ethynyl-6-fluoro-4-((5aS,6S,9R)-1-fluoro-12-((hexahydro-1H-pyrrolizin-3-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalen-2-yl)naphthalen-2-ol)(Z383,甲酸盐，49.0mg,收率:41％)，黄色固体。ES-API:[M+1] +＝611.3。 1H NMR(500MHz,CD 3OD)δ8.43(s,2H),7.88-7.83(m,1H),7.35-7.16(m,3H),5.07(d,J＝13.7Hz,1H),4.72-4.60(m,2H),4.57-4.46(m,1H),4.37-4.19(m,2H),4.11(s,1H),3.86(d,J＝21.8Hz,2H),3.66-3.40(m,3H),2.47-1.66(m,13H)。
实施例12：合成1-(8-((5aS,6S,9R)-1-氟-12-((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-5a,6,7,8,9,10-六氢-5H-4-氧代-3,10a,11,13,14-五氮杂-6,9-亚甲基萘[1,8-ab]庚烯-2-基)萘-1-基)丙醇(Z385)
Figure PCTCN2022081443-appb-000065
步骤一：氮气保护下，向圆底烧瓶中加入1,8-二溴萘(4g,13.99mmol)，四氢呋喃(40mL)。将之冷至-70℃，向上述溶液中滴加2.5M丁基锂的正己烷溶液(6.15mL,15.39mmol)。滴加完毕，反应在-70℃下搅拌30分钟。向其中滴加3M环氧乙烷的四氢呋喃溶液(28mL,84mmol)。滴加完毕，将反应升温至0℃，搅拌1小时。向其中加入冰水(100mL)。用乙酸乙酯(50mLX3)萃取。有机相用饱和食盐水洗涤，以无水硫酸钠干燥后浓缩得到粗品，粗品用快速硅胶柱纯化(乙酸乙酯/石油醚：0-40％)得到2-(8-溴代萘-1-基)乙烷-1-醇(2g,收率:56.9％)，黄色固体。ES-API:[M+Na] +＝273.1。
步骤二：向圆底烧瓶中加入2-(8-溴代萘-1-基)乙烷-1-醇(1.4g,5.75mmol)和二氯甲烷(30mL)。氮气保护下，将之冷至0℃。搅拌下，向上述反应液中加入戴斯-马丁氧化剂(3.55g,8.36mmol)。反应在0℃下搅拌1小时。向上述反应液中加入饱和硫代硫酸钠溶液(50mL)和饱和碳酸氢钠水溶液(50mL)，在室温下搅拌5分钟。用乙酸乙酯萃取(100mLX3)。有机相用饱和食盐水洗涤，以无水硫酸钠干燥后浓缩，粗品用快速硅胶柱纯化(乙酸乙酯/石油醚：0-20％)得到2-(8-溴代萘-1-基)乙醛(1.1g,收率:79.2％)，黄色固体。ES-API:[M+H] +＝249.1。
步骤三：氮气保护下，向反应瓶中加入2-(8-溴代萘-1-基)乙醛(1.8g,7.23mmol)和四氢呋喃(40mL)，冷至-30℃。搅拌下，向上述反应液中滴加3M甲基溴化镁的四氢呋喃溶液(2.65mL,7.95mmol)。在-20℃下搅拌反应30分钟。撤去冰浴。向反应液中加入饱和氯化铵水溶液(50mL)，用乙酸乙酯萃取(50mLX3)。有机相用饱和食盐水洗涤，用无水硫酸钠干燥，浓缩后粗品用快速硅胶柱纯化(乙酸乙酯/石油醚：0-30％)得到1-(8-溴代萘-1-基)丙烷-2-醇(1.4g,收率:73％)。ES-API:[M+H] +＝287.0。
步骤四：向反应瓶中加入1-(8-溴代萘-1-基)丙烷-2-醇(1.4g,5.28mmol)和咪唑(0.719g,10.56mmol)的无水N,N-二甲基甲酰胺(15mL)溶液中加入叔丁基二甲基氯硅烷(1.03g,6.86mmol)。在室温下搅拌反应2小时。向反应液中加入饱和氯化铵水溶液(100mL)，用乙酸乙酯萃取(50mLX2)。有机相用饱和食 盐水洗涤，用无水硫酸钠干燥，浓缩后粗品用快速硅胶柱纯化(乙酸乙酯/石油醚：0-15％)得到((1-(8-溴代萘-1-基)丙烷-2-基)氧)(叔丁基)二甲基硅烷(1.9g,收率:94.8％)。ES-API:[2M+Na] +＝779.5。
步骤五：向圆底烧瓶中加入((1-(8-溴代萘-1-基)丙烷-2-基)氧)(叔丁基)二甲基硅烷(1.8g,4.74mmol)，联硼酸频那醇酯(2.41g,9.49mmol)、[1,1'-双(二苯基膦基)二茂铁]二氯化钯((347mg,0.47mmol)，醋酸钾(1.40g,14.23mmol)和1,4-二氧六环(30mL)。在氮气保护下，体系于95℃油浴中加热搅12小时。向反应液中加入水(50mL)，用乙酸乙酯萃取(30mLX3)，有机相无水硫酸钠干燥后浓缩，粗品用快速硅胶柱纯化(乙酸乙酯/石油醚：0-10％)得到叔丁基二甲基((1-(8-(4,4,5,5-四甲基-1,3,2-二氧硼烷-2-基)萘-1-基)丙烷-2-基)氧基)硅烷(1.3g,粗品)，黄色油。ES-API:[M+Na] +＝449.4。
步骤六：向圆底烧瓶中加入叔丁基二甲基((1-(8-(4,4,5,5-四甲基-1,3,2-二氧硼烷-2-基)萘-1-基)丙烷-2-基)氧基)硅烷(260mg,0.43mmol)，叔丁基(5aS,6S,9R)-2-氯-1-氟-12-(甲硫基)-5a,6,7,8,9,10-六氢-5H-4-氧-3,10a,11,13,14-五氮杂-6,9-亚甲基萘[1,8-ab]庚烯-14-羧酸酯(80mg，0.17mmol)、甲磺酸[正丁基二(1-金刚烷基)膦](2-氨基-1,1'-联苯-2-基)钯(II)(12.4mg,0.017mmol)，磷酸钾(109mg,0.51mmol)，四氢呋喃(5mL)和水(1mL)。在氮气保护下，体系于80℃微波反应器中加热40分钟。向反应液中加入水(30mL)，用乙酸乙酯萃取(30mLX3)，有机相无水硫酸钠干燥后浓缩，粗品用快速硅胶柱纯化(乙酸乙酯/石油醚：0-30％)得到叔丁基(5aS,6S,9R)-2-(8-(2-((叔丁基二甲基硅基)氧基)丙基)萘-1-基)-1-氟-12-(甲硫基)-5a,6,7,8,9,10-六氢-5H-4-氧代-3,10a,11,13,14-五氮杂-6,9-亚甲基萘[1,8-ab]庚烯-14-羧酸盐(100mg,收率:79.9％)，黄色固体。ES-API:[M+H] +＝732.3。
步骤七：向圆底烧瓶中加入叔丁基(5aS,6S,9R)-2-(8-(2-((叔丁基二甲基硅基)氧基)丙基)萘-1-基)-1-氟-12-(甲硫基)-5a,6,7,8,9,10-六氢-5H-4-氧代-3,10a,11,13,14-五氮杂-6,9-亚甲基萘[1,8-ab]庚烯-14-羧酸盐(100mg,0.14mmol)和二氯甲烷(8mL)。将之冷至0℃，向上述反应液中加入间氯过氧苯甲酸(36mg,0.20mmol)。反应在0℃搅拌1小时。向反应液中加入水(30mL)，用乙酸乙酯萃取(30mLX3)，有机相无水硫酸钠干燥后浓缩，粗品用快速硅胶柱纯化(乙酸乙酯/石油醚：0-100％)得到叔丁基(5aS,6S,9R)-2-(8-(2-((叔丁基二甲基硅基)氧基)丙基)萘-1-基)-1-氟-12-(甲基亚砜基)-5a,6,7,8,9,10-六氢-5H-4-氧-3,10a,11,13,14-五氮杂-6,9-亚甲基萘[1,8-ab]庚烯-14-羧酸盐(100mg,收率:97.8％)，黄色固体。ES-API:[M+H] +＝748.3。
步骤八：向圆底烧瓶中加入钠氢(16mg,0.40mmol)和四氢呋喃(5mL)。将之冷至0度，向上述反应液中加入((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲醇(64mg,0.40mmol)。反应在0℃下搅拌10分钟。向其中滴加叔丁基(5aS,6S,9R)-2-(8-(2-((叔丁基二甲基硅基)氧基)丙基)萘-1-基)-1-氟-12-(甲基亚砜基)-5a,6,7,8,9,10-六氢-5H-4-氧-3,10a,11,13,14-五氮杂-6,9-亚甲基萘[1,8-ab]庚烯-14-羧酸盐(100mg,0.13mmol)的四氢呋喃溶液(2mL)。滴加完毕，反应在0℃下搅拌30分钟。向反应液中加入水(30mL)，用乙酸乙酯萃取(30mLX3)，有机相无水硫酸钠干燥后浓缩，粗品用制备层析板纯化(乙酸乙酯)得到叔丁基(5aS,6S,9R)-2-(8-(2-((叔丁基二甲基硅基)氧基)丙基)萘-1-基)-1-氟-12-((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-5a,6,7,8,9,10-六氢-5H-4-氧基-3,10a,11,13,14-五氮杂-6,9-亚甲基萘[1,8-ab]庚烯-14-羧酸盐(20mg,收率:17.7％)，ES-API:[M+H] +＝843.3。
步骤九：向圆底烧瓶中加入叔丁基(5aS,6S,9R)-2-(8-(2-((叔丁基二甲基硅基)氧基)丙基)萘-1-基)-1-氟-12-((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-5a,6,7,8,9,10-六氢-5H-4-氧基-3,10a,11,13,14-五氮杂-6,9-亚甲基萘[1,8-ab]庚烯-14-羧酸盐(20mg,0.024mmol)，四丁基氟化铵(1mL,1mmol,1M四氢呋喃溶液)，和四氢呋喃(1mL)。反应在室温下搅拌24小时。向反应液中加入水(30mL)，用乙酸乙酯萃取(30mLX2)，有机相用饱和食盐水洗涤3次。有机相无水硫酸钠干燥后浓缩得到叔丁基(5aS,6S,9R)-1- 氟-12-((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基甲氧基)-2-(8-(2-羟丙基)萘-1-基)-5a,6,7,8,9,10-六氢-5H-4-氧基-3,10a,11,13,14-五氮杂-6,9亚甲基萘[1,8-ab]庚烯-14-羧酸盐(16mg,粗品)，直接用于下一步反应。ES-API:[M+H] +＝729.3。
步骤十：向圆底烧瓶中加入叔丁基(5aS,6S,9R)-1-氟-12-((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基甲氧基)-2-(8-(2-羟丙基)萘-1-基)-5a,6,7,8,9,10-六氢-5H-4-氧基-3,10a,11,13,14-五氮杂-6,9-亚甲基萘[1,8-ab]庚烯-14-羧酸盐(16mg,0.022mmol)和乙腈(1mL)。向其中加入4M的氯化氢/二氧六环溶液(1mL)。反应在室温下搅拌1小时。反应液浓缩干，粗品用高效液相制备(碳酸氢铵法)得到1-(8-((5aS,6S,9R)-1-氟-12-((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-5a,6,7,8,9,10-六氢-5H-4-氧代-3,10a,11,13,14-五氮杂-6,9-亚甲基萘[1,8-ab]庚烯-2-基)萘-1-基)丙醇(1-(8-((5aS,6S,9R)-1-fluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalen-2-yl)naphthalen-1-yl)propan-2-ol)(Z385,6mg,收率:43.4％)，白色固体。ES-API:[M+H] +＝629.3。
表A、表B或表C化合物分别参照以上实施例的制备方法通过更改部分原料制得。
表A
Figure PCTCN2022081443-appb-000066
Figure PCTCN2022081443-appb-000067
Figure PCTCN2022081443-appb-000068
Figure PCTCN2022081443-appb-000069
表B
Figure PCTCN2022081443-appb-000070
Figure PCTCN2022081443-appb-000071
Figure PCTCN2022081443-appb-000072
表C
Figure PCTCN2022081443-appb-000073
Figure PCTCN2022081443-appb-000074
Figure PCTCN2022081443-appb-000075
Figure PCTCN2022081443-appb-000076
Figure PCTCN2022081443-appb-000077
测试例1：细胞p-ERK检测实验
AGS购自ATCC；货号：CRL-1739；F12K购自Gibco；货号：21127-022；FBS购自Gibco；货号：10099-141C；胰酶(含EDTA)购自Gibco；货号：25200-072；DMSO购自VWRAMRESCO；货号：0231-500ML；96孔细胞培养板购自Corning；货号：3599；白色底不透光的96孔板购自Cisbio；货号：66PL96025；Advance ERK phospho-T202/Y204kit购自Cisbio；货号：64AERPEH；细胞计数仪购自CHEMOMETEC；型号：NC-200；酶标仪购自PerkinElmer；型号：Envison。
AGS为内源性含有KRAS G12D突变的人胃腺癌细胞株，培养于F12K+10％FBS培养基中。实验第一天，取对数生长期的细胞，用胰酶(含EDTA)消化、收集和计数细胞，并接种约20000个细胞/孔于96孔细胞培养板中，置于5％CO 2培养箱中培养过夜。使用DMSO配制1000X的化合物3.16倍梯度浓度储液，使用上述培养基稀释200倍至5X化合物储液，于细胞接种后的第二天，向每个细胞培养孔加入5X化合物储液，终浓度为1X，DMSO含量为0.1％。使用DMSO作为实验对照。加入化合物继续培养3小时之后，去除培养孔中的培养基，向每孔加入50μl细胞裂解液(来自Advance ERK phospho-T202/Y204kit，下同),混匀孵育30分钟后转移16μl混合液至白色底不透光的96孔板中，并另外取孔加入16μl细胞裂解液作为空白孔。转移完毕之后，向每个孔加入4μl p-ERK HTRF抗体混合液(来自Advance ERK phospho-T202/Y204kit)，孵育4小时后酶标仪读取HTRF荧光值(RLU)，并计算化合物的p-ERK水平抑制率IR(％)＝(RLU对照-RLU化合物)/(RLU对照-RLU空白)×100％，使用Prism 8四参数法拟合化合物浓度和对应的细胞p-ERK水平抑制率，并计算出IC 50值。结果显示：本发明化合物对p-ERK的抑制活性较高。部分化合物抑制IC 50小于1μM，或者部分化合物的IC 50小于500nM，甚至小于100nM或50nM。部分示例性化合物的结果如下表1所示。
表1
编号 AGS p-ERK IC 50(nM) 编号 AGS p-ERK IC 50(nM)
Z2 10.65 Z131-1 1.58
Z140-1 2.85 Z350 46.98
Z381 435.88    
测试例2：细胞增殖抑制实验
AsPC-1购自ATCC；货号：CRL-1682；AGS购自ATCC；货号：CRL-1739；RPMI1640购自Gibco；货号：11875-093 2235123；F12K购自Gibco；货号：21127-022；FBS购自Gibco；货号：10099-141C；胰酶(含EDTA)购自Gibco；货号：25200-072；CellTiter Glo-3D购自Progema；货号：G9683；384孔球体板购自Corning；货号：3830；白色底不透384孔板购自Corning；货号：3570；细胞计数仪购自CHEMOMETEC；型号：NC-200；酶标仪购自PerkinElmer；型号：Envison；
AsPC-1为内源性含有KRAS G12D突变的人胰腺癌细胞，培养于含10％FBS的RPMI-1640培养基中；AGS含有KRAS G12D突变的人胃癌细胞株，培养于含10％FBS的F-12K培养基中。取对数生长期的细胞，用胰酶(含EDTA)消化、收集和计数细胞，并分别接种800个AsPC-1细胞/孔或400个AGS细胞/孔于384孔球体板中，置于5％CO 2培养过夜建立3D细胞模型。使用DMSO配制1000X的化合物3.16倍梯度浓度储液，使用培养基稀释100倍至10X化合物储液，于细胞接种后的第二天，向每个 细胞培养孔中加入10X化合物储液，终浓度为1X，DMSO含量为0.1％。使用DMSO作为实验对照(control)，培养基作为空白对照(blank)。加入化合物后继续培养细胞5天后，向每孔加入30μl CellTiter-Glo工作液，混匀孵育30分钟,室温静止30分钟后转移40μl混合液到白色底不透384孔板中，酶标仪读取luminescence化学发光值，计算细胞增殖抑制率IR(％)＝(RLU对照-RLU化合物)/(RLU对照-RLU空白)×100％，使用XLFit四参数法拟合化合物梯度稀释浓度和对应的细胞增殖抑制率，计算出IC 50值。结果可知，本发明化合物对KRAS G12D突变的细胞具有较高的抑制活性，部分化合物IC 50低于1000nM；或者IC 50低于500nM；甚至低于100nM或50nM。部分示例性化合物的结果如下表2所示。
表2
编号 AGS IC 50(nM) AsPC-1IC 50(nM)
Z2 10.35 127.31
Z131-1 2.53 32.80
Z140-1 4.00 21.11
Z350 181.24 202.81
尽管本发明的具体实施方式已经得到详细的描述，根据已经公开的所有教导，本领域技术人员可以对本发明技术方案的细节进行各种修改和替换，这些改变均在本发明的保护范围之内。本发明的全部范围由所附权利要求及其任何等同物给出。

Claims (15)

  1. 一种化合物或其药学上可接受的盐、立体异构体、溶剂化物或前药：其中，
    所述化合物为式(I)所示的化合物：
    Figure PCTCN2022081443-appb-100001
    式(I)中，
    X为O或NR 11；其中，R 11选自H和C1-C6烷基；
    Y为CR 12R 13、CR 14R 15CR 16R 17、C(O)或C(O)CR 18R 19；其中，R 12、R 13、R 14和R 15各自独立地选自H、C1-C3烷基、C1-C3氘代烷基和C1-C3卤代烷基；R 16、R 17、R 18、R 19各自独立地选自H、C1-C3烷基和卤素；
    W为N或CR 20；其中，R 20为H、C1-C6烷基、卤素、C1-C6卤代烷基、C1-C6烷氧基、环烷基、环烷基-O-、杂环基或杂环基-O-；其中，所述环烷基、所述杂环基各自独立地任选地被卤素取代；
    环A选自下组：芳基、杂芳基；
    R 1为环A上任意位置的取代基；各个R 1各自独立地选自：C1-C6烷基、卤素、羟基、C1-C6烷氧基、C1-C6卤代烷基、C1-C6卤代烷氧基、氰基、NR 21R 22、C(O)NR 23R 24、CH 2R 25、N＝S(O)(C1-C6烷基) 2、S(O)C1-C6烷基、S(O) 2R 26、-S-C1-C6烷基、C2-C6烯基、C2-C6炔基、C2-C6羟基炔基、C1-C6氰基烷基、***基、-S-C1-C6卤代烷基、C1-C6羟基烷基、-CH 2C(O)NR 27R 28、-C2-C6炔基NR 29R 30、C2-C6氘代炔基、(C1-C6烷氧基)C1-C6卤代烷基-或环烷基；其中，所述环烷基任选地被卤素或C1-C6烷基取代；其中，
    R 21为H、C1-C6烷基、C1-C6卤代烷基、C(O)C1-C6烷基或C(O) 2C1-C6烷基；R 22为H、C1-C6烷基或C1-C6卤代烷基；或者R 21、R 22与和它们相连的氮原子共同构成3到6元含氮杂环基，所述3到6元含氮杂环基任选地被1个或2个选自卤素、甲基、三氟甲基、甲氧基、三氟甲氧基的基团取代；
    R 23、R 24各自独立地为H、C1-C6烷基或C1-C6卤代烷基；或者R 23、R 24与和它们相连的氮原子共同构成3到6元含氮杂环基，所述3到6元含氮杂环基任选地被1个或2个选自卤素、甲基、三氟甲基、甲氧基、三氟甲氧基的基团取代；
    R 25为羟基、氰基、杂环基、NR 251R 252、C(O)NR 253R 254或SO 2C1-C6烷基；其中，R 251、R 252、R 253、R 254各自独立地为H或C1-C6烷基；R 251、R 252与和它们相连的氮原子共同构成3到6元含氮杂环基，所述3到6元含氮杂环基任选地被1个或2个选自卤素、甲基、三氟甲基、甲氧基、三氟甲氧基的基团取代；R 253、R 254与和它们相连的氮原子共同构成3到6元含氮杂环基，所述3到6元含氮杂环基任选地被1个或2个选自卤素、甲基、三氟甲基、甲氧基、三氟甲氧基的基团取代；
    R 26为C1-C6烷基、C1-C6卤代烷基或NR 261R 262；其中，R 261、R 262各自独立地为H或C1-C6烷基；或者R 261、R 262与和它们相连的氮原子共同构成3到6元含氮杂环基，所述3到6元含氮杂环基任 选地被1个或2个选自卤素、甲基、三氟甲基、甲氧基、三氟甲氧基的基团取代；
    R 27、R 28各自独立地为H、C1-C6烷基或C1-C6卤代烷基；或者R 27、R 28与和它们相连的氮原子共同构成3到6元含氮杂环基，所述3到6元含氮杂环基任选地被1个或2个选自卤素、甲基、三氟甲基、甲氧基、三氟甲氧基的基团取代；
    R 29、R 30各自独立地为H、C1-C6烷基或C1-C6卤代烷基；或者R 29、R 30与和它们相连的氮原子共同构成3到6元含氮杂环基，所述3到6元含氮杂环基任选地被1个或2个选自卤素、甲基、三氟甲基、甲氧基、三氟甲氧基的基团取代；
    n1是0、1、2或3；
    R 2为H、氰基、卤素、C1-C6烷基、C1-C6烷氧基、C1-C6卤代烷基、C1-C6卤代烷氧基、C1-C6氘代烷氧基、NR 31R 32、C2-C4炔基或CH 2OR 33；其中，R 31、R 32、R 33各自独立地为氢或C1-C6烷基；
    R 3a、R 3b、R 3c各自独立地为氢、卤素、羟基、氰基、C1-C3烷基、C1-C3氘代烷基或C1-C3卤代烷基；
    L 1为一个键、O或NR 34；
    L 2为C1-C4亚烷基或杂芳基；其中，所述C1-C4亚烷基任意碳原子上的或任意同一个碳原子上的1个或2个氢原子任选地各自独立地被氘、C1-C6烷基或C1-C6卤代烷基取代；或者所述C1-C4亚烷基任意同一个碳原子上的2个氢原子任选地同时被-(CH 2) m3-、-(CH 2) m1-O-(CH 2) m2-、-(CH 2) m1-N-(CH 2) m2-取代从而形成环状取代基；m3为1或2；各个m1各自独立地为0、1、2或3；各个m2各自独立地为0、1、2或3；且m1、m2不同时为0；
    环B为3到6元含氮杂环基；
    环C为3到6元含氮杂环基；
    R 4为环B上任意位置的取代基；n2为0、1、2或3；
    R 5为环C上任意位置的取代基；n3为0、1、2或3；
    R 4、R 5定义如下：
    (a)每个R 4、每个R 5各自独立地为卤素、羟基、C1-C3羟基烷基、C1-C3烷基、C1-C3卤代烷基、C1-C3烷氧基、氰基、-苯基、-苯基-SO 2F、-O-苯基、-O-苯基-SO 2F、-NHC(O)苯基、-NHC(O)苯基-SO 2F、C1-C3烷基取代的吡唑基、芳C1-C3烷基-、叔丁基二甲基甲硅烷基CH 2-、-N(R 34) 2、(C1-C3烷氧基)C1-C3烷基、(C1-C3烷基)C(O)、氧代、(C1-C3卤代烷基)C(O)-、-SO 2F、(C1-C3烷氧基)C1-C3烷氧基、-CH 2OC(O)N(R 34) 2、-CH 2NHC(O)OC1-C6烷基、-CH 2NHC(O)N(R 34) 2、-CH 2NHC(O)C1-C6烷基、-CH 2(吡唑基)、-CH 2NHSO 2C1-C6烷基、-CH 2OC(O)杂环基、-OC(O)N(R 34) 2、-OC(O)NH(C1-C3烷基)O(C1-C3烷基)、-OC(O)NH(C1-C3烷基)O(C1-C3烷基)苯基(C1-C3烷基)N(CH 3) 2、-OC(O)NH(C1-C3烷基)O(C1-C3烷基)苯基、-OC(O)杂环基或-CH 2杂环基；其中，-NHC(O)苯基或-OC(O)NH(C1-C3烷基)O(C1-C3烷基)苯基中的苯基任选地被-C(O)H或OH取代；-CH 2杂环基中的杂环基任选地被氧代取代；或者，
    (b)1个R 4为-CH 2CH 2-或-CH 2CH 2CH 2-且与和它相连的碳原子共同构成环丙基或环丁基；其余R 4、每个R 5各自独立地为卤素、羟基、C1-C3羟基烷基、C1-C3烷基、C1-C3卤代烷基、C1-C3烷氧基、氰基、-苯基、-苯基-SO 2F、-O-苯基、-O-苯基-SO 2F、-NHC(O)苯基、-NHC(O)苯基-SO 2F、C1-C3烷基取代的吡唑基、芳C1-C3烷基-、叔丁基二甲基甲硅烷基CH 2-、-N(R 34) 2、(C1-C3烷氧基)C1-C3烷基、(C1-C3烷基)C(O)、氧代、(C1-C3卤代烷基)C(O)-、-SO 2F、(C1-C3烷氧基)C1-C3烷氧基、-CH 2OC(O)N(R 34) 2、-CH 2NHC(O)OC1-C6烷基、-CH 2NHC(O)N(R 34) 2、-CH 2NHC(O)C1-C6烷基、-CH 2(吡唑基)、-CH 2NHSO 2C1-C6烷基、-CH 2OC(O)杂环基、-OC(O)N(R 34) 2、-OC(O)NH(C1-C3烷基)O(C1-C3 烷基)、-OC(O)NH(C1-C3烷基)O(C1-C3烷基)苯基(C1-C3烷基)N(CH 3) 2、-OC(O)NH(C1-C3烷基)O(C1-C3烷基)苯基、-OC(O)杂环基或-CH 2杂环基；其中，-NHC(O)苯基或-OC(O)NH(C1-C3烷基)O(C1-C3烷基)苯基中的苯基任选地被-C(O)H或OH取代；-CH 2杂环基中的杂环基任选地被氧代取代；或者
    (c)1个R 5为-CH 2CH 2-或-CH 2CH 2CH 2-且与和它相连的碳原子共同构成环丙基或环丁基；其余R 5、每个R 4各自独立地为卤素、羟基、C1-C3羟基烷基、C1-C3烷基、C1-C3卤代烷基、C1-C3烷氧基、氰基、-苯基、-苯基-SO 2F、-O-苯基、-O-苯基-SO 2F、-NHC(O)苯基、-NHC(O)苯基-SO 2F、C1-C3烷基取代的吡唑基、芳C1-C3烷基-、叔丁基二甲基甲硅烷基CH 2-、-N(R 34) 2、(C1-C3烷氧基)C1-C3烷基、(C1-C3烷基)C(O)、氧代、(C1-C3卤代烷基)C(O)-、-SO 2F、(C1-C3烷氧基)C1-C3烷氧基、-CH 2OC(O)N(R 34) 2、-CH 2NHC(O)OC1-C6烷基、-CH 2NHC(O)N(R 34) 2、-CH 2NHC(O)C1-C6烷基、-CH 2(吡唑基)、-CH 2NHSO 2C1-C6烷基、-CH 2OC(O)杂环基、-OC(O)N(R 34) 2、-OC(O)NH(C1-C3烷基)O(C1-C3烷基)、-OC(O)NH(C1-C3烷基)O(C1-C3烷基)苯基(C1-C3烷基)N(CH 3) 2、-OC(O)NH(C1-C3烷基)O(C1-C3烷基)苯基、-OC(O)杂环基或-CH 2杂环基；其中，-NHC(O)苯基或-OC(O)NH(C1-C3烷基)O(C1-C3烷基)苯基中的苯基任选地被-C(O)H或OH取代；-CH 2杂环基中的杂环基任选地被氧代取代；或者
    (d)1个R 4为-CH 2CH 2-或-CH 2CH 2CH 2-且与和它相连的碳原子共同构成环丙基或环丁基；1个R 5为-CH 2CH 2-或-CH 2CH 2CH 2-且与和它相连的碳原子共同构成环丙基或环丁基；其余R 4、其余R 5各自独立地为卤素、羟基、C1-C3羟基烷基、C1-C3烷基、C1-C3卤代烷基、C1-C3烷氧基、氰基、-苯基、-苯基-SO 2F、-O-苯基、-O-苯基-SO 2F、-NHC(O)苯基、-NHC(O)苯基-SO 2F、C1-C3烷基取代的吡唑基、芳C1-C3烷基-、叔丁基二甲基甲硅烷基CH 2-、-N(R 34) 2、(C1-C3烷氧基)C1-C3烷基、(C1-C3烷基)C(O)、氧代、(C1-C3卤代烷基)C(O)-、-SO 2F、(C1-C3烷氧基)C1-C3烷氧基、-CH 2OC(O)N(R 34) 2、-CH 2NHC(O)OC1-C6烷基、-CH 2NHC(O)N(R 34) 2、-CH 2NHC(O)C1-C6烷基、-CH 2(吡唑基)、-CH 2NHSO 2C1-C6烷基、-CH 2OC(O)杂环基、-OC(O)N(R 34) 2、-OC(O)NH(C1-C3烷基)O(C1-C3烷基)、-OC(O)NH(C1-C3烷基)O(C1-C3烷基)苯基(C1-C3烷基)N(CH 3) 2、-OC(O)NH(C1-C3烷基)O(C1-C3烷基)苯基、-OC(O)杂环基或-CH 2杂环基；其中，-NHC(O)苯基或-OC(O)NH(C1-C3烷基)O(C1-C3烷基)苯基中的苯基任选地被-C(O)H或OH取代；-CH 2杂环基中的杂环基任选地被氧代取代；
    每个R 34各自独立地为氢、C1-C3烷基或C1-C3卤代烷基；或者两个R 34与和它们相连的氮原子共同构成3到6元含氮杂环基，所述3到6元含氮杂环基任选地被1个或2个选自卤素、甲基、三氟甲基、甲氧基、三氟甲氧基的基团取代；
    或者
    所述化合物为式(II-1)或式(II-2)所示化合物：
    Figure PCTCN2022081443-appb-100002
    式(II-1)或式(II-2)中，
    q为1或2；
    X为O或NR 11；其中，R 11选自H和C1-C6烷基；
    Y为CR 12R 13、CR 14R 15CR 16R 17、C(O)或C(O)CR 18R 19；其中，R 12、R 13、R 14和R 15各自独立地选自H、C1-C3烷基、C1-C3氘代烷基和C1-C3卤代烷基；R 16、R 17、R 18、R 19各自独立地选自H、C1-C3 烷基和卤素；
    W为N或CR 20；其中，R 20为H、C1-C6烷基、卤素、C1-C6卤代烷基、C1-C6烷氧基、环烷基、环烷基-O-、杂环基或杂环基-O-；其中，所述环烷基、所述杂环基各自独立地任选地被卤素取代；
    环A选自下组：芳基、杂芳基；
    R 1为环A上任意位置的取代基；各个R 1各自独立地选自：C1-C6烷基、卤素、羟基、C1-C6烷氧基、C1-C6卤代烷基、C1-C6卤代烷氧基、氰基、NR 21R 22、C(O)NR 23R 24、CH 2R 25、N＝S(O)(C1-C6烷基) 2、S(O)C1-C6烷基、S(O) 2R 26、-S-C1-C6烷基、C2-C6烯基、C2-C6炔基、C2-C6羟基炔基、C1-C6氰基烷基、***基、-S-C1-C6卤代烷基、C1-C6羟基烷基、-CH 2C(O)NR 27R 28、-C2-C6炔基NR 29R 30、C2-C6氘代炔基、(C1-C6烷氧基)C1-C6卤代烷基-或环烷基；其中，所述环烷基任选地被卤素或C1-C6烷基取代；其中，
    R 21为H、C1-C6烷基、C1-C6卤代烷基、C(O)C1-C6烷基或C(O) 2C1-C6烷基；R 22为H、C1-C6烷基或C1-C6卤代烷基；或者R 21、R 22与和它们相连的氮原子共同构成3到6元含氮杂环基，所述3到6元含氮杂环基任选地被1个或2个选自卤素、甲基、三氟甲基、甲氧基、三氟甲氧基的基团取代；
    R 23、R 24各自独立地为H、C1-C6烷基或C1-C6卤代烷基；或者R 23、R 24与和它们相连的氮原子共同构成3到6元含氮杂环基，所述3到6元含氮杂环基任选地被1个或2个选自卤素、甲基、三氟甲基、甲氧基、三氟甲氧基的基团取代；
    R 25为羟基、氰基、杂环基、NR 251R 252、C(O)NR 253R 254或SO 2C1-C6烷基；其中，R 251、R 252、R 253、R 254各自独立地为H或C1-C6烷基；R 251、R 252与和它们相连的氮原子共同构成3到6元含氮杂环基，所述3到6元含氮杂环基任选地被1个或2个选自卤素、甲基、三氟甲基、甲氧基、三氟甲氧基的基团取代；R 253、R 254与和它们相连的氮原子共同构成3到6元含氮杂环基，所述3到6元含氮杂环基任选地被1个或2个选自卤素、甲基、三氟甲基、甲氧基、三氟甲氧基的基团取代；
    R 26为C1-C6烷基、C1-C6卤代烷基或NR 261R 262；其中，R 261、R 262各自独立地为H或C1-C6烷基；或者R 261、R 262与和它们相连的氮原子共同构成3到6元含氮杂环基，所述3到6元含氮杂环基任选地被1个或2个选自卤素、甲基、三氟甲基、甲氧基、三氟甲氧基的基团取代；
    R 27、R 28各自独立地为H、C1-C6烷基或C1-C6卤代烷基；或者R 27、R 28与和它们相连的氮原子共同构成3到6元含氮杂环基，所述3到6元含氮杂环基任选地被1个或2个选自卤素、甲基、三氟甲基、甲氧基、三氟甲氧基的基团取代；
    R 29、R 30各自独立地为H、C1-C6烷基或C1-C6卤代烷基；或者R 29、R 30与和它们相连的氮原子共同构成3到6元含氮杂环基，所述3到6元含氮杂环基任选地被1个或2个选自卤素、甲基、三氟甲基、甲氧基、三氟甲氧基的基团取代；
    n1是0、1、2或3；
    R 2为H、氰基、卤素、C1-C6烷基、C1-C6烷氧基、C1-C6卤代烷基、C1-C6卤代烷氧基、C1-C6氘代烷氧基、NR 31R 32、C2-C4炔基或CH 2OR 33；其中，R 31、R 32、R 33各自独立地为氢或C1-C6烷基；
    R 3为桥环上任意位置的取代基且为氢、卤素、羟基、氰基、C1-C3烷基、C1-C3氘代烷基或C1-C3卤代烷基；
    L 3为一个键、O或NR 34；
    R 6是氢、-N(R 34) 2、杂环基、C1-C6烷基、-L-杂环基、-L-芳基、-L-杂芳基、-L-环烷基、-L-N(R 34) 2、-L-NHC(＝NH)NH 2、-L-C(O)N(R 34) 2、-L-C1-C6卤代烷基、-L-OR 34、-L-(CH 2OR 34)(CH 2) nOR 34、-L-NR 34C(O)-芳基、-L-COOH或-L-C(O)OC1-C6烷基；其中，所述杂环基、所述-L-NR 34C(O)-芳基中的 芳基、所述-L-杂环基中的杂环基、所述-L-环烷基的环烷基各自可任选地被一个或多个R 35取代或者任选地同一个碳原子上的两个氢原子同时被-CH 2CH 2-或-CH 2CH 2CH 2-取代成为环丙基或环丁基；所述-L-芳基中的芳基、所述-L-杂芳基中的杂芳基各自可任选地被一个或多个R 36取代；
    其中，每个L各自独立地为C1-C4亚烷基或杂芳基；其中，所述C1-C4亚烷基任意碳原子上的或任意同一个碳原子上的1个或2个氢原子任选地各自独立地被氘、C1-C6烷基或C1-C6卤代烷基取代；或者所述C1-C4亚烷基任意同一个碳原子上的2个氢原子任选地同时被-(CH 2) m3-、-(CH 2) m1-O-(CH 2) m2-、-(CH 2) m1-N-(CH 2) m2-取代从而形成环状取代基；m3为1或2；各个m1各自独立地为0、1、2或3；各个m2各自独立地为0、1、2或3；且m1、m2不同时为0；
    每个R 35各自独立地为卤素、羟基、C1-C3羟基烷基、C1-C3烷基、C1-C3卤代烷基、C1-C3烷氧基、氰基、-苯基、-苯基-SO 2F、-O-苯基、-O-苯基-SO 2F、-NHC(O)苯基、-NHC(O)苯基-SO 2F、C1-C3烷基取代的吡唑基、芳C1-C3烷基-、叔丁基二甲基甲硅烷基CH 2-、-N(R 34) 2、(C1-C3烷氧基)C1-C3烷基、(C1-C3烷基)C(O)、氧代、(C1-C3卤代烷基)C(O)-、-SO 2F、(C1-C3烷氧基)C1-C3烷氧基、-CH 2OC(O)N(R 34) 2、-CH 2NHC(O)OC1-C6烷基、-CH 2NHC(O)N(R 34) 2、-CH 2NHC(O)C1-C6烷基、-CH 2(吡唑基)、-CH 2NHSO 2C1-C6烷基、-CH 2OC(O)杂环基、-OC(O)N(R 34) 2、-OC(O)NH(C1-C3烷基)O(C1-C3烷基)、-OC(O)NH(C1-C3烷基)O(C1-C3烷基)苯基(C1-C3烷基)N(CH 3) 2、-OC(O)NH(C1-C3烷基)O(C1-C3烷基)苯基、-OC(O)杂环基或-CH 2杂环基；其中，-NHC(O)苯基或-OC(O)NH(C1-C3烷基)O(C1-C3烷基)苯基中的苯基任选地被-C(O)H或OH取代；-CH 2杂环基中的杂环基任选地被氧代取代；
    每个R 36各自独立地为卤素、羟基、HC(O)-、C1-C4烷基、C1-C4烷氧基、C1-C4卤代烷基、C1-C4羟基烷基或-N(R 34) 2；
    每个R 34各自独立地为氢、C1-C3烷基或C1-C3卤代烷基；或者两个R 34与和它们相连的氮原子共同构成3到6元含氮杂环基，所述3到6元含氮杂环基任选地被1个或2个选自卤素、甲基、三氟甲基、甲氧基、三氟甲氧基的基团取代；
    或者
    所述化合物为式(III)所示的化合物：
    Figure PCTCN2022081443-appb-100003
    式(III)中，
    X为O或NR 11；其中，R 11选自H和C1-C6烷基；
    Y为CR 12R 13、CR 14R 15CR 16R 17、C(O)或C(O)CR 18R 19；其中，R 12、R 13、R 14和R 15各自独立地选自H、C1-C3烷基、C1-C3氘代烷基和C1-C3卤代烷基；R 16、R 17、R 18、R 19各自独立地选自H、C1-C3烷基和卤素；
    W为N或CR 20；其中，R 20为H、C1-C6烷基、卤素、C1-C6卤代烷基、C1-C6烷氧基、环烷基、环烷基-O-、杂环基或杂环基-O-；其中，所述环烷基、所述杂环基各自独立地任选地被卤素取代；
    环A选自下组：芳基、杂芳基；
    R 1为环A上任意位置的取代基；各个R 1各自独立地选自：C1-C6烷基、卤素、羟基、C1-C6烷氧 基、C1-C6卤代烷基、C1-C6卤代烷氧基、氰基、NR 21R 22、C(O)NR 23R 24、CH 2R 25、N＝S(O)(C1-C6烷基) 2、S(O)C1-C6烷基、S(O) 2R 26、-S-C1-C6烷基、C2-C6烯基、C2-C6炔基、C2-C6羟基炔基、C1-C6氰基烷基、***基、-S-C1-C6卤代烷基、C1-C6羟基烷基、-CH 2C(O)NR 27R 28、-C2-C6炔基NR 29R 30、C2-C6氘代炔基、(C1-C6烷氧基)C1-C6卤代烷基-或环烷基；其中，所述环烷基任选地被卤素或C1-C6烷基取代；其中，
    R 21为H、C1-C6烷基、C1-C6卤代烷基、C(O)C1-C6烷基或C(O) 2C1-C6烷基；R 22为H、C1-C6烷基或C1-C6卤代烷基；或者R 21、R 22与和它们相连的氮原子共同构成3到6元含氮杂环基，所述3到6元含氮杂环基任选地被1个或2个选自卤素、甲基、三氟甲基、甲氧基、三氟甲氧基的基团取代；
    R 23、R 24各自独立地为H、C1-C6烷基或C1-C6卤代烷基；或者R 23、R 24与和它们相连的氮原子共同构成3到6元含氮杂环基，所述3到6元含氮杂环基任选地被1个或2个选自卤素、甲基、三氟甲基、甲氧基、三氟甲氧基的基团取代；
    R 25为羟基、氰基、杂环基、NR 251R 252、C(O)NR 253R 254或SO 2C1-C6烷基；其中，R 251、R 252、R 253、R 254各自独立地为H或C1-C6烷基；R 251、R 252与和它们相连的氮原子共同构成3到6元含氮杂环基，所述3到6元含氮杂环基任选地被1个或2个选自卤素、甲基、三氟甲基、甲氧基、三氟甲氧基的基团取代；R 253、R 254与和它们相连的氮原子共同构成3到6元含氮杂环基，所述3到6元含氮杂环基任选地被1个或2个选自卤素、甲基、三氟甲基、甲氧基、三氟甲氧基的基团取代；
    R 26为C1-C6烷基、C1-C6卤代烷基或NR 261R 262；其中，R 261、R 262各自独立地为H或C1-C6烷基；或者R 261、R 262与和它们相连的氮原子共同构成3到6元含氮杂环基，所述3到6元含氮杂环基任选地被1个或2个选自卤素、甲基、三氟甲基、甲氧基、三氟甲氧基的基团取代；
    R 27、R 28各自独立地为H、C1-C6烷基或C1-C6卤代烷基；或者R 27、R 28与和它们相连的氮原子共同构成3到6元含氮杂环基，所述3到6元含氮杂环基任选地被1个或2个选自卤素、甲基、三氟甲基、甲氧基、三氟甲氧基的基团取代；
    R 29、R 30各自独立地为H、C1-C6烷基或C1-C6卤代烷基；或者R 29、R 30与和它们相连的氮原子共同构成3到6元含氮杂环基，所述3到6元含氮杂环基任选地被1个或2个选自卤素、甲基、三氟甲基、甲氧基、三氟甲氧基的基团取代；
    n1是0、1、2或3；
    R 3d、R 3e、R 3f各自独立地为氢、卤素、羟基、氰基、C1-C3烷基、C1-C3氘代烷基或C1-C3卤代烷基；或者
    R 3d与R 3e相连形成-CHR 3d1-或-CHR 3d2CHR 3d3-；R 3f为氢、卤素、羟基、氰基、C1-C3烷基、C1-C3氘代烷基或C1-C3卤代烷基；R 3d1、R 3d2、R 3d3各自独立地为氢、卤素、羟基、氰基、C1-C3烷基、C1-C3氘代烷基或C1-C3卤代烷基；或者
    R 3d与R 3f相连形成-CHR 3f1-或-CHR 3f2CHR 3f3-；R 3e为氢、卤素、羟基、氰基、C1-C3烷基、C1-C3氘代烷基或C1-C3卤代烷基；R 3f1、R 3f2、R 3f3各自独立地为氢、卤素、羟基、氰基、C1-C3烷基、C1-C3氘代烷基或C1-C3卤代烷基；
    L 3为一个键、O或NR 34；
    R 6是氢、-N(R 34) 2、杂环基、C1-C6烷基、-L-杂环基、-L-芳基、-L-杂芳基、-L-环烷基、-L-N(R 34) 2、-L-NHC(＝NH)NH 2、-L-C(O)N(R 34) 2、-L-C1-C6卤代烷基、-L-OR 34、-L-(CH 2OR 34)(CH 2) nOR 34、-L-NR 34C(O)-芳基、-L-COOH或-L-C(O)OC1-C6烷基；其中，所述杂环基、所述-L-NR 34C(O)-芳基中的芳基、所述-L-杂环基中的杂环基、所述-L-环烷基的环烷基各自可任选地被一个或多个R 35取代或者任 选地同一个碳原子上的两个氢原子同时被-CH 2CH 2-或-CH 2CH 2CH 2-取代成为环丙基或环丁基；所述-L-芳基中的芳基、所述-L-杂芳基中的杂芳基各自可任选地被一个或多个R 36取代；
    其中，每个L各自独立地为C1-C4亚烷基或杂芳基；其中，所述C1-C4亚烷基任意碳原子上的或任意同一个碳原子上的1个或2个氢原子任选地各自独立地被氘、C1-C6烷基或C1-C6卤代烷基取代；或者所述C1-C4亚烷基任意同一个碳原子上的2个氢原子任选地同时被-(CH 2) m3-、-(CH 2) m1-O-(CH 2) m2-、-(CH 2) m1-N-(CH 2) m2-取代从而形成环状取代基；m3为1或2；各个m1各自独立地为0、1、2或3；各个m2各自独立地为0、1、2或3；且m1、m2不同时为0；
    每个R 35各自独立地为卤素、羟基、C1-C3羟基烷基、C1-C3烷基、C1-C3卤代烷基、C1-C3烷氧基、氰基、-苯基、-苯基-SO 2F、-O-苯基、-O-苯基-SO 2F、-NHC(O)苯基、-NHC(O)苯基-SO 2F、C1-C3烷基取代的吡唑基、芳C1-C3烷基-、叔丁基二甲基甲硅烷基CH 2-、-N(R 34) 2、(C1-C3烷氧基)C1-C3烷基、(C1-C3烷基)C(O)、氧代、(C1-C3卤代烷基)C(O)-、-SO 2F、(C1-C3烷氧基)C1-C3烷氧基、-CH 2OC(O)N(R 34) 2、-CH 2NHC(O)OC1-C6烷基、-CH 2NHC(O)N(R 34) 2、-CH 2NHC(O)C1-C6烷基、-CH 2(吡唑基)、-CH 2NHSO 2C1-C6烷基、-CH 2OC(O)杂环基、-OC(O)N(R 34) 2、-OC(O)NH(C1-C3烷基)O(C1-C3烷基)、-OC(O)NH(C1-C3烷基)O(C1-C3烷基)苯基(C1-C3烷基)N(CH 3) 2、-OC(O)NH(C1-C3烷基)O(C1-C3烷基)苯基、-OC(O)杂环基或-CH 2杂环基；其中，-NHC(O)苯基或-OC(O)NH(C1-C3烷基)O(C1-C3烷基)苯基中的苯基任选地被-C(O)H或OH取代；-CH 2杂环基中的杂环基任选地被氧代取代；
    每个R 36各自独立地为卤素、羟基、HC(O)-、C1-C4烷基、C1-C4烷氧基、C1-C4卤代烷基、C1-C4羟基烷基或-N(R 34) 2；
    每个R 34各自独立地为氢、C1-C3烷基或C1-C3卤代烷基；或者两个R 34与和它们相连的氮原子共同构成3到6元含氮杂环基，所述3到6元含氮杂环基任选地被1个或2个选自卤素、甲基、三氟甲基、甲氧基、三氟甲氧基的基团取代。
  2. 如权利要求1所述的化合物或其药学上可接受的盐、立体异构体、溶剂化物或前药，其中，所述化合物为式(II-1C1)或式(II-1C2)所示的化合物：
    Figure PCTCN2022081443-appb-100004
    各式中，X、Y、W、R 1、R 2、R 3、R 6、n1、L 3、环A各自定义同式(II-1)或式(II-2)。
  3. 如权利要求1所述的化合物或其药学上可接受的盐、立体异构体、溶剂化物或前药，其中，所述化合物为式(III-1c1)或式(III-1c2)所示的化合物：
    Figure PCTCN2022081443-appb-100005
    各式中，R 3为桥环上任意位置的取代基且为氢、卤素、羟基、氰基、C1-C3烷基、C1-C3氘代烷基或C1-C3卤代烷基；X、Y、W、环A、R 1、n1、L 3、R 6定义同式(III)。
  4. 如权利要求1所述的化合物或其药学上可接受的盐、立体异构体、溶剂化物或前药，其中，W为N或CR 20；其中，R 20为氢、氟、氯、甲基、环丙基、甲氧基或环丙氧基。
  5. 如权利要求1所述的化合物或其药学上可接受的盐、立体异构体、溶剂化物或前药，其中，X为O。
  6. 如权利要求1所述的化合物或其药学上可接受的盐、立体异构体、溶剂化物或前药，其中，Y为-CH 2-。
  7. 如权利要求1所述的化合物或其药学上可接受的盐、立体异构体、溶剂化物或前药，其中，R 2为氟、氯、羟基、甲氧基或氰基。
  8. 如权利要求1所述的化合物或其药学上可接受的盐、立体异构体、溶剂化物或前药，其中，
    环A为苯基、萘基、吡啶基、嘧啶基、吡嗪基、哒嗪基、吡咯基、吡唑基、咪唑基、1,2,3,4-四氢化萘基、2,3-二氢-1H-茚基、喹啉基、喹唑啉基、异喹啉基、吲哚基、吲唑基或苯并[d][l,3]二氧戊环；
    和/或
    R 1为环A上任意位置的取代基；n1是0、1、2或3；
    各个R 1各自独立地选自：C1-C3烷基、卤素、羟基、C1-C3烷氧基、C1-C3卤代烷基、C1-C3卤代烷氧基、氰基、NR 21R 22、C(O)NR 23R 24、CH 2R 25、N＝S(O)(C1-C3烷基) 2、S(O)C1-C3烷基、S(O) 2R 26、-S-C1-C3烷基、C2-C4烯基、C2-C4炔基、C2-C4羟基炔基、C1-C3氰基烷基、***基、-S-C1-C3卤代烷基、C1-C3羟基烷基、-CH 2C(O)NR 27R 28、-C2-C4炔基NR 29R 30、C2-C4氘代炔基、(C1-C3烷氧基)C1-C3卤代烷基-或环烷基；其中，所述环烷基任选地被卤素或C1-C3烷基取代；其中，
    R 21为H、C1-C3烷基、C1-C3卤代烷基、C(O)C1-C3烷基或C(O) 2C1-C3烷基；R 22为H、C1-C3烷基或C1-C3卤代烷基；或者R 21、R 22与和它们相连的氮原子共同构成3到6元含氮杂环基，所述3到6元含氮杂环基任选地被1个或2个选自卤素、甲基、三氟甲基、甲氧基、三氟甲氧基的基团取代；
    R 23、R 24各自独立地为H、C1-C3烷基或C1-C3卤代烷基；或者R 23、R 24与和它们相连的氮原子共同构成3到6元含氮杂环基，所述3到6元含氮杂环基任选地被1个或2个选自卤素、甲基、三氟甲基、甲氧基、三氟甲氧基的基团取代；
    R 25为羟基、氰基、杂环基、NR 251R 252、C(O)NR 253R 254或SO 2C1-C3烷基；其中，R 251、R 252、R 253、R 254各自独立地为H或C1-C3烷基；R 251、R 252与和它们相连的氮原子共同构成3到6元含氮杂环基，所述3到6元含氮杂环基任选地被1个或2个选自卤素、甲基、三氟甲基、甲氧基、三氟甲氧基的基团取代；R 253、R 254与和它们相连的氮原子共同构成3到6元含氮杂环基，所述3到6元含氮杂环基任选地被1个或2个选自卤素、甲基、三氟甲基、甲氧基、三氟甲氧基的基团取代；
    R 26为C1-C3烷基、C1-C3卤代烷基或NR 261R 262；其中，R 261、R 262各自独立地为H或C1-C3烷基；或者R 261、R 262与和它们相连的氮原子共同构成3到6元含氮杂环基，所述3到6元含氮杂环基任选地被1个或2个选自卤素、甲基、三氟甲基、甲氧基、三氟甲氧基的基团取代；
    R 27、R 28各自独立地为H、C1-C3烷基或C1-C3卤代烷基；或者R 27、R 28与和它们相连的氮原子共同构成3到6元含氮杂环基，所述3到6元含氮杂环基任选地被1个或2个选自卤素、甲基、三氟甲基、甲氧基、三氟甲氧基的基团取代；
    R 29、R 30各自独立地为H、C1-C3烷基或C1-C3卤代烷基；或者R 29、R 30与和它们相连的氮原子共同构成3到6元含氮杂环基，所述3到6元含氮杂环基任选地被1个或2个选自卤素、甲基、三氟甲基、甲氧基、三氟甲氧基的基团取代。
  9. 如权利要求1所述的化合物或其药学上可接受的盐、立体异构体、溶剂化物或前药，其中，L 3 为一根键或O。
  10. 如权利要求1所述的化合物或其药学上可接受的盐、立体异构体、溶剂化物或前药，其中，每个R 6各自独立地为
    Figure PCTCN2022081443-appb-100006
    R 4、R 5、L 2、环B、环C、n2、n3各自定义同式(I)。
  11. 如权利要求1所述的化合物或其药学上可接受的盐、立体异构体、溶剂化物或前药，其中，R 6选自下组：
    Figure PCTCN2022081443-appb-100007
  12. 如权利要求1所述的化合物或其药学上可接受的盐、立体异构体、溶剂化物或前药，其中，所述化合物选自下组：
    Figure PCTCN2022081443-appb-100008
  13. 一种药物组合物，其包含治疗有效量的如权利要求1-12任一项所述的化合物或其药学上可接受的盐、立体异构体、溶剂化物或前药；和药学上可接受的赋形剂。
  14. 如权利要求1-12任一项所述的化合物或其药学上可接受的盐、立体异构体、溶剂化物或前药或如权利要求13所述的药物组合物在制备预防和/或治疗疾病或病症的药物中的用途；所述疾病或病症为KRAS G12D相关疾病或障碍。
  15. 如权利要求14所述的用途，其中，所述疾病或病症为KRAS G12D相关癌症；所述KRAS G12D相关癌症选自下组：非小细胞肺癌、小细胞肺癌、结肠直肠癌、直肠癌或胰腺癌。
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