WO2022253250A1 - Bruton's tyrosine kinase degrader containing fused-ring or spiro-ring - Google Patents

Bruton's tyrosine kinase degrader containing fused-ring or spiro-ring Download PDF

Info

Publication number
WO2022253250A1
WO2022253250A1 PCT/CN2022/096512 CN2022096512W WO2022253250A1 WO 2022253250 A1 WO2022253250 A1 WO 2022253250A1 CN 2022096512 W CN2022096512 W CN 2022096512W WO 2022253250 A1 WO2022253250 A1 WO 2022253250A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
alkyl
reaction
membered
alternatively
Prior art date
Application number
PCT/CN2022/096512
Other languages
French (fr)
Chinese (zh)
Inventor
张寅生
任景
汪纪楠
杨晓骏
张晓平
Original Assignee
正大天晴药业集团股份有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 正大天晴药业集团股份有限公司 filed Critical 正大天晴药业集团股份有限公司
Priority to CN202280037318.XA priority Critical patent/CN117377675A/en
Publication of WO2022253250A1 publication Critical patent/WO2022253250A1/en

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present application relates to a Bruton's tyrosine kinase degradation agent containing a ring or spiro ring, its preparation method, a pharmaceutical composition containing the degradation agent, and its use in treating BTK-related diseases.
  • BTK Bruton's tyrosine kinase
  • B cells distributed in the lymphatic system, hematopoietic and blood systems, and is a member of the non-receptor tyrosine kinase Tec family, which also includes TEC, ITK/TSK/EMT and BMX have high homology in structure.
  • BTK often has abnormal expression. Because it is mainly expressed in B cells and myeloid cells, BTK is a target with better targeting and safety.
  • PROTAC proteolysis targeting chimera
  • PROTAC proteolysis targeting chimera
  • E3 ubiquitin ligases These compounds can induce target proteins to be recognized by proteasomes in cells, causing degradation of target proteins, and can effectively Reduce the amount of target protein in the cell.
  • the application relates to a compound of formula I, its stereoisomer or a pharmaceutically acceptable salt thereof,
  • L 1 is selected from -O- or -NHCO-;
  • each R is independently selected from halogen, -CN, C 1-4 alkoxy, or C 1-4 alkyl optionally substituted with one or more halogens;
  • each R 2 is independently selected from halogen or C 1-4 alkyl
  • n and n are independently selected from 0, 1, 2, or 3;
  • X is selected from CH or N;
  • X 1 , X 2 , or X 3 are independently selected from CH, C, or N;
  • the LNK group is selected from -Ak 1 -, -Ak 2 -Cy 1 -Cy 2 -, or -Ak 2 -Cy 1 -;
  • Ak is selected from a bond or -C 1-12 alkyl-, one or more carbon atoms in the -C 1-12 alkyl- are optionally replaced by O or N atoms;
  • Ak 2 is selected from a bond or -C 1-6 alkyl-;
  • Cy 1 and Cy 2 are each independently selected from 3-12 membered cycloalkyl or 3-12 membered heterocycloalkyl, the cycloalkyl or heterocycloalkyl optionally substituted by one or more halogens;
  • R 3 is selected from hydrogen, halogen, amino, or C 1-4 alkyl.
  • the proviso is that the fragment not the following snippet:
  • the proviso is that the fragment not the following snippet:
  • X 4 is -CH 2 -, and other substituents are as defined above;
  • R is selected from halogen, amino, or C 1-4 alkyl, and other substituents are as defined above;
  • R is hydrogen
  • the LNK group is selected from -Ak 1 -, -Ak 2 -Cy 1 -Cy 2 -, or -Ak 2 -Cy 1 -; and no The other substituents are as defined above.
  • L1 is selected from -O-. In some embodiments, L is selected from -NHCO-.
  • L is selected from -NHCO-, and other substituents are as defined above;
  • L is selected from -O-
  • each R is independently selected from fluoro, chloro, -CN, C alkoxy , or C optionally substituted with one or more F or chloro or bromo or iodo -3 alkyl.
  • each R is independently selected from fluoro, chloro, -CN, C 1-3 alkoxy, or C 1-3 alkyl optionally substituted with one or more F or chloro .
  • each R 1 is independently selected from fluoro, chloro, -CN, methoxy, ethoxy, or methyl optionally substituted with one or more F or chloro.
  • each R 1 is independently selected from fluoro, chloro, -CN, methoxy, or methyl optionally substituted with one or more F or chloro.
  • each R 1 is independently selected from chloro or -CF 3 .
  • each R 2 is independently selected from fluoro, chloro, bromo, iodo, or C 1-3 alkyl.
  • each R 2 is independently selected from fluoro, chloro, or C 1-3 alkyl.
  • each R 2 is independently selected from fluoro, chloro, methyl, or ethyl.
  • each R 2 is independently selected from fluoro, chloro, or methyl. In some embodiments, R is selected from fluoro.
  • n is selected from 0, 1, or 2. In some embodiments, m is selected from 0 or 1. In some embodiments, m is selected from zero.
  • n is selected from 0, 1, or 2. In some embodiments, n is selected from 0 or 1. In some embodiments, n is selected from zero.
  • X is selected from C or N. In some embodiments, X is selected from C or N. In some embodiments, X is selected from CH or N.
  • X1 is selected from C
  • X2 is selected from N
  • X3 is selected from CH
  • X1 is selected from N
  • X2 is selected from C
  • X3 is selected from N.
  • X1 is selected from C
  • X2 is selected from N
  • X3 is selected from CH
  • X1 is selected from N
  • X2 is selected from C
  • X3 is selected from N.
  • Cy is selected from the group consisting of 7-12 membered spirobicycloalkyl, 7-12 membered heterospirobicycloalkyl, 6- 12-membered bicycloalkyl or 6-12-membered heterobicycloalkyl.
  • the heterospirobicycloalkyl or heterobicycloalkyl contains 1, 2, or 3 heteroatoms selected from N, O, or S. In some embodiments, the heterospirobicycloalkyl or heterobicycloalkyl contains 1 or 2 heteroatoms selected from N or O. In some embodiments, the heterospirobicycloalkyl or heterobicycloalkyl contains 1 or 2 N atoms, or 1 N atom and 1 O atom.
  • Cy is selected from
  • the LNK group is selected from -Ak 1 -, -Ak 2 -Cy 1 -Cy 2 -, or -Ak 2 -Cy 1 -;
  • Ak is selected from a bond or -C 1-12 alkyl-; or, Ak is selected from -C 1-12 alkyl-, one or more carbon atoms in the -C 1-12 alkyl- ( For example 1-5, preferably 1-3 carbon atoms) are optionally replaced by atoms selected from O or N;
  • Ak 2 is selected from a bond or -C 1-6 alkyl-; Or; Ak 2 is selected from -C 1-6 alkyl-;
  • Cy 1 and Cy 2 are each independently selected from a 3-12 membered cycloalkyl group or a 3-12 membered heterocycloalkyl group, the cycloalkyl group or heterocycloalkyl group being optionally substituted by one or more halogens.
  • the LNK group is selected from -Ak 1 -. In some embodiments, the LNK group is selected from -Ak 2 -Cy 1 -Cy 2 -. In some embodiments, the LNK group is selected from -Ak 2 -Cy 1 -.
  • Ak 1 is selected from a bond or -C 1-10 alkyl-, one or more carbon atoms in the -C 1-10 alkyl- are optionally replaced by O or N atoms. In some embodiments, Ak is selected from a bond or -C 1-10 alkyl-, 1-5, preferably 1-3 carbon atoms in the -C 1-10 alkyl- are optionally replaced by O Or N atom replacement.
  • Ak is selected from a bond, -C 1-9 alkyl-, -C 1-9 alkyl-O-, -C 1-9 alkyl-NH-, -C 1-5 alkyl -OC 1-5 alkyl-O-, -C 1-3 alkyl-OC 1-3 alkyl-OC 1-3 alkyl-O-, or -C 1-3 alkyl-OC 1-3 alkane The group -OC 1-3 alkyl-NH-.
  • Ak is selected from a bond, -C 1-3 alkyl-, -C 8-9 alkyl-, -C 2-8 alkyl-O-, -C 2-8 alkyl-NH -, -C 2-4 alkyl-OC 3-5 alkyl-O-, -C 1-2 alkyl-OC 1-2 alkyl-OC 1-2 alkyl-O-, or -C 1- 2Alkyl - OC1-2Alkyl - OC1-2Alkyl -NH-.
  • Ak 1 is selected from a bond, -CH 2 -, -(CH 2 ) 2 -, -(CH 2 ) 9 -, -(CH 2 ) 2 O-, -(CH 2 ) 3 O- , -(CH 2 ) 4 O-, -(CH 2 ) 5 O-, -(CH 2 ) 8 O-, -(CH 2 ) 4 NH-, -(CH 2 ) 8 NH-, -(CH 2 ) 2 O(CH 2 ) 5 O-, -(CH 2 ) 2 O(CH 2 ) 3 O-, -(CH 2 ) 3 O(CH 2 ) 3 O-, -(CH 2 ) 4 O(CH 2 ) 4 O-, -(CH 2 ) 2 O(CH 2 ) 2 O(CH 2 ) 2 O(CH 2 ) 2 O-, or -(CH 2 ) 2 O(CH 2 ) 2 O(CH 2 ) 2 NH-.
  • Ak 1 is selected from -C 1-10 alkyl-, and one or more carbon atoms in the -C 1-10 alkyl- are optionally replaced by O or N atoms.
  • Ak 1 is selected from -C 1-9 alkyl-, -C 1-9 alkyl-O-, -C 1-9 alkyl-NH-, -C 1-5 alkyl- OC 1-5 alkyl-O-, -C 1-3 alkyl-OC 1-3 alkyl-OC 1-3 alkyl-O-, or -C 1-3 alkyl-OC 1-3 alkyl -OC 1-3 alkyl-NH-.
  • Ak 1 is selected from -C 1-3 alkyl-, -C 8-9 alkyl-, -C 2-8 alkyl-O-, -C 2-8 alkyl-NH- , -C 2-4 Alkyl-OC 3-5 Alkyl-O-, -C 1-2 Alkyl-OC 1-2 Alkyl-OC 1-2 Alkyl-O-, or -C 1-2 Alkyl-OC 1-2 alkyl-OC 1-2 alkyl-NH-.
  • Ak 1 is selected from -CH 2 -, -(CH 2 ) 2 -, -(CH 2 ) 9 -, -(CH 2 ) 2 O-, -(CH 2 ) 3 O-, -(CH 2 ) 4 O-, -(CH 2 ) 5 O-, -(CH 2 ) 8 O-, -(CH 2 ) 4 NH-, -(CH 2 ) 8 NH-, -(CH 2 ) 8 NH-, -(CH 2 ) 2 O(CH 2 ) 5 O-, -(CH 2 ) 2 O(CH 2 ) 3 O-, -(CH 2 ) 3 O(CH 2 ) 3 O-, -(CH 2 ) 4 O(CH 2 ) 4 O-, -(CH 2 ) 2 O(CH 2 ) 2 O(CH 2 ) 2 O(CH 2 ) 2 O-, or -(CH 2 ) 2 O(CH 2 ) 2 O(CH 2 ) 2 NH
  • Ak is selected from a bond or -C 1-4 alkyl-.
  • Ak is selected from a bond or -C 1-3 alkyl-.
  • Ak 2 is selected from a bond, -CH 2 -, or -(CH 2 ) 2 -. In some embodiments, Ak 2 is selected from a bond or -CH 2 -.
  • Ak 2 is selected from -C 1-4 alkyl-.
  • Ak 2 is selected from -C 1-3 alkyl-.
  • Ak 2 is selected from -CH 2 -, or -(CH 2 ) 2 -. In other embodiments, Ak 2 is selected from -CH 2 -.
  • Cy 1 and Cy 2 are independently selected from 3-10 membered cycloalkyl or 3-10 membered heterocycloalkyl, and the cycloalkyl or heterocycloalkyl is optionally replaced by one or more a halogen substitution.
  • Cy 1 and Cy 2 are independently selected from 3-8 membered cycloalkyl or 3-8 membered heterocycloalkyl, and the cycloalkyl or heterocycloalkyl is optionally replaced by one or more a halogen substitution.
  • Cy 1 and Cy 2 are independently selected from 3-6 membered cycloalkyl or 3-6 membered heterocycloalkyl, and the cycloalkyl or heterocycloalkyl is optionally replaced by one or more a halogen substitution.
  • Cy 1 and Cy 2 are independently selected from 4-6 membered cycloalkyl or 4-6 membered heterocycloalkyl, and the cycloalkyl or heterocycloalkyl is optionally replaced by one or more a halogen substitution.
  • Cy 1 and Cy 2 are each independently selected from 4-6 membered heterocycloalkyl optionally substituted by one or more halogens.
  • the heterocycloalkyl group contains 1, 2, or 3 heteroatoms selected from N, O, or S. In some embodiments, the heterocycloalkyl group contains 1 or 2 heteroatoms selected from N or O. In some embodiments, the heterocycloalkyl group contains 1 or 2 N atoms.
  • Cy 1 and Cy 2 are each independently selected from 3-7 membered (eg 4-6 membered) containing 1-3 (eg 1-2) heteroatoms selected from N or O or S atoms. ) heterocycloalkyl group, preferably a 4-6 membered heterocycloalkyl group containing 1-2 N atoms.
  • Cy 1 and Cy 2 are each independently selected from azetidinyl, pyrrolidinyl, piperidine ring group, piperazine ring group or azabicyclo[3.1.0]hexyl group, so The azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl or azabicyclo[3.1.0]hexyl groups are optionally substituted by one or more halogens.
  • Cy 1 is selected from azetidinyl, pyrrolidinyl, piperidine ring, piperazine ring or azabicyclo[3.1.0]hexyl, the azetidine
  • the radical, pyrrolidinyl, piperidinecyclyl, piperazinecyclyl or azabicyclo[3.1.0]hexyl is optionally substituted with one or more halogens.
  • Cy 1 is selected from
  • Cy 2 is selected from azetidinyl, pyrrolidinyl, or piperidinecyclyl.
  • Cy 2 is selected from azetidinyl. In some embodiments, Cy 2 is selected from
  • Cy 1 and Cy 2 are independently selected from said Optionally substituted with one or more halogens.
  • Cy 1 and Cy 2 are independently selected from
  • -Ak 2 -Cy 1 -Cy 2 - is selected from
  • -Ak 2 -Cy 1 -Cy 2 - is selected from
  • -Ak 2 -Cy 1 - is selected from
  • -Ak 2 -Cy 1 - is selected from
  • LNK is selected from a bond, -CH 2 -, -(CH 2 ) 2 -, -(CH 2 ) 9 -, -(CH 2 ) 2 O-, -(CH 2 ) 3 O-, -(CH 2 ) 4 O-, -(CH 2 ) 5 O-, -(CH 2 ) 8 O-, -(CH 2 ) 4 NH-, -(CH 2 ) 8 NH-, -(CH 2 ) 2 O(CH 2 ) 5 O-, -(CH 2 ) 2 O(CH 2 ) 3 O-, -(CH 2 ) 3 O(CH 2 ) 3 O-, -(CH 2 ) 4 O-(CH 2 ) 4 O-, -(CH 2 ) 2 O(CH 2 ) 2 O(CH 2 ) 2 O-, -(CH 2 ) 2 O(CH 2 ) 2 O(CH 2 ) 2 O(CH 2 ) 2 NH-,
  • LNK is selected from -CH 2 -, -(CH 2 ) 2 -, -(CH 2 ) 9 -, -(CH 2 ) 2 O-, -(CH 2 ) 3 O-, - (CH 2 ) 4 O-, -(CH 2 ) 5 O-, -(CH 2 ) 8 O-, -(CH 2 ) 4 NH-, -(CH 2 ) 8 NH-, -(CH 2 ) 2 O(CH 2 ) 5 O-, -(CH 2 ) 2 O(CH 2 ) 3 O-, -(CH 2 ) 3 O(CH 2 ) 3 O-, -(CH 2 ) 4 O-(CH 2 ) 4 O-, -(CH 2 ) 2 O(CH 2 ) 2 O(CH 2 ) 2 O-, -(CH 2 ) 2 O(CH 2 ) 2 O(CH 2 ) 2 O(CH 2 ) 2 NH-,
  • LNK is selected from a bond, -CH 2 -, -(CH 2 ) 2 -, -(CH 2 ) 9 -, -(CH 2 ) 2 O-, -(CH 2 ) 3 O-, -(CH 2 ) 4 O-, -(CH 2 ) 5 O-, -(CH 2 ) 8 O-, -(CH 2 ) 4 NH-, -(CH 2 ) 8 NH-, -(CH 2 ) 2 O(CH 2 ) 5 O-, -(CH 2 ) 2 O(CH 2 ) 3 O-, -(CH 2 ) 3 O(CH 2 ) 3 O-, -(CH 2 ) 4 O-(CH 2 ) 4 O-, -(CH 2 ) 2 O(CH 2 ) 2 O(CH 2 ) 2 O(CH 2 ) 2 O-, or -(CH 2 ) 2 O(CH 2 ) 2 O(CH 2 ) 2 NH-.
  • LNK is
  • R 3 is selected from hydrogen, halogen, amino, or C 1-3 alkyl.
  • R is selected from hydrogen, fluoro, chloro, bromo, iodo, or amino.
  • R is selected from hydrogen, fluoro, chloro, bromo, or amino.
  • R is selected from hydrogen, fluoro, or amino.
  • the "one or more” is selected from one, two, three, four, five or six. In some embodiments, the “one or more” is selected from one, two, or three. In some embodiments, the “one or more” is selected from one, or two.
  • the present application encompasses the above-defined variables and embodiments thereof, and any combination thereof.
  • the present application also relates to compounds of formula II or formula II-1, stereoisomers thereof or pharmaceutically acceptable salts thereof,
  • L 1 , R 1 , R 2 , m, n, X, X 1 , X 2 , X 3 , X 4 , LNK, R 3 are as defined above;
  • X 5 is selected from CH, CH 2 or N.
  • the present application also relates to compounds of formula III, formula IV or formula III-1, stereoisomers thereof or pharmaceutically acceptable salts thereof,
  • R 1 , R 2 , m, n, X, X 4 , LNK, R 3 are as defined above.
  • the present application also relates to compounds of formula V, formula VI, formula VII, formula VIII, formula V-1 or formula VI-1, stereoisomers thereof or pharmaceutically acceptable salts thereof,
  • R 1 , R 2 , m, n, X, X 4 , Ak 2 , Cy 1 , Cy 2 and R 3 are as defined above.
  • the aforementioned -Ak 2 -Cy 1 - is selected from -CH 2 -Cy 1 -.
  • the present application also relates to the following compounds, their stereoisomers or pharmaceutically acceptable salts thereof:
  • the present application also relates to the following compounds, their stereoisomers or pharmaceutically acceptable salts thereof:
  • the pharmaceutically acceptable salts include salts formed with inorganic acids, salts formed with organic acids, or salts formed with acidic amino acids.
  • the present application relates to a pharmaceutical composition
  • a pharmaceutical composition comprising the above-mentioned compound of the present application, its stereoisomer or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical composition of the present application further includes pharmaceutically acceptable excipients.
  • the present application relates to a method for preventing or treating BTK-related diseases in mammals, comprising administering a therapeutically effective amount of the above-mentioned compound of the present application, its stereoisomer or Its pharmaceutically acceptable salt, or its pharmaceutical composition.
  • the present application relates to the use of the above-mentioned compound, its stereoisomer or its pharmaceutically acceptable salt, or its pharmaceutical composition in the preparation of medicines for preventing or treating BTK-related diseases.
  • the present application relates to the use of the above compound, its stereoisomer or pharmaceutically acceptable salt thereof, or its pharmaceutical composition in preventing or treating BTK-related diseases.
  • the present application relates to the above compound, its stereoisomer or pharmaceutically acceptable salt thereof, or its pharmaceutical composition for preventing or treating BTK-related diseases.
  • the above-mentioned BTK-related diseases are selected from autoimmune diseases, inflammatory diseases or cancers.
  • the present application relates to a BTK degradation agent, including the above-mentioned compound of the present application, its stereoisomer or a pharmaceutically acceptable salt thereof. In some embodiments, the present application relates to the above-mentioned compound, its stereoisomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for preparing a BTK degradation agent.
  • the compounds of the present application have a degradative effect on BTK (such as OCI-LY10 cells); in vitro cell proliferation inhibitory activity; for example, for OCI-LY10 cells and TMD8-BTK (C481S) cells; compared with the kinase EGFR and TEC, it has BTK (WT) and BTK (C481S) kinase selective inhibitory activity; stable in vitro liver microsome metabolism, especially human and mouse liver microsomes; excellent in vivo pharmacokinetic data (for example, for mice); good in vivo efficacy (for example, for TMD-8 mouse subcutaneous transplanted tumor); the degradation kinetics of BTK protein in TMD8 cells is good, such as the degradation rate is high, and the degradation rate gradually increases with time.
  • BTK such as OCI-LY10 cells
  • in vitro cell proliferation inhibitory activity for example, for OCI-LY10 cells and TMD8-BTK (C481S) cells
  • WT BTK
  • C481S
  • substituted means that any one or more hydrogen atoms on the specified atom are replaced by a substituent, as long as the valence of the specified atom is normal and the substituted compound is stable.
  • Optionally substituted means substituted or unsubstituted, for example, the ethyl group is "optionally” substituted by halogen, which means that the ethyl group can be unsubstituted (CH 2 CH 3 ), monosubstituted (such as CH 2 CH 2 F), polysubstituted (eg CHFCH 2 F, CH 2 CHF 2 etc.) or fully substituted (CF 2 CF 3 ). It will be appreciated by those skilled in the art that for any group containing one or more substituents, no sterically impossible and/or synthetically impossible substitution or substitution pattern is introduced.
  • C mn herein is that moiety has an integer number of carbon atoms in the given range mn.
  • C 1-6 means that the group can have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms.
  • variable e.g, R
  • R any variable
  • its definition is independent at each occurrence. For example, if a group contains 2 R, each R has independent options.
  • halo or halogen refers to fluorine, chlorine, bromine and iodine.
  • hydroxyl refers to a -OH group.
  • amino refers to a -NH2 group.
  • alkyl refers to a hydrocarbon group with the general formula C n H 2n+1 , such as C 1 - 10 , C 1 - 6 , C 1 - 4 alkyl.
  • the alkyl group may be linear or branched.
  • C 1-6 alkyl refers to an alkyl group containing 1 to 6 carbon atoms (such as methyl, ethyl, n-propyl, isopropyl, n - butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, neopentyl, hexyl, 2-methylpentyl, etc.).
  • the alkyl portion ie, alkyl group of alkoxy, alkylamino, dialkylamino, alkylsulfonyl and alkylthio has the same definition as above.
  • alkoxy refers to -O-alkyl, such as -OC 1 -10 alkyl, -OC 1 -6 alkyl, -OC 1 -4 alkyl.
  • alkenyl refers to a straight or branched unsaturated aliphatic hydrocarbon group consisting of carbon atoms and hydrogen atoms and having at least one double bond.
  • alkenyl include, but are not limited to, C 2-10 , C 2-6 , C 2-5 alkenyl, such as ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, isobutenyl , 1,3-butadienyl, etc.
  • alkynyl refers to a straight or branched unsaturated aliphatic hydrocarbon group consisting of carbon atoms and hydrogen atoms, having at least one triple bond.
  • alkynyl include, but are not limited to, C 2-10 , C 2-6 , C 2-5 alkynyl, such as ethynyl (-C ⁇ CH), 1-propynyl (-C ⁇ C-CH 3 ), 2-propynyl (-CH 2 -C ⁇ CH), 1,3-butadiynyl (-C ⁇ CC ⁇ CH), etc.
  • cycloalkyl refers to a carbocyclic ring that is fully saturated and may exist as a monocyclic, bridged, or spiro ring. Unless otherwise indicated, the carbocycle is typically a 3 to 10 membered ring.
  • Non-limiting examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl (bicyclo[2.2.1]heptyl), bicyclo[2.2.2]octyl, Adamantyl, etc.
  • heterocycloalkyl refers to a cyclic group that is fully saturated and can exist as a monocyclic, bridged (eg, fused) or spiro ring. Unless otherwise indicated, the heterocycle is typically a 3 to 7 membered ring, a 3 to 6 membered ring containing 1 to 3 heteroatoms (preferably 1 or 2 heteroatoms) independently selected from sulfur, oxygen and/or nitrogen or a 3 to 5 membered ring.
  • 3-membered heterocycloalkyl groups include, but are not limited to, oxiranyl, thioethyl, cycloazaethyl
  • 4-membered heterocycloalkyl groups include, but are not limited to, azetidinyl, oxetyl, Cyclic, thiabutanyl
  • 5-membered heterocycloalkyl include, but are not limited to, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, isoxazolidinyl, oxazolidinyl, isothiazolidinyl, thiazolidine , imidazolidinyl, tetrahydropyrazolyl
  • 6-membered heterocycloalkyl include, but are not limited to, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, piperazin
  • heteroaryl refers to a monocyclic or fused polycyclic ring system containing at least one ring atom selected from N, O, S, the remaining ring atoms being C, and having at least one aromatic ring.
  • Preferred heteroaryl groups have a single 4 to 8 membered ring, especially a 5 to 8 membered ring, or multiple fused rings comprising 6 to 14, especially 6 to 10 ring atoms.
  • heteroaryl include, but are not limited to, pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, quinolinyl, isoquinolyl , tetrazolyl, triazolyl, triazinyl, benzofuryl, benzothienyl, indolyl, isoindolyl, etc.
  • Structural units Indicates a heteroaryl system, the linkage
  • X 1 , X 2 , and X 3 in this application they are represented as single bonds or double bonds, so that the above-mentioned structural units are heteroaryl systems, and will not violate the rules of valence bond connection, for example, it can be
  • Groups or structural fragments in this application such as LNK, Cy, Ak 1 , Cy 1 , Cy 2 , -Ak 2 -Cy 1 -Cy 2 -, -Ak 2 -Cy 1 - and specific options thereof can optionally be used
  • the reading order from left to right is correspondingly connected to the left group and the right group of the group or fragment in the general formula, for example, when Cy is selected from According to the reading order from left to right, the left side of Cy and the fragment corresponding to the left side in the general formula Link, right and right fragments connected, the resulting fragments are
  • groups or structural fragments in this application such as LNK, Cy, Ak 1 , Cy 1 , Cy 2 , -Ak 2 -Cy 1 -Cy 2 -, -Ak 2 -Cy 1 - and their specific options can be Using the reading order from right to left, they are respectively connected to the left side group and the right side group of the group or fragment in the general formula, for example, when Cy
  • treating means administering a compound or formulation described herein to improve or eliminate a disease or one or more symptoms associated with the disease, and includes:
  • prevention means administering a compound or formulation described herein to prevent a disease or one or more symptoms associated with the disease, including: preventing a disease or disease state from occurring in a mammal, especially when the when the mammalian mammal is susceptible to the disease state but has not been diagnosed as having the disease state.
  • terapéuticaally effective amount means (i) treating or preventing a particular disease, condition or disorder, (ii) alleviating, ameliorating or eliminating one or more symptoms of a particular disease, condition or disorder, or (iii) preventing or delaying The amount of a compound of the application for the onset of one or more symptoms of a particular disease, condition or disorder described herein.
  • the amount of a compound of the present application that constitutes a “therapeutically effective amount” will vary depending on the compound, the disease state and its severity, the mode of administration, and the age of the mammal to be treated, but can be routinely determined by a person skilled in the art according to its own knowledge and this disclosure.
  • pharmaceutically acceptable refers to those compounds, materials, compositions and/or dosage forms which, within the scope of sound medical judgment, are suitable for use in contact with human and animal tissues without excessive Toxicity, irritation, allergic reaction or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • salts for example, metal salts, ammonium salts, salts with organic bases, salts with inorganic acids, salts with organic acids, salts with basic or acidic amino acids, etc. .
  • composition refers to a mixture of one or more compounds of the present application or their salts and pharmaceutically acceptable auxiliary materials.
  • the purpose of a pharmaceutical composition is to facilitate administration of a compound of the present application to an organism.
  • pharmaceutically acceptable excipients refers to those excipients that have no obvious stimulating effect on the organism and will not impair the biological activity and performance of the active compound. Suitable excipients are well known to those skilled in the art, such as carbohydrates, waxes, water-soluble and/or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water and the like.
  • parameter values should be understood as being modified by the term "about”.
  • the term “about” indicates an error value exists, for example, it means a variation within ⁇ 5%, such as ⁇ 1% or ⁇ 0.1%, of a certain value.
  • tautomer or "tautomeric form” refers to structural isomers of different energies that can interconvert via a low energy barrier.
  • proton tautomers also known as prototropic tautomers
  • proton tautomers include interconversions via migration of a proton, such as keto-enol and imine-enamine isomerizations.
  • a specific example of a proton tautomer is the imidazole moiety, where a proton can migrate between two ring nitrogens.
  • Valence tautomers include interconversions through recombination of some of the bonding electrons.
  • the present application also includes isotopically labeled compounds of the present application that are identical to those described herein, but wherein one or more atoms are replaced by an atom having an atomic mass or mass number different from that normally found in nature.
  • isotopes that may be incorporated into the compounds of the present application include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F, 123 I, 125 I and 36 Cl, etc.
  • Certain isotopically labeled compounds of the present application are useful in compound and/or substrate tissue distribution assays.
  • Tritiated (ie3H ) and carbon-14 (ie14C ) isotopes are especially preferred for their ease of preparation and detectability.
  • Positron-emitting isotopes such as 15 O, 13 N, 11 C, and 18 F, can be used in positron emission tomography (PET) studies to determine substrate occupancy.
  • Isotopically labeled compounds of the present application can generally be prepared by following procedures similar to those disclosed in the Schemes and/or Examples below, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.
  • substitution with heavier isotopes such as deuterium may confer certain therapeutic advantages resulting from greater metabolic stability (e.g. increased in vivo half-life or reduced dosage requirements), and thus in some cases
  • deuterium substitution may be partial or complete, partial deuterium substitution meaning at least one hydrogen is replaced by at least one deuterium.
  • Compounds of the present application may be asymmetric, for example, having one or more stereoisomers. Unless otherwise stated, all stereoisomers are included as enantiomers and diastereomers.
  • the compounds of the present application containing asymmetric carbon atoms can be isolated in optically pure or racemic forms. Optically pure forms can be resolved from racemic mixtures or synthesized by using chiral starting materials or reagents.
  • the pharmaceutical composition of the present application can be prepared by combining the compound of the present application with suitable pharmaceutically acceptable auxiliary materials, for example, it can be formulated into solid, semi-solid, liquid or gaseous preparations, such as tablets, pills, capsules, powders , granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres and aerosols, etc.
  • Typical routes of administering a compound of the present application or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, Intramuscular, subcutaneous, intravenous administration.
  • the pharmaceutical composition of the present application can be produced by methods well known in the art, such as conventional mixing methods, dissolving methods, granulating methods, dragee-making methods, pulverizing methods, emulsifying methods, freeze-drying methods and the like.
  • the pharmaceutical composition is in oral form.
  • the pharmaceutical compositions can be formulated by mixing the active compounds with pharmaceutically acceptable excipients well known in the art. These excipients enable the compounds of the present application to be formulated into tablets, pills, lozenges, dragees, capsules, liquids, gels, slurries, suspensions, etc. for oral administration to patients.
  • Solid oral compositions can be prepared by conventional methods of mixing, filling or tabletting. It can be obtained, for example, by mixing the active compound with solid excipients, optionally milling the resulting mixture, adding other suitable excipients if desired, and then processing the mixture into granules to obtain tablets or The core of the icing.
  • Suitable auxiliary materials include but are not limited to: binders, diluents, disintegrants, lubricants, glidants, sweeteners or flavoring agents, etc.
  • the pharmaceutical composition may also be adapted for parenteral administration as a suitable unit dosage form of sterile solutions, suspensions or lyophilized products.
  • the daily dose is administered in a dose of 0.01 to 200 mg/kg body weight, in single or divided doses.
  • the compounds of the present application can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, the embodiments formed by combining them with other chemical synthesis methods, and equivalents well known to those skilled in the art Alternatives, preferred implementations include but are not limited to the examples of this application.
  • the compound of formula I of the present application can be prepared by those skilled in the art of organic synthesis through the following routes:
  • the compound of general formula (1-1) obtains the compound of general formula (1-2) through nucleophilic substitution reaction or Guangyan reaction, then obtains the compound of general formula (1-3) by coupling reaction, obtains general formula ( 1-4) compound, the corresponding compound of general formula (1-5) is obtained by nucleophilic substitution reaction or reductive amination, if the reaction site of the compound of general formula (1-5) has an amino protecting group, first remove the amino protecting group and then The compound of general formula I is obtained by nucleophilic substitution reaction, coupling reaction or reductive amination.
  • the preparation of a longer chain can be obtained by repeating the fourth step and removing the amino protecting group.
  • the compound of general formula (2-2) is reacted with the compound of general formula (1-4) to obtain the compound of general formula (2-3) through reductive amination or nucleophilic substitution reaction, and then the compound of general formula I is obtained through ring closure reaction.
  • the compound of the general formula (3-1) obtains the compound of the general formula (3-2) through a nucleophilic substitution reaction or the Mitsunobu reaction, and then removes the protecting group to obtain a compound of the general formula (3-3).
  • chemical reaction or coupling reaction to obtain the corresponding compound of general formula (3-4) if there is an amino protecting group at the reaction site of the compound of general formula (3-4), first remove the amino protecting group and then pass nucleophilic substitution reaction, reductive amination or The coupling reaction gives the compound of general formula I.
  • the preparation of a longer chain can be obtained by repeating the third step and removing the amino protecting group.
  • X6 is selected from halogen
  • X7 is selected from H, and other substituents are as defined above;
  • the compound of general formula (4-1) obtains the compound of general formula (4-2) through nucleophilic substitution reaction or coupling reaction, then obtains the compound of general formula (4-3) through oxidation reaction, and the compound of general formula (4-3) and The compound of general formula (3-3) is obtained by reductive amination to the compound of general formula I.
  • HATU stands for 2-(7-benzotriazole oxide)-N,N,N',N'-tetramethyluronium hexafluorophosphate
  • DMF stands for N,N-di Methylformamide
  • DCM represents dichloromethane
  • NBS represents N-bromosuccinimide
  • EA represents ethyl acetate
  • DMSO represents dimethyl sulfoxide
  • Boc represents tert-butoxycarbonyl
  • PdCl 2 (dppf) ⁇ CH 2 Cl 2 stands for [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex
  • PE stands for petroleum ether
  • THF stands for tetrahydrofuran
  • AIBN stands for azobisisobutyronitrile
  • MeOH represents methanol
  • AcOH represents acetic acid
  • NMP represents methylpyrrolidone
  • IBX represents 2-iodano
  • intermediate 1u (267mg), DMF (2mL), 1j (450mg) and triethylamine (398mg) were sequentially added, and the mixture was reacted at 60°C for 1h under the protection of N 2 .
  • the reaction liquid was cooled to room temperature, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (EA/CH 3 OH/NH 4 OH) to obtain 0.283 g of intermediate 1v.
  • intermediate 2a (20.93g), DMSO (50mL), intermediate 2b (10g), slowly drop the solution of potassium hydroxide (8.09g) in H 2 O (2mL)
  • the reaction solution was stirred at 0° C. for 10 min, then transferred to room temperature and stirred for 6 h.
  • Water (200 mL) was added to the reaction solution to quench it.
  • the organic phase was separated, washed with 200 mL of saturated brine, dried with anhydrous sodium sulfate, filtered, and the filtrate was evaporated to remove the solvent under reduced pressure to obtain 30 g of intermediate 2c.
  • intermediate 3a Into a one-necked flask, intermediate 3a (5 g), triethylamine (4.50 g) and DCM (30 mL) were sequentially added. The temperature was lowered to about 0°C, p-toluenesulfonyl chloride (6.52 g) was slowly added, and the mixture was reacted overnight at room temperature under the protection of N 2 . After the reaction, DCM (100 mL) and water (200 mL) were added to the reaction solution.
  • the intermediate 1t (2g) was dissolved in N,N-dimethylformamide (20mL), and then 1,5-dibromopentane (5.95g) and cesium carbonate (6.02g) were added, React at room temperature for 2 hours. After the reaction was complete, ethyl acetate (200 mL) and water (200 mL) were added to the system. The organic phase was separated, the aqueous phase was extracted with ethyl acetate (50 mL ⁇ 2), and the organic phases were combined. The organic phase was washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, and filtered. The solvent was distilled off from the filtrate under reduced pressure, and the crude product was separated by silica gel column chromatography (eluent: dichloromethane/methanol) to obtain the target intermediate 7b (1.5 g).
  • silica gel column chromatography eluent: dichloromethane/methanol
  • Embodiment 8 the synthesis of compound 8
  • intermediate 8a (1021mg), DMF (20mL), potassium carbonate (546mg) and intermediate 1t (500mg) were added sequentially, and the mixture was reacted at 80°C for 16.5h.
  • the reaction solution was cooled to room temperature, the solvent was evaporated under reduced pressure, and EA (200 mL) and water (200 mL) were added to the residue.
  • EA 200 mL
  • water 200 mL
  • the organic phase was separated, washed with 100 mL of saturated brine, dried with anhydrous sodium sulfate, filtered, and the filtrate was evaporated under reduced pressure to remove the solvent, then purified by reverse phase column chromatography (H 2 O/CH 3 CN) to obtain 0.220 g of intermediate Body 8b.
  • intermediate 9b (642mg), intermediate 1j (600mg), potassium carbonate (383mg) and DMF (10mL) successively, under N2 protection, oil bath to 50 °C for 2 hours, the reaction is complete, the reaction Add water (100mL) to the solution, extract with DCM-MeOH (20:1) (50mL ⁇ 2), combine organic layers, wash with water (50mL ⁇ 1), and saturated brine (50mL ⁇ 1), dry the extract, filter, After the filtrate was rotary evaporated, the residue was purified by silica gel column chromatography (DCM-MeOH) to obtain the target compound 9c (302 mg).
  • DCM-MeOH silica gel column chromatography
  • the intermediate 11c (2 g) and allyl benzyl ether (0.807 g) were dissolved in dioxane (20 mL), and tetrakis(triphenylphosphine) palladium (1.16 g) and carbonic acid Potassium (1.38g), under the protection of N 2 , the mixture was heated to 100°C for 16 hours. After the reaction was completed, the reaction liquid was cooled to room temperature, and the solvent was evaporated under reduced pressure. The crude product was separated by silica gel column chromatography (eluent: dichloromethane/methanol) to obtain the target intermediate 11d (1.5 g).
  • the intermediate 11d (1g) was dissolved in methanol (10mL), and then Pd/C (0.1g, 0.094mmol) was added, and the reaction solution was first replaced with nitrogen for 2-3 times, and then replaced with hydrogen for 2 -3 times, stirred at 50°C for 17 hours. After the reaction was completed, the reaction liquid was cooled to room temperature, filtered, and rinsed with methanol solvent (50 mL). The filtrate was evaporated to remove the solvent under reduced pressure, and the crude product was separated by silica gel column chromatography (eluent: dichloromethane/methanol) to obtain the target intermediate 11e (400 mg).
  • the intermediate 11e (300 mg) was dissolved in dichloromethane (5 mL), and Dess Martin oxidant (1.053 g) was added, and reacted at room temperature for 1 hour. After the reaction was complete, dichloromethane (50 mL) and water (50 mL) were added to the system. The organic phase was separated, and the aqueous phase was extracted with dichloromethane (50 mL ⁇ 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and no purification was required. The solvent was evaporated under reduced pressure to obtain intermediate 11f (300 mg).
  • intermediate 11f 250 mg
  • intermediate 1j 352 mg
  • sodium cyanoborohydride 131 mg
  • acetic acid 1 drop
  • dichloromethane 50 mL
  • water 50 mL
  • intermediate 15c (2.20g), iron powder (1.655g), ammonium chloride (3.17g), ethanol (50mL) and water (5mL) in sequence, and heat at 80°C for 2 hours under the protection of N2 , the reaction was complete, the iron powder residue was filtered off, the filter cake was washed with methanol and DCM-MeOH (10:1) successively, the filtrate and washings were combined, and spin-dried to obtain the target object 15d (1.85g).
  • intermediate 15g (550mg), acetone (100mL) and sodium iodide (5110mg) in sequence, under the protection of N2 , heat at 100°C to react overnight, the reaction is complete, and the residue after the reaction liquid is rotary evaporated is used EA (30mL ⁇ 2) was extracted, the organic layers were combined and washed with saturated brine (50mL ⁇ 1), the organic layer extract was dried and filtered, and the filtrate was rotary evaporated to dryness to obtain intermediate 15h (782mg).
  • intermediate 16c (280mg), acetonitrile (25mL) and IBX (494mg) successively, under the protection of N2 , react at 80°C for 2.5 hours, the reaction is complete, filter, and obtain intermediate 16d (610mg ).
  • intermediate 17h (1.8g), intermediate 1b (1.636g), potassium carbonate (1.500g), H2O (3mL), 1,4-dioxane (15mL) and PdCl2 to the reaction flask in sequence (dppf) ⁇ CH 2 Cl 2 (0.265 g), replaced by N 2 three times, then the mixture was heated to 85° C. for 2 h, and the heating was stopped. 200 mL of water was added to the reaction liquid, and then extracted twice with 100 mL of DCM. The combined organic layers were washed twice with 100 mL of saturated sodium chloride solution. After washing, it was dried over anhydrous sodium sulfate, filtered, concentrated, and the concentrate was separated and purified by silica gel column chromatography to obtain intermediate 17i (1.109 g).
  • reaction solution was cooled to room temperature, 200 mL of ethyl acetate and 300 mL of water were added, the organic phase was separated, washed with saturated sodium chloride solution (100 mL), dried with anhydrous sodium sulfate, filtered, and the concentrate was separated and purified by silica gel column chromatography to obtain intermediate Body 18b (5.039 g).
  • intermediate 18b (5g), intermediate 1b (6.90g), potassium carbonate (5.07g) and PdCl 2 (dppf) ⁇ CH 2 Cl 2 (0.998g) in the reaction flask, add solvent water (6mL) and 1 , 4-dioxane (30mL), under the protection of N 2 , the mixture was heated to 80°C for 14h.
  • the reaction solution was cooled to room temperature, 100mL EA and 100mL water were added, the organic phase was separated, washed with saturated sodium chloride solution (100mL), dried over anhydrous sodium sulfate, filtered, concentrated, and the concentrate was separated and purified by silica gel column chromatography to obtain the intermediate 18c (5.0 g).
  • intermediate 20a 25g
  • NBS 29.6g
  • azobisisobutyronitrile 6.83g
  • carbon tetrachloride 200mL
  • intermediate 21a (12.8g), NBS (13.13g), azobisisobutyronitrile (3.03g) and carbon tetrachloride (130mL) in sequence, and heat to 85°C under N2 protection 4.5 hours. After the reaction solution was cooled to room temperature, it was filtered, the filtrate was washed with water (150mL ⁇ 2), and saturated brine (150mL ⁇ 1), the organic layer was stirred and dried with anhydrous sodium sulfate, and then suction filtered, and the filtrate was rotary evaporated to dryness to obtain intermediate 21b ( 19.27g).
  • Embodiment 23 the synthesis of compound 23
  • intermediate 25b (1.198g), intermediate 15d (1.5g), acetic acid (0.270g) and methanol (30mL) successively, add sodium cyanoborohydride (1.131g), under N 2 protection, The reaction was stirred overnight at room temperature. After the reaction, add saturated sodium bicarbonate solution (30mL) and saturated sodium chloride solution (30mL) to the reaction solution, extract with EA (70mL ⁇ 2), combine the organic phases, wash once with saturated brine, dry over anhydrous sodium sulfate, and filter , concentrated, and subjected to silica gel column chromatography to obtain 1.876 g of intermediate 25c.
  • intermediate 26b (1.9g), DCM (100mL) and dess-martin oxidant (4.49g) successively, under the protection of N 2 , stir at room temperature for 1.5 hours, the reaction is complete, and the reaction solution is watered (50mL ⁇ 2) After washing, the organic layer was washed with saturated brine (100 mL ⁇ 1), the extract was dried and filtered, and the filtrate was rotary evaporated to dryness to obtain intermediate 26c (3.67 g).
  • intermediate 27b (0.72g), DCM (30mL) and Dess Martin oxidant (1.691g) in turn, under N2 protection, stir at room temperature for 1.5 hours, the reaction is complete, the reaction solution is water (50mL ⁇ 2) After washing, the organic layer was washed with saturated brine (100 mL ⁇ 1), the extract was dried and filtered, and the filtrate was rotary evaporated to dryness to obtain intermediate 27c (1.405 g).
  • compound 28d (868 mg) and compound 1j (500 mg) were dissolved in methanol (5 mL), sodium cyanoborohydride (147 mg) was added, 1 drop of acetic acid was added, and the reaction was carried out at room temperature for 2 hours. After the reaction was complete, dichloromethane (50 mL) and water (50 mL) were added to the system.
  • intermediate 29c (1.4g), bromoacetaldehyde diethyl acetal (2.418g), N,N-diisopropylethylamine (2.64g) and DMSO (10mL) to the reaction flask, under N 2 protection, The mixture was heated to 80°C for 6h. The reaction solution was cooled to room temperature, and DCM (100 mL) and water (100 mL) were added. The organic phase was separated, washed with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and the concentrate was separated and purified by silica gel column chromatography to obtain intermediate 29d (0.495 g).
  • compound 30d (352 mg) and compound 1j (500 mg) were dissolved in methanol (5 mL), then sodium cyanoborohydride (147 mg) was added, and 1 drop of acetic acid was added, and reacted at room temperature for 2 hours. After the reaction was complete, dichloromethane (50 mL) and water (50 mL) were added to the system.
  • compound 31b (1.300 g) was dissolved in N-methylpyrrolidone (10 mL), and (1R, 5S, 6R)-3-azabicyclo[3.1.0]hexane-6-methanol ( 0.5g) and N,N-diisopropylethylamine (1.713g), heated to 80°C for 9 hours. After the reaction was completed, the reaction liquid was cooled to room temperature, and the solvent was evaporated. The crude product was separated by silica gel column chromatography (eluent: dichloromethane/methanol) to obtain intermediate 31c (1.21g).
  • intermediate 31c (550mg), DCM (20mL) and dess-martin oxidant (1193mg) successively, under N protection, react at room temperature for 2 hours, the reaction is complete, after adding water in the reaction solution, use DCM-MeOH ( 20:1, 50mL ⁇ 2) extraction, the organic layers were combined and washed with saturated brine (50mL ⁇ 1), the extract was dried and filtered, and the filtrate was rotary evaporated to dryness to obtain intermediate 31d (555mg).
  • DCM-MeOH 20:1, 50mL ⁇ 2
  • intermediate 33c (0.36g), intermediate 13b (0.080g), N,N-diisopropylethylamine (0.075g) and DMSO (6mL) to the reaction flask in sequence, and heat the mixture to 80°C for 5h . After cooling to room temperature, 100 mL of DCM and 100 mL of water were added to the reaction solution. The organic phase was separated, washed with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated, and the concentrate was separated and purified by silica gel column chromatography to obtain compound 33 (0.052 g).
  • compound 33c 200mg
  • compound 31b 115mg
  • dimethyl sulfoxide 5mL
  • N,N-diisopropylethylamine 230mg
  • the temperature was raised to 90°C for reaction 4 Hour.
  • the reaction solution was cooled to room temperature, and the crude product was purified by reverse phase (eluent: water/acetonitrile) to obtain compound 34 (70 mg).
  • intermediate 35c (0.4g), intermediate 13b (0.054g), N,N-diisopropylethylamine (0.050g) and DMSO (6mL) to the reaction flask in sequence, and heat the mixture to 80°C for 5h . After cooling to room temperature, 100 mL of DCM and 100 mL of water were added to the reaction solution. The organic phase was separated, washed with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated, and the concentrate was separated and purified by silica gel column chromatography to obtain compound 35 (0.015 g).
  • intermediate 13b (1.0g), 3-hydroxymethylazetidine hydrochloride (0.534g), NMP (15mL) and N,N-diisopropylethylamine (1.863 g), under the protection of N 2 , heated at 80°C for 4 hours, the reaction was complete, and the residue was extracted with DCM-MeOH (10:1, 30mL ⁇ 3) after the reaction solution was rotary evaporated, and the organic layers were combined and washed with saturated brine (50mL ⁇ 3) 1) Washing, drying and filtering the extract, and rotary evaporation of the filtrate to obtain intermediate 36b (2.49g).
  • intermediate 36b (0.25g), DCM (10mL) and Dess Martin oxidant (0.911g) successively, under N protection, react at room temperature for 2 hours, the reaction is complete, and the reaction solution is washed with DCM-MeOH (20 :1, 30mL ⁇ 2) extraction, the organic layers were combined and washed with saturated brine (50mL ⁇ 1), the extract was dried and filtered, and the filtrate was rotary evaporated and dried to obtain intermediate 36c (400mg).
  • the S-configuration intermediate 37b-1 600 mg was the first peak
  • the R-configuration intermediate 37b-2 510 mg was the last peak.
  • compound 37c 300 mg
  • tert-butyl 3-oxazetidine-1-carboxylate 128 mg
  • sodium cyanoborohydride 62.8 mg
  • Embodiment 39 Preparation of compound 39
  • Embodiment 40 the synthesis of compound 40
  • Embodiment 41 Preparation of compound 41
  • compound 41c 300 mg
  • tert-butyl 3-oxazetidine-1-carboxylate 110 mg
  • sodium cyanoborohydride 53.9 mg
  • reaction flask Into the reaction flask, add intermediate 44c (120mg), intermediate 13b (63.8mg), DMSO (3mL) and N,N-diisopropylethylamine (124mg) in turn, under N 2 protection, react at 90°C 4 Hours, the reaction was complete, and the reaction solution was directly eluted with a C18 reverse-phase column (10nM ammonium acetate aqueous solution-acetonitrile), and the column liquid was combined, extracted with DCM-MeOH (10:1) and then evaporated to dryness to obtain the target object 44 (62mg ).
  • a C18 reverse-phase column 10nM ammonium acetate aqueous solution-acetonitrile
  • intermediate 46a (1.12g), tert-butyl-7-hydroxy-2-azaspiro[3.5]nonane-2-carboxylate (0.89g), triphenyl Phosphorus (1.94g) and tetrahydrofuran (150mL) were cooled to 0°C, diisopropyl azodicarboxylate (2.24g) was added dropwise, and the addition was completed in about 15 minutes, and the temperature was raised to 25°C for 16 hours.
  • reaction solution was poured into 200 mL of purified water, ethyl acetate (200 mL) was added for extraction and layering, the organic phase was washed with saturated aqueous sodium chloride solution (100 mL), and the organic phase was concentrated to obtain a crude product, which was purified by a silica gel column (petroleum ether /ethyl acetate) to obtain intermediate 46b (5.26g).
  • Embodiment 47 the preparation of compound 47
  • intermediate 46c (170 mg), intermediate 36c (253 mg), DCM (30 mL) and glacial acetic acid (22.26 mg) were sequentially added, and the mixture was stirred at room temperature for 20 min under N 2 protection.
  • Sodium cyanoborohydride (69.9mg) was added to the reaction solution, and continued to stir at room temperature under N2 protection for 2 hours. The reaction was complete.
  • Step 1 Preparation of intermediates 51b-1 and 51b-2
  • Embodiment 53 Preparation of compound 53

Abstract

The present application relates to a Bruton's tyrosine kinase (BTK) degrader containing a fused-ring or spiro-ring, a preparation method therefor, a pharmaceutical composition containing the compound, and a use thereof in preventing or treating BTK-related diseases.

Description

含有并环或螺环的布鲁顿酪氨酸激酶降解剂Bruton's tyrosine kinase degraders containing fused or spiro rings 技术领域technical field
本申请涉及含有并环或螺环的布鲁顿酪氨酸激酶降解剂、其制备方法、含有该降解剂的药物组合物、以及其在治疗BTK相关疾病中的用途。The present application relates to a Bruton's tyrosine kinase degradation agent containing a ring or spiro ring, its preparation method, a pharmaceutical composition containing the degradation agent, and its use in treating BTK-related diseases.
背景技术Background technique
布鲁顿酪氨酸激酶(Bruton's tyrosine kinase，BTK)主要在B细胞中表达，分布于淋巴系统、造血及血液系统，是非受体型酪氨酸激酶Tec家族中一员，该家族成员还包括TEC、ITK/TSK/EMT和BMX，在结构上具有高度同源性。近年来有关B细胞特别是针对B细胞非霍奇金性淋巴癌和类风湿关节炎的研究发现，BTK往往会出现异常表达。由于主要在B细胞和髓细胞中表达，BTK是一种靶向性和安全性较好的靶点。Bruton's tyrosine kinase (BTK) is mainly expressed in B cells, distributed in the lymphatic system, hematopoietic and blood systems, and is a member of the non-receptor tyrosine kinase Tec family, which also includes TEC, ITK/TSK/EMT and BMX have high homology in structure. In recent years, studies on B cells, especially B cell non-Hodgkin's lymphoma and rheumatoid arthritis, have found that BTK often has abnormal expression. Because it is mainly expressed in B cells and myeloid cells, BTK is a target with better targeting and safety.
PROTAC(proteolysis targeting chimera)分子是一类能够同时结合靶向蛋白和E3泛素连接酶的双功能化合物，此类化合物能够诱导靶蛋白被细胞的蛋白酶体识别，引起靶蛋白的降解，能够有效地降低靶蛋白在细胞中的含量。通过在PROTAC分子引入能结合不同靶向蛋白的配体，使PROTAC技术应用于各种疾病的治疗成为可能，该技术近年来同时得到了广泛的关注。PROTAC (proteolysis targeting chimera) molecules are a class of bifunctional compounds that can simultaneously bind targeting proteins and E3 ubiquitin ligases. These compounds can induce target proteins to be recognized by proteasomes in cells, causing degradation of target proteins, and can effectively Reduce the amount of target protein in the cell. By introducing ligands that can bind different targeting proteins into PROTAC molecules, it is possible to apply PROTAC technology to the treatment of various diseases. This technology has also received extensive attention in recent years.
发明详述Detailed description of the invention
本申请涉及式I化合物、其立体异构体或其药学上可接受的盐，The application relates to a compound of formula I, its stereoisomer or a pharmaceutically acceptable salt thereof,
Figure PCTCN2022096512-appb-000001
Figure PCTCN2022096512-appb-000001
其中，in,
Figure PCTCN2022096512-appb-000002
表示单键或者双键；
Figure PCTCN2022096512-appb-000002
Indicates a single bond or a double bond;
L 1选自-O-或-NHCO-； L 1 is selected from -O- or -NHCO-;
每个R 1各自独立地选自卤素、-CN、C 1-4烷氧基、或任选地被一个或多个卤素取代的C 1-4烷基； each R is independently selected from halogen, -CN, C 1-4 alkoxy, or C 1-4 alkyl optionally substituted with one or more halogens;
每个R 2各自独立地选自卤素或C 1-4烷基； each R 2 is independently selected from halogen or C 1-4 alkyl;
m和n分别独立地选自0、1、2、或3；m and n are independently selected from 0, 1, 2, or 3;
X选自CH或N；X is selected from CH or N;
X 1、X 2、或X 3分别独立地选自CH、C、或N； X 1 , X 2 , or X 3 are independently selected from CH, C, or N;
X 4选自-CH 2-或-C(＝O)-； X 4 is selected from -CH 2 - or -C(=O)-;
Cy选自任选地被一个或多个卤素或＝O取代的如下基团：7-12元螺环烷基、7-12元杂螺环烷基、6-12元并环烷基、或6-12元杂并环烷基；Cy is selected from the following groups optionally substituted by one or more halogens or =O: 7-12 membered spirocycloalkyl, 7-12 membered heterospirocycloalkyl, 6-12 membered and cycloalkyl, or 6-12 membered heterocycloalkyl;
LNK基团选自-Ak 1-、-Ak 2-Cy 1-Cy 2-、或-Ak 2-Cy 1-； The LNK group is selected from -Ak 1 -, -Ak 2 -Cy 1 -Cy 2 -, or -Ak 2 -Cy 1 -;
Ak 1选自键或-C 1-12烷基-，所述-C 1-12烷基-中的1个或者多个碳原子任选地被O或N原子替换； Ak is selected from a bond or -C 1-12 alkyl-, one or more carbon atoms in the -C 1-12 alkyl- are optionally replaced by O or N atoms;
Ak 2选自键或-C 1-6烷基-； Ak 2 is selected from a bond or -C 1-6 alkyl-;
Cy 1和Cy 2分别独立地选自3-12元环烷基或3-12元杂环烷基，所述环烷基或杂环烷基任选地被一个或者多个卤素取代； Cy 1 and Cy 2 are each independently selected from 3-12 membered cycloalkyl or 3-12 membered heterocycloalkyl, the cycloalkyl or heterocycloalkyl optionally substituted by one or more halogens;
R 3选自氢、卤素、氨基、或C 1-4烷基。 R 3 is selected from hydrogen, halogen, amino, or C 1-4 alkyl.
在一些实施方案中，条件是，上述式I化合物不是以下化合物：In some embodiments, with the proviso that the compound of formula I above is not:
Figure PCTCN2022096512-appb-000003
Figure PCTCN2022096512-appb-000003
Figure PCTCN2022096512-appb-000004
Figure PCTCN2022096512-appb-000004
在一些实施方案中，条件是，片段
Figure PCTCN2022096512-appb-000005
不是以下片段： In some embodiments, the proviso is that the fragment
Figure PCTCN2022096512-appb-000005
not the following snippet:
Figure PCTCN2022096512-appb-000006
Figure PCTCN2022096512-appb-000006
在一些实施方案中，条件是，片段
Figure PCTCN2022096512-appb-000007
不是以下片段： In some embodiments, the proviso is that the fragment
Figure PCTCN2022096512-appb-000007
not the following snippet:
Figure PCTCN2022096512-appb-000008
Figure PCTCN2022096512-appb-000008
在一些实施方案中，X 4为-CH 2-，其它取代基的定义同上； In some embodiments, X 4 is -CH 2 -, and other substituents are as defined above;
或者，X 4为-C(＝O)-，Cy选自任选地被一个或多个卤素或＝O取代的如下基团：7-12元螺环烷基、7-12元杂螺环烷基、6-12元并环烷基、或6-12元杂并环烷基；LNK基团选自-Ak 1-、-Ak 2-Cy 1-Cy 2-、或-Ak 2-Cy 1-；且
Figure PCTCN2022096512-appb-000009
不是
Figure PCTCN2022096512-appb-000010
Figure PCTCN2022096512-appb-000011
其它取代基的定义同上。 Alternatively, X is -C(=O)-, Cy is selected from the following groups optionally substituted by one or more halogens or =O: 7-12 membered spirocycloalkyl, 7-12 membered heterospirocycle Alkyl, 6-12 membered and cycloalkyl, or 6-12 membered heterocycloalkyl; LNK group selected from -Ak 1 -, -Ak 2 -Cy 1 -Cy 2 -, or -Ak 2 -Cy 1 -; and
Figure PCTCN2022096512-appb-000009
no
Figure PCTCN2022096512-appb-000010
Figure PCTCN2022096512-appb-000011
The other substituents are as defined above.
在一些实施方案中，R 3选自卤素、氨基、或C 1-4烷基，其它取代基的定义同上； In some embodiments, R is selected from halogen, amino, or C 1-4 alkyl, and other substituents are as defined above;
或者，R 3为氢，Cy选自任选地被一个或多个卤素或＝O取代的如下基团：7-12元螺环烷基、7-12元杂螺环烷基、6-12元并环烷基、或6-12元杂并环烷基；LNK基团选自-Ak 1-、-Ak 2-Cy 1-Cy 2-、或-Ak 2-Cy 1-；且
Figure PCTCN2022096512-appb-000012
不是
Figure PCTCN2022096512-appb-000013
Figure PCTCN2022096512-appb-000014
其它取代基的定义同上。 Alternatively, R is hydrogen, and Cy is selected from the following groups optionally substituted by one or more halogens or =O: 7-12 membered spirocycloalkyl, 7-12 membered heterospirocycloalkyl, 6-12 A membered cycloalkyl group, or a 6-12 membered heterocycloalkyl group; the LNK group is selected from -Ak 1 -, -Ak 2 -Cy 1 -Cy 2 -, or -Ak 2 -Cy 1 -; and
Figure PCTCN2022096512-appb-000012
no
Figure PCTCN2022096512-appb-000013
Figure PCTCN2022096512-appb-000014
The other substituents are as defined above.
在一些实施方案中，L 1选自-O-。在一些实施方案中，L 1选自-NHCO-。 In some embodiments, L1 is selected from -O-. In some embodiments, L is selected from -NHCO-.
在一些实施方案中，L 1选自-NHCO-，其它取代基的定义同上； In some embodiments, L is selected from -NHCO-, and other substituents are as defined above;
或者，L 1选自-O-，Cy选自任选地被一个或多个卤素或＝O取代的如下基团：7-12元螺环烷基、7-12元杂螺环烷基、6-12元并环烷基、或6-12元杂并环烷基；LNK基团选自-Ak 1-、-Ak 2-Cy 1-Cy 2-、或-Ak 2-Cy 1-；且
Figure PCTCN2022096512-appb-000015
不是
Figure PCTCN2022096512-appb-000016
Figure PCTCN2022096512-appb-000017
其它取代基的定义同上。 Alternatively, L is selected from -O-, Cy is selected from the following groups optionally substituted by one or more halogens or =O: 7-12 membered spirocycloalkyl, 7-12 membered heterospirocycloalkyl, 6-12 membered cycloalkyl, or 6-12 heterocycloalkyl; LNK group selected from -Ak 1 -, -Ak 2 -Cy 1 -Cy 2 -, or -Ak 2 -Cy 1 -; and
Figure PCTCN2022096512-appb-000015
no
Figure PCTCN2022096512-appb-000016
Figure PCTCN2022096512-appb-000017
The other substituents are as defined above.
在一些实施方案中，每个R 1各自独立地选自氟、氯、-CN、C 1-3烷氧基、或任选地被一个或多个F或者氯或溴或碘取代的C 1-3烷基。 In some embodiments, each R is independently selected from fluoro, chloro, -CN, C alkoxy , or C optionally substituted with one or more F or chloro or bromo or iodo -3 alkyl.
在一些实施方案中，每个R 1各自独立地选自氟、氯、-CN、C 1-3烷氧基、或任选地被一个或多个F或者氯取代的C 1-3烷基。 In some embodiments, each R is independently selected from fluoro, chloro, -CN, C 1-3 alkoxy, or C 1-3 alkyl optionally substituted with one or more F or chloro .
在一些实施方案中，每个R 1各自独立地选自氟、氯、-CN、甲氧基、乙氧基、或任选地被一个或多个F或者氯取代的甲基。 In some embodiments, each R 1 is independently selected from fluoro, chloro, -CN, methoxy, ethoxy, or methyl optionally substituted with one or more F or chloro.
在一些实施方案中，每个R 1各自独立地选自氟、氯、-CN、甲氧基、或任选地被一个或多个F或者氯取代的甲基。 In some embodiments, each R 1 is independently selected from fluoro, chloro, -CN, methoxy, or methyl optionally substituted with one or more F or chloro.
在一些实施方案中，每个R 1各自独立地选自氯或-CF 3。 In some embodiments, each R 1 is independently selected from chloro or -CF 3 .
在一些实施方案中，每个R 2各自独立地选自氟、氯、溴、碘、或C 1-3烷基。 In some embodiments, each R 2 is independently selected from fluoro, chloro, bromo, iodo, or C 1-3 alkyl.
在一些实施方案中，每个R 2各自独立地选自氟、氯、或C 1-3烷基。 In some embodiments, each R 2 is independently selected from fluoro, chloro, or C 1-3 alkyl.
在一些实施方案中，每个R 2各自独立地选自氟、氯、甲基、或乙基。 In some embodiments, each R 2 is independently selected from fluoro, chloro, methyl, or ethyl.
在一些实施方案中，每个R 2各自独立地选自氟、氯、或甲基。在一些实施方案中，R 2选自氟。 In some embodiments, each R 2 is independently selected from fluoro, chloro, or methyl. In some embodiments, R is selected from fluoro.
在一些实施方案中，m选自0、1、或2。在一些实施方案中，m选自0或1。在一些实施方案中，m选自0。In some embodiments, m is selected from 0, 1, or 2. In some embodiments, m is selected from 0 or 1. In some embodiments, m is selected from zero.
在一些实施方案中，n选自0、1、或2。在一些实施方案中，n选自0或1。在一些实施方案中，n选自0。In some embodiments, n is selected from 0, 1, or 2. In some embodiments, n is selected from 0 or 1. In some embodiments, n is selected from zero.
在一些实施方案中，X 1选自C或N。在一些实施方案中，X 2选自C或N。在一些实施方案中，X 3选自CH或N。 In some embodiments, X is selected from C or N. In some embodiments, X is selected from C or N. In some embodiments, X is selected from CH or N.
在一些实施方案中，X 1选自C，X 2选自N，X 3选自CH；或者，X 1选自N，X 2选自C，X 3选自N。 In some embodiments, X1 is selected from C, X2 is selected from N, and X3 is selected from CH; alternatively, X1 is selected from N, X2 is selected from C, and X3 is selected from N.
在一些实施方案中，X 1选自C，X 2选自N，X 3选自CH。在一些实施方案中，X 1选自N，X 2选自C，X 3选自N。 In some embodiments, X1 is selected from C, X2 is selected from N, and X3 is selected from CH. In some embodiments, X1 is selected from N, X2 is selected from C, and X3 is selected from N.
在一些实施方案中，Cy选自任选地被一个或多个卤素或＝O取代的如下基团：7-12元螺二环烷基、7-12元杂螺二环烷基、6-12元并二环烷基或6-12元杂并二环烷基。In some embodiments, Cy is selected from the group consisting of 7-12 membered spirobicycloalkyl, 7-12 membered heterospirobicycloalkyl, 6- 12-membered bicycloalkyl or 6-12-membered heterobicycloalkyl.
在一些实施方案中，Cy选自任选地被一个或多个卤素或＝O取代的如下基团：7-12元螺二环烷基、7-12元杂螺二环烷基、7-10元并二环烷基或6-10元杂并二环烷基。In some embodiments, Cy is selected from the following groups optionally substituted with one or more halogens or =O: 7-12 membered spirobicycloalkyl, 7-12 membered heterospirobicycloalkyl, 7- 10-membered bicycloalkyl or 6-10-membered heterobicycloalkyl.
在一些实施方案中，Cy选自任选地被一个或多个卤素或＝O取代的如下基团：7元、8元、9元、10元、11元或12元杂螺二环烷基，或6元、7元、8元、9元或10元杂并二环烷基。In some embodiments, Cy is selected from the group consisting of 7-, 8-, 9-, 10-, 11-, or 12-membered heterospirobicycloalkyl optionally substituted with one or more halogens or =O , or 6-, 7-, 8-, 9-, or 10-membered heterobicycloalkyl.
在一些实施方案中，所述杂螺二环烷基或杂并二环烷基含有1个、2个、或3个选自N、O或S的杂原子。在一些实施方案中，所述杂螺二环烷基或杂并二环烷基含有1个或2个选自N或O的杂原子。在一些实施方案中，所述杂螺二环烷基或杂并二环烷基含有1个或2个N原子、或含有1个N原子和1个O原子。In some embodiments, the heterospirobicycloalkyl or heterobicycloalkyl contains 1, 2, or 3 heteroatoms selected from N, O, or S. In some embodiments, the heterospirobicycloalkyl or heterobicycloalkyl contains 1 or 2 heteroatoms selected from N or O. In some embodiments, the heterospirobicycloalkyl or heterobicycloalkyl contains 1 or 2 N atoms, or 1 N atom and 1 O atom.
在一些实施方案中，Cy选自任选地被1-3个卤素原子或＝O取代的如下基团：含有1-3个选自N、O或S的杂原子的7-11元杂螺二环烷基，或含有1-3个选自N、O或S的杂原子的6-10元杂并二环烷基。在一些实施方案中，Cy选自任选地被1个或2个氟原子或氯原子或＝O取代的如下基团：含有1-2个N原子或O原子的7-11元杂螺二环烷基，或含有1-2个N原子或O原子的6-10元杂并二环烷基。在一些实施方案中，Cy选自任选地被1个氟原子或＝O取代的含有1-2个N原子的7-11元杂螺二环烷基，或含有1-2个N原子或O原子(例如含有1个或2个N原子、或含有1个N原子和1个O原子)的6-10元杂并二环烷基。In some embodiments, Cy is selected from the following groups optionally substituted with 1-3 halogen atoms or =O: 7-11 membered heterospiro containing 1-3 heteroatoms selected from N, O or S Bicycloalkyl, or 6-10 membered heterobicycloalkyl containing 1-3 heteroatoms selected from N, O or S. In some embodiments, Cy is selected from the following groups optionally substituted with 1 or 2 fluorine or chlorine atoms or =O: 7-11 membered heterospirobis containing 1-2 N or O atoms Cycloalkyl, or 6-10 membered heterobicycloalkyl containing 1-2 N atoms or O atoms. In some embodiments, Cy is selected from a 7-11 membered heterospirobicycloalkyl group containing 1-2 N atoms optionally substituted with 1 fluorine atom or =O, or containing 1-2 N atoms or 6-10 membered heterobicycloalkyl group with O atom (for example, containing 1 or 2 N atoms, or containing 1 N atom and 1 O atom).
在一些实施方案中，Cy选自任选地被一个或多个卤素或＝O取代的如下基团：二氮杂螺[3.5]壬烷、氮杂螺[3.5]壬烷、氮杂螺[5.5]十一烷、氮杂螺[3.3]庚烷、氮杂螺[3.4]辛烷、二氮杂螺[3.3]庚烷、氮杂螺[4.5]癸烷、二氮杂螺[4.5]癸烷、氮杂螺[5.5]十一烷、八氢环戊[c]吡咯、呋喃[3,4-b]吡咯、氮杂双环[3.1.0]己烷、氮杂双环[3.2.0]庚烷、八氢-1H-异吲哚、十氢异喹啉、或八氢-1H-环戊[c]吡啶。In some embodiments, Cy is selected from the group consisting of diazaspiro[3.5]nonane, azaspiro[3.5]nonane, azaspiro[3.5]nonane optionally substituted with one or more halogens or =0 5.5] Undecane, Azaspiro[3.3] Heptane, Azaspiro[3.4] Octane, Diazaspiro[3.3] Heptane, Azaspiro[4.5] Decane, Diazaspiro[4.5] Decane, azaspiro[5.5]undecane, octahydrocyclopenta[c]pyrrole, furo[3,4-b]pyrrole, azabicyclo[3.1.0]hexane, azabicyclo[3.2.0 ]heptane, octahydro-1H-isoindole, decahydroisoquinoline, or octahydro-1H-cyclopenta[c]pyridine.
在一些实施方案中，Cy选自任选地被一个或多个氟或＝O取代的如下基团：
Figure PCTCN2022096512-appb-000018
Figure PCTCN2022096512-appb-000019
Figure PCTCN2022096512-appb-000020
In some embodiments, Cy is selected from the following groups optionally substituted with one or more fluorine or =0:
Figure PCTCN2022096512-appb-000018
Figure PCTCN2022096512-appb-000019
Figure PCTCN2022096512-appb-000020
在一些实施方案中，Cy选自任选地被一个或多个氟或＝O取代的如下基团：
Figure PCTCN2022096512-appb-000021
Figure PCTCN2022096512-appb-000022
In some embodiments, Cy is selected from the following groups optionally substituted with one or more fluorine or =0:
Figure PCTCN2022096512-appb-000021
Figure PCTCN2022096512-appb-000022
在一些实施方案中，Cy选自
Figure PCTCN2022096512-appb-000023
Figure PCTCN2022096512-appb-000024
In some embodiments, Cy is selected from
Figure PCTCN2022096512-appb-000023
Figure PCTCN2022096512-appb-000024
在另外一些实施方案中，LNK基团选自-Ak 1-、-Ak 2-Cy 1-Cy 2-、或-Ak 2-Cy 1-； In other embodiments, the LNK group is selected from -Ak 1 -, -Ak 2 -Cy 1 -Cy 2 -, or -Ak 2 -Cy 1 -;
Ak 1选自键或-C 1-12烷基-；或者，Ak 1选自-C 1-12烷基-，所述-C 1-12烷基-中的1个或者多个碳原子(例如1-5个、优选1-3个碳原子)任选地被选自O或N原子替换； Ak is selected from a bond or -C 1-12 alkyl-; or, Ak is selected from -C 1-12 alkyl-, one or more carbon atoms in the -C 1-12 alkyl- ( For example 1-5, preferably 1-3 carbon atoms) are optionally replaced by atoms selected from O or N;
Ak 2选自键或-C 1-6烷基-；或者；Ak 2选自-C 1-6烷基-； Ak 2 is selected from a bond or -C 1-6 alkyl-; Or; Ak 2 is selected from -C 1-6 alkyl-;
Cy 1和Cy 2分别独立地选自3-12元环烷基或3-12元杂环烷基，所述环烷基或杂环烷基任选地被一个或者多个卤素取代。 Cy 1 and Cy 2 are each independently selected from a 3-12 membered cycloalkyl group or a 3-12 membered heterocycloalkyl group, the cycloalkyl group or heterocycloalkyl group being optionally substituted by one or more halogens.
在一些实施方案中，LNK基团选自-Ak 1-。在一些实施方案中，LNK基团选自-Ak 2-Cy 1-Cy 2-。在一些实施方案中，LNK基团选自-Ak 2-Cy 1-。 In some embodiments, the LNK group is selected from -Ak 1 -. In some embodiments, the LNK group is selected from -Ak 2 -Cy 1 -Cy 2 -. In some embodiments, the LNK group is selected from -Ak 2 -Cy 1 -.
在一些实施方案中，Ak 1选自键或-C 1-10烷基-，所述-C 1-10烷基-中的1个或者多个碳原子任选地被O或者N原子替换。在一些实施方案中，Ak 1选自键或-C 1-10烷基-，所述-C 1-10烷基-中的1-5个、优选1-3个碳原子任选地被O或者N原子替换。 In some embodiments, Ak 1 is selected from a bond or -C 1-10 alkyl-, one or more carbon atoms in the -C 1-10 alkyl- are optionally replaced by O or N atoms. In some embodiments, Ak is selected from a bond or -C 1-10 alkyl-, 1-5, preferably 1-3 carbon atoms in the -C 1-10 alkyl- are optionally replaced by O Or N atom replacement.
在一些实施方案中，Ak 1选自键、-C 1-9烷基-、-C 1-9烷基-O-、-C 1-9烷基-NH-、-C 1-5烷基-O-C 1-5烷基-O-、-C 1-3烷基-O-C 1-3烷基-O-C 1-3烷基-O-、或-C 1-3烷基-O-C 1-3烷基-O-C 1-3烷基-NH-。 In some embodiments, Ak is selected from a bond, -C 1-9 alkyl-, -C 1-9 alkyl-O-, -C 1-9 alkyl-NH-, -C 1-5 alkyl -OC 1-5 alkyl-O-, -C 1-3 alkyl-OC 1-3 alkyl-OC 1-3 alkyl-O-, or -C 1-3 alkyl-OC 1-3 alkane The group -OC 1-3 alkyl-NH-.
在一些实施方案中，Ak 1选自键、-C 1-3烷基-、-C 8-9烷基-、-C 2-8烷基-O-、-C 2-8烷基-NH-、-C 2-4烷基-O-C 3-5烷基-O-、-C 1-2烷基-O-C 1-2烷基-O-C 1-2烷基-O-、或-C 1-2烷基-O-C 1-2烷基-O-C 1-2烷基-NH-。 In some embodiments, Ak is selected from a bond, -C 1-3 alkyl-, -C 8-9 alkyl-, -C 2-8 alkyl-O-, -C 2-8 alkyl-NH -, -C 2-4 alkyl-OC 3-5 alkyl-O-, -C 1-2 alkyl-OC 1-2 alkyl-OC 1-2 alkyl-O-, or -C 1- 2Alkyl - OC1-2Alkyl - OC1-2Alkyl -NH-.
在一些实施方案中，Ak 1选自键、-CH 2-、-(CH 2) 2-、-(CH 2) 9-、-(CH 2) 2O-、-(CH 2) 3O-、-(CH 2) 4O-、-(CH 2) 5O-、-(CH 2) 8O-、-(CH 2) 4NH-、-(CH 2) 8NH-、-(CH 2) 2O(CH 2) 5O-、-(CH 2) 2O(CH 2) 3O-、-(CH 2) 3O(CH 2) 3O-、-(CH 2) 4O(CH 2) 4O-、-(CH 2) 2O(CH 2) 2O(CH 2) 2O-、或-(CH 2) 2O(CH 2) 2O(CH 2) 2NH-。 In some embodiments, Ak 1 is selected from a bond, -CH 2 -, -(CH 2 ) 2 -, -(CH 2 ) 9 -, -(CH 2 ) 2 O-, -(CH 2 ) 3 O- , -(CH 2 ) 4 O-, -(CH 2 ) 5 O-, -(CH 2 ) 8 O-, -(CH 2 ) 4 NH-, -(CH 2 ) 8 NH-, -(CH 2 ) 2 O(CH 2 ) 5 O-, -(CH 2 ) 2 O(CH 2 ) 3 O-, -(CH 2 ) 3 O(CH 2 ) 3 O-, -(CH 2 ) 4 O(CH 2 ) 4 O-, -(CH 2 ) 2 O(CH 2 ) 2 O(CH 2 ) 2 O-, or -(CH 2 ) 2 O(CH 2 ) 2 O(CH 2 ) 2 NH-.
在另外一些实施方案中，Ak 1选自-C 1-10烷基-，所述-C 1-10烷基-中的1个或者多个碳原子任选地被O或者N原子替换。 In some other embodiments, Ak 1 is selected from -C 1-10 alkyl-, and one or more carbon atoms in the -C 1-10 alkyl- are optionally replaced by O or N atoms.
在另外一些实施方案中，Ak 1选自-C 1-9烷基-、-C 1-9烷基-O-、-C 1-9烷基-NH-、-C 1-5烷基-O-C 1-5烷基-O-、-C 1-3烷基-O-C 1-3烷基-O-C 1-3烷基-O-、或-C 1-3烷基-O-C 1-3烷基-O-C 1-3烷基-NH-。 In some other embodiments, Ak 1 is selected from -C 1-9 alkyl-, -C 1-9 alkyl-O-, -C 1-9 alkyl-NH-, -C 1-5 alkyl- OC 1-5 alkyl-O-, -C 1-3 alkyl-OC 1-3 alkyl-OC 1-3 alkyl-O-, or -C 1-3 alkyl-OC 1-3 alkyl -OC 1-3 alkyl-NH-.
在另外一些实施方案中，Ak 1选自-C 1-3烷基-、-C 8-9烷基-、-C 2-8烷基-O-、-C 2-8烷基-NH-、-C 2-4烷基-O-C 3-5烷基-O-、-C 1-2烷基-O-C 1-2烷基-O-C 1-2烷基-O-、或-C 1-2烷基-O-C 1-2烷基-O-C 1-2烷基-NH-。 In some other embodiments, Ak 1 is selected from -C 1-3 alkyl-, -C 8-9 alkyl-, -C 2-8 alkyl-O-, -C 2-8 alkyl-NH- , -C 2-4 Alkyl-OC 3-5 Alkyl-O-, -C 1-2 Alkyl-OC 1-2 Alkyl-OC 1-2 Alkyl-O-, or -C 1-2 Alkyl-OC 1-2 alkyl-OC 1-2 alkyl-NH-.
在另外一些实施方案中，Ak 1选自-CH 2-、-(CH 2) 2-、-(CH 2) 9-、-(CH 2) 2O-、-(CH 2) 3O-、-(CH 2) 4O-、-(CH 2) 5O-、-(CH 2) 8O-、-(CH 2) 4NH-、-(CH 2) 8NH-、-(CH 2) 2O(CH 2) 5O-、-(CH 2) 2O(CH 2) 3O-、-(CH 2) 3O(CH 2) 3O-、-(CH 2) 4O(CH 2) 4O-、-(CH 2) 2O(CH 2) 2O(CH 2) 2O-、或-(CH 2) 2O(CH 2) 2O(CH 2) 2NH-。 In other embodiments, Ak 1 is selected from -CH 2 -, -(CH 2 ) 2 -, -(CH 2 ) 9 -, -(CH 2 ) 2 O-, -(CH 2 ) 3 O-, -(CH 2 ) 4 O-, -(CH 2 ) 5 O-, -(CH 2 ) 8 O-, -(CH 2 ) 4 NH-, -(CH 2 ) 8 NH-, -(CH 2 ) 2 O(CH 2 ) 5 O-, -(CH 2 ) 2 O(CH 2 ) 3 O-, -(CH 2 ) 3 O(CH 2 ) 3 O-, -(CH 2 ) 4 O(CH 2 ) 4 O-, -(CH 2 ) 2 O(CH 2 ) 2 O(CH 2 ) 2 O-, or -(CH 2 ) 2 O(CH 2 ) 2 O(CH 2 ) 2 NH-.
在一些实施方案中，Ak 2选自键或-C 1-4烷基-。 In some embodiments, Ak is selected from a bond or -C 1-4 alkyl-.
在一些实施方案中，Ak 2选自键或-C 1-3烷基-。 In some embodiments, Ak is selected from a bond or -C 1-3 alkyl-.
在一些实施方案中，Ak 2选自键、-CH 2-、或-(CH 2) 2-。在一些实施方案中，Ak 2选自键或-CH 2-。 In some embodiments, Ak 2 is selected from a bond, -CH 2 -, or -(CH 2 ) 2 -. In some embodiments, Ak 2 is selected from a bond or -CH 2 -.
在另外一些实施方案中，Ak 2选自-C 1-4烷基-。 In other embodiments, Ak 2 is selected from -C 1-4 alkyl-.
在另外一些实施方案中，Ak 2选自-C 1-3烷基-。 In other embodiments, Ak 2 is selected from -C 1-3 alkyl-.
在另外一些实施方案中，Ak 2选自-CH 2-、或-(CH 2) 2-。在另外一些实施方案中，Ak 2选自-CH 2-。 In other embodiments, Ak 2 is selected from -CH 2 -, or -(CH 2 ) 2 -. In other embodiments, Ak 2 is selected from -CH 2 -.
在一些实施方案中，Cy 1与Cy 2分别独立地选自3-10元环烷基或3-10元杂环烷基，所述环烷基或杂环烷基任选地被一个或者多个卤素取代。 In some embodiments, Cy 1 and Cy 2 are independently selected from 3-10 membered cycloalkyl or 3-10 membered heterocycloalkyl, and the cycloalkyl or heterocycloalkyl is optionally replaced by one or more a halogen substitution.
在一些实施方案中，Cy 1与Cy 2分别独立地选自3-8元环烷基或3-8元杂环烷基，所述环烷基或杂环烷基任选地被一个或者多个卤素取代。 In some embodiments, Cy 1 and Cy 2 are independently selected from 3-8 membered cycloalkyl or 3-8 membered heterocycloalkyl, and the cycloalkyl or heterocycloalkyl is optionally replaced by one or more a halogen substitution.
在一些实施方案中，Cy 1与Cy 2分别独立地选自3-6元环烷基或3-6元杂环烷基，所述环烷基或杂环烷基任选地被一个或者多个卤素取代。 In some embodiments, Cy 1 and Cy 2 are independently selected from 3-6 membered cycloalkyl or 3-6 membered heterocycloalkyl, and the cycloalkyl or heterocycloalkyl is optionally replaced by one or more a halogen substitution.
在一些实施方案中，Cy 1与Cy 2分别独立地选自4-6元环烷基或4-6元杂环烷基，所述环烷基或杂环烷基任选地被一个或者多个卤素取代。 In some embodiments, Cy 1 and Cy 2 are independently selected from 4-6 membered cycloalkyl or 4-6 membered heterocycloalkyl, and the cycloalkyl or heterocycloalkyl is optionally replaced by one or more a halogen substitution.
在一些实施方案中，Cy 1与Cy 2分别独立地选自4-6元杂环烷基，所述杂环烷基任选地被一个或者多个卤素取代。 In some embodiments, Cy 1 and Cy 2 are each independently selected from 4-6 membered heterocycloalkyl optionally substituted by one or more halogens.
在一些实施方案中，所述杂环烷基含有1个、2个、或3个选自N、O或S的杂原子。在一些实施方案中，所述杂环烷基含有1个或2个选自N或O的杂原子。在一些实施方案中，所述杂环烷基含有1个或2个N原子。In some embodiments, the heterocycloalkyl group contains 1, 2, or 3 heteroatoms selected from N, O, or S. In some embodiments, the heterocycloalkyl group contains 1 or 2 heteroatoms selected from N or O. In some embodiments, the heterocycloalkyl group contains 1 or 2 N atoms.
在一些实施方案中，Cy 1和Cy 2分别独立地选自含有1-3个(例如1-2个)选自N或O或S原子的杂原子的3-7元(例如4-6元)杂环烷基，优选含有1-2个N原子的4-6元杂环烷基。 In some embodiments, Cy 1 and Cy 2 are each independently selected from 3-7 membered (eg 4-6 membered) containing 1-3 (eg 1-2) heteroatoms selected from N or O or S atoms. ) heterocycloalkyl group, preferably a 4-6 membered heterocycloalkyl group containing 1-2 N atoms.
在一些实施方案中，Cy 1与Cy 2分别独立地选自氮杂环丁烷基、吡咯烷基、哌啶环基、哌嗪环基或氮杂双环[3.1.0]己烷基，所述氮杂环丁烷基、吡咯烷基、哌啶环基、哌嗪环基或氮杂双环[3.1.0]己烷基任选地被一个或者多个卤素取代。 In some embodiments, Cy 1 and Cy 2 are each independently selected from azetidinyl, pyrrolidinyl, piperidine ring group, piperazine ring group or azabicyclo[3.1.0]hexyl group, so The azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl or azabicyclo[3.1.0]hexyl groups are optionally substituted by one or more halogens.
在一些实施方案中，Cy 1选自氮杂环丁烷基、吡咯烷基、哌啶环基、哌嗪环基或氮杂双环[3.1.0]己烷基，所述氮杂环丁烷基、吡咯烷基、哌啶环基、哌嗪环基或氮杂双环[3.1.0]己烷基任选地被一个或者多个卤素取代。 In some embodiments, Cy 1 is selected from azetidinyl, pyrrolidinyl, piperidine ring, piperazine ring or azabicyclo[3.1.0]hexyl, the azetidine The radical, pyrrolidinyl, piperidinecyclyl, piperazinecyclyl or azabicyclo[3.1.0]hexyl is optionally substituted with one or more halogens.
在一些实施方案中，Cy 1选自
Figure PCTCN2022096512-appb-000025
Figure PCTCN2022096512-appb-000026
In some embodiments, Cy 1 is selected from
Figure PCTCN2022096512-appb-000025
Figure PCTCN2022096512-appb-000026
在一些实施方案中，Cy 2选自氮杂环丁烷基、吡咯烷基、或哌啶环基。 In some embodiments, Cy 2 is selected from azetidinyl, pyrrolidinyl, or piperidinecyclyl.
在一些实施方案中，Cy 2选自氮杂环丁烷基。在一些实施方案中，Cy 2选自
Figure PCTCN2022096512-appb-000027
In some embodiments, Cy 2 is selected from azetidinyl. In some embodiments, Cy 2 is selected from
Figure PCTCN2022096512-appb-000027
在一些实施方案中，Cy 1与Cy 2分别独立地选自
Figure PCTCN2022096512-appb-000028
Figure PCTCN2022096512-appb-000029
所述
Figure PCTCN2022096512-appb-000030
Figure PCTCN2022096512-appb-000031
Figure PCTCN2022096512-appb-000032
任选地被一个或者多个卤素取代。 In some embodiments, Cy 1 and Cy 2 are independently selected from
Figure PCTCN2022096512-appb-000028
Figure PCTCN2022096512-appb-000029
said
Figure PCTCN2022096512-appb-000030
Figure PCTCN2022096512-appb-000031
Figure PCTCN2022096512-appb-000032
Optionally substituted with one or more halogens.
在一些实施方案中，Cy 1与Cy 2分别独立地选自
Figure PCTCN2022096512-appb-000033
Figure PCTCN2022096512-appb-000034
In some embodiments, Cy 1 and Cy 2 are independently selected from
Figure PCTCN2022096512-appb-000033
Figure PCTCN2022096512-appb-000034
在一些实施方案中，-Ak 2-Cy 1-Cy 2-选自
Figure PCTCN2022096512-appb-000035
Figure PCTCN2022096512-appb-000036
In some embodiments, -Ak 2 -Cy 1 -Cy 2 - is selected from
Figure PCTCN2022096512-appb-000035
Figure PCTCN2022096512-appb-000036
在另外一些实施方案中，-Ak 2-Cy 1-Cy 2-选自
Figure PCTCN2022096512-appb-000037
Figure PCTCN2022096512-appb-000038
In other embodiments, -Ak 2 -Cy 1 -Cy 2 -is selected from
Figure PCTCN2022096512-appb-000037
Figure PCTCN2022096512-appb-000038
在一些实施方案中，-Ak 2-Cy 1-选自
Figure PCTCN2022096512-appb-000039
Figure PCTCN2022096512-appb-000040
Figure PCTCN2022096512-appb-000041
In some embodiments, -Ak 2 -Cy 1 -is selected from
Figure PCTCN2022096512-appb-000039
Figure PCTCN2022096512-appb-000040
Figure PCTCN2022096512-appb-000041
在另外一些实施方案中，-Ak 2-Cy 1-选自
Figure PCTCN2022096512-appb-000042
Figure PCTCN2022096512-appb-000043
In other embodiments, -Ak 2 -Cy 1 -is selected from
Figure PCTCN2022096512-appb-000042
Figure PCTCN2022096512-appb-000043
在一些实施方案中，LNK选自键、-CH 2-、-(CH 2) 2-、-(CH 2) 9-、-(CH 2) 2O-、-(CH 2) 3O-、-(CH 2) 4O-、-(CH 2) 5O-、-(CH 2) 8O-、-(CH 2) 4NH-、-(CH 2) 8NH-、-(CH 2) 2O(CH 2) 5O-、-(CH 2) 2O(CH 2) 3O-、-(CH 2) 3O(CH 2) 3O-、-(CH 2) 4O-(CH 2) 4O-、-(CH 2) 2O(CH 2) 2O(CH 2) 2O-、-(CH 2) 2O(CH 2) 2O(CH 2) 2NH-、
Figure PCTCN2022096512-appb-000044
Figure PCTCN2022096512-appb-000045
In some embodiments, LNK is selected from a bond, -CH 2 -, -(CH 2 ) 2 -, -(CH 2 ) 9 -, -(CH 2 ) 2 O-, -(CH 2 ) 3 O-, -(CH 2 ) 4 O-, -(CH 2 ) 5 O-, -(CH 2 ) 8 O-, -(CH 2 ) 4 NH-, -(CH 2 ) 8 NH-, -(CH 2 ) 2 O(CH 2 ) 5 O-, -(CH 2 ) 2 O(CH 2 ) 3 O-, -(CH 2 ) 3 O(CH 2 ) 3 O-, -(CH 2 ) 4 O-(CH 2 ) 4 O-, -(CH 2 ) 2 O(CH 2 ) 2 O(CH 2 ) 2 O-, -(CH 2 ) 2 O(CH 2 ) 2 O(CH 2 ) 2 NH-,
Figure PCTCN2022096512-appb-000044
Figure PCTCN2022096512-appb-000045
在另外一些实施方案中，LNK选自-CH 2-、-(CH 2) 2-、-(CH 2) 9-、-(CH 2) 2O-、-(CH 2) 3O-、-(CH 2) 4O-、-(CH 2) 5O-、-(CH 2) 8O-、-(CH 2) 4NH-、-(CH 2) 8NH-、-(CH 2) 2O(CH 2) 5O-、-(CH 2) 2O(CH 2) 3O-、-(CH 2) 3O(CH 2) 3O-、-(CH 2) 4O-(CH 2) 4O-、-(CH 2) 2O(CH 2) 2O(CH 2) 2O-、-(CH 2) 2O(CH 2) 2O(CH 2) 2NH-、
Figure PCTCN2022096512-appb-000046
Figure PCTCN2022096512-appb-000047
In other embodiments, LNK is selected from -CH 2 -, -(CH 2 ) 2 -, -(CH 2 ) 9 -, -(CH 2 ) 2 O-, -(CH 2 ) 3 O-, - (CH 2 ) 4 O-, -(CH 2 ) 5 O-, -(CH 2 ) 8 O-, -(CH 2 ) 4 NH-, -(CH 2 ) 8 NH-, -(CH 2 ) 2 O(CH 2 ) 5 O-, -(CH 2 ) 2 O(CH 2 ) 3 O-, -(CH 2 ) 3 O(CH 2 ) 3 O-, -(CH 2 ) 4 O-(CH 2 ) 4 O-, -(CH 2 ) 2 O(CH 2 ) 2 O(CH 2 ) 2 O-, -(CH 2 ) 2 O(CH 2 ) 2 O(CH 2 ) 2 NH-,
Figure PCTCN2022096512-appb-000046
Figure PCTCN2022096512-appb-000047
在一些实施方案中，LNK选自键、-CH 2-、-(CH 2) 2-、-(CH 2) 9-、-(CH 2) 2O-、-(CH 2) 3O-、-(CH 2) 4O-、-(CH 2) 5O-、-(CH 2) 8O-、-(CH 2) 4NH-、-(CH 2) 8NH-、-(CH 2) 2O(CH 2) 5O-、-(CH 2) 2O(CH 2) 3O-、-(CH 2) 3O(CH 2) 3O-、-(CH 2) 4O-(CH 2) 4O-、-(CH 2) 2O(CH 2) 2O(CH 2) 2O-、或-(CH 2) 2O(CH 2) 2O(CH 2) 2NH-。在一些实施方案中，LNK 选自
Figure PCTCN2022096512-appb-000048
在一些实施方案中，LNK选自
Figure PCTCN2022096512-appb-000049
在一些实施方案中，LNK选自
Figure PCTCN2022096512-appb-000050
在一些实施方案中，LNK选自
Figure PCTCN2022096512-appb-000051
Figure PCTCN2022096512-appb-000052
In some embodiments, LNK is selected from a bond, -CH 2 -, -(CH 2 ) 2 -, -(CH 2 ) 9 -, -(CH 2 ) 2 O-, -(CH 2 ) 3 O-, -(CH 2 ) 4 O-, -(CH 2 ) 5 O-, -(CH 2 ) 8 O-, -(CH 2 ) 4 NH-, -(CH 2 ) 8 NH-, -(CH 2 ) 2 O(CH 2 ) 5 O-, -(CH 2 ) 2 O(CH 2 ) 3 O-, -(CH 2 ) 3 O(CH 2 ) 3 O-, -(CH 2 ) 4 O-(CH 2 ) 4 O-, -(CH 2 ) 2 O(CH 2 ) 2 O(CH 2 ) 2 O-, or -(CH 2 ) 2 O(CH 2 ) 2 O(CH 2 ) 2 NH-. In some embodiments, LNK is selected from
Figure PCTCN2022096512-appb-000048
In some embodiments, LNK is selected from
Figure PCTCN2022096512-appb-000049
In some embodiments, LNK is selected from
Figure PCTCN2022096512-appb-000050
In some embodiments, LNK is selected from
Figure PCTCN2022096512-appb-000051
Figure PCTCN2022096512-appb-000052
在一些实施方案中，
Figure PCTCN2022096512-appb-000053
选自-Cy-Ak 1-、-Cy-Ak 2-Cy 1-Cy 2-、或-Cy-Ak 2-Cy 1-。 In some embodiments,
Figure PCTCN2022096512-appb-000053
selected from -Cy-Ak 1 -, -Cy-Ak 2 -Cy 1 -Cy 2 -, or -Cy-Ak 2 -Cy 1 -.
在一些实施方案中，
Figure PCTCN2022096512-appb-000054
选自-Cy-Ak 1-、-Cy-Cy 1-Cy 2-、-Cy-CH 2-Cy 1-、-Cy-(CH 2) 2-Cy 1-、或-Cy-Cy 1-。 In some embodiments,
Figure PCTCN2022096512-appb-000054
selected from -Cy-Ak 1 -, -Cy-Cy 1 -Cy 2 -, -Cy-CH 2 -Cy 1 -, -Cy-(CH 2 ) 2 -Cy 1 -, or -Cy-Cy 1 -.
在一些实施方案中，
Figure PCTCN2022096512-appb-000055
选自
Figure PCTCN2022096512-appb-000056
Figure PCTCN2022096512-appb-000057
Figure PCTCN2022096512-appb-000058
Figure PCTCN2022096512-appb-000059
In some embodiments,
Figure PCTCN2022096512-appb-000055
selected from
Figure PCTCN2022096512-appb-000056
Figure PCTCN2022096512-appb-000057
Figure PCTCN2022096512-appb-000058
Figure PCTCN2022096512-appb-000059
在另外一些实施方案中，
Figure PCTCN2022096512-appb-000060
选自
Figure PCTCN2022096512-appb-000061
Figure PCTCN2022096512-appb-000062
Figure PCTCN2022096512-appb-000063
In other embodiments,
Figure PCTCN2022096512-appb-000060
selected from
Figure PCTCN2022096512-appb-000061
Figure PCTCN2022096512-appb-000062
Figure PCTCN2022096512-appb-000063
在另外一些实施方案中，
Figure PCTCN2022096512-appb-000064
选自
Figure PCTCN2022096512-appb-000065
Figure PCTCN2022096512-appb-000066
Figure PCTCN2022096512-appb-000067
In other embodiments,
Figure PCTCN2022096512-appb-000064
selected from
Figure PCTCN2022096512-appb-000065
Figure PCTCN2022096512-appb-000066
Figure PCTCN2022096512-appb-000067
在另外一些实施方案中，
Figure PCTCN2022096512-appb-000068
选自
Figure PCTCN2022096512-appb-000069
Figure PCTCN2022096512-appb-000070
In other embodiments,
Figure PCTCN2022096512-appb-000068
selected from
Figure PCTCN2022096512-appb-000069
Figure PCTCN2022096512-appb-000070
在另外一些实施方案中，
Figure PCTCN2022096512-appb-000071
选自
Figure PCTCN2022096512-appb-000072
Figure PCTCN2022096512-appb-000073
Figure PCTCN2022096512-appb-000074
In other embodiments,
Figure PCTCN2022096512-appb-000071
selected from
Figure PCTCN2022096512-appb-000072
Figure PCTCN2022096512-appb-000073
Figure PCTCN2022096512-appb-000074
在一些实施方案中，R 3选自氢、卤素、氨基、或C 1-3烷基。 In some embodiments, R 3 is selected from hydrogen, halogen, amino, or C 1-3 alkyl.
在一些实施方案中，R 3选自氢、氟、氯、溴、碘、或氨基。 In some embodiments, R is selected from hydrogen, fluoro, chloro, bromo, iodo, or amino.
在一些实施方案中，R 3选自氢、氟、氯、溴、或氨基。 In some embodiments, R is selected from hydrogen, fluoro, chloro, bromo, or amino.
在一些实施方案中，R 3选自氢、氟、或氨基。 In some embodiments, R is selected from hydrogen, fluoro, or amino.
在一些实施方案中，所述“一个或多个”选自一个、两个、三个、四个、五个或六个。在一些实施方案中，所述“一个或多个”选自一个、两个、或三个。在一些实施方案中，所述“一个或多个”选自一个、或两个。In some embodiments, the "one or more" is selected from one, two, three, four, five or six. In some embodiments, the "one or more" is selected from one, two, or three. In some embodiments, the "one or more" is selected from one, or two.
在一些方案中，本申请包含上述定义的变量及其实施方案，以及它们的任意组合。In some aspects, the present application encompasses the above-defined variables and embodiments thereof, and any combination thereof.
本申请还涉及式II或式II-1化合物、其立体异构体或其药学上可接受的盐，The present application also relates to compounds of formula II or formula II-1, stereoisomers thereof or pharmaceutically acceptable salts thereof,
Figure PCTCN2022096512-appb-000075
Figure PCTCN2022096512-appb-000075
其中，L 1、R 1、R 2、m、n、X、X 1、X 2、X 3、X 4、LNK、R 3定义如前所述； Wherein, L 1 , R 1 , R 2 , m, n, X, X 1 , X 2 , X 3 , X 4 , LNK, R 3 are as defined above;
X 5选自CH、CH 2或者N。 X 5 is selected from CH, CH 2 or N.
本申请还涉及式III、式IV或式III-1化合物、其立体异构体或其药学上可接受的盐，The present application also relates to compounds of formula III, formula IV or formula III-1, stereoisomers thereof or pharmaceutically acceptable salts thereof,
Figure PCTCN2022096512-appb-000076
Figure PCTCN2022096512-appb-000076
其中，R 1、R 2、m、n、X、X 4、LNK、R 3定义如前所述。 Wherein, R 1 , R 2 , m, n, X, X 4 , LNK, R 3 are as defined above.
本申请还涉及式V、式VI、式VII、式VIII、式V-1或式VI-1化合物、其立体异构体或其药学上可接受的盐，The present application also relates to compounds of formula V, formula VI, formula VII, formula VIII, formula V-1 or formula VI-1, stereoisomers thereof or pharmaceutically acceptable salts thereof,
Figure PCTCN2022096512-appb-000077
Figure PCTCN2022096512-appb-000077
其中，R 1、R 2、m、n、X、X 4、Ak 2、Cy 1、Cy 2、R 3定义如前所述。 Wherein, R 1 , R 2 , m, n, X, X 4 , Ak 2 , Cy 1 , Cy 2 and R 3 are as defined above.
在一些实施方案中，上述-Ak 2-Cy 1-选自-CH 2-Cy 1-。 In some embodiments, the aforementioned -Ak 2 -Cy 1 - is selected from -CH 2 -Cy 1 -.
本申请还涉及以下化合物、其立体异构体或其药学上可接受的盐：The present application also relates to the following compounds, their stereoisomers or pharmaceutically acceptable salts thereof:
Figure PCTCN2022096512-appb-000078
Figure PCTCN2022096512-appb-000078
Figure PCTCN2022096512-appb-000079
Figure PCTCN2022096512-appb-000079
Figure PCTCN2022096512-appb-000080
Figure PCTCN2022096512-appb-000080
Figure PCTCN2022096512-appb-000081
Figure PCTCN2022096512-appb-000081
Figure PCTCN2022096512-appb-000082
Figure PCTCN2022096512-appb-000082
Figure PCTCN2022096512-appb-000083
Figure PCTCN2022096512-appb-000083
Figure PCTCN2022096512-appb-000084
Figure PCTCN2022096512-appb-000084
本申请还涉及以下化合物、其立体异构体或其药学上可接受的盐：The present application also relates to the following compounds, their stereoisomers or pharmaceutically acceptable salts thereof:
Figure PCTCN2022096512-appb-000085
Figure PCTCN2022096512-appb-000085
在一些实施方案中，所述药学上可接受的盐包括本申请化合物与无机酸形成的盐、与有机酸形成的盐、或者与酸性氨基酸形成的盐。In some embodiments, the pharmaceutically acceptable salts include salts formed with inorganic acids, salts formed with organic acids, or salts formed with acidic amino acids.
另一方面，本申请涉及药物组合物，其包含本申请的上述化合物、其立体异构体或其药学上可接受的盐。在一些实施方案中，本申请的药物组合物还包括药学上可接受的辅料。In another aspect, the present application relates to a pharmaceutical composition comprising the above-mentioned compound of the present application, its stereoisomer or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition of the present application further includes pharmaceutically acceptable excipients.
另一方面，本申请涉及预防或者治疗哺乳动物中的与BTK相关疾病的方法，包括对需要该治疗的哺乳动物(优选人类)给予治疗有效量的本申请的上述化合物、其立体异构体或其药学上可接受的盐、或其药物组合物。In another aspect, the present application relates to a method for preventing or treating BTK-related diseases in mammals, comprising administering a therapeutically effective amount of the above-mentioned compound of the present application, its stereoisomer or Its pharmaceutically acceptable salt, or its pharmaceutical composition.
另一方面，本申请涉及上述化合物、其立体异构体或其药学上可接受的盐、或其药物组合物在制备预防或者治疗与BTK相关疾病的药物中的用途。In another aspect, the present application relates to the use of the above-mentioned compound, its stereoisomer or its pharmaceutically acceptable salt, or its pharmaceutical composition in the preparation of medicines for preventing or treating BTK-related diseases.
另一方面，本申请涉及上述化合物、其立体异构体或其药学上可接受的盐、或其药物组合物在预防或者治疗与BTK相关疾病中的用途。In another aspect, the present application relates to the use of the above compound, its stereoisomer or pharmaceutically acceptable salt thereof, or its pharmaceutical composition in preventing or treating BTK-related diseases.
另一方面，本申请涉及用于预防或者治疗与BTK相关疾病的上述化合物、其立体异构体或其药学上可接受的盐、或其药物组合物。In another aspect, the present application relates to the above compound, its stereoisomer or pharmaceutically acceptable salt thereof, or its pharmaceutical composition for preventing or treating BTK-related diseases.
在一些具体实施方案中，上述BTK相关疾病选自自身免疫性疾病、炎症疾病或癌症。In some specific embodiments, the above-mentioned BTK-related diseases are selected from autoimmune diseases, inflammatory diseases or cancers.
在一些实施方式中，本申请涉及一种BTK降解剂，包括本申请的上述化合物、其立体异构体或其药学上可接受的盐。在一些实施方案中，本申请涉及一种用于制备BTK降解剂的上述化合物、其立体异构体或其药学上可接受的盐、或其药物组合物。In some embodiments, the present application relates to a BTK degradation agent, including the above-mentioned compound of the present application, its stereoisomer or a pharmaceutically acceptable salt thereof. In some embodiments, the present application relates to the above-mentioned compound, its stereoisomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for preparing a BTK degradation agent.
技术效果technical effect
本申请化合物对BTK具有降解作用(如OCI-LY10细胞)；体外抑制细胞增殖活性；例如针对OCI-LY10细胞及TMD8-BTK(C481S)细胞；相较于激酶EGFR及TEC，具有BTK(WT)及BTK(C481S)激酶选择性抑制活性；体外肝微粒体代谢稳定，特别是人和小鼠肝微粒体；体内药代数据优良(例如针对小鼠)；体内药效好(如针对TMD-8小鼠皮下移植瘤)；对TMD8细胞内BTK蛋白降解动力学好，如降解率高，且随着时间延长，降解率逐渐提高。The compounds of the present application have a degradative effect on BTK (such as OCI-LY10 cells); in vitro cell proliferation inhibitory activity; for example, for OCI-LY10 cells and TMD8-BTK (C481S) cells; compared with the kinase EGFR and TEC, it has BTK (WT) and BTK (C481S) kinase selective inhibitory activity; stable in vitro liver microsome metabolism, especially human and mouse liver microsomes; excellent in vivo pharmacokinetic data (for example, for mice); good in vivo efficacy (for example, for TMD-8 mouse subcutaneous transplanted tumor); the degradation kinetics of BTK protein in TMD8 cells is good, such as the degradation rate is high, and the degradation rate gradually increases with time.
定义definition
除非另有说明，本申请中所用的下列术语具有下列含义。一个特定的术语在没有特别定义的情况下不应该被认为是不确定的或不清楚的，而应该按照本领域普通的含义去理解。当本文中出现商品名时，意在指代其对应的商品或其活性成分。Unless otherwise stated, the following terms used in this application have the following meanings. A specific term should not be regarded as indeterminate or unclear if there is no special definition, but should be understood according to the ordinary meaning in the art. When a trade name appears herein, it is intended to refer to its corresponding trade name or its active ingredient.
术语“被取代”是指特定原子上的任意一个或多个氢原子被取代基取代，只要特定原子的价态是正常的并且取代后的化合物是稳定的。当取代基为氧代(即＝O)时，意味着两个氢原子被取代，氧代不会发生在芳香基上。The term "substituted" means that any one or more hydrogen atoms on the specified atom are replaced by a substituent, as long as the valence of the specified atom is normal and the substituted compound is stable. When a substituent is oxo (ie, =0), it means that two hydrogen atoms are replaced, and oxo does not occur on an aromatic group.
术语“任选”或“任选地”是指随后描述的事件或情况可以发生或不发生，该描述包括发生所述事件或情况和不发生所述事件或情况。“任选被取代的”表示取代或未取代的，例如，乙基“任选”被卤素取代，指乙基可以是未被取代的(CH 2CH 3)、单取代的(如CH 2CH 2F)、多取代的(如CHFCH 2F、CH 2CHF 2等)或完全被取代的(CF 2CF 3)。本领域技术人员可理解，对于包含一个或多个取代基的任何基团，不会引入任何在空间上不可能存在和/或不能合成的取代或取代模式。 The term "optional" or "optionally" means that the subsequently described event or circumstance can or cannot occur, and that description includes that said event or circumstance occurs and that it does not. "Optionally substituted" means substituted or unsubstituted, for example, the ethyl group is "optionally" substituted by halogen, which means that the ethyl group can be unsubstituted (CH 2 CH 3 ), monosubstituted (such as CH 2 CH 2 F), polysubstituted (eg CHFCH 2 F, CH 2 CHF 2 etc.) or fully substituted (CF 2 CF 3 ). It will be appreciated by those skilled in the art that for any group containing one or more substituents, no sterically impossible and/or synthetically impossible substitution or substitution pattern is introduced.
本文中的C m-n是该部分具有给定范围m-n中的整数个碳原子。例如“C 1-6”是指该基团可具有1个碳原子、2个碳原子、3个碳原子、4个碳原子、5个碳原子或6个碳原子。 C mn herein is that moiety has an integer number of carbon atoms in the given range mn. For example "C 1-6 " means that the group can have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms.
当任何变量(例如R)在化合物的组成或结构中出现一次以上时，其在每一种情况下的定义都是独立的。例如，如果一个基团含2个R，则每个R都有独立的选项。When any variable (eg, R) occurs more than once in the composition or structure of a compound, its definition is independent at each occurrence. For example, if a group contains 2 R, each R has independent options.
术语“卤”或“卤素”是指氟、氯、溴和碘。The term "halo" or "halogen" refers to fluorine, chlorine, bromine and iodine.
术语“羟基”指-OH基团。The term "hydroxyl" refers to a -OH group.
术语“氨基”指-NH 2基团。 The term "amino" refers to a -NH2 group.
术语“烷基”是指通式为C nH 2n+1的烃基，例如C 1- 10、C 1- 6、C 1- 4烷基。该烷基可以是直链或支链的。例如，术语“C 1- 6烷基”指含有1至6个碳原子的烷基(例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、1-甲基丁基、2-甲基丁基、3-甲基丁基、新戊基、己基、2-甲基戊基等)。类似地，烷氧基、烷基氨基、二烷基氨基、烷基磺酰基和烷硫基的烷基部分(即烷基)具有上述相同定义。 The term "alkyl" refers to a hydrocarbon group with the general formula C n H 2n+1 , such as C 1 - 10 , C 1 - 6 , C 1 - 4 alkyl. The alkyl group may be linear or branched. For example, the term "C 1-6 alkyl" refers to an alkyl group containing 1 to 6 carbon atoms (such as methyl, ethyl, n-propyl, isopropyl, n - butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, neopentyl, hexyl, 2-methylpentyl, etc.). Similarly, the alkyl portion (ie, alkyl group) of alkoxy, alkylamino, dialkylamino, alkylsulfonyl and alkylthio has the same definition as above.
术语“烷氧基”指-O-烷基，例如-O-C 1- 10烷基、-O-C 1- 6烷基、-O-C 1- 4烷基。 The term "alkoxy" refers to -O-alkyl, such as -OC 1 -10 alkyl, -OC 1 -6 alkyl, -OC 1 -4 alkyl.
术语“烯基”是指由碳原子和氢原子组成的直链或支链的具有至少一个双键的不饱和脂肪族烃基。烯基的非限制性实例包括但不限于C 2-10、C 2-6、C 2-5烯基，例如乙烯基、1-丙烯基、2-丙烯基、1-丁烯基、异丁烯基、1,3-丁二烯基等。 The term "alkenyl" refers to a straight or branched unsaturated aliphatic hydrocarbon group consisting of carbon atoms and hydrogen atoms and having at least one double bond. Non-limiting examples of alkenyl include, but are not limited to, C 2-10 , C 2-6 , C 2-5 alkenyl, such as ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, isobutenyl , 1,3-butadienyl, etc.
术语“炔基”是指由碳原子和氢原子组成的直链或支链的具有至少一个三键的不饱和脂肪族烃基。炔基的非限制性实例包括但不限于C 2-10、C 2-6、C 2-5炔基，例如乙炔基(-C≡CH)、1-丙炔基(-C≡C-CH 3)、2-丙炔基(-CH 2-C≡CH)、1,3-丁二炔基(-C≡C-C≡CH)等。 The term "alkynyl" refers to a straight or branched unsaturated aliphatic hydrocarbon group consisting of carbon atoms and hydrogen atoms, having at least one triple bond. Non-limiting examples of alkynyl include, but are not limited to, C 2-10 , C 2-6 , C 2-5 alkynyl, such as ethynyl (-C≡CH), 1-propynyl (-C≡C-CH 3 ), 2-propynyl (-CH 2 -C≡CH), 1,3-butadiynyl (-C≡CC≡CH), etc.
术语“环烷基”指完全饱和的并且可以呈单环、桥环或螺环存在的碳环。除非另有指示，该碳环通常为3至10元环。环烷基的非限制性实例包括但不限于环丙基、环丁基、环戊基、环己基、降冰片基(双环[2.2.1]庚基)、双环[2.2.2]辛基、金刚烷基等。The term "cycloalkyl" refers to a carbocyclic ring that is fully saturated and may exist as a monocyclic, bridged, or spiro ring. Unless otherwise indicated, the carbocycle is typically a 3 to 10 membered ring. Non-limiting examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl (bicyclo[2.2.1]heptyl), bicyclo[2.2.2]octyl, Adamantyl, etc.
术语“杂环烷基”是指完全饱和的并且可以以单环、桥环(例如并环)或螺环存在的环状基团。除非另有指示，该杂环通常为含有1至3个独立地选自硫、氧和/或氮的杂原子(优选1或2个杂原子)的3至7元环、3至6元环或3至5元环。3元杂环烷基的实例包括但不限于环氧乙烷基、环硫乙烷基、环氮乙烷基，4元杂环烷基的非限制性实例包括但不限于吖丁啶基、噁丁环基、噻丁环基，5元杂环烷基的实例包括但不限于四氢呋喃基、四氢噻吩基、吡咯烷基、异噁唑烷基、噁唑烷基、异噻唑烷基、噻唑烷基、咪唑烷基、四氢吡唑基，6元杂环烷基的实例包括但不限于哌啶基、四氢吡喃基、四氢噻喃基、吗啉基、哌嗪基、1,4-噻噁烷基、1,4-二氧六环基、硫代吗啉基、1,3-二噻烷基、1,4-二噻烷基，7元杂环烷基的实例包括但不限于氮杂环庚烷基、氧杂环庚烷基、硫杂环庚烷基。优选为具有5或6个环原子的单环杂环烷基。The term "heterocycloalkyl" refers to a cyclic group that is fully saturated and can exist as a monocyclic, bridged (eg, fused) or spiro ring. Unless otherwise indicated, the heterocycle is typically a 3 to 7 membered ring, a 3 to 6 membered ring containing 1 to 3 heteroatoms (preferably 1 or 2 heteroatoms) independently selected from sulfur, oxygen and/or nitrogen or a 3 to 5 membered ring. Examples of 3-membered heterocycloalkyl groups include, but are not limited to, oxiranyl, thioethyl, cycloazaethyl, and non-limiting examples of 4-membered heterocycloalkyl groups include, but are not limited to, azetidinyl, oxetyl, Cyclic, thiabutanyl, and 5-membered heterocycloalkyl include, but are not limited to, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, isoxazolidinyl, oxazolidinyl, isothiazolidinyl, thiazolidine , imidazolidinyl, tetrahydropyrazolyl, examples of 6-membered heterocycloalkyl include, but are not limited to, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, piperazinyl, 1, Examples of 4-thioxanyl, 1,4-dioxanyl, thiomorpholinyl, 1,3-dithianyl, 1,4-dithianyl, 7-membered heterocycloalkyl include But not limited to azepanyl, oxepanyl, thiepanyl. Preference is given to monocyclic heterocycloalkyl having 5 or 6 ring atoms.
术语“杂芳基”是指单环或稠合多环体系，其中含有至少一个选自N、O、S的环原子，其余环原子为C，并且具有至少一个芳香环。优选的杂芳基具有单个4至8元环，尤其是5至8元环，或包含6至14个、尤其是6至10个环原子的多个稠合环。杂芳基的非限制性实例包括但不限于吡咯基、呋喃基、噻吩基、咪唑基、噁唑基、吡唑基、吡啶基、嘧啶基、吡嗪基、喹啉基、异喹啉基、四唑基、三唑基、三嗪基、苯并呋喃基、苯并噻吩基、吲哚基、异吲哚基等。结构单元
Figure PCTCN2022096512-appb-000086
表示杂芳基体系，连接键
Figure PCTCN2022096512-appb-000087
根据本申请中X 1、X 2、X 3的具体选择，相应的表示为单键或者双键，使上述结构单元为杂芳基体系，且不会违反价键连接规则，例如可以是
Figure PCTCN2022096512-appb-000088
The term "heteroaryl" refers to a monocyclic or fused polycyclic ring system containing at least one ring atom selected from N, O, S, the remaining ring atoms being C, and having at least one aromatic ring. Preferred heteroaryl groups have a single 4 to 8 membered ring, especially a 5 to 8 membered ring, or multiple fused rings comprising 6 to 14, especially 6 to 10 ring atoms. Non-limiting examples of heteroaryl include, but are not limited to, pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, quinolinyl, isoquinolyl , tetrazolyl, triazolyl, triazinyl, benzofuryl, benzothienyl, indolyl, isoindolyl, etc. Structural units
Figure PCTCN2022096512-appb-000086
Indicates a heteroaryl system, the linkage
Figure PCTCN2022096512-appb-000087
According to the specific selection of X 1 , X 2 , and X 3 in this application, they are represented as single bonds or double bonds, so that the above-mentioned structural units are heteroaryl systems, and will not violate the rules of valence bond connection, for example, it can be
Figure PCTCN2022096512-appb-000088
本申请中的基团或结构片段如LNK、Cy、Ak 1、Cy 1、Cy 2、-Ak 2-Cy 1-Cy 2-、-Ak 2-Cy 1-及其具体选项任选地可以采用从左至右的阅读顺序，对应地分别与通式中该基团或者片段左侧基团及右侧基团连接，例如当Cy选自
Figure PCTCN2022096512-appb-000089
按照从左至右的阅读顺序，Cy左侧与通式中对应左侧的片段
Figure PCTCN2022096512-appb-000090
连接，右侧与右侧片段
Figure PCTCN2022096512-appb-000091
连接，形成的片段为
Figure PCTCN2022096512-appb-000092
任选地，本申请中的基团或结构片段如LNK、Cy、Ak 1、Cy 1、Cy 2、-Ak 2-Cy 1-Cy 2-、-Ak 2-Cy 1-及其具体选项可以采用从右至左的阅读顺序，对应地分别与通式中该基团或者片段左侧基团及右侧基团连接，例如当Cy选自
Figure PCTCN2022096512-appb-000093
按照从右至左的阅读顺序，Cy右侧与通式中对应左侧的片段
Figure PCTCN2022096512-appb-000094
连接，左侧与通式中对应右侧的片段
Figure PCTCN2022096512-appb-000095
连接形成的片段为
Figure PCTCN2022096512-appb-000096
其他基团同上所述。 Groups or structural fragments in this application such as LNK, Cy, Ak 1 , Cy 1 , Cy 2 , -Ak 2 -Cy 1 -Cy 2 -, -Ak 2 -Cy 1 - and specific options thereof can optionally be used The reading order from left to right is correspondingly connected to the left group and the right group of the group or fragment in the general formula, for example, when Cy is selected from
Figure PCTCN2022096512-appb-000089
According to the reading order from left to right, the left side of Cy and the fragment corresponding to the left side in the general formula
Figure PCTCN2022096512-appb-000090
Link, right and right fragments
Figure PCTCN2022096512-appb-000091
connected, the resulting fragments are
Figure PCTCN2022096512-appb-000092
Optionally, groups or structural fragments in this application such as LNK, Cy, Ak 1 , Cy 1 , Cy 2 , -Ak 2 -Cy 1 -Cy 2 -, -Ak 2 -Cy 1 - and their specific options can be Using the reading order from right to left, they are respectively connected to the left side group and the right side group of the group or fragment in the general formula, for example, when Cy is selected from
Figure PCTCN2022096512-appb-000093
According to the reading order from right to left, the right side of Cy corresponds to the fragment on the left side in the general formula
Figure PCTCN2022096512-appb-000094
Concatenation, the left side and the fragment corresponding to the right side in the general formula
Figure PCTCN2022096512-appb-000095
The fragments formed by the connection are
Figure PCTCN2022096512-appb-000096
Other groups are the same as above.
术语“治疗”意为将本申请所述化合物或制剂进行给药以改善或消除疾病或与所述疾病相关的一个或多个症状，且包括：The term "treating" means administering a compound or formulation described herein to improve or eliminate a disease or one or more symptoms associated with the disease, and includes:
(i)抑制疾病或疾病状态，即遏制其发展；(i) inhibiting a disease or disease state, i.e. arresting its development;
(ii)缓解疾病或疾病状态，即，使该疾病或疾病状态消退。(ii) Alleviating a disease or disease state, ie, causing the disease or disease state to regress.
术语“预防”意为将本申请所述化合物或制剂进行给药以预防疾病或与所述疾病相关的一个或多个症状，包括：预防疾病或疾病状态在哺乳动物中出现，特别是当这类哺乳动物易患有该疾病状态，但尚未被诊断为已患有该疾病状态时。The term "prevention" means administering a compound or formulation described herein to prevent a disease or one or more symptoms associated with the disease, including: preventing a disease or disease state from occurring in a mammal, especially when the when the mammalian mammal is susceptible to the disease state but has not been diagnosed as having the disease state.
术语“治疗有效量”意指(i)治疗或预防特定疾病、病况或障碍，(ii)减轻、改善或消除特定疾病、病况或障碍的一种或多种症状，或(iii)预防或延迟本文中所述的特定疾病、病况或障碍的一种或多种症状发作的本申请化合物的用量。构成“治疗有效量”的本申请化合物的量取决于该化合物、疾病状态及其严重性、给药方式以及待被治疗的哺乳动物的年龄而改变，但可例行性地由本领域技术人员根据其自身的知识及本公开内容而确定。The term "therapeutically effective amount" means (i) treating or preventing a particular disease, condition or disorder, (ii) alleviating, ameliorating or eliminating one or more symptoms of a particular disease, condition or disorder, or (iii) preventing or delaying The amount of a compound of the application for the onset of one or more symptoms of a particular disease, condition or disorder described herein. The amount of a compound of the present application that constitutes a "therapeutically effective amount" will vary depending on the compound, the disease state and its severity, the mode of administration, and the age of the mammal to be treated, but can be routinely determined by a person skilled in the art according to its own knowledge and this disclosure.
术语“药学上可接受的”是针对那些化合物、材料、组合物和/或剂型而言，它们在可靠的医学判断的范围之内，适用于与人类和动物的组织接触使用，而没有过多的毒性、刺激性、过敏性反应或其它问题或并发症，与合理的利益/风险比相称。The term "pharmaceutically acceptable" refers to those compounds, materials, compositions and/or dosage forms which, within the scope of sound medical judgment, are suitable for use in contact with human and animal tissues without excessive Toxicity, irritation, allergic reaction or other problems or complications, commensurate with a reasonable benefit/risk ratio.
作为药学上可接受的盐，例如，可以提及金属盐、铵盐、与有机碱形成的盐、与无机酸形成的盐、与有机酸形成的盐、与碱性或者酸性氨基酸形成的盐等。As pharmaceutically acceptable salts, for example, metal salts, ammonium salts, salts with organic bases, salts with inorganic acids, salts with organic acids, salts with basic or acidic amino acids, etc. .
术语“药物组合物”是指一种或多种本申请的化合物或其盐与药学上可接受的辅料组成的混合物。药物组合物的目的是有利于对有机体给予本申请的化合物。The term "pharmaceutical composition" refers to a mixture of one or more compounds of the present application or their salts and pharmaceutically acceptable auxiliary materials. The purpose of a pharmaceutical composition is to facilitate administration of a compound of the present application to an organism.
术语“药学上可接受的辅料”是指对有机体无明显刺激作用，而且不会损害该活性化合物的生物活性及性能的那些辅料。合适的辅料是本领域技术人员熟知的，例如碳水化合物、蜡、水溶性和/或水可膨胀的聚合物、亲水性或疏水性材料、明胶、油、溶剂、水等。The term "pharmaceutically acceptable excipients" refers to those excipients that have no obvious stimulating effect on the organism and will not impair the biological activity and performance of the active compound. Suitable excipients are well known to those skilled in the art, such as carbohydrates, waxes, water-soluble and/or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water and the like.
词语“包括(comprise)”或“包含(comprise)”及其英文变体例如comprises或comprising应理解为开放的、非排他性的意义，即“包括但不限于”。The word "comprise" or "comprise" and its English variants such as comprises or comprising should be interpreted in an open and non-exclusive sense, ie "including but not limited to".
在本文中，除非上下文另有明确规定，否则单数术语涵盖复数指代物，反之亦然。类似地，除非上下文另有明确指示，词语“或”意在包括“和”。Herein, unless the context clearly dictates otherwise, singular terms encompass plural referents and vice versa. Similarly, the word "or" is intended to include "and" unless the context clearly dictates otherwise.
除非另有说明，在本文中，参数值应当被理解为由术语“约”修饰。当用术语“约”描述本申请的参数时，术语“约”表示存在的误差值，例如表示在某一特定值的±5％、例如±1％或±0.1％的范围内变化。Unless otherwise stated, herein, parameter values should be understood as being modified by the term "about". When the term "about" is used to describe a parameter in the present application, the term "about" indicates an error value exists, for example, it means a variation within ±5%, such as ±1% or ±0.1%, of a certain value.
为了描述和公开的目的，以引用的方式将所有的专利、专利申请和其它已确定的出版物在此明确地并入本文。这些出版物仅因为它们的公开早于本申请的申请日而提供。所有关于这些文件的日期的声明或这些文件的内容的表述是基于申请者可得的信息，并且不构成任何关于这些文件的日期或这些文件的内容的正确性的承认。而且，在任何国家，在本文中对这些出版物的任何引用并不构成关于该出版物成为本领域的公知常识的一部分的认可。All patents, patent applications, and other identified publications are hereby expressly incorporated herein by reference for the purposes of description and disclosure. These publications are provided solely for their disclosure prior to the filing date of the present application. All statements as to the date of these documents or representations of the contents of these documents are based on the information available to the applicant and do not constitute any admission as to the correctness of the dates of these documents or the contents of these documents. Furthermore, any citation herein of these publications does not constitute an admission that the publications form part of the common general knowledge in the field in any country.
本申请的化合物和中间体还可以以不同的互变异构体形式存在，并且所有这样的形式包含于本申请的范围内。术语“互变异构体”或“互变异构体形式”是指可经由低能垒互变的不同能量的结构异构体。例如，质子互变异构体(也称为质子转移互变异构体)包括经由质子迁移的互变，如酮-烯醇及亚胺-烯胺异构化。质子互变异构体的具体实例是咪唑部分，其中质子可在两个环氮间迁移。价互变异构体包括通过一些成键电子的重组的互变。The compounds and intermediates of the present application may also exist in different tautomeric forms, and all such forms are included within the scope of the present application. The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that can interconvert via a low energy barrier. For example, proton tautomers (also known as prototropic tautomers) include interconversions via migration of a proton, such as keto-enol and imine-enamine isomerizations. A specific example of a proton tautomer is the imidazole moiety, where a proton can migrate between two ring nitrogens. Valence tautomers include interconversions through recombination of some of the bonding electrons.
本申请还包括与本文中记载的那些相同的，但一个或多个原子被原子量或质量数不同于自然中通常发现的原子量或质量数的原子置换的同位素标记的本申请化合物。可结合到本申请化合物的同位素的实例包括氢、碳、氮、氧、磷、硫、氟、碘和氯的同位素，诸如分别为 2H、 3H、 11C、 13C、 14C、 13N、 15N、 15O、 17O、 18O、 31P、 32P、 35S、 18F、 123I、 125I和 36Cl等。 The present application also includes isotopically labeled compounds of the present application that are identical to those described herein, but wherein one or more atoms are replaced by an atom having an atomic mass or mass number different from that normally found in nature. Examples of isotopes that may be incorporated into the compounds of the present application include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F, 123 I, 125 I and 36 Cl, etc.
某些同位素标记的本申请化合物(例如用 3H及 14C标记的那些)可用于化合物和/或底物组织分布分析中。氚化(即 3H)和碳-14(即 14C)同位素对于由于它们易于制备和可检测性是尤其优选的。正电子发射同位素，诸如 15O、 13N、 11C和 18F可用于正电子发射断层扫描(PET)研究以测定底物占有率。通常可以通过与公开于下文的方案和/或实施例中的那些类似的下列程序，通过同位素标记试剂取代未经同位素标记的试剂来制备同位素标记的本申请化合物。 Certain isotopically labeled compounds of the present application (eg, those labeled with3H and14C ) are useful in compound and/or substrate tissue distribution assays. Tritiated ( ie3H ) and carbon-14 ( ie14C ) isotopes are especially preferred for their ease of preparation and detectability. Positron-emitting isotopes, such as 15 O, 13 N, 11 C, and 18 F, can be used in positron emission tomography (PET) studies to determine substrate occupancy. Isotopically labeled compounds of the present application can generally be prepared by following procedures similar to those disclosed in the Schemes and/or Examples below, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.
此外，用较重同位素(诸如氘(即 2H))取代可以提供某些由更高的代谢稳定性产生的治疗优点(例如增加的体内半衰期或降低的剂量需求)，并且因此在某些情形下可能是优选的，其中氘取代可以是部分或完全的，部分氘取代是指至少一个氢被至少一个氘取代。 Furthermore, substitution with heavier isotopes such as deuterium (i.e. 2 H) may confer certain therapeutic advantages resulting from greater metabolic stability (e.g. increased in vivo half-life or reduced dosage requirements), and thus in some cases The following may be preferred, where deuterium substitution may be partial or complete, partial deuterium substitution meaning at least one hydrogen is replaced by at least one deuterium.
本申请化合物可以是不对称的，例如，具有一个或多个立体异构体。除非另有说明，所有立体异构体都包括如对映异构体和非对映异构体。本申请的含有不对称碳原子的化合物可以以光学活性纯的形式或外消旋形式被分离出来。光学活性纯的形式可以从外消旋混合物拆分，或通过使用手性原料或手性试剂合成。Compounds of the present application may be asymmetric, for example, having one or more stereoisomers. Unless otherwise stated, all stereoisomers are included as enantiomers and diastereomers. The compounds of the present application containing asymmetric carbon atoms can be isolated in optically pure or racemic forms. Optically pure forms can be resolved from racemic mixtures or synthesized by using chiral starting materials or reagents.
本申请的药物组合物可通过将本申请的化合物与适宜的药学上可接受的辅料组合而制备，例如可配制成固态、半固态、液态或气态制剂，如片剂、丸剂、胶囊剂、粉剂、颗粒剂、膏剂、乳剂、悬浮剂、栓剂、注射剂、吸入剂、凝胶剂、微球及气溶胶等。The pharmaceutical composition of the present application can be prepared by combining the compound of the present application with suitable pharmaceutically acceptable auxiliary materials, for example, it can be formulated into solid, semi-solid, liquid or gaseous preparations, such as tablets, pills, capsules, powders , granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres and aerosols, etc.
给予本申请化合物或其药学上可接受的盐或其药物组合物的典型途径包括但不限于口服、直肠、局部、吸入、肠胃外、舌下、阴道内、鼻内、眼内、腹膜内、肌内、皮下、静脉内给药。Typical routes of administering a compound of the present application or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, Intramuscular, subcutaneous, intravenous administration.
本申请的药物组合物可以采用本领域众所周知的方法制造，如常规的混合法、溶解法、制粒法、制糖衣药丸法、磨细法、乳化法、冷冻干燥法等。The pharmaceutical composition of the present application can be produced by methods well known in the art, such as conventional mixing methods, dissolving methods, granulating methods, dragee-making methods, pulverizing methods, emulsifying methods, freeze-drying methods and the like.
在一些实施方案中，药物组合物是口服形式。对于口服给药，可以通过将活性化合物与本领域熟知的药学上可接受的辅料混合来配制该药物组合物。这些辅料能使本申请的化合物被配制成片剂、丸剂、锭剂、糖衣剂、胶囊剂、液体、凝胶剂、浆剂、悬浮剂等，用于对患者的口服给药。In some embodiments, the pharmaceutical composition is in oral form. For oral administration, the pharmaceutical compositions can be formulated by mixing the active compounds with pharmaceutically acceptable excipients well known in the art. These excipients enable the compounds of the present application to be formulated into tablets, pills, lozenges, dragees, capsules, liquids, gels, slurries, suspensions, etc. for oral administration to patients.
可以通过常规的混合、填充或压片方法来制备固体口服组合物。例如，可通过下述方法获得：将所述的活性化合物与固体辅料混合，任选地碾磨所得的混合物，如果需要则加入其它合适的辅料，然后将该混合物加工成颗粒，得到片剂或糖衣剂的核心。适合的辅料包括但不限于：粘合剂、稀释剂、崩解剂、润滑剂、助流剂、甜味剂或矫味剂等。Solid oral compositions can be prepared by conventional methods of mixing, filling or tabletting. It can be obtained, for example, by mixing the active compound with solid excipients, optionally milling the resulting mixture, adding other suitable excipients if desired, and then processing the mixture into granules to obtain tablets or The core of the icing. Suitable auxiliary materials include but are not limited to: binders, diluents, disintegrants, lubricants, glidants, sweeteners or flavoring agents, etc.
药物组合物还可适用于肠胃外给药，如合适的单位剂型的无菌溶液剂、混悬剂或冻干产品。The pharmaceutical composition may also be adapted for parenteral administration as a suitable unit dosage form of sterile solutions, suspensions or lyophilized products.
本文所述的通式Ⅰ化合物的所有施用方法中，每天给药的剂量为0.01到200mg/kg体重，以单独或分开剂量的形式。In all methods of administration of the compounds of general formula I described herein, the daily dose is administered in a dose of 0.01 to 200 mg/kg body weight, in single or divided doses.
本申请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申请的实施例。The compounds of the present application can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, the embodiments formed by combining them with other chemical synthesis methods, and equivalents well known to those skilled in the art Alternatives, preferred implementations include but are not limited to the examples of this application.
本申请具体实施方式的化学反应是在合适的溶剂中完成的，所述的溶剂须适合于本申请的化学变化及 其所需的试剂和物料。为了获得本申请的化合物，有时需要本领域技术人员在已有实施方式的基础上对合成步骤或者反应流程进行修改或选择。The chemical reactions of the specific embodiments of the application are completed in a suitable solvent, and the solvent must be suitable for the chemical changes of the application and the reagents and materials required therefor. In order to obtain the compounds of the present application, it is sometimes necessary for those skilled in the art to modify or select synthetic steps or reaction schemes on the basis of existing embodiments.
本领域合成路线规划中的一个重要考量因素是为反应性官能团(如本申请中的氨基)选择合适的保护基，例如，可参考Greene's Protective Groups in Organic Synthesis(4th Ed).Hoboken,New Jersey:John Wiley&Sons,Inc.An important consideration in the planning of synthetic routes in the art is the selection of suitable protecting groups for reactive functional groups (such as amino groups in this application), for example, see Greene's Protective Groups in Organic Synthesis (4th Ed). Hoboken, New Jersey: John Wiley & Sons, Inc.
在一些实施方案中，本申请的式I化合物可以由有机合成领域技术人员通过以下路线来制备：In some embodiments, the compound of formula I of the present application can be prepared by those skilled in the art of organic synthesis through the following routes:
路线1：Route 1:
Figure PCTCN2022096512-appb-000097
Figure PCTCN2022096512-appb-000097
通式(1-1)化合物通过亲核取代反应或者光延反应得到通式(1-2)化合物，然后通过偶联反应得到通式(1-3)化合物，脱除保护基后得到通式(1-4)化合物，通过亲核取代反应或者还原胺化得到对应通式(1-5)化合物，如果通式(1-5)化合物反应位有氨基保护基，先脱除氨基保护基后再通过亲核取代反应、偶联反应或者还原胺化得到通式I化合物。更长链的制备可以重复第四步方法及脱除氨基保护基制备得到。The compound of general formula (1-1) obtains the compound of general formula (1-2) through nucleophilic substitution reaction or Guangyan reaction, then obtains the compound of general formula (1-3) by coupling reaction, obtains general formula ( 1-4) compound, the corresponding compound of general formula (1-5) is obtained by nucleophilic substitution reaction or reductive amination, if the reaction site of the compound of general formula (1-5) has an amino protecting group, first remove the amino protecting group and then The compound of general formula I is obtained by nucleophilic substitution reaction, coupling reaction or reductive amination. The preparation of a longer chain can be obtained by repeating the fourth step and removing the amino protecting group.
路线2：Route 2:
Figure PCTCN2022096512-appb-000098
Figure PCTCN2022096512-appb-000098
通式(2-2)化合物与通式(1-4)化合物通过还原胺化或者亲核取代反应得到通式(2-3)化合物，然后通过环合反应得到通式I化合物。The compound of general formula (2-2) is reacted with the compound of general formula (1-4) to obtain the compound of general formula (2-3) through reductive amination or nucleophilic substitution reaction, and then the compound of general formula I is obtained through ring closure reaction.
路线3：Route 3:
Figure PCTCN2022096512-appb-000099
Figure PCTCN2022096512-appb-000099
通式(3-1)化合物通过亲核取代反应或者光延反应得到通式(3-2)化合物，然后脱除保护基后得到通式(3-3)化合物，通过亲核取代反应、还原胺化或者偶联反应得到对应通式(3-4)化合物，如果通式(3-4)化合物反应位有氨基保护基，先脱除氨基保护基后再通过亲核取代反应、还原胺化或者偶联反应得到通式I化合物。更长链的制备可以重复第三步方法及脱除氨基保护基制备得到。The compound of the general formula (3-1) obtains the compound of the general formula (3-2) through a nucleophilic substitution reaction or the Mitsunobu reaction, and then removes the protecting group to obtain a compound of the general formula (3-3). chemical reaction or coupling reaction to obtain the corresponding compound of general formula (3-4), if there is an amino protecting group at the reaction site of the compound of general formula (3-4), first remove the amino protecting group and then pass nucleophilic substitution reaction, reductive amination or The coupling reaction gives the compound of general formula I. The preparation of a longer chain can be obtained by repeating the third step and removing the amino protecting group.
路线4：Route 4:
Figure PCTCN2022096512-appb-000100
Figure PCTCN2022096512-appb-000100
其中X 6选自卤素，X 7选自H，其它取代基的定义同上； Wherein X6 is selected from halogen, X7 is selected from H, and other substituents are as defined above;
通式(4-1)化合物通过亲核取代反应或者偶联反应得到通式(4-2)化合物，然后通过氧化反应得到通式(4-3)化合物，通式(4-3)化合物与通式(3-3)化合物通过还原胺化得到通式I化合物。The compound of general formula (4-1) obtains the compound of general formula (4-2) through nucleophilic substitution reaction or coupling reaction, then obtains the compound of general formula (4-3) through oxidation reaction, and the compound of general formula (4-3) and The compound of general formula (3-3) is obtained by reductive amination to the compound of general formula I.
本申请采用下述缩略词：HATU代表2-(7-氧化苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯；DMF代表N,N-二甲基甲酰胺；DCM代表二氯甲烷；NBS代表N-溴代丁二酰亚胺；EA代表乙酸乙酯；DMSO代表二甲基亚砜；Boc代表叔丁氧羰基；PdCl 2(dppf)·CH 2Cl 2代表[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物；PE代表石油醚；THF代表四氢呋喃；AIBN代表偶氮二异丁腈；MeOH代表甲醇；AcOH代表乙酸；NMP代表甲基吡咯烷酮；IBX代表2-碘酰基苯甲酸；TBAF代表四丁基氟化铵；PCC代表氯铬酸吡啶；RuphosPdG3代表(2-二环己基膦基-2′,6′-二异丙氧基-1,1′-联苯)2-(2′-氨基-1,1′-联苯基)钯(II)甲磺酸盐；DIPEA代表N,N'-二异丙基乙胺；DIAD代表偶氮二甲酸二异丙酯；EGTA代表乙二醇双(2-氨基乙基醚)四乙酸；HEPES代表N-(2-羟乙基)哌嗪-N'-2-乙烷磺酸；DTT代表二硫苏糖醇；PBS缓冲液代表磷酸缓冲盐溶液。 This application uses the following abbreviations: HATU stands for 2-(7-benzotriazole oxide)-N,N,N',N'-tetramethyluronium hexafluorophosphate; DMF stands for N,N-di Methylformamide; DCM represents dichloromethane; NBS represents N-bromosuccinimide; EA represents ethyl acetate; DMSO represents dimethyl sulfoxide; Boc represents tert-butoxycarbonyl; PdCl 2 (dppf)· CH 2 Cl 2 stands for [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex; PE stands for petroleum ether; THF stands for tetrahydrofuran; AIBN stands for azobisisobutyronitrile ; MeOH represents methanol; AcOH represents acetic acid; NMP represents methylpyrrolidone; IBX represents 2-iodanoylbenzoic acid; TBAF represents tetrabutylammonium fluoride; PCC represents pyridinium chlorochromate; -2′,6′-Diisopropoxy-1,1′-biphenyl) 2-(2′-amino-1,1′-biphenyl)palladium(II) methanesulfonate; DIPEA represents N , N'-diisopropylethylamine; DIAD stands for diisopropyl azodicarboxylate; EGTA stands for ethylene glycol bis(2-aminoethyl ether) tetraacetic acid; HEPES stands for N-(2-hydroxyethyl) Piperazine-N'-2-ethanesulfonic acid; DTT stands for dithiothreitol; PBS buffer stands for phosphate buffered saline.
为清楚起见，进一步用实施例来阐述本发明，但是实施例并非限制本申请的范围。本申请所使用的所有试剂是市售的，无需进一步纯化即可使用。For the sake of clarity, the present invention is further illustrated by examples, but the examples do not limit the scope of the application. All reagents used in this application are commercially available and used without further purification.
具体实施方式Detailed ways
实施例1 化合物1的合成The synthesis of embodiment 1 compound 1
Figure PCTCN2022096512-appb-000101
Figure PCTCN2022096512-appb-000101
Figure PCTCN2022096512-appb-000102
Figure PCTCN2022096512-appb-000102
步骤1：中间体1b的制备Step 1: Preparation of intermediate 1b
向反应瓶中，依次加入中间体1a(50g)、2-氨基-4-氯吡啶(25.4g)、HATU(85.74g)及DMF(300mL)，最后加入三乙胺(57.0g,564mmol)，N 2保护下，60℃加热5hr，反应液冷却至室温后滴加至1M稀盐酸水溶液(3L)中得到固体，抽滤后滤饼水洗烘干得中间体1b(39.4g) In the reaction flask, add intermediate 1a (50g), 2-amino-4-chloropyridine (25.4g), HATU (85.74g) and DMF (300mL) successively, and finally add triethylamine (57.0g, 564mmol), Under the protection of N 2 , heated at 60°C for 5hr, cooled the reaction solution to room temperature and added dropwise to 1M dilute hydrochloric acid aqueous solution (3L) to obtain a solid. After suction filtration, the filter cake was washed with water and dried to obtain intermediate 1b (39.4g)
MS(ESI,[M+H] +)m/z：295.1。 1H NMR(500MHz,DMSO-d 6)δ11.18(s,1H),8.46–8.38(m,3H),8.30(d,J＝1.9Hz,1H),7.83(dd,J＝7.8,1.5Hz,1H),7.74(dd,J＝9.9,1.6Hz,1H),7.67(dd,J＝7.7,6.1Hz,1H),7.34(dd,J＝5.3,1.9Hz,1H). MS (ESI, [M+H] + ) m/z: 295.1. 1 H NMR (500MHz, DMSO-d 6 ) δ11.18(s, 1H), 8.46–8.38(m, 3H), 8.30(d, J=1.9Hz, 1H), 7.83(dd, J=7.8, 1.5 Hz,1H),7.74(dd,J=9.9,1.6Hz,1H),7.67(dd,J=7.7,6.1Hz,1H),7.34(dd,J=5.3,1.9Hz,1H).
步骤2：中间体1d的制备Step 2: Preparation of intermediate 1d
向反应瓶中依次加入化合物1c(100g)和原甲酸三甲酯(707g,729mL)，加热至110℃搅拌过夜。反应液浓缩后旋蒸干得到中间体1d(96.5g)。Compound 1c (100 g) and trimethyl orthoformate (707 g, 729 mL) were sequentially added into the reaction flask, heated to 110° C. and stirred overnight. The reaction solution was concentrated and evaporated to dryness to obtain intermediate 1d (96.5 g).
MS(ESI,[M+H] +)m/z：172.0。 1H NMR(500MHz,DMSO-d 6):δ8.67-8.64(d,J-14.5hz,1H),8.58(br,1H),8.45(s,1H),8.18(s,1H),4.58(s,2H). MS (ESI, [M+H] + ) m/z: 172.0. 1 H NMR(500MHz,DMSO-d 6 ):δ8.67-8.64(d,J-14.5hz,1H),8.58(br,1H),8.45(s,1H),8.18(s,1H),4.58 (s,2H).
步骤3：中间体1e的制备Step 3: Preparation of intermediate 1e
向反应瓶中依次加入中间体1d(96.5g)、乙腈(500mL)和DMF(10mL)，N 2保护，冰水浴条件下10min后，加入POCl 3(313g，190mL)，加毕，恢复至室温搅拌1小时。冰浴下，缓慢滴加氨水淬灭反应，DCM萃取，用饱和食盐水洗，无水硫酸钠干燥，过滤、滤液浓缩得中间体1e(78.5g)。 Add intermediate 1d (96.5g), acetonitrile (500mL) and DMF (10mL) successively to the reaction flask, N 2 protection, after 10min under ice-water bath conditions, add POCl 3 (313g, 190mL), after addition, return to room temperature Stir for 1 hour. Under ice bath, ammonia water was slowly added dropwise to quench the reaction, extracted with DCM, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain intermediate 1e (78.5 g).
MS(ESI,[M+H] +)m/z：154.1。 1H NMR(500MHz,DMSO-d 6):δ8.70(s,1H),8.40-8.39(d,J＝3hz,1H),7.87(s,1H),7.42-7.41(d,J＝3hz,1H). MS (ESI, [M+H] + ) m/z: 154.1. 1 H NMR (500MHz, DMSO-d 6 ): δ8.70(s, 1H), 8.40-8.39(d, J=3hz, 1H), 7.87(s, 1H), 7.42-7.41(d, J=3hz ,1H).
步骤4：中间体1f的制备Step 4: Preparation of Intermediate 1f
向反应瓶中加入中间体1e(78.5g)和DMF(500mL)。冰浴下，分批加入NBS(193g)，补加DMF(20mL)，在N 2保护下，恢复至室温搅拌过夜。反应液在冰水浴下依次加入水和硫代硫酸钠水溶液，加入EA萃取，分出有机层后，分别用饱和食盐水洗，无水硫酸钠干燥，过滤，滤液浓缩得中间体1f(150g)。 Intermediate 1e (78.5 g) and DMF (500 mL) were added to the reaction vial. Under ice-cooling, NBS (193 g) was added in batches, DMF (20 mL) was added, and under the protection of N 2 , the mixture was returned to room temperature and stirred overnight. The reaction solution was sequentially added with water and sodium thiosulfate aqueous solution under an ice-water bath, added EA for extraction, and the organic layer was separated, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain intermediate 1f (150 g).
MS(ESI,[M+H] +)m/z：310.2。 1H NMR(500MHz,DMSO-d 6):δ8.18-8.16(m,1H),7.52-7.51(d,J＝5hz,1H). MS (ESI, [M+H] + ) m/z: 310.2. 1 H NMR (500MHz, DMSO-d 6 ): δ8.18-8.16 (m, 1H), 7.52-7.51 (d, J=5hz, 1H).
步骤5：中间体1g的制备Step 5: Preparation of Intermediate 1g
向耐压密封罐中，依次加入中间体1f(150g)、仲丁醇(180mL)和氨水(381g,423mL)，密闭反应装置，加热至95℃反应过夜。反应液冷却至室温后长时间搅拌，有固体析出，抽滤后用水少量多次洗得中间体1g(116g)。Into a pressure-resistant sealed tank, sequentially add intermediate 1f (150 g), sec-butanol (180 mL) and ammonia water (381 g, 423 mL), seal the reaction device, and heat to 95° C. to react overnight. After the reaction solution was cooled to room temperature, it was stirred for a long time, and a solid precipitated out. After suction filtration, it was washed with a small amount of water several times to obtain 1 g (116 g) of the intermediate.
MS(ESI,[M+H] +)m/z：290.9。 1H NMR(500MHz,DMSO-d 6):δ7.43-7.42(d,J＝5Hz,1H),7.14-7.13(d,J＝5hz,1H),6.81(br,2H). MS (ESI, [M+H] + ) m/z: 290.9. 1 H NMR (500MHz, DMSO-d 6 ): δ7.43-7.42(d, J=5Hz, 1H), 7.14-7.13(d, J=5hz, 1H), 6.81(br, 2H).
步骤6：中间体1h的合成Step 6: Synthesis of intermediate 1h
在单口瓶中，将化合物1g(54.0g)溶于N-甲基吡咯烷酮(500mL)中，再加入2-Boc-7-羟基-2-氮杂螺[3.5]壬烷(41.4g)和N,N-二异丙基乙胺(59.1g,82mL)，升温至180℃反应6小时。反应完毕后，反应液冷至室温，减压蒸除溶剂，粗品经过硅胶柱层析分离(洗脱剂：二氯甲烷/甲醇)得到目标中间体1h(65.5g)。In a single-necked bottle, dissolve compound 1g (54.0g) in N-methylpyrrolidone (500mL), then add 2-Boc-7-hydroxy-2-azaspiro[3.5]nonane (41.4g) and N , N-diisopropylethylamine (59.1g, 82mL), heated to 180°C for 6 hours. After the reaction was completed, the reaction liquid was cooled to room temperature, and the solvent was evaporated under reduced pressure. The crude product was separated by silica gel column chromatography (eluent: dichloromethane/methanol) to obtain the target intermediate 1h (65.5 g).
MS(ESI,[M+H] +)m/z:437.3。 1H NMR(500MHz,DMSO-d 6)δ7.20(d,J＝5.0Hz,1H),6.90(d,J＝5.0Hz,1H),6.76–6.41(m,2H),3.61(s,4H),2.99(t,J＝5.4Hz,4H),1.84(t,J＝5.4Hz,4H),1.39(s,9H). MS (ESI, [M+H] + ) m/z: 437.3. 1 H NMR (500MHz, DMSO-d 6 )δ7.20(d, J=5.0Hz, 1H), 6.90(d, J=5.0Hz, 1H), 6.76–6.41(m, 2H), 3.61(s, 4H), 2.99(t, J=5.4Hz, 4H), 1.84(t, J=5.4Hz, 4H), 1.39(s, 9H).
步骤7：中间体1i的合成Step 7: Synthesis of intermediate 1i
向单口瓶中，依次加入1h(40g)、1b(43.6g)、碳酸钾(26.4g)及PdCl 2(dppf)·CH 2Cl 2(5.19g)，加入水(100mL)和1,4-二氧六环(500mL)，N 2保护下，将混合物加热至80℃反应5小时。反应完毕后，反应液冷至室温，减压蒸除溶剂，粗品经过硅胶柱层析分离(洗脱剂：二氯甲烷/甲醇)得到目标中间体1i(50.2g)。 To the one-necked flask, add 1h (40g), 1b (43.6g), potassium carbonate (26.4g) and PdCl 2 (dppf)·CH 2 Cl 2 (5.19g) in sequence, add water (100mL) and 1,4- Dioxane (500 mL), under the protection of N 2 , the mixture was heated to 80° C. for 5 hours. After the reaction was completed, the reaction liquid was cooled to room temperature, and the solvent was evaporated under reduced pressure. The crude product was separated by silica gel column chromatography (eluent: dichloromethane/methanol) to obtain the target intermediate 1i (50.2 g).
MS(ESI,[M+H] +)m/z:607.2。 1H NMR(500MHz,DMSO-d 6)δ11.24(s,1H),8.42(d,J＝5.4Hz,1H),8.32(d,J＝1.9Hz,1H),8.02–7.94(m,2H),7.63(t,J＝7.9Hz,1H),7.35(dd,J＝5.4,2.0Hz,1H),7.27(d,J＝4.9Hz,1H),7.01(d,J＝5.0Hz,1H),6.01(s,2H),3.63(s,4H),3.07(t,J＝5.2Hz,4H),1.88(t,J＝5.4Hz,4H),1.39(s,9H). MS (ESI, [M+H] + ) m/z: 607.2. 1 H NMR (500MHz, DMSO-d 6 ) δ11.24(s, 1H), 8.42(d, J=5.4Hz, 1H), 8.32(d, J=1.9Hz, 1H), 8.02–7.94(m, 2H), 7.63(t, J=7.9Hz, 1H), 7.35(dd, J=5.4, 2.0Hz, 1H), 7.27(d, J=4.9Hz, 1H), 7.01(d, J=5.0Hz, 1H), 6.01(s, 2H), 3.63(s, 4H), 3.07(t, J=5.2Hz, 4H), 1.88(t, J=5.4Hz, 4H), 1.39(s, 9H).
步骤8：中间体1j的合成Step 8: Synthesis of Intermediate 1j
向单口瓶中，依次加入1i(50g)、二氯甲烷(300mL)及三氟乙酸(80g,53.9mL)，将混合物室温反应24小时。反应完毕后，减压蒸除溶剂及部分三氟乙酸，用200mL二氯甲烷溶解后，加入饱和碳酸氢钠溶液调节pH至弱碱性(pH＝8～9)。大量固体析出，过滤。滤饼用300mL PE/EA＝1：1打浆，过滤，烘干，得到目标中间体1j(22.5g)。Into a one-necked flask, 1i (50 g), dichloromethane (300 mL) and trifluoroacetic acid (80 g, 53.9 mL) were sequentially added, and the mixture was reacted at room temperature for 24 hours. After the reaction was completed, the solvent and part of trifluoroacetic acid were distilled off under reduced pressure, dissolved in 200 mL of dichloromethane, and then saturated sodium bicarbonate solution was added to adjust the pH to weakly alkaline (pH=8-9). A large amount of solid precipitated out and was filtered. The filter cake was beaten with 300mL PE/EA=1:1, filtered and dried to obtain the target intermediate 1j (22.5g).
MS(ESI,[M+H] +)m/z:507.2。 1H NMR(500MHz,DMSO-d 6)δ11.25(s,1H)8.42(d,J＝5.3Hz,1H),8.32(d,J＝1.9Hz,1H),8.03–7.96(m,2H),7.63(t,J＝7.9Hz,1H),7.36(dd,J＝5.4,2.0Hz,1H),7.30(d,J＝5.1Hz,1H),7.02(d,J＝5.0Hz,1H),6.32(s,2H),3.81(s,4H),3.10(t,J＝5.4Hz,4H),1.98(t,J＝5.4Hz,4H). MS (ESI, [M+H] + ) m/z: 507.2. 1 H NMR (500MHz, DMSO-d 6 ) δ11.25(s, 1H) 8.42(d, J=5.3Hz, 1H), 8.32(d, J=1.9Hz, 1H), 8.03–7.96(m, 2H ),7.63(t,J=7.9Hz,1H),7.36(dd,J=5.4,2.0Hz,1H),7.30(d,J=5.1Hz,1H),7.02(d,J=5.0Hz,1H ),6.32(s,2H),3.81(s,4H),3.10(t,J=5.4Hz,4H),1.98(t,J=5.4Hz,4H).
步骤9：中间体1l的制备Step 9: Preparation of Intermediate 1l
向三口瓶中加入2-氨基乙酰胺盐酸盐(10g)、1,2-二氯乙烷(120mL)，N 2置换三次后，将中间体1k(16.40g,15.18mL)、1,2-二氯乙烷(40mL)和三乙胺(10.07g,13.79mL)混合并室温搅拌5min后，缓慢滴入三口瓶中。30min滴加完毕，85℃下回流反应5.5h。反应结束后，反应液冷至室温，向残留物中加入DCM(100mL)和水(500mL)。分离有机相，分别用500mL和饱和食盐水洗涤后用无水硫酸钠干燥，过滤，滤液通过减压蒸除溶剂，得到20.22g中间体1l。 Add 2-aminoacetamide hydrochloride (10g), 1,2-dichloroethane (120mL) into the three-necked flask, and after N2 replacement three times, intermediate 1k (16.40g, 15.18mL), 1,2 - Dichloroethane (40 mL) and triethylamine (10.07 g, 13.79 mL) were mixed and stirred at room temperature for 5 min, and then slowly dropped into a three-neck flask. The dropwise addition was completed in 30 minutes, and the reaction was refluxed at 85° C. for 5.5 hours. After the reaction, the reaction solution was cooled to room temperature, and DCM (100 mL) and water (500 mL) were added to the residue. The organic phase was separated, washed with 500 mL and saturated brine respectively, dried with anhydrous sodium sulfate, filtered, and the filtrate was evaporated to remove the solvent under reduced pressure to obtain 20.22 g of intermediate 1l.
MS(ESI,[M+H] +)m/z：239.1。 1H NMR(500MHz,DMSO-d 6)δ7.68–7.63(m,2H),7.55–7.44(m,5H),7.42–7.37(m,2H),7.34(s,1H),7.25–7.20(m,2H),3.83(s,2H). MS (ESI, [M+H] + ) m/z: 239.1. 1 H NMR (500MHz,DMSO-d 6 )δ7.68–7.63(m,2H),7.55–7.44(m,5H),7.42–7.37(m,2H),7.34(s,1H),7.25–7.20 (m,2H),3.83(s,2H).
步骤10：中间体1m的制备Step 10: Preparation of Intermediate 1m
向单口瓶中，0℃下依次加入中间体1l(10g)、THF(100mL)、丙烯酸叔丁酯(8.07g,9.14mL)及叔丁醇钾(0.706g)，N 2保护下，将混合物0℃反应0.5h。反应结束后，反应液用乙酸铵淬灭后，加入EA(300mL)。分离有机相，分别用300mL饱和食盐水洗涤后用无水硫酸钠干燥，过滤，滤液通过减压蒸除溶剂，得到13.36g中间体1m。 Into a one-necked flask, add intermediate 1l (10g), THF (100mL), tert-butyl acrylate (8.07g, 9.14mL) and potassium tert-butoxide (0.706g) successively at 0°C, and under the protection of N2 , the mixture Reaction at 0°C for 0.5h. After the reaction was completed, the reaction solution was quenched with ammonium acetate, and then EA (300 mL) was added. The organic phase was separated, washed with 300 mL of saturated brine, dried with anhydrous sodium sulfate, filtered, and the filtrate was evaporated to remove the solvent under reduced pressure to obtain 13.36 g of intermediate 1m.
MS(ESI,[M+H] +)m/z：367.3。 MS (ESI, [M+H] + ) m/z: 367.3.
步骤11：中间体1n的制备Step 11: Preparation of intermediate 1n
向单口瓶中，依次加入中间体1m(130g)、1,4-二氧六环(500mL)、HCl(30g,514mL,823mmol)，H 2O(11.50g)，将混合物室温反应过夜，反应逐渐析出固体，将反应液过滤，用EA洗涤三次，收集滤饼得到65g中间体1n。 Into a one-necked flask, sequentially add intermediate 1m (130g), 1,4-dioxane (500mL), HCl (30g, 514mL, 823mmol), H 2 O (11.50g), react the mixture at room temperature overnight, and react Solids were gradually precipitated out, the reaction solution was filtered, washed three times with EA, and the filter cake was collected to obtain 65 g of intermediate 1n.
步骤12：中间体1p的制备Step 12: Preparation of Intermediate 1p
在单口瓶中，将浓硫酸(13.73g,10.00mL,140mmol)缓慢滴入中间体1o(10g)的甲醇(50mL)搅拌液中，10分钟后滴加完毕，混合物在80℃搅拌反应16h。反应结束后，反应液冷至室温，减压蒸除溶剂，用饱和碳酸氢钠中和至pH＝7，向残留物中加入DCM(250mL)和水(100mL)。有机相分离，分别用200mL饱和食盐水洗涤后无水硫酸钠干燥，过滤，滤液通过减压蒸除溶剂，得到10.31g中间体1p。In a one-necked flask, concentrated sulfuric acid (13.73g, 10.00mL, 140mmol) was slowly dropped into the methanol (50mL) stirring solution of intermediate 1o (10g), and the addition was completed after 10 minutes, and the mixture was stirred and reacted at 80°C for 16h. After the reaction, the reaction liquid was cooled to room temperature, the solvent was evaporated under reduced pressure, neutralized with saturated sodium bicarbonate to pH=7, and DCM (250 mL) and water (100 mL) were added to the residue. The organic phase was separated, washed with 200 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to remove the solvent under reduced pressure to obtain 10.31 g of intermediate 1p.
MS(ESI,[M-H] -)m/z：165.1。 1H NMR(500MHz,DMSO-d 6)δ10.13(s,1H),7.787.71(m,1H),6.66(dd,J＝9.0,1.6Hz,2H),3.75(s,3H),2.46(s,3H). MS (ESI, [MH] - ) m/z: 165.1. 1 H NMR (500MHz, DMSO-d 6 )δ10.13(s,1H),7.787.71(m,1H),6.66(dd,J=9.0,1.6Hz,2H),3.75(s,3H), 2.46(s,3H).
步骤13：中间体1q的制备Step 13: Preparation of intermediate 1q
向单口瓶中，依次加入中间体1p(10g)、三乙胺(18.27g,181mmol)、醋酸酐(12.29g)及DCM(150mL)，将混合物室温搅拌反应4.5h。反应液中加入水(200mL)。有机相分离，分别用200mL饱和食盐水洗涤后用无水硫酸钠干燥，过滤，滤液通过减压蒸除溶剂，得到16g中间体1q。Intermediate 1p (10 g), triethylamine (18.27 g, 181 mmol), acetic anhydride (12.29 g) and DCM (150 mL) were sequentially added to a one-necked flask, and the mixture was stirred at room temperature for 4.5 h. Water (200 mL) was added to the reaction solution. The organic phase was separated, washed with 200 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to remove the solvent under reduced pressure to obtain 16 g of intermediate 1q.
MS(ESI,[M-H] -)m/z：206.8。 1H NMR(500MHz,DMSO-d 6)δ7.88(d,J＝8.5Hz,1H),7.12(d,J＝2.4Hz,1H),7.09(dd,J＝8.5,2.4Hz,1H),3.84–3.81(m,3H),2.52(s,3H),2.29(s,3H). MS (ESI, [MH] - ) m/z: 206.8. 1 H NMR (500MHz, DMSO-d 6 ) δ7.88(d, J=8.5Hz, 1H), 7.12(d, J=2.4Hz, 1H), 7.09(dd, J=8.5, 2.4Hz, 1H) ,3.84–3.81(m,3H),2.52(s,3H),2.29(s,3H).
步骤14：中间体1r的制备Step 14: Preparation of intermediate 1r
向单口瓶中，依次加入中间体1q(11g)、NBS(18.8g)、AIBN(0.087g)及1,2-二氯乙烷(150mL)，N 2保护下，将混合物加热至85℃反应20h。反应完毕后，反应液冷至室温，向反应液中加入DCM(250mL)和水(250mL)。有机相分离，分别用250mL饱和食盐水洗涤后用无水硫酸钠干燥，过滤，滤液通过减压蒸除溶剂，残留物通过硅胶柱层析纯化(PE/EA)得到7.74g中间体1r。 Add intermediate 1q (11g), NBS (18.8g), AIBN (0.087g) and 1,2-dichloroethane (150mL) to the one-necked flask in turn, and heat the mixture to 85°C under N2 protection 20h. After the reaction was completed, the reaction liquid was cooled to room temperature, and DCM (250 mL) and water (250 mL) were added to the reaction liquid. The organic phase was separated, washed with 250 mL of saturated brine, dried with anhydrous sodium sulfate, filtered, the filtrate was evaporated to remove the solvent under reduced pressure, and the residue was purified by silica gel column chromatography (PE/EA) to obtain 7.74 g of intermediate 1r.
1H NMR(500MHz,DMSO-d 6)δ7.95(d,J＝8.5Hz,1H),7.42(d,J＝2.4Hz,1H),7.27(dd,J＝8.5,2.4Hz,1H),5.01(s,2H),3.88(s,3H),2.31(s,3H). 1 H NMR (500MHz, DMSO-d 6 ) δ7.95 (d, J=8.5Hz, 1H), 7.42 (d, J=2.4Hz, 1H), 7.27 (dd, J=8.5, 2.4Hz, 1H) ,5.01(s,2H),3.88(s,3H),2.31(s,3H).
步骤15：中间体1s的制备Step 15: Preparation of Intermediate 1s
向单口瓶中，依次加入中间体1r(4g)、乙酸铵(2.217g)及THF(50mL)，将混合物室温反应30h。反应结束后，反应液通过减压蒸除溶剂，向残留物中加入EA(100mL)和水(200mL)。有机相分离，分别用100mL饱和食盐水洗涤后用无水硫酸钠干燥，过滤，滤液通过减压蒸除溶剂，残留物通过硅胶柱层析纯化(PE/EA)得到3.07g中间体1s。Into a one-necked flask, intermediate 1r (4 g), ammonium acetate (2.217 g) and THF (50 mL) were sequentially added, and the mixture was reacted at room temperature for 30 h. After the reaction, the solvent was evaporated from the reaction solution under reduced pressure, and EA (100 mL) and water (200 mL) were added to the residue. The organic phase was separated, washed with 100 mL of saturated brine, dried with anhydrous sodium sulfate, filtered, the filtrate was evaporated under reduced pressure to remove the solvent, and the residue was purified by silica gel column chromatography (PE/EA) to obtain 3.07 g of intermediate 1s.
1H NMR(500MHz,DMSO-d 6)δ10.45(s,1H),7.81(d,J＝8.6Hz,1H),6.95(d,J＝2.5Hz,1H),6.82(dd,J＝8.6,2.6Hz,1H),4.99(s,2H),3.81(s,3H). 1 H NMR (500MHz, DMSO-d 6 )δ10.45(s, 1H), 7.81(d, J=8.6Hz, 1H), 6.95(d, J=2.5Hz, 1H), 6.82(dd, J= 8.6,2.6Hz,1H),4.99(s,2H),3.81(s,3H).
步骤16：中间体1t的制备Step 16: Preparation of intermediate 1t
向微波管中依次加入中间体1s(1g)、乙腈(60mL)、中间体1n(0.614g)和N,N-二异丙基乙胺(1.177g)，搅拌1分钟后，放入微波反应器中，在200W下加热至100℃反应60分钟。微波管中反应液转移到圆底瓶中，向残留物中加入EA(100)mL和水(100)mL。有机相分离，分别用100mL饱和食盐水洗涤后用无水硫酸钠干燥，过滤，减压蒸除溶剂，粗品通过硅胶柱层析纯化(EA/CH3OH)得到0.55g中间体1t。Add intermediate 1s (1g), acetonitrile (60mL), intermediate 1n (0.614g) and N,N-diisopropylethylamine (1.177g) to the microwave tube in turn, stir for 1 minute, then put into microwave reaction In the container, it was heated to 100°C under 200W to react for 60 minutes. The reaction solution in the microwave tube was transferred to a round bottom flask, and EA (100) mL and water (100) mL were added to the residue. The organic phase was separated, washed with 100 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The crude product was purified by silica gel column chromatography (EA/CH3OH) to obtain 0.55 g of intermediate 1t.
MS(ESI,[M-H] -)m/z：333.2。 1H NMR(500MHz,DMSO-d 6)δ10.11(s,1H),7.53–7.46(m,2H),7.14(s,1H),6.93(d,J＝2.1Hz,1H),6.85(dd,J＝8.2,2.2Hz,1H),4.67(dd,J＝9.1,3.4Hz,1H),4.52–4.31(m,2H),2.13(d,J＝2.0Hz,3H),1.99(s,1H),1.33(s,9H). MS (ESI, [MH] - ) m/z: 333.2. 1 H NMR (500MHz, DMSO-d 6 ) δ10.11(s, 1H), 7.53–7.46(m, 2H), 7.14(s, 1H), 6.93(d, J=2.1Hz, 1H), 6.85( dd,J=8.2,2.2Hz,1H),4.67(dd,J=9.1,3.4Hz,1H),4.52–4.31(m,2H),2.13(d,J=2.0Hz,3H),1.99(s ,1H),1.33(s,9H).
步骤17：中间体1u的制备Step 17: Preparation of intermediate 1u
向单口瓶中，依次加入1,2-双(2-碘代乙氧基)乙烷(3.26g)、DMF(20mL)、碳酸铯(1907mg)、及中间体1t(450mg)，将混合物遮光室温反应1.5h。反应结束后，反应液中加入EA(200mL)和水(300mL)。有机相分离，分别用300mL饱和食盐水洗涤后用无水硫酸钠干燥，过滤，减压蒸除溶剂，粗品通过硅胶柱 层析纯化(DCM/CH 3OH/NH 4OH)得到0.52g中间体1u。 To a one-necked flask, add 1,2-bis(2-iodoethoxy)ethane (3.26g), DMF (20mL), cesium carbonate (1907mg), and intermediate 1t (450mg) in sequence, and shield the mixture from light Reaction at room temperature for 1.5h. After the reaction, EA (200 mL) and water (300 mL) were added to the reaction solution. The organic phase was separated, washed with 300 mL of saturated brine, dried with anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The crude product was purified by silica gel column chromatography (DCM/CH 3 OH/NH 4 OH) to obtain 0.52 g of an intermediate 1u.
MS(ESI,[M+H] +)m/z：577.3。 1H NMR(500MHz,DMSO-d 6)δ7.59(d,J＝8.4Hz,1H),7.54(s,1H),7.18(d,J＝2.2Hz,1H),7.16(s,1H),7.04(dd,J＝8.4,2.3Hz,1H),4.73–4.66(m,1H),4.55(d,J＝17.5Hz,1H),4.39(d,J＝17.4Hz,1H),4.21–4.14(m,2H),3.86–3.76(m,2H),3.67(t,J＝6.4Hz,2H),3.63–3.56(m,4H),3.31(d,J＝6.5Hz,2H),2.20–2.07(m,3H),2.01–1.91(m,1H),1.33(s,9H). MS (ESI, [M+H] + ) m/z: 577.3. 1 H NMR (500MHz, DMSO-d 6 )δ7.59(d, J=8.4Hz, 1H), 7.54(s, 1H), 7.18(d, J=2.2Hz, 1H), 7.16(s, 1H) ,7.04(dd,J=8.4,2.3Hz,1H),4.73–4.66(m,1H),4.55(d,J=17.5Hz,1H),4.39(d,J=17.4Hz,1H),4.21– 4.14(m, 2H), 3.86–3.76(m, 2H), 3.67(t, J=6.4Hz, 2H), 3.63–3.56(m, 4H), 3.31(d, J=6.5Hz, 2H), 2.20 –2.07(m,3H),2.01–1.91(m,1H),1.33(s,9H).
步骤18：中间体1v的制备Step 18: Preparation of Intermediate 1v
向单口瓶中，依次加入中间体1u(267mg)、DMF(2mL)、1j(450mg)及三乙胺(398mg)，N 2保护下，将混合物60℃反应1h。反应结束后，反应液冷至室温，减压蒸除溶剂，残留物通过硅胶柱层析纯化(EA/CH 3OH/NH 4OH)得到0.283g中间体1v。 Into a one-necked flask, intermediate 1u (267mg), DMF (2mL), 1j (450mg) and triethylamine (398mg) were sequentially added, and the mixture was reacted at 60°C for 1h under the protection of N 2 . After the reaction, the reaction liquid was cooled to room temperature, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (EA/CH 3 OH/NH 4 OH) to obtain 0.283 g of intermediate 1v.
MS(ESI,[M+H] +)m/z：955.7。 1H NMR(500MHz,DMSO-d 6)δ11.25(s,1H),8.42(d,J＝5.4Hz,1H),8.32(d,J＝1.9Hz,1H),8.01–7.93(m,2H),7.65–7.53(m,3H),7.36(dd,J＝5.4,1.9Hz,1H),7.24(d,J＝5.0Hz,1H),7.20–7.14(m,2H),7.04(dd,J＝8.5,2.2Hz,1H),7.00(d,J＝4.9Hz,1H),6.00(s,2H),4.73–4.65(m,1H),4.55(d,J＝17.4Hz,1H),4.38(d,J＝17.4Hz,1H),4.18(t,J＝4.7Hz,2H),3.78(t,J＝4.6Hz,2H),3.59(d,J＝5.0Hz,2H),3.52(s,2H),3.41–3.35(m,1H),3.32(d,J＝4.5Hz,2H),3.03(s,6H),2.13(d,J＝2.5Hz,2H),1.85(s,4H),1.31(s,9H). 13C NMR(126MHz,DMSO-d 6)δ172.43,171.82,168.15,161.95,158.62,157.52,156.74,155.90,154.09,145.13,143.26,130.59,130.47,128.56,124.87,124.63,124.26,119.47,119.40,115.63,109.06,97.91,80.20,70.38,70.18,69.25,68.14,60.22,53.76,47.15,32.23,28.12,25.35,25.35,14.56. MS (ESI, [M+H] + ) m/z: 955.7. 1 H NMR (500MHz, DMSO-d 6 ) δ11.25(s, 1H), 8.42(d, J=5.4Hz, 1H), 8.32(d, J=1.9Hz, 1H), 8.01–7.93(m, 2H),7.65–7.53(m,3H),7.36(dd,J＝5.4,1.9Hz,1H),7.24(d,J＝5.0Hz,1H),7.20–7.14(m,2H),7.04(dd ,J=8.5,2.2Hz,1H),7.00(d,J=4.9Hz,1H),6.00(s,2H),4.73–4.65(m,1H),4.55(d,J=17.4Hz,1H) ,4.38(d,J=17.4Hz,1H),4.18(t,J=4.7Hz,2H),3.78(t,J=4.6Hz,2H),3.59(d,J=5.0Hz,2H),3.52 (s,2H),3.41–3.35(m,1H),3.32(d,J＝4.5Hz,2H),3.03(s,6H),2.13(d,J＝2.5Hz,2H),1.85(s, 4H),1.31(s,9H). 13 C NMR(126MHz,DMSO-d 6 )δ172.43,171.82,168.15,161.95,158.62,157.52,156.74,155.90,154.09,145.13,143.26,130.59,1328.45 ,124.63,124.26,119.47,119.40,115.63,109.06,97.91,80.20,70.38,70.18,69.25,68.14,60.22,53.76,47.15,32.23,28.12,25.35,25.365,14.5
步骤19：化合物1的制备Step 19: Preparation of Compound 1
向微波管中依次加入中间体1v(250mg)、乙腈(10mL)、和苯磺酸(142mg)，搅拌1分钟后，放入微波反应器中，在200W下加热至100℃反应60分钟。反应结束后，微波管中反应液转移到圆底瓶中，通过220g C 18反相柱纯化(1％乙酸铵水溶液/CH 3CN)得到0.187g化合物1。 Add intermediate 1v (250mg), acetonitrile (10mL), and benzenesulfonic acid (142mg) to the microwave tube in turn, stir for 1 minute, put into a microwave reactor, and heat at 200W to 100°C for 60 minutes. After the reaction, the reaction solution in the microwave tube was transferred to a round-bottomed bottle, and purified by a 220 g C 18 reverse phase column (1% ammonium acetate aqueous solution/CH 3 CN) to obtain 0.187 g of compound 1.
MS(ESI,[M+H] +)m/z：881.6。 1H NMR(500MHz,DMSO-d 6)δ10.96(s,1H),8.23(s,1H),7.69–7.63(m,2H),7.61(d,J＝8.4Hz,1H),7.47–7.39(m,2H),7.21–7.11(m,6H),7.06(dd,J＝8.4,2.3Hz,1H),5.06(dd,J＝13.3,5.1Hz,1H),4.64(s,1H),4.36(d,J＝17.2Hz,1H),4.24(d,J＝17.1Hz,1H),4.20(dd,J＝5.7,3.6Hz,2H),3.83–3.76(m,2H),3.62(dd,J＝5.9,3.4Hz,2H),3.58–3.51(m,4H),3.02(d,J＝5.7Hz,2H),2.89(ddd,J＝17.9,13.5,5.4Hz,1H),2.62–2.51(m,3H),2.36(qd,J＝13.1,4.4Hz,1H),2.18(d,J＝8.6Hz,4H),1.96(ddt,J＝11.5,6.5,3.5Hz,1H),1.86(s,2H). 13C NMR(126MHz,DMSO-d 6)δ173.35,171.61,168.35,162.13,158.61,157.51,156.74,155.90,154.07,144.86,143.24,130.59,130.47,128.57,124.77,124.63,124.26,119.46,119.40,115.86,109.10,97.90,70.40,70.18,69.25,69.04,68.18,57.51,53.16,51.96,49.20,47.42,31.70,31.48,27.30,22.98. MS (ESI, [M+H] + ) m/z: 881.6. 1 H NMR (500MHz,DMSO-d 6 )δ10.96(s,1H),8.23(s,1H),7.69–7.63(m,2H),7.61(d,J＝8.4Hz,1H),7.47– 7.39(m,2H),7.21–7.11(m,6H),7.06(dd,J＝8.4,2.3Hz,1H),5.06(dd,J＝13.3,5.1Hz,1H),4.64(s,1H) ,4.36(d,J=17.2Hz,1H),4.24(d,J=17.1Hz,1H),4.20(dd,J=5.7,3.6Hz,2H),3.83–3.76(m,2H),3.62( dd,J=5.9,3.4Hz,2H),3.58–3.51(m,4H),3.02(d,J=5.7Hz,2H),2.89(ddd,J=17.9,13.5,5.4Hz,1H),2.62 –2.51(m,3H),2.36(qd,J=13.1,4.4Hz,1H),2.18(d,J=8.6Hz,4H),1.96(ddt,J=11.5,6.5,3.5Hz,1H), 1.86(s,2H). 13 C NMR(126MHz,DMSO-d 6 )δ173.35,171.61,168.35,162.13,158.61,157.51,156.74,155.90,154.07,144.86,143.24,130.576,130.47.1,23 124.26,119.46,119.40,115.86,109.10,97.90,70.40,70.18,69.25,69.04,68.18,57.51,53.16,51.96,49.20,47.42,31.70,31.48,27.30,22.98.
实施例2 化合物2的合成The synthesis of embodiment 2 compound 2
Figure PCTCN2022096512-appb-000103
Figure PCTCN2022096512-appb-000103
Figure PCTCN2022096512-appb-000104
Figure PCTCN2022096512-appb-000104
步骤1：中间体2c的制备Step 1: Preparation of Intermediate 2c
向单口瓶中，0℃下，依次加入中间体2a(20.93g)、DMSO(50mL)、中间体2b(10g)，将氢氧化钾(8.09g)的H 2O(2mL)溶液缓慢滴入反应液中，将混合物0℃搅拌10min，转移至室温搅拌反应6h。反应液中加入水(200mL)淬灭。有机相分离，分别用200mL饱和食盐水洗涤后用无水硫酸钠干燥，过滤，滤液通过减压蒸除溶剂，得到30g中间体2c。 Into the one-necked flask, at 0°C, sequentially add intermediate 2a (20.93g), DMSO (50mL), intermediate 2b (10g), slowly drop the solution of potassium hydroxide (8.09g) in H 2 O (2mL) In the reaction solution, the mixture was stirred at 0° C. for 10 min, then transferred to room temperature and stirred for 6 h. Water (200 mL) was added to the reaction solution to quench it. The organic phase was separated, washed with 200 mL of saturated brine, dried with anhydrous sodium sulfate, filtered, and the filtrate was evaporated to remove the solvent under reduced pressure to obtain 30 g of intermediate 2c.
步骤2：中间体2d的制备Step 2: Preparation of Intermediate 2d
在单口瓶中，0℃及N 2保护下，将甲基磺酰氯(6.97g)缓慢滴入中间体2c(10g)的DCM(50mL)和三乙胺(7.28g)搅拌液中，30分钟后滴加完毕，混合物在室温搅拌反应1h。将反应液加入氯化铵淬灭后，加入200mL H 2O萃取反应，有机相用100mL饱和食盐水水洗后，用无水硫酸钠干燥，过滤，得到20g中间体2d。 In a one-necked flask, methanesulfonyl chloride (6.97g) was slowly dropped into a stirred solution of DCM (50mL) and triethylamine (7.28g) of intermediate 2c (10g) under the protection of 0°C and N2 for 30 minutes After the dropwise addition was completed, the mixture was stirred at room temperature for 1 h. The reaction liquid was quenched by adding ammonium chloride, and 200 mL of H 2 O was added to extract the reaction. The organic phase was washed with 100 mL of saturated brine, dried with anhydrous sodium sulfate, and filtered to obtain 20 g of intermediate 2d.
步骤3：中间体2e的制备Step 3: Preparation of Intermediate 2e
向单口瓶中，依次加入中间体2d(2042mg)、DMF(20mL)、碳酸钾(546mg)及中间体1t(500mg)，将混合物80℃反应16.5h。反应液冷至室温，减压蒸除溶剂，向残留物中加入EA(200mL)和水(200mL)。有机相分离，分别用100mL饱和食盐水洗涤后无水硫酸钠干燥，过滤，滤液通过反相柱层析纯化(H 2O/CH 3CN)得到0.220g中间体2e。 Intermediate 2d (2042mg), DMF (20mL), potassium carbonate (546mg) and intermediate 1t (500mg) were sequentially added to the one-necked bottle, and the mixture was reacted at 80°C for 16.5h. The reaction solution was cooled to room temperature, the solvent was evaporated under reduced pressure, and EA (200 mL) and water (200 mL) were added to the residue. The organic phase was separated, washed with 100 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was purified by reverse phase column chromatography (H 2 O/CH 3 CN) to obtain 0.220 g of intermediate 2e.
MS(ESI,[M+H] +)m/z：497.4. 1H NMR(500MHz,DMSO-d 6)δ7.58(d,J＝8.4Hz,1H),7.55(s,1H),7.19–7.14(m,2H),7.01(dd,J＝8.4,2.2Hz,1H),4.74–4.65(m,1H),4.54(d,J＝17.4Hz,1H),4.38(d,J＝17.5Hz,1H),4.07(t,J＝6.5Hz,2H),3.65(t,J＝6.6Hz,2H),3.40(dt,J＝12.7,6.3Hz,4H),2.17–2.07(m,3H),2.00–1.93(m,1H),1.76(ddd,J＝14.7,11.2,6.7Hz,4H),1.63(ddd,J＝20.8,8.6,6.1Hz,4H),1.33(s,9H). MS (ESI, [M+H] + ) m/z: 497.4. 1 H NMR (500MHz, DMSO-d 6 ) δ7.58 (d, J=8.4Hz, 1H), 7.55 (s, 1H), 7.19 –7.14(m,2H),7.01(dd,J=8.4,2.2Hz,1H),4.74–4.65(m,1H),4.54(d,J=17.4Hz,1H),4.38(d,J=17.5 Hz, 1H), 4.07(t, J=6.5Hz, 2H), 3.65(t, J=6.6Hz, 2H), 3.40(dt, J=12.7, 6.3Hz, 4H), 2.17–2.07(m, 3H ),2.00–1.93(m,1H),1.76(ddd,J＝14.7,11.2,6.7Hz,4H),1.63(ddd,J＝20.8,8.6,6.1Hz,4H),1.33(s,9H).
步骤4：中间体2f的制备Step 4: Preparation of Intermediate 2f
向单口瓶中，依次加入中间体2e(220mg)、丙酮(10mL)、碘化钠(632mg)，将混合物60℃反应20h。反应液冷至室温，反应液减压除去溶剂后，残留物通过硅胶柱层析纯化(DCM/CH 3OH)得到0.2g中间体2f。 Intermediate 2e (220mg), acetone (10mL) and sodium iodide (632mg) were sequentially added to a one-necked flask, and the mixture was reacted at 60°C for 20h. The reaction solution was cooled to room temperature, and the solvent was removed from the reaction solution under reduced pressure. The residue was purified by silica gel column chromatography (DCM/CH 3 OH) to obtain 0.2 g of intermediate 2f.
MS(ESI,[M+H] +)m/z：589.4。 MS (ESI, [M+H] + ) m/z: 589.4.
步骤5：中间体2g的制备Step 5: Preparation of intermediate 2g
向单口瓶中，依次加入中间体1j(176mg)、DMF(10mL)、中间体2f(200mg)及碳酸钾(141mg)，N 2保护下，将混合物室温反应20h，反应结束后，反应液中加入EA(200mL)和H 2O(100mL)萃取三次后，有机相混合用无水硫酸钠干燥后过滤，滤液通过硅胶柱层析纯化(EA/CH 3OH/NH 4OH)得到0.142g中间体2g。 Into the single-necked bottle, add intermediate 1j (176mg), DMF (10mL), intermediate 2f (200mg) and potassium carbonate (141mg) successively, under N 2 protection, react the mixture at room temperature for 20h, after the reaction, the reaction liquid After adding EA (200 mL) and H 2 O (100 mL) for extraction three times, the organic phases were mixed and dried over anhydrous sodium sulfate and filtered, and the filtrate was purified by silica gel column chromatography (EA/CH 3 OH/NH 4 OH) to obtain 0.142 g of intermediate Body 2g.
MS(ESI,[M+H] +)m/z：967.7。 MS (ESI, [M+H] + ) m/z: 967.7.
步骤6：化合物2的制备Step 6: Preparation of Compound 2
向微波管中依次加入中间体2g(120mg)、乙腈(10mL)、和苯磺酸(87mg)，搅拌1分钟后，放入微波反应器中，在200W下加热至100℃反应120分钟。反应结束后，微波管中反应液转移到圆底瓶中，减压 蒸除溶液，通过220g反相柱(1％乙酸铵水溶液/乙腈)纯化得到0.08g化合物2。Add intermediate 2g (120mg), acetonitrile (10mL) and benzenesulfonic acid (87mg) to the microwave tube successively, stir for 1 minute, put into microwave reactor, heat to 100°C under 200W and react for 120 minutes. After the reaction, the reaction solution in the microwave tube was transferred to a round-bottom flask, the solution was evaporated under reduced pressure, and purified by a 220 g reverse-phase column (1% aqueous ammonium acetate/acetonitrile) to obtain 0.08 g of compound 2.
MS(ESI,[M+H] +)m/z：893.7。 1H NMR(500MHz,DMSO-d 6)δ11.23(s,1H),11.02–10.89(m,1H),8.42(d,J＝5.4Hz,1H),8.32(d,J＝1.9Hz,1H),8.01–7.94(m,2H),7.62(dd,J＝8.1,6.4Hz,2H),7.35(dd,J＝5.3,2.0Hz,1H),7.24(d,J＝5.0Hz,1H),7.15(d,J＝2.1Hz,1H),7.04(dd,J＝8.4,2.2Hz,1H),7.00(d,J＝5.0Hz,1H),5.99(s,2H),5.07(dd,J＝13.3,5.1Hz,1H),4.41–4.22(m,2H),4.08(t,J＝6.5Hz,2H),3.41(t,J＝6.3Hz,4H),3.04(t,J＝5.2Hz,4H),2.95(s,4H),2.91–2.83(m,1H),2.63–2.54(m,1H),2.43–2.31(m,3H),1.97(ddd,J＝7.3,5.3,2.4Hz,1H),1.84(t,J＝5.4Hz,4H),1.79(dd,J＝8.5,6.1Hz,2H),1.65(dd,J＝8.6,5.9Hz,2H),1.52–1.44(m,2H),1.30(t,J＝7.5Hz,2H). 13C NMR(126MHz,DMSO-d 6)δ173.35,171.63,168.39,162.29,153.65,151.92,149.92,145.56,144.90,144.46,132.96,124.78,124.63,124.48,115.79,114.70,113.82,109.05,70.34,69.97,68.32,64.06,51.96,47.60,47.43,35.79,34.31,31.70,27.55,26.22,26.03,24.43,22.99. MS (ESI, [M+H] + ) m/z: 893.7. 1 H NMR (500MHz, DMSO-d 6 ) δ11.23(s, 1H), 11.02–10.89(m, 1H), 8.42(d, J=5.4Hz, 1H), 8.32(d, J=1.9Hz, 1H), 8.01–7.94(m, 2H), 7.62(dd, J＝8.1, 6.4Hz, 2H), 7.35(dd, J＝5.3, 2.0Hz, 1H), 7.24(d, J＝5.0Hz, 1H ),7.15(d,J=2.1Hz,1H),7.04(dd,J=8.4,2.2Hz,1H),7.00(d,J=5.0Hz,1H),5.99(s,2H),5.07(dd ,J=13.3,5.1Hz,1H),4.41–4.22(m,2H),4.08(t,J=6.5Hz,2H),3.41(t,J=6.3Hz,4H),3.04(t,J= 5.2Hz, 4H), 2.95(s, 4H), 2.91–2.83(m, 1H), 2.63–2.54(m, 1H), 2.43–2.31(m, 3H), 1.97(ddd, J＝7.3, 5.3, 2.4Hz, 1H), 1.84(t, J=5.4Hz, 4H), 1.79(dd, J=8.5, 6.1Hz, 2H), 1.65(dd, J=8.6, 5.9Hz, 2H), 1.52–1.44( m,2H),1.30(t,J=7.5Hz,2H). 13 C NMR(126MHz,DMSO-d 6 )δ173.35,171.63,168.39,162.29,153.65,151.92,149.92,145.56,144.90,144.46,132.96, 124.78,124.63,124.48,115.79,114.70,113.82,109.05,70.34,69.97,68.32,64.06,51.96,47.60,47.43,35.79,34.31,31.70,27.55,26.232,226.93
实施例3 化合物3的合成The synthesis of embodiment 3 compound 3
Figure PCTCN2022096512-appb-000105
Figure PCTCN2022096512-appb-000105
步骤1：中间体3b的制备Step 1: Preparation of Intermediate 3b
向单口瓶中，依次加入中间体3a(5g)、三乙胺(4.50g)及DCM(30mL)。降温至0℃左右，缓慢加入对甲苯磺酰氯(6.52g)，N 2保护下，将混合物室温反应过夜。反应结束后，向反应液中加入DCM(100mL)和水(200mL)。有机相分离，分别用200mL饱和食盐水洗后用无水硫酸钠干燥，过滤，粗品通过硅胶柱层析纯化(PE/EA)得到3g中间体3b。 Into a one-necked flask, intermediate 3a (5 g), triethylamine (4.50 g) and DCM (30 mL) were sequentially added. The temperature was lowered to about 0°C, p-toluenesulfonyl chloride (6.52 g) was slowly added, and the mixture was reacted overnight at room temperature under the protection of N 2 . After the reaction, DCM (100 mL) and water (200 mL) were added to the reaction solution. The organic phase was separated, washed with 200 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the crude product was purified by silica gel column chromatography (PE/EA) to obtain 3 g of intermediate 3b.
MS(ESI,[M+H] +)m/z：301.2。 1H NMR(500MHz,DMSO-d 6)δ7.85–7.73(m,2H),7.48(d,J＝8.0Hz,2H),4.00(t,J＝6.3Hz,2H),3.71(s,1H),3.36(t,J＝6.6Hz,2H),2.42(s,3H),1.58–1.50(m,2H),1.42–1.32(m,2H),1.26–1.08(m,8H). MS (ESI, [M+H] + ) m/z: 301.2. 1 H NMR (500MHz, DMSO-d 6 )δ7.85–7.73(m, 2H), 7.48(d, J=8.0Hz, 2H), 4.00(t, J=6.3Hz, 2H), 3.71(s, 1H), 3.36(t, J=6.6Hz, 2H), 2.42(s, 3H), 1.58–1.50(m, 2H), 1.42–1.32(m, 2H), 1.26–1.08(m, 8H).
步骤2：中间体3c的制备Step 2: Preparation of Intermediate 3c
向单口瓶中，依次加入中间体1t(1172mg)、DMF(10mL)、中间体3b(500mg)及碳酸钾(270mg)，N 2保护下，将混合物加热至80℃反应19h。反应结束后，反应液冷至室温，加入EA(200mL)和水(300mL)。有机相分离，分别用100mL饱和食盐水洗涤后用无水硫酸钠干燥，过滤，减压蒸除溶剂，残留物通过硅胶柱层析纯化(DCM/CH 3OH/NH 4OH)得到0.52g中间体3c。 Intermediate 1t (1172 mg), DMF (10 mL), Intermediate 3b (500 mg) and potassium carbonate (270 mg) were sequentially added to a one-necked flask, and the mixture was heated to 80° C. for 19 h under the protection of N 2 . After the reaction, the reaction solution was cooled to room temperature, and EA (200 mL) and water (300 mL) were added. The organic phase was separated, washed with 100 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (DCM/CH 3 OH/NH 4 OH) to obtain 0.52 g of intermediate Body 3c.
MS(ESI,[M+H] +)m/z：463.5。 MS (ESI, [M+H] + ) m/z: 463.5.
步骤3：中间体3d的制备Step 3: Preparation of intermediate 3d
向三口瓶中，依次加入中间体3c(0.662mg)、DCM(10mL)、对甲苯磺酰氯(1.092g)及三乙胺(290mg)，反应液升温至50℃反应20h。反应结束后，反应液冷至室温，减压蒸除溶剂，向残留物中加入DCM(100mL)和水(100mL)。有机相分离，分别用100mL饱和食盐水洗涤后用无水硫酸钠干燥，过滤，残留物通过硅胶柱层析纯化(DCM/EA)得到0.596g中间体3d。Into the three-necked flask, intermediate 3c (0.662 mg), DCM (10 mL), p-toluenesulfonyl chloride (1.092 g) and triethylamine (290 mg) were sequentially added, and the reaction solution was heated to 50° C. for 20 h. After the reaction, the reaction liquid was cooled to room temperature, the solvent was evaporated under reduced pressure, and DCM (100 mL) and water (100 mL) were added to the residue. The organic phase was separated, washed with 100 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the residue was purified by silica gel column chromatography (DCM/EA) to obtain 0.596 g of intermediate 3d.
MS(ESI,[M+H] +)m/z：617.6。 MS (ESI, [M+H] + ) m/z: 617.6.
步骤4：中间体3e的制备Step 4: Preparation of Intermediate 3e
向单口瓶中，依次加入中间体1j(351mg)、DMF(10mL)、中间体3d(450mg)及碳酸钾(248mg)，N 2 保护下，将混合物60℃反应3h。反应结束后，反应液中加EA(100mL)和水(100mL)萃取三次，有机相用无水硫酸钠干燥，过滤，滤液通过减压蒸除溶剂，以220g C 12反相柱层析(H 2O/CH 3CN)得到0.65g中间体3e。 Intermediate 1j (351 mg), DMF (10 mL), Intermediate 3d (450 mg) and potassium carbonate (248 mg) were sequentially added to a one-necked flask, and the mixture was reacted at 60° C. for 3 h under the protection of N 2 . After the reaction finished, add EA (100mL) and water (100mL) to extract three times in the reaction solution, the organic phase was dried with anhydrous sodium sulfate, filtered, and the filtrate was evaporated under reduced pressure to remove the solvent, and 220g C 12 reversed-phase column chromatography (H 2 O/CH 3 CN) afforded 0.65 g of intermediate 3e.
MS(ESI,[M+H] +)m/z：951.7。 MS (ESI, [M+H] + ) m/z: 951.7.
步骤5：化合物3的制备Step 5: Preparation of compound 3
向微波管中，依次加入中间体3e(65mg)、乙腈(10mL)和苯磺酸(52.4mg)，搅拌1分钟后，放入微波反应器中，在200W下加热至100℃反应120分钟。反应结束后，微波管中反应液转移到圆底瓶中，减压蒸除溶剂，通过220g C 18反相柱纯化(1％乙酸铵水溶液/CH 3CN)得到0.055g化合物3。 Intermediate 3e (65mg), acetonitrile (10mL) and benzenesulfonic acid (52.4mg) were sequentially added to the microwave tube, stirred for 1 minute, then placed in a microwave reactor, heated to 100°C at 200W for 120 minutes. After the reaction, the reaction solution in the microwave tube was transferred to a round-bottom flask, the solvent was evaporated under reduced pressure, and purified by 220 g C 18 reverse phase column (1% ammonium acetate aqueous solution/CH 3 CN) to obtain 0.055 g of compound 3.
MS(ESI,[M+H] +)m/z：877.7。 1H NMR(500MHz,DMSO-d 6)δ11.24(s,1H),10.97(s,1H),8.42(d,J＝5.4Hz,1H),8.32(d,J＝1.9Hz,1H),7.98(t,J＝8.3Hz,2H),7.62(t,J＝7.6Hz,2H),7.35(dd,J＝5.4,2.0Hz,1H),7.25(d,J＝4.9Hz,1H),7.15(d,J＝2.1Hz,1H),7.09–6.95(m,2H),6.00(s,2H),5.07(dd,J＝13.3,5.1Hz,1H),4.38(d,J＝17.1Hz,1H),4.26(d,J＝17.0Hz,1H),4.04(q,J＝6.4Hz,2H),3.05(d,J＝5.1Hz,4H),2.90(td,J＝13.2,6.9Hz,1H),2.59(dt,J＝17.8,2.9Hz,1H),2.37(qd,J＝13.2,4.4Hz,1H),1.99–1.93(m,1H),1.87(t,J＝5.4Hz,4H),1.74(p,J＝6.7Hz,2H),1.42(t,J＝7.6Hz,2H),1.35–1.26(m,8H). 13C NMR(126MHz,DMSO-d 6)δ173.36,171.62,168.42,165.30,162.34,160.50,158.53,153.63,151.92,149.92,145.49,144.91,144.46,135.56,135.50,132.94,127.90,126.64,126.52,124.78,124.64,124.61,124.46,120.52,116.36,116.17,115.81,114.71,113.82,109.03,106.05,68.47,63.78,51.99,47.46,35.43,34.23,31.70,29.31,29.09,28.98,26.96,25.87,23.00. MS (ESI, [M+H] + ) m/z: 877.7. 1 H NMR (500MHz,DMSO-d 6 )δ11.24(s,1H),10.97(s,1H),8.42(d,J=5.4Hz,1H),8.32(d,J=1.9Hz,1H) ,7.98(t,J=8.3Hz,2H),7.62(t,J=7.6Hz,2H),7.35(dd,J=5.4,2.0Hz,1H),7.25(d,J=4.9Hz,1H) ,7.15(d,J=2.1Hz,1H),7.09–6.95(m,2H),6.00(s,2H),5.07(dd,J=13.3,5.1Hz,1H),4.38(d,J=17.1 Hz, 1H), 4.26(d, J=17.0Hz, 1H), 4.04(q, J=6.4Hz, 2H), 3.05(d, J=5.1Hz, 4H), 2.90(td, J=13.2, 6.9 Hz, 1H), 2.59(dt, J=17.8, 2.9Hz, 1H), 2.37(qd, J=13.2, 4.4Hz, 1H), 1.99–1.93(m, 1H), 1.87(t, J=5.4Hz ,4H),1.74(p,J=6.7Hz,2H),1.42(t,J=7.6Hz,2H),1.35–1.26(m,8H). 13 C NMR(126MHz,DMSO-d 6 )δ173. 36,171.62,168.42,165.30,162.34,160.50,158.53,153.63,151.92,149.92,145.49,144.91,144.46,135.56,135.50,132.94,127.90,126.64,126.52,124.78,124.64,124.61,124.46,120.52,116.36,116.17, 115.81, 114.71, 113.82, 109.03, 106.05, 68.47, 63.78, 51.99, 47.46, 35.43, 34.23, 31.70, 29.31, 29.09, 28.98, 26.96, 25.87, 23.00.
实施例4 化合物4的合成The synthesis of embodiment 4 compound 4
Figure PCTCN2022096512-appb-000106
Figure PCTCN2022096512-appb-000106
步骤1：中间体4b的制备Step 1: Preparation of intermediate 4b
向单口瓶中，依次加入中间体1t(2.3g)、1,8-二碘辛烷(12.59g)、DMF(30mL)及碳酸铯(6.72g)，N 2保护下，室温反应。反应结束后，加水(150mL)，用EA萃取2次，有机层合并后，依次用水和饱和食盐水洗涤，有机层用无水硫酸钠干燥，过滤，浓缩，硅胶柱层析，得3.91g中间体4b。 Into the one-necked flask, the intermediate 1t (2.3g), 1,8-diiodooctane (12.59g), DMF (30mL) and cesium carbonate (6.72g) were sequentially added, and reacted at room temperature under the protection of N 2 . After the reaction, add water (150 mL), extract twice with EA, combine the organic layers, wash with water and saturated brine successively, dry the organic layer with anhydrous sodium sulfate, filter, concentrate, and perform silica gel column chromatography to obtain 3.91 g of intermediate Body 4b.
MS(ESI,[M+H] +)m/z：573.4。 MS (ESI, [M+H] + ) m/z: 573.4.
步骤2：中间体4d的制备Step 2: Preparation of Intermediate 4d
向单口瓶中依次加入中间体1h(2.5g)、中间体4c(3.52g)、碳酸钾(2.370g)、PdCl 2(dppf)·CH 2Cl 2(0.467 g)、水(6mL)和1,4-二氧六环(30mL)，N 2保护下，将混合物加热至80℃反应。反应结束，反应液冷至室温，加入水(10mL)，EA萃取(100mL×2)，合并有机相，饱和食盐水洗一次，无水硫酸钠干燥，过滤，浓缩，硅胶柱层析，得到2.85g中间体4d。 Intermediate 1h (2.5 g), Intermediate 4c (3.52 g), potassium carbonate (2.370 g), PdCl 2 (dppf)·CH 2 Cl 2 (0.467 g), water (6 mL) and 1 , 4-dioxane (30mL), under the protection of N 2 , the mixture was heated to 80°C for reaction. After the reaction was completed, the reaction solution was cooled to room temperature, added water (10 mL), extracted with EA (100 mL×2), combined the organic phases, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and silica gel column chromatography to obtain 2.85 g Intermediate 4d.
MS(ESI,[M+H] +)m/z：641.5。 MS (ESI, [M+H] + ) m/z: 641.5.
步骤3：中间体4e的制备Step 3: Preparation of Intermediate 4e
向单口瓶中，依次加入中间体4d(2.85g)、DCM(30mL)及三氟乙酸(7.94g)，将混合物室温反应。反应结束后，减压蒸除溶剂及部分三氟乙酸，用200mL EA溶解后，加入饱和碳酸氢钠溶液调节水相pH至弱碱性(pH＝8～9)。萃取，有机相用饱和食盐水洗一次，无水硫酸钠干燥，过滤，浓缩，得1.75g中间体4e。Intermediate 4d (2.85 g), DCM (30 mL) and trifluoroacetic acid (7.94 g) were sequentially added to a one-necked flask, and the mixture was reacted at room temperature. After the reaction, the solvent and part of trifluoroacetic acid were distilled off under reduced pressure, dissolved with 200mL EA, and then saturated sodium bicarbonate solution was added to adjust the pH of the aqueous phase to weakly alkaline (pH=8-9). After extraction, the organic phase was washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 1.75 g of intermediate 4e.
MS(ESI,[M+H] +)m/z：541.3。 MS (ESI, [M+H] + ) m/z: 541.3.
步骤4：中间体4f的制备Step 4: Preparation of intermediate 4f
向单口瓶中，依次加入中间体4e(662mg)、中间体4b(500mg)、DMF(10mL)及碳酸钾(384mg)，将混合物加热至50℃反应2h。反应结束后，反应液中加入水(100mL)，EA萃取三次，有机相用无水硫酸钠干燥，过滤，浓缩，反相柱层析纯化，得到250mg中间体4f。Intermediate 4e (662 mg), Intermediate 4b (500 mg), DMF (10 mL) and potassium carbonate (384 mg) were sequentially added to a one-necked flask, and the mixture was heated to 50° C. for 2 h. After the reaction was completed, water (100 mL) was added to the reaction solution, extracted three times with EA, the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by reverse phase column chromatography to obtain 250 mg of intermediate 4f.
MS(ESI,[M+H] +)m/z：985.7。 MS (ESI, [M+H] + ) m/z: 985.7.
步骤5：化合物4的制备Step 5: Preparation of compound 4
向微波管中依次加入中间体4f(250mg)、乙腈(10mL)和苯磺酸(201mg)，搅拌1分钟后，放入微波反应器中，100℃反应120分钟。反应结束后，微波管中的反应液转移到圆底瓶中，减压蒸除溶剂，通过220g C 18反相柱纯化(1％乙酸铵水溶液/CH 3CN)得到120mg化合物4。 Intermediate 4f (250mg), acetonitrile (10mL) and benzenesulfonic acid (201mg) were sequentially added into the microwave tube, stirred for 1 minute, put into a microwave reactor, and reacted at 100°C for 120 minutes. After the reaction, the reaction solution in the microwave tube was transferred to a round-bottomed bottle, the solvent was evaporated under reduced pressure, and purified by 220 g C 18 reverse phase column (1% ammonium acetate aqueous solution/CH 3 CN) to obtain 120 mg of compound 4.
MS(ESI,[M+H] +)m/z：911.6。 1H NMR(500MHz,DMSO-d 6)δ11.43(s,1H),10.97(s,1H),8.71(d,J＝5.2Hz,1H),8.56(s,1H),8.05–7.97(m,2H),7.67–7.55(m,3H),7.26(d,J＝5.0Hz,1H),7.16(s,1H),7.06–6.98(m,2H),6.00(s,2H),5.07(dd,J＝13.3,5.2Hz,1H),4.38(d,J＝17.1Hz,1H),4.26(d,J＝17.1Hz,1H),4.05(t,J＝6.6Hz,2H),3.27–3.00(m,8H),2.96–2.85(m,1H),2.66–2.55(m,2H),2.43–2.31(m,1H),2.05–1.84(m,5H),1.79–1.70(m,2H),1.45–1.38(m,2H),1.36–1.24(m,8H). MS (ESI, [M+H] + ) m/z: 911.6. 1 H NMR (500MHz, DMSO-d 6 ) δ11.43(s, 1H), 10.97(s, 1H), 8.71(d, J=5.2Hz, 1H), 8.56(s, 1H), 8.05–7.97( m,2H),7.67–7.55(m,3H),7.26(d,J=5.0Hz,1H),7.16(s,1H),7.06–6.98(m,2H),6.00(s,2H),5.07 (dd, J=13.3,5.2Hz,1H),4.38(d,J=17.1Hz,1H),4.26(d,J=17.1Hz,1H),4.05(t,J=6.6Hz,2H),3.27 –3.00(m,8H),2.96–2.85(m,1H),2.66–2.55(m,2H),2.43–2.31(m,1H),2.05–1.84(m,5H),1.79–1.70(m, 2H),1.45–1.38(m,2H),1.36–1.24(m,8H).
实施例5 化合物5的合成The synthesis of embodiment 5 compound 5
Figure PCTCN2022096512-appb-000107
Figure PCTCN2022096512-appb-000107
步骤1：中间体5b的制备Step 1: Preparation of Intermediate 5b
向反应瓶中加入丙二醇(15.60g)和氢氧化钾(6.90g)，升温至70℃搅拌10min至体系澄清，然后加入2-(2-溴乙基)-1,3-二氧杂环己烷(8g)，升温至120℃反应过夜。反应液冷却至室温，加入水(300mL)和DCM(300mL)。有机相分离，用300mL饱和氯化钠溶液洗涤后用无水硫酸钠干燥，过滤、浓缩得到中间体5b(2.8g)。Add propylene glycol (15.60g) and potassium hydroxide (6.90g) to the reaction flask, raise the temperature to 70°C and stir for 10 minutes until the system is clear, then add 2-(2-bromoethyl)-1,3-dioxane Alkanes (8g), heated up to 120°C and reacted overnight. The reaction solution was cooled to room temperature, and water (300 mL) and DCM (300 mL) were added. The organic phase was separated, washed with 300 mL saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated to obtain intermediate 5b (2.8 g).
步骤2：中间体5c的制备Step 2: Preparation of intermediate 5c
向三口瓶中加入碘(5.60g)、三苯基膦(4.63g)、咪唑(1.202g)及THF(20mL)，N 2保护下，将中间体5b(2.8g)用THF溶解后缓慢滴加至反应液，室温反应2h。反应停止，向反应液中加入200mL水和200mL EA，有机相分离，用饱和氯化钠溶液(200mL)洗涤。洗涤后无水硫酸钠干燥、过滤，浓缩，浓缩物经硅 胶柱层析分离纯化得到中间体5c(1.03g)。 Add iodine (5.60g), triphenylphosphine (4.63g), imidazole (1.202g) and THF (20mL) into the three-necked flask, under the protection of N2 , dissolve the intermediate 5b (2.8g) in THF and slowly drop Added to the reaction solution, reacted at room temperature for 2h. After the reaction was stopped, 200 mL of water and 200 mL of EA were added to the reaction solution, and the organic phase was separated and washed with saturated sodium chloride solution (200 mL). After washing, it was dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrate was separated and purified by silica gel column chromatography to obtain intermediate 5c (1.03 g).
1H NMR(500MHz,Chloroform-d)δ4.67(t,J＝5.3Hz,1H),4.14–4.06(m,2H),3.78(td,J＝11.0,9.9,2.0Hz,2H),3.53(t,J＝6.4Hz,2H),3.47(t,J＝5.8Hz,2H),3.28(t,J＝6.8Hz,2H),2.09–2.00(m,3H),1.86(td,J＝6.4,4.5Hz,3H). 1 H NMR (500MHz, Chloroform-d) δ4.67 (t, J = 5.3Hz, 1H), 4.14–4.06 (m, 2H), 3.78 (td, J = 11.0, 9.9, 2.0Hz, 2H), 3.53 (t,J=6.4Hz,2H),3.47(t,J=5.8Hz,2H),3.28(t,J=6.8Hz,2H),2.09–2.00(m,3H),1.86(td,J= 6.4,4.5Hz,3H).
步骤3：中间体5d的制备Step 3: Preparation of intermediate 5d
向反应瓶中加入中间体1t(1g)、中间体5c(0.987g)、碳酸铯(2.92g)及DMF(15mL)，将混合物室温反应2h。反应液中加入EA(100mL)和水(100mL)。有机相分离，用饱和氯化钠溶液(100mL)洗涤后用无水硫酸钠干燥，过滤，浓缩得到中间体5d(1.21g)。Intermediate 1t (1 g), intermediate 5c (0.987 g), cesium carbonate (2.92 g) and DMF (15 mL) were added to the reaction flask, and the mixture was reacted at room temperature for 2 h. EA (100 mL) and water (100 mL) were added to the reaction solution. The organic phase was separated, washed with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give intermediate 5d (1.21 g).
MS(ESI,[M+H] +)m/z：507.5. MS (ESI, [M+H] + ) m/z: 507.5.
步骤4：中间体5e的制备Step 4: Preparation of Intermediate 5e
向反应瓶中加入中间体5d(1.1g)、0.5M稀盐酸(0.792g,43.4mL,21.72mmol)和THF(20mL)，加热至50℃反应过夜。反应液中加入EA(200mL)和水(100mL)。有机相分离，用饱和氯化钠溶液(200mL)洗涤后用无水硫酸钠干燥，过滤，浓缩得到中间体5e(1.09g)。Add intermediate 5d (1.1g), 0.5M dilute hydrochloric acid (0.792g, 43.4mL, 21.72mmol) and THF (20mL) into the reaction flask, heat to 50°C overnight. EA (200 mL) and water (100 mL) were added to the reaction solution. The organic phase was separated, washed with saturated sodium chloride solution (200 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give intermediate 5e (1.09 g).
MS(ESI,[M+H] +)m/z：449.4. MS (ESI, [M+H] + ) m/z: 449.4.
步骤5：中间体5f的制备Step 5: Preparation of Intermediate 5f
向反应瓶中加入中间体1j(0.5g)、中间体5e(1.035g)、氰基硼氢化钠(0.145g)、乙酸(0.1mL)及MeOH(10mL)，将混合物室温反应2h。反应液中加入少量饱和氯化铵水溶液，然后浓缩，经硅胶柱层析分离纯化得到中间体5f(0.13g)。Intermediate 1j (0.5 g), Intermediate 5e (1.035 g), sodium cyanoborohydride (0.145 g), acetic acid (0.1 mL) and MeOH (10 mL) were added to the reaction flask, and the mixture was reacted at room temperature for 2 h. A small amount of saturated aqueous ammonium chloride solution was added to the reaction liquid, then concentrated, separated and purified by silica gel column chromatography to obtain intermediate 5f (0.13 g).
MS(ESI,[M+H] +)m/z：939.6. MS (ESI, [M+H] + ) m/z: 939.6.
步骤6：化合物5的制备Step 6: Preparation of compound 5
微波管中加入中间体5f(0.13g)、苯磺酸(0.066g)和乙腈(4mL)，微波至100℃反应60分钟。将反应液浓缩后，经反相柱层析分离纯化得到化合物5(0.041g)。Intermediate 5f (0.13 g), benzenesulfonic acid (0.066 g) and acetonitrile (4 mL) were added into a microwave tube, and reacted at 100° C. for 60 minutes by microwave. After the reaction solution was concentrated, it was separated and purified by reverse phase column chromatography to obtain compound 5 (0.041 g).
MS(ESI,[M+H] +)m/z：865.57。 1H NMR(500MHz,DMSO-d 6)δ11.22(s,1H),10.96(s,1H),8.41(d,J＝5.4Hz,1H),8.31(s,1H),7.97(t,J＝7.7Hz,2H),7.62(dt,J＝8.2,3.8Hz,2H),7.34(d,J＝5.3Hz,1H),7.23(d,J＝5.0Hz,1H),7.16(s,1H),7.04(d,J＝8.4Hz,1H),7.00(d,J＝5.0Hz,1H),5.98(s,2H),5.06(dd,J＝13.3,5.1Hz,1H),4.38(d,J＝17.1Hz,1H),4.26(d,J＝17.1Hz,1H),4.11(t,J＝6.4Hz,2H),3.51(t,J＝6.2Hz,2H),3.11–2.95(m,8H),2.88(td,J＝13.3,6.8Hz,1H),2.60–2.55(m,1H),2.35(tt,J＝13.2,6.6Hz,1H),1.97(dd,J＝10.7,4.9Hz,3H),1.83(t,J＝5.4Hz,4H),1.53(p,J＝6.7Hz,2H). 13C NMR(126MHz,DMSO-d 6)δ173.34,171.61,168.40,165.30,162.27,160.49,158.52,153.63,151.91,149.92,145.52,144.93,144.45,135.55,132.94,127.90,126.65,124.80,124.64,120.51,116.36,115.84,114.72,113.82,109.05,106.04,68.55,66.80,65.62,63.88,51.99,47.51,47.48,35.59,34.17,31.69,29.46,23.00. MS (ESI, [M+H] + ) m/z: 865.57. 1 H NMR (500MHz, DMSO-d 6 )δ11.22(s,1H),10.96(s,1H),8.41(d,J=5.4Hz,1H),8.31(s,1H),7.97(t, J＝7.7Hz, 2H), 7.62(dt, J＝8.2, 3.8Hz, 2H), 7.34(d, J＝5.3Hz, 1H), 7.23(d, J＝5.0Hz, 1H), 7.16(s, 1H), 7.04(d, J=8.4Hz, 1H), 7.00(d, J=5.0Hz, 1H), 5.98(s, 2H), 5.06(dd, J=13.3, 5.1Hz, 1H), 4.38( d, J＝17.1Hz, 1H), 4.26(d, J＝17.1Hz, 1H), 4.11(t, J＝6.4Hz, 2H), 3.51(t, J＝6.2Hz, 2H), 3.11–2.95( m,8H),2.88(td,J=13.3,6.8Hz,1H),2.60–2.55(m,1H),2.35(tt,J=13.2,6.6Hz,1H),1.97(dd,J=10.7, 4.9Hz, 3H), 1.83(t, J＝5.4Hz, 4H), 1.53(p, J＝6.7Hz, 2H). 13 C NMR (126MHz, DMSO-d 6 ) δ173.34, 171.61, 168.40, 165.30, 162.27 ,160.49,158.52,153.63,151.91,149.92,145.52,144.93,144.45,135.55,132.94,127.90,126.65,124.80,124.64,120.51,116.36,115.84,114.72,113.82,109.05,106.04,68.55,66.80,65.62,63.88 ,51.99,47.51,47.48,35.59,34.17,31.69,29.46,23.00.
实施例6 化合物6的合成The synthesis of embodiment 6 compound 6
Figure PCTCN2022096512-appb-000108
Figure PCTCN2022096512-appb-000108
步骤1：中间体6b的制备Step 1: Preparation of Intermediate 6b
向反应瓶中加入丙二醇(7.72g)和氢氧化钾(6.83g)，升温至70℃搅拌10min至体系澄清，然后加入中 间体6a(4g)，升温至120℃反应过夜。反应液冷却至室温，加入水(200mL)和DCM(200mL)。有机相分离，用300mL饱和氯化钠溶液洗涤后无水硫酸钠干燥，过滤、浓缩得到中间体6b(3.42g)。Add propylene glycol (7.72g) and potassium hydroxide (6.83g) to the reaction flask, raise the temperature to 70°C and stir for 10 minutes until the system is clear, then add intermediate 6a (4g), and raise the temperature to 120°C to react overnight. The reaction solution was cooled to room temperature, and water (200 mL) and DCM (200 mL) were added. The organic phase was separated, washed with 300 mL saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated to obtain intermediate 6b (3.42 g).
步骤2：中间体6c的制备Step 2: Preparation of intermediate 6c
向三口瓶中加入碘(6.77g)、三苯基膦(5.60g)、咪唑(1.453g)及THF(20mL)，N 2保护下，将中间体6b(3.42g)用THF溶解后缓慢滴加至反应液，室温反应2h。反应停止，向反应液中加入200mL水和200mL EA，有机相分离，用饱和氯化钠溶液(200mL)洗涤。洗涤后无水硫酸钠干燥、过滤，浓缩，浓缩物经硅胶柱层析分离纯化得到中间体6c(2.05g)。 Add iodine (6.77g), triphenylphosphine (5.60g), imidazole (1.453g) and THF (20mL) into the three-necked flask, under the protection of N2 , dissolve the intermediate 6b (3.42g) in THF and slowly drop Added to the reaction solution, reacted at room temperature for 2h. After the reaction was stopped, 200 mL of water and 200 mL of EA were added to the reaction solution, and the organic phase was separated and washed with saturated sodium chloride solution (200 mL). After washing, it was dried over anhydrous sodium sulfate, filtered, concentrated, and the concentrate was separated and purified by silica gel column chromatography to obtain intermediate 6c (2.05 g).
1H NMR(500MHz,Chloroform-d)δ4.62(t,J＝5.3Hz,1H),3.70(dq,J＝9.4,7.1,6.5Hz,2H),3.61–3.53(m,4H),3.50(d,J＝5.3Hz,2H),3.28(t,J＝6.8Hz,2H),2.11–2.02(m,2H),1.23(t,J＝7.1Hz,6H). 1 H NMR (500MHz, Chloroform-d) δ4.62 (t, J = 5.3Hz, 1H), 3.70 (dq, J = 9.4, 7.1, 6.5Hz, 2H), 3.61–3.53 (m, 4H), 3.50 (d, J=5.3Hz, 2H), 3.28(t, J=6.8Hz, 2H), 2.11–2.02(m, 2H), 1.23(t, J=7.1Hz, 6H).
步骤3：中间体6d的制备Step 3: Preparation of Intermediate 6d
向反应瓶中加入中间体1t(1g)、中间体6c(1.084g)、碳酸铯(2.92g)及DMF(15mL)，将混合物室温反应2h。反应液中加入EA(100mL)和水(100mL)。有机相分离，用饱和氯化钠溶液(100mL)洗涤后用无水硫酸钠干燥，过滤，浓缩得到中间体6d(2.01g)。Intermediate 1t (1 g), intermediate 6c (1.084 g), cesium carbonate (2.92 g) and DMF (15 mL) were added to the reaction flask, and the mixture was reacted at room temperature for 2 h. EA (100 mL) and water (100 mL) were added to the reaction solution. The organic phase was separated, washed with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give intermediate 6d (2.01 g).
MS(ESI,[M+H] +)m/z：509.5. MS (ESI, [M+H] + ) m/z: 509.5.
步骤4：中间体6e的制备Step 4: Preparation of intermediate 6e
向反应瓶中加入中间体6d(1.2g)和THF(50mL)，搅拌溶清后加入0.5M稀盐酸(11.86mL)，N 2保护下，50℃加热4小时，反应完全，蒸干反应溶剂后加入乙酸乙酯(150mL)，依次用水(100mL)、饱和碳酸氢钠水溶液(100mL)、饱和食盐水(100mL)洗涤后，有机层干燥过滤浓缩即得目标物6e(795mg)。 Add intermediate 6d (1.2g) and THF (50mL) to the reaction flask, stir to dissolve and add 0.5M dilute hydrochloric acid (11.86mL), under N2 protection, heat at 50°C for 4 hours, the reaction is complete, and the reaction solvent is evaporated to dryness Then ethyl acetate (150 mL) was added, washed with water (100 mL), saturated aqueous sodium bicarbonate (100 mL) and saturated brine (100 mL) successively, and the organic layer was dried, filtered and concentrated to obtain the target compound 6e (795 mg).
MS(ESI,[M+H] +)m/z：435.4。 MS (ESI, [M+H] + ) m/z: 435.4.
步骤5：中间体6f的制备Step 5: Preparation of Intermediate 6f
在反应瓶中依次加入中间体1j(500mg)、中间体6e(743mg)及MeOH(20mL)，搅拌下加入氰基硼氢化钠(97mg)，N 2保护下，室温搅拌3小时，反应完全，反应液加少量水淬灭反应后旋干直接制砂，用硅胶柱层析纯化(DCM/MeOH)得目标物6f(100mg)。 Add intermediate 1j (500mg), intermediate 6e (743mg) and MeOH (20mL) successively in the reaction flask, add sodium cyanoborohydride (97mg) under stirring, under N 2 protection, stir at room temperature for 3 hours, the reaction is complete, The reaction solution was quenched by adding a small amount of water, then spin-dried to make sand directly, and purified by silica gel column chromatography (DCM/MeOH) to obtain the target compound 6f (100 mg).
MS(ESI,[M+H] +)m/z：925.6。 MS (ESI, [M+H] + ) m/z: 925.6.
步骤6：化合物6的制备Step 6: Preparation of compound 6
在微波管中依次加入6f(95mg)、乙腈(20mL)和无水苯磺酸(64.9mg)，搅拌1分钟后，微波加热至100℃反应120分钟。反应液浓缩后，用反相C 18柱纯化(10nM乙酸铵水溶液/乙腈)，洗脱液合并萃取后旋蒸干得到粗品，再用甲基叔丁基醚(5mL)打浆得到目标物6(26mg)。 6f (95 mg), acetonitrile (20 mL) and anhydrous benzenesulfonic acid (64.9 mg) were sequentially added into a microwave tube, stirred for 1 minute, and then heated to 100° C. by microwave for 120 minutes. After the reaction solution was concentrated, it was purified with a reversed-phase C18 column (10nM ammonium acetate aqueous solution/acetonitrile), and the eluent was combined and extracted, and then rotary evaporated to dryness to obtain the crude product, which was then beaten with methyl tert-butyl ether (5mL) to obtain the target object 6 ( 26 mg).
MS(ESI,[M+H] +)m/z：851.6。 1H NMR(500MHz,DMSO-d 6)δ11.22(s,1H),10.95(s,1H),8.41(d,J＝5.3Hz,1H),8.32(d,J＝1.8Hz,1H),8.02–7.94(m,2H),7.62(dt,J＝8.2,3.7Hz,2H),7.35(dd,J＝5.4,1.9Hz,1H),7.23(d,J＝4.9Hz,1H),7.17(d,J＝2.1Hz,1H),7.05(dd,J＝8.4,2.2Hz,1H),7.00(d,J＝5.0Hz,1H),5.98(s,2H),5.05(dd,J＝13.3,5.1Hz,1H),4.38(d,J＝17.1Hz,1H),4.27(d,J＝17.1Hz,1H),4.13(t,J＝6.3Hz,2H),3.53(t,J＝6.2Hz,2H),3.38(d,J＝11.4Hz,2H),3.01(d,J＝5.1Hz,8H),2.88(ddd,J＝17.2,13.6,5.4Hz,1H),2.65–2.52(m,3H),2.34(qd,J＝13.2,4.5Hz,1H),1.95(ddt,J＝19.8,12.5,6.8Hz,3H),1.81(t,J＝5.4Hz,4H). MS (ESI, [M+H] + ) m/z: 851.6. 1 H NMR (500MHz,DMSO-d 6 )δ11.22(s,1H),10.95(s,1H),8.41(d,J=5.3Hz,1H),8.32(d,J=1.8Hz,1H) ,8.02–7.94(m,2H),7.62(dt,J＝8.2,3.7Hz,2H),7.35(dd,J＝5.4,1.9Hz,1H),7.23(d,J＝4.9Hz,1H), 7.17(d,J=2.1Hz,1H),7.05(dd,J=8.4,2.2Hz,1H),7.00(d,J=5.0Hz,1H),5.98(s,2H),5.05(dd,J =13.3,5.1Hz,1H),4.38(d,J=17.1Hz,1H),4.27(d,J=17.1Hz,1H),4.13(t,J=6.3Hz,2H),3.53(t,J =6.2Hz,2H),3.38(d,J=11.4Hz,2H),3.01(d,J=5.1Hz,8H),2.88(ddd,J=17.2,13.6,5.4Hz,1H),2.65–2.52 (m,3H),2.34(qd,J=13.2,4.5Hz,1H),1.95(ddt,J=19.8,12.5,6.8Hz,3H),1.81(t,J=5.4Hz,4H).
实施例7 化合物7的合成The synthesis of embodiment 7 compound 7
Figure PCTCN2022096512-appb-000109
Figure PCTCN2022096512-appb-000109
步骤1：中间体7b的合成Step 1: Synthesis of Intermediate 7b
在单口瓶中，将中间体1t(2g)溶于N,N-二甲基甲酰胺(20mL)中，再加入1,5-二溴戊烷(5.95g)和碳酸铯(6.02g)，室温反应2小时。反应完毕后，向体系中加入乙酸乙酯(200mL)和水(200mL)。有机相分离，水相再用乙酸乙酯萃取(50mL×2)，合并有机相。有机相用饱和食盐水(200mL)洗涤后用无水硫酸钠干燥，过滤。滤液减压蒸馏除去溶剂，粗品经过硅胶柱层析分离(洗脱剂：二氯甲烷/甲醇)得到目标中间体7b(1.5g)。In a one-necked flask, the intermediate 1t (2g) was dissolved in N,N-dimethylformamide (20mL), and then 1,5-dibromopentane (5.95g) and cesium carbonate (6.02g) were added, React at room temperature for 2 hours. After the reaction was complete, ethyl acetate (200 mL) and water (200 mL) were added to the system. The organic phase was separated, the aqueous phase was extracted with ethyl acetate (50 mL×2), and the organic phases were combined. The organic phase was washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, and filtered. The solvent was distilled off from the filtrate under reduced pressure, and the crude product was separated by silica gel column chromatography (eluent: dichloromethane/methanol) to obtain the target intermediate 7b (1.5 g).
MS(ESI,[M+H] +)m/z:483.2。 1H NMR(500MHz,DMSO-d 6)δ7.58(d,J＝8.4Hz,1H),7.53(s,1H),7.16(t,J＝3.4Hz,2H),7.02(dd,J＝8.4,2.2Hz,1H),4.73–4.67(m,1H),4.55(d,J＝17.4Hz,1H),4.38(d,J＝17.4Hz,1H),4.06(t,J＝6.4Hz,2H),3.56(t,J＝6.7Hz,2H),2.22–2.09(m,3H),2.01–1.95(m,1H),1.88(p,J＝6.9Hz,2H),1.77(t,J＝7.4Hz,2H),1.63–1.52(m,2H),1.33(s,9H). 13C NMR(126MHz,DMSO-d 6)δ172.45,171.85,168.21,162.12,145.17,124.76,115.60,109.04,80.22,68.28,53.77,47.16,36.25,35.51,32.39,32.24,28.14,25.35,24.72. MS (ESI, [M+H] + ) m/z: 483.2. 1 H NMR (500MHz, DMSO-d 6 ) δ7.58(d, J=8.4Hz, 1H), 7.53(s, 1H), 7.16(t, J=3.4Hz, 2H), 7.02(dd, J= 8.4,2.2Hz,1H),4.73–4.67(m,1H),4.55(d,J=17.4Hz,1H),4.38(d,J=17.4Hz,1H),4.06(t,J=6.4Hz, 2H), 3.56(t, J＝6.7Hz, 2H), 2.22–2.09(m, 3H), 2.01–1.95(m, 1H), 1.88(p, J＝6.9Hz, 2H), 1.77(t,J ＝7.4Hz, 2H), 1.63–1.52(m, 2H), 1.33(s, 9H). 13 C NMR (126MHz, DMSO-d 6 ) δ172.45, 171.85, 168.21, 162.12, 145.17, 124.76, 115.60, 109.04, 80.22, 68.28, 53.77, 47.16, 36.25, 35.51, 32.39, 32.24, 28.14, 25.35, 24.72.
步骤2：中间体7c的合成Step 2: Synthesis of Intermediate 7c
在单口瓶中，将化合物7b(600mg)溶于N,N-二甲基甲酰胺(10mL)中，再加入化合物1j(555mg)和碳酸钾(383mg)，升温至50℃反应3小时。反应完毕后，反应液冷至室温，向体系中加入乙酸乙酯(200mL)和水(200mL)萃取分液，有机相再用乙酸乙酯(50mL)萃取2次，用饱和食盐水(200mL)洗涤后无水硫酸钠干燥，过滤，滤液减压蒸馏除去溶剂，粗品经过柱层析分离(洗脱剂：二氯甲烷/甲醇)得到目标中间体7c(420mg)。In a one-necked bottle, compound 7b (600 mg) was dissolved in N,N-dimethylformamide (10 mL), compound 1j (555 mg) and potassium carbonate (383 mg) were added, and the temperature was raised to 50°C for 3 hours. After the reaction was completed, the reaction solution was cooled to room temperature, ethyl acetate (200mL) and water (200mL) were added to the system for extraction and separation, the organic phase was extracted twice with ethyl acetate (50mL), and saturated brine (200mL) After washing, it was dried over anhydrous sodium sulfate, filtered, and the filtrate was distilled off under reduced pressure to remove the solvent. The crude product was separated by column chromatography (eluent: dichloromethane/methanol) to obtain the target intermediate 7c (420 mg).
MS(ESI,[M+H] +)m/z:909.7。 1H NMR(500MHz,DMSO-d 6)δ11.22(s,1H),8.41(d,J＝5.4Hz,1H),8.31(d,J＝1.9Hz,1H),8.00–7.94(m,3H),7.65–7.57(m,2H),7.54(s,1H),7.34(dd,J＝5.4,1.9Hz,1H),7.26(d,J＝5.0Hz,1H),7.15(t,J＝2.9Hz,2H),7.04–6.99(m,2H),5.99(s,2H),4.74–4.66(m,1H),4.55(d,J＝17.5Hz,1H),4.38(d,J＝17.5Hz,1H),4.05(t,J＝6.4Hz,2H),3.17(s,2H),3.07(t,J＝5.2Hz,4H),2.89(s,2H),2.73(s,2H),2.18–2.11(m,3H),1.99–1.93(m,4H),1.76(q,J＝6.8Hz,2H),1.52–1.43(m,4H),1.32(s,9H). MS (ESI, [M+H] + ) m/z: 909.7. 1 H NMR (500MHz, DMSO-d 6 )δ11.22(s, 1H), 8.41(d, J=5.4Hz, 1H), 8.31(d, J=1.9Hz, 1H), 8.00–7.94(m, 3H),7.65–7.57(m,2H),7.54(s,1H),7.34(dd,J=5.4,1.9Hz,1H),7.26(d,J=5.0Hz,1H),7.15(t,J =2.9Hz,2H),7.04–6.99(m,2H),5.99(s,2H),4.74–4.66(m,1H),4.55(d,J=17.5Hz,1H),4.38(d,J= 17.5Hz, 1H), 4.05(t, J=6.4Hz, 2H), 3.17(s, 2H), 3.07(t, J=5.2Hz, 4H), 2.89(s, 2H), 2.73(s, 2H) ,2.18–2.11(m,3H),1.99–1.93(m,4H),1.76(q,J＝6.8Hz,2H),1.52–1.43(m,4H),1.32(s,9H).
步骤3：化合物7的合成Step 3: Synthesis of Compound 7
在微波管中，将中间体7c(300mg)溶于乙腈(4mL)中，再加入苯磺酸(142mg)，搅拌3分钟后，放入微波反应器中，在100W下加热至100℃反应1小时。反应完毕后，反应液冷至室温，减压蒸馏除去溶剂，反相纯化(洗脱剂：水/乙腈)得到化合物7(50mg)。In a microwave tube, dissolve intermediate 7c (300mg) in acetonitrile (4mL), then add benzenesulfonic acid (142mg), stir for 3 minutes, put it into a microwave reactor, and heat it to 100°C under 100W to react 1 Hour. After the reaction was completed, the reaction liquid was cooled to room temperature, the solvent was distilled off under reduced pressure, and reverse-phase purification (eluent: water/acetonitrile) gave compound 7 (50 mg).
HRMS(ESI)m/z[M+H] +found:835.23735。 1H NMR(500MHz,DMSO-d 6)δ11.22(s,1H),10.96(s,1H),8.53–8.19(m,2H),7.98(t,J＝8.1Hz,2H),7.62(t,J＝7.7Hz,2H),7.30(dd,J＝49.6,5.0Hz,2H),7.16(s,1H),7.02(dd,J＝19.3,6.7Hz,2H),5.98(s,2H),5.07(dd,J＝13.3,5.1Hz,1H),4.38(d,J＝17.0Hz,1H),4.26(d,J＝17.1Hz,1H),4.05(q,J＝8.9,7.8Hz,2H),3.12–2.95(m,8H),2.91(td,J＝13.6,7.1Hz,1H),2.59(d,J＝17.3Hz,1H),2.45(s,2H),2.37(dt,J＝14.9,7.4Hz,1H),1.99(s,1H),1.86(t,J＝5.2Hz,4H),1.74(p,J＝6.9Hz,2H),1.47–1.41(m,2H),1.37–1.33(m,2H). 13C NMR(126MHz,DMSO-d 6)δ173.37,171.64,168.41,165.33,162.34,153.66,151.93,149.94,145.53,144.93,144.47,132.97,124.79,124.65,124.58,124.50,120.53,115.85,114.72,109.06,106.06,68.42,63.94,51.99,47.54,47.46,35.62,34.29,31.71,28.91,23.69,23.00. HRMS (ESI) m/z [M+H] + found: 835.23735. 1 H NMR (500MHz, DMSO-d 6 ) δ11.22(s, 1H), 10.96(s, 1H), 8.53–8.19(m, 2H), 7.98(t, J=8.1Hz, 2H), 7.62( t,J=7.7Hz,2H),7.30(dd,J=49.6,5.0Hz,2H),7.16(s,1H),7.02(dd,J=19.3,6.7Hz,2H),5.98(s,2H ), 5.07(dd, J=13.3, 5.1Hz, 1H), 4.38(d, J=17.0Hz, 1H), 4.26(d, J=17.1Hz, 1H), 4.05(q, J=8.9, 7.8Hz ,2H),3.12–2.95(m,8H),2.91(td,J=13.6,7.1Hz,1H),2.59(d,J=17.3Hz,1H),2.45(s,2H),2.37(dt, J＝14.9, 7.4Hz, 1H), 1.99(s, 1H), 1.86(t, J＝5.2Hz, 4H), 1.74(p, J＝6.9Hz, 2H), 1.47–1.41(m, 2H), 1.37–1.33(m,2H). 13 C NMR(126MHz,DMSO-d 6 )δ173.37,171.64,168.41,165.33,162.34,153.66,151.93,149.94,145.53,144.93,144.45,132.99,124.7 124.50, 120.53, 115.85, 114.72, 109.06, 106.06, 68.42, 63.94, 51.99, 47.54, 47.46, 35.62, 34.29, 31.71, 28.91, 23.69, 23.00.
实施例8：化合物8的合成Embodiment 8: the synthesis of compound 8
Figure PCTCN2022096512-appb-000110
Figure PCTCN2022096512-appb-000110
步骤1：中间体8b的制备Step 1: Preparation of Intermediate 8b
在单口瓶中，依次加入中间体8a(1021mg)、DMF(20mL)、碳酸钾(546mg)及中间体1t(500mg)，将混合物80℃反应16.5h。反应液冷至室温，减压蒸除溶剂，向残留物中加入EA(200mL)和水(200mL)。有机相分离，分别用100mL饱和食盐水洗涤后用无水硫酸钠干燥，过滤，滤液通过减压蒸除溶剂后，通过反相柱层析纯化(H 2O/CH 3CN)得到0.220g中间体8b。 In a single-necked flask, intermediate 8a (1021mg), DMF (20mL), potassium carbonate (546mg) and intermediate 1t (500mg) were added sequentially, and the mixture was reacted at 80°C for 16.5h. The reaction solution was cooled to room temperature, the solvent was evaporated under reduced pressure, and EA (200 mL) and water (200 mL) were added to the residue. The organic phase was separated, washed with 100 mL of saturated brine, dried with anhydrous sodium sulfate, filtered, and the filtrate was evaporated under reduced pressure to remove the solvent, then purified by reverse phase column chromatography (H 2 O/CH 3 CN) to obtain 0.220 g of intermediate Body 8b.
MS(ESI,[M+H] +)m/z：425.7。 MS (ESI, [M+H] + ) m/z: 425.7.
步骤2：中间体8c的制备Step 2: Preparation of Intermediate 8c
向单口瓶中，依次加入中间体8b(220mg)、丙酮(10mL)及碘化钠(776mg)，将混合物60℃反应过夜。反应结束后，反应液冷至室温，减压蒸除溶剂，向残留物中加入DCM(100mL)和水(100mL)。有机相分离，分别用100mL饱和食盐水洗涤后用无水硫酸钠干燥，过滤，滤液通过减压蒸除溶剂，得到0.2g中间体8c。Intermediate 8b (220 mg), acetone (10 mL) and sodium iodide (776 mg) were sequentially added to a one-necked flask, and the mixture was reacted at 60° C. overnight. After the reaction, the reaction liquid was cooled to room temperature, the solvent was evaporated under reduced pressure, and DCM (100 mL) and water (100 mL) were added to the residue. The organic phase was separated, washed with 100 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to remove the solvent under reduced pressure to obtain 0.2 g of intermediate 8c.
1H NMR(500MHz,DMSO-d 6)δ8.21(s,1H),7.58(d,J＝8.4Hz,1H),7.53(s,1H),7.16(d,J＝2.1Hz,1H),7.02(dd,J＝8.4,2.3Hz,1H),4.74–4.65(m,1H),4.54(d,J＝17.4Hz,1H),4.38(d,J＝17.5Hz,1H),4.09(d,J＝6.6Hz,2H),2.15(d,J＝8.3Hz,2H),1.97–1.93(m,2H),1.82(dd,J＝6.6,3.2Hz,2H),1.63(dd,J＝8.8,6.1Hz,2H),1.55(t,J＝6.7Hz,2H),1.33(s,9H). 1 H NMR (500MHz,DMSO-d 6 )δ8.21(s,1H),7.58(d,J＝8.4Hz,1H),7.53(s,1H),7.16(d,J＝2.1Hz,1H) ,7.02(dd,J=8.4,2.3Hz,1H),4.74–4.65(m,1H),4.54(d,J=17.4Hz,1H),4.38(d,J=17.5Hz,1H),4.09( d,J=6.6Hz,2H),2.15(d,J=8.3Hz,2H),1.97–1.93(m,2H),1.82(dd,J=6.6,3.2Hz,2H),1.63(dd,J =8.8,6.1Hz,2H),1.55(t,J=6.7Hz,2H),1.33(s,9H).
步骤3：中间体8d的制备Step 3: Preparation of intermediate 8d
向单口瓶中，依次加入中间体1j(200mg)、DMF(10mL)、中间体8c(200mg)及三乙胺(118mg)，N 2保护下，将混合物室温反应19h。反应液通过减压蒸馏除去溶剂后，通过220g C 12反相柱纯化(H 2O/CH 3CN)得到中间体8d。 Intermediate 1j (200 mg), DMF (10 mL), Intermediate 8c (200 mg) and triethylamine (118 mg) were sequentially added to a one-necked flask, and the mixture was reacted at room temperature for 19 h under N2 protection. After the reaction solution was distilled off the solvent under reduced pressure, it was purified by 220 g C 12 reverse phase column (H 2 O/CH 3 CN) to obtain intermediate 8d.
MS(ESI,[M+H] +)m/z：895.5。 1H NMR(500MHz,DMSO-d 6)δ11.22(s,1H),8.42(d,J＝5.3Hz,1H),8.32(d,J＝1.9Hz,1H),8.02–7.94(m,2H),7.62(t,J＝7.9Hz,1H),7.58(d,J＝8.4Hz,1H),7.53(s,1H),7.35(dd,J＝5.4,1.9Hz,1H),7.25(d,J＝4.9Hz,1H),7.16(d,J＝2.1Hz,1H),7.01(d,J＝1.5Hz,1H),5.98(s,2H),4.72–4.65(m,1H),4.55(d,J＝17.5Hz,1H),4.38(d,J＝17.4Hz,1H),4.06(t,J＝6.5Hz,2H),3.05(s,4H),2.98(s,2H),2.18–2.09(m,3H),2.07(s,1H),1.97(t,J＝9.4Hz,1H),1.87(s,4H),1.76(q,J＝7.5,7.1Hz,2H),1.44(d,J＝9.9Hz,2H),1.32(s,9H),1.28–1.20(m,2H). MS (ESI, [M+H] + ) m/z: 895.5. 1 H NMR (500MHz, DMSO-d 6 )δ11.22(s, 1H), 8.42(d, J=5.3Hz, 1H), 8.32(d, J=1.9Hz, 1H), 8.02–7.94(m, 2H), 7.62(t, J=7.9Hz, 1H), 7.58(d, J=8.4Hz, 1H), 7.53(s, 1H), 7.35(dd, J=5.4, 1.9Hz, 1H), 7.25( d,J=4.9Hz,1H),7.16(d,J=2.1Hz,1H),7.01(d,J=1.5Hz,1H),5.98(s,2H),4.72–4.65(m,1H), 4.55(d, J=17.5Hz, 1H), 4.38(d, J=17.4Hz, 1H), 4.06(t, J=6.5Hz, 2H), 3.05(s, 4H), 2.98(s, 2H), 2.18–2.09(m,3H),2.07(s,1H),1.97(t,J=9.4Hz,1H),1.87(s,4H),1.76(q,J=7.5,7.1Hz,2H),1.44 (d, J=9.9Hz, 2H), 1.32(s, 9H), 1.28–1.20(m, 2H).
步骤4：化合物8的制备Step 4: Preparation of Compound 8
向微波管中依次加入中间体8d(100mg)、乙腈(10mL)和苯磺酸(88mg)，搅拌1分钟后，放入微波反应器中，在200W下加热至100℃反应120分钟。反应结束后，微波管中的反应液转移到圆底瓶中，减压蒸除溶剂，通过220g C 18反相柱纯化(1％乙酸铵水溶液/CH 3CN)得到0.070g化合物8。 Intermediate 8d (100mg), acetonitrile (10mL) and benzenesulfonic acid (88mg) were sequentially added into the microwave tube, stirred for 1 minute, put into a microwave reactor, and heated to 100°C at 200W for 120 minutes. After the reaction, the reaction solution in the microwave tube was transferred to a round-bottomed flask, the solvent was evaporated under reduced pressure, and purified by a 220 g C 18 reverse phase column (1% ammonium acetate aqueous solution/CH 3 CN) to obtain 0.070 g of compound 8.
MS(ESI,[M+H] +)m/z：821.6。 1H NMR(500MHz,DMSO-d 6)δ11.23(s,1H),10.96(s,1H),8.42(d,J＝5.3Hz,1H),8.32(d,J＝1.9Hz,1H),8.03–7.93(m,2H),7.63(dd,J＝8.0,5.5Hz,2H),7.35(dd,J＝5.3,2.0Hz,1H),7.25(d,J＝4.9Hz,1H),7.16(d,J＝2.1Hz,1H),7.04(dd,J＝8.4,2.2Hz,1H),7.00(d,J＝4.9Hz,1H),5.99(s,2H),5.07(dd,J＝13.3,5.1Hz,1H),4.44–4.24(m,2H),4.07(t,J＝6.5Hz,2H),3.05(t,J＝5.5Hz,6H),2.93–2.85(m,1H),2.64–2.56(m,1H),2.37(dd,J＝13.2,4.6Hz,1H),1.99–1.94(m,1H),1.87(t,J＝5.4Hz,4H),1.80–1.70(m,2H),1.46(t,J＝7.5Hz,2H),1.35–1.18(m,2H). 13C NMR(126MHz,DMSO-d 6)δ173.35,171.63,168.39,165.30,162.30,160.50,158.53,153.65,151.92,149.92,145.53,144.90,144.45,135.49,132.95,127.92,126.56,124.78,124.57,124.49,120.51,116.37,116.17,115.82,114.71,113.83,109.08,106.04,68.34,63.96,51.98,47.56,47.45,35.68,34.31,31.71,26.81,23.00. MS (ESI, [M+H] + ) m/z: 821.6. 1 H NMR (500MHz,DMSO-d 6 )δ11.23(s,1H),10.96(s,1H),8.42(d,J=5.3Hz,1H),8.32(d,J=1.9Hz,1H) ,8.03–7.93(m,2H),7.63(dd,J＝8.0,5.5Hz,2H),7.35(dd,J＝5.3,2.0Hz,1H),7.25(d,J＝4.9Hz,1H), 7.16(d,J=2.1Hz,1H),7.04(dd,J=8.4,2.2Hz,1H),7.00(d,J=4.9Hz,1H),5.99(s,2H),5.07(dd,J =13.3,5.1Hz,1H),4.44–4.24(m,2H),4.07(t,J=6.5Hz,2H),3.05(t,J=5.5Hz,6H),2.93–2.85(m,1H) ,2.64–2.56(m,1H),2.37(dd,J＝13.2,4.6Hz,1H),1.99–1.94(m,1H),1.87(t,J＝5.4Hz,4H),1.80–1.70(m ,2H),1.46(t,J＝7.5Hz,2H),1.35–1.18(m,2H). 13 C NMR(126MHz,DMSO-d 6 )δ173.35,171.63,168.39,165.30,162.30,160.50,158.53, 153.65,151.92,149.92,145.53,144.90,144.45,135.49,132.95,127.92,126.56,124.78,124.57,124.49,120.51,116.37,116.17,115.82,114.71,113.83,109.08,106.04,68.34,63.96,51.98,47.56, 47.45, 35.68, 34.31, 31.71, 26.81, 23.00.
实施例9 化合物9的合成The synthesis of embodiment 9 compound 9
Figure PCTCN2022096512-appb-000111
Figure PCTCN2022096512-appb-000111
Figure PCTCN2022096512-appb-000112
Figure PCTCN2022096512-appb-000112
步骤1：中间体9b的制备Step 1: Preparation of Intermediate 9b
向反应瓶中，依次加入中间体1t(2.0g)、DMF(20mL)、1,3-二溴丙烷(5.23g)及碳酸铯(6.02g，N 2保护下，室温反应2小时，反应完全后，向反应液中加水(150mL)，用EA(50mL×3)萃取，有机层合并后饱和食盐水(100mL×1)洗涤，干燥、过滤，滤液旋蒸后得到的残余物用硅胶柱层析纯化(DCM/EA/MeOH)洗脱，得到目标物9b(1.885g)。 Into the reaction flask, add intermediate 1t (2.0g), DMF (20mL), 1,3-dibromopropane (5.23g) and cesium carbonate (6.02g) in sequence, under the protection of N2 , react at room temperature for 2 hours, and the reaction is complete Finally, add water (150mL) to the reaction solution, extract with EA (50mL×3), wash the organic layers with saturated brine (100mL×1), dry and filter, and the residue obtained after rotary evaporation of the filtrate is applied to a silica gel column layer Purification (DCM/EA/MeOH) was carried out to obtain the target compound 9b (1.885g).
MS(ESI,[M+H] +)m/z：455.2。 MS (ESI, [M+H] + ) m/z: 455.2.
步骤2：中间体9c的制备Step 2: Preparation of Intermediate 9c
向反应瓶中，依次加入中间体9b(642mg)、中间体1j(600mg)、碳酸钾(383mg)及DMF(10mL)，N 2保护下，油浴至50℃反应2小时，反应完全，反应液加水(100mL)，用DCM-MeOH(20:1)(50mL×2)萃取，有机层合并后水(50mL×1)洗涤，饱和食盐水(50mL×1)洗涤，萃取液干燥、过滤，滤液旋蒸后残余物用硅胶柱层析纯化(DCM-MeOH)洗脱，得到目标物9c(302mg)。 Into the reaction bottle, add intermediate 9b (642mg), intermediate 1j (600mg), potassium carbonate (383mg) and DMF (10mL) successively, under N2 protection, oil bath to 50 ℃ for 2 hours, the reaction is complete, the reaction Add water (100mL) to the solution, extract with DCM-MeOH (20:1) (50mL×2), combine organic layers, wash with water (50mL×1), and saturated brine (50mL×1), dry the extract, filter, After the filtrate was rotary evaporated, the residue was purified by silica gel column chromatography (DCM-MeOH) to obtain the target compound 9c (302 mg).
MS(ESI,[M+H] +)m/z：881.5。 MS (ESI, [M+H] + ) m/z: 881.5.
步骤3：化合物9的制备Step 3: Preparation of Compound 9
向微波管中依次加入9c(280mg)、乙腈(20mL)和无水苯磺酸(161mg)，搅拌1分钟后，微波至110℃反应90分钟，反应完全，反应液旋蒸后残余物用C 18反相柱层析纯化(10nM乙酸铵水溶液-乙腈)洗脱，过柱液合并萃取后旋蒸干得到目标物9(103mg)。 Add 9c (280mg), acetonitrile (20mL) and anhydrous benzenesulfonic acid (161mg) to the microwave tube successively, stir for 1 minute, microwave to 110°C for 90 minutes, the reaction is complete, and the residue is washed with C 18 was purified by reverse-phase column chromatography (10 nM ammonium acetate aqueous solution-acetonitrile) and eluted, passed through the column, combined and extracted, and then evaporated to dryness to obtain the target compound 9 (103 mg).
MS(ESI,[M+H] +)m/z：807.5。 1H NMR(500MHz,DMSO-d 6)δ11.23(s,1H),10.96(s,1H),8.42(d,J＝5.4Hz,1H),8.32(d,J＝1.9Hz,1H),8.02–7.94(m,2H),7.62(t,J＝7.4Hz,2H),7.35(dd,J＝5.3,1.9Hz,1H),7.25(d,J＝5.0Hz,1H),7.16(d,J＝2.1Hz,1H),7.07–6.96(m,2H),5.98(s,2H),5.07(dd,J＝13.3,5.2Hz,1H),4.39(d,J＝17.1Hz,1H),4.27(d,J＝17.2Hz,1H),4.09(t,J＝6.4Hz,2H),3.11–2.96(m,6H),2.94–2.85(m,1H),2.63–2.56(m,1H),2.50(p,J＝1.8Hz,4H),2.38(qd,J＝13.2,4.5Hz,1H),1.98(ddt,J＝7.8,5.5,2.7Hz,1H),1.89(q,J＝7.8,5.4Hz,4H),1.78(q,J＝6.7Hz,2H). MS (ESI, [M+H] + ) m/z: 807.5. 1 H NMR (500MHz,DMSO-d 6 )δ11.23(s,1H),10.96(s,1H),8.42(d,J=5.4Hz,1H),8.32(d,J=1.9Hz,1H) ,8.02–7.94(m,2H),7.62(t,J=7.4Hz,2H),7.35(dd,J=5.3,1.9Hz,1H),7.25(d,J=5.0Hz,1H),7.16( d,J=2.1Hz,1H),7.07–6.96(m,2H),5.98(s,2H),5.07(dd,J=13.3,5.2Hz,1H),4.39(d,J=17.1Hz,1H ),4.27(d,J=17.2Hz,1H),4.09(t,J=6.4Hz,2H),3.11–2.96(m,6H),2.94–2.85(m,1H),2.63–2.56(m, 1H), 2.50(p, J=1.8Hz, 4H), 2.38(qd, J=13.2, 4.5Hz, 1H), 1.98(ddt, J=7.8, 5.5, 2.7Hz, 1H), 1.89(q, J =7.8,5.4Hz,4H),1.78(q,J=6.7Hz,2H).
实施例10 化合物10的合成The synthesis of embodiment 10 compound 10
Figure PCTCN2022096512-appb-000113
Figure PCTCN2022096512-appb-000113
Figure PCTCN2022096512-appb-000114
Figure PCTCN2022096512-appb-000114
步骤1：中间体10b的制备Step 1: Preparation of Intermediate 10b
向反应瓶中，依次加入中间体1t(2g)、DMF(20mL)、1,2-二溴乙烷(4.86g)及碳酸铯(6.02g)，N 2保护下，50℃加热12小时，反应液旋蒸后，残余物用EA(30mL×2)萃取，有机层合并后饱和食盐水(50mL×1)洗。萃取液抽滤、浓缩后，残余物用硅胶柱纯化(DCM-EA-MeOH)得到中间体10b(1.00g)。 Into the reaction flask, sequentially add intermediate 1t (2g), DMF (20mL), 1,2-dibromoethane (4.86g) and cesium carbonate (6.02g), under the protection of N2 , heat at 50°C for 12 hours, After the reaction solution was rotary evaporated, the residue was extracted with EA (30 mL×2), and the organic layers were combined and washed with saturated brine (50 mL×1). After the extract was filtered with suction and concentrated, the residue was purified by silica gel column (DCM-EA-MeOH) to obtain intermediate 10b (1.00 g).
MS(ESI,[M+H] +)m/z：441.2。 MS (ESI, [M+H] + ) m/z: 441.2.
步骤2：中间体10c的制备Step 2: Preparation of intermediate 10c
向反应瓶中，依次加入中间体1j(770mg)、中间体10b(756mg)、碳酸钾(491mg)及DMF(15mL)，N 2保护下，50℃加热2小时，反应完全，反应液旋蒸后残余物用EA(30mL×3)萃取，有机层合并后饱和食盐水(50mL×1)洗。萃取液抽滤浓缩后，残余物用硅胶柱纯化(DCM-MeOH)得到粗品。粗品再用C 18反相柱层析纯化(10nM乙酸铵水溶液-乙腈)得到中间体10c(125mg)。 Into the reaction flask, add intermediate 1j (770mg), intermediate 10b (756mg), potassium carbonate (491mg) and DMF (15mL) successively, under the protection of N2 , heat at 50°C for 2 hours, the reaction is complete, and the reaction solution is rotary evaporated The residue was extracted with EA (30mL×3), and the organic layers were combined and washed with saturated brine (50mL×1). After the extract was concentrated by suction filtration, the residue was purified by a silica gel column (DCM-MeOH) to obtain a crude product. The crude product was purified by C 18 reverse phase column chromatography (10 nM aqueous ammonium acetate-acetonitrile) to obtain intermediate 10c (125 mg).
MS(ESI,[M+H] +)m/z：867.6。 MS (ESI, [M+H] + ) m/z: 867.6.
步骤3：化合物10的制备Step 3: Preparation of Compound 10
向微波管中依次加入化合物10c(120mg)、乙腈(10mL)和无水苯磺酸(74.4mg)，微波110℃反应1小时。反应完全，反应液旋蒸后残余物用C 18反相柱层析纯化(10nM乙酸铵水溶液-乙腈)得到粗品。粗品采用制备组纯化得目标物10(44mg)。 Compound 10c (120 mg), acetonitrile (10 mL) and anhydrous benzenesulfonic acid (74.4 mg) were sequentially added into a microwave tube, and reacted by microwave at 110° C. for 1 hour. After the reaction was complete, the residue was purified by C 18 reverse phase column chromatography (10 nM ammonium acetate aqueous solution-acetonitrile) after rotary evaporation of the reaction solution to obtain a crude product. The crude product was purified by the preparation group to obtain the target compound 10 (44mg).
MS(ESI,[M+H] +)m/z：793.3。 1H NMR(500MHz,DMSO-d 6)δ11.23(s,1H),10.96(s,1H),8.42(d,J＝5.3Hz,1H),8.32(d,J＝1.9Hz,1H),7.98(t,J＝8.3Hz,2H),7.62(t,J＝7.1Hz,2H),7.35(dd,J＝5.4,1.9Hz,1H),7.25(d,J＝5.0Hz,1H),7.20–7.13(m,1H),7.08–6.97(m,2H),5.98(s,2H),5.07(dd,J＝13.2,5.2Hz,1H),4.39(d,J＝17.1Hz,1H),4.26(d,J＝17.0Hz,1H),4.05(t,J＝5.6Hz,2H),3.12(s,4H),3.05(t,J＝5.4Hz,4H),2.95–2.81(m,3H),2.63–2.55(m,1H),2.38(qd,J＝13.2,4.5Hz,1H),1.98(dt,J＝12.3,5.8Hz,1H),1.89(q,J＝6.7,5.5Hz,4H). MS (ESI, [M+H] + ) m/z: 793.3. 1 H NMR (500MHz,DMSO-d 6 )δ11.23(s,1H),10.96(s,1H),8.42(d,J=5.3Hz,1H),8.32(d,J=1.9Hz,1H) ,7.98(t,J=8.3Hz,2H),7.62(t,J=7.1Hz,2H),7.35(dd,J=5.4,1.9Hz,1H),7.25(d,J=5.0Hz,1H) ,7.20–7.13(m,1H),7.08–6.97(m,2H),5.98(s,2H),5.07(dd,J＝13.2,5.2Hz,1H),4.39(d,J＝17.1Hz,1H ), 4.26(d, J=17.0Hz, 1H), 4.05(t, J=5.6Hz, 2H), 3.12(s, 4H), 3.05(t, J=5.4Hz, 4H), 2.95–2.81(m ,3H),2.63–2.55(m,1H),2.38(qd,J=13.2,4.5Hz,1H),1.98(dt,J=12.3,5.8Hz,1H),1.89(q,J=6.7,5.5 Hz,4H).
实施例11 化合物11的合成The synthesis of embodiment 11 compound 11
Figure PCTCN2022096512-appb-000115
Figure PCTCN2022096512-appb-000115
步骤1：中间体11b的制备Step 1: Preparation of Intermediate 11b
向反应瓶中，依次加入中间体11a(25g)、CCl 4(300mL)、N-溴化丁二酰亚胺(21.37g)及偶氮二异丁腈(3.58g)，N 2保护下，80℃加热6小时。反应液加水300mL并振荡静置分出有机层，水层再用DCM(200mL×2) 萃取，有机层合并后，饱和食盐水洗(500mL×1)次，有机层干燥抽滤旋蒸干得到中间体11b(39.53g)。 Into the reaction flask, sequentially add intermediate 11a (25g), CCl 4 (300mL), N-bromosuccinimide (21.37g) and azobisisobutyronitrile (3.58g), under N 2 protection, Heat at 80°C for 6 hours. Add 300mL of water to the reaction solution, shake it and let it stand to separate the organic layer. The aqueous layer was extracted with DCM (200mL×2). After the organic layers were combined, they were washed with saturated brine (500mL×1) times. Body 11b (39.53g).
步骤2：中间体11c的制备Step 2: Preparation of Intermediate 11c
向反应瓶中，依次加入中间体11b(38.38g)、乙腈(200mL)、中间体1n(37.4g)及N,N-二异丙基乙胺(67.4g)，N 2保护下，90℃加热4小时。反应液室温搅拌过夜，有大量固体析出，抽滤并用水-乙腈(1:1)洗，滤饼烘干得目标物11c(21.83g)。 Into the reaction flask, sequentially add intermediate 11b (38.38g), acetonitrile (200mL), intermediate 1n (37.4g) and N,N-diisopropylethylamine (67.4g), under N 2 protection, 90°C Heat for 4 hours. The reaction solution was stirred overnight at room temperature, and a large amount of solids precipitated out, which was filtered by suction and washed with water-acetonitrile (1:1), and the filter cake was dried to obtain the target compound 11c (21.83 g).
1H NMR(500MHz,DMSO-d 6)δ7.88(d,J＝1.6Hz,1H),7.70–7.61(m,2H),7.58(s,1H),7.20(s,1H),4.76–4.69(m,1H),4.61(d,J＝17.9Hz,1H),4.47(d,J＝17.9Hz,1H),2.21–2.09(m,3H),2.03–1.92(m,1H),1.33(s,9H). 1 H NMR (500MHz,DMSO-d 6 )δ7.88(d,J=1.6Hz,1H),7.70–7.61(m,2H),7.58(s,1H),7.20(s,1H),4.76– 4.69(m,1H),4.61(d,J=17.9Hz,1H),4.47(d,J=17.9Hz,1H),2.21–2.09(m,3H),2.03–1.92(m,1H),1.33 (s,9H).
步骤3：中间体11d的合成Step 3: Synthesis of Intermediate 11d
在单口瓶中，将中间体11c(2g)和烯丙基苄基醚(0.807g)溶于二氧六环(20mL)中，再加入四(三苯基膦)钯(1.16g)和碳酸钾(1.38g)，N 2保护下，将混合物加热至100℃反应16小时。反应完毕后，反应液冷至室温，减压蒸除溶剂，粗品经过硅胶柱层析分离(洗脱剂：二氯甲烷/甲醇)得到目标中间体11d(1.5g)。 In a one-necked flask, the intermediate 11c (2 g) and allyl benzyl ether (0.807 g) were dissolved in dioxane (20 mL), and tetrakis(triphenylphosphine) palladium (1.16 g) and carbonic acid Potassium (1.38g), under the protection of N 2 , the mixture was heated to 100°C for 16 hours. After the reaction was completed, the reaction liquid was cooled to room temperature, and the solvent was evaporated under reduced pressure. The crude product was separated by silica gel column chromatography (eluent: dichloromethane/methanol) to obtain the target intermediate 11d (1.5 g).
MS(ESI,[M+H] +)m/z:451.2。 MS (ESI, [M+H] + ) m/z: 451.2.
步骤2：中间体11e的合成Step 2: Synthesis of Intermediate 11e
在单口瓶中，将中间体11d(1g)溶于甲醇(10mL)中，再加入Pd/C(0.1g,0.094mmol)，将反应液先用氮气置换2-3次，再用氢气置换2-3次，50℃搅拌反应17小时。反应完毕后，反应液冷至室温，过滤，再用甲醇溶剂(50mL)淋洗。滤液通过减压蒸除溶剂，粗品经过硅胶柱层析分离(洗脱剂：二氯甲烷/甲醇)得到目标中间体11e(400mg)。In a single-necked flask, the intermediate 11d (1g) was dissolved in methanol (10mL), and then Pd/C (0.1g, 0.094mmol) was added, and the reaction solution was first replaced with nitrogen for 2-3 times, and then replaced with hydrogen for 2 -3 times, stirred at 50°C for 17 hours. After the reaction was completed, the reaction liquid was cooled to room temperature, filtered, and rinsed with methanol solvent (50 mL). The filtrate was evaporated to remove the solvent under reduced pressure, and the crude product was separated by silica gel column chromatography (eluent: dichloromethane/methanol) to obtain the target intermediate 11e (400 mg).
MS(ESI,[M+Na] +)m/z:385.3。 1H NMR(500MHz,DMSO-d 6)δ7.60(d,J＝7.7Hz,1H),7.54(s,1H),7.45(s,1H),7.34(dd,J＝7.8,1.4Hz,1H),7.16(s,1H),4.72(dd,J＝10.4,4.2Hz,1H),4.68(t,J＝5.2Hz,1H),4.56(d,J＝17.4Hz,1H),4.42(d,J＝17.3Hz,1H),3.64(td,J＝6.9,5.1Hz,2H),2.83(t,J＝6.9Hz,2H),2.20–2.11(m,3H),1.33(s,9H). MS (ESI, [M+Na] + ) m/z: 385.3. 1 H NMR (500MHz, DMSO-d 6 )δ7.60(d, J=7.7Hz, 1H), 7.54(s, 1H), 7.45(s, 1H), 7.34(dd, J=7.8, 1.4Hz, 1H), 7.16(s, 1H), 4.72(dd, J=10.4, 4.2Hz, 1H), 4.68(t, J=5.2Hz, 1H), 4.56(d, J=17.4Hz, 1H), 4.42( d, J=17.3Hz, 1H), 3.64(td, J=6.9, 5.1Hz, 2H), 2.83(t, J=6.9Hz, 2H), 2.20–2.11(m, 3H), 1.33(s, 9H ).
步骤3：中间体11f的合成Step 3: Synthesis of intermediate 11f
在单口瓶中，将中间体11e(300mg)溶于二氯甲烷(5mL)中，加入戴斯马丁氧化剂(1.053g)，室温反应1小时。反应完毕后，向体系中加入二氯甲烷(50mL)和水(50mL)。有机相分离，水相用二氯甲烷(50mL×2)萃取，合并有机相，无水硫酸钠干燥，过滤，不需要纯化，减压蒸除溶剂，得到中间体11f(300mg)。In a one-necked flask, the intermediate 11e (300 mg) was dissolved in dichloromethane (5 mL), and Dess Martin oxidant (1.053 g) was added, and reacted at room temperature for 1 hour. After the reaction was complete, dichloromethane (50 mL) and water (50 mL) were added to the system. The organic phase was separated, and the aqueous phase was extracted with dichloromethane (50 mL×2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and no purification was required. The solvent was evaporated under reduced pressure to obtain intermediate 11f (300 mg).
MS(ESI,[M+Na] +)m/z:383.3。 MS (ESI, [M+Na] + ) m/z: 383.3.
步骤4：中间体11g的合成Step 4: Synthesis of Intermediate 11g
在单口瓶中，将中间体11f(250mg)和中间体1j(352mg)溶于甲醇(5mL)中，再加入氰基硼氢化钠(131mg)，加入1滴醋酸，室温反应2小时。反应完毕后，向体系中加入二氯甲烷(50mL)和水(50mL)。有机相分离，水相用二氯甲烷(50mL×2)萃取，合并有机相，无水硫酸钠干燥，过滤，减压蒸除溶剂，粗品经过硅胶柱层析分离(洗脱剂：二氯甲烷/甲醇)得到中间体11g(200mg)。In a one-necked bottle, intermediate 11f (250 mg) and intermediate 1j (352 mg) were dissolved in methanol (5 mL), then sodium cyanoborohydride (131 mg) was added, 1 drop of acetic acid was added, and the reaction was carried out at room temperature for 2 hours. After the reaction was complete, dichloromethane (50 mL) and water (50 mL) were added to the system. The organic phase was separated, the aqueous phase was extracted with dichloromethane (50mL×2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the solvent was evaporated under reduced pressure, and the crude product was separated by silica gel column chromatography (eluent: dichloromethane /methanol) to give intermediate 11 g (200 mg).
MS(ESI,[M+H] +)m/z:851.6。 1H NMR(500MHz,DMSO-d 6)δ11.23(s,1H),8.42(d,J＝5.3Hz,1H),8.32(d,J＝1.8Hz,1H),8.03–7.96(m,2H),7.68(d,J＝7.8Hz,1H),7.62(t,J＝7.9Hz,1H),7.58(s,1H),7.53(s,1H),7.45–7.38(m,1H),7.35(dd,J＝5.3,2.0Hz,1H),7.28(d,J＝5.0Hz,1H),7.18(s,1H),7.03(d,J＝5.0Hz,1H),6.04(s,2H),4.74(dd,J＝10.3,4.0Hz,1H),4.62(d,J＝17.6Hz,1H),4.46(d,J＝17.6Hz,1H),3.83(d,J＝17.4Hz,4H),3.10(d,J＝5.7Hz,4H),2.91(t,J＝7.9Hz,2H),2.25–2.08(m,4H),2.06–1.93(m,6H),1.33(s,9H). MS (ESI, [M+H] + ) m/z: 851.6. 1 H NMR (500MHz, DMSO-d 6 )δ11.23(s, 1H), 8.42(d, J=5.3Hz, 1H), 8.32(d, J=1.8Hz, 1H), 8.03–7.96(m, 2H), 7.68(d, J=7.8Hz, 1H), 7.62(t, J=7.9Hz, 1H), 7.58(s, 1H), 7.53(s, 1H), 7.45–7.38(m, 1H), 7.35(dd,J=5.3,2.0Hz,1H),7.28(d,J=5.0Hz,1H),7.18(s,1H),7.03(d,J=5.0Hz,1H),6.04(s,2H ),4.74(dd,J=10.3,4.0Hz,1H),4.62(d,J=17.6Hz,1H),4.46(d,J=17.6Hz,1H),3.83(d,J=17.4Hz,4H ), 3.10(d, J＝5.7Hz, 4H), 2.91(t, J＝7.9Hz, 2H), 2.25–2.08(m, 4H), 2.06–1.93(m, 6H), 1.33(s, 9H) .
步骤5：化合物11的合成Step 5: Synthesis of compound 11
在微波管中，将中间体11g(200mg)溶于乙腈(3mL)中，再加入苯磺酸(96mg)，搅拌3分钟后，放入微波反应器中，在100W下加热至100℃反应1小时。反应完毕后，反应液冷至室温，减压蒸馏除去溶剂，反相色谱纯化(洗脱剂：水/乙腈)得到化合物11(20mg)。In a microwave tube, 11 g (200 mg) of the intermediate was dissolved in acetonitrile (3 mL), then benzenesulfonic acid (96 mg) was added, stirred for 3 minutes, put into a microwave reactor, and heated to 100 ° C under 100 W to react 1 Hour. After the reaction was completed, the reaction solution was cooled to room temperature, the solvent was distilled off under reduced pressure, and purified by reverse phase chromatography (eluent: water/acetonitrile) to obtain compound 11 (20 mg).
HRMS(ESI)m/z[M+H]+：777.28216。 1H NMR(500MHz,DMSO-d 6)δ11.23(s,1H),10.98(s,1H),8.42(d,J＝5.3Hz,1H),8.32(d,J＝1.9Hz,1H),8.02–7.94(m,2H),7.66–7.60(m,2H),7.45(s,1H),7.40–7.31(m,2H),7.25(d,J＝4.9Hz,1H),7.00(d,J＝4.9Hz,1H),5.98(s,2H),5.10(dd,J＝13.3,5.1Hz,1H),4.42(d,J＝17.2Hz,1H),4.29(d,J＝17.2Hz,1H),3.11–2.97(m,8H),2.97–2.86(m,1H),2.69(s,4H),2.60(ddd,J＝17.3,4.5,2.4Hz,1H),2.39(qd,J＝13.2,4.5Hz,1H),2.01(td,J＝5.3,2.4Hz,1H),1.86(t,J＝5.5Hz,4H). 13C NMR(126MHz,DMSO-d 6)δ173.36,171.56,168.55,165.32,153.66,151.94,149.94,145.57,144.47,142.77,132.97,130.08,129.11,127.93,126.57,124.64,124.07,123.21,120.52,116.38,116.18,114.72,113.84,106.06,64.06,60.22,52.02,47.62,35.80,34.36,31.70,22.99,14.56. HRMS (ESI) m/z [M+H]+: 777.28216. 1 H NMR (500MHz,DMSO-d 6 )δ11.23(s,1H),10.98(s,1H),8.42(d,J=5.3Hz,1H),8.32(d,J=1.9Hz,1H) ,8.02–7.94(m,2H),7.66–7.60(m,2H),7.45(s,1H),7.40–7.31(m,2H),7.25(d,J＝4.9Hz,1H),7.00(d ,J=4.9Hz,1H),5.98(s,2H),5.10(dd,J=13.3,5.1Hz,1H),4.42(d,J=17.2Hz,1H),4.29(d,J=17.2Hz ,1H),3.11–2.97(m,8H),2.97–2.86(m,1H),2.69(s,4H),2.60(ddd,J＝17.3,4.5,2.4Hz,1H),2.39(qd,J ＝13.2, 4.5Hz, 1H), 2.01(td, J＝5.3, 2.4Hz, 1H), 1.86(t, J＝5.5Hz, 4H). 13 C NMR (126MHz, DMSO-d 6 ) δ173.36, 171.56, 168.55,165.32,153.66,151.94,149.94,145.57,144.47,142.77,132.97,130.08,129.11,127.93,126.57,124.64,124.07,123.21,120.52,116.38,116.18,114.72,113.84,106.06,64.06,60.22,52.02, 47.62, 35.80, 34.36, 31.70, 22.99, 14.56.
实施例12 化合物12的合成The synthesis of embodiment 12 compound 12
Figure PCTCN2022096512-appb-000116
Figure PCTCN2022096512-appb-000116
步骤1：中间体12b的制备Step 1: Preparation of Intermediate 12b
在微波管中加入中间体11c(1.5g)、叔丁基异腈(0.785g)、2-(二叔丁基膦)联苯(0.225g)、三乙胺(1.317g)、醋酸钯(0.085g)、碳酸钠(0.480g)和DMF(2mL)，N 2鼓泡1分钟后，微波至100℃反应60分钟。反应液冷却至室温，加入水(100mL)和DCM(100mL)。有机相分离，用100mL饱和氯化钠溶液洗涤后用无水硫酸钠干燥，过滤，浓缩，经硅胶柱层析分离纯化得到中间体12b(0.937g)。 Intermediate 11c (1.5 g), tert-butylisonitrile (0.785 g), 2-(di-tert-butylphosphine)biphenyl (0.225 g), triethylamine (1.317 g), palladium acetate (0.085 g) were added to a microwave tube ), sodium carbonate (0.480g) and DMF (2mL), N 2 was bubbled for 1 minute, then microwaved to 100°C for 60 minutes. The reaction solution was cooled to room temperature, and water (100 mL) and DCM (100 mL) were added. The organic phase was separated, washed with 100 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated, separated and purified by silica gel column chromatography to obtain intermediate 12b (0.937 g).
MS(ESI,[M+H] +)m/z：347.2。 1H NMR(500MHz,DMSO-d 6)δ10.15(s,1H),8.15(d,J＝1.2Hz,1H),8.03(dd,J＝7.7,1.3Hz,1H),7.90(d,J＝7.8Hz,1H),7.68–7.57(m,2H),4.80–4.75(m,1H),4.71(d,J＝17.9Hz,1H),4.61–4.56(m,1H),3.17(d,J＝5.2Hz,2H),2.19(d,J＝3.1Hz,2H),1.33(s,9H). MS (ESI, [M+H] + ) m/z: 347.2. 1 H NMR (500MHz, DMSO-d 6 )δ10.15(s, 1H), 8.15(d, J=1.2Hz, 1H), 8.03(dd, J=7.7, 1.3Hz, 1H), 7.90(d, J＝7.8Hz, 1H), 7.68–7.57(m, 2H), 4.80–4.75(m, 1H), 4.71(d, J＝17.9Hz, 1H), 4.61–4.56(m, 1H), 3.17(d ,J=5.2Hz,2H),2.19(d,J=3.1Hz,2H),1.33(s,9H).
步骤2：中间体12c的制备Step 2: Preparation of Intermediate 12c
在反应瓶中加入中间体1j(0.563g)、中间体12b(0.3g)、氰基硼氢化钠(0.163g)、乙酸(0.1mL)及MeOH(10mL)，将混合物室温反应2h。反应液中加入少量饱和氯化铵水溶液，然后浓缩，经硅胶柱层析分离纯化得到中间体12c(0.343g)。Intermediate 1j (0.563 g), Intermediate 12b (0.3 g), sodium cyanoborohydride (0.163 g), acetic acid (0.1 mL) and MeOH (10 mL) were added to the reaction flask, and the mixture was reacted at room temperature for 2 h. A small amount of saturated ammonium chloride aqueous solution was added to the reaction liquid, then concentrated, separated and purified by silica gel column chromatography to obtain intermediate 12c (0.343 g).
MS(ESI,[M+H] +)m/z：837.6。 1H NMR(500MHz,DMSO-d 6)δ11.23(s,1H),8.42(d,J＝5.4Hz,1H),8.32(d,J＝1.9Hz,1H),8.03–7.95(m,2H),7.78(d,J＝7.8Hz,1H),7.73(s,1H),7.66–7.57(m,3H),7.35(dd,J＝5.3,1.9Hz,1H),7.29(d,J＝5.1Hz,1H),7.20(s,1H),7.01(d,J＝5.1Hz,1H),6.28(s,2H),4.75(dd,J＝10.4,4.1Hz,1H),4.66(d,J＝17.8Hz,1H),4.55–4.46(m,2H),3.93(s,3H),3.10(s,4H),2.23–2.14(m,3H),2.05–2.00(m,4H),1.33(s,9H). MS (ESI, [M+H] + ) m/z: 837.6. 1 H NMR (500MHz, DMSO-d 6 ) δ11.23(s, 1H), 8.42(d, J=5.4Hz, 1H), 8.32(d, J=1.9Hz, 1H), 8.03–7.95(m, 2H),7.78(d,J=7.8Hz,1H),7.73(s,1H),7.66–7.57(m,3H),7.35(dd,J=5.3,1.9Hz,1H),7.29(d,J =5.1Hz,1H),7.20(s,1H),7.01(d,J=5.1Hz,1H),6.28(s,2H),4.75(dd,J=10.4,4.1Hz,1H),4.66(d ,J＝17.8Hz,1H),4.55–4.46(m,2H),3.93(s,3H),3.10(s,4H),2.23–2.14(m,3H),2.05–2.00(m,4H), 1.33(s,9H).
步骤3：化合物12的制备Step 3: Preparation of Compound 12
在微波管中加入中间体12c(0.33g)、苯磺酸(0.187g)和乙腈(4mL)，微波100℃反应60分钟。将反应液浓缩后，经反相柱层析分离纯化得到化合物12(0.072g)Intermediate 12c (0.33g), benzenesulfonic acid (0.187g) and acetonitrile (4mL) were added into a microwave tube, and reacted in microwave at 100°C for 60 minutes. After the reaction solution was concentrated, it was separated and purified by reverse phase column chromatography to obtain compound 12 (0.072g)
MS(ESI,[M+H] +)m/z：763.3。 1H NMR(500MHz,DMSO-d 6)δ11.23(s,1H),10.99(s,1H),8.41(d,J＝5.4Hz,1H),8.32(d,J＝1.8Hz,1H),8.02–7.94(m,2H),7.68(d,J＝7.7Hz,1H),7.62(t,J＝7.9Hz,1H),7.53(s,1H),7.44(d,J＝7.8Hz,1H),7.35(dd,J＝5.3,2.0Hz,1H),7.25(d,J＝5.0Hz,1H),7.00(d,J＝4.9Hz,1H),5.99(s,2H),5.11(dd,J＝13.3,5.2Hz,1H),4.45(d,J＝17.2Hz,1H),4.32(d,J＝17.2Hz,1H),3.76(s,2H),3.07(dd,J＝13.3,8.3Hz,8H),2.92(ddd,J＝17.2,13.6,5.5Hz,1H),2.61(ddd,J＝17.3,4.4,2.3Hz,1H),2.39(qd,J＝13.2,4.5Hz,1H),2.06–2.00(m,1H),1.93–1.87(m,4H). 13C NMR(126MHz,DMSO-d 6)δ173.34,171.52,168.43,165.30,160.50,158.53,153.65,151.92,149.92,145.54,144.45,142.78,135.54,132.95,127.91,126.67,124.63,123.63,123.27,120.51,116.37,116.17,114.71,113.82,106.05,66.82,64.05,60.22,52.05,47.59,35.73,34.47,31.70,22.99,21.23,14.56. MS (ESI, [M+H] + ) m/z: 763.3. 1 H NMR (500MHz,DMSO-d 6 )δ11.23(s,1H),10.99(s,1H),8.41(d,J=5.4Hz,1H),8.32(d,J=1.8Hz,1H) ,8.02–7.94(m,2H),7.68(d,J＝7.7Hz,1H),7.62(t,J＝7.9Hz,1H),7.53(s,1H),7.44(d,J＝7.8Hz, 1H), 7.35(dd, J=5.3, 2.0Hz, 1H), 7.25(d, J=5.0Hz, 1H), 7.00(d, J=4.9Hz, 1H), 5.99(s, 2H), 5.11( dd,J=13.3,5.2Hz,1H),4.45(d,J=17.2Hz,1H),4.32(d,J=17.2Hz,1H),3.76(s,2H),3.07(dd,J=13.3 ,8.3Hz,8H),2.92(ddd,J=17.2,13.6,5.5Hz,1H),2.61(ddd,J=17.3,4.4,2.3Hz,1H),2.39(qd,J=13.2,4.5Hz, 1H),2.06–2.00(m,1H),1.93–1.87(m,4H). 13 C NMR(126MHz,DMSO-d 6 )δ173.34,171.52,168.43,165.30,160.50,158.53,153.65,151.92,149.92, 145.54,144.45,142.78,135.54,132.95,127.91,126.67,124.63,123.63,123.27,120.51,116.37,116.17,114.71,113.82,106.05,66.82,64.05,60.22,52.05,47.59,35.73,34.47,31.70,22.99, 21.23, 14.56.
实施例13 化合物13的合成The synthesis of embodiment 13 compound 13
Figure PCTCN2022096512-appb-000117
Figure PCTCN2022096512-appb-000117
Figure PCTCN2022096512-appb-000118
Figure PCTCN2022096512-appb-000118
步骤1：中间体13b的制备Step 1: Preparation of Intermediate 13b
向单口瓶中加入中间体13a(25g)、3-氨基-2,6-哌啶二酮盐酸盐(29.73g)、醋酸钠(18.52g)及AcOH(200mL)，N 2保护下，将混合物加热至120℃反应3h。反应液冷却至室温，浓缩，加水抽滤，干燥后得到中间体13b(38.6g)。 Add intermediate 13a (25g), 3-amino-2,6-piperidinedione hydrochloride (29.73g), sodium acetate (18.52g) and AcOH (200mL) to the single-necked bottle, under N 2 protection, the The mixture was heated to 120°C for 3h. The reaction solution was cooled to room temperature, concentrated, filtered with water, and dried to obtain intermediate 13b (38.6 g).
MS(ESI,[M+H] +)m/z：277.1。 1H NMR(500MHz,DMSO-d 6)δ11.14(s,1H),8.01(dd,J＝8.2,4.5Hz,1H),7.85(dd,J＝7.5,2.3Hz,1H),7.72(ddd,J＝9.4,8.2,2.4Hz,1H),5.17(dd,J＝12.9,5.4Hz,1H),2.90(ddd,J＝17.1,13.9,5.5Hz,1H),2.61(ddd,J＝17.1,4.5,2.4Hz,1H),2.53(dd,J＝13.1,4.1Hz,1H),2.07(dtd,J＝13.1,5.4,2.3Hz,1H). MS (ESI, [M+H] + ) m/z: 277.1. 1 H NMR (500MHz, DMSO-d 6 ) δ11.14(s, 1H), 8.01(dd, J=8.2, 4.5Hz, 1H), 7.85(dd, J=7.5, 2.3Hz, 1H), 7.72( ddd, J=9.4, 8.2, 2.4Hz, 1H), 5.17(dd, J=12.9, 5.4Hz, 1H), 2.90(ddd, J=17.1, 13.9, 5.5Hz, 1H), 2.61(ddd, J= 17.1,4.5,2.4Hz,1H),2.53(dd,J=13.1,4.1Hz,1H),2.07(dtd,J=13.1,5.4,2.3Hz,1H).
步骤2：化合物13的制备Step 2: Preparation of compound 13
向反应瓶中，依次加入中间体1j(400mg)、中间体13b(205mg)、NMP(20mL)及N,N-二异丙基乙胺(239mg)，N 2保护下，80℃加热过夜，反应完全，反应液旋蒸后残余物用C 18反相柱层析纯化(10nM乙酸铵水溶液-乙腈)得到目标物13(152mg)。 Into the reaction flask, add intermediate 1j (400mg), intermediate 13b (205mg), NMP (20mL) and N,N-diisopropylethylamine (239mg) in sequence, and heat at 80°C overnight under N2 protection. The reaction was complete, and the residue was purified by C 18 reverse phase column chromatography (10 nM ammonium acetate aqueous solution-acetonitrile) after rotary evaporation of the reaction solution to obtain the target compound 13 (152 mg).
MS(ESI,[M+H] +)m/z：763.2。 1H NMR(500MHz,DMSO-d 6)δ11.24(s,1H),11.07(s,1H),8.42(d,J＝5.4Hz,1H),8.32(d,J＝2.0Hz,1H),8.03–7.96(m,2H),7.65(t,J＝8.5Hz,2H),7.38–7.29(m,2H),7.02(d,J＝4.9Hz,1H),6.82(d,J＝2.1Hz,1H),6.68(dd,J＝8.3,2.1Hz,1H),6.01(s,2H),5.06(dd,J＝12.8,5.4Hz,1H),3.88(s,4H),3.15(q,J＝6.1,5.5Hz,4H),2.94–2.83(m,1H),2.61–2.54(m,1H),2.18(t,J＝8.1Hz,1H),2.00(t,J＝5.6Hz,4H),1.90(p,J＝7.6Hz,1H). MS (ESI, [M+H] + ) m/z: 763.2. 1 H NMR (500MHz,DMSO-d 6 )δ11.24(s,1H),11.07(s,1H),8.42(d,J=5.4Hz,1H),8.32(d,J=2.0Hz,1H) ,8.03–7.96(m,2H),7.65(t,J=8.5Hz,2H),7.38–7.29(m,2H),7.02(d,J=4.9Hz,1H),6.82(d,J=2.1 Hz, 1H), 6.68(dd, J=8.3, 2.1Hz, 1H), 6.01(s, 2H), 5.06(dd, J=12.8, 5.4Hz, 1H), 3.88(s, 4H), 3.15(q ,J＝6.1,5.5Hz,4H),2.94–2.83(m,1H),2.61–2.54(m,1H),2.18(t,J＝8.1Hz,1H),2.00(t,J＝5.6Hz, 4H), 1.90 (p, J=7.6Hz, 1H).
实施例14 化合物14的合成The synthesis of embodiment 14 compound 14
Figure PCTCN2022096512-appb-000119
Figure PCTCN2022096512-appb-000119
步骤1：中间体14b的制备Step 1: Preparation of Intermediate 14b
向反应瓶中依次加入中间体1h(3g)、4-(吡啶-2-基)甲酰氨苯基硼酸(2.490g)、碳酸钾(2.84g)、H 2O(6mL)、1,4-二氧六环(30mL)及PdCl 2(dppf)·CH 2Cl 2(0.560g)，N 2置换3次，然后混合物加热至80℃反应3h，停止加热。向反应液中加入200mL水，再用100mL DCM萃取2次。合并有机层用饱和氯化钠溶液(100mL)洗涤两次。洗涤后无水硫酸钠干燥、过滤，浓缩，浓缩物经硅胶柱层析分离纯化得到中间体14b(2.43g)。 Add intermediate 1h (3g), 4-(pyridin-2-yl)formamidophenylboronic acid (2.490g), potassium carbonate (2.84g), H 2 O (6mL), 1,4 -Dioxane (30 mL) and PdCl 2 (dppf)·CH 2 Cl 2 (0.560 g), replaced by N 2 three times, then the mixture was heated to 80° C. for 3 h, and the heating was stopped. 200 mL of water was added to the reaction liquid, and then extracted twice with 100 mL of DCM. The combined organic layers were washed twice with saturated sodium chloride solution (100 mL). After washing, it was dried over anhydrous sodium sulfate, filtered, concentrated, and the concentrate was separated and purified by silica gel column chromatography to obtain intermediate 14b (2.43 g).
MS(ESI,[M+H] +)m/z：555.6。 1H NMR(500MHz,DMSO-d 6)δ10.81(s,1H),8.41(dd,J＝4.9,1.8Hz, 1H),8.22(d,J＝8.3Hz,1H),8.17–8.08(m,2H),7.86(ddd,J＝8.9,7.4,2.0Hz,1H),7.78–7.71(m,2H),7.27(d,J＝5.0Hz,1H),7.21–7.15(m,1H),7.02(d,J＝4.9Hz,1H),6.13(s,2H),3.64(s,4H),3.14–3.03(m,4H),1.89(t,J＝5.4Hz,4H),1.39(s,9H). MS (ESI, [M+H] + ) m/z: 555.6. 1 H NMR (500MHz, DMSO-d 6 ) δ10.81(s, 1H), 8.41(dd, J=4.9, 1.8Hz, 1H), 8.22(d, J=8.3Hz, 1H), 8.17–8.08( m,2H),7.86(ddd,J=8.9,7.4,2.0Hz,1H),7.78–7.71(m,2H),7.27(d,J=5.0Hz,1H),7.21–7.15(m,1H) ,7.02(d,J=4.9Hz,1H),6.13(s,2H),3.64(s,4H),3.14–3.03(m,4H),1.89(t,J=5.4Hz,4H),1.39( s,9H).
步骤2：中间体14c的制备Step 2: Preparation of Intermediate 14c
向反应瓶中加入中间体14b(2.42g)、DCM(30mL)、三氟乙酸(0.994g)，将混合物室温反应过夜。反应液中加入饱和碳酸氢钠溶液(100mL)。然后用100mL DCM萃取2次，有机相分离，用饱和氯化钠溶液洗涤后无水硫酸钠干燥，过滤，浓缩得到中间体14c(0.763g)。Intermediate 14b (2.42 g), DCM (30 mL), trifluoroacetic acid (0.994 g) were added to the reaction flask, and the mixture was reacted at room temperature overnight. A saturated sodium bicarbonate solution (100 mL) was added to the reaction solution. Then it was extracted twice with 100mL DCM, the organic phase was separated, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated to give intermediate 14c (0.763g).
MS(ESI,[M+H] +)m/z：455.39。 1H NMR(500MHz,Chloroform-d)δ8.92(s,1H),8.41(d,J＝8.3Hz,1H),8.31(ddd,J＝4.9,2.0,0.9Hz,1H),8.07–8.02(m,2H),7.83–7.74(m,3H),7.17–7.06(m,2H),7.02(d,J＝5.0Hz,1H),5.21(s,2H),3.47(s,4H),3.15(t,J＝5.5Hz,4H),2.00(t,J＝5.5Hz,4H). 13C NMR(126MHz,Chloroform-d)δ165.30,151.57,151.44,147.89,145.86,138.70,138.52,133.30,131.78,129.78,127.78,127.04,120.02,114.30,112.26,106.39,57.16,47.44,40.99,38.23,35.78. MS (ESI, [M+H] + ) m/z: 455.39. 1 H NMR (500MHz, Chloroform-d) δ8.92 (s, 1H), 8.41 (d, J = 8.3Hz, 1H), 8.31 (ddd, J = 4.9, 2.0, 0.9Hz, 1H), 8.07–8.02 (m,2H),7.83–7.74(m,3H),7.17–7.06(m,2H),7.02(d,J＝5.0Hz,1H),5.21(s,2H),3.47(s,4H), 3.15(t, J=5.5Hz, 4H), 2.00(t, J=5.5Hz, 4H). 13 C NMR(126MHz, Chloroform-d) δ165.30, 151.57, 151.44, 147.89, 145.86, 138.70, 138.52, 133.30, 131.78, 129.78, 127.78, 127.04, 120.02, 114.30, 112.26, 106.39, 57.16, 47.44, 40.99, 38.23, 35.78.
步骤3：中间体14d的制备Step 3: Preparation of Intermediate 14d
向反应瓶中加入中间体14c(0.36g)、中间体1u(0.550g)、碳酸钾(0.487g)及DMF(10mL)，将混合物50℃反应8h。反应液中加入DCM(100mL)和水(100mL)。有机相分离，用饱和氯化钠溶液(100mL)洗涤后无水硫酸钠干燥，过滤，浓缩物经硅胶柱层析分离纯化得到中间体14d(0.26g)。Intermediate 14c (0.36g), intermediate 1u (0.550g), potassium carbonate (0.487g) and DMF (10mL) were added to the reaction flask, and the mixture was reacted at 50°C for 8h. DCM (100 mL) and water (100 mL) were added to the reaction solution. The organic phase was separated, washed with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, filtered, and the concentrate was separated and purified by silica gel column chromatography to obtain intermediate 14d (0.26 g).
MS(ESI,[M+H] +)m/z：903.7. MS (ESI, [M+H] + ) m/z: 903.7.
步骤4：化合物14的制备Step 4: Preparation of compound 14
向微波管中加入中间体14d(0.26g)、苯磺酸(0.137g)和乙腈(4mL)，微波至100℃反应60分钟。将反应液浓缩后，经反相柱层析分离纯化得到化合物14(0.072g)。Intermediate 14d (0.26g), benzenesulfonic acid (0.137g) and acetonitrile (4mL) were added to a microwave tube, microwaved to 100°C for 60 minutes. After the reaction liquid was concentrated, it was separated and purified by reverse phase column chromatography to obtain compound 14 (0.072 g).
MS(ESI,[M+H] +)m/z：829.6。 1H NMR(500MHz,DMSO-d 6)δ10.90(s,1H),10.73(s,1H),8.34(d,J＝4.6Hz,1H),8.15(d,J＝8.3Hz,1H),8.07(d,J＝8.1Hz,2H),7.79(t,J＝7.8Hz,1H),7.67(d,J＝8.1Hz,2H),7.55(d,J＝8.4Hz,1H),7.17(d,J＝4.9Hz,1H),7.12(t,J＝3.4Hz,2H),7.00(dd,J＝8.4,2.2Hz,1H),6.95(d,J＝4.9Hz,1H),6.04(s,2H),5.00(dd,J＝13.3,5.1Hz,1H),4.30(d,J＝17.2Hz,1H),4.19(d,J＝17.2Hz,1H),4.15–4.09(m,2H),3.72(dd,J＝5.6,3.4Hz,2H),3.56–3.51(m,2H),3.45(t,J＝4.7Hz,2H),2.97(d,J＝8.2Hz,8H),2.82(ddd,J＝18.2,13.6,5.4Hz,1H),2.56–2.47(m,3H),2.28(qd,J＝13.2,4.6Hz,1H),1.89(dq,J＝12.3,6.1,5.2Hz,1H),1.78(t,J＝5.3Hz,4H). 13C NMR(126MHz,DMSO-d 6)δ173.33,171.60,168.37,166.12,162.15,152.66,152.01,148.42,145.58,144.88,138.59,138.52,132.88,131.20,129.34,128.70,127.79,124.80,124.66,120.28,115.86,115.20,112.33,109.13,106.13,70.42,70.22,69.35,69.25,68.21,64.64,58.55,51.98,47.60,47.45,35.65,34.73,31.69,22.97. MS (ESI, [M+H] + ) m/z: 829.6. 1 H NMR (500MHz,DMSO-d 6 )δ10.90(s,1H),10.73(s,1H),8.34(d,J=4.6Hz,1H),8.15(d,J=8.3Hz,1H) ,8.07(d,J=8.1Hz,2H),7.79(t,J=7.8Hz,1H),7.67(d,J=8.1Hz,2H),7.55(d,J=8.4Hz,1H),7.17 (d,J=4.9Hz,1H),7.12(t,J=3.4Hz,2H),7.00(dd,J=8.4,2.2Hz,1H),6.95(d,J=4.9Hz,1H),6.04 (s,2H),5.00(dd,J=13.3,5.1Hz,1H),4.30(d,J=17.2Hz,1H),4.19(d,J=17.2Hz,1H),4.15–4.09(m, 2H), 3.72(dd, J=5.6, 3.4Hz, 2H), 3.56–3.51(m, 2H), 3.45(t, J=4.7Hz, 2H), 2.97(d, J=8.2Hz, 8H), 2.82(ddd, J＝18.2, 13.6, 5.4Hz, 1H), 2.56–2.47(m, 3H), 2.28(qd, J＝13.2, 4.6Hz, 1H), 1.89(dq, J＝12.3, 6.1, 5.2 Hz,1H),1.78(t,J=5.3Hz,4H). 13 C NMR(126MHz,DMSO-d 6 )δ173.33,171.60,168.37,166.12,162.15,152.66,152.01,148.42,145.58,144.88,138.59, 138.52,132.88,131.20,129.34,128.70,127.79,124.80,124.66,120.28,115.86,115.20,112.33,109.13,106.13,70.42,70.22,69.35,69.25,68.21,64.64,58.55,51.98,47.60,47.45,35.65, 34.73, 31.69, 22.97.
实施例15 化合物15的合成The synthesis of embodiment 15 compound 15
Figure PCTCN2022096512-appb-000120
Figure PCTCN2022096512-appb-000120
步骤1：中间体15b的制备Step 1: Preparation of intermediate 15b
在单口瓶中，将化合物15a(10g)溶于四氯化碳(90mL)中，加入NBS(10.03g)和偶氮二异丁腈(3.85g)，将混合物加热至85℃反应6小时，反应完毕后，反应液冷至室温，减压蒸除溶剂，向残留物中加入二氯甲烷(200mL)和水(200mL)。有机相分离，用二氯甲烷(100mL×3)萃取，再用饱和食盐水200mL洗涤后用无水硫酸钠干燥，过滤。减压蒸除溶剂，粗品经过硅胶柱层析分离(洗脱剂：石油醚/乙酸乙酯)得到 中间体15b(8.5g)。In a one-necked flask, compound 15a (10 g) was dissolved in carbon tetrachloride (90 mL), NBS (10.03 g) and azobisisobutyronitrile (3.85 g) were added, and the mixture was heated to 85° C. for 6 hours, After the reaction was completed, the reaction liquid was cooled to room temperature, the solvent was evaporated under reduced pressure, and dichloromethane (200 mL) and water (200 mL) were added to the residue. The organic phase was separated, extracted with dichloromethane (100 mL×3), washed with 200 mL of saturated brine, dried over anhydrous sodium sulfate, and filtered. The solvent was evaporated under reduced pressure, and the crude product was separated by silica gel column chromatography (eluent: petroleum ether/ethyl acetate) to obtain Intermediate 15b (8.5g).
MS(ESI,[M+H] +)m/z：274.3。 MS (ESI, [M+H] + ) m/z: 274.3.
步骤2：中间体15c的制备Step 2: Preparation of intermediate 15c
在耐压密封罐中，依次加入中间体1n(6.86g)和乙腈(200mL)，混悬液在冰水浴中搅拌5min，再缓慢滴加N,N-二异丙基乙胺(5.94g)，室温搅拌20min，最后加入中间体15b(5.0g)，100℃反应4小时，反应完全，反应液旋蒸后残余物用EA(100mL×2)萃取，有机层合并后饱和食盐水(100mL×1)洗，萃取液干燥过滤，滤液旋蒸后残余物用硅胶柱层析纯化(DCM-MeOH)得到中间体15c(2.33g)。In a pressure-resistant sealed tank, the intermediate 1n (6.86g) and acetonitrile (200mL) were added successively, the suspension was stirred in an ice-water bath for 5min, and N,N-diisopropylethylamine (5.94g) was slowly added dropwise , stirred at room temperature for 20min, finally added intermediate 15b (5.0g), reacted at 100°C for 4 hours, and the reaction was complete. After the reaction solution was rotary evaporated, the residue was extracted with EA (100mL×2). 1) Wash, dry and filter the extract, spin evaporate the filtrate, and purify the residue by silica gel column chromatography (DCM-MeOH) to obtain intermediate 15c (2.33g).
1H NMR(500MHz,DMSO-d 6)δ8.53(d,J＝2.0Hz,1H),8.33(dd,J＝8.3,2.1Hz,1H),7.94(d,J＝8.3Hz,1H),7.64(s,1H),7.26(s,1H),4.80–4.71(m,2H),4.61(d,J＝18.3Hz,1H),2.26–2.13(m,3H),2.07–1.95(m,1H),1.33(s,9H)。 1 H NMR (500MHz, DMSO-d 6 ) δ8.53 (d, J=2.0Hz, 1H), 8.33 (dd, J=8.3, 2.1Hz, 1H), 7.94 (d, J=8.3Hz, 1H) ,7.64(s,1H),7.26(s,1H),4.80–4.71(m,2H),4.61(d,J＝18.3Hz,1H),2.26–2.13(m,3H),2.07–1.95(m ,1H), 1.33(s,9H).
步骤3：中间体15d的制备Step 3: Preparation of intermediate 15d
在反应瓶中，依次加入中间体15c(2.20g)、铁粉(1.655g)、氯化铵(3.17g)、乙醇(50mL)及水(5mL)，N 2保护下，80℃加热2小时，反应完全，滤除铁粉残渣，滤饼依次用甲醇和DCM-MeOH(10:1)洗涤，合并滤液和洗液、旋干得目标物15d(1.85g)。 In the reaction flask, add intermediate 15c (2.20g), iron powder (1.655g), ammonium chloride (3.17g), ethanol (50mL) and water (5mL) in sequence, and heat at 80°C for 2 hours under the protection of N2 , the reaction was complete, the iron powder residue was filtered off, the filter cake was washed with methanol and DCM-MeOH (10:1) successively, the filtrate and washings were combined, and spin-dried to obtain the target object 15d (1.85g).
MS(ESI,[M+H] +)m/z：334.3。 1H NMR(500MHz,DMSO-d 6)δ7.45(s,1H),7.31(d,J＝8.2Hz,1H),7.10(s,1H),6.65–6.57(m,2H),5.76(s,2H),4.67–4.60(m,1H),4.39(d,J＝16.9Hz,1H),4.24(d,J＝17.0Hz,1H),2.16–2.04(m,3H),1.92(dddd,J＝15.4,10.3,8.0,5.5Hz,1H),1.34(s,9H). MS (ESI, [M+H] + ) m/z: 334.3. 1 H NMR (500MHz, DMSO-d 6 ) δ7.45(s, 1H), 7.31(d, J=8.2Hz, 1H), 7.10(s, 1H), 6.65–6.57(m, 2H), 5.76( s,2H),4.67–4.60(m,1H),4.39(d,J=16.9Hz,1H),4.24(d,J=17.0Hz,1H),2.16–2.04(m,3H),1.92(dddd ,J=15.4,10.3,8.0,5.5Hz,1H),1.34(s,9H).
步骤4：中间体15f的制备Step 4: Preparation of Intermediate 15f
在反应瓶中，依次加入中间体15e(5g)、DCM(100mL)及IBX(24.91g)，N 2保护下，室温搅拌过夜，反应完全，过滤，合并滤液和洗液、旋蒸，残余物用硅胶柱层析纯化(PE-EA)得到目标物15f(4.15g)。 In the reaction flask, add intermediate 15e (5g), DCM (100mL) and IBX (24.91g) in turn, under N 2 protection, stir at room temperature overnight, the reaction is complete, filter, combine the filtrate and washings, rotary evaporation, the residue Purification by silica gel column chromatography (PE-EA) gave the target compound 15f (4.15 g).
步骤5：中间体15g的制备Step 5: Preparation of Intermediate 15g
在反应瓶中，依次加入中间体15d(800mg)、中间体15f(1999mg)、MeOH(30mL)及冰乙酸(288mg)，搅拌20分钟后加入氰基硼氢化钠(1.51g)，N 2保护下，50℃加热4小时，反应完全，反应液旋蒸后残余物用EA(30mL×2)萃取，有机层合并后，饱和食盐水(50mL×1)洗涤，有机层萃取液干燥过滤，滤液旋蒸后残余物用硅胶柱层析纯化(DCM-MeOH)得到中间体15g(605mg)。 In the reaction flask, sequentially add intermediate 15d (800mg), intermediate 15f (1999mg), MeOH (30mL) and glacial acetic acid (288mg), stir for 20 minutes and add sodium cyanoborohydride (1.51g), N 2 protection , heated at 50°C for 4 hours, the reaction was complete, the residue was extracted with EA (30mL×2) after the reaction solution was rotary evaporated, the organic layers were combined, washed with saturated brine (50mL×1), the organic layer extract was dried and filtered, and the filtrate After rotary evaporation, the residue was purified by silica gel column chromatography (DCM-MeOH) to obtain 15 g (605 mg) of the intermediate.
MS(ESI,[M+H] +)m/z：484.4。 1H NMR(500MHz,DMSO-d 6)δ7.46(s,1H),7.38–7.33(m,1H),7.10(s,1H),6.67(d,J＝7.5Hz,2H),6.32(t,J＝5.7Hz,1H),4.68–4.61(m,1H),4.43(d,J＝17.0Hz,1H),4.26(d,J＝17.1Hz,1H),3.69(tddd,J＝11.9,6.2,4.3,2.8Hz,4H),3.58(tdd,J＝7.5,5.1,2.4Hz,6H),3.26(q,J＝5.7Hz,2H),2.14–2.06(m,3H),1.97–1.88(m,1H),1.34(s,9H). MS (ESI, [M+H] + ) m/z: 484.4. 1 H NMR (500MHz, DMSO-d 6 ) δ7.46(s, 1H), 7.38–7.33(m, 1H), 7.10(s, 1H), 6.67(d, J=7.5Hz, 2H), 6.32( t,J=5.7Hz,1H),4.68–4.61(m,1H),4.43(d,J=17.0Hz,1H),4.26(d,J=17.1Hz,1H),3.69(tddd,J=11.9 ,6.2,4.3,2.8Hz,4H),3.58(tdd,J＝7.5,5.1,2.4Hz,6H),3.26(q,J＝5.7Hz,2H),2.14–2.06(m,3H),1.97– 1.88(m,1H),1.34(s,9H).
步骤6：中间体15h的制备Step 6: Preparation of Intermediate 15h
在耐压密封罐中，依次加入中间体15g(550mg)、丙酮(100mL)及碘化钠(5110mg)，N 2保护下，加热100℃反应过夜，反应完全，反应液旋蒸后残余物用EA(30mL×2)萃取，有机层合并后饱和食盐水(50mL×1)洗，有机层萃取液干燥过滤，滤液旋蒸干得到中间体15h(782mg)。 In a pressure-resistant sealed tank, add intermediate 15g (550mg), acetone (100mL) and sodium iodide (5110mg) in sequence, under the protection of N2 , heat at 100°C to react overnight, the reaction is complete, and the residue after the reaction liquid is rotary evaporated is used EA (30mL×2) was extracted, the organic layers were combined and washed with saturated brine (50mL×1), the organic layer extract was dried and filtered, and the filtrate was rotary evaporated to dryness to obtain intermediate 15h (782mg).
MS(ESI,[M+H] +)m/z：576.4。 MS (ESI, [M+H] + ) m/z: 576.4.
步骤7：中间体15i的制备Step 7: Preparation of intermediate 15i
向反应瓶中，依次加入中间体1j(362mg)、中间体15h(650mg)、碳酸钾(781mg)及DMF(20mL)，N 2保护下，50℃加热6小时，反应完全，反应液旋蒸后残余物用DCM-MeOH(10:1，100mL×2)萃取，有机层合并后饱和食盐水(100mL×1)洗涤，萃取液干燥过滤，滤液旋蒸后残余物用硅胶柱层析纯化(DCM-MeOH)得到中间体15i(249mg)。 Into the reaction flask, add intermediate 1j (362mg), intermediate 15h (650mg), potassium carbonate (781mg) and DMF (20mL) successively, under the protection of N2 , heat at 50°C for 6 hours, the reaction is complete, and the reaction solution is rotary evaporated The residue was extracted with DCM-MeOH (10:1, 100mL×2), the organic layers were combined and washed with saturated brine (100mL×1), the extract was dried and filtered, and the filtrate was rotary evaporated and the residue was purified by silica gel column chromatography ( DCM-MeOH) afforded intermediate 15i (249 mg).
MS(ESI,[M+H] +)m/z：954.6。 MS (ESI, [M+H] + ) m/z: 954.6.
步骤8：化合物15的制备Step 8: Preparation of compound 15
向微波管中依次加入中间体15i(200mg)、无水苯磺酸(166mg)和乙腈(20mL)，微波加热至100℃反应60分钟，反应完全，反应液旋蒸后残余物用C 18反相柱层析纯化(10nM乙酸铵水溶液-乙腈＝40:60)得到目标物粗品(70mg)，采用反相柱纯化，过柱液合并，旋蒸后残余物调pH至6-7萃取后，用甲基叔丁基醚(5mL)打浆得目标物15(35mg)。 Add intermediate 15i (200mg), anhydrous benzenesulfonic acid (166mg) and acetonitrile (20mL) to the microwave tube successively, heat to 100°C for 60 minutes in microwave, and the reaction is complete . Purified by phase column chromatography (10nM ammonium acetate aqueous solution-acetonitrile=40:60) to obtain the crude product (70 mg) of the target product, which was purified by reverse-phase column, and the column liquid was combined. After rotary evaporation, the pH of the residue was adjusted to 6-7. After extraction, Slurry with methyl tert-butyl ether (5 mL) to obtain the target compound 15 (35 mg).
MS(ESI,[M+H] +)m/z：880.6。 1H NMR(500MHz,DMSO-d 6)δ11.22(s,1H),10.91(s,1H),8.41(d,J＝5.4Hz,1H),8.32(d,J＝1.8Hz,1H),7.98(t,J＝8.5Hz,2H),7.62(t,J＝7.8Hz,1H),7.41–7.32(m,2H),7.24(d,J＝5.0Hz,1H),7.00(d,J＝5.0Hz,1H),6.73–6.65(m,2H),6.37(t,J＝5.6Hz,1H),5.98(s,2H),5.00(dd,J＝13.3,5.1Hz,1H),4.26(d,J＝16.6Hz,1H),4.13(d,J＝16.6Hz,1H),3.62–3.48(m,6H),3.38(t,J＝5.8Hz,2H),3.28(t,J＝5.7Hz,2H),3.06–2.97(m,7H),2.88(ddd,J＝18.3,13.7,5.4Hz,1H),2.65–2.52(m,3H), 2.31(qd,J＝13.3,4.5Hz,1H),1.92(d,J＝9.9Hz,2H),1.84(t,J＝5.3Hz,4H). MS (ESI, [M+H] + ) m/z: 880.6. 1 H NMR (500MHz,DMSO-d 6 )δ11.22(s,1H),10.91(s,1H),8.41(d,J=5.4Hz,1H),8.32(d,J=1.8Hz,1H) ,7.98(t,J=8.5Hz,2H),7.62(t,J=7.8Hz,1H),7.41–7.32(m,2H),7.24(d,J=5.0Hz,1H),7.00(d, J＝5.0Hz, 1H), 6.73–6.65(m, 2H), 6.37(t, J＝5.6Hz, 1H), 5.98(s, 2H), 5.00(dd, J＝13.3, 5.1Hz, 1H), 4.26(d, J=16.6Hz, 1H), 4.13(d, J=16.6Hz, 1H), 3.62–3.48(m, 6H), 3.38(t, J=5.8Hz, 2H), 3.28(t, J ＝5.7Hz,2H),3.06–2.97(m,7H),2.88(ddd,J＝18.3,13.7,5.4Hz,1H),2.65–2.52(m,3H), 2.31(qd,J＝13.3,4.5 Hz,1H),1.92(d,J=9.9Hz,2H),1.84(t,J=5.3Hz,4H).
实施例16 化合物16的合成The synthesis of embodiment 16 compound 16
Figure PCTCN2022096512-appb-000121
Figure PCTCN2022096512-appb-000121
步骤1：中间体16b的制备Step 1: Preparation of intermediate 16b
向反应瓶中依次加入(2-(2-(2-羟基乙氧基)乙氧基)4-甲苯磺酸乙酯(1901mg)、中间体1t(800mg)、碳酸钾(575mg)及DMF(20mL)，N 2保护下，80℃加热4小时，反应完全，反应液旋蒸后残余物用EA(30mL×2)萃取，有机层合并后饱和食盐水(50mL×1)洗涤，萃取液干燥过滤，滤液旋蒸后残余物用硅胶柱纯化(DCM-MeOH)得到目标物16b(977mg)。 Add (2-(2-(2-hydroxyethoxy) ethoxy) ethyl 4-toluenesulfonate (1901 mg), intermediate 1t (800 mg), potassium carbonate (575 mg) and DMF ( 20mL), under the protection of N2 , heated at 80°C for 4 hours, the reaction was complete, the residue was extracted with EA (30mL×2) after the reaction solution was rotary evaporated, the organic layers were combined, washed with saturated brine (50mL×1), and the extract was dried After filtration, the filtrate was rotary evaporated and the residue was purified by a silica gel column (DCM-MeOH) to obtain the target compound 16b (977 mg).
MS(ESI,[M+H] +)m/z：467.4。 1H NMR(500MHz,DMSO-d 6)δ7.59(d,J＝8.4Hz,1H),7.54(s,1H),7.20–7.12(m,2H),7.04(dd,J＝8.4,2.3Hz,1H),4.75–4.67(m,1H),4.60–4.52(m,2H),4.39(d,J＝17.4Hz,1H),4.18(dd,J＝5.7,3.8Hz,2H),3.79–3.76(m,2H),3.60(dd,J＝5.8,3.4Hz,2H),3.55(td,J＝4.8,1.6Hz,2H),3.53–3.46(m,2H),3.44(d,J＝5.2Hz,2H),2.23–2.08(m,3H),2.05–1.92(m,1H),1.33(s,9H). MS (ESI, [M+H] + ) m/z: 467.4. 1 H NMR (500MHz, DMSO-d 6 )δ7.59(d, J=8.4Hz, 1H), 7.54(s, 1H), 7.20–7.12(m, 2H), 7.04(dd, J=8.4, 2.3 Hz, 1H), 4.75–4.67(m, 1H), 4.60–4.52(m, 2H), 4.39(d, J＝17.4Hz, 1H), 4.18(dd, J＝5.7, 3.8Hz, 2H), 3.79 –3.76(m,2H),3.60(dd,J＝5.8,3.4Hz,2H),3.55(td,J＝4.8,1.6Hz,2H),3.53–3.46(m,2H),3.44(d,J ＝5.2Hz, 2H), 2.23–2.08(m, 3H), 2.05–1.92(m, 1H), 1.33(s, 9H).
步骤2：中间体16c的制备Step 2: Preparation of intermediate 16c
在微波管中依次加入中间体16b(800mg)、乙腈(20mL)和无水苯磺酸(1103mg)，搅拌1分钟后，微波100℃反应1小时，反应完全，反应液旋蒸后残余物用C 18反相柱纯化(10nM乙酸铵水溶液-乙腈)洗脱，过柱液合并，DCM-MeOH(10:1)萃取后旋蒸干得到中间体16c(330mg)。 Add intermediate 16b (800mg), acetonitrile (20mL) and anhydrous benzenesulfonic acid (1103mg) to the microwave tube successively, stir for 1 minute, react in microwave at 100°C for 1 hour, the reaction is complete, and the residue after the reaction solution is rotary evaporated is used C 18 reverse phase column purification (10nM ammonium acetate aqueous solution-acetonitrile) was eluted, the liquid was combined through the column, extracted with DCM-MeOH (10:1) and then evaporated to dryness to obtain intermediate 16c (330 mg).
MS(ESI,[M+H] +)m/z：393.1。 1H NMR(500MHz,DMSO-d 6)δ10.95(s,1H),7.63(d,J＝8.4Hz,1H),7.40(s,1H),7.19(d,J＝2.2Hz,1H),7.07(dd,J＝8.4,2.3Hz,1H),5.08(dd,J＝13.3,5.2Hz,1H),4.58(t,J＝5.4Hz,1H),4.40(d,J＝17.1Hz,1H),4.27(d,J＝17.1Hz,1H),4.23–4.16(m,2H),3.81–3.75(m,1H),3.61(dd,J＝5.9,3.5Hz,2H),3.55(dd,J＝5.8,3.5Hz,2H),3.49(t,J＝5.1Hz,2H),3.44(d,J＝5.2Hz,2H),2.91(ddd,J＝17.2,13.6,5.4Hz,1H),2.60(ddd,J＝17.2,4.5,2.3Hz,1H),2.39(qd,J＝13.2,4.4Hz,1H),1.99(dtd,J＝12.7,5.2,2.6Hz,1H). MS (ESI, [M+H] + ) m/z: 393.1. 1 H NMR (500MHz,DMSO-d 6 )δ10.95(s,1H),7.63(d,J=8.4Hz,1H),7.40(s,1H),7.19(d,J=2.2Hz,1H) ,7.07(dd,J=8.4,2.3Hz,1H),5.08(dd,J=13.3,5.2Hz,1H),4.58(t,J=5.4Hz,1H),4.40(d,J=17.1Hz, 1H), 4.27(d, J＝17.1Hz, 1H), 4.23–4.16(m, 2H), 3.81–3.75(m, 1H), 3.61(dd, J＝5.9, 3.5Hz, 2H), 3.55(dd ,J=5.8,3.5Hz,2H),3.49(t,J=5.1Hz,2H),3.44(d,J=5.2Hz,2H),2.91(ddd,J=17.2,13.6,5.4Hz,1H) ,2.60(ddd,J=17.2,4.5,2.3Hz,1H),2.39(qd,J=13.2,4.4Hz,1H),1.99(dtd,J=12.7,5.2,2.6Hz,1H).
步骤3：中间体16d的制备Step 3: Preparation of intermediate 16d
向反应瓶中，依次加入中间体16c(280mg)、乙腈(25mL)及IBX(494mg)，N 2保护下，80℃反应2.5小时，反应完全，过滤，滤液旋蒸后得到中间体16d(610mg)。 Into the reaction bottle, add intermediate 16c (280mg), acetonitrile (25mL) and IBX (494mg) successively, under the protection of N2 , react at 80°C for 2.5 hours, the reaction is complete, filter, and obtain intermediate 16d (610mg ).
MS(ESI,[M+H] +)m/z：391.3。 MS (ESI, [M+H] + ) m/z: 391.3.
步骤4：化合物16的制备Step 4: Preparation of compound 16
向反应瓶中，依次加入中间体16d(200mg)、4-(8-氨基-3-(((2S，3aR，6aS)-六氢-1H-呋喃[3,4-b]吡咯-2-基)咪唑并[1,5-a]吡嗪-1-基)-N-(吡啶-2-基)苯甲酰胺(113mg)、MeOH(10mL)及冰乙酸(0.1mL)，最后加入氰基硼氢化钠(80mg)，N 2保护下，室温搅拌2小时，反应完全，反应液旋蒸后残余物用硅胶柱纯化(DCM-MeOH)得到粗品，再用C 18反相柱纯化(10nM乙酸铵水溶液-乙腈)洗脱，过柱液合并萃取后旋蒸干，最后用甲基叔丁基醚(5mL)打浆，得到化合物16(88mg)。 Into the reaction flask, add intermediate 16d (200 mg), 4-(8-amino-3-(((2S, 3aR, 6aS)-hexahydro-1H-furo[3,4-b]pyrrole-2- base) imidazo[1,5-a]pyrazin-1-yl)-N-(pyridin-2-yl)benzamide (113mg), MeOH (10mL) and glacial acetic acid (0.1mL), and finally add cyanide Sodium borohydride (80mg), under N 2 protection, stirred at room temperature for 2 hours, the reaction was complete, and the residue was purified by silica gel column (DCM-MeOH) after the reaction solution was rotary evaporated to obtain the crude product, and then purified by C 18 reverse phase column (10nM Ammonium acetate aqueous solution-acetonitrile) was eluted, the column liquid was combined and extracted, and then rotary evaporated to dryness, and finally slurried with methyl tert-butyl ether (5 mL) to obtain compound 16 (88 mg).
MS(ESI,[M+H] +)m/z：816.6。 1H NMR(500MHz,DMSO-d 6)δ10.97(s,1H),10.82(s,1H),8.41(dd,J＝5.0,1.9Hz,1H),8.23(d,J＝8.3Hz,1H),8.16(d,J＝8.0Hz,2H),7.90–7.81(m,2H),7.77(d,J＝7.9Hz,2H),7.62(d,J＝8.4Hz,1H),7.22–7.12(m,2H),7.11–7.01(m,2H),6.13(s,1H),5.07(dd,J＝13.4,5.1Hz,1H), 4.72(t,J＝5.7Hz,1H),4.38(d,J＝17.2Hz,1H),4.30–4.22(m,1H),4.18–4.13(m,2H),3.95(t,J＝6.7Hz,1H),3.86(d,J＝9.7Hz,1H),3.73(t,J＝4.5Hz,2H),3.64(d,J＝8.9Hz,1H),3.54(dt,J＝15.3,5.7Hz,3H),3.38(q,J＝4.8,4.3Hz,2H),3.11(td,J＝12.0,11.3,4.3Hz,1H),2.96–2.85(m,2H),2.76–2.63(m,2H),2.63–2.55(m,1H),2.40(dtt,J＝44.0,13.2,6.5Hz,3H),2.17(ddd,J＝13.2,9.1,4.9Hz,1H),1.95(ddt,J＝25.3,11.7,4.6Hz,2H). MS (ESI, [M+H] + ) m/z: 816.6. 1 H NMR (500MHz, DMSO-d 6 )δ10.97(s,1H),10.82(s,1H),8.41(dd,J=5.0,1.9Hz,1H),8.23(d,J=8.3Hz, 1H), 8.16(d, J=8.0Hz, 2H), 7.90–7.81(m, 2H), 7.77(d, J=7.9Hz, 2H), 7.62(d, J=8.4Hz, 1H), 7.22– 7.12(m,2H),7.11–7.01(m,2H),6.13(s,1H),5.07(dd,J＝13.4,5.1Hz,1H), 4.72(t,J＝5.7Hz,1H),4.38 (d,J=17.2Hz,1H),4.30–4.22(m,1H),4.18–4.13(m,2H),3.95(t,J=6.7Hz,1H),3.86(d,J=9.7Hz, 1H), 3.73(t, J=4.5Hz, 2H), 3.64(d, J=8.9Hz, 1H), 3.54(dt, J=15.3, 5.7Hz, 3H), 3.38(q, J=4.8, 4.3 Hz,2H),3.11(td,J＝12.0,11.3,4.3Hz,1H),2.96–2.85(m,2H),2.76–2.63(m,2H),2.63–2.55(m,1H),2.40( dtt,J=44.0,13.2,6.5Hz,3H),2.17(ddd,J=13.2,9.1,4.9Hz,1H),1.95(ddt,J=25.3,11.7,4.6Hz,2H).
实施例17 化合物17的合成The synthesis of embodiment 17 compound 17
Figure PCTCN2022096512-appb-000122
Figure PCTCN2022096512-appb-000122
步骤1：中间体17b的制备Step 1: Preparation of intermediate 17b
向反应瓶中加入中间体1g(5g)、对甲氧基氯苄(0.550g)、碳酸铯(16.74g)及DMF(30mL)，将混合物80℃反应过夜。冷却至室温，向反应液中加入300mL EA和300mL水。有机相分离，用饱和氯化钠溶液300mL洗涤后无水硫酸钠干燥，过滤浓缩，浓缩物经硅胶柱层析分离纯化得到中间体17b(4.15g)。1 g (5 g) of the intermediate, p-methoxybenzyl chloride (0.550 g), cesium carbonate (16.74 g) and DMF (30 mL) were added to the reaction flask, and the mixture was reacted at 80° C. overnight. After cooling to room temperature, 300 mL of EA and 300 mL of water were added to the reaction solution. The organic phase was separated, washed with 300 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated by filtration, and the concentrate was separated and purified by silica gel column chromatography to obtain intermediate 17b (4.15 g).
MS(ESI,[M+H] +)m/z：531.2. MS (ESI, [M+H] + ) m/z: 531.2.
步骤2：中间体17c的制备Step 2: Preparation of intermediate 17c
向反应瓶中依次加入中间体17b(4.15g)、2,8-氮杂-[4,5]十螺环酮盐酸盐(1.784g)、N,N-二异丙基乙胺(3.02g)、氟化铯(3.55g)和NMP(30mL)，将混合物加热至180℃反应12h。冷却至室温，向反应液中加入300mL DCM和300mL水。有机相分离，用饱和氯化钠溶液(300mL)洗涤后无水硫酸钠干燥，过滤浓缩，浓缩物经硅胶柱层析分离纯化得到中间体17c(2.51g)。Add intermediate 17b (4.15g), 2,8-aza-[4,5]decaspirone hydrochloride (1.784g), N,N-diisopropylethylamine (3.02 g), cesium fluoride (3.55g) and NMP (30mL), the mixture was heated to 180°C for 12h. After cooling to room temperature, 300 mL of DCM and 300 mL of water were added to the reaction solution. The organic phase was separated, washed with saturated sodium chloride solution (300 mL), dried over anhydrous sodium sulfate, filtered and concentrated, and the concentrate was separated and purified by silica gel column chromatography to obtain intermediate 17c (2.51 g).
MS(ESI,[M+H] +)m/z：605.4。 1H NMR(500MHz,DMSO-d 6)δ7.61(s,1H),7.46(d,J＝5.0Hz,1H),7.09–7.05(m,4H),6.98(d,J＝5.0Hz,1H),6.88–6.83(m,4H),4.40(s,4H),3.72(s,6H),3.39(dt,J＝12.8,4.0Hz,2H),3.21(t,J＝6.8Hz,2H),2.99(td,J＝12.3,2.7Hz,2H),2.03(t,J＝6.8Hz,2H),1.94–1.89(m,2H),1.48(d,J＝13.1Hz,2H). MS (ESI, [M+H] + ) m/z: 605.4. 1 H NMR (500MHz, DMSO-d 6 )δ7.61(s, 1H), 7.46(d, J=5.0Hz, 1H), 7.09–7.05(m, 4H), 6.98(d, J=5.0Hz, 1H), 6.88–6.83(m, 4H), 4.40(s, 4H), 3.72(s, 6H), 3.39(dt, J＝12.8, 4.0Hz, 2H), 3.21(t, J＝6.8Hz, 2H ), 2.99(td, J=12.3, 2.7Hz, 2H), 2.03(t, J=6.8Hz, 2H), 1.94–1.89(m, 2H), 1.48(d, J=13.1Hz, 2H).
步骤3：中间体17e的制备Step 3: Preparation of intermediate 17e
向反应瓶中加入中间体17d(5g)和THF(50mL)，冰浴下缓慢加入钠氢(1.779g)，搅拌30min后加入溴苄(5.58g)，逐渐升至室温反应过夜。向反应液中加入200mL EA和200mL水。有机相分离，用饱和氯化钠溶液(200mL)洗涤后无水硫酸钠干燥，过滤浓缩，得到中间体17e(8.12g)。Intermediate 17d (5g) and THF (50mL) were added to the reaction flask, sodium hydrogen (1.779g) was slowly added under ice-cooling, benzyl bromide (5.58g) was added after stirring for 30min, and the mixture was gradually raised to room temperature for overnight reaction. Add 200mL EA and 200mL water to the reaction solution. The organic phase was separated, washed with saturated sodium chloride solution (200 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give intermediate 17e (8.12 g).
1H NMR(500MHz,Chloroform-d)δ7.37–7.31(m,4H),7.30–7.26(m,1H),4.57(s,2H),3.76(t,J＝6.0Hz,2H),3.71–3.66(m,6H),3.65–3.60(m,4H). 1 H NMR (500MHz, Chloroform-d) δ7.37–7.31(m,4H),7.30–7.26(m,1H),4.57(s,2H),3.76(t,J=6.0Hz,2H),3.71 –3.66(m,6H),3.65–3.60(m,4H).
步骤4：中间体17f的制备Step 4: Preparation of intermediate 17f
向反应瓶中加入中间体17e(7.67g)、碘化钠(5.33g)及丙酮(50mL)，将混合物60℃反应过夜。冷却至室温，向反应液中加入200mL EA和200mL水。有机相分离，用饱和氯化钠溶液(200mL)洗涤后无水硫酸钠干燥，过滤浓缩，得到中间体17f(8.32g)。Intermediate 17e (7.67g), sodium iodide (5.33g) and acetone (50mL) were added to the reaction flask, and the mixture was reacted at 60°C overnight. After cooling to room temperature, 200 mL of EA and 200 mL of water were added to the reaction solution. The organic phase was separated, washed with saturated sodium chloride solution (200 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give intermediate 17f (8.32 g).
1H NMR(500MHz,Chloroform-d)δ7.36–7.32(m,4H),7.31–7.26(m,1H),4.57(s,2H),3.76(t,J＝6.9Hz,2H),3.71–3.66(m,6H),3.64(ddd,J＝8.0,4.3,2.6Hz,2H),3.30–3.20(m,2H). 1 H NMR (500MHz, Chloroform-d) δ7.36–7.32(m,4H),7.31–7.26(m,1H),4.57(s,2H),3.76(t,J=6.9Hz,2H),3.71 –3.66(m,6H),3.64(ddd,J＝8.0,4.3,2.6Hz,2H),3.30–3.20(m,2H).
步骤5：中间体17g的制备Step 5: Preparation of Intermediate 17g
向反应瓶中加入中间体17c(2.5g)和DMF(25mL)，冰浴下缓慢加入钠氢(0.330g)，搅拌15min后加入中间体17f(1.735g)，逐渐升至室温反应2h。向反应液中加入200mL EA和200mL水。有机相分离，用饱和氯化钠溶液200mL洗涤后无水硫酸钠干燥，过滤浓缩，浓缩物经硅胶柱层析分离纯化得到中间体17g(3.71g)。Add intermediate 17c (2.5g) and DMF (25mL) to the reaction flask, slowly add sodium hydrogen (0.330g) under ice bath, stir for 15min, then add intermediate 17f (1.735g), gradually raise to room temperature for 2h. Add 200mL EA and 200mL water to the reaction solution. The organic phase was separated, washed with 200 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated by filtration, and the concentrate was separated and purified by silica gel column chromatography to obtain 17 g (3.71 g) of the intermediate.
MS(ESI,[M+H] +)m/z：827.6. MS (ESI, [M+H] + ) m/z: 827.6.
步骤6：中间体17h的制备Step 6: Preparation of intermediate 17h
向反应瓶中加入中间体17g(3.4g)及三氟乙酸(20mL)，将混合物80℃反应过夜。反应液冷却至室温，浓缩除去大量溶剂后，残留物溶于MeOH(50mL)中，加入碳酸钾(2.84g)，室温搅拌2h。抽滤，滤液浓缩后得到中间体17h(1.903g)。17 g (3.4 g) of the intermediate and trifluoroacetic acid (20 mL) were added to the reaction flask, and the mixture was reacted at 80° C. overnight. The reaction solution was cooled to room temperature, concentrated to remove a large amount of solvent, the residue was dissolved in MeOH (50 mL), potassium carbonate (2.84 g) was added, and stirred at room temperature for 2 h. After suction filtration, the filtrate was concentrated to obtain intermediate 17h (1.903g).
MS(ESI,[M+H] +)m/z：497.2. MS (ESI, [M+H] + ) m/z: 497.2.
步骤7：中间体17i的制备Step 7: Preparation of intermediate 17i
向反应瓶中依次加入中间体17h(1.8g)、中间体1b(1.636g)、碳酸钾(1.500g)、H 2O(3mL)、1,4-二氧六环(15mL)及PdCl 2(dppf)·CH 2Cl 2(0.265g)，N 2置换3次，然后混合物加热至85℃反应2h，停止加热。向反应液中加入200mL水，再用100mL DCM萃取2次。合并有机层用饱和氯化钠溶液100mL洗涤两次。洗涤后无水硫酸钠干燥、过滤，浓缩，浓缩物经硅胶柱层析分离纯化得到中间体17i(1.109g)。 Add intermediate 17h (1.8g), intermediate 1b (1.636g), potassium carbonate (1.500g), H2O (3mL), 1,4-dioxane (15mL) and PdCl2 to the reaction flask in sequence (dppf)·CH 2 Cl 2 (0.265 g), replaced by N 2 three times, then the mixture was heated to 85° C. for 2 h, and the heating was stopped. 200 mL of water was added to the reaction liquid, and then extracted twice with 100 mL of DCM. The combined organic layers were washed twice with 100 mL of saturated sodium chloride solution. After washing, it was dried over anhydrous sodium sulfate, filtered, concentrated, and the concentrate was separated and purified by silica gel column chromatography to obtain intermediate 17i (1.109 g).
MS(ESI,[M+H] +)m/z：667.4. MS (ESI, [M+H] + ) m/z: 667.4.
步骤8：中间体17j的制备Step 8: Preparation of intermediate 17j
向反应瓶中加入中间体17i(870mg)、三乙胺(264mg)和DCM(20mL)，冰浴下缓慢加入甲磺酰氯(224mg)，逐渐升至室温反应10h。向反应液中加入100mL DCM和100mL水。有机相分离，用饱和氯化钠溶液(100mL)洗涤后无水硫酸钠干燥，过滤浓缩，浓缩物经硅胶柱层析分离纯化得到中间体17j(1.13g)。Intermediate 17i (870 mg), triethylamine (264 mg) and DCM (20 mL) were added to the reaction flask, methanesulfonyl chloride (224 mg) was added slowly under ice-cooling, and the reaction was gradually raised to room temperature for 10 h. 100 mL of DCM and 100 mL of water were added to the reaction solution. The organic phase was separated, washed with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated, and the concentrate was separated and purified by silica gel column chromatography to obtain intermediate 17j (1.13 g).
MS(ESI,[M+H] +)m/z：745.5. MS (ESI, [M+H] + ) m/z: 745.5.
步骤9：中间体17k的制备Step 9: Preparation of intermediate 17k
向反应瓶中加入中间体17j(0.798g)、中间体1t(0.179g)、碳酸铯(0.523g)及DMF(5mL)，将混合物80℃反应24h。反应液中加入DCM(50mL)和水(50mL)。有机相分离，用饱和氯化钠溶液(100mL)洗涤后用无水硫酸钠干燥，过滤，浓缩物经硅胶柱层析分离纯化得到中间体17k(0.28g)。Intermediate 17j (0.798g), intermediate 1t (0.179g), cesium carbonate (0.523g) and DMF (5mL) were added to the reaction flask, and the mixture was reacted at 80°C for 24h. DCM (50 mL) and water (50 mL) were added to the reaction solution. The organic phase was separated, washed with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, filtered, and the concentrate was separated and purified by silica gel column chromatography to obtain intermediate 17k (0.28 g).
MS(ESI,[M+H] +)m/z：983.6. MS (ESI, [M+H] + ) m/z: 983.6.
步骤10：化合物17的制备Step 10: Preparation of Compound 17
向微波管中加入中间体17k(0.3g)、苯磺酸(0.145g)和乙腈(4mL)，微波至100℃反应60分钟。将反应液浓缩后，经反相柱层析分离纯化得到化合物17(0.15g)Intermediate 17k (0.3 g), benzenesulfonic acid (0.145 g) and acetonitrile (4 mL) were added to a microwave tube, and microwaved to 100° C. for 60 minutes. After the reaction solution was concentrated, it was separated and purified by reverse phase column chromatography to obtain compound 17 (0.15g)
MS(ESI,[M+H] +)m/z：909.6。 1H NMR(500MHz,DMSO-d 6)δ11.23(s,1H),10.97(s,1H),8.42(d,J＝5.3Hz,1H),8.33(d,J＝1.9Hz,1H),8.03–7.95(m,2H),7.63(dd,J＝15.5,8.0Hz,2H),7.35(dd,J＝5.4,2.0Hz,1H),7.30(d,J＝5.0Hz,1H),7.18(d,J＝2.1Hz,1H),7.06(dd,J＝8.4,2.2Hz,1H),7.00(d,J＝4.9Hz,1H),6.01(s,2H),5.07(dd,J＝13.3,5.1Hz,1H),4.37(d,J＝17.1Hz,1H),4.26(d,J＝17.2Hz,1H),4.19(dd,J＝5.7,3.4Hz,2H),3.81–3.75(m,2H),3.60(dd,J＝6.1,3.4Hz,2H),3.57–3.51(m,4H),3.41–3.36(m,6H),3.00–2.84(m,3H),2.58(ddd,J＝17.1,4.4,2.3Hz,1H),2.36(qd,J＝13.3,4.5Hz,1H),1.95(q,J＝8.9,6.6Hz,5H),1.47(d,J＝12.8Hz,2H). 13C NMR(126MHz,DMSO-d 6)δ182.36,178.08,176.35,173.10,170.06,166.90,163.29,158.40,156.67,154.66,150.36,149.63,149.21,140.28,137.70,132.67,131.39,129.54,129.45,125.26,121.32,120.41,119.46,118.62,113.88,110.88,75.15,74.68,74.00,72.95,56.74,52.21,51.61,49.05,47.54,46.97,36.86,36.45,34.13,27.72. MS (ESI, [M+H] + ) m/z: 909.6. 1 H NMR (500MHz,DMSO-d 6 )δ11.23(s,1H),10.97(s,1H),8.42(d,J=5.3Hz,1H),8.33(d,J=1.9Hz,1H) ,8.03–7.95(m,2H),7.63(dd,J＝15.5,8.0Hz,2H),7.35(dd,J＝5.4,2.0Hz,1H),7.30(d,J＝5.0Hz,1H), 7.18(d,J=2.1Hz,1H),7.06(dd,J=8.4,2.2Hz,1H),7.00(d,J=4.9Hz,1H),6.01(s,2H),5.07(dd,J =13.3,5.1Hz,1H),4.37(d,J=17.1Hz,1H),4.26(d,J=17.2Hz,1H),4.19(dd,J=5.7,3.4Hz,2H),3.81–3.75 (m,2H),3.60(dd,J＝6.1,3.4Hz,2H),3.57–3.51(m,4H),3.41–3.36(m,6H),3.00–2.84(m,3H),2.58(ddd ,J=17.1,4.4,2.3Hz,1H),2.36(qd,J=13.3,4.5Hz,1H),1.95(q,J=8.9,6.6Hz,5H),1.47(d,J=12.8Hz, 2H). 13 C NMR(126MHz,DMSO-d 6 )δ182.36,178.08,176.35,173.10,170.06,166.90,163.29,158.40,156.67,154.66,150.36,149.63,149.21,140.28,137.70,132.67,131.39,129.54, 129.45,125.26,121.32,120.41,119.46,118.62,113.88,110.88,75.15,74.68,74.00,72.95,56.74,52.21,51.61,49.05,47.54,46.97,36.856,246.2
实施例18 化合物18的合成The synthesis of embodiment 18 compound 18
Figure PCTCN2022096512-appb-000123
Figure PCTCN2022096512-appb-000123
步骤1：中间体18b的制备Step 1: Preparation of Intermediate 18b
向反应瓶中加入中间体1g(7g)、2,6-二氮杂螺[3.3]庚烷-2-甲酸叔丁酯(7.00g)、N,N-二异丙基乙胺(9.30g)、氟化铯(10.93g)及NMP(50mL)，将混合物加热至180℃反应40h。反应液冷至室温，加入200mL乙酸乙酯和300mL水，有机相分离，用饱和氯化钠溶液(100mL)洗涤后用无水硫酸钠干燥，过滤，浓缩物经硅胶柱层析分离纯化得到中间体18b(5.039g)。Add intermediate 1g (7g), 2,6-diazaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (7.00g), N,N-diisopropylethylamine (9.30g) to the reaction flask ), cesium fluoride (10.93g) and NMP (50mL), the mixture was heated to 180°C for 40h. The reaction solution was cooled to room temperature, 200 mL of ethyl acetate and 300 mL of water were added, the organic phase was separated, washed with saturated sodium chloride solution (100 mL), dried with anhydrous sodium sulfate, filtered, and the concentrate was separated and purified by silica gel column chromatography to obtain intermediate Body 18b (5.039 g).
MS(ESI,[M+H] +)m/z：410.9。 1H NMR(500MHz,DMSO-d 6)δ7.06(d,J＝5.0Hz,1H),6.78(d,J＝5.0Hz,1H),6.48(s,2H),4.22(s,4H),4.02(s,4H),1.38(s,9H). 13C NMR(126MHz,DMSO-d 6)δ155.77,151.30,144.95,127.70,112.75,105.99,103.90,79.11,62.15,34.20,28.52. MS (ESI, [M+H] + ) m/z: 410.9. 1 H NMR (500MHz, DMSO-d 6 )δ7.06(d, J=5.0Hz, 1H), 6.78(d, J=5.0Hz, 1H), 6.48(s, 2H), 4.22(s, 4H) . _
步骤2：中间体18c的制备Step 2: Preparation of intermediate 18c
向反应瓶中加入中间体18b(5g)、中间体1b(6.90g)、碳酸钾(5.07g)及PdCl 2(dppf)·CH 2Cl 2(0.998g)，加入溶剂水(6mL)和1,4-二氧六环(30mL)，N 2保护下，将混合物加热至80℃反应14h。反应液冷至室温，加入100mL EA和100mL水，有机相分离，用饱和氯化钠溶液(100mL)洗涤后无水硫酸钠干燥、过滤，浓缩，浓缩物经硅胶柱层析分离纯化得到中间体18c(5.0g)。 Add intermediate 18b (5g), intermediate 1b (6.90g), potassium carbonate (5.07g) and PdCl 2 (dppf) · CH 2 Cl 2 (0.998g) in the reaction flask, add solvent water (6mL) and 1 , 4-dioxane (30mL), under the protection of N 2 , the mixture was heated to 80°C for 14h. The reaction solution was cooled to room temperature, 100mL EA and 100mL water were added, the organic phase was separated, washed with saturated sodium chloride solution (100mL), dried over anhydrous sodium sulfate, filtered, concentrated, and the concentrate was separated and purified by silica gel column chromatography to obtain the intermediate 18c (5.0 g).
MS(ESI,[M+H] +)m/z：579.5。 MS (ESI, [M+H] + ) m/z: 579.5.
步骤3：中间体18d的制备Step 3: Preparation of intermediate 18d
向反应瓶中加入中间体18c(5g)，加入二氯甲烷(100mL)和甲烷磺酸(14.80g)，加毕，室温搅拌反应。反应结束后，反应液通过10％氢氧化钠水溶液调节pH至10，用二氯甲烷：甲醇＝(10:1)萃取(5×200mL)，大量絮状物生成，过滤除去絮状物后再次萃取，合并有机相，饱和食盐水(30mL)洗涤，无水硫酸钠干燥。有机相过滤，滤液通过减压浓缩溶剂，残留物中加入50mL DCM溶解后，20mL EA重结晶，过滤得到中间体18d(1.6g)。Add intermediate 18c (5 g) to the reaction flask, add dichloromethane (100 mL) and methanesulfonic acid (14.80 g), after the addition is complete, stir the reaction at room temperature. After the reaction, the pH of the reaction solution was adjusted to 10 by 10% aqueous sodium hydroxide solution, extracted with dichloromethane:methanol=(10:1) (5×200mL), a large number of flocs were generated, and filtered to remove the flocs again After extraction, the organic phases were combined, washed with saturated brine (30 mL), and dried over anhydrous sodium sulfate. The organic phase was filtered, and the filtrate was concentrated by reducing the solvent. After adding 50 mL of DCM to the residue to dissolve, 20 mL of EA was recrystallized and filtered to obtain intermediate 18d (1.6 g).
MS(ESI,[M+H] +)m/z：479.3。 1H NMR(500MHz,DMSO-d 6)δ8.41(d,J＝5.4Hz,1H),8.32(d,J＝1.9Hz,1H),8.01–7.93(m,2H),7.61(t,J＝7.9Hz,1H),7.35(dd,J＝5.3,2.0Hz,1H),7.17(d,J＝5.0Hz,1H),6.88(d,J＝5.0Hz,1H),5.89(s,2H),4.22(s,4H),3.63(s,4H). 13C NMR(126MHz,DMSO-d 6)δ165.31,160.49,158.52,153.67,151.86,149.92,145.96,144.44,135.52,132.91,127.30,126.73,124.60,124.38,120.49,116.35,116.16,114.72,113.38,105.96,63.06,56.99,31.64. MS (ESI, [M+H] + ) m/z: 479.3. 1 H NMR (500MHz, DMSO-d 6 ) δ8.41(d, J=5.4Hz, 1H), 8.32(d, J=1.9Hz, 1H), 8.01–7.93(m, 2H), 7.61(t, J＝7.9Hz, 1H), 7.35(dd, J＝5.3, 2.0Hz, 1H), 7.17(d, J＝5.0Hz, 1H), 6.88(d, J＝5.0Hz, 1H), 5.89(s, 2H), 4.22(s, 4H), 3.63(s, 4H). 13 C NMR (126MHz, DMSO-d 6 ) δ165.31, 160.49, 158.52, 153.67, 151.86, 149.92, 145.96, 144.44, 135.52, 132.91, 127.30, 126.73, 124.60, 124.38, 120.49, 116.35, 116.16, 114.72, 113.38, 105.96, 63.06, 56.99, 31.64.
步骤4：化合物18的制备Step 4: Preparation of Compound 18
向反应瓶中加入中间体18d(0.563g)、中间体16d(0.3g)、氰基硼氢化钠(0.163g)、乙酸(0.1mL)及MeOH(10mL)，将混合物室温反应2h。反应液中加入少量饱和氯化铵水溶液，然后浓缩，经硅胶柱层析分离纯化得到化合物18(0.098g)。Intermediate 18d (0.563 g), Intermediate 16d (0.3 g), sodium cyanoborohydride (0.163 g), acetic acid (0.1 mL) and MeOH (10 mL) were added to the reaction flask, and the mixture was reacted at room temperature for 2 h. A small amount of saturated aqueous ammonium chloride solution was added to the reaction liquid, then concentrated, separated and purified by silica gel column chromatography to obtain compound 18 (0.098 g).
MS(ESI,[M+H] +)m/z：853.6。 1H NMR(500MHz,DMSO-d 6)δ11.22(s,1H),11.06–10.85(m,1H),8.41(d,J＝5.3Hz,1H),8.32(d,J＝1.9Hz,1H),7.97(t,J＝8.3Hz,2H),7.61(t,J＝8.1Hz,2H),7.35(dd,J＝5.3, 1.9Hz,1H),7.16(dd,J＝17.8,3.6Hz,2H),7.07(dd,J＝8.4,2.2Hz,1H),6.88(d,J＝5.0Hz,1H),5.89(s,2H),5.06(dd,J＝13.3,5.1Hz,1H),4.37(d,J＝17.1Hz,1H),4.25(d,J＝17.1Hz,1H),4.20(s,6H),3.78(t,J＝4.4Hz,2H),3.62–3.57(m,2H),3.54–3.48(m,2H),3.37(d,J＝6.7Hz,6H),2.89(ddd,J＝18.0,13.6,5.5Hz,1H),2.62–2.56(m,1H),2.54(d,J＝6.3Hz,2H),2.35(qd,J＝13.2,4.5Hz,1H),1.99–1.92(m,1H). 13C NMR(126MHz,DMSO-d 6)δ173.34,171.61,168.37,165.30,162.15,158.52,153.64,151.86,149.92,145.88,144.88,144.46,135.52,132.91,127.32,126.65,124.80,124.71,120.51,116.35,116.16,115.85,114.71,113.37,109.16,105.92,70.41,70.20,69.27,68.19,64.73,62.27,51.98,47.44,36.03,31.70,22.97. MS (ESI, [M+H] + ) m/z: 853.6. 1 H NMR (500MHz, DMSO-d 6 )δ11.22(s,1H),11.06–10.85(m,1H),8.41(d,J=5.3Hz,1H),8.32(d,J=1.9Hz, 1H), 7.97(t, J=8.3Hz, 2H), 7.61(t, J=8.1Hz, 2H), 7.35(dd, J=5.3, 1.9Hz, 1H), 7.16(dd, J=17.8, 3.6 Hz, 2H), 7.07(dd, J=8.4, 2.2Hz, 1H), 6.88(d, J=5.0Hz, 1H), 5.89(s, 2H), 5.06(dd, J=13.3, 5.1Hz, 1H ), 4.37(d, J=17.1Hz, 1H), 4.25(d, J=17.1Hz, 1H), 4.20(s, 6H), 3.78(t, J=4.4Hz, 2H), 3.62–3.57(m ,2H),3.54–3.48(m,2H),3.37(d,J＝6.7Hz,6H),2.89(ddd,J＝18.0,13.6,5.5Hz,1H),2.62–2.56(m,1H), 2.54(d,J=6.3Hz,2H),2.35(qd,J=13.2,4.5Hz,1H),1.99–1.92(m,1H). 13 C NMR(126MHz,DMSO-d 6 )δ173.34,171.61, 168.37,165.30,162.15,158.52,153.64,151.86,149.92,145.88,144.88,144.46,135.52,132.91,127.32,126.65,124.80,124.71,120.51,116.35,116.16,115.85,114.71,113.37,109.16,105.92,70.41, 70.20, 69.27, 68.19, 64.73, 62.27, 51.98, 47.44, 36.03, 31.70, 22.97.
实施例19 化合物19的制备The preparation of embodiment 19 compound 19
Figure PCTCN2022096512-appb-000124
Figure PCTCN2022096512-appb-000124
步骤1：中间体19b的合成Step 1: Synthesis of Intermediate 19b
在单口瓶中，将化合物19a(25g)溶于甲醇(200mL)中，冰浴条件下，将硫酸(68.650g,50.0mL,700mmol)缓慢滴入反应液中，混合物升温至80℃搅拌反应5小时。反应完毕后，反应液冷至室温，减压蒸除溶剂，向残留物中加入二氯甲烷(250mL)和水(250mL)稀释，用饱和碳酸氢钠水溶液调节pH＝7，分液。有机相再用二氯甲烷(100mL)萃取3次，合并有机相，再用饱和食盐水洗涤后无水硫酸钠干燥，过滤，减压蒸除溶剂，得到目标中间体19b(24.5g)。In a single-necked flask, compound 19a (25g) was dissolved in methanol (200mL), and sulfuric acid (68.650g, 50.0mL, 700mmol) was slowly dropped into the reaction solution under ice-cooling conditions, and the mixture was heated to 80°C and stirred for reaction 5 Hour. After the reaction was completed, the reaction solution was cooled to room temperature, and the solvent was evaporated under reduced pressure. Dichloromethane (250 mL) and water (250 mL) were added to the residue for dilution, and the pH was adjusted to 7 with saturated aqueous sodium bicarbonate solution, and the layers were separated. The organic phase was extracted three times with dichloromethane (100 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain the target intermediate 19b (24.5 g).
MS(ESI,[M-H] -)m/z:165.0。 1H NMR(500MHz,DMSO-d 6)δ9.52(s,1H),7.23(d,J＝2.7Hz,1H),7.11(d,J＝8.3Hz,1H),6.88(dd,J＝8.2,2.7Hz,1H),3.80(s,3H),2.38(s,3H). MS (ESI, [MH] - ) m/z: 165.0. 1 H NMR (500MHz, DMSO-d 6 )δ9.52(s, 1H), 7.23(d, J=2.7Hz, 1H), 7.11(d, J=8.3Hz, 1H), 6.88(dd, J= 8.2,2.7Hz,1H),3.80(s,3H),2.38(s,3H).
步骤2：中间体19c的合成Step 2: Synthesis of Intermediate 19c
在单口瓶中，将化合物19b(10g)溶于二氯甲烷(50mL)中，加入三乙胺(17.98g,24.76mL)和乙酸酐(12.09g)，室温反应3小时。反应完毕后，减压蒸除溶剂，向残留物中加入二氯甲烷(200mL)和水(200mL)。有机相分离，有机相用二氯甲烷(100mL×3)萃取，再用饱和食盐水(200mL)洗涤后无水硫酸钠干燥，过滤。减压蒸除溶剂，然后经过硅胶柱层析分离(洗脱剂：石油醚/乙酸乙酯)得到中间体19c(15.5g)。In a one-necked flask, compound 19b (10 g) was dissolved in dichloromethane (50 mL), triethylamine (17.98 g, 24.76 mL) and acetic anhydride (12.09 g) were added, and reacted at room temperature for 3 hours. After the reaction was completed, the solvent was distilled off under reduced pressure, and dichloromethane (200 mL) and water (200 mL) were added to the residue. The organic phase was separated, and the organic phase was extracted with dichloromethane (100 mL×3), washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, and filtered. The solvent was distilled off under reduced pressure, and then separated by silica gel column chromatography (eluent: petroleum ether/ethyl acetate) to obtain intermediate 19c (15.5 g).
MS(ESI,[M+H] +)m/z:209.2。 1H NMR(500MHz,DMSO-d 6)δ7.56(d,J＝2.5Hz,1H),7.37(d,J＝8.3Hz,1H),7.26(dd,J＝8.3,2.6Hz,1H),3.83(s,3H),2.27(s,3H). MS (ESI, [M+H] + ) m/z: 209.2. 1 H NMR (500MHz, DMSO-d 6 )δ7.56(d, J=2.5Hz, 1H), 7.37(d, J=8.3Hz, 1H), 7.26(dd, J=8.3, 2.6Hz, 1H) ,3.83(s,3H),2.27(s,3H).
步骤3：中间体19d的合成Step 3: Synthesis of intermediate 19d
在单口瓶中，将化合物19c(9g)溶于四氯化碳(90mL)中，加入NBS(9.22g)和偶氮二异丁腈(3.54g)，将混合物加热至85℃反应6小时，反应完毕后，反应液冷至室温，减压蒸除溶剂，向残留物中加入二氯甲烷200mL和水200mL。有机相分离，用二氯甲烷(100mL×3)萃取，再用饱和食盐水200mL洗涤后无水硫酸钠干燥，过滤。减压蒸除溶剂，粗品经过硅胶柱层析分离(洗脱剂：石油醚/乙酸乙酯)得到中间体19d(10.2g)。In a one-necked flask, compound 19c (9 g) was dissolved in carbon tetrachloride (90 mL), NBS (9.22 g) and azobisisobutyronitrile (3.54 g) were added, and the mixture was heated to 85° C. for 6 hours, After the reaction was completed, the reaction liquid was cooled to room temperature, the solvent was evaporated under reduced pressure, and 200 mL of dichloromethane and 200 mL of water were added to the residue. The organic phase was separated, extracted with dichloromethane (100 mL×3), washed with 200 mL of saturated brine, dried over anhydrous sodium sulfate, and filtered. The solvent was evaporated under reduced pressure, and the crude product was separated by silica gel column chromatography (eluent: petroleum ether/ethyl acetate) to obtain intermediate 19d (10.2 g).
MS(ESI,[M+H] +)m/z:287.2。 1H NMR(500MHz,DMSO-d 6)δ7.69–7.63(m,2H),7.39(dd,J＝8.3,2.5Hz,1H),5.03(s,2H),3.88(s,3H),2.29(s,3H). MS (ESI, [M+H] + ) m/z: 287.2. 1 H NMR (500MHz, DMSO-d 6 )δ7.69–7.63 (m, 2H), 7.39 (dd, J=8.3, 2.5Hz, 1H), 5.03 (s, 2H), 3.88 (s, 3H), 2.29(s,3H).
步骤4：中间体19e的合成Step 4: Synthesis of Intermediate 19e
在封管中，将化合物19d(5g)溶于乙腈(30mL)中，加入化合物1n(5.92g)和N,N-二异丙基乙胺(11.04g)，将混合物加热至100℃反应3小时，反应完毕后，反应液冷至室温，减压蒸除溶剂，粗品经过硅胶柱层析 分离(洗脱剂：二氯甲烷/甲醇)得到目标中间体19e(2.5g)。In a sealed tube, compound 19d (5 g) was dissolved in acetonitrile (30 mL), compound 1n (5.92 g) and N,N-diisopropylethylamine (11.04 g) were added, and the mixture was heated to 100 °C to react 3 After the completion of the reaction, the reaction solution was cooled to room temperature, and the solvent was evaporated under reduced pressure. The crude product was separated by silica gel column chromatography (eluent: dichloromethane/methanol) to obtain the target intermediate 19e (2.5 g).
MS(ESI,[M+H] +)m/z:335.2。 1H NMR(500MHz,DMSO-d 6)δ7.55(s,1H),7.38(d,J＝8.1Hz,1H),7.16(s,1H),7.06–7.00(m,2H),4.70(dd,J＝10.4,4.1Hz,1H),4.47(d,J＝16.8Hz,1H),4.32(d,J＝17.0Hz,1H),2.18–2.10(m,3H),2.02–1.94(m,1H),1.34(s,9H). MS (ESI, [M+H] + ) m/z: 335.2. 1 H NMR (500MHz, DMSO-d 6 ) δ7.55(s, 1H), 7.38(d, J=8.1Hz, 1H), 7.16(s, 1H), 7.06–7.00(m, 2H), 4.70( dd,J=10.4,4.1Hz,1H),4.47(d,J=16.8Hz,1H),4.32(d,J=17.0Hz,1H),2.18–2.10(m,3H),2.02–1.94(m ,1H),1.34(s,9H).
步骤5：中间体19f的合成Step 5: Synthesis of intermediate 19f
在单口瓶中，将化合物19e(2g)溶于N,N-二甲基甲酰胺(20mL)中，加入1,2-双(2-碘乙氧基)乙烷(9.49g)和碳酸铯(5.02g)，避光室温反应15小时。反应完毕后，向反应液中加入乙酸乙酯(200mL)和水(200mL)。有机相分离，有机相再用乙酸乙酯(100mL×2)萃取，用饱和食盐水(200mL)洗涤后用无水硫酸钠干燥，过滤。减压蒸除溶剂，粗品经过硅胶柱层析分离(洗脱剂：二氯甲烷/甲醇)得到中间体19f(2.2g)。In a one-necked flask, compound 19e (2 g) was dissolved in N,N-dimethylformamide (20 mL), and 1,2-bis(2-iodoethoxy)ethane (9.49 g) and cesium carbonate were added (5.02g), react at room temperature for 15 hours in the dark. After the reaction was complete, ethyl acetate (200 mL) and water (200 mL) were added to the reaction solution. The organic phase was separated, and the organic phase was extracted with ethyl acetate (100 mL×2), washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, and filtered. The solvent was evaporated under reduced pressure, and the crude product was separated by silica gel column chromatography (eluent: dichloromethane/methanol) to obtain intermediate 19f (2.2 g).
MS(ESI,[M+H] +)m/z:577.3。 1H NMR(500MHz,DMSO-d 6)δ7.55(s,1H),7.49(d,J＝8.0Hz,1H),7.19(q,J＝2.8,2.2Hz,2H),7.18–7.14(m,1H),4.73(dt,J＝10.1,3.9Hz,1H),4.52(d,J＝17.1Hz,1H),4.37(d,J＝17.2Hz,1H),4.20–4.13(m,2H),3.81–3.75(m,2H),3.66(t,J＝6.4Hz,2H),3.65–3.56(m,4H),3.31(t,J＝6.4Hz,2H),2.20–2.09(m,3H),2.03–1.95(m,1H),1.33(s,9H). MS (ESI, [M+H] + ) m/z: 577.3. 1 H NMR (500MHz, DMSO-d 6 ) δ7.55(s, 1H), 7.49(d, J=8.0Hz, 1H), 7.19(q, J=2.8, 2.2Hz, 2H), 7.18–7.14( m,1H),4.73(dt,J=10.1,3.9Hz,1H),4.52(d,J=17.1Hz,1H),4.37(d,J=17.2Hz,1H),4.20–4.13(m,2H ),3.81–3.75(m,2H),3.66(t,J＝6.4Hz,2H),3.65–3.56(m,4H),3.31(t,J＝6.4Hz,2H),2.20–2.09(m, 3H), 2.03–1.95(m,1H), 1.33(s,9H).
步骤6：中间体19g的合成Step 6: Synthesis of Intermediate 19g
在单口瓶中，将化合物19f(0.5g)溶于N,N-二甲基甲酰胺(10mL)中，加入化合物1j(0.525g)和碳酸钾(0.322g)，升温至50℃反应4小时。反应完毕后，反应液冷至室温，向反应液中加入乙酸乙酯(100mL)和水(200mL)。有机相分离，用乙酸乙酯(50mL×2)萃取，用饱和食盐水(200mL)洗涤后用无水硫酸钠干燥，过滤。减压蒸除溶剂，粗品经过硅胶柱层析分离(洗脱剂：二氯甲烷/甲醇)得到中间体19g(0.2g)。In a one-necked bottle, dissolve compound 19f (0.5g) in N,N-dimethylformamide (10mL), add compound 1j (0.525g) and potassium carbonate (0.322g), heat up to 50°C for 4 hours . After the reaction was completed, the reaction liquid was cooled to room temperature, and ethyl acetate (100 mL) and water (200 mL) were added to the reaction liquid. The organic phase was separated, extracted with ethyl acetate (50 mL×2), washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, and filtered. The solvent was evaporated under reduced pressure, and the crude product was separated by silica gel column chromatography (eluent: dichloromethane/methanol) to obtain 19 g (0.2 g) of the intermediate.
MS(ESI,[M+H] +)m/z:955.5。 1H NMR(500MHz,DMSO-d 6)δ11.21(s,1H),8.41(d,J＝5.3Hz,1H),8.31(d,J＝1.9Hz,1H),8.00–7.94(m,2H),7.61(t,J＝7.9Hz,1H),7.55(s,1H),7.48(d,J＝8.2Hz,1H),7.34(dd,J＝5.4,2.0Hz,1H),7.24(d,J＝4.9Hz,1H),7.21–7.17(m,2H),7.17–7.16(m,1H),7.00(d,J＝4.9Hz,1H),5.97(s,1H),4.72(dd,J＝10.3,4.1Hz,1H),4.51(d,J＝17.2Hz,1H),4.35(d,J＝17.2Hz,1H),4.16(dd,J＝5.6,3.5Hz,2H),3.79–3.75(m,2H),3.60(t,J＝3.2Hz,2H),3.55–3.52(m,2H),3.18–3.14(m,4H),3.03(t,J＝5.4Hz,4H),2.70(s,2H),2.13(q,J＝3.2,2.8Hz,2H),2.07(s,4H),1.91–1.83(m,4H),1.32(s,9H). MS (ESI, [M+H] + ) m/z: 955.5. 1 H NMR (500MHz, DMSO-d 6 )δ11.21(s, 1H), 8.41(d, J=5.3Hz, 1H), 8.31(d, J=1.9Hz, 1H), 8.00–7.94(m, 2H), 7.61(t, J=7.9Hz, 1H), 7.55(s, 1H), 7.48(d, J=8.2Hz, 1H), 7.34(dd, J=5.4, 2.0Hz, 1H), 7.24( d,J=4.9Hz,1H),7.21–7.17(m,2H),7.17–7.16(m,1H),7.00(d,J=4.9Hz,1H),5.97(s,1H),4.72(dd ,J=10.3,4.1Hz,1H),4.51(d,J=17.2Hz,1H),4.35(d,J=17.2Hz,1H),4.16(dd,J=5.6,3.5Hz,2H),3.79 –3.75(m,2H),3.60(t,J=3.2Hz,2H),3.55–3.52(m,2H),3.18–3.14(m,4H),3.03(t,J=5.4Hz,4H), 2.70(s,2H),2.13(q,J=3.2,2.8Hz,2H),2.07(s,4H),1.91–1.83(m,4H),1.32(s,9H).
步骤7：化合物19的合成Step 7: Synthesis of compound 19
在微波管中，将化合物19g(500mg)溶于乙腈(5mL)中，再加入苯磺酸(214mg)，搅拌3分钟后，放入微波反应器中，在100W下加热至100℃反应1小时。反应完毕后，反应液冷至室温，减压蒸馏除去溶剂，反相纯化(洗脱剂：水/乙腈)得到目标产物19(30mg)。In a microwave tube, dissolve compound 19g (500mg) in acetonitrile (5mL), add benzenesulfonic acid (214mg), stir for 3 minutes, put it in a microwave reactor, and heat it to 100°C under 100W for 1 hour . After the reaction was completed, the reaction liquid was cooled to room temperature, the solvent was distilled off under reduced pressure, and reverse-phase purification (eluent: water/acetonitrile) gave the target product 19 (30 mg).
HRMS(ESI)m/z[M+H] +:881.28129。 1H NMR(500MHz,DMSO-d 6)δ11.22(s,1H),10.97(s,1H),8.41(d,J＝5.4Hz,1H),8.32(d,J＝1.9Hz,1H),8.03–7.92(m,2H),7.62(t,J＝7.9Hz,1H),7.49(d,J＝8.3Hz,1H),7.35(dd,J＝5.4,1.9Hz,1H),7.28–7.18(m,3H),7.00(d,J＝5.0Hz,1H),5.98(s,2H),5.09(dd,J＝13.3,5.1Hz,1H),4.35(d,J＝16.9Hz,1H),4.23(d,J＝16.9Hz,1H),4.18(t,J＝4.5Hz,2H),3.82–3.74(m,2H),3.60(dd,J＝5.9,3.6Hz,2H),3.52(dd,J＝5.9,3.6Hz,2H),3.39(d,J＝5.9Hz,2H),3.08–3.00(m,8H),2.89(ddd,J＝17.4,13.6,5.4Hz,1H),2.59(dt,J＝7.6,3.6Hz,3H),2.36(qd,J＝13.2,4.5Hz,1H),2.00–1.95(m,1H),1.83(t,J＝5.3Hz,4H). 13C NMR(126MHz,DMSO-d 6)δ173.32,168.48,165.33,153.67,151.94,149.94,145.57,144.47,138.63,138.01,135.66,134.66,133.46,132.98,127.93,126.69,124.98,120.45,116.38,114.73,113.83,107.38,106.06,72.89,70.44,70.24,69.34,68.19,64.71,52.16,47.59,47.08,35.66,34.73,33.13,31.68,29.44,22.95. HRMS (ESI) m/z [M+H] + : 881.28129. 1 H NMR (500MHz,DMSO-d 6 )δ11.22(s,1H),10.97(s,1H),8.41(d,J=5.4Hz,1H),8.32(d,J=1.9Hz,1H) ,8.03–7.92(m,2H),7.62(t,J=7.9Hz,1H),7.49(d,J=8.3Hz,1H),7.35(dd,J=5.4,1.9Hz,1H),7.28– 7.18(m,3H),7.00(d,J=5.0Hz,1H),5.98(s,2H),5.09(dd,J=13.3,5.1Hz,1H),4.35(d,J=16.9Hz,1H ), 4.23(d, J=16.9Hz, 1H), 4.18(t, J=4.5Hz, 2H), 3.82–3.74(m, 2H), 3.60(dd, J=5.9, 3.6Hz, 2H), 3.52 (dd,J=5.9,3.6Hz,2H),3.39(d,J=5.9Hz,2H),3.08–3.00(m,8H),2.89(ddd,J=17.4,13.6,5.4Hz,1H), 13 C NMR(126MHz,DMSO-d 6 )δ173.32,168.48,165.33,153.67,151.94,149.94,145.57,144.47,138.63,138.01,135.66,134.66,133.46,132.98,127.93,126.69,124.98,120.45,116.38,114.73, 113.83, 107.38, 106.06, 72.89, 70.44, 70.24, 69.34, 68.19, 64.71, 52.16, 47.59, 47.08, 35.66, 34.73, 33.13, 31.68, 29.44, 22.95.
实施例20 化合物20的合成The synthesis of embodiment 20 compound 20
Figure PCTCN2022096512-appb-000125
Figure PCTCN2022096512-appb-000125
Figure PCTCN2022096512-appb-000126
Figure PCTCN2022096512-appb-000126
步骤1：中间体20b的制备Step 1: Preparation of Intermediate 20b
向反应瓶中，依次加入中间体20a(25g)、NBS(29.6g)、偶氮二异丁腈(6.83g)及四氯化碳(200mL)，N 2保护下，85℃加热10小时，反应完全，反应液用DCM(100mL×2)萃取，有机层合并后饱和食盐水(200mL×1)洗涤，萃取液干燥过滤，滤液旋蒸干得到中间体20b(35.0g)。 Into the reaction flask, add intermediate 20a (25g), NBS (29.6g), azobisisobutyronitrile (6.83g) and carbon tetrachloride (200mL) in sequence, and heat at 85°C for 10 hours under N protection. After the reaction was complete, the reaction solution was extracted with DCM (100 mL×2), the organic layers were combined and washed with saturated brine (200 mL×1), the extract was dried and filtered, and the filtrate was rotary evaporated to dryness to obtain intermediate 20b (35.0 g).
MS(ESI,[M-H] -)m/z：257.1。 MS (ESI, [MH] - ) m/z: 257.1.
步骤2：中间体20c的制备Step 2: Preparation of intermediate 20c
在耐压密封罐中，0℃下依次加入中间体1n(2.501g)、乙腈(20mL)和N,N-二异丙基乙胺(4.51g)，室温搅拌30min后加入中间体20b(5.0g)，100℃反应3小时，反应完全，过滤，滤液旋蒸后残余物用硅胶柱纯化(DCM-MeOH)得到目标物20c(2.32g)。In a pressure-resistant sealed tank, add intermediate 1n (2.501g), acetonitrile (20mL) and N,N-diisopropylethylamine (4.51g) sequentially at 0°C, stir at room temperature for 30min, then add intermediate 20b (5.0 g), reacted at 100°C for 3 hours, the reaction was complete, filtered, the filtrate was rotary evaporated, and the residue was purified by silica gel column (DCM-MeOH) to obtain the target compound 20c (2.32g).
MS(ESI,[M-H] -)m/z：333.2。 MS (ESI, [MH] - ) m/z: 333.2.
步骤3：中间体20d的制备Step 3: Preparation of intermediate 20d
在反应瓶中，依次加入中间体20c(2.3g)、DMF(30mL)、1,2-双(2-碘代乙氧基)乙烷(6.84g)及碳酸铯(5.60g)，N 2保护下，室温避光搅拌过夜，反应完全，反应液加水(200mL)，用EA(100mL×2)萃取，有机层合并后水(100mL×2)洗涤，饱和食盐水(100mL×1)洗涤，萃取液干燥过滤，滤液旋蒸后残余物用硅胶柱纯化(DCM-MeOH)得到目标物粗品(1.5g)。粗品再用硅胶柱纯化(DCM/EA/MeOH)得到中间体20d(602mg)。 In the reaction flask, sequentially add intermediate 20c (2.3g), DMF (30mL), 1,2-bis(2-iodoethoxy)ethane (6.84g) and cesium carbonate (5.60g), N 2 Under protection, stir overnight at room temperature in the dark, the reaction is complete, add water (200mL) to the reaction solution, extract with EA (100mL×2), combine the organic layers, wash with water (100mL×2), and wash with saturated brine (100mL×1), The extract was dried and filtered. After the filtrate was rotary evaporated, the residue was purified by a silica gel column (DCM-MeOH) to obtain the crude product of the target product (1.5 g). The crude product was purified by silica gel column (DCM/EA/MeOH) to give intermediate 20d (602 mg).
MS(ESI,[M+H] +)m/z：577.3。 1H NMR(500MHz,DMSO-d 6)δ7.53–7.45(m,2H),7.12(d,J＝7.8Hz,2H),7.02(d,J＝8.3Hz,1H),4.66(dd,J＝10.4,4.1Hz,1H),4.49(d,J＝17.6Hz,1H),4.36(d,J＝17.6Hz,1H),4.22(dd,J＝5.7,3.8Hz,2H),3.82–3.77(m,2H),3.70–3.65(m,4H),3.61–3.57(m,2H),3.30(d,J＝6.4Hz,2H),2.23–2.07(m,3H),2.01–1.89(m,1H),1.34(s,9H). MS (ESI, [M+H] + ) m/z: 577.3. 1 H NMR (500MHz, DMSO-d 6 ) δ7.53–7.45(m, 2H), 7.12(d, J=7.8Hz, 2H), 7.02(d, J=8.3Hz, 1H), 4.66(dd, J=10.4, 4.1Hz, 1H), 4.49(d, J=17.6Hz, 1H), 4.36(d, J=17.6Hz, 1H), 4.22(dd, J=5.7, 3.8Hz, 2H), 3.82– 3.77(m,2H),3.70–3.65(m,4H),3.61–3.57(m,2H),3.30(d,J＝6.4Hz,2H),2.23–2.07(m,3H),2.01–1.89( m,1H),1.34(s,9H).
步骤4：中间体20e的制备Step 4: Preparation of intermediate 20e
向反应瓶中，依次加入中间体1j(430mg)、中间体20d(525mg)、碳酸钾(274mg)及DMF(10mL)，N 2保护下，室温搅拌过夜，反应完全，反应液旋蒸后残余物用DCM-MeOH(10:1，50mL×2)萃取，有机层合并后饱和食盐水(50mL×1)洗，萃取液干燥过滤，滤液旋蒸后残余物用硅胶柱纯化(DCM-MeOH)得到目标物粗品。粗品再用C 18反相柱纯化(10nM乙酸铵水溶液-乙腈)洗脱，过柱液合并，DCM-MeOH(10:1)萃取后旋蒸干得到中间体20e(56mg)。 Into the reaction flask, add intermediate 1j (430mg), intermediate 20d (525mg), potassium carbonate (274mg) and DMF (10mL) successively, under the protection of N 2 , stir at room temperature overnight, the reaction is complete, and the reaction liquid remains after rotary evaporation. The product was extracted with DCM-MeOH (10:1, 50mL×2), the organic layers were combined and washed with saturated brine (50mL×1), the extract was dried and filtered, and the residue was purified with a silica gel column (DCM-MeOH) after rotary evaporation of the filtrate Obtain the crude product of the target. The crude product was purified by a C 18 reverse phase column (10nM ammonium acetate aqueous solution-acetonitrile), and the column solution was combined, extracted with DCM-MeOH (10:1) and evaporated to dryness to obtain intermediate 20e (56 mg).
MS(ESI,[M+H] +)m/z：955.6。 1H NMR(500MHz,DMSO-d 6)δ11.22(s,1H),8.42(d,J＝5.3Hz,1H),8.32(d,J＝1.9Hz,1H),8.02–7.94(m,2H),7.61(t,J＝7.9Hz,1H),7.49(t,J＝7.9Hz,2H),7.35(dd,J＝5.4,1.9Hz,1H),7.23(d,J＝5.0Hz,1H),7.16–7.09(m,2H),7.01(dd,J＝6.6,4.9Hz,2H),5.99(s,2H),4.65(dd,J＝10.5,4.0Hz,1H),4.49(d,J＝17.7Hz,1H),4.36(d,J＝17.5Hz,2H),4.22(dd,J＝5.7,3.7Hz,2H),3.79(dd,J＝5.4,3.9Hz,2H),3.68(dd,J＝5.8,3.5Hz,2H),3.55(t,J＝8.6Hz,3H),3.16(dd,J＝11.1,4.9Hz,2H),3.03(s,3H),2.19–2.11(m,3H),1.99–1.90(m,2H),1.88(s,2H),1.37(dd,J＝19.6,3.6Hz,2H),1.33(s,9H),1.28–1.21(m,4H). MS (ESI, [M+H] + ) m/z: 955.6. 1 H NMR (500MHz, DMSO-d 6 )δ11.22(s, 1H), 8.42(d, J=5.3Hz, 1H), 8.32(d, J=1.9Hz, 1H), 8.02–7.94(m, 2H), 7.61(t, J=7.9Hz, 1H), 7.49(t, J=7.9Hz, 2H), 7.35(dd, J=5.4, 1.9Hz, 1H), 7.23(d, J=5.0Hz, 1H), 7.16–7.09(m, 2H), 7.01(dd, J=6.6, 4.9Hz, 2H), 5.99(s, 2H), 4.65(dd, J=10.5, 4.0Hz, 1H), 4.49(d ,J=17.7Hz,1H),4.36(d,J=17.5Hz,2H),4.22(dd,J=5.7,3.7Hz,2H),3.79(dd,J=5.4,3.9Hz,2H),3.68 (dd,J=5.8,3.5Hz,2H),3.55(t,J=8.6Hz,3H),3.16(dd,J=11.1,4.9Hz,2H),3.03(s,3H),2.19–2.11( m,3H),1.99–1.90(m,2H),1.88(s,2H),1.37(dd,J＝19.6,3.6Hz,2H),1.33(s,9H),1.28–1.21(m,4H) .
步骤5：化合物20的制备Step 5: Preparation of Compound 20
向微波管中依次加入中间体20e(50mg)、乙腈(10mL)和无水苯磺酸(33.1mg)，微波110℃反应120分钟，反应完全，反应液用DCM(50mL×2)萃取，有机层合并后饱和食盐水(50mL×1)洗涤，萃取液干燥过滤，滤液旋蒸后用甲基叔丁基醚打浆得到化合物20(18mg)。Add intermediate 20e (50 mg), acetonitrile (10 mL) and anhydrous benzenesulfonic acid (33.1 mg) to a microwave tube in sequence, react in microwave at 110 ° C for 120 minutes, the reaction is complete, the reaction solution is extracted with DCM (50 mL × 2), organic After the layers were combined, they were washed with saturated brine (50 mL×1), and the extract was dried and filtered. After rotary evaporation, the filtrate was slurried with methyl tert-butyl ether to obtain compound 20 (18 mg).
MS(ESI,[M+H] +)m/z：881.5。 1H NMR(500MHz,DMSO-d 6)δ11.24(s,1H),10.97(s,1H),10.56(s,1H),8.42(d,J＝5.4Hz,1H),8.32(s,1H),8.00(t,J＝8.4Hz,2H),7.62(q,J＝10.1,8.9Hz,1H),7.52(t,J＝7.9Hz,1H),7.40–7.33(m,1H),7.26(d,J＝5.2Hz,1H),7.10(d,J＝7.5Hz,1H),7.04(dd,J＝17.5,6.7Hz,2H),6.46(s,2H),4.99(dd,J＝13.3,5.2Hz,1H),4.37(d,J＝17.4Hz,1H),4.25(dd,J＝10.5,6.1Hz,3H),3.94(d,J＝26.6Hz,4H),3.82(t,J＝4.4Hz,2H),3.72(p,J＝4.3Hz,4H),3.60(t,J＝4.5Hz,2H),3.11(s,2H),3.00(s,2H),2.88(ddd,J＝18.3,13.6,5.4Hz,1H),2.59(d,J＝17.5Hz,1H),2.42–2.31(m,1H),2.08–1.87(m,4H),1.38– 1.14(m,2H). MS (ESI, [M+H] + ) m/z: 881.5. 1 H NMR (500MHz, DMSO-d 6 )δ11.24(s, 1H), 10.97(s, 1H), 10.56(s, 1H), 8.42(d, J=5.4Hz, 1H), 8.32(s, 1H), 8.00(t, J=8.4Hz, 2H), 7.62(q, J=10.1, 8.9Hz, 1H), 7.52(t, J=7.9Hz, 1H), 7.40–7.33(m, 1H), 7.26(d,J=5.2Hz,1H),7.10(d,J=7.5Hz,1H),7.04(dd,J=17.5,6.7Hz,2H),6.46(s,2H),4.99(dd,J =13.3,5.2Hz,1H), 4.37(d,J=17.4Hz,1H),4.25(dd,J=10.5,6.1Hz,3H),3.94(d,J=26.6Hz,4H),3.82(t ,J=4.4Hz,2H),3.72(p,J=4.3Hz,4H),3.60(t,J=4.5Hz,2H),3.11(s,2H),3.00(s,2H),2.88(ddd ,J=18.3,13.6,5.4Hz,1H),2.59(d,J=17.5Hz,1H),2.42–2.31(m,1H),2.08–1.87(m,4H),1.38–1.14(m,2H ).
实施例21 化合物21的合成Synthesis of Example 21 Compound 21
Figure PCTCN2022096512-appb-000127
Figure PCTCN2022096512-appb-000127
步骤1：中间体21b的制备Step 1: Preparation of Intermediate 21b
向反应瓶中，依次加入中间体21a(12.8g)、NBS(13.13g)、偶氮二异丁腈(3.03g)及四氯化碳(130mL)，N 2保护下，加热至85℃反应4.5小时。反应液冷却至室温后，过滤，滤液用水(150mL×2)洗涤，饱和食盐水(150mL×1)洗涤，有机层用无水硫酸钠搅拌干燥后抽滤，滤液旋蒸干得中间体21b(19.27g)。 Into the reaction flask, add intermediate 21a (12.8g), NBS (13.13g), azobisisobutyronitrile (3.03g) and carbon tetrachloride (130mL) in sequence, and heat to 85°C under N2 protection 4.5 hours. After the reaction solution was cooled to room temperature, it was filtered, the filtrate was washed with water (150mL×2), and saturated brine (150mL×1), the organic layer was stirred and dried with anhydrous sodium sulfate, and then suction filtered, and the filtrate was rotary evaporated to dryness to obtain intermediate 21b ( 19.27g).
步骤2：中间体21c的制备Step 2: Preparation of Intermediate 21c
向耐压密封罐中，0℃下依次加入中间体1n(2.195g)、乙腈(30mL)和N,N-二异丙基乙胺(3.96g)，室温搅拌30min后加入中间体21b(2.0g)，加热至100℃反应4小时，反应完全。反应液冷却至室温后，过滤，滤液旋蒸后残余物用硅胶柱纯化(DCM-MeOH)得到目标物21c(1.70g)。In a pressure-resistant sealed tank, sequentially add intermediate 1n (2.195g), acetonitrile (30mL) and N,N-diisopropylethylamine (3.96g) at 0°C, stir at room temperature for 30min, then add intermediate 21b (2.0 g), heated to 100° C. for 4 hours, and the reaction was complete. After the reaction liquid was cooled to room temperature, it was filtered, and the residue was purified by silica gel column (DCM-MeOH) after rotary evaporation of the filtrate to obtain the target compound 21c (1.70 g).
MS(ESI,[M-H] -)m/z：333.2。 MS (ESI, [MH] - ) m/z: 333.2.
步骤3：中间体21d的制备Step 3: Preparation of Intermediate 21d
向反应瓶中，依次加入中间体21c(1.65g)、DMF(30mL)、1,2-双(2-碘代乙氧基)乙烷(8.19g)及碳酸铯(6.71g)，N 2保护下，避光室温搅拌过夜，反应完全，向反应液中加入水(200mL)，用EA(100mL×2)萃取，有机层合并后水(100mL×2)洗涤，饱和食盐水(100mL×1)洗涤，萃取液干燥过滤，滤液旋蒸后残余物用硅胶柱纯化(DCM-MeOH)得到目标物粗品(1.05g)。粗品再用硅胶柱纯化(DCM/EA/MeOH)得到中间体21d(480mg)。 Into the reaction flask, add intermediate 21c (1.65g), DMF (30mL), 1,2-bis(2-iodoethoxy)ethane (8.19g) and cesium carbonate (6.71g), N 2 Under protection, avoid light and stir overnight at room temperature, the reaction is complete, add water (200mL) to the reaction solution, extract with EA (100mL×2), wash with water (100mL×2) after the organic layer is combined, and saturated saline (100mL×1 ), the extract was dried and filtered, the filtrate was rotary evaporated, and the residue was purified by silica gel column (DCM-MeOH) to obtain the crude product of the target (1.05 g). The crude product was further purified by silica gel column (DCM/EA/MeOH) to give intermediate 21d (480 mg).
MS(ESI,[M+H] +)m/z：577.3。 1H NMR(500MHz,DMSO-d 6)δ7.57(s,1H),7.45(t,J＝7.8Hz,1H),7.31–7.27(m,1H),7.26–7.21(m,1H),7.17(s,1H),4.76–4.69(m,1H),4.53(d,J＝17.5Hz,1H),4.36(d,J＝17.6Hz,1H),4.27–4.21(m,2H),3.83–3.78(m,2H),3.73–3.64(m,3H),3.64–3.57(m,4H),3.37–3.28(m,3H),2.21–2.09(m,1H),2.09–1.96(m,1H),1.33(s,9H). MS (ESI, [M+H] + ) m/z: 577.3. 1 H NMR (500MHz, DMSO-d 6 )δ7.57(s,1H),7.45(t,J＝7.8Hz,1H),7.31–7.27(m,1H),7.26–7.21(m,1H), 7.17(s,1H),4.76–4.69(m,1H),4.53(d,J=17.5Hz,1H),4.36(d,J=17.6Hz,1H),4.27–4.21(m,2H),3.83 –3.78(m,2H),3.73–3.64(m,3H),3.64–3.57(m,4H),3.37–3.28(m,3H),2.21–2.09(m,1H),2.09–1.96(m, 1H), 1.33(s, 9H).
步骤4：中间体21e的制备Step 4: Preparation of Intermediate 21e
向反应瓶中，依次加入中间体1j(325mg)、中间体21d(409mg)、碳酸钾(207mg)及DMF(10mL)，N 2保护下，反应完全，反应液旋蒸后残余物用DCM-MeOH(10:1，50mL×2)萃取，有机层合并后饱和食盐水(50mL×1)洗涤，萃取液干燥过滤，滤液旋蒸后残余物用硅胶柱纯化(DCM-MeOH)得到目标物粗品。粗品再用C 18反相柱纯化(10nM乙酸铵水溶液-乙腈)洗脱，过柱液合并，DCM-MeOH(10:1)萃取后旋蒸干得到中间体21e(53mg)。 Into the reaction flask, add intermediate 1j (325mg), intermediate 21d (409mg), potassium carbonate (207mg) and DMF (10mL) successively, under the protection of N 2 , the reaction was complete, and the residue was washed with DCM- MeOH (10:1, 50mL×2) was extracted, the organic layers were combined and washed with saturated brine (50mL×1), the extract was dried and filtered, and the filtrate was rotary evaporated and the residue was purified with silica gel column (DCM-MeOH) to obtain the crude product of the target product . The crude product was purified by a C 18 reverse phase column (10nM ammonium acetate aqueous solution-acetonitrile), and the column solution was combined, extracted with DCM-MeOH (10:1) and evaporated to dryness to obtain intermediate 21e (53 mg).
MS(ESI,[M+H] +)m/z：955.5。 1H NMR(500MHz,DMSO-d 6)δ11.22(s,1H),8.42(d,J＝5.4Hz,1H),8.32(d,J＝1.9Hz,1H),8.02–7.94(m,2H),7.61(dd,J＝16.6,8.5Hz,2H),7.44(t,J＝7.8Hz,1H),7.35(dd,J＝5.3,1.9Hz,1H),7.28(d,J＝7.4Hz,1H),7.23(h,J＝5.7Hz,2H),7.18(s,1H),7.01(d,J＝4.9Hz,1H),5.98(s,2H),4.76–4.69(m,1H),4.53(d,J＝17.5Hz,1H),4.37(d,J＝17.5Hz,1H),4.24(dd,J＝5.7,3.5Hz,2H),3.83–3.77(m,2H),3.61(dd,J＝5.9,3.6Hz,2H),3.53(dd,J＝5.8,3.6Hz,2H),3.02(t,J＝5.5Hz,4H),2.20–1.97(m,5H),1.84(s,4H),1.41–1.33(m,2H),1.31(s,9H),1.28–1.21(m,4H),1.00(d,J＝6.2Hz,1H). MS (ESI, [M+H] + ) m/z: 955.5. 1 H NMR (500MHz, DMSO-d 6 )δ11.22(s, 1H), 8.42(d, J=5.4Hz, 1H), 8.32(d, J=1.9Hz, 1H), 8.02–7.94(m, 2H), 7.61(dd, J=16.6, 8.5Hz, 2H), 7.44(t, J=7.8Hz, 1H), 7.35(dd, J=5.3, 1.9Hz, 1H), 7.28(d, J=7.4 Hz, 1H), 7.23(h, J=5.7Hz, 2H), 7.18(s, 1H), 7.01(d, J=4.9Hz, 1H), 5.98(s, 2H), 4.76–4.69(m, 1H ),4.53(d,J=17.5Hz,1H),4.37(d,J=17.5Hz,1H),4.24(dd,J=5.7,3.5Hz,2H),3.83–3.77(m,2H),3.61 (dd,J=5.9,3.6Hz,2H),3.53(dd,J=5.8,3.6Hz,2H),3.02(t,J=5.5Hz,4H),2.20–1.97(m,5H),1.84( s,4H),1.41–1.33(m,2H),1.31(s,9H),1.28–1.21(m,4H),1.00(d,J＝6.2Hz,1H).
步骤5：化合物21的制备Step 5: Preparation of Compound 21
向微波管中依次加入中间体21e(50mg)、乙腈(10mL)和无水苯磺酸(33.1mg)，搅拌1分钟后，微波110℃反应120分钟，反应完全，反应液用DCM(50mL×2)萃取，有机层合并后用饱和食盐水(50mL×1)洗涤，萃取液干燥过滤，滤液旋蒸后用甲基叔丁基醚打浆得到化合物21(18mg)。Add intermediate 21e (50mg), acetonitrile (10mL) and anhydrous benzenesulfonic acid (33.1mg) to the microwave tube in turn, stir for 1 minute, microwave at 110°C for 120 minutes, the reaction is complete, and the reaction solution is washed with DCM (50mL× 2) Extraction, the organic layers were combined and washed with saturated brine (50 mL×1), the extract was dried and filtered, and the filtrate was rotary evaporated and beaten with methyl tert-butyl ether to obtain compound 21 (18 mg).
MS(ESI,[M+H] +)m/z：881.5。 1H NMR(500MHz,DMSO-d 6)δ11.22(s,1H),10.98(s,1H),8.42(d,J＝5.4Hz,1H),8.32(d,J＝1.9Hz,1H),8.02–7.93(m,2H),7.61(t,J＝7.9Hz,1H),7.46(t,J＝7.8Hz,1H),7.36–7.30(m,2H),7.28–7.22(m,2H),7.02(d,J＝5.0Hz,1H),6.06–5.93(m,2H),5.12(dd,J＝13.3,5.1Hz,1H),4.40–4.36(m,1H),4.29–4.21(m,3H),3.79(dd,J＝5.5,3.5Hz,2H),3.62(t,J＝4.5Hz,2H),3.54(dd,J＝14.6,9.3Hz,4H),3.25(d,J＝5.4Hz,1H),3.15(dt,J＝10.9,5.7Hz,1H),3.03(s,4H),2.91(ddd,J＝17.2,13.6,5.4Hz,2H),2.58(ddd,J＝17.1,4.4,2.2Hz,1H),2.43(td,J＝13.2,4.5Hz,1H),2.02–1.97(m,2H),1.90(d,J＝10.2Hz,4H). MS (ESI, [M+H] + ) m/z: 881.5. 1 H NMR (500MHz,DMSO-d 6 )δ11.22(s,1H),10.98(s,1H),8.42(d,J=5.4Hz,1H),8.32(d,J=1.9Hz,1H) ,8.02–7.93(m,2H),7.61(t,J＝7.9Hz,1H),7.46(t,J＝7.8Hz,1H),7.36–7.30(m,2H),7.28–7.22(m,2H ),7.02(d,J=5.0Hz,1H),6.06–5.93(m,2H),5.12(dd,J=13.3,5.1Hz,1H),4.40–4.36(m,1H),4.29–4.21( m,3H),3.79(dd,J=5.5,3.5Hz,2H),3.62(t,J=4.5Hz,2H),3.54(dd,J=14.6,9.3Hz,4H),3.25(d,J =5.4Hz,1H),3.15(dt,J=10.9,5.7Hz,1H),3.03(s,4H),2.91(ddd,J=17.2,13.6,5.4Hz,2H),2.58(ddd,J= 17.1,4.4,2.2Hz,1H),2.43(td,J=13.2,4.5Hz,1H),2.02–1.97(m,2H),1.90(d,J=10.2Hz,4H).
实施例22 化合物22的合成The synthesis of embodiment 22 compound 22
Figure PCTCN2022096512-appb-000128
Figure PCTCN2022096512-appb-000128
步骤1：中间体22b的制备Step 1: Preparation of intermediate 22b
向三口瓶中，依次加入叔丁基二甲基氯硅烷(10g)、中间体22a(10.67g)及DCM(50mL)，降温至0℃左右，加入钠氢(3.18g)，N 2保护下，室温搅拌7h。反应结束后，向反应液中加入饱和氯化铵水溶液以淬灭反应，加入DCM(100mL)和水(200mL)。有机相分离，分别用200mL饱和食盐水洗涤后用无水硫酸钠干燥，过滤，滤液通过硅胶柱层析纯化(PE/EA)得到11.7g中间体22b。 Into the three-necked flask, add tert-butyldimethylsilyl chloride (10g), intermediate 22a (10.67g) and DCM (50mL) successively, cool down to about 0°C, add sodium hydrogen (3.18g), under N2 protection , Stir at room temperature for 7h. After the reaction was completed, saturated ammonium chloride aqueous solution was added to the reaction solution to quench the reaction, and DCM (100 mL) and water (200 mL) were added. The organic phase was separated, washed with 200 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was purified by silica gel column chromatography (PE/EA) to obtain 11.7 g of intermediate 22b.
1H NMR(500MHz,DMSO-d 6)δ4.28(t,J＝5.2Hz,1H),3.54(t,J＝6.4Hz,2H),3.35(td,J＝6.6,5.1Hz,2H),1.44–1.34(m,4H),1.24(q,J＝4.8Hz,8H),0.84(s,9H),0.06(s,6H). 1 H NMR (500MHz, DMSO-d 6 ) δ4.28(t, J=5.2Hz, 1H), 3.54(t, J=6.4Hz, 2H), 3.35(td, J=6.6, 5.1Hz, 2H) ,1.44–1.34(m,4H),1.24(q,J＝4.8Hz,8H),0.84(s,9H),0.06(s,6H).
步骤2：中间体22c的制备Step 2: Preparation of intermediate 22c
向单口瓶中，依次加入中间体22b(4.8g)、DCM(150mL)及戴斯马丁氧化剂(8.60g)，N 2保护下，室温搅拌0.5h。反应液中加入DCM(20mL)和水(20mL)。有机相分离，分别用50mL饱和食盐水洗涤后用无水硫酸钠干燥，过滤，减压蒸除溶剂，得到4.5g中间体22c。 Intermediate 22b (4.8g), DCM (150mL) and Dess Martin oxidant (8.60g) were sequentially added to a one-necked flask, and stirred at room temperature for 0.5h under N 2 protection. DCM (20 mL) and water (20 mL) were added to the reaction solution. The organic phase was separated, washed with 50 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain 4.5 g of intermediate 22c.
1H NMR(500MHz,DMSO-d 6)δ9.64(t,J＝1.7Hz,1H),3.54(t,J＝6.4Hz,2H),2.39(td,J＝7.2,1.7Hz,2H),1.53–1.46(m,2H),1.42(qd,J＝7.0,3.7Hz,2H),1.27–1.22(m,J＝3.4,2.5Hz,6H),0.84(s,9H),0.06(s,6H). 1 H NMR (500MHz, DMSO-d 6 ) δ9.64(t, J=1.7Hz, 1H), 3.54(t, J=6.4Hz, 2H), 2.39(td, J=7.2, 1.7Hz, 2H) ,1.53–1.46(m,2H),1.42(qd,J＝7.0,3.7Hz,2H),1.27–1.22(m,J＝3.4,2.5Hz,6H),0.84(s,9H),0.06(s ,6H).
步骤3：中间体22d的制备Step 3: Preparation of intermediate 22d
向单口瓶中，依次加入中间体15d(1.5g)、中间体22c(3.49g)、MeOH(40mL)及乙酸(0.4mL)，然后加入氰基硼氢化钠(1.414g)，N 2保护下，室温搅拌21h，向反应液中加入水(30mL)，用DCM萃取(20mL×3)，有机层合并后，饱和食盐水(30mL)洗涤，有机层用无水硫酸钠搅拌干燥，过滤，滤液旋蒸通过硅胶柱层 析纯化(DCM/MeOH)得到2.15g中间体22d。 In a single-necked flask, add intermediate 15d (1.5g), intermediate 22c (3.49g), MeOH (40mL) and acetic acid (0.4mL) in sequence, then add sodium cyanoborohydride (1.414g), under N 2 protection , stirred at room temperature for 21h, added water (30mL) to the reaction solution, extracted with DCM (20mL×3), after the organic layers were combined, washed with saturated brine (30mL), the organic layer was stirred and dried with anhydrous sodium sulfate, filtered, and the filtrate Purification by rotary evaporation via silica gel column chromatography (DCM/MeOH) afforded 2.15 g of intermediate 22d.
MS(ESI,[M+H] +)m/z：576.6。 MS (ESI, [M+H] + ) m/z: 576.6.
步骤4：中间体22e的制备Step 4: Preparation of Intermediate 22e
向单口瓶中，依次加入中间体22d(2g)、THF(14mL)及TBAF(2.6g)，室温搅拌1h。反应结束后，减压蒸除溶剂，选择330g C 18反相柱纯化(1％乙酸铵水溶液/乙腈)得0.7g中间体22e。 Intermediate 22d (2 g), THF (14 mL) and TBAF (2.6 g) were sequentially added to a one-necked flask, and stirred at room temperature for 1 h. After the reaction, the solvent was evaporated under reduced pressure, and 330 g of C 18 reverse phase column purification (1% ammonium acetate aqueous solution/acetonitrile) was selected to obtain 0.7 g of intermediate 22e.
MS(ESI,[M+H] +)m/z：462.4。 1H NMR(500MHz,DMSO-d 6)δ7.49–7.41(m,1H),7.39–7.28(m,1H),7.09(s,1H),6.65–6.59(m,2H),6.28(t,J＝5.4Hz,1H),4.68–4.60(m,1H),4.42(d,J＝17.0Hz,1H),4.31(t,J＝5.2Hz,1H),4.26(d,J＝17.0Hz,1H),3.38(td,J＝6.5,5.1Hz,2H),3.05(td,J＝7.0,5.4Hz,2H),2.17–2.07(m,3H),1.97–1.88(m,1H),1.55(p,J＝7.1Hz,2H),1.41(t,J＝6.6Hz,2H),1.36(d,J＝1.2Hz,2H),1.34(s,9H),1.29(dd,J＝6.4,3.5Hz,6H). 13C NMR(126MHz,DMSO-d 6)δ172.72,171.88,169.01,152.66,145.15,124.22,119.31,112.72,104.58,80.18,61.18,53.48,46.92,43.07,33.01,32.24,29.44,29.40,28.93,28.15,27.09,25.96,25.32. MS (ESI, [M+H] + ) m/z: 462.4. 1 H NMR (500MHz,DMSO-d 6 )δ7.49–7.41(m,1H),7.39–7.28(m,1H),7.09(s,1H),6.65–6.59(m,2H),6.28(t ,J=5.4Hz,1H),4.68–4.60(m,1H),4.42(d,J=17.0Hz,1H),4.31(t,J=5.2Hz,1H),4.26(d,J=17.0Hz ,1H),3.38(td,J＝6.5,5.1Hz,2H),3.05(td,J＝7.0,5.4Hz,2H),2.17–2.07(m,3H),1.97–1.88(m,1H), 1.55(p, J=7.1Hz, 2H), 1.41(t, J=6.6Hz, 2H), 1.36(d, J=1.2Hz, 2H), 1.34(s, 9H), 1.29(dd, J=6.4 ,3.5Hz,6H). 13 C NMR(126MHz,DMSO-d 6 )δ172.72,171.88,169.01,152.66,145.15,124.22,119.31,112.72,104.58,80.18,61.18,53.48,46.92,23.401,32 29.44, 29.40, 28.93, 28.15, 27.09, 25.96, 25.32.
步骤5：中间体22f的制备Step 5: Preparation of Intermediate 22f
向单口瓶中，依次加入中间体22e(600mg)、DCM(2mL)及戴斯马丁氧化剂(686mg)，室温反应4h。反应结束后，反应液加水淬灭，加入DCM(50mL)和水(50mL)。有机相分离，分别用50mL饱和食盐水洗涤后用无水硫酸钠干燥，过滤，得到1.135g中间体22f。Intermediate 22e (600 mg), DCM (2 mL) and Dess-Martin oxidant (686 mg) were sequentially added to the one-necked bottle, and reacted at room temperature for 4 h. After the reaction was completed, the reaction solution was quenched with water, and DCM (50 mL) and water (50 mL) were added. The organic phase was separated, washed with 50 mL of saturated brine, dried over anhydrous sodium sulfate, and filtered to obtain 1.135 g of intermediate 22f.
MS(ESI,[M+H] +)m/z：460.4。 MS (ESI, [M+H] + ) m/z: 460.4.
步骤6：中间体22g的制备Step 6: Preparation of Intermediate 22g
向单口瓶中，依次加入中间体1j(400mg)、中间体22f(816mg)及MeOH(40mL)，搅拌下加入氰基硼氢化钠(89mg)、乙酸(4.26mg)，N 2保护下，室温搅拌3h。反应结束后，反应液加水淬灭反应，用DCM萃取3次，有机层合并后，水洗涤(100mL×1)，饱和食盐水洗涤(100mL×1)，有机层用无水硫酸钠搅拌干燥，滤液旋蒸，通过220g C 12反相制备纯化得到0.05g中间体22g。 Into the one-necked bottle, sequentially add intermediate 1j (400mg), intermediate 22f (816mg) and MeOH (40mL), add sodium cyanoborohydride (89mg), acetic acid (4.26mg) under stirring, under N 2 protection, room temperature Stir for 3h. After the reaction was completed, the reaction solution was quenched with water, extracted three times with DCM, the organic layers were combined, washed with water (100mL×1), washed with saturated brine (100mL×1), and the organic layer was stirred and dried with anhydrous sodium sulfate. The filtrate was rotary evaporated, and 0.05 g of intermediate 22 g was obtained by 220 g of C 12 reverse phase preparation and purification.
MS(ESI,[M+H] +)m/z：950.6。 MS (ESI, [M+H] + ) m/z: 950.6.
步骤7：化合物22的制备Step 7: Preparation of compound 22
向微波管中依次加入中间体22g(50mg)、乙腈(10mL)和苯磺酸(41.6mg)，搅拌1分钟后，放入微波反应器中，在200W下加热至100℃反应120分钟。反应结束后，微波管中反应液转移到圆底瓶中，减压蒸除溶剂，用1mL DMSO溶解，通过220g C 18反相柱纯化(1％乙酸铵水溶液/CH 3CN)得到化合物22。 22g (50mg) of the intermediate, acetonitrile (10mL) and benzenesulfonic acid (41.6mg) were sequentially added to the microwave tube, stirred for 1 minute, put into a microwave reactor, and heated to 100°C at 200W for 120 minutes. After the reaction, the reaction solution in the microwave tube was transferred to a round-bottom flask, the solvent was evaporated under reduced pressure, dissolved in 1 mL DMSO, and purified by 220 g C 18 reverse phase column (1% ammonium acetate aqueous solution/CH 3 CN) to obtain compound 22.
MS(ESI,[M+H] +)m/z：876.6。 1H NMR(500MHz,DMSO-d 6)δ11.23(s,1H),10.92(s,1H),8.42(d,J＝5.4Hz,1H),8.32(d,J＝1.8Hz,1H),7.98(t,J＝8.0Hz,2H),7.62(t,J＝7.8Hz,1H),7.42–7.31(m,2H),7.25(d,J＝4.9Hz,1H),7.01(d,J＝5.0Hz,1H),6.65(d,J＝8.7Hz,1H),6.61(s,1H),6.34(t,J＝5.4Hz,1H),5.99(s,2H),5.01(dd,J＝13.3,5.1Hz,1H),4.26(d,J＝16.7Hz,1H),4.14(d,J＝16.6Hz,1H),3.23(s,5H),3.06(q,J＝6.3,5.5Hz,6H),2.88(td,J＝13.2,6.7Hz,1H),2.56(t,J＝3.2Hz,2H),2.33(qd,J＝13.2,4.5Hz,1H),2.03–1.85(m,5H),1.56(p,J＝7.0Hz,2H),1.36–1.25(m,10H). MS (ESI, [M+H] + ) m/z: 876.6. 1 H NMR (500MHz,DMSO-d 6 )δ11.23(s,1H),10.92(s,1H),8.42(d,J=5.4Hz,1H),8.32(d,J=1.8Hz,1H) ,7.98(t,J=8.0Hz,2H),7.62(t,J=7.8Hz,1H),7.42–7.31(m,2H),7.25(d,J=4.9Hz,1H),7.01(d, J＝5.0Hz, 1H), 6.65(d, J＝8.7Hz, 1H), 6.61(s, 1H), 6.34(t, J＝5.4Hz, 1H), 5.99(s, 2H), 5.01(dd, J=13.3,5.1Hz,1H), 4.26(d,J=16.7Hz,1H),4.14(d,J=16.6Hz,1H),3.23(s,5H),3.06(q,J=6.3,5.5 Hz, 6H), 2.88(td, J＝13.2, 6.7Hz, 1H), 2.56(t, J＝3.2Hz, 2H), 2.33(qd, J＝13.2, 4.5Hz, 1H), 2.03–1.85(m ,5H), 1.56(p,J=7.0Hz,2H),1.36–1.25(m,10H).
实施例23：化合物23的合成Embodiment 23: the synthesis of compound 23
Figure PCTCN2022096512-appb-000129
Figure PCTCN2022096512-appb-000129
步骤1：中间体23b的制备Step 1: Preparation of intermediate 23b
向微波管中依次加入中间体11c(700mg)、中间体23a(456mg)、双乙腈氯化钯(112mg)、2-二环己基膦-2',4',6'-三异丙基联苯(207mg)、碳酸铯(1412mg)、碘化亚铜(41.3mg)和N,N-二甲基甲酰胺(5mL)，氮气鼓吹搅拌5分钟后，放入微波反应器中，在100W下加热至110℃反应90分钟，监控反应结束，微波管中的反应液转移到圆底瓶中，抽滤，滤液浓缩干，粗品以硅胶拌样，以硅胶柱层析纯化，得到中间体23b(242mg)。Intermediate 11c (700 mg), Intermediate 23a (456 mg), bisacetonitrile palladium chloride (112 mg), 2-dicyclohexylphosphine-2',4',6'-triisopropylbis Benzene (207mg), cesium carbonate (1412mg), cuprous iodide (41.3mg) and N,N-dimethylformamide (5mL), nitrogen blowing and stirring for 5 minutes, put into a microwave reactor, under 100W Heating to 110° C. for 90 minutes, monitoring the completion of the reaction, transferring the reaction solution in the microwave tube to a round bottom flask, suction filtration, and concentrating the filtrate to dryness. The crude product was mixed with silica gel as a sample and purified by silica gel column chromatography to obtain intermediate 23b ( 242 mg).
MS(ESI,[M+H] +)m/z：383.3。 MS (ESI, [M+H] + ) m/z: 383.3.
步骤2:中间体23c的制备Step 2: Preparation of intermediate 23c
向单口瓶中，依次加入中间体23b(240mg)、钯碳催化剂(100mg,0.940mmol)、氢氧化钯(100mg)及MeOH(20mL)，H 2保护下，将混合物室温反应2h。反应完全，抽滤，滤液通过减压蒸除溶剂，得中间体23c(0.17g)。 Intermediate 23b (240 mg), palladium carbon catalyst (100 mg, 0.940 mmol), palladium hydroxide (100 mg) and MeOH (20 mL) were sequentially added to a one-necked flask, and the mixture was reacted at room temperature for 2 h under the protection of H 2 . After the reaction was complete, it was filtered with suction, and the filtrate was evaporated to remove the solvent under reduced pressure to obtain intermediate 23c (0.17g).
MS(ESI,[M+H] +)m/z：387.3。 MS (ESI, [M+H] + ) m/z: 387.3.
步骤3：中间体23d的制备Step 3: Preparation of intermediate 23d
25℃下，向单口瓶中，先后加入中间体23c(170mg)、二氯甲烷(60mL)及戴斯马丁氧化剂(373mg)，常温搅拌5h，反应完全，反应液中加入水(50mL)、饱和亚硫酸氢钠水溶液(2mL)，分层，水相用二氯甲烷/甲醇＝10/1萃取(30mL×2)，有机层合并，无水硫酸钠干燥，抽滤，旋蒸干得中间体23d(408mg)。At 25°C, add intermediate 23c (170mg), dichloromethane (60mL) and Dess Martin oxidant (373mg) to the one-necked bottle successively, stir at room temperature for 5h, the reaction is complete, add water (50mL) to the reaction solution, saturate Sodium bisulfite aqueous solution (2mL), separate layers, extract the aqueous phase with dichloromethane/methanol=10/1 (30mL×2), combine the organic layers, dry over anhydrous sodium sulfate, filter with suction, and rotary evaporate to dryness to obtain the intermediate 23d (408 mg).
MS(ESI,[M+H] +)m/z：385.2。 MS (ESI, [M+H] + ) m/z: 385.2.
步骤4：化合物23的制备Step 4: Preparation of Compound 23
向单口瓶中依次加入中间体1j(377mg)、乙酸(32.5mg)、氰基硼氢化钠(51mg)、DCM(150mL)及异丙醇(10mL)，常温搅拌反应0.5h，加入中间体23d(400mg)，反应2h，反应完全，将反应液倒入纯化水(50mL)中，加入二氯甲烷/甲醇＝10/1溶液(150mL)，萃取分层，有机相用饱和氯化钠水溶液洗涤，用无水硫酸钠干燥，浓缩有机相得粗品，通过120g C 18反相柱纯化得化合物23(85mg)。 Add intermediate 1j (377mg), acetic acid (32.5mg), sodium cyanoborohydride (51mg), DCM (150mL) and isopropanol (10mL) to the one-necked bottle in turn, stir at room temperature for 0.5h, and add intermediate 23d (400mg), reacted for 2h, the reaction was complete, the reaction solution was poured into purified water (50mL), and dichloromethane/methanol=10/1 solution (150mL) was added, the layers were extracted, and the organic phase was washed with saturated aqueous sodium chloride solution , dried over anhydrous sodium sulfate, concentrated the organic phase to obtain a crude product, and purified it through a 120 g C 18 reverse phase column to obtain compound 23 (85 mg).
HR-MS(ESI,[M+1])m/z：875.39141。 1H NMR(500MHz,DMSO-d 6)δ11.23(s,1H),10.96(s,1H),8.41(d,J＝5.4Hz,1H),8.32(d,J＝1.9Hz,1H),7.98(t,J＝8.1Hz,2H),7.62(t,J＝7.5Hz,2H),7.42(s,1H),7.37–7.31(m,2H),7.25(d,J＝4.9Hz,1H),7.00(d,J＝5.0Hz,1H),5.98(s,2H),5.10(dd,J＝13.3,5.1Hz,1H),4.41(d,J＝17.1Hz,1H),4.29(d,J＝17.1Hz,1H),3.08–2.97(m,7H),2.69(t,J＝7.6Hz,2H),2.61(dd,J＝4.5,2.4Hz,1H),2.38(qd,J＝13.2,12.4,3.9Hz,3H),2.02–1.96(m,1H),1.86(t,J＝5.5Hz,4H),1.60(t,J＝7.4Hz,2H),1.30–1.22(m,14H). HR-MS (ESI, [M+1]) m/z: 875.39141. 1 H NMR (500MHz,DMSO-d 6 )δ11.23(s,1H),10.96(s,1H),8.41(d,J=5.4Hz,1H),8.32(d,J=1.9Hz,1H) ,7.98(t,J=8.1Hz,2H),7.62(t,J=7.5Hz,2H),7.42(s,1H),7.37–7.31(m,2H),7.25(d,J=4.9Hz, 1H), 7.00(d, J=5.0Hz, 1H), 5.98(s, 2H), 5.10(dd, J=13.3, 5.1Hz, 1H), 4.41(d, J=17.1Hz, 1H), 4.29( d,J=17.1Hz,1H),3.08–2.97(m,7H),2.69(t,J=7.6Hz,2H),2.61(dd,J=4.5,2.4Hz,1H),2.38(qd,J =13.2,12.4,3.9Hz,3H),2.02–1.96(m,1H),1.86(t,J=5.5Hz,4H),1.60(t,J=7.4Hz,2H),1.30–1.22(m, 14H).
实施例24 化合物24的合成The synthesis of embodiment 24 compound 24
Figure PCTCN2022096512-appb-000130
Figure PCTCN2022096512-appb-000130
步骤1：中间体24b的制备Step 1: Preparation of intermediate 24b
向反应瓶中，依次加入氢氧化钾(8.54g)及1,5-戊二醇(37.0g)，全部溶解后再加入中间体24a(10g)，N 2保护下，115℃加热16小时。反应完全，反应液旋蒸后残余物加水用DCM(200mL×3)萃取，有机层合并后用饱和食盐水(500mL×1)洗涤。萃取液抽滤浓缩得到中间体24b(8.77g)。 Potassium hydroxide (8.54g) and 1,5-pentanediol (37.0g) were sequentially added into the reaction flask, and intermediate 24a (10g) was added after all dissolved, and heated at 115°C for 16 hours under the protection of N 2 . After the reaction was completed, the residue was added with water and extracted with DCM (200 mL×3) after the reaction solution was rotary evaporated, and the organic layers were combined and washed with saturated brine (500 mL×1). The extract was concentrated by suction filtration to obtain intermediate 24b (8.77g).
步骤2：中间体24c的制备Step 2: Preparation of intermediate 24c
向反应瓶中，依次加入碘(15.12g)、三苯基膦(12.50g)、咪唑(3.24g)和THF(100mL)得到混合溶液，在N 2保护下，中间体24b(8.75g)的THF(50mL)溶液缓慢滴入上述混合溶液中，滴完室温搅拌2小时。反应完全，反应液中加入饱和亚硫酸钠溶液以淬灭反应，旋蒸后残余物加水，用EA(100mL×3)萃取，有机层合并后饱和食盐水(200mL×1)洗涤。萃取液抽滤浓缩后，残余物用硅胶柱纯化(PE-EA)得到中间体24c(7.84g)。 In the reaction flask, add iodine (15.12g), triphenylphosphine (12.50g), imidazole (3.24g) and THF (100mL) successively to obtain a mixed solution, under N 2 protection, the intermediate 24b (8.75g) The THF (50 mL) solution was slowly dropped into the above mixed solution, and stirred at room temperature for 2 hours after the drop was completed. After the reaction was complete, saturated sodium sulfite solution was added to the reaction solution to quench the reaction. After rotary evaporation, the residue was added with water, extracted with EA (100 mL×3), and the organic layers were combined and washed with saturated brine (200 mL×1). After the extract was concentrated by suction filtration, the residue was purified by silica gel column (PE-EA) to obtain intermediate 24c (7.84g).
1H NMR(500MHz,DMSO-d 6)δ4.55(t,J＝5.2Hz,1H),3.60(dq,J＝9.6,7.1Hz,2H),3.48(dq,J＝9.6,7.0Hz,2H),3.40(t,J＝6.4Hz,2H),3.34(d,J＝5.3Hz,2H),3.27(t,J＝6.9Hz,2H),1.76(p,J＝7.0Hz,2H),1.53–1.46(m,2H),1.41–1.35(m,2H),1.11(t,J＝7.0Hz,6H). 1 H NMR (500MHz, DMSO-d 6 ) δ4.55(t, J=5.2Hz, 1H), 3.60(dq, J=9.6, 7.1Hz, 2H), 3.48(dq, J=9.6, 7.0Hz, 2H), 3.40(t, J=6.4Hz, 2H), 3.34(d, J=5.3Hz, 2H), 3.27(t, J=6.9Hz, 2H), 1.76(p, J=7.0Hz, 2H) ,1.53–1.46(m,2H),1.41–1.35(m,2H),1.11(t,J＝7.0Hz,6H).
步骤3：中间体24d的制备Step 3: Preparation of Intermediate 24d
向反应瓶中，依次加入中间体1t(2.5g)、中间体24c(3.11g)、碳酸铯(7.09g)及DMF(25mL)，避光室温搅拌过夜。反应完全，反应液旋蒸后残余物加水，用EA(100mL×3)萃取，有机层合并后饱和食盐水(150mL×1)洗。萃取液抽滤浓缩旋蒸干得到中间体24d(4.93g)。Intermediate 1t (2.5 g), intermediate 24c (3.11 g), cesium carbonate (7.09 g) and DMF (25 mL) were sequentially added to the reaction flask, and stirred overnight at room temperature in the dark. After the reaction was complete, the residue was added with water after rotary evaporation of the reaction liquid, extracted with EA (100 mL×3), and the organic layers were combined and washed with saturated brine (150 mL×1). The extract was concentrated by suction filtration and evaporated to dryness to obtain intermediate 24d (4.93g).
MS(ESI,[M+Na] +)m/z：559.4。 1H NMR(500MHz,DMSO-d 6)δ7.58(d,J＝8.4Hz,1H),7.53(s,1H),7.17–7.12(m,2H),7.01(dd,J＝8.4,2.3Hz,1H),4.73–4.66(m,1H),4.57–4.52(m,2H),4.38(d,J＝17.4Hz,1H),4.06–4.03(m,2H),3.61–3.57(m,2H),3.49–3.45(m,2H),3.43(t,J＝6.4Hz,2H),3.35(d,J＝5.3Hz,2H),2.16–2.12(m,2H),2.02–1.93(m,2H),1.60–1.41(m,6H),1.33(s,9H),1.11(td,J＝7.1,3.8Hz,6H). MS (ESI, [M+Na] + ) m/z: 559.4. 1 H NMR (500MHz, DMSO-d 6 )δ7.58(d, J=8.4Hz, 1H), 7.53(s, 1H), 7.17–7.12(m, 2H), 7.01(dd, J=8.4, 2.3 Hz,1H),4.73–4.66(m,1H),4.57–4.52(m,2H),4.38(d,J＝17.4Hz,1H),4.06–4.03(m,2H),3.61–3.57(m, 2H), 3.49–3.45(m, 2H), 3.43(t, J＝6.4Hz, 2H), 3.35(d, J＝5.3Hz, 2H), 2.16–2.12(m, 2H), 2.02–1.93(m ,2H),1.60–1.41(m,6H),1.33(s,9H),1.11(td,J＝7.1,3.8Hz,6H).
步骤4：中间体24e的制备Step 4: Preparation of Intermediate 24e
向反应瓶中，依次加入中间体24d(4.90g)、THF(100mL)，搅拌溶清后加入0.5M稀盐酸(41.4mL,20.68mmol)，N 2保护下，50℃加热4小时。反应完全，反应液旋蒸后残余物加水，用EA(100mL×3)萃取，有机层合并后饱和食盐水(150mL×1)洗。萃取液抽滤浓缩后，残余物用硅胶柱纯化(DCM-MeOH)得到目标物24e(1.17g)。 Intermediate 24d (4.90g) and THF (100mL) were sequentially added to the reaction flask, stirred to dissolve and then added with 0.5M dilute hydrochloric acid (41.4mL, 20.68mmol), and heated at 50°C for 4 hours under the protection of N 2 . After the reaction was complete, the residue was added with water after rotary evaporation of the reaction liquid, extracted with EA (100 mL×3), and the organic layers were combined and washed with saturated brine (150 mL×1). After the extract was concentrated by suction filtration, the residue was purified by silica gel column (DCM-MeOH) to obtain the target compound 24e (1.17g).
MS(ESI,[M+H] +)m/z：463.2。 MS (ESI, [M+H] + ) m/z: 463.2.
步骤5：中间体24f的制备Step 5: Preparation of Intermediate 24f
向反应瓶中，依次加入中间体1j(550mg)、中间体24e(580mg)及MeOH(20mL)，搅拌下加入氰基硼氢化钠(106mg)和冰乙酸(5.08mg,4.84μl)，N 2保护下，室温搅拌2小时。反应完全，反应液加少量水淬灭后直接旋蒸干，残余物用硅胶柱纯化(DCM-MeOH)得到中间体24f(581mg)。 Into the reaction flask, add Intermediate 1j (550mg), Intermediate 24e (580mg) and MeOH (20mL) sequentially, add sodium cyanoborohydride (106mg) and glacial acetic acid (5.08mg, 4.84μl) under stirring, N 2 Under protection, stir at room temperature for 2 hours. After the reaction was complete, the reaction solution was quenched by adding a small amount of water and then directly evaporated to dryness. The residue was purified by silica gel column (DCM-MeOH) to obtain intermediate 24f (581 mg).
MS(ESI,[M+H] +)m/z：953.5。 MS (ESI, [M+H] + ) m/z: 953.5.
步骤6：中间体24的制备Step 6: Preparation of Intermediate 24
向微波管中依次加入中间体24f(570mg)、乙腈(15mL)和无水苯磺酸(451mg)，微波110℃加热1.5小时。反应完全，反应液旋蒸后残余物用C 18反相柱层析纯化(10nM乙酸铵水溶液-乙腈)得到粗品。粗品采用制备柱纯化得目标物24(82mg)。 Intermediate 24f (570 mg), acetonitrile (15 mL) and anhydrous benzenesulfonic acid (451 mg) were sequentially added to a microwave tube, and heated at 110° C. for 1.5 hours by microwave. After the reaction was complete, the residue was purified by C 18 reverse phase column chromatography (10 nM ammonium acetate aqueous solution-acetonitrile) after rotary evaporation of the reaction solution to obtain a crude product. The crude product was purified by a preparative column to obtain the target compound 24 (82 mg).
MS(ESI,[M+H] +)m/z：879.5。 1H NMR(500MHz,DMSO-d 6)δ11.28(s,1H),11.02(s,1H),8.47(d,J＝5.4Hz,1H),8.38(d,J＝1.9Hz,1H),8.04(t,J＝8.5Hz,2H),7.67(t,J＝8.6Hz,2H),7.40(dd,J＝5.4,1.9Hz,1H),7.29(d,J＝5.0Hz,1H),7.24–7.17(m,1H),7.15–7.01(m,2H),6.24–5.85(m,2H),5.12(dd,J＝13.3,5.1Hz,1H),4.42(d,J＝17.1Hz,1H),4.31(d,J＝17.1Hz,1H),4.11(t,J＝6.5Hz,2H),3.41(dt,J＝18.0,6.0Hz,4H),3.23(s,2H),3.09(d,J＝5.0Hz,4H),2.95(ddd,J＝18.2,13.6,5.5Hz,1H),2.68–2.59(m,3H),2.41(qd,J＝13.2,4.5Hz,1H),2.06–1.99(m,1H),1.90(t,J＝5.3Hz,4H),1.81(p,J＝6.8Hz,2H),1.61(p,J＝6.8Hz,2H),1.52(tt,J＝9.4,5.9Hz,2H),1.46–1.27(m,2H). MS (ESI, [M+H] + ) m/z: 879.5. 1 H NMR (500MHz,DMSO-d 6 )δ11.28(s,1H),11.02(s,1H),8.47(d,J=5.4Hz,1H),8.38(d,J=1.9Hz,1H) ,8.04(t,J=8.5Hz,2H),7.67(t,J=8.6Hz,2H),7.40(dd,J=5.4,1.9Hz,1H),7.29(d,J=5.0Hz,1H) ,7.24–7.17(m,1H),7.15–7.01(m,2H),6.24–5.85(m,2H),5.12(dd,J＝13.3,5.1Hz,1H),4.42(d,J＝17.1Hz ,1H),4.31(d,J=17.1Hz,1H),4.11(t,J=6.5Hz,2H),3.41(dt,J=18.0,6.0Hz,4H),3.23(s,2H),3.09 (d,J=5.0Hz,4H),2.95(ddd,J=18.2,13.6,5.5Hz,1H),2.68–2.59(m,3H),2.41(qd,J=13.2,4.5Hz,1H), 2.06–1.99(m,1H),1.90(t,J=5.3Hz,4H),1.81(p,J=6.8Hz,2H),1.61(p,J=6.8Hz,2H),1.52(tt,J ＝9.4,5.9Hz,2H),1.46–1.27(m,2H).
实施例25 化合物25的合成The synthesis of embodiment 25 compound 25
Figure PCTCN2022096512-appb-000131
Figure PCTCN2022096512-appb-000131
步骤1：中间体25b的制备Step 1: Preparation of intermediate 25b
室温下，将PCC(10.13g)加入到4-氯-1-丁醇(4g)的DCM(80mL)搅拌液中，室温反应0.5h。反应结束，往反应液中加入乙醚80mL，搅拌2min后，硅藻土和中性氧化铝过滤，滤饼用乙醚洗两遍，收集滤液，浓缩，得4.270g中间体25b。At room temperature, PCC (10.13 g) was added into a stirred solution of 4-chloro-1-butanol (4 g) in DCM (80 mL), and reacted at room temperature for 0.5 h. After the reaction was completed, 80 mL of diethyl ether was added to the reaction liquid, and after stirring for 2 min, the mixture was filtered through diatomaceous earth and neutral alumina. The filter cake was washed twice with diethyl ether, and the filtrate was collected and concentrated to obtain 4.270 g of intermediate 25b.
1H NMR(500MHz,DMSO-d 6)δ9.68(s,1H),3.65(t,J＝6.6Hz,2H),2.59(td,J＝7.2,1.3Hz,2H),1.97(p,J＝6.9Hz,2H). 1 H NMR (500MHz, DMSO-d 6 ) δ9.68(s, 1H), 3.65(t, J=6.6Hz, 2H), 2.59(td, J=7.2, 1.3Hz, 2H), 1.97(p, J＝6.9Hz, 2H).
步骤2：中间体25c的制备Step 2: Preparation of intermediate 25c
向单口瓶中，依次加入中间体25b(1.198g)、中间体15d(1.5g)、醋酸(0.270g)及甲醇(30mL)，加入氰基硼氢化钠(1.131g)，N 2保护下，室温搅拌反应过夜。反应结束后，反应液中加入饱和碳酸氢钠溶液(30mL)、饱和氯化钠溶液(30mL)，EA萃取(70mL×2)，合并有机相，饱和食盐水洗一次，无水硫酸钠干燥，过滤，浓缩，硅胶柱层析，得1.876g中间体25c。 In the single-necked bottle, add intermediate 25b (1.198g), intermediate 15d (1.5g), acetic acid (0.270g) and methanol (30mL) successively, add sodium cyanoborohydride (1.131g), under N 2 protection, The reaction was stirred overnight at room temperature. After the reaction, add saturated sodium bicarbonate solution (30mL) and saturated sodium chloride solution (30mL) to the reaction solution, extract with EA (70mL×2), combine the organic phases, wash once with saturated brine, dry over anhydrous sodium sulfate, and filter , concentrated, and subjected to silica gel column chromatography to obtain 1.876 g of intermediate 25c.
MS(ESI,[M+H] +)m/z：424.3。 1H NMR(500MHz,DMSO-d 6)δ7.47–7.43(m,1H),7.10(s,1H),6.66–6.63(m,1H),6.63–6.58(m,1H),5.99(s,2H),4.70–4.62(m,1H),4.52–4.40(m,1H),4.34–4.24(m,1H),3.72–3.61(m,2H),2.18–2.06(m,3H),1.99–1.94(m,3H),1.89–1.78(m,3H),1.34(s,9H). MS (ESI, [M+H] + ) m/z: 424.3. 1 H NMR (500MHz,DMSO-d 6 )δ7.47–7.43(m,1H),7.10(s,1H),6.66–6.63(m,1H),6.63–6.58(m,1H),5.99(s ,2H),4.70–4.62(m,1H),4.52–4.40(m,1H),4.34–4.24(m,1H),3.72–3.61(m,2H),2.18–2.06(m,3H),1.99 –1.94(m,3H),1.89–1.78(m,3H),1.34(s,9H).
步骤3：中间体25d的制备Step 3: Preparation of intermediate 25d
0℃、氮气保护下，将氯甲酸苄酯(0.56g)缓慢滴入到中间体25c(1.2g)和碳酸钠(0.60g)的四氢呋喃(80mL)搅拌液中，5分钟后滴加完毕，混合物在常温下搅拌反应16h。反应完全，反应液倒入到乙酸乙酯100mL和水100mL的混合溶液中，搅拌分层，有机相用饱和食盐水100mL洗涤，浓缩，过柱得中间体25d(1.60g)。0°C, under the protection of nitrogen, slowly drop benzyl chloroformate (0.56g) into the stirring solution of intermediate 25c (1.2g) and sodium carbonate (0.60g) in tetrahydrofuran (80mL), and the dropwise addition was completed after 5 minutes. The mixture was stirred and reacted at room temperature for 16h. After the reaction was complete, the reaction liquid was poured into a mixed solution of 100 mL of ethyl acetate and 100 mL of water, stirred and separated, and the organic phase was washed with 100 mL of saturated brine, concentrated, and passed through a column to obtain intermediate 25d (1.60 g).
MS(ESI,[M+H] +)m/z：558.4。 1H NMR(500MHz,DMSO-d 6)δ7.69(d,J＝8.1Hz,1H),7.59–7.53(m,2H),7.50–7.36(m,2H),7.37–7.27(m,4H),7.18(s,1H),5.11(s,2H),4.76–4.69(m,1H),4.59(d,J＝17.6Hz,1H),4.45(d,J＝17.5Hz,1H),3.74(t,J＝7.2Hz,2H),3.60(t,J＝6.5Hz,2H),2.20–2.14(m,3H),2.03–1.94(m,3H),1.74–1.67(m,2H),1.30(s,9H). MS (ESI, [M+H] + ) m/z: 558.4. 1 H NMR (500MHz, DMSO-d 6 ) δ7.69 (d, J=8.1Hz, 1H), 7.59–7.53 (m, 2H), 7.50–7.36 (m, 2H), 7.37–7.27 (m, 4H ),7.18(s,1H),5.11(s,2H),4.76–4.69(m,1H),4.59(d,J=17.6Hz,1H),4.45(d,J=17.5Hz,1H),3.74 (t,J=7.2Hz,2H),3.60(t,J=6.5Hz,2H),2.20–2.14(m,3H),2.03–1.94(m,3H),1.74–1.67(m,2H), 1.30(s,9H).
步骤4：中间体25e的制备Step 4: Preparation of Intermediate 25e
向单口瓶中，依次加入中间体25d(1.6g)、碘化钠(12.89g)、丙酮(50mL)，氮气保护下，将混合物加热至70℃反应16h。反应完全，将反应液倒入水200mL中，加入乙酸乙酯溶液100mL，萃取分层，有机相用饱和食盐水100mL洗涤，减压蒸除溶剂，得中间体25e(1.93g)。Intermediate 25d (1.6 g), sodium iodide (12.89 g), and acetone (50 mL) were sequentially added to a one-necked flask, and the mixture was heated to 70° C. for 16 h under nitrogen protection. After the reaction was complete, the reaction solution was poured into 200 mL of water, 100 mL of ethyl acetate was added, the layers were extracted, the organic phase was washed with 100 mL of saturated brine, and the solvent was evaporated under reduced pressure to obtain intermediate 25e (1.93 g).
MS(ESI,[M+H] +)m/z：650.3。 1H NMR(500MHz,DMSO-d 6)δ7.69(d,J＝8.1Hz,1H),7.59–7.53(m,2H),7.42–7.26(m,6H),7.18(s,1H),5.11(s,2H),4.75–4.69(m,1H),4.59(d,J＝17.5Hz,1H),4.44(d,J＝ 17.6Hz,1H),3.74(t,J＝7.2Hz,2H),3.24(t,J＝6.8Hz,2H),2.21–2.11(m,3H),1.75(p,J＝7.0Hz,2H),1.60–1.50(m,2H),1.31(s,9H),1.18(t,J＝7.1Hz,1H). MS (ESI, [M+H] + ) m/z: 650.3. 1 H NMR (500MHz, DMSO-d 6 )δ7.69 (d, J=8.1Hz, 1H), 7.59–7.53 (m, 2H), 7.42–7.26 (m, 6H), 7.18 (s, 1H), 5.11(s, 2H), 4.75–4.69(m, 1H), 4.59(d, J=17.5Hz, 1H), 4.44(d, J=17.6Hz, 1H), 3.74(t, J=7.2Hz, 2H ),3.24(t,J=6.8Hz,2H),2.21–2.11(m,3H),1.75(p,J=7.0Hz,2H),1.60–1.50(m,2H),1.31(s,9H) ,1.18(t,J=7.1Hz,1H).
步骤5：中间体25f的制备Step 5: Preparation of intermediate 25f
向单口瓶中，依次加入中间体1j(1.93g)、中间体25e(1.907g)、DMF(30mL)及碳酸钾(1.232g)，将混合物加热至50℃反应。反应完全，将反应液倒入水(200mL)中，加入乙酸乙酯溶液(200mL)，萃取分层，有机相用饱和食盐水(100mL)洗涤，减压蒸除溶剂，粗品过硅胶柱纯化得中间体25f(1.8049g)。Intermediate 1j (1.93g), Intermediate 25e (1.907g), DMF (30mL) and potassium carbonate (1.232g) were sequentially added to a one-necked flask, and the mixture was heated to 50°C for reaction. After the reaction is complete, pour the reaction solution into water (200 mL), add ethyl acetate solution (200 mL), extract and separate layers, wash the organic phase with saturated brine (100 mL), evaporate the solvent under reduced pressure, and purify the crude product through a silica gel column to obtain Intermediate 25f (1.8049g).
MS(ESI,[M+H] +)m/z：1028.6。 1H NMR(500MHz,DMSO-d 6)δ11.23(s,1H),8.42(d,J＝5.4Hz,1H),8.32(d,J＝1.9Hz,1H),8.02–7.95(m,2H),7.69(d,J＝8.1Hz,1H),7.62(t,J＝7.9Hz,1H),7.59–7.53(m,2H),7.42–7.23(m,9H),7.19(s,1H),7.00(d,J＝5.0Hz,1H),5.98(s,2H),5.11(s,2H),4.76–4.69(m,1H),4.60(d,J＝17.7Hz,1H),4.45(d,J＝17.7Hz,1H),3.71(t,J＝7.2Hz,2H),3.17(d,J＝4.7Hz,1H),3.06–3.00(m,4H),2.91(s,1H),2.35(s,1H),2.26–2.10(m,4H),1.99(q,J＝7.9,6.6Hz,1H),1.82(t,J＝5.3Hz,4H),1.46(h,J＝6.9Hz,2H),1.30(s,9H). MS (ESI, [M+H] + ) m/z: 1028.6. 1 H NMR (500MHz, DMSO-d 6 )δ11.23(s, 1H), 8.42(d, J=5.4Hz, 1H), 8.32(d, J=1.9Hz, 1H), 8.02–7.95(m, 2H), 7.69(d, J=8.1Hz, 1H), 7.62(t, J=7.9Hz, 1H), 7.59–7.53(m, 2H), 7.42–7.23(m, 9H), 7.19(s, 1H ),7.00(d,J=5.0Hz,1H),5.98(s,2H),5.11(s,2H),4.76–4.69(m,1H),4.60(d,J=17.7Hz,1H),4.45 (d, J=17.7Hz, 1H), 3.71(t, J=7.2Hz, 2H), 3.17(d, J=4.7Hz, 1H), 3.06–3.00(m, 4H), 2.91(s, 1H) ,2.35(s,1H),2.26–2.10(m,4H),1.99(q,J=7.9,6.6Hz,1H),1.82(t,J=5.3Hz,4H),1.46(h,J=6.9 Hz,2H),1.30(s,9H).
步骤6：中间体25g的制备Step 6: Preparation of Intermediate 25g
向微波管中依次加入中间体25f(350mg)、乙腈(30mL)和无水苯磺酸(269mg)，搅拌1分钟后，放入微波反应器中，在200W下加热至100℃反应2h。反应完全，将微波管中反应液倒入(150mL)水中，向残留物中加入二氯甲烷(200mL)。有机相分离，用饱和食盐水(100mL)洗涤后无水硫酸钠干燥，过滤，得中间体25g(400mg)。Intermediate 25f (350mg), acetonitrile (30mL) and anhydrous benzenesulfonic acid (269mg) were sequentially added to the microwave tube, stirred for 1 minute, put into a microwave reactor, and heated to 100°C at 200W for 2h. After the reaction was complete, the reaction solution in the microwave tube was poured into water (150 mL), and dichloromethane (200 mL) was added to the residue. The organic phase was separated, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and filtered to obtain 25 g (400 mg) of the intermediate.
MS(ESI,[M+H] +)m/z：954.5。 MS (ESI, [M+H] + ) m/z: 954.5.
步骤7：化合物25的制备Step 7: Preparation of compound 25
向单口瓶中，依次加中间体25g(350mg)、33％溴化氢溶液(5.4mL,0.37mmol)及乙酸(7mL)，氮气保护下，常温反应15分钟，反应完全，将反应液倒入水(200mL)中，用二氯甲烷/乙腈＝2/1溶液(100mL)洗涤水相，水相中加入二氯甲烷/乙腈＝2/1溶液(200mL)，碳酸氢钠调节pH＝7.5，有机相分离，用饱和食盐水(100mL)洗涤后用无水硫酸钠干燥，过滤，滤液浓缩，粗品用120g C 18反相柱纯化得到化合物25(45mg)。 Add 25g (350mg) of the intermediate, 33% hydrogen bromide solution (5.4mL, 0.37mmol) and acetic acid (7mL) to the single-necked bottle successively, and react at room temperature for 15 minutes under nitrogen protection. After the reaction is complete, pour the reaction solution into In water (200mL), wash the aqueous phase with dichloromethane/acetonitrile=2/1 solution (100mL), add dichloromethane/acetonitrile=2/1 solution (200mL) to the aqueous phase, adjust pH=7.5 with sodium bicarbonate, The organic phase was separated, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated, and the crude product was purified by 120 g C 18 reverse phase column to obtain compound 25 (45 mg).
MS(ESI,[M+H] +)m/z：820.5。 1H NMR(500MHz,DMSO-d 6)δ11.23(s,1H),10.91(s,1H),8.42(d,J＝5.4Hz,1H),8.32(d,J＝1.9Hz,1H),7.98(t,J＝8.1Hz,2H),7.62(t,J＝7.8Hz,1H),7.38(d,J＝8.3Hz,1H),7.35(dd,J＝5.4,1.9Hz,1H),7.25(d,J＝5.0Hz,1H),7.00(d,J＝5.0Hz,1H),6.69–6.64(m,1H),6.63(s,1H),6.37(t,J＝5.4Hz,1H),5.99(s,2H),5.01(dd,J＝13.3,5.1Hz,1H),4.26(d,J＝16.6Hz,1H),4.14(d,J＝16.6Hz,1H),3.07(dt,J＝11.8,6.0Hz,8H),2.89(ddd,J＝18.1,13.5,5.4Hz,1H),2.57(dt,J＝17.4,3.8Hz,2H),2.33(qd,J＝13.2,4.5Hz,1H),2.07(s,1H),1.97–1.84(m,5H),1.58(p,J＝7.1Hz,2H),1.46–1.32(m,3H),1.28(d,J＝6.3Hz,1H). MS (ESI, [M+H] + ) m/z: 820.5. 1 H NMR (500MHz,DMSO-d 6 )δ11.23(s,1H),10.91(s,1H),8.42(d,J=5.4Hz,1H),8.32(d,J=1.9Hz,1H) ,7.98(t,J=8.1Hz,2H),7.62(t,J=7.8Hz,1H),7.38(d,J=8.3Hz,1H),7.35(dd,J=5.4,1.9Hz,1H) ,7.25(d,J=5.0Hz,1H),7.00(d,J=5.0Hz,1H),6.69–6.64(m,1H),6.63(s,1H),6.37(t,J=5.4Hz, 1H), 5.99(s, 2H), 5.01(dd, J=13.3, 5.1Hz, 1H), 4.26(d, J=16.6Hz, 1H), 4.14(d, J=16.6Hz, 1H), 3.07( dt,J=11.8,6.0Hz,8H),2.89(ddd,J=18.1,13.5,5.4Hz,1H),2.57(dt,J=17.4,3.8Hz,2H),2.33(qd,J=13.2, 4.5Hz, 1H), 2.07(s, 1H), 1.97–1.84(m, 5H), 1.58(p, J=7.1Hz, 2H), 1.46–1.32(m, 3H), 1.28(d, J=6.3 Hz,1H).
实施例26 化合物26的合成The synthesis of embodiment 26 compound 26
Figure PCTCN2022096512-appb-000132
Figure PCTCN2022096512-appb-000132
步骤1：中间体26b的制备Step 1: Preparation of intermediate 26b
向反应瓶中，依次加入中间体13b(5.0g)、(S)-吡咯烷-3-甲醇(2.014g)、NMP(30mL)及N,N-二异丙基乙胺(7.02g)，N 2保护下，将混合物加热至80℃反应10小时，反应完全，反应液旋蒸后残余物用EA(50mL×2)萃取，有机层合并后饱和食盐水(100mL×1)洗涤，萃取液干燥过滤，滤液旋蒸后残余物用硅胶柱纯化(DCM-MeOH)得到中间体26b(3.60g)。 Into the reaction flask, sequentially add intermediate 13b (5.0g), (S)-pyrrolidine-3-methanol (2.014g), NMP (30mL) and N,N-diisopropylethylamine (7.02g), Under the protection of N 2 , the mixture was heated to 80°C for 10 hours, and the reaction was complete. After the reaction solution was rotary evaporated, the residue was extracted with EA (50mL×2). After the organic layers were combined, they were washed with saturated brine (100mL×1). After drying and filtering, the filtrate was rotary evaporated and the residue was purified by silica gel column (DCM-MeOH) to obtain intermediate 26b (3.60 g).
MS(ESI,[M+H] +)m/z：358.1。 1H NMR(500MHz,DMSO-d 6)δ11.06(s,1H),7.63(d,J＝8.5Hz,1H),6.88(d,J＝2.2Hz,1H),6.80(dd,J＝8.5,2.3Hz,1H),5.05(dd,J＝12.9,5.4Hz,1H),4.75(t,J＝5.2Hz,1H),3.53–3.37(m,2H),3.30(d,J＝7.1Hz,1H),3.22–3.18(m,1H),2.88(ddd,J＝17.0,13.9,5.3Hz,1H),2.70(s,2H),2.62–2.52(m,1H),2.18(t,J＝8.1Hz,1H),2.10–1.98(m,2H),1.94–1.86(m,1H),1.84–1.76(m,1H).步骤2：中间体26c的制备 MS (ESI, [M+H] + ) m/z: 358.1. 1 H NMR (500MHz, DMSO-d 6 ) δ11.06(s, 1H), 7.63(d, J=8.5Hz, 1H), 6.88(d, J=2.2Hz, 1H), 6.80(dd, J= 8.5,2.3Hz,1H),5.05(dd,J=12.9,5.4Hz,1H),4.75(t,J=5.2Hz,1H),3.53–3.37(m,2H),3.30(d,J=7.1 Hz,1H),3.22–3.18(m,1H),2.88(ddd,J＝17.0,13.9,5.3Hz,1H),2.70(s,2H),2.62–2.52(m,1H),2.18(t, J=8.1Hz,1H), 2.10–1.98(m,2H), 1.94–1.86(m,1H), 1.84–1.76(m,1H). Step 2: Preparation of intermediate 26c
向反应瓶中，依次加入中间体26b(1.9g)、DCM(100mL)及dess-martin氧化剂(4.49g)，N 2保护下，室温搅拌1.5小时，反应完全，反应液用水(50mL×2)洗涤，有机层再用饱和食盐水(100mL×1)洗涤，萃取液干燥过滤，滤液旋蒸干得到中间体26c(3.67g)。 Into the reaction flask, add intermediate 26b (1.9g), DCM (100mL) and dess-martin oxidant (4.49g) successively, under the protection of N 2 , stir at room temperature for 1.5 hours, the reaction is complete, and the reaction solution is watered (50mL×2) After washing, the organic layer was washed with saturated brine (100 mL×1), the extract was dried and filtered, and the filtrate was rotary evaporated to dryness to obtain intermediate 26c (3.67 g).
步骤3：中间体26的制备Step 3: Preparation of Intermediate 26
向反应瓶中，依次加入中间体26c(629mg)、中间体1j(690mg)及MeOH(30mL)，搅拌下加入氰基硼氢化钠(200mg)和冰乙酸(63.8mg)，N 2保护下，室温搅拌3小时，反应完全，反应液旋蒸后残余物用硅胶柱纯化(DCM-MeOH)得到粗品。粗品再用C 18反相柱纯化(10nM乙酸铵水溶液-乙腈)得到目标物26(290mg)。 Into the reaction flask, add intermediate 26c (629mg), intermediate 1j (690mg) and MeOH (30mL) sequentially, add sodium cyanoborohydride (200mg) and glacial acetic acid (63.8mg) under stirring, under N2 protection, After stirring at room temperature for 3 hours, the reaction was complete, and the residue was purified by silica gel column (DCM-MeOH) after rotary evaporation of the reaction solution to obtain a crude product. The crude product was purified by a C 18 reverse phase column (10 nM aqueous ammonium acetate-acetonitrile) to obtain the target compound 26 (290 mg).
MS(ESI,[M+H] +)m/z：846.4。 1H NMR(500MHz,DMSO-d 6)δ11.23(s,1H),11.06(s,1H),8.41(d,J＝5.4Hz,1H),8.32(s,1H),7.98(t,J＝8.0Hz,2H),7.63(dt,J＝8.1,3.7Hz,2H),7.35(d,J＝6.1Hz,1H),7.26(d,J＝4.9Hz,1H),7.01(d,J＝4.9Hz,1H),6.89(s,1H),6.80(dd,J＝8.5,2.2Hz,1H),5.99(s,2H),5.05(dd,J＝12.9,5.4Hz,1H),3.57–3.43(m,2H),3.38(t,J＝8.6Hz,2H),3.14–3.03(m,8H),2.88(ddd,J＝18.0,14.1,5.4Hz,1H),2.63–2.52(m,3H),2.33(dq,J＝14.0,6.9Hz,1H),2.11(h,J＝5.7Hz,1H),2.05–1.97(m,1H),1.89(q,J＝6.4,5.5Hz,4H),1.78–1.67(m,1H). MS (ESI, [M+H] + ) m/z: 846.4. 1 H NMR (500MHz, DMSO-d 6 )δ11.23(s,1H),11.06(s,1H),8.41(d,J=5.4Hz,1H),8.32(s,1H),7.98(t, J＝8.0Hz, 2H), 7.63(dt, J＝8.1, 3.7Hz, 2H), 7.35(d, J＝6.1Hz, 1H), 7.26(d, J＝4.9Hz, 1H), 7.01(d, J=4.9Hz,1H),6.89(s,1H),6.80(dd,J=8.5,2.2Hz,1H),5.99(s,2H),5.05(dd,J=12.9,5.4Hz,1H), 3.57–3.43(m,2H),3.38(t,J=8.6Hz,2H),3.14–3.03(m,8H),2.88(ddd,J=18.0,14.1,5.4Hz,1H),2.63–2.52( m, 3H), 2.33(dq, J=14.0, 6.9Hz, 1H), 2.11(h, J=5.7Hz, 1H), 2.05–1.97(m, 1H), 1.89(q, J=6.4, 5.5Hz ,4H),1.78–1.67(m,1H).
实施例27 化合物27的合成The synthesis of embodiment 27 compound 27
Figure PCTCN2022096512-appb-000133
Figure PCTCN2022096512-appb-000133
步骤1：中间体27b的制备Step 1: Preparation of intermediate 27b
向反应瓶中，依次加入中间体13b(1.0g)、(R)-吡咯烷-3-甲醇(0.403g)、NMP(10mL)及N,N-二异丙基乙胺(1.404g)，N 2保护下，80℃加热10小时，反应完全，反应液旋蒸后残余物用EA(50mL×2)萃取，有机层合并后饱和食盐水(50mL×1)洗涤，萃取液干燥过滤，滤液旋蒸后残余物用硅胶柱纯化(DCM-MeOH)得到中间体27b(744mg)。 Into the reaction flask, sequentially add intermediate 13b (1.0g), (R)-pyrrolidine-3-methanol (0.403g), NMP (10mL) and N,N-diisopropylethylamine (1.404g), Under the protection of N 2 , heated at 80°C for 10 hours, and the reaction was complete. After the reaction solution was rotary evaporated, the residue was extracted with EA (50mL×2). After the organic layers were combined, they were washed with saturated brine (50mL×1). The extract was dried and filtered. After rotary evaporation, the residue was purified by silica gel column (DCM-MeOH) to obtain intermediate 27b (744mg).
MS(ESI,[M+H] +)m/z：358.1。 1H NMR(500MHz,DMSO-d 6)δ11.06(s,1H),7.63(d,J＝8.5Hz,1H),6.88(d,J＝2.2Hz,1H),6.80(dd,J＝8.5,2.3Hz,1H),5.05(dd,J＝12.9,5.4Hz,1H),4.75(t,J＝5.3Hz,1H),3.53–3.38(m,4H),3.22–3.16(m,1H),2.88(ddd,J＝17.2,14.0,5.4Hz,1H),2.62–2.44(m,3H),2.21–1.76(m,4H). MS (ESI, [M+H] + ) m/z: 358.1. 1 H NMR (500MHz, DMSO-d 6 ) δ11.06(s, 1H), 7.63(d, J=8.5Hz, 1H), 6.88(d, J=2.2Hz, 1H), 6.80(dd, J= 8.5,2.3Hz,1H),5.05(dd,J＝12.9,5.4Hz,1H),4.75(t,J＝5.3Hz,1H),3.53–3.38(m,4H),3.22–3.16(m,1H ),2.88(ddd,J＝17.2,14.0,5.4Hz,1H),2.62–2.44(m,3H),2.21–1.76(m,4H).
步骤2：中间体27c的制备Step 2: Preparation of intermediate 27c
向反应瓶中，依次加入中间体27b(0.72g)、DCM(30mL)及戴斯马丁氧化剂(1.691g)，N 2保护下，室温搅拌1.5小时，反应完全，反应液用水(50mL×2)洗涤，有机层再用饱和食盐水(100mL×1)洗涤，萃取液干燥过滤，滤液旋蒸干得到中间体27c(1.405g)。 Into the reaction bottle, add intermediate 27b (0.72g), DCM (30mL) and Dess Martin oxidant (1.691g) in turn, under N2 protection, stir at room temperature for 1.5 hours, the reaction is complete, the reaction solution is water (50mL×2) After washing, the organic layer was washed with saturated brine (100 mL×1), the extract was dried and filtered, and the filtrate was rotary evaporated to dryness to obtain intermediate 27c (1.405 g).
步骤3：化合物27的制备Step 3: Preparation of compound 27
向反应瓶中，依次加入中间体27c(706m)、中间体1j(775mg)及MeOH(30mL)，搅拌下加入氰基硼氢化钠(225mgl)和冰乙酸(71.6mg)，N 2保护下，室温搅拌3小时，反应完全，反应液旋蒸后残余物用硅胶柱纯化(DCM-MeOH)得到粗品。粗品用C 18反相柱纯化(10nM乙酸铵水溶液-乙腈)得到化合物27(170mg)。 Into the reaction flask, add intermediate 27c (706m), intermediate 1j (775mg) and MeOH (30mL) successively, add sodium cyanoborohydride (225mgl) and glacial acetic acid (71.6mg) under stirring, under N2 protection, After stirring at room temperature for 3 hours, the reaction was complete, and the residue was purified by silica gel column (DCM-MeOH) after rotary evaporation of the reaction solution to obtain a crude product. The crude product was purified by C 18 reverse phase column (10 nM aqueous ammonium acetate-acetonitrile) to obtain compound 27 (170 mg).
MS(ESI,[M+H] +)m/z：846.4。 1H NMR(500MHz,DMSO-d 6)δ11.23(s,1H),11.06(s,1H),8.41(d,J＝5.3Hz,1H),8.32(d,J＝1.9Hz,1H),8.02–7.95(m,2H),7.62(dd,J＝8.5,6.3Hz,2H),7.35(dd,J＝5.4,1.9Hz,1H),7.26(d,J＝4.9Hz,1H),7.01(d,J＝5.0Hz,1H),6.89(d,J＝2.1Hz,1H),6.80(dd,J＝8.5,2.2Hz,1H),5.99(s,2H),5.05(dd,J＝12.9,5.4Hz,1H),3.53(dd,J＝10.3,7.3Hz,1H),3.50–3.44(m,1H),3.42–3.33(m,4H),3.09(dt,J＝19.9,6.6Hz,8H),2.88(ddd,J＝17.3,14.0,5.5Hz,1H),2.63–2.51(m,2H),2.35(p,J＝7.6Hz,1H),2.12(td,J＝9.9,7.9,4.4Hz,1H),2.06–1.97(m,1H),1.90(q,J＝5.5,5.1Hz,4H),1.73(dq,J＝11.9,8.1Hz,1H). MS (ESI, [M+H] + ) m/z: 846.4. 1 H NMR (500MHz,DMSO-d 6 )δ11.23(s,1H),11.06(s,1H),8.41(d,J=5.3Hz,1H),8.32(d,J=1.9Hz,1H) ,8.02–7.95(m,2H),7.62(dd,J＝8.5,6.3Hz,2H),7.35(dd,J＝5.4,1.9Hz,1H),7.26(d,J＝4.9Hz,1H), 7.01(d,J=5.0Hz,1H),6.89(d,J=2.1Hz,1H),6.80(dd,J=8.5,2.2Hz,1H),5.99(s,2H),5.05(dd,J =12.9,5.4Hz,1H),3.53(dd,J=10.3,7.3Hz,1H),3.50–3.44(m,1H),3.42–3.33(m,4H),3.09(dt,J=19.9,6.6 Hz, 8H), 2.88(ddd, J=17.3, 14.0, 5.5Hz, 1H), 2.63–2.51(m, 2H), 2.35(p, J=7.6Hz, 1H), 2.12(td, J=9.9, 7.9,4.4Hz,1H),2.06–1.97(m,1H),1.90(q,J=5.5,5.1Hz,4H),1.73(dq,J=11.9,8.1Hz,1H).
实施例28 化合物28的合成Synthesis of Example 28 Compound 28
Figure PCTCN2022096512-appb-000134
Figure PCTCN2022096512-appb-000134
步骤1：中间体28c的合成Step 1: Synthesis of Intermediate 28c
在单口瓶中，将化合物13b(1.00g)溶于N-甲基吡咯烷酮(10mL)中，加入化合物28b(0.409g)和N,N-二异丙基乙胺(1.376g)，升温至80℃反应15小时。反应完毕后，反应液冷至室温，蒸除溶剂，粗品经过硅胶柱层析分离(洗脱剂：二氯甲烷/甲醇)得到目标中间体28c(1.3g)。In a single-necked bottle, dissolve compound 13b (1.00g) in N-methylpyrrolidone (10mL), add compound 28b (0.409g) and N,N-diisopropylethylamine (1.376g), and heat up to 80 °C for 15 hours. After the reaction was completed, the reaction liquid was cooled to room temperature, and the solvent was evaporated. The crude product was separated by silica gel column chromatography (eluent: dichloromethane/methanol) to obtain the target intermediate 28c (1.3 g).
MS(ESI,[M+H] +)m/z:372.3。 1H NMR(500MHz,DMSO-d 6)δ11.07(s,1H),7.64(d,J＝8.6Hz,1H),7.30(d,J＝2.4Hz,1H),7.23(dd,J＝8.7,2.4Hz,1H),5.06(dd,J＝12.8,5.4Hz,1H),4.49(t,J＝5.3Hz,1H),4.05(dt,J＝13.4,3.2Hz,2H),3.30–3.24(m,2H),3.00–2.84(m,3H),2.70(s,1H),2.64–2.52(m,1H),2.01(ddd,J＝10.6,5.6,3.3Hz,1H),1.74(dd,J＝13.8,3.5Hz,2H),1.66(tq,J＝11.0,3.5,2.5Hz,1H),1.19(qt,J＝12.3,6.1Hz,2H). MS (ESI, [M+H] + ) m/z: 372.3. 1 H NMR (500MHz, DMSO-d 6 )δ11.07(s, 1H), 7.64(d, J=8.6Hz, 1H), 7.30(d, J=2.4Hz, 1H), 7.23(dd, J= 8.7,2.4Hz,1H),5.06(dd,J=12.8,5.4Hz,1H),4.49(t,J=5.3Hz,1H),4.05(dt,J=13.4,3.2Hz,2H),3.30– 3.24(m,2H),3.00–2.84(m,3H),2.70(s,1H),2.64–2.52(m,1H),2.01(ddd,J＝10.6,5.6,3.3Hz,1H),1.74( dd,J=13.8,3.5Hz,2H), 1.66(tq,J=11.0,3.5,2.5Hz,1H),1.19(qt,J=12.3,6.1Hz,2H).
步骤2：中间体28d的合成Step 2: Synthesis of Intermediate 28d
在单口瓶中，将化合物28c(100mg)溶于二氯甲烷(5mL)中，加入戴斯马丁氧化剂(225mg)，室温反应1小时。反应完毕后，向体系中加入二氯甲烷(50mL)和水(50mL)。有机相分离，水相用二氯甲烷(50mL×2)萃取，合并有机相，无水硫酸钠干燥，过滤，不需要纯化，减压蒸除溶剂，得到中间体28d(200mg)。In a one-necked bottle, compound 28c (100 mg) was dissolved in dichloromethane (5 mL), and Dess Martin oxidant (225 mg) was added, and reacted at room temperature for 1 hour. After the reaction was complete, dichloromethane (50 mL) and water (50 mL) were added to the system. The organic phase was separated, and the aqueous phase was extracted with dichloromethane (50 mL×2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and no purification was required. The solvent was evaporated under reduced pressure to obtain intermediate 28d (200 mg).
MS(ESI,[M+H] +)m/z:370.3。 MS (ESI, [M+H] + ) m/z: 370.3.
步骤3：化合物28的合成Step 3: Synthesis of Compound 28
在单口瓶中，将化合物28d(868mg)和化合物1j(500mg)溶于甲醇(5mL)中，加入氰基硼氢化钠(147mg)，加入1滴醋酸，室温反应2小时。反应完毕后，向体系中加入二氯甲烷(50mL)和水(50mL)。有机相分 离，水相用二氯甲烷(50mL×2)萃取，合并有机相，无水硫酸钠干燥，过滤，减压蒸除溶剂，粗品经过反相纯化(洗脱剂：水/乙腈)得到化合物28(40mg)。In a single-necked bottle, compound 28d (868 mg) and compound 1j (500 mg) were dissolved in methanol (5 mL), sodium cyanoborohydride (147 mg) was added, 1 drop of acetic acid was added, and the reaction was carried out at room temperature for 2 hours. After the reaction was complete, dichloromethane (50 mL) and water (50 mL) were added to the system. The organic phase was separated, the aqueous phase was extracted with dichloromethane (50mL×2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the solvent was evaporated under reduced pressure, and the crude product was purified by reverse phase (eluent: water/acetonitrile) to obtain Compound 28 (40 mg).
HRMS(ESI)m/z[M+H] +:860.57845。 1H NMR(500MHz,DMSO-d 6)δ11.23(s,1H),11.07(s,1H),8.42(d,J＝5.3Hz,1H),8.32(d,J＝1.9Hz,1H),7.98(t,J＝8.1Hz,2H),7.70–7.59(m,2H),7.35(dd,J＝5.4,2.0Hz,1H),7.29(d,J＝2.3Hz,1H),7.27–7.18(m,2H),7.00(d,J＝4.9Hz,1H),5.98(s,2H),5.06(dd,J＝12.8,5.4Hz,1H),4.02(dd,J＝10.0,6.5Hz,2H),3.12–2.98(m,8H),2.99–2.81(m,4H),2.55(d,J＝11.6Hz,2H),2.32(d,J＝6.7Hz,2H),2.01(ddt,J＝8.5,6.1,3.2Hz,1H),1.87(t,J＝5.3Hz,4H),1.81–1.73(m,2H),1.68–1.49(m,2H). 13C NMR(126MHz,DMSO-d 6)δ173.28,170.58,169.50,168.11,167.43,165.32,158.57,155.33,153.65,151.92,149.96,145.34,144.48,132.96,126.64,125.49,124.65,120.55,118.21,116.39,114.72,113.86,106.08,94.32,64.13,49.23,47.43,40.59,34.20,31.46,29.48,24.20,22.79,16.23. HRMS (ESI) m/z [M+H] + : 860.57845. 1 H NMR(500MHz,DMSO-d 6 )δ11.23(s,1H),11.07(s,1H),8.42(d,J=5.3Hz,1H),8.32(d,J=1.9Hz,1H) ,7.98(t,J=8.1Hz,2H),7.70–7.59(m,2H),7.35(dd,J=5.4,2.0Hz,1H),7.29(d,J=2.3Hz,1H),7.27– 7.18(m,2H),7.00(d,J=4.9Hz,1H),5.98(s,2H),5.06(dd,J=12.8,5.4Hz,1H),4.02(dd,J=10.0,6.5Hz ,2H),3.12–2.98(m,8H),2.99–2.81(m,4H),2.55(d,J＝11.6Hz,2H),2.32(d,J＝6.7Hz,2H),2.01(ddt, J＝8.5, 6.1, 3.2Hz, 1H), 1.87(t, J＝5.3Hz, 4H), 1.81–1.73(m, 2H), 1.68–1.49(m, 2H). 13 C NMR (126MHz, DMSO- d 6 )δ173.28,170.58,169.50,168.11,167.43,165.32,158.57,155.33,153.65,151.92,149.96,145.34,144.48,132.96,126.64,125.49,124.65,120.55,118.21,116.39,114.72,113.86,106.08,94.32 ,64.13,49.23,47.43,40.59,34.20,31.46,29.48,24.20,22.79,16.23.
实施例29 化合物29的合成Synthesis of Example 29 Compound 29
Figure PCTCN2022096512-appb-000135
Figure PCTCN2022096512-appb-000135
步骤1：中间体29b的制备Step 1: Preparation of Intermediate 29b
向反应瓶中加入中间体13b(2g)、1-叔丁氧羰基哌嗪(1.349g)、N,N-二异丙基乙胺(2.81g)及NMP(10mL)，N 2保护下，将混合物加热至80℃反应过夜。反应液冷却至室温，加入DCM(100mL)和水(100mL)。有机相分离，用饱和氯化钠溶液100mL洗涤后用无水硫酸钠干燥，过滤，滤液浓缩后得到中间体29b(2.25g)。 Add intermediate 13b (2g), 1-tert-butoxycarbonylpiperazine (1.349g), N,N-diisopropylethylamine (2.81g) and NMP (10mL) to the reaction flask, under N2 protection, The mixture was heated to 80°C overnight. The reaction solution was cooled to room temperature, and DCM (100 mL) and water (100 mL) were added. The organic phase was separated, washed with 100 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain intermediate 29b (2.25 g).
MS(ESI,[M+H] +)m/z：443.3。 1H NMR(500MHz,DMSO-d 6)δ11.07(s,1H),7.70(d,J＝8.5Hz,1H),7.34(d,J＝2.4Hz,1H),7.24(dd,J＝8.6,2.4Hz,1H),5.07(dd,J＝12.8,5.4Hz,1H),3.47(s,8H),2.88(ddd,J＝16.5,13.5,5.3Hz,1H),2.63–2.51(m,2H),2.02(ddq,J＝12.9,5.8,3.6,2.4Hz,1H),1.43(s,9H). MS (ESI, [M+H] + ) m/z: 443.3. 1 H NMR (500MHz, DMSO-d 6 ) δ11.07(s, 1H), 7.70(d, J=8.5Hz, 1H), 7.34(d, J=2.4Hz, 1H), 7.24(dd, J= 8.6,2.4Hz,1H),5.07(dd,J＝12.8,5.4Hz,1H),3.47(s,8H),2.88(ddd,J＝16.5,13.5,5.3Hz,1H),2.63–2.51(m ,2H),2.02(ddq,J=12.9,5.8,3.6,2.4Hz,1H),1.43(s,9H).
步骤2：中间体29c的制备Step 2: Preparation of Intermediate 29c
向反应瓶中加入中间体29b(2.2g)、DCM(40mL)及4M盐酸的二氧六环溶液(1.088g,7.46mL,29.8mmol)，将混合物室温反应2h。反应液中加入饱和碳酸氢钠溶液100mL。然后用100mL DCM萃取2次，有机相分离，用饱和氯化钠溶液洗涤后无水硫酸钠干燥，过滤，浓缩得到中间体29c(1.48g)。Intermediate 29b (2.2 g), DCM (40 mL) and 4M hydrochloric acid in dioxane (1.088 g, 7.46 mL, 29.8 mmol) were added to the reaction flask, and the mixture was reacted at room temperature for 2 h. 100 mL of saturated sodium bicarbonate solution was added to the reaction solution. Then extracted twice with 100mL DCM, the organic phase was separated, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated to give intermediate 29c (1.48g).
MS(ESI,[M+H] +)m/z：343.3。 1H NMR(500MHz,DMSO-d 6)δ11.09(s,1H),7.74(d,J＝8.4Hz,1H),7.45(d,J＝2.3Hz,1H),7.32(dd,J＝8.6,2.4Hz,1H),5.09(dd,J＝12.8,5.4Hz,1H),3.71(q,J＝8.6,6.9Hz,4H),3.19(h,J＝4.4Hz,4H),2.89(ddd,J＝16.6,13.7,5.4Hz,1H),2.64–2.52(m,2H),2.09–1.98(m,1H). MS (ESI, [M+H] + ) m/z: 343.3. 1 H NMR (500MHz, DMSO-d 6 ) δ11.09(s, 1H), 7.74(d, J=8.4Hz, 1H), 7.45(d, J=2.3Hz, 1H), 7.32(dd, J= 8.6,2.4Hz,1H),5.09(dd,J=12.8,5.4Hz,1H),3.71(q,J=8.6,6.9Hz,4H),3.19(h,J=4.4Hz,4H),2.89( ddd,J＝16.6,13.7,5.4Hz,1H),2.64–2.52(m,2H),2.09–1.98(m,1H).
步骤3：中间体29d的制备Step 3: Preparation of intermediate 29d
向反应瓶中加入中间体29c(1.4g)、溴代乙醛缩二乙醇(2.418g)、N,N-二异丙基乙胺(2.64g)及DMSO(10mL)，N 2保护下，将混合物加热至80℃反应6h。反应液冷却至室温，加入DCM(100mL)和水(100mL)。有机相分离，用饱和氯化钠溶液(100mL)洗涤后无水硫酸钠干燥，过滤，浓缩，浓缩物经硅胶柱层析分离纯化得到中间体29d(0.495g)。 Add intermediate 29c (1.4g), bromoacetaldehyde diethyl acetal (2.418g), N,N-diisopropylethylamine (2.64g) and DMSO (10mL) to the reaction flask, under N 2 protection, The mixture was heated to 80°C for 6h. The reaction solution was cooled to room temperature, and DCM (100 mL) and water (100 mL) were added. The organic phase was separated, washed with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and the concentrate was separated and purified by silica gel column chromatography to obtain intermediate 29d (0.495 g).
MS(ESI,[M+H] +)m/z：459.3。 1H NMR(500MHz,DMSO-d 6)δ11.07(s,1H),7.67(d,J＝8.5Hz,1H),7.33(d,J＝2.3Hz,1H),7.25(dd,J＝8.7,2.4Hz,1H),5.07(dt,J＝12.7,6.0Hz,1H),4.63(t,J＝5.2Hz,1H),3.61(dq,J＝9.6,7.1Hz,2H),3.53–3.47(m,2H),3.42(t,J＝5.1Hz,4H),2.92–2.85(m,1H),2.63–2.59(m,4H),2.58–2.53(m,1H),2.48(d,J＝5.2Hz,2H),2.02(ddd,J＝10.5,5.6,3.2Hz,1H),1.12(t,J＝7.0Hz,6H). 步骤4：中间体29e的制备 MS (ESI, [M+H] + ) m/z: 459.3. 1 H NMR (500MHz, DMSO-d 6 ) δ11.07(s, 1H), 7.67(d, J=8.5Hz, 1H), 7.33(d, J=2.3Hz, 1H), 7.25(dd, J= 8.7,2.4Hz,1H),5.07(dt,J=12.7,6.0Hz,1H),4.63(t,J=5.2Hz,1H),3.61(dq,J=9.6,7.1Hz,2H),3.53– 3.47(m,2H),3.42(t,J＝5.1Hz,4H),2.92–2.85(m,1H),2.63–2.59(m,4H),2.58–2.53(m,1H),2.48(d, J=5.2Hz, 2H), 2.02(ddd, J=10.5, 5.6, 3.2Hz, 1H), 1.12(t, J=7.0Hz, 6H). Step 4: Preparation of intermediate 29e
向反应瓶中加入中间体29d(0.495g)、2M稀盐酸(0.787g,10.79mL,21.59mmol)和THF(20mL)，加热至50℃反应过夜。反应液冷却至室温，加入EA(50mL)和饱和碳酸氢钠(50mL)。有机相分离，用饱和氯化钠溶液(50mL)洗涤后用无水硫酸钠干燥，过滤，浓缩得到中间体29e(0.21g)。Intermediate 29d (0.495g), 2M dilute hydrochloric acid (0.787g, 10.79mL, 21.59mmol) and THF (20mL) were added to the reaction flask, heated to 50°C overnight. The reaction solution was cooled to room temperature, and EA (50 mL) and saturated sodium bicarbonate (50 mL) were added. The organic phase was separated, washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give intermediate 29e (0.21 g).
MS(ESI,[M+H] +)m/z：385.2. MS (ESI, [M+H] + ) m/z: 385.2.
步骤5：化合物29的制备Step 5: Preparation of compound 29
向反应瓶中加入中间体29e(0.2g)、中间体1j(0.264g)、氰基硼氢化钠(0.098g)、乙酸(0.1mL)及MeOH(10mL)，将混合物室温反应2h。反应液中加入少量饱和氯化铵水溶液，然后浓缩，经硅胶柱层析分离纯化得到化合物29(0.134g)。Intermediate 29e (0.2 g), Intermediate 1j (0.264 g), sodium cyanoborohydride (0.098 g), acetic acid (0.1 mL) and MeOH (10 mL) were added to the reaction flask, and the mixture was reacted at room temperature for 2 h. A small amount of saturated aqueous ammonium chloride solution was added to the reaction solution, then concentrated, separated and purified by silica gel column chromatography to obtain compound 29 (0.134 g).
MS(ESI,[M+H] +)m/z：875.5。 1H NMR(500MHz,DMSO-d 6)δ11.23(s,1H),11.08(s,1H),8.42(d,J＝5.3Hz,1H),8.32(s,1H),7.98(t,J＝8.2Hz,2H),7.70–7.59(m,2H),7.37–7.31(m,2H),7.28–7.22(m,2H),7.01(d,J＝5.0Hz,1H),5.99(s,2H),5.07(dd,J＝12.7,5.5Hz,1H),3.43(t,J＝4.9Hz,6H),3.17–2.96(m,8H),2.89(ddd,J＝18.1,13.8,5.4Hz,1H),2.67–2.52(m,6H),2.35(s,2H),2.02(dt,J＝12.8,5.7Hz,1H),1.88(s,4H). 13C NMR(126MHz,DMSO-d 6)δ173.26,170.53,168.01,167.44,165.29,160.49,158.52,155.70,153.63,151.92,149.92,145.54,144.45,135.49,134.30,132.95,127.91,126.66,125.33,124.64,120.51,118.74,118.23,114.71,113.82,108.32,106.04,64.26,53.04,49.24,47.55,47.35,34.64,31.45,22.66. MS (ESI, [M+H] + ) m/z: 875.5. 1 H NMR (500MHz, DMSO-d 6 )δ11.23(s,1H),11.08(s,1H),8.42(d,J=5.3Hz,1H),8.32(s,1H),7.98(t, J＝8.2Hz, 2H), 7.70–7.59(m, 2H), 7.37–7.31(m, 2H), 7.28–7.22(m, 2H), 7.01(d, J＝5.0Hz, 1H), 5.99(s ,2H),5.07(dd,J＝12.7,5.5Hz,1H),3.43(t,J＝4.9Hz,6H),3.17–2.96(m,8H),2.89(ddd,J＝18.1,13.8,5.4 Hz, 1H), 2.67–2.52(m, 6H), 2.35(s, 2H), 2.02(dt, J=12.8, 5.7Hz, 1H), 1.88(s, 4H). 13 C NMR (126MHz, DMSO- d 6 )δ173.26,170.53,168.01,167.44,165.29,160.49,158.52,155.70,153.63,151.92,149.92,145.54,144.45,135.49,134.30,132.95,127.91,126.66,125.33,124.64,120.51,118.74,118.23,114.71 ,113.82,108.32,106.04,64.26,53.04,49.24,47.55,47.35,34.64,31.45,22.66.
实施例30 化合物30的合成The synthesis of embodiment 30 compound 30
Figure PCTCN2022096512-appb-000136
Figure PCTCN2022096512-appb-000136
步骤1：中间体30c的合成Step 1: Synthesis of Intermediate 30c
在单口瓶中，将化合物13b(1.25g)溶于N-甲基吡咯烷酮(10mL)中，加入化合物30b(0.5g)和N,N-二异丙基乙胺(1.713g)，升温至80℃反应9小时。反应完毕后，反应液冷至室温，蒸除溶剂，粗品经过硅胶柱层析分离(洗脱剂：二氯甲烷/甲醇)得到目标中间体30c(1.00g)。In a single-necked bottle, dissolve compound 13b (1.25g) in N-methylpyrrolidone (10mL), add compound 30b (0.5g) and N,N-diisopropylethylamine (1.713g), and heat up to 80 °C for 9 hours. After the reaction was completed, the reaction solution was cooled to room temperature, and the solvent was evaporated. The crude product was separated by silica gel column chromatography (eluent: dichloromethane/methanol) to obtain the target intermediate 30c (1.00 g).
MS(ESI,[M+H] +)m/z：370.3。 1H NMR(500MHz,DMSO-d 6)δ11.06(s,1H),7.62(d,J＝8.5Hz,1H),6.90(d,J＝2.2Hz,1H),6.81(dd,J＝8.5,2.3Hz,1H),5.05(dd,J＝12.8,5.4Hz,1H),4.57(t,J＝5.5Hz,1H),3.61(d,J＝10.2Hz,2H),3.44(dt,J＝10.2,2.0Hz,2H),3.35(t,J＝6.0Hz,2H),2.88(ddd,J＝16.8,13.8,5.3Hz,1H),2.64–2.53(m,2H),2.01(ddd,J＝10.5,5.5,3.1Hz,1H),1.68(td,J＝3.3,1.3Hz,2H),0.82(tt,J＝6.5,3.5Hz,1H). MS (ESI, [M+H] + ) m/z: 370.3. 1 H NMR (500MHz, DMSO-d 6 ) δ11.06(s, 1H), 7.62(d, J=8.5Hz, 1H), 6.90(d, J=2.2Hz, 1H), 6.81(dd, J= 8.5,2.3Hz,1H),5.05(dd,J=12.8,5.4Hz,1H),4.57(t,J=5.5Hz,1H),3.61(d,J=10.2Hz,2H),3.44(dt, J＝10.2, 2.0Hz, 2H), 3.35(t, J＝6.0Hz, 2H), 2.88(ddd, J＝16.8, 13.8, 5.3Hz, 1H), 2.64–2.53(m, 2H), 2.01(ddd ,J=10.5,5.5,3.1Hz,1H),1.68(td,J=3.3,1.3Hz,2H),0.82(tt,J=6.5,3.5Hz,1H).
步骤2：中间体30d的合成Step 2: Synthesis of Intermediate 30d
在单口瓶中，将化合物30c(500mg)溶于二氯甲烷(10mL)中，加入戴斯马丁氧化剂(1.132g)，室温反应1小时。反应完毕后，向体系中加入二氯甲烷(50mL)和水(50mL)。有机相分离，水相用二氯甲烷(50mL×2)萃取，合并有机相，无水硫酸钠干燥，过滤，不需要纯化，减压蒸除溶剂，得到中间体30d(0.95g)。In a one-necked bottle, compound 30c (500 mg) was dissolved in dichloromethane (10 mL), and Dess Martin oxidant (1.132 g) was added, and reacted at room temperature for 1 hour. After the reaction was complete, dichloromethane (50 mL) and water (50 mL) were added to the system. The organic phase was separated, and the aqueous phase was extracted with dichloromethane (50 mL×2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and no purification was required. The solvent was evaporated under reduced pressure to obtain intermediate 30d (0.95 g).
MS(ESI,[M+H] +)m/z:368.1。 MS (ESI, [M+H] + ) m/z: 368.1.
步骤3：化合物30的合成Step 3: Synthesis of Compound 30
在单口瓶中，将化合物30d(352mg)和化合物1j(500mg)溶于甲醇(5mL)中，再加入氰基硼氢化钠(147mg)，加入1滴醋酸，室温反应2小时。反应完毕后，向体系中加入二氯甲烷(50mL)和水(50mL)。有机相分离，水相用二氯甲烷(50mL×2)萃取，合并有机相，无水硫酸钠干燥，过滤，减压蒸除溶剂，粗品经过反相纯化(洗脱剂：水/乙腈)得到目标化合物30(80mg)。In a one-necked bottle, compound 30d (352 mg) and compound 1j (500 mg) were dissolved in methanol (5 mL), then sodium cyanoborohydride (147 mg) was added, and 1 drop of acetic acid was added, and reacted at room temperature for 2 hours. After the reaction was complete, dichloromethane (50 mL) and water (50 mL) were added to the system. The organic phase was separated, the aqueous phase was extracted with dichloromethane (50mL×2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the solvent was evaporated under reduced pressure, and the crude product was purified by reverse phase (eluent: water/acetonitrile) to obtain Target compound 30 (80 mg).
HRMS(ESI)m/z[M+H] +：858.55846。 1H NMR(500MHz,DMSO-d 6)δ11.23(s,1H),11.07(s,1H),8.42(d,J＝5.4Hz,1H),8.32(d,J＝1.9Hz,1H),7.98(t,J＝8.0Hz,2H),7.63(t,J＝7.4Hz,2H),7.35(dd,J＝5.4, 1.9Hz,1H),7.26(d,J＝4.9Hz,1H),7.00(d,J＝5.0Hz,1H),6.90(d,J＝2.2Hz,1H),6.80(dd,J＝8.5,2.2Hz,1H),5.99(s,2H),5.05(dd,J＝12.8,5.5Hz,1H),3.63(d,J＝10.2Hz,2H),3.43(s,3H),3.05(d,J＝7.7Hz,8H),2.95–2.83(m,1H),2.63–2.52(m,2H),2.39(d,J＝6.6Hz,2H),2.01(ddt,J＝12.6,7.3,4.4Hz,1H),1.93–1.81(m,4H),1.65(d,J＝3.3Hz,2H). 13C NMR(126MHz,DMSO-d 6)δ173.27,170.58,168.11,167.67,165.31,153.66,152.83,151.94,149.93,145.59,144.47,134.35,132.97,127.93,125.32,124.60,120.52,116.75,116.34,116.19,114.72,113.84,106.53,106.06,64.08,60.37,50.93,49.18,47.64,35.69,34.73,31.46,22.71,21.57. HRMS (ESI) m/z [M+H] + : 858.55846. 1 H NMR (500MHz,DMSO-d 6 )δ11.23(s,1H),11.07(s,1H),8.42(d,J=5.4Hz,1H),8.32(d,J=1.9Hz,1H) ,7.98(t,J=8.0Hz,2H),7.63(t,J=7.4Hz,2H),7.35(dd,J=5.4,1.9Hz,1H),7.26(d,J=4.9Hz,1H) ,7.00(d,J=5.0Hz,1H),6.90(d,J=2.2Hz,1H),6.80(dd,J=8.5,2.2Hz,1H),5.99(s,2H),5.05(dd, J=12.8,5.5Hz,1H),3.63(d,J=10.2Hz,2H),3.43(s,3H),3.05(d,J=7.7Hz,8H),2.95–2.83(m,1H), 2.63–2.52(m,2H),2.39(d,J=6.6Hz,2H),2.01(ddt,J=12.6,7.3,4.4Hz,1H),1.93–1.81(m,4H),1.65(d, J＝3.3Hz, 2H). 13 C NMR (126MHz, DMSO-d 6 ) δ173.27, 170.58, 168.11, 167.67, 165.31, 153.66, 152.83, 151.94, 149.93, 145.59, 144.47, 134.365, 132.933, 125.7 .
实施例31 化合物31的合成Synthesis of Example 31 Compound 31
Figure PCTCN2022096512-appb-000137
Figure PCTCN2022096512-appb-000137
步骤1：中间体31b的制备Step 1: Preparation of Intermediate 31b
向单口瓶中加入中间体31a(5g)、3-氨基-2,6-哌啶二酮盐酸盐(5.36g)、醋酸钠(3.34g)及AcOH(50mL)，N 2保护下，将混合物加热至120℃反应3h。反应液冷却至室温，浓缩，加水抽滤，干燥后得到中间体31b(7.1g)。 Add intermediate 31a (5g), 3-amino-2,6-piperidinedione hydrochloride (5.36g), sodium acetate (3.34g) and AcOH (50mL) to the single-necked bottle, under N 2 protection, the The mixture was heated to 120°C for 3h. The reaction solution was cooled to room temperature, concentrated, filtered with water, and dried to obtain intermediate 31b (7.1 g).
1H NMR(500MHz,DMSO-d 6)δ11.14(s,1H),8.16(t,J＝7.7Hz,2H),5.17(dd,J＝13.0,5.4Hz,1H),2.89(ddd,J＝17.2,13.9,5.5Hz,1H),2.67–2.51(m,2H),2.07(dtd,J＝13.1,5.5,2.4Hz,1H). 1 H NMR (500MHz, DMSO-d 6 ) δ11.14(s, 1H), 8.16(t, J=7.7Hz, 2H), 5.17(dd, J=13.0, 5.4Hz, 1H), 2.89(ddd, J=17.2,13.9,5.5Hz,1H),2.67–2.51(m,2H),2.07(dtd,J=13.1,5.5,2.4Hz,1H).
步骤2：中间体31c的制备Step 2: Preparation of Intermediate 31c
在单口瓶中，将化合物31b(1.300g)溶于N-甲基吡咯烷酮(10mL)中，加入(1R,5S,6R)-3-氮杂双环[3.1.0]己烷-6-甲醇(0.5g)和N,N-二异丙基乙胺(1.713g)，升温至80℃反应9小时。反应完毕后，反应液冷至室温，蒸除溶剂，粗品经过硅胶柱层析分离(洗脱剂：二氯甲烷/甲醇)得到中间体31c(1.21g)。In a one-necked bottle, compound 31b (1.300 g) was dissolved in N-methylpyrrolidone (10 mL), and (1R, 5S, 6R)-3-azabicyclo[3.1.0]hexane-6-methanol ( 0.5g) and N,N-diisopropylethylamine (1.713g), heated to 80°C for 9 hours. After the reaction was completed, the reaction liquid was cooled to room temperature, and the solvent was evaporated. The crude product was separated by silica gel column chromatography (eluent: dichloromethane/methanol) to obtain intermediate 31c (1.21g).
MS(ESI,[M+H] +)m/z:388.1。 1H NMR(500MHz,DMSO-d6)δ11.07(s,1H),7.59(d,J＝12.9Hz,1H),7.07(d,J＝7.5Hz,1H),5.06(dd,J＝12.8,5.4Hz,1H),4.54(t,J＝5.5Hz,1H),3.78(dd,J＝10.3,3.6Hz,2H),3.57(dd,J＝10.1,2.6Hz,2H),3.34(t,J＝6.0Hz,2H),2.88(ddd,J＝16.9,13.8,5.4Hz,1H),2.57(t,J＝3.3Hz,1H),2.01(dtd,J＝13.0,5.3,2.2Hz,1H),1.64(d,J＝3.3Hz,2H),0.89(tt,J＝6.5,3.4Hz,1H). MS (ESI, [M+H] + ) m/z: 388.1. 1 H NMR (500MHz, DMSO-d6) δ11.07(s, 1H), 7.59(d, J=12.9Hz, 1H), 7.07(d, J=7.5Hz, 1H), 5.06(dd, J=12.8 ,5.4Hz,1H),4.54(t,J=5.5Hz,1H),3.78(dd,J=10.3,3.6Hz,2H),3.57(dd,J=10.1,2.6Hz,2H),3.34(t ,J=6.0Hz,2H),2.88(ddd,J=16.9,13.8,5.4Hz,1H),2.57(t,J=3.3Hz,1H),2.01(dtd,J=13.0,5.3,2.2Hz, 1H), 1.64(d, J=3.3Hz, 2H), 0.89(tt, J=6.5, 3.4Hz, 1H).
步骤3：中间体31d的制备Step 3: Preparation of Intermediate 31d
向反应瓶中，依次加入中间体31c(550mg)、DCM(20mL)及dess-martin氧化剂(1193mg)，N 2保护下，室温反应2小时，反应完全，反应液中加水后用DCM-MeOH(20:1，50mL×2)萃取，有机层合并后饱和食盐水(50mL×1)洗涤，萃取液干燥过滤，滤液旋蒸干得到中间体31d(555mg)。 In the reaction flask, add intermediate 31c (550mg), DCM (20mL) and dess-martin oxidant (1193mg) successively, under N protection, react at room temperature for 2 hours, the reaction is complete, after adding water in the reaction solution, use DCM-MeOH ( 20:1, 50mL×2) extraction, the organic layers were combined and washed with saturated brine (50mL×1), the extract was dried and filtered, and the filtrate was rotary evaporated to dryness to obtain intermediate 31d (555mg).
步骤4：化合物31的制备Step 4: Preparation of compound 31
向反应瓶中，依次加入中间体31d(541mg)、中间体1j(700mg)、MeOH(20mL))及冰乙酸(64.7mg)，N 2保护下，室温搅拌30min后再加入氰基硼氢化钠(203mg)，将混合物室温反应过夜，反应完全，反应液加少量水淬灭反应，反应液旋蒸后残余物用硅胶柱纯化(DCM-MeOH)得到粗品，粗品再用C 18反相柱纯化(10nM乙酸铵水溶液-乙腈)洗脱，过柱液合并，DCM-MeOH(10:1)萃取后旋蒸干得到化合物31(160mg)。 Into the reaction flask, sequentially add intermediate 31d (541mg), intermediate 1j (700mg), MeOH (20mL)) and glacial acetic acid (64.7mg), under N2 protection, stir at room temperature for 30min, then add sodium cyanoborohydride (203 mg), the mixture was reacted at room temperature overnight, the reaction was complete, the reaction solution was quenched by adding a small amount of water, the residue was purified by silica gel column (DCM-MeOH) after the reaction solution was rotary evaporated to obtain the crude product, and the crude product was purified by C 18 reverse phase column (10nM ammonium acetate aqueous solution-acetonitrile) was eluted, the liquid was combined through the column, extracted with DCM-MeOH (10:1) and evaporated to dryness to obtain compound 31 (160 mg).
MS(ESI,[M+H] +)m/z：876.5。 1H NMR(500MHz,DMSO-d 6)δ11.23(s,1H),11.09(s,1H),8.41(d,J＝5.4Hz,1H),8.32(d,J＝1.9Hz,1H),8.05–7.95(m,2H),7.66–7.55(m,2H),7.35(dd,J＝5.3,2.0Hz,1H),7.26(d,J＝5.0Hz,1H),7.07(d,J＝7.5Hz,1H),7.00(d,J＝4.9Hz,1H),5.99(s,2H),5.06(dd,J＝12.8,5.5Hz,1H),3.79(dd,J＝10.4,3.6Hz,2H),3.56(d,J＝9.8Hz,2H),3.23–2.95(m,8H),2.88(ddd,J＝16.8,13.8,5.5Hz,1H),2.65–2.52(m,2H),2.45(d,J＝24.3Hz,2H),2.01(ddd,J＝10.6,6.2,3.5Hz,1H),1.89(q,J＝5.5Hz,4H),1.62(s,2H). MS (ESI, [M+H] + ) m/z: 876.5. 1 H NMR (500MHz,DMSO-d 6 )δ11.23(s,1H),11.09(s,1H),8.41(d,J=5.4Hz,1H),8.32(d,J=1.9Hz,1H) ,8.05–7.95(m,2H),7.66–7.55(m,2H),7.35(dd,J＝5.3,2.0Hz,1H),7.26(d,J＝5.0Hz,1H),7.07(d,J =7.5Hz,1H),7.00(d,J=4.9Hz,1H),5.99(s,2H),5.06(dd,J=12.8,5.5Hz,1H),3.79(dd,J=10.4,3.6Hz ,2H),3.56(d,J＝9.8Hz,2H),3.23–2.95(m,8H),2.88(ddd,J＝16.8,13.8,5.5Hz,1H),2.65–2.52(m,2H), 2.45(d,J=24.3Hz,2H),2.01(ddd,J=10.6,6.2,3.5Hz,1H),1.89(q,J=5.5Hz,4H),1.62(s,2H).
实施例32 化合物32的合成Synthesis of Example 32 Compound 32
Figure PCTCN2022096512-appb-000138
Figure PCTCN2022096512-appb-000138
步骤1：中间体32b的制备Step 1: Preparation of intermediate 32b
向微波管中加入中间体11c(2g)、苯磺酸(2.389g)和乙腈(10mL)，微波100℃反应120分钟。将反应液抽滤，用100mL EA洗涤，干燥后得到中间体32b(1.35g)。Intermediate 11c (2 g), benzenesulfonic acid (2.389 g) and acetonitrile (10 mL) were added to a microwave tube, and microwaved at 100° C. for 120 minutes. The reaction solution was suction filtered, washed with 100mL EA, and dried to obtain intermediate 32b (1.35g).
MS(ESI,[M+H] +)m/z：322.9。 1H NMR(500MHz,DMSO-d 6)δ10.99(s,1H),7.89(d,J＝1.6Hz,1H),7.75–7.64(m,2H),5.11(dd,J＝13.3,5.1Hz,1H),4.47(d,J＝17.6Hz,1H),4.35(d,J＝17.6Hz,1H),2.91(ddd,J＝17.3,13.6,5.4Hz,1H),2.66–2.56(m,1H),2.39(qd,J＝13.3,4.5Hz,1H),2.01(dtd,J＝12.6,5.3,2.2Hz,1H). MS (ESI, [M+H] + ) m/z: 322.9. 1 H NMR (500MHz, DMSO-d 6 ) δ10.99(s, 1H), 7.89(d, J=1.6Hz, 1H), 7.75–7.64(m, 2H), 5.11(dd, J=13.3, 5.1 Hz, 1H), 4.47(d, J=17.6Hz, 1H), 4.35(d, J=17.6Hz, 1H), 2.91(ddd, J=17.3, 13.6, 5.4Hz, 1H), 2.66–2.56(m ,1H),2.39(qd,J=13.3,4.5Hz,1H),2.01(dtd,J=12.6,5.3,2.2Hz,1H).
步骤2：中间体32c的制备Step 2: Preparation of intermediate 32c
向微波管中加入中间体32b(0.88g)、(S)-吡咯烷-3-甲醇(0.413g)、Ruphos Pd G3(0.342g)、碳酸铯(2.66g)和DMF(20mL)，微波120℃反应60分钟。反应液冷却至室温，加入DCM(100mL)和水(100mL)。有机相分离，用饱和氯化钠溶液(100mL)洗涤后用无水硫酸钠干燥，过滤，浓缩，浓缩物经硅胶柱层析分离纯化得到中间体32c(0.292g)。Intermediate 32b (0.88 g), (S)-pyrrolidine-3-methanol (0.413 g), Ruphos Pd G3 (0.342 g), cesium carbonate (2.66 g) and DMF (20 mL) were added to a microwave tube and microwaved at 120 °C for 60 minutes. The reaction solution was cooled to room temperature, and DCM (100 mL) and water (100 mL) were added. The organic phase was separated, washed with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and the concentrate was separated and purified by silica gel column chromatography to obtain intermediate 32c (0.292 g).
MS(ESI,[M+H] +)m/z：344.1。 1H NMR(500MHz,DMSO-d 6)δ10.92(s,1H),7.50–7.45(m,1H),6.61(d,J＝7.4Hz,2H),5.03(dd,J＝13.3,5.1Hz,1H),4.72(t,J＝5.2Hz,1H),4.30(d,J＝16.6Hz,1H),4.18(d,J＝16.6Hz,1H),3.48–3.34(m,5H),3.11(ddd,J＝9.5,6.3,2.5Hz,1H),2.90(ddd,J＝17.2,13.7,5.4Hz,1H),2.58(ddd,J＝17.3,4.5,2.3Hz,1H),2.45(dq,J＝13.9,6.9Hz,1H),2.38–2.30(m,1H),2.05(dtd,J＝12.2,7.4,5.0Hz,1H),1.95(dtd,J＝12.7,5.2,2.2Hz,1H),1.78(dq,J＝12.2,7.6Hz,1H). MS (ESI, [M+H] + ) m/z: 344.1. 1 H NMR (500MHz, DMSO-d 6 ) δ10.92(s, 1H), 7.50–7.45(m, 1H), 6.61(d, J=7.4Hz, 2H), 5.03(dd, J=13.3, 5.1 Hz,1H),4.72(t,J=5.2Hz,1H),4.30(d,J=16.6Hz,1H),4.18(d,J=16.6Hz,1H),3.48–3.34(m,5H), 3.11(ddd, J=9.5,6.3,2.5Hz,1H),2.90(ddd,J=17.2,13.7,5.4Hz,1H),2.58(ddd,J=17.3,4.5,2.3Hz,1H),2.45( dq,J=13.9,6.9Hz,1H),2.38–2.30(m,1H),2.05(dtd,J=12.2,7.4,5.0Hz,1H),1.95(dtd,J=12.7,5.2,2.2Hz, 1H), 1.78(dq, J=12.2, 7.6Hz, 1H).
步骤3：中间体32d的制备Step 3: Preparation of intermediate 32d
向反应瓶中加入溶于DCM(10mL)中的化合物32c(0.28g)，加入戴斯马丁氧化剂(1.038g)，室温反应1小时。向反应液中加入二氯甲烷(50mL)和饱和碳酸氢钠(50mL)。有机相分离，用饱和氯化钠溶液(50mL)洗涤后用无水硫酸钠干燥，过滤，浓缩得到中间体32d(0.21g)。Compound 32c (0.28 g) dissolved in DCM (10 mL) was added to the reaction flask, followed by Dess Martin oxidant (1.038 g), and reacted at room temperature for 1 hour. Dichloromethane (50 mL) and saturated sodium bicarbonate (50 mL) were added to the reaction solution. The organic phase was separated, washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give intermediate 32d (0.21 g).
MS(ESI,[M+H] +)m/z：342.2. MS (ESI, [M+H] + ) m/z: 342.2.
步骤4：化合物32的制备Step 4: Preparation of compound 32
向反应瓶中加入中间体32d(0.109g)、中间体1j(0.15g)、氰基硼氢化钠(0.050g)、乙酸(0.1mL)及MeOH(10mL)，将混合物室温反应2h。反应液中加入二氯甲烷(50mL)和水(50mL)，有机相分离，水相用二氯甲烷(50mL×2)萃取，合并有机相，无水硫酸钠干燥，过滤，浓缩，浓缩物经硅胶柱层析分离纯化得到化合物32(0.06g)。Intermediate 32d (0.109 g), Intermediate 1j (0.15 g), sodium cyanoborohydride (0.050 g), acetic acid (0.1 mL) and MeOH (10 mL) were added to the reaction flask, and the mixture was reacted at room temperature for 2 h. Dichloromethane (50mL) and water (50mL) were added to the reaction solution, the organic phase was separated, the aqueous phase was extracted with dichloromethane (50mL×2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the concentrate was washed with Compound 32 (0.06 g) was obtained by separation and purification by silica gel column chromatography.
MS(ESI,[M+H] +)m/z：832.5。 1H NMR(500MHz,DMSO-d 6)δ11.23(s,1H),10.93(s,1H),8.42(d,J＝5.4Hz,1H),8.32(s,1H),7.98(t,J＝8.0Hz,2H),7.63(t,J＝7.8Hz,1H),7.48(d,J＝8.3Hz,1H),7.35(d,J＝5.4Hz,1H),7.27(d,J＝5.0Hz,1H),7.01(d,J＝5.0Hz,1H),6.62(d,J＝9.0Hz,2H),6.00(s,2H),5.03(dd,J＝13.3,5.2Hz,1H),4.33–4.26(m,1H),4.18(d,J＝16.6Hz,1H),3.45(t,J＝7.6Hz,2H),3.29(d,J＝8.5Hz,5H),3.11–3.01(m,6H),2.90(ddd,J＝17.8,13.7,5.5Hz,1H),2.64–2.54(m,2H),2.34(ddd,J＝17.8,13.6,6.9Hz,2H),2.12(dt,J＝12.1,5.8Hz,1H),1.98–1.88(m,5H),1.72(dq,J＝16.5,8.7Hz,1H). MS (ESI, [M+H] + ) m/z: 832.5. 1 H NMR (500MHz, DMSO-d 6 )δ11.23(s,1H),10.93(s,1H),8.42(d,J=5.4Hz,1H),8.32(s,1H),7.98(t, J=8.0Hz, 2H), 7.63(t, J=7.8Hz, 1H), 7.48(d, J=8.3Hz, 1H), 7.35(d, J=5.4Hz, 1H), 7.27(d, J= 5.0Hz, 1H), 7.01(d, J=5.0Hz, 1H), 6.62(d, J=9.0Hz, 2H), 6.00(s, 2H), 5.03(dd, J=13.3, 5.2Hz, 1H) ,4.33–4.26(m,1H),4.18(d,J=16.6Hz,1H),3.45(t,J=7.6Hz,2H),3.29(d,J=8.5Hz,5H),3.11–3.01( m,6H),2.90(ddd,J＝17.8,13.7,5.5Hz,1H),2.64–2.54(m,2H),2.34(ddd,J＝17.8,13.6,6.9Hz,2H),2.12(dt, J=12.1,5.8Hz,1H), 1.98–1.88(m,5H),1.72(dq,J=16.5,8.7Hz,1H).
实施例33 化合物33的合成Synthesis of Example 33 Compound 33
Figure PCTCN2022096512-appb-000139
Figure PCTCN2022096512-appb-000139
步骤1：中间体33b的制备Step 1: Preparation of Intermediate 33b
向反应瓶中依次加入中间体1j(0.7g)、1-Boc-3-氮杂环丁酮(0.473g)、氰基硼氢化钠(0.585g)、MeOH(50mL)和乙酸(0.166g)，将混合物室温反应过夜。反应液中加入二氯甲烷(150mL)和水(150mL)，有机相分离，无水硫酸钠干燥，过滤，浓缩，浓缩得到中间体33b(1.33g)。Intermediate 1j (0.7 g), 1-Boc-3-azetidinone (0.473 g), sodium cyanoborohydride (0.585 g), MeOH (50 mL) and acetic acid (0.166 g) were sequentially added to the reaction flask , and the mixture was reacted overnight at room temperature. Dichloromethane (150 mL) and water (150 mL) were added to the reaction solution, the organic phase was separated, dried over anhydrous sodium sulfate, filtered, concentrated, and concentrated to obtain intermediate 33b (1.33 g).
MS(ESI,[M+H] +)m/z：662.5。 1H NMR(500MHz,DMSO-d 6)δ11.22(s,1H),8.41(d,J＝5.4Hz,1H),8.31(d,J＝1.9Hz,1H),8.01–7.95(m,2H),7.62(t,J＝7.9Hz,1H),7.34(dd,J＝5.4,1.9Hz,1H),7.27(t,J＝4.4Hz,1H),7.00(t,J＝5.2Hz,1H),6.03(s,2H),3.92–3.86(m,1H),3.64–3.56(m,4H),3.14(s,4H),3.06(t,J＝5.4Hz,4H),1.90(d,J＝6.6Hz,4H),1.38(d,J＝13.5Hz,9H). MS (ESI, [M+H] + ) m/z: 662.5. 1 H NMR (500MHz, DMSO-d 6 )δ11.22(s, 1H), 8.41(d, J=5.4Hz, 1H), 8.31(d, J=1.9Hz, 1H), 8.01–7.95(m, 2H), 7.62(t, J=7.9Hz, 1H), 7.34(dd, J=5.4, 1.9Hz, 1H), 7.27(t, J=4.4Hz, 1H), 7.00(t, J=5.2Hz, 1H), 6.03(s, 2H), 3.92–3.86(m, 1H), 3.64–3.56(m, 4H), 3.14(s, 4H), 3.06(t, J＝5.4Hz, 4H), 1.90(d ,J=6.6Hz,4H),1.38(d,J=13.5Hz,9H).
步骤2：中间体33c的制备Step 2: Preparation of intermediate 33c
向反应瓶中加入中间体33b(0.914g)、DCM(40mL)、4M盐酸的二氧六环溶液(0.655g,4.49mL,17.97mmol)，将混合物室温反应2h。反应液中加入饱和碳酸氢钠溶液(100mL)。然后用100mL DCM萃取2次，有机相分离，用饱和氯化钠溶液洗涤后用无水硫酸钠干燥，过滤，浓缩得到中间体33c(1.03g)。Intermediate 33b (0.914 g), DCM (40 mL), 4M hydrochloric acid in dioxane (0.655 g, 4.49 mL, 17.97 mmol) were added to the reaction flask, and the mixture was reacted at room temperature for 2 h. A saturated sodium bicarbonate solution (100 mL) was added to the reaction solution. Then extracted twice with 100mL DCM, the organic phase was separated, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated to give intermediate 33c (1.03g).
MS(ESI,[M+H] +)m/z：562.5. MS (ESI, [M+H] + ) m/z: 562.5.
步骤3：化合物33的制备Step 3: Preparation of compound 33
向反应瓶中依次加入中间体33c(0.36g)、中间体13b(0.080g)、N,N-二异丙基乙胺(0.075g)和DMSO(6mL)，将混合物加热至80℃反应5h。冷却至室温，向反应液中加入100mL DCM和100mL水。有机相分离，用饱和氯化钠溶液(100mL)洗涤后无水硫酸钠干燥，过滤浓缩，浓缩物经硅胶柱层析分离纯化得到化合物33(0.052g)。Add intermediate 33c (0.36g), intermediate 13b (0.080g), N,N-diisopropylethylamine (0.075g) and DMSO (6mL) to the reaction flask in sequence, and heat the mixture to 80°C for 5h . After cooling to room temperature, 100 mL of DCM and 100 mL of water were added to the reaction solution. The organic phase was separated, washed with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated, and the concentrate was separated and purified by silica gel column chromatography to obtain compound 33 (0.052 g).
MS(ESI,[M+H] +)m/z：818.5。 1H NMR(500MHz,DMSO-d 6)δ11.23(s,1H),11.07(s,1H),8.42(d,J＝5.4Hz,1H),8.32(d,J＝1.9Hz,1H),8.02–7.96(m,2H),7.67–7.61(m,2H),7.35(dd,J＝5.4,2.0Hz,1H),7.26(d,J＝5.0Hz,1H),7.01(d,J＝5.0Hz,1H),6.79(d,J＝2.1Hz,1H),6.65(dd,J＝8.4,2.1Hz,1H),5.99(s,2H),5.06(dd,J＝12.7,5.5Hz,1H),4.05(t,J＝7.8Hz,2H),3.83(dd,J＝9.0,4.3Hz,2H),3.67(q,J＝6.2,5.6Hz,1H),3.48(q,J＝5.3Hz,1H),3.39–3.36(m,2H),3.06(d,J＝5.1Hz,5H),2.88(ddd,J＝16.5,13.6,5.3Hz,1H),2.63–2.53(m,2H),2.05–1.98(m,1H),1.90(t,J＝5.4Hz,4H). MS (ESI, [M+H] + ) m/z: 818.5. 1 H NMR (500MHz,DMSO-d 6 )δ11.23(s,1H),11.07(s,1H),8.42(d,J=5.4Hz,1H),8.32(d,J=1.9Hz,1H) ,8.02–7.96(m,2H),7.67–7.61(m,2H),7.35(dd,J＝5.4,2.0Hz,1H),7.26(d,J＝5.0Hz,1H),7.01(d,J =5.0Hz,1H),6.79(d,J=2.1Hz,1H),6.65(dd,J=8.4,2.1Hz,1H),5.99(s,2H),5.06(dd,J=12.7,5.5Hz ,1H),4.05(t,J=7.8Hz,2H),3.83(dd,J=9.0,4.3Hz,2H),3.67(q,J=6.2,5.6Hz,1H),3.48(q,J= 5.3Hz, 1H), 3.39–3.36(m, 2H), 3.06(d, J＝5.1Hz, 5H), 2.88(ddd, J＝16.5, 13.6, 5.3Hz, 1H), 2.63–2.53(m, 2H ),2.05–1.98(m,1H),1.90(t,J＝5.4Hz,4H).
实施例34 化合物34的合成Synthesis of Example 34 Compound 34
Figure PCTCN2022096512-appb-000140
Figure PCTCN2022096512-appb-000140
Figure PCTCN2022096512-appb-000141
Figure PCTCN2022096512-appb-000141
步骤1：化合物34的合成Step 1: Synthesis of Compound 34
在单口瓶中，将化合物33c(200mg)和化合物31b(115mg)溶于二甲亚砜(5mL)中，再加入N,N-二异丙基乙胺(230mg)，升温至90℃反应4小时。反应完毕后，反应液冷至室温，粗品经过反相纯化(洗脱剂：水/乙腈)得到化合物34(70mg)。In a single-necked bottle, compound 33c (200mg) and compound 31b (115mg) were dissolved in dimethyl sulfoxide (5mL), then N,N-diisopropylethylamine (230mg) was added, and the temperature was raised to 90°C for reaction 4 Hour. After the reaction was completed, the reaction solution was cooled to room temperature, and the crude product was purified by reverse phase (eluent: water/acetonitrile) to obtain compound 34 (70 mg).
HRMS(ESI)m/z[M+H] +：837.26402。 1H NMR(500MHz,DMSO-d 6)δ11.22(s,1H),11.08(s,1H),8.41(d,J＝5.4Hz,1H),8.32(s,1H),7.98(t,J＝8.0Hz,2H),7.71–7.52(m,2H),7.35(d,J＝5.8Hz,1H),7.26(d,J＝5.0Hz,1H),7.00(d,J＝5.0Hz,1H),6.91(d,J＝7.6Hz,1H),5.98(s,2H),5.06(dd,J＝12.8,5.5Hz,1H),4.19(t,J＝7.8Hz,2H),3.96(t,J＝6.5Hz,2H),3.63(t,J＝6.1Hz,1H),3.08(d,J＝9.8Hz,8H),2.88(ddd,J＝17.6,13.9,5.5Hz,1H),2.58(d,J＝19.2Hz,1H),2.08–1.97(m,2H),1.96–1.85(m,4H). 13C NMR(126MHz,DMSO-d 6)δ173.23,170.47,167.29,166.89,165.31,158.55,153.66,151.94,149.93,145.55,144.46,135.55,132.97,129.81,127.93,124.58,120.52,118.88,116.38,116.18,114.72,113.84,106.07,59.87,56.91,54.58,49.40,47.59,35.53,33.95,31.44,22.62,14.56. HRMS (ESI) m/z [M+H] + : 837.26402. 1 H NMR (500MHz, DMSO-d 6 )δ11.22(s,1H),11.08(s,1H),8.41(d,J=5.4Hz,1H),8.32(s,1H),7.98(t, J＝8.0Hz, 2H), 7.71–7.52(m, 2H), 7.35(d, J＝5.8Hz, 1H), 7.26(d, J＝5.0Hz, 1H), 7.00(d, J＝5.0Hz, 1H), 6.91(d, J=7.6Hz, 1H), 5.98(s, 2H), 5.06(dd, J=12.8, 5.5Hz, 1H), 4.19(t, J=7.8Hz, 2H), 3.96( t,J=6.5Hz,2H),3.63(t,J=6.1Hz,1H),3.08(d,J=9.8Hz,8H),2.88(ddd,J=17.6,13.9,5.5Hz,1H), 2.58(d,J=19.2Hz,1H),2.08–1.97(m,2H),1.96–1.85(m,4H). 13 C NMR(126MHz,DMSO-d 6 )δ173.23,170.47,167.29,166.89,165.31 ,158.55,153.66,151.94,149.93,145.55,144.46,135.55,132.97,129.81,127.93,124.58,120.52,118.88,116.38,116.18,114.72,113.84,106.07,59.87,56.91,54.58,49.40,47.59,35.53,33.95 ,31.44,22.62,14.56.
实施例35 化合物35的制备The preparation of embodiment 35 compound 35
Figure PCTCN2022096512-appb-000142
Figure PCTCN2022096512-appb-000142
步骤1：中间体35b的制备Step 1: Preparation of Intermediate 35b
向反应瓶中依次加入中间体33c(0.5g)、1-Boc-3-氮杂环丁酮(0.305g)、氰基硼氢化钠(0.112g)、MeOH(20mL)和乙酸(0.107g)，将混合物室温反应过夜。反应液中加入二氯甲烷(150mL)和水(150mL)，有机相分离，无水硫酸钠干燥，过滤，浓缩，浓缩得到中间体35b(0.68g)。Intermediate 33c (0.5 g), 1-Boc-3-azetidinone (0.305 g), sodium cyanoborohydride (0.112 g), MeOH (20 mL) and acetic acid (0.107 g) were sequentially added to the reaction flask , and the mixture was reacted overnight at room temperature. Dichloromethane (150 mL) and water (150 mL) were added to the reaction solution, the organic phase was separated, dried over anhydrous sodium sulfate, filtered, concentrated, and concentrated to obtain intermediate 35b (0.68 g).
MS(ESI,[M+H] +)m/z：717.5. MS (ESI, [M+H] + ) m/z: 717.5.
步骤2：中间体35c的制备Step 2: Preparation of Intermediate 35c
向反应瓶中加入中间体35b(0.63g)、DCM(40mL)、4M盐酸的二氧六环溶液(0.483mL,1.932mmol)，将混合物室温反应2h。反应液中加入饱和碳酸氢钠溶液(100mL)。然后用100mL DCM萃取2次，有机相分离，用饱和氯化钠溶液洗涤后用无水硫酸钠干燥，过滤，浓缩得到中间体35c(0.42g)。Intermediate 35b (0.63 g), DCM (40 mL), 4M hydrochloric acid in dioxane (0.483 mL, 1.932 mmol) were added to the reaction flask, and the mixture was reacted at room temperature for 2 h. A saturated sodium bicarbonate solution (100 mL) was added to the reaction solution. Then it was extracted twice with 100mL DCM, the organic phase was separated, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated to give intermediate 35c (0.42g).
MS(ESI,[M+H] +)m/z：617.5. MS (ESI, [M+H] + ) m/z: 617.5.
步骤3：化合物35的制备Step 3: Preparation of compound 35
向反应瓶中依次加入中间体35c(0.4g)、中间体13b(0.054g)、N,N-二异丙基乙胺(0.050g)和DMSO(6mL)，将混合物加热至80℃反应5h。冷却至室温，向反应液中加入100mL DCM和100mL水。有机相分离，用饱和氯化钠溶液(100mL)洗涤后用无水硫酸钠干燥，过滤浓缩，浓缩物经硅胶柱层析分离纯化得到化合物35(0.015g)。Add intermediate 35c (0.4g), intermediate 13b (0.054g), N,N-diisopropylethylamine (0.050g) and DMSO (6mL) to the reaction flask in sequence, and heat the mixture to 80°C for 5h . After cooling to room temperature, 100 mL of DCM and 100 mL of water were added to the reaction solution. The organic phase was separated, washed with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated, and the concentrate was separated and purified by silica gel column chromatography to obtain compound 35 (0.015 g).
MS(ESI,[M+H] +)m/z：873.5。 1H NMR(500MHz,DMSO-d 6)δ11.13(s,2H),8.41(d,J＝5.3Hz,1H), 8.32(d,J＝2.0Hz,1H),8.02–7.94(m,2H),7.63(dd,J＝7.9,2.2Hz,2H),7.35(dd,J＝5.4,2.0Hz,1H),7.25(d,J＝4.9Hz,1H),6.99(dd,J＝7.7,4.9Hz,1H),6.78(d,J＝2.1Hz,1H),6.64(dd,J＝8.3,2.2Hz,1H),5.98(s,2H),5.05(dd,J＝12.8,5.5Hz,1H),4.06–3.99(m,2H),3.81–3.76(m,2H),3.60(td,J＝7.1,3.4Hz,3H),3.27(t,J＝6.6Hz,4H),3.08–3.04(m,4H),2.99(t,J＝6.1Hz,2H),2.89–2.83(m,1H),2.65–2.54(m,2H),2.00(dp,J＝10.8,3.5Hz,1H),1.92–1.83(m,4H). MS (ESI, [M+H] + ) m/z: 873.5. 1 H NMR (500MHz, DMSO-d 6 )δ11.13(s, 2H), 8.41(d, J=5.3Hz, 1H), 8.32(d, J=2.0Hz, 1H), 8.02–7.94(m, 2H), 7.63(dd, J=7.9, 2.2Hz, 2H), 7.35(dd, J=5.4, 2.0Hz, 1H), 7.25(d, J=4.9Hz, 1H), 6.99(dd, J=7.7 ,4.9Hz,1H),6.78(d,J=2.1Hz,1H),6.64(dd,J=8.3,2.2Hz,1H),5.98(s,2H),5.05(dd,J=12.8,5.5Hz ,1H),4.06–3.99(m,2H),3.81–3.76(m,2H),3.60(td,J＝7.1,3.4Hz,3H),3.27(t,J＝6.6Hz,4H),3.08– 3.04(m,4H),2.99(t,J=6.1Hz,2H),2.89–2.83(m,1H),2.65–2.54(m,2H),2.00(dp,J=10.8,3.5Hz,1H) ,1.92–1.83(m,4H).
实施例36 化合物36的制备The preparation of embodiment 36 compound 36
Figure PCTCN2022096512-appb-000143
Figure PCTCN2022096512-appb-000143
步骤1：中间体36b的制备Step 1: Preparation of intermediate 36b
向反应瓶中，依次加入中间体13b(1.0g)、3-羟甲基氮杂环丁烷盐酸盐(0.534g)、NMP(15mL)及N,N-二异丙基乙胺(1.863g)，N 2保护下，80℃加热4小时，反应完全，反应液旋蒸后残余物用DCM-MeOH(10:1，30mL×3)萃取，有机层合并后用饱和食盐水(50mL×1)洗涤，萃取液干燥过滤，滤液旋蒸干得到中间体36b(2.49g)。 In the reaction flask, add intermediate 13b (1.0g), 3-hydroxymethylazetidine hydrochloride (0.534g), NMP (15mL) and N,N-diisopropylethylamine (1.863 g), under the protection of N 2 , heated at 80°C for 4 hours, the reaction was complete, and the residue was extracted with DCM-MeOH (10:1, 30mL×3) after the reaction solution was rotary evaporated, and the organic layers were combined and washed with saturated brine (50mL×3) 1) Washing, drying and filtering the extract, and rotary evaporation of the filtrate to obtain intermediate 36b (2.49g).
MS(ESI,[M-H] -)m/z：342.0。 1H NMR(500MHz,DMSO-d 6)δ11.06(s,1H),7.63(d,J＝8.3Hz,1H),6.76(d,J＝2.1Hz,1H),6.63(dd,J＝8.3,2.1Hz,1H),5.06(dd,J＝12.9,5.4Hz,1H),4.84(t,J＝5.3Hz,1H),4.04(td,J＝7.7,7.1,5.2Hz,2H),3.77(dd,J＝8.4,5.3Hz,2H),3.60(t,J＝5.7Hz,2H),2.88(dddd,J＝15.3,6.8,4.8,2.4Hz,2H),2.58–2.48(m,3H). MS (ESI, [MH] - ) m/z: 342.0. 1 H NMR (500MHz, DMSO-d 6 )δ11.06(s, 1H), 7.63(d, J=8.3Hz, 1H), 6.76(d, J=2.1Hz, 1H), 6.63(dd, J= 8.3,2.1Hz,1H),5.06(dd,J=12.9,5.4Hz,1H),4.84(t,J=5.3Hz,1H),4.04(td,J=7.7,7.1,5.2Hz,2H), 3.77(dd, J=8.4,5.3Hz,2H),3.60(t,J=5.7Hz,2H),2.88(dddd,J=15.3,6.8,4.8,2.4Hz,2H),2.58–2.48(m, 3H).
步骤2：中间体36c的制备Step 2: Preparation of Intermediate 36c
向反应瓶中，依次加入中间体36b(0.25g)、DCM(10mL)及戴斯马丁氧化剂(0.911g)，N 2保护下，室温反应2小时，反应完全，反应液用DCM-MeOH(20:1，30mL×2)萃取，有机层合并后用饱和食盐水(50mL×1)洗涤，萃取液干燥过滤，滤液旋蒸后干得到中间体36c(400mg)。 In the reaction flask, add intermediate 36b (0.25g), DCM (10mL) and Dess Martin oxidant (0.911g) successively, under N protection, react at room temperature for 2 hours, the reaction is complete, and the reaction solution is washed with DCM-MeOH (20 :1, 30mL×2) extraction, the organic layers were combined and washed with saturated brine (50mL×1), the extract was dried and filtered, and the filtrate was rotary evaporated and dried to obtain intermediate 36c (400mg).
步骤3：化合物36的制备Step 3: Preparation of compound 36
向反应瓶中，依次加入中间体1j(230mgl)、中间体36c(360mg)、MeOH(10mL)，再加入氰基硼氢化钠(77mg)及冰乙酸(24.52mg)，N 2保护下，室温反应过夜，反应完全，反应液旋蒸后残余物用C 18反相柱纯化(10nM乙酸铵水溶液-乙腈)洗脱，过柱液合并，DCM-MeOH(10:1)萃取后旋蒸干得到化合物36(80mg)。 Into the reaction flask, sequentially add intermediate 1j (230mgl), intermediate 36c (360mg), MeOH (10mL), then add sodium cyanoborohydride (77mg) and glacial acetic acid (24.52mg), under N2 protection, room temperature Reacted overnight, the reaction was complete, and the residue was purified by C 18 reverse phase column (10nM ammonium acetate aqueous solution-acetonitrile) after the reaction solution was evaporated, and the column liquid was combined, extracted with DCM-MeOH (10:1) and evaporated to dryness to obtain Compound 36 (80 mg).
MS(ESI,[M+H] +)m/z：832.5。 1H NMR(500MHz,DMSO-d 6)δ11.23(s,1H),11.06(s,1H),8.42(d,J＝5.3Hz,1H),8.32(d,J＝1.8Hz,1H),8.02–7.94(m,2H),7.63(dt,J＝8.1,3.7Hz,2H),7.35(dd,J＝5.4,2.0Hz,1H),7.26(d,J＝5.0Hz,1H),7.00(d,J＝4.9Hz,1H),6.76(d,J＝2.1Hz,1H),6.63(dd,J＝8.4,2.1Hz,1H),5.98(s,2H),5.05(dd,J＝12.7,5.5Hz,1H),4.09(t,J＝7.9Hz,2H),3.69(dd,J＝8.4,5.1Hz,2H),3.06(d,J＝5.0Hz,8H),2.92–2.83(m,1H),2.78–2.73(m,1H),2.70(d,J＝7.2Hz,2H),2.62–2.53(m,2H),2.00(ddd,J＝10.5,5.9,3.2Hz,1H),1.87(t,J＝5.4Hz,4H). 13C NMR(126MHz,DMSO-d 6)δ173.25,170.56,167.95,167.63,165.31,155.66,153.65,151.92,149.93,145.57,144.46,134.28,132.97,127.93,126.68,126.56,125.25,124.64,120.52,117.09,116.17,114.71,114.49,113.82,104.78,64.48,63.01,55.79,49.17,47.62,35.78,34.68,31.45,28.47,22.68. MS (ESI, [M+H] + ) m/z: 832.5. 1 H NMR (500MHz,DMSO-d 6 )δ11.23(s,1H),11.06(s,1H),8.42(d,J=5.3Hz,1H),8.32(d,J=1.8Hz,1H) ,8.02–7.94(m,2H),7.63(dt,J＝8.1,3.7Hz,2H),7.35(dd,J＝5.4,2.0Hz,1H),7.26(d,J＝5.0Hz,1H), 7.00(d,J=4.9Hz,1H),6.76(d,J=2.1Hz,1H),6.63(dd,J=8.4,2.1Hz,1H),5.98(s,2H),5.05(dd,J =12.7,5.5Hz,1H),4.09(t,J=7.9Hz,2H),3.69(dd,J=8.4,5.1Hz,2H),3.06(d,J=5.0Hz,8H),2.92–2.83 (m,1H),2.78–2.73(m,1H),2.70(d,J＝7.2Hz,2H),2.62–2.53(m,2H),2.00(ddd,J＝10.5,5.9,3.2Hz,1H ),1.87(t,J=5.4Hz,4H). 13 C NMR(126MHz,DMSO-d 6 )δ173.25,170.56,167.95,167.63,165.31,155.66,153.65,151.92,149.93,145.57,144.46,1332.298, ,127.93,126.68,126.56,125.25,124.64,120.52,117.09,116.17,114.71,114.49,113.82,104.78,64.48,63.01,55.79,49.17,47.62,35.78,21.48,34.65
实施例37 化合物37的制备The preparation of embodiment 37 compound 37
Figure PCTCN2022096512-appb-000144
Figure PCTCN2022096512-appb-000144
步骤1：中间体37b-1和37b-2的合成Step 1: Synthesis of intermediates 37b-1 and 37b-2
向单口瓶中依次加入中间体1j(2.0g)、1-叔丁氧羰基-3-吡咯烷酮(0.88g)、乙酸(0.02g)、氰基硼氢化钠(0.74g)及甲醇(50mL)，常温搅拌反应4h，反应完全，将反应液倒入纯化水(50mL)中，加入二氯甲烷/甲醇＝10/1溶液(150mL)，萃取分层，有机相用饱和氯化钠水溶液洗涤，用无水硫酸钠干燥，浓缩有机相，过硅胶柱纯化得粗品37b(1.34g)，所得粗品中间体37b经高压制备液相分离(CHIRALARTCellulose-SC色谱柱；乙醇：正己烷＝30:70)，先出峰的为S构型中间体37b-1(600mg)，后出峰的为R构型中间体37b-2(510mg)。Intermediate 1j (2.0g), 1-tert-butoxycarbonyl-3-pyrrolidone (0.88g), acetic acid (0.02g), sodium cyanoborohydride (0.74g) and methanol (50mL) were added sequentially to the one-necked flask, Stir the reaction at room temperature for 4 h, and the reaction is complete. Pour the reaction solution into purified water (50 mL), add dichloromethane/methanol=10/1 solution (150 mL), extract and separate layers, and wash the organic phase with saturated aqueous sodium chloride solution. Dry over anhydrous sodium sulfate, concentrate the organic phase, and purify the crude product 37b (1.34g) through a silica gel column. The obtained crude intermediate 37b is separated by high-pressure preparative liquid phase (CHIRALARTCellulose-SC column; ethanol:n-hexane=30:70), The S-configuration intermediate 37b-1 (600 mg) was the first peak, and the R-configuration intermediate 37b-2 (510 mg) was the last peak.
MS(ESI,[M+H] +)m/z：676.3。 1H NMR(500MHz,DMSO-d 6)δ8.42(d,J＝5.3Hz,1H),8.32(d,J＝1.9Hz,1H),8.03–7.94(m,2H),7.62(t,J＝7.9Hz,1H),7.35(dd,J＝5.3,2.0Hz,1H),7.25(d,J＝4.9Hz,1H),7.00(d,J＝5.0Hz,1H),5.98(s,2H),3.44(q,J＝7.0Hz,2H),3.24(dd,J＝9.1,4.3Hz,2H),3.18(td,J＝11.2,5.5Hz,2H),3.05(dd,J＝7.3,4.2Hz,4H),2.96(d,J＝2.5Hz,2H),2.92(s,1H),2.81(q,J＝7.2Hz,2H),1.91–1.78(m,4H),1.74(d,J＝8.7Hz,1H),1.39(s,9H). MS (ESI, [M+H] + ) m/z: 676.3. 1 H NMR (500MHz, DMSO-d 6 )δ8.42(d, J=5.3Hz, 1H), 8.32(d, J=1.9Hz, 1H), 8.03–7.94(m, 2H), 7.62(t, J＝7.9Hz, 1H), 7.35(dd, J＝5.3, 2.0Hz, 1H), 7.25(d, J＝4.9Hz, 1H), 7.00(d, J＝5.0Hz, 1H), 5.98(s, 2H), 3.44(q, J=7.0Hz, 2H), 3.24(dd, J=9.1, 4.3Hz, 2H), 3.18(td, J=11.2, 5.5Hz, 2H), 3.05(dd, J=7.3 ,4.2Hz,4H),2.96(d,J=2.5Hz,2H),2.92(s,1H),2.81(q,J=7.2Hz,2H),1.91–1.78(m,4H),1.74(d ,J＝8.7Hz,1H),1.39(s,9H).
步骤2：中间体37c的合成Step 2: Synthesis of intermediate 37c
在单口瓶中，将化合物37b-1(600mg)溶于二氯甲烷(5mL)中，再加入4M盐酸二氧六环溶液(647mg,4.44mL,17.75mmol)，室温反应1小时。反应完毕后，反应液减压蒸除溶剂，用50mL二氯甲烷和50mL水溶解后，加入饱和碳酸氢钠溶液调节pH至弱碱性(pH＝8～9)，有机相分离，有机相再用二氯甲烷：甲醇＝10：1(50mL)萃取2次，合并有机相，无水硫酸钠干燥，过滤，减压蒸除溶剂，得到中间体37c(500mg)。In a one-necked bottle, compound 37b-1 (600mg) was dissolved in dichloromethane (5mL), and then 4M dioxane hydrochloride solution (647mg, 4.44mL, 17.75mmol) was added, and reacted at room temperature for 1 hour. After the reaction was completed, the reaction solution was evaporated under reduced pressure to remove the solvent, dissolved with 50mL of dichloromethane and 50mL of water, added saturated sodium bicarbonate solution to adjust the pH to weakly alkaline (pH=8～9), the organic phase was separated, and the organic phase was re-dissolved. Extracted twice with dichloromethane: methanol = 10:1 (50 mL), combined the organic phases, dried over anhydrous sodium sulfate, filtered, and evaporated the solvent under reduced pressure to obtain intermediate 37c (500 mg).
MS(ESI,[M+H] +)m/z：575.9。 1H NMR(500MHz,DMSO-d 6)δ8.42(dd,J＝5.4,0.6Hz,1H),8.32(dd,J＝2.0,0.6Hz,1H),8.03–7.94(m,2H),7.62(t,J＝7.9Hz,1H),7.35(dd,J＝5.4,2.0Hz,1H),7.25(d,J＝4.9Hz,1H),7.00(d,J＝5.0Hz,1H),5.99(s,2H),3.05(t,J＝5.5Hz,5H),2.96(p,J＝7.3Hz,5H),2.89–2.81(m,2H),2.74–2.63(m,2H),2.54(d,J＝3.1Hz,1H),1.84(t,J＝5.5Hz,4H),1.58(dq,J＝14.4,7.3,6.4Hz,1H),1.44–1.37(m,1H). 13C NMR(126MHz,DMSO-d 6)δ165.31,158.55,153.68,151.94,149.93,145.57,144.46,132.95,127.93,124.63,124.57,120.51,116.37,116.18,114.72,113.83,106.04,68.71,62.61,50.72,47.60,46.09,35.85,33.52,30.37. MS (ESI, [M+H] + ) m/z: 575.9. 1 H NMR (500MHz, DMSO-d 6 )δ8.42(dd, J=5.4,0.6Hz,1H),8.32(dd,J=2.0,0.6Hz,1H),8.03–7.94(m,2H), 7.62(t, J=7.9Hz, 1H), 7.35(dd, J=5.4, 2.0Hz, 1H), 7.25(d, J=4.9Hz, 1H), 7.00(d, J=5.0Hz, 1H), 5.99(s,2H),3.05(t,J=5.5Hz,5H),2.96(p,J=7.3Hz,5H),2.89–2.81(m,2H),2.74–2.63(m,2H),2.54 (d,J=3.1Hz,1H), 1.84 (t,J=5.5Hz,4H),1.58(dq,J=14.4,7.3,6.4Hz,1H),1.44–1.37(m,1H). NMR(126MHz,DMSO-d 6 )δ165.31,158.55,153.68,151.94,149.93,145.57,144.46,132.95,127.93,124.63,124.57,120.51,116.37,116.18,114.72,113.83,106.04,68.71,62.61,50.72,47.60 ,46.09,35.85,33.52,30.37.
步骤3：化合物37的合成Step 3: Synthesis of Compound 37
在单口瓶中，将化合物37c(150mg)和化合物13b(69.0mg)溶于二甲亚砜(5mL)中，再加入N,N-二异丙基乙胺(161mg)，升温至90℃反应4小时。反应完毕后，反应液冷至室温，粗品经过反相纯化(洗脱剂：水/乙腈)得到化合物37(100mg)。In a single-necked bottle, dissolve compound 37c (150 mg) and compound 13b (69.0 mg) in dimethyl sulfoxide (5 mL), then add N,N-diisopropylethylamine (161 mg), and heat up to 90 ° C for reaction 4 hours. After the reaction was completed, the reaction liquid was cooled to room temperature, and the crude product was purified by reverse phase (eluent: water/acetonitrile) to obtain compound 37 (100 mg).
HRMS(ESI)m/z[M+H] +:832.28785。 1H NMR(500MHz,DMSO-d 6)δ11.22(s,1H),11.07(s,1H),8.41(d,J＝5.3Hz,1H),8.32(d,J＝1.9Hz,1H),8.04–7.94(m,2H),7.62(t,J＝7.9Hz,2H),7.35(dd,J＝5.3,1.9Hz,1H),7.25(d,J＝5.0Hz,1H),7.00(d,J＝4.9Hz,1H),6.90(d,J＝2.2Hz,1H),6.79(dd,J＝8.6,2.2Hz,1H), 5.98(s,2H),5.05(dd,J＝12.9,5.4Hz,1H),3.42(s,2H),3.40–3.35(m,1H),3.17(d,J＝10.2Hz,2H),3.06(d,J＝6.3Hz,8H),2.89(ddd,J＝17.3,14.0,5.5Hz,1H),2.53(d,J＝8.9Hz,2H),1.99(dddd,J＝24.2,16.5,7.4,3.4Hz,2H),1.86(t,J＝5.6Hz,5H). 13C NMR(126MHz,DMSO-d 6)δ173.28,170.62,168.19,167.71,165.32,153.66,152.34,151.93,149.93,145.56,144.47,134.51,132.97,127.93,125.41,124.65,124.58,120.52,116.38,115.97,115.67,114.72,105.95,66.83,66.57,62.43,51.78,49.16,47.59,46.95,35.82,33.41,31.47,28.80,22.74. HRMS (ESI) m/z [M+H] + : 832.28785. 1 H NMR (500MHz,DMSO-d 6 )δ11.22(s,1H),11.07(s,1H),8.41(d,J=5.3Hz,1H),8.32(d,J=1.9Hz,1H) ,8.04–7.94(m,2H),7.62(t,J=7.9Hz,2H),7.35(dd,J=5.3,1.9Hz,1H),7.25(d,J=5.0Hz,1H),7.00( d,J=4.9Hz,1H),6.90(d,J=2.2Hz,1H),6.79(dd,J=8.6,2.2Hz,1H), 5.98(s,2H),5.05(dd,J=12.9 ,5.4Hz,1H),3.42(s,2H),3.40–3.35(m,1H),3.17(d,J＝10.2Hz,2H),3.06(d,J＝6.3Hz,8H),2.89(ddd ,J=17.3,14.0,5.5Hz,1H), 2.53(d,J=8.9Hz,2H),1.99(dddd,J=24.2,16.5,7.4,3.4Hz,2H),1.86(t,J=5.6 Hz,5H) .13C NMR(126MHz,DMSO-d 6 )δ173.28,170.62,168.19,167.71,165.32,153.66,152.34,151.93,149.93,145.56,144.47,134.51,132.95,1124.943, 120.52, 116.38, 115.97, 115.67, 114.72, 105.95, 66.83, 66.57, 62.43, 51.78, 49.16, 47.59, 46.95, 35.82, 33.41, 31.47, 28.80, 22.74.
实施例38 化合物38的制备Example 38 Preparation of Compound 38
Figure PCTCN2022096512-appb-000145
Figure PCTCN2022096512-appb-000145
步骤1：中间体38b的合成Step 1: Synthesis of intermediate 38b
在单口瓶中，将化合物37c(300mg)和3-氧杂氮杂环丁烷-1-羧酸叔丁酯(128mg)溶于甲醇(5mL)中，再加入氰基硼氢化钠(62.8mg)，加入1滴醋酸，室温反应2小时，补加3-氧杂氮杂环丁烷-1-羧酸叔丁酯(128mg)，室温反应16小时。反应完毕后，向体系中加入二氯甲烷(50mL)和水(100mL)，有机相分离，水相用二氯甲烷(50mL)萃取2次，合并有机相，无水硫酸钠干燥，过滤，减压蒸除溶剂，得到中间体38b(250mg)。In a one-necked bottle, compound 37c (300 mg) and tert-butyl 3-oxazetidine-1-carboxylate (128 mg) were dissolved in methanol (5 mL), and then sodium cyanoborohydride (62.8 mg ), add 1 drop of acetic acid, react at room temperature for 2 hours, add tert-butyl 3-oxazetidine-1-carboxylate (128 mg), and react at room temperature for 16 hours. After completion of the reaction, add dichloromethane (50mL) and water (100mL) to the system, separate the organic phase, extract the aqueous phase twice with dichloromethane (50mL), combine the organic phases, dry over anhydrous sodium sulfate, filter, reduce The solvent was removed by autoclaving to afford intermediate 38b (250 mg).
MS(ESI,[M+H] +)m/z：731.3。 1H NMR(500MHz,DMSO-d 6)δ8.41(d,J＝5.3Hz,1H),8.32(d,J＝1.9Hz,1H),8.03–7.94(m,2H),7.62(t,J＝7.9Hz,1H),7.35(dd,J＝5.4,2.0Hz,1H),7.25(d,J＝5.0Hz,1H),7.00(d,J＝4.9Hz,1H),5.98(s,2H),4.37(tt,J＝6.7,4.5Hz,2H),3.98(t,J＝7.9Hz,4H),3.57(dd,J＝9.1,4.5Hz,4H),3.05(t,J＝5.5Hz,4H),2.93(s,5H),2.15(dd,J＝9.2,4.3Hz,1H),1.85(t,J＝5.5Hz,4H),1.37(s,9H). 13C NMR(126MHz,DMSO-d 6)δ165.32,156.13,156.07,153.69,151.94,149.93,145.57,144.46,132.96,127.93,124.57,120.50,116.38,116.18,114.72,106.05,78.91,78.85,66.34,62.25,60.36,54.28,52.43,49.75,47.61,35.80,33.77,28.53. MS (ESI, [M+H] + ) m/z: 731.3. 1 H NMR (500MHz, DMSO-d 6 ) δ8.41(d, J=5.3Hz, 1H), 8.32(d, J=1.9Hz, 1H), 8.03–7.94(m, 2H), 7.62(t, J＝7.9Hz, 1H), 7.35(dd, J＝5.4, 2.0Hz, 1H), 7.25(d, J＝5.0Hz, 1H), 7.00(d, J＝4.9Hz, 1H), 5.98(s, 2H), 4.37(tt, J=6.7, 4.5Hz, 2H), 3.98(t, J=7.9Hz, 4H), 3.57(dd, J=9.1, 4.5Hz, 4H), 3.05(t, J=5.5 Hz, 4H), 2.93(s, 5H), 2.15(dd, J＝9.2, 4.3Hz, 1H), 1.85(t, J＝5.5Hz, 4H), 1.37(s, 9H). 13 C NMR (126MHz ,DMSO-d 6 )δ165.32,156.13,156.07,153.69,151.94,149.93,145.57,144.46,132.96,127.93,124.57,120.50,116.38,116.18,114.72,106.05,78.91,78.85,66.34,62.25,60.36,54.28, 52.43, 49.75, 47.61, 35.80, 33.77, 28.53.
步骤2：中间体38c的合成Step 2: Synthesis of intermediate 38c
在单口瓶中，将化合物38b(230mg)溶于二氯甲烷(3mL)中，再加入4M盐酸二氧六环溶液(196mg,1.344mL,5.38mmol)，室温反应1小时。反应完毕后，反应液减压蒸除溶剂，用50mL二氯甲烷和50mL水溶解后，加入饱和碳酸氢钠溶液调节pH至弱碱性(pH＝8～9)，有机相分离，有机相再用二氯甲烷：甲醇＝10：1(50mL)萃取2次，合并有机相，无水硫酸钠干燥，过滤，减压蒸除溶剂，得到中间体38c(200mg)。In a one-necked bottle, compound 38b (230 mg) was dissolved in dichloromethane (3 mL), and 4M dioxane hydrochloride solution (196 mg, 1.344 mL, 5.38 mmol) was added, and reacted at room temperature for 1 hour. After the reaction was completed, the reaction solution was evaporated under reduced pressure to remove the solvent, dissolved with 50mL of dichloromethane and 50mL of water, added saturated sodium bicarbonate solution to adjust the pH to weakly alkaline (pH=8～9), the organic phase was separated, and the organic phase was re-dissolved. Extracted twice with dichloromethane: methanol = 10:1 (50 mL), combined the organic phases, dried over anhydrous sodium sulfate, filtered, and evaporated the solvent under reduced pressure to obtain intermediate 38c (200 mg).
MS(ESI,[M+H] +)m/z：631.3。 1H NMR(500MHz,DMSO-d 6)δ8.41(dt,J＝5.6,1.8Hz,1H),8.31(d,J＝2.0Hz,1H),8.00(dtd,J＝9.7,4.8,1.7Hz,2H),7.62(tt,J＝8.0,1.5Hz,1H),7.38–7.21(m,2H),7.07–6.95(m,1H),6.05–5.93(m,2H),3.40–3.33(m,4H),3.10–3.01(m,4H),2.92(d,J＝7.9Hz,5H),2.71–2.62(m,1H),2.43–2.34(m,1H),2.08(dq,J＝17.4,6.7,5.8Hz,2H),1.84(d,J＝5.9Hz,3H). 13C NMR(126MHz,DMSO-d 6)δ165.37,153.96,151.93,149.94,145.56,145.13,144.39,132.92,124.65,120.38,114.80,113.81,106.07,72.47,70.44,62.28,47.60,47.05,44.93,42.51,35.81,33.79,31.82,30.09,27.09,19.30,14.27. MS (ESI, [M+H] + ) m/z: 631.3. 1 H NMR (500MHz, DMSO-d 6 ) δ8.41(dt, J=5.6, 1.8Hz, 1H), 8.31(d, J=2.0Hz, 1H), 8.00(dtd, J=9.7, 4.8, 1.7 Hz,2H),7.62(tt,J＝8.0,1.5Hz,1H),7.38–7.21(m,2H),7.07–6.95(m,1H),6.05–5.93(m,2H),3.40–3.33( m,4H),3.10–3.01(m,4H),2.92(d,J＝7.9Hz,5H),2.71–2.62(m,1H),2.43–2.34(m,1H),2.08(dq,J＝ 17.4,6.7,5.8Hz,2H),1.84(d,J=5.9Hz,3H). 13 C NMR(126MHz,DMSO-d 6 )δ165.37,153.96,151.93,149.94,145.56,145.13,144.39,132.92,124.65 ,120.38,114.80,113.81,106.07,72.47,70.44,62.28,47.60,47.05,44.93,42.51,35.81,33.79,31.82,30.09,27.09,19.30,14.27.
步骤3：化合物38的合成Step 3: Synthesis of Compound 38
在单口瓶中，将化合物38c(200mg)和13b(53.5mg)溶于二甲亚砜(4mL)中，再加入N,N-二异丙基乙胺(125mg)，升温至90℃反应4小时。反应完毕后，反应液冷至室温，粗品经过反相纯化(洗脱剂：水/乙腈)得到化合物38(30mg)。In a single-necked bottle, compounds 38c (200mg) and 13b (53.5mg) were dissolved in dimethylsulfoxide (4mL), then N,N-diisopropylethylamine (125mg) was added, and the temperature was raised to 90°C for reaction 4 Hour. After the reaction was completed, the reaction solution was cooled to room temperature, and the crude product was purified by reverse phase (eluent: water/acetonitrile) to obtain compound 38 (30 mg).
HRMS(ESI)m/z[M+H] +:887.33558。 1H NMR(500MHz,DMSO-d 6)δ11.23(s,1H),11.07(s,1H),8.42(d,J＝5.4Hz,1H),8.32(d,J＝1.9Hz,1H),8.04–7.94(m,2H),7.69–7.58(m,2H),7.35(dd,J＝5.3,2.0Hz,1H),7.25(d,J＝5.0Hz,1H),7.00(d,J＝4.9Hz,1H),6.77(d,J＝2.1Hz,1H),6.63(dd,J＝8.4,2.2Hz,1H), 5.98(s,2H),5.05(dd,J＝12.7,5.4Hz,1H),4.08(t,J＝7.8Hz,2H),3.88(dd,J＝8.8,4.8Hz,2H),3.50(tt,J＝10.6,4.9Hz,2H),3.18–2.97(m,8H),2.88(ddd,J＝16.5,13.6,5.4Hz,2H),2.64(dd,J＝9.4,6.6Hz,1H),2.61–2.52(m,3H),2.28(d,J＝6.6Hz,1H),2.06–1.96(m,1H),1.86(t,J＝5.3Hz,4H),1.80–1.73(m,1H),1.49(dd,J＝12.1,5.8Hz,1H). 13C NMR(126MHz,DMSO-d 6)δ173.26,170.58,167.64,165.32,155.38,153.66,151.94,149.94,145.55,144.47,134.31,132.97,127.94,125.30,120.53,117.21,116.38,116.19,114.72,113.84,104.90,62.22,55.94,53.08,49.77,49.18,47.57,35.71,33.74,31.45,22.68. HRMS (ESI) m/z [M+H] + : 887.33558. 1 H NMR (500MHz,DMSO-d 6 )δ11.23(s,1H),11.07(s,1H),8.42(d,J=5.4Hz,1H),8.32(d,J=1.9Hz,1H) ,8.04–7.94(m,2H),7.69–7.58(m,2H),7.35(dd,J＝5.3,2.0Hz,1H),7.25(d,J＝5.0Hz,1H),7.00(d,J =4.9Hz,1H),6.77(d,J=2.1Hz,1H),6.63(dd,J=8.4,2.2Hz,1H), 5.98(s,2H),5.05(dd,J=12.7,5.4Hz ,1H),4.08(t,J=7.8Hz,2H),3.88(dd,J=8.8,4.8Hz,2H),3.50(tt,J=10.6,4.9Hz,2H),3.18–2.97(m, 8H), 2.88(ddd, J＝16.5, 13.6, 5.4Hz, 2H), 2.64(dd, J＝9.4, 6.6Hz, 1H), 2.61–2.52(m, 3H), 2.28(d, J＝6.6Hz 13C NMR(126MHz,DMSO-d 6 )δ173.26,170.58,167.64,165.32,155.38,153.66,151.94,149.94,145.55,144.47,134.31,132.97,127.94,125.30,120.53,117.21,116.38,116.19,114.72,113.84,104.90 ,62.22,55.94,53.08,49.77,49.18,47.57,35.71,33.74,31.45,22.68.
实施例39：化合物39的制备Embodiment 39: Preparation of compound 39
Figure PCTCN2022096512-appb-000146
Figure PCTCN2022096512-appb-000146
步骤1：中间体39b的制备Step 1: Preparation of intermediate 39b
向反应瓶中依次加入中间体37b-2(500mg)、盐酸二氧六环溶液(4M，5mL)、乙酸乙酯(10mL)，25℃搅拌反应3.5h。反应完全，反应液浓缩至干，加入纯化水(50mL)、二氯甲烷/甲醇＝10/1溶液(50mL)，搅拌状态下加入饱和碳酸氢钠水溶液(20mL)，萃取分层，有机相用饱和氯化钠水溶液洗涤，用无水硫酸钠干燥，浓缩有机相得中间体39b(468mg)。Intermediate 37b-2 (500mg), dioxane hydrochloride solution (4M, 5mL) and ethyl acetate (10mL) were sequentially added to the reaction flask, and the reaction was stirred at 25°C for 3.5h. The reaction was complete, the reaction solution was concentrated to dryness, purified water (50mL), dichloromethane/methanol=10/1 solution (50mL) was added, saturated aqueous sodium bicarbonate solution (20mL) was added under stirring, the layers were extracted, and the organic phase was used Wash with saturated aqueous sodium chloride, dry over anhydrous sodium sulfate, and concentrate the organic phase to obtain intermediate 39b (468 mg).
MS(ESI,[M+H] +)m/z：576.3。 MS (ESI, [M+H] + ) m/z: 576.3.
步骤3：化合物39的制备Step 3: Preparation of Compound 39
向单口瓶中依次加入中间体39b(180mg)、中间体13b(173mg)、N,N-二异丙基乙胺(81mg)、二甲基亚砜(5mL)，80℃搅拌反应5h，反应完全，反应液通过120g C 18反相柱纯化得化合物39(130mg)。 Add intermediate 39b (180mg), intermediate 13b (173mg), N,N-diisopropylethylamine (81mg) and dimethyl sulfoxide (5mL) to the one-necked bottle in turn, stir at 80°C for 5h, and react Completely, the reaction solution was purified by a 120 g C 18 reverse phase column to obtain compound 39 (130 mg).
HR-MS(ESI,[M+H] +)m/z：854.26393。 1H NMR(500MHz,DMSO-d 6)δ11.23(s,1H),11.11–11.02(m,1H),8.42(d,J＝5.4Hz,1H),8.32(d,J＝1.9Hz,1H),8.02–7.95(m,2H),7.63(q,J＝8.4Hz,2H),7.35(dd,J＝5.3,1.9Hz,1H),7.26(d,J＝4.9Hz,1H),7.00(d,J＝5.0Hz,1H),6.94–6.90(m,1H),6.84–6.78(m,1H),6.01(s,2H),5.06(dd,J＝12.9,5.4Hz,1H),3.64–3.40(m,4H),3.09–3.03(m,4H),2.89(ddd,J＝17.5,14.0,5.5Hz,2H),2.67–2.52(m,2H),2.09–1.96(m,2H),1.90(s,3H),1.23(s,2H). 13C NMR(126MHz,DMSO-d 6)δ173.28,170.61,168.16,167.70,165.31,160.52,158.56,153.66,152.27,151.91,149.94,145.51,144.47,135.58,135.52,134.48,132.97,127.84,126.65,126.53,125.42,124.67,120.53,116.39,116.19,114.72,113.83,106.09,62.30,55.39,49.17,47.48,46.85,33.37,31.83,31.47,22.73. HR-MS (ESI, [M+H] + ) m/z: 854.26393. 1 H NMR (500MHz, DMSO-d 6 )δ11.23(s,1H),11.11–11.02(m,1H),8.42(d,J=5.4Hz,1H),8.32(d,J=1.9Hz, 1H),8.02–7.95(m,2H),7.63(q,J=8.4Hz,2H),7.35(dd,J=5.3,1.9Hz,1H),7.26(d,J=4.9Hz,1H), 7.00(d,J=5.0Hz,1H),6.94–6.90(m,1H),6.84–6.78(m,1H),6.01(s,2H),5.06(dd,J=12.9,5.4Hz,1H) ,3.64–3.40(m,4H),3.09–3.03(m,4H),2.89(ddd,J＝17.5,14.0,5.5Hz,2H),2.67–2.52(m,2H),2.09–1.96(m, 2H),1.90(s,3H),1.23(s,2H). 13 C NMR(126MHz,DMSO-d 6 )δ173.28,170.61,168.16,167.70,165.31,160.52,158.56,153.66,152.27,151.91,149.94, 145.51,144.47,135.58,135.52,134.48,132.97,127.84,126.65,126.53,125.42,124.67,120.53,116.39,116.19,114.72,113.83,106.09,62.30,55.39,49.17,47.48,46.85,33.37,31.83,31.47, 22.73.
实施例40：化合物40的合成Embodiment 40: the synthesis of compound 40
Figure PCTCN2022096512-appb-000147
Figure PCTCN2022096512-appb-000147
Figure PCTCN2022096512-appb-000148
Figure PCTCN2022096512-appb-000148
步骤1：中间体40b的制备Step 1: Preparation of Intermediate 40b
向单口瓶中依次加入中间体39b(285mg)、1-叔丁氧羰基-3-氮杂环丁酮(424mg)、乙酸(44.6mg)、氰基硼氢化钠(187mg)及甲醇(50mL)，常温搅拌反应16h，反应完全，将反应液倒入纯化水(50mL)中，加入二氯甲烷/甲醇＝10/1溶液(50mL)，萃取分层，有机相用饱和氯化钠水溶液洗涤，用无水硫酸钠干燥，浓缩有机相得粗品，过硅胶柱纯化得中间体40b(240mg)。Add intermediate 39b (285mg), 1-tert-butoxycarbonyl-3-azetidinone (424mg), acetic acid (44.6mg), sodium cyanoborohydride (187mg) and methanol (50mL) in turn to a one-necked bottle , stirred at room temperature for 16 hours, the reaction was complete, the reaction solution was poured into purified water (50mL), dichloromethane/methanol=10/1 solution (50mL) was added, the layers were extracted, and the organic phase was washed with saturated aqueous sodium chloride solution. After drying with anhydrous sodium sulfate, the organic phase was concentrated to obtain a crude product, which was purified by silica gel column to obtain intermediate 40b (240 mg).
MS(ESI,[M+H] +)m/z：731.3。 MS (ESI, [M+H] + ) m/z: 731.3.
步骤2：中间体40c的制备Step 2: Preparation of Intermediate 40c
向反应瓶中依次加入中间体40b(240mg)、盐酸二氧六环溶液(4M，5mL)、二氯甲烷(10mL)，25℃搅拌反应3.5h。反应完全，反应液浓缩至干，加入纯化水(50mL)、二氯甲烷/甲醇＝10/1溶液(50mL)，搅拌状态下加入饱和碳酸氢钠水溶液(20mL)，萃取分层，有机相用饱和氯化钠水溶液洗涤，用无水硫酸钠干燥，浓缩有机相得中间体40c(194mg)。Intermediate 40b (240mg), dioxane hydrochloride solution (4M, 5mL) and dichloromethane (10mL) were sequentially added to the reaction flask, and the reaction was stirred at 25°C for 3.5h. The reaction was complete, the reaction solution was concentrated to dryness, purified water (50mL), dichloromethane/methanol=10/1 solution (50mL) was added, saturated aqueous sodium bicarbonate solution (20mL) was added under stirring, the layers were extracted, and the organic phase was used After washing with saturated aqueous sodium chloride, drying over anhydrous sodium sulfate, the organic phase was concentrated to obtain intermediate 40c (194 mg).
MS(ESI,[M+H] +)m/z：631.3。 MS (ESI, [M+H] + ) m/z: 631.3.
步骤3：化合物40的制备Step 3: Preparation of Compound 40
向单口瓶中依次加入中间体40c(194mg)、中间体13b(170mg)、N,N-二异丙基乙胺(79mg)及二甲基亚砜(5mL)，80℃搅拌反应5h，反应完全，反应液通过120g C 18反相柱纯化得化合物40(15mg)。 Add intermediate 40c (194mg), intermediate 13b (170mg), N,N-diisopropylethylamine (79mg) and dimethyl sulfoxide (5mL) to the one-necked bottle in turn, stir at 80°C for 5h, and react Completely, the reaction solution was purified by a 120 g C 18 reverse phase column to obtain compound 40 (15 mg).
HR-MS(ESI,[M+H] +)m/z：887.33094。 1H NMR(500MHz,DMSO-d 6)δ11.23(s,1H),11.06(s,1H),8.42(d,J＝5.3Hz,1H),8.32(d,J＝1.9Hz,1H),8.01–7.95(m,2H),7.67–7.59(m,2H),7.35(dd,J＝5.3,2.0Hz,1H),7.26(d,J＝5.0Hz,1H),7.00(d,J＝5.0Hz,1H),6.78(d,J＝2.1Hz,1H),6.64(dd,J＝8.4,2.2Hz,1H),5.98(s,2H),5.05(dd,J＝12.7,5.5Hz,1H),4.10(t,J＝7.9Hz,2H),3.89(dd,J＝8.9,4.5Hz,2H),3.54–3.46(m,2H),3.37(td,J＝6.0,5.4,2.8Hz,6H),3.06(t,J＝5.5Hz,4H),2.88(ddd,J＝16.5,13.6,5.4Hz,2H),2.60(dd,J＝10.6,6.6Hz,2H),2.58–2.52(m,2H),2.05–1.95(m,3H),1.89(s,3H). HR-MS (ESI, [M+H] + ) m/z: 887.33094. 1 H NMR (500MHz,DMSO-d 6 )δ11.23(s,1H),11.06(s,1H),8.42(d,J=5.3Hz,1H),8.32(d,J=1.9Hz,1H) ,8.01–7.95(m,2H),7.67–7.59(m,2H),7.35(dd,J＝5.3,2.0Hz,1H),7.26(d,J＝5.0Hz,1H),7.00(d,J =5.0Hz,1H),6.78(d,J=2.1Hz,1H),6.64(dd,J=8.4,2.2Hz,1H),5.98(s,2H),5.05(dd,J=12.7,5.5Hz ,1H),4.10(t,J=7.9Hz,2H),3.89(dd,J=8.9,4.5Hz,2H),3.54–3.46(m,2H),3.37(td,J=6.0,5.4,2.8 Hz,6H),3.06(t,J=5.5Hz,4H),2.88(ddd,J=16.5,13.6,5.4Hz,2H),2.60(dd,J=10.6,6.6Hz,2H),2.58–2.52 (m,2H),2.05–1.95(m,3H),1.89(s,3H).
实施例41：化合物41的制备Embodiment 41: Preparation of compound 41
Figure PCTCN2022096512-appb-000149
Figure PCTCN2022096512-appb-000149
Figure PCTCN2022096512-appb-000150
Figure PCTCN2022096512-appb-000150
步骤1：中间体41b的制备Step 1: Preparation of Intermediate 41b
向单口瓶中依次加入中间体1j(1.28mg)、N-叔丁氧羰基-4-哌啶酮(520mg)、乙酸(20mg)、氰基硼氢化钠(186mg)及甲醇(50mL)，常温搅拌反应4h，反应完全，将反应液倒入纯化水(50mL)中，加入二氯甲烷/甲醇＝10/1溶液(50mL)，萃取分层，有机相用饱和氯化钠水溶液洗涤，用无水硫酸钠干燥，浓缩有机相得粗品，过硅胶柱纯化(二氯甲烷/甲醇)得中间体41b(1.13g)。Add intermediate 1j (1.28mg), N-tert-butoxycarbonyl-4-piperidone (520mg), acetic acid (20mg), sodium cyanoborohydride (186mg) and methanol (50mL) sequentially to a one-necked bottle, and Stir the reaction for 4h, the reaction is complete, pour the reaction solution into purified water (50mL), add dichloromethane/methanol=10/1 solution (50mL), extract and separate layers, the organic phase is washed with saturated aqueous sodium chloride solution, and After drying over sodium sulfate, the organic phase was concentrated to obtain a crude product, which was purified by a silica gel column (dichloromethane/methanol) to obtain intermediate 41b (1.13 g).
MS(ESI,[M+H] +)m/z：690.4。 1H NMR(500MHz,DMSO-d 6)δ11.23(s,1H),8.42(d,J＝5.4Hz,1H),8.32(d,J＝1.9Hz,1H),8.02–7.96(m,2H),7.62(t,J＝7.9Hz,1H),7.35(dd,J＝5.4,2.0Hz,1H),7.29(d,J＝5.0Hz,1H),7.02(d,J＝4.9Hz,1H),6.09(s,2H),3.95(d,J＝41.4Hz,6H),1.98(s,4H),1.91(s,4H),1.41(s,9H),1.20–1.10(m,2H). MS (ESI, [M+H] + ) m/z: 690.4. 1 H NMR (500MHz, DMSO-d 6 )δ11.23(s, 1H), 8.42(d, J=5.4Hz, 1H), 8.32(d, J=1.9Hz, 1H), 8.02–7.96(m, 2H), 7.62(t, J=7.9Hz, 1H), 7.35(dd, J=5.4, 2.0Hz, 1H), 7.29(d, J=5.0Hz, 1H), 7.02(d, J=4.9Hz, 1H), 6.09(s, 2H), 3.95(d, J=41.4Hz, 6H), 1.98(s, 4H), 1.91(s, 4H), 1.41(s, 9H), 1.20–1.10(m, 2H ).
步骤2：中间体41c的制备Step 2: Preparation of Intermediate 41c
向反应瓶中依次加入中间体41b(1.10g)、三氟乙酸(0.91g)、二氯甲烷(50mL)，25℃搅拌反应3.5h。反应完全，反应液浓缩至干，加入二氯甲烷后旋蒸3次，浓缩有机相得中间体41c(1.60g)。Intermediate 41b (1.10 g), trifluoroacetic acid (0.91 g), and dichloromethane (50 mL) were sequentially added to the reaction flask, and the reaction was stirred at 25° C. for 3.5 h. After the reaction was complete, the reaction solution was concentrated to dryness, dichloromethane was added and then rotary evaporated three times, and the organic phase was concentrated to obtain intermediate 41c (1.60 g).
MS(ESI,[M+H] +)m/z：590.4。 MS (ESI, [M+H] + ) m/z: 590.4.
步骤3：化合物41的制备Step 3: Preparation of Compound 41
向单口瓶中依次加入41c(200mg)、中间体13b(187mg)、N,N-二异丙基乙胺(131mg)及二甲基亚砜(5mL)，80℃搅拌反应5h，反应完全，反应液通过120g C 18反相柱纯化得化合物41(120mg)。 Add 41c (200mg), intermediate 13b (187mg), N,N-diisopropylethylamine (131mg) and dimethyl sulfoxide (5mL) to the single-necked flask in sequence, stir and react at 80°C for 5h, and the reaction is complete. The reaction solution was purified by a 120 g C 18 reverse phase column to obtain compound 41 (120 mg).
HR-MS(ESI,[M+H] +)m/z：846.29482。 1H NMR(500MHz,DMSO-d 6)δ11.23(s,1H),11.07(s,1H),8.42(d,J＝5.4Hz,1H),8.32(d,J＝1.9Hz,1H),8.02–7.95(m,2H),7.64(q,J＝8.3Hz,2H),7.39–7.30(m,2H),7.24(dd,J＝12.0,5.7Hz,2H),7.00(d,J＝5.0Hz,1H),5.99(s,2H),5.07(dd,J＝12.8,5.4Hz,1H),3.88(s,2H),3.08(d,J＝8.8Hz,6H),2.89(ddd,J＝16.1,13.4,5.0Hz,1H),2.63–2.52(m,2H),2.34(s,1H),2.01(dp,J＝11.6,4.1,3.7Hz,1H),1.87(t,J＝5.3Hz,4H),1.74(s,2H),1.24(d,J＝10.0Hz,2H). HR-MS (ESI, [M+H] + ) m/z: 846.29482. 1 H NMR (500MHz,DMSO-d 6 )δ11.23(s,1H),11.07(s,1H),8.42(d,J=5.4Hz,1H),8.32(d,J=1.9Hz,1H) ,8.02–7.95(m,2H),7.64(q,J＝8.3Hz,2H),7.39–7.30(m,2H),7.24(dd,J＝12.0,5.7Hz,2H),7.00(d,J =5.0Hz,1H),5.99(s,2H),5.07(dd,J=12.8,5.4Hz,1H),3.88(s,2H),3.08(d,J=8.8Hz,6H),2.89(ddd ,J=16.1,13.4,5.0Hz,1H),2.63–2.52(m,2H),2.34(s,1H),2.01(dp,J=11.6,4.1,3.7Hz,1H),1.87(t,J =5.3Hz, 4H), 1.74(s, 2H), 1.24(d, J=10.0Hz, 2H).
实施例42 化合物42的制备Example 42 Preparation of Compound 42
Figure PCTCN2022096512-appb-000151
Figure PCTCN2022096512-appb-000151
Figure PCTCN2022096512-appb-000152
Figure PCTCN2022096512-appb-000152
步骤1：中间体42b的合成Step 1: Synthesis of intermediate 42b
在单口瓶中，将化合物41c(300mg)和3-氧杂氮杂环丁烷-1-羧酸叔丁酯(110mg)溶于甲醇(5mL)中，再加入氰基硼氢化钠(53.9mg)，加入1滴醋酸，室温反应2小时，补加3-氧杂氮杂环丁烷-1-羧酸叔丁酯(110mg)，室温反应2小时。反应完毕后，向体系中加入二氯甲烷(50mL)和水(100mL)，有机相分离，水相用二氯甲烷(50mL)萃取2次，合并有机相，用无水硫酸钠干燥，过滤，减压蒸除溶剂，粗品经过硅胶柱层析分离(洗脱剂：二氯甲烷/甲醇)得到中间体42b(250mg)。In a one-necked bottle, compound 41c (300 mg) and tert-butyl 3-oxazetidine-1-carboxylate (110 mg) were dissolved in methanol (5 mL), and then sodium cyanoborohydride (53.9 mg ), add 1 drop of acetic acid, react at room temperature for 2 hours, add tert-butyl 3-oxazetidine-1-carboxylate (110 mg), and react at room temperature for 2 hours. After completion of the reaction, add dichloromethane (50mL) and water (100mL) to the system, separate the organic phase, extract the aqueous phase twice with dichloromethane (50mL), combine the organic phases, dry with anhydrous sodium sulfate, filter, The solvent was evaporated under reduced pressure, and the crude product was separated by silica gel column chromatography (eluent: dichloromethane/methanol) to obtain intermediate 42b (250 mg).
MS(ESI,[M+H] +)m/z:745.4。 1H NMR(500MHz,DMSO-d 6)δ11.22(s,1H),8.41(d,J＝5.3Hz,1H),8.31(d,J＝2.0Hz,1H),8.03–7.94(m,2H),7.61(t,J＝7.9Hz,1H),7.35(dd,J＝5.4,1.9Hz,1H),7.27(d,J＝5.0Hz,1H),7.01(d,J＝5.0Hz,1H),3.82(s,2H),3.66(d,J＝30.8Hz,8H),3.08(t,J＝5.3Hz,5H),2.79(d,J＝10.3Hz,2H),1.95(t,J＝5.3Hz,4H),1.87–1.75(m,4H),1.37(s,9H),1.28–1.22(m,2H). MS (ESI, [M+H] + ) m/z: 745.4. 1 H NMR (500MHz, DMSO-d 6 )δ11.22(s, 1H), 8.41(d, J=5.3Hz, 1H), 8.31(d, J=2.0Hz, 1H), 8.03–7.94(m, 2H), 7.61(t, J=7.9Hz, 1H), 7.35(dd, J=5.4, 1.9Hz, 1H), 7.27(d, J=5.0Hz, 1H), 7.01(d, J=5.0Hz, 1H), 3.82(s, 2H), 3.66(d, J=30.8Hz, 8H), 3.08(t, J=5.3Hz, 5H), 2.79(d, J=10.3Hz, 2H), 1.95(t, J＝5.3Hz, 4H), 1.87–1.75(m, 4H), 1.37(s, 9H), 1.28–1.22(m, 2H).
步骤2：中间体42c的合成Step 2: Synthesis of Intermediate 42c
在单口瓶中，将化合物42b(350mg)溶于二氯甲烷(5mL)中，再加入4M盐酸二氧六环溶液(308mg,2.112mL,8.45mmol)，室温反应1小时。反应完毕后，反应液减压蒸除溶剂，用50mL二氯甲烷和50mL水溶解后，加入饱和碳酸氢钠溶液调节pH至弱碱性(pH＝8～9)，有机相分离，有机相再用二氯甲烷：甲醇＝10：1(50mL)萃取2次，合并有机相，无水硫酸钠干燥，过滤，减压蒸除溶剂，得到中间体42c(200mg)。In a one-necked bottle, compound 42b (350 mg) was dissolved in dichloromethane (5 mL), and 4M dioxane hydrochloride solution (308 mg, 2.112 mL, 8.45 mmol) was added, and reacted at room temperature for 1 hour. After the reaction was completed, the reaction solution was evaporated under reduced pressure to remove the solvent, dissolved with 50mL of dichloromethane and 50mL of water, added saturated sodium bicarbonate solution to adjust the pH to weakly alkaline (pH=8～9), the organic phase was separated, and the organic phase was re-dissolved. Extracted twice with dichloromethane: methanol = 10:1 (50 mL), combined the organic phases, dried over anhydrous sodium sulfate, filtered, and evaporated the solvent under reduced pressure to obtain intermediate 42c (200 mg).
MS(ESI,[M+H] +)m/z:645.4。 MS (ESI, [M+H] + ) m/z: 645.4.
步骤3：化合物42的合成Step 3: Synthesis of Compound 42
在单口瓶中，将化合物42c(150mg)和中间体13b(64.2mg)溶于二甲亚砜(4mL)中，再加入N,N-二异丙基乙胺(150mg)，升温至90℃反应4小时。反应完毕后，反应液冷至室温，粗品经过反相纯化(洗脱剂：水/乙腈)得到化合物42(80mg)。In a single-necked bottle, dissolve compound 42c (150 mg) and intermediate 13b (64.2 mg) in dimethyl sulfoxide (4 mL), then add N,N-diisopropylethylamine (150 mg), and heat up to 90°C React for 4 hours. After the reaction was completed, the reaction liquid was cooled to room temperature, and the crude product was purified by reverse phase (eluent: water/acetonitrile) to obtain compound 42 (80 mg).
HRMS(ESI)m/z[M+H] +:901.34737。 1H NMR(500MHz,DMSO-d 6)δ11.23(s,1H),8.42(d,J＝5.4Hz,1H),8.32(d,J＝1.9Hz,1H),8.03–7.94(m,2H),7.69–7.59(m,2H),7.35(dd,J＝5.4,1.9Hz,1H),7.25(d,J＝5.0Hz,1H),7.00(d,J＝4.9Hz,1H),6.78(d,J＝2.1Hz,1H),6.64(dd,J＝8.5,2.1Hz,1H),5.99(s,2H),5.05(dd,J＝12.7,5.5Hz,1H),4.09(t,J＝7.7Hz,2H),3.82(dd,J＝8.8,5.0Hz,2H),3.06(t,J＝5.3Hz,7H),2.88(ddd,J＝16.4,13.6,5.3Hz,2H),2.74(s,2H),2.65–2.52(m,2H),2.01(ddt,J＝8.1,5.6,3.0Hz,1H),1.89(dd,J＝17.1,5.3Hz,6H),1.68(s,2H),1.19(s,2H). 13C NMR(126MHz,DMSO-d 6)δ173.26,170.57,167.94,167.63,165.31,155.41,153.66,151.93,149.94,145.55,144.47,134.30,132.97,127.94,125.30,124.64,124.58,120.52,117.31,116.38,116.19,114.72,113.84,106.05,104.94,55.87,54.74,49.19,47.96,47.57,33.59,31.46,22.68. HRMS (ESI) m/z [M+H] + : 901.34737. 1 H NMR (500MHz, DMSO-d 6 )δ11.23(s, 1H), 8.42(d, J=5.4Hz, 1H), 8.32(d, J=1.9Hz, 1H), 8.03–7.94(m, 2H),7.69–7.59(m,2H),7.35(dd,J=5.4,1.9Hz,1H),7.25(d,J=5.0Hz,1H),7.00(d,J=4.9Hz,1H), 6.78(d, J=2.1Hz, 1H), 6.64(dd, J=8.5, 2.1Hz, 1H), 5.99(s, 2H), 5.05(dd, J=12.7, 5.5Hz, 1H), 4.09(t ,J=7.7Hz,2H),3.82(dd,J=8.8,5.0Hz,2H),3.06(t,J=5.3Hz,7H),2.88(ddd,J=16.4,13.6,5.3Hz,2H) ,2.74(s,2H),2.65–2.52(m,2H),2.01(ddt,J＝8.1,5.6,3.0Hz,1H),1.89(dd,J＝17.1,5.3Hz,6H),1.68(s ,2H),1.19(s,2H). 13 C NMR(126MHz,DMSO-d 6 )δ173.26,170.57,167.94,167.63,165.31,155.41,153.66,151.93,149.94,145.55,144.47,134.34,132.9 125.30, 124.64, 124.58, 120.52, 117.31, 116.38, 116.19, 114.72, 113.84, 106.05, 104.94, 55.87, 54.74, 49.19, 47.96, 47.57, 33.59, 31.46, 22.68.
实施例43 化合物43的制备Example 43 Preparation of Compound 43
Figure PCTCN2022096512-appb-000153
Figure PCTCN2022096512-appb-000153
Figure PCTCN2022096512-appb-000154
Figure PCTCN2022096512-appb-000154
步骤1：中间体43b的合成Step 1: Synthesis of Intermediate 43b
在单口瓶中，将化合物1h(3g)和4-苯氧基苯基硼酸(2.145g)溶于1,4-二氧六环(20mL)和水(5mL)中，再加入碳酸钾(2.77g)和PdCl 2(dppf)·CH 2Cl 2(0.489g)，N 2保护下，80℃加热反应5小时。反应完毕后，反应液冷至室温，减压蒸除溶剂，粗品经过硅胶柱层析分离(洗脱剂：二氯甲烷/甲醇＝100：1，体积比)得到中间体43b(2.00g)。 In a one-necked flask, compound 1h (3 g) and 4-phenoxyphenylboronic acid (2.145 g) were dissolved in 1,4-dioxane (20 mL) and water (5 mL), and potassium carbonate (2.77 g) and PdCl 2 (dppf)·CH 2 Cl 2 (0.489 g), heated at 80° C. for 5 hours under the protection of N 2 . After the reaction was completed, the reaction liquid was cooled to room temperature, and the solvent was evaporated under reduced pressure. The crude product was separated by silica gel column chromatography (eluent: dichloromethane/methanol=100:1, volume ratio) to obtain intermediate 43b (2.00g).
MS(ESI,[M+H] +)m/z:527.4。 1H NMR(500MHz,DMSO-d 6)δ7.63–7.55(m,2H),7.45–7.39(m,2H),7.21(d,J＝4.9Hz,1H),7.20–7.15(m,1H),7.13–7.06(m,4H),6.98–6.93(m,1H),6.01(s,2H),3.63(s,4H),3.06(dd,J＝6.9,3.9Hz,4H),1.87(t,J＝5.4Hz,4H),1.39(s,9H). MS (ESI, [M+H] + ) m/z: 527.4. 1 H NMR (500MHz, DMSO-d 6 ) δ7.63–7.55(m,2H),7.45–7.39(m,2H),7.21(d,J＝4.9Hz,1H),7.20–7.15(m,1H ),7.13–7.06(m,4H),6.98–6.93(m,1H),6.01(s,2H),3.63(s,4H),3.06(dd,J＝6.9,3.9Hz,4H),1.87( t,J=5.4Hz,4H),1.39(s,9H).
步骤2：中间体43c的合成Step 2: Synthesis of intermediate 43c
在单口瓶中，将化合物43b(2.00g)溶于二氯甲烷(20mL)中，再加入三氟乙酸(7.64g)，室温反应1小时。反应完毕后，反应液减压蒸除溶剂及部分三氟乙酸，用50mL二氯甲烷溶解后，加入饱和碳酸氢钠溶液调节pH至弱碱性(pH＝8～9)，有机相分离，有机相用二氯甲烷：甲醇＝10：1(50mL)萃取2次，合并有机相，无水硫酸钠干燥，过滤，减压蒸除溶剂，粗品经过硅胶柱层析分离(洗脱剂：二氯甲烷/甲醇)得到中间体43c(1.00g)。In a one-necked bottle, compound 43b (2.00 g) was dissolved in dichloromethane (20 mL), and trifluoroacetic acid (7.64 g) was added, and reacted at room temperature for 1 hour. After the reaction was completed, the reaction solution was evaporated under reduced pressure to remove the solvent and part of trifluoroacetic acid, dissolved in 50mL of dichloromethane, then added saturated sodium bicarbonate solution to adjust the pH to weakly alkaline (pH=8-9), the organic phase was separated, and the organic phase was separated. The phase was extracted twice with dichloromethane:methanol=10:1 (50mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The crude product was separated by silica gel column chromatography (eluent: dichloro Methane/methanol) afforded intermediate 43c (1.00 g).
MS(ESI,[M+H] +)m/z:427.3。 1H NMR(500MHz,DMSO-d 6)δ7.64–7.56(m,2H),7.45–7.39(m,2H),7.21–7.15(m,2H),7.14–7.03(m,4H),6.96(d,J＝4.9Hz,1H),6.02(s,2H),3.28(s,4H),3.02(t,J＝5.3Hz,4H),1.87(t,J＝5.4Hz,4H). MS (ESI, [M+H] + ) m/z: 427.3. 1 H NMR (500MHz,DMSO-d 6 )δ7.64–7.56(m,2H),7.45–7.39(m,2H),7.21–7.15(m,2H),7.14–7.03(m,4H),6.96 (d, J=4.9Hz, 1H), 6.02(s, 2H), 3.28(s, 4H), 3.02(t, J=5.3Hz, 4H), 1.87(t, J=5.4Hz, 4H).
步骤3：中间体43d的合成Step 3: Synthesis of intermediate 43d
在单口瓶中，将化合物43c(502mg)溶于N,N-二甲基甲酰胺(10mL)中，加入化合物4b(300mg)和碳酸钾(281mg)，升温至50℃反应2小时。反应完毕后，反应液冷至室温，向反应液中加入乙酸乙酯(100mL)和水(200mL)。有机相分离，有机相再用乙酸乙酯50mL萃取2次，再用饱和食盐水(200mL)洗涤后用无水硫酸钠干燥，过滤。减压蒸除溶剂，粗品经过硅胶柱层析分离(洗脱剂：二氯甲烷/甲醇)得到中间体43d(250mg)。In a single-necked flask, compound 43c (502 mg) was dissolved in N,N-dimethylformamide (10 mL), compound 4b (300 mg) and potassium carbonate (281 mg) were added, and the temperature was raised to 50°C for 2 hours. After the reaction was completed, the reaction liquid was cooled to room temperature, and ethyl acetate (100 mL) and water (200 mL) were added to the reaction liquid. The organic phase was separated, and the organic phase was extracted twice with 50 mL of ethyl acetate, washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, and filtered. The solvent was evaporated under reduced pressure, and the crude product was separated by silica gel column chromatography (eluent: dichloromethane/methanol) to obtain intermediate 43d (250 mg).
MS(ESI,[M+H] +)m/z:871.7。 1H NMR(500MHz,DMSO-d 6)δ7.65–7.56(m,3H),7.54(s,1H),7.46–7.38(m,2H),7.21(d,J＝5.0Hz,1H),7.20–7.14(m,3H),7.13–7.07(m,4H),7.01(dd,J＝8.4,2.2Hz,1H),6.96(d,J＝5.0Hz,1H),6.01(s,2H),4.05(t,J＝6.5Hz,2H),3.17(d,J＝3.2Hz,3H),3.06(t,J＝5.3Hz,4H),2.20–2.09(m,3H),2.03–1.94(m,4H),1.74(p,J＝6.7Hz,2H),1.43(q,J＝7.5,6.7Hz,4H),1.33(s,15H). MS (ESI, [M+H] + ) m/z: 871.7. 1 H NMR (500MHz, DMSO-d 6 )δ7.65–7.56(m,3H),7.54(s,1H),7.46–7.38(m,2H),7.21(d,J＝5.0Hz,1H), 7.20–7.14(m,3H),7.13–7.07(m,4H),7.01(dd,J=8.4,2.2Hz,1H),6.96(d,J=5.0Hz,1H),6.01(s,2H) ,4.05(t,J=6.5Hz,2H),3.17(d,J=3.2Hz,3H),3.06(t,J=5.3Hz,4H),2.20–2.09(m,3H),2.03–1.94( m, 4H), 1.74(p, J=6.7Hz, 2H), 1.43(q, J=7.5, 6.7Hz, 4H), 1.33(s, 15H).
步骤4：化合物43的合成Step 4: Synthesis of Compound 43
在微波管中，将化合物43d(200mg)溶于乙腈(4mL)中，再加入苯磺酸(95mg)，搅拌3分钟后，放入微波反应器中，在100W下加热至100℃反应1小时。反应完毕后，反应液冷至室温，减压蒸馏除去溶剂，反相纯化(洗脱剂：水/乙腈)得到目标产物43(70mg)。In a microwave tube, dissolve compound 43d (200 mg) in acetonitrile (4 mL), then add benzenesulfonic acid (95 mg), stir for 3 minutes, put it in a microwave reactor, and heat it to 100 ° C under 100 W for 1 hour . After the reaction was completed, the reaction liquid was cooled to room temperature, the solvent was distilled off under reduced pressure, and reverse-phase purification (eluent: water/acetonitrile) gave the target product 43 (70 mg).
HRMS(ESI)m/z[M+H] +:797.41249。 1H NMR(500MHz,DMSO-d 6)δ10.96(s,1H),7.66–7.54(m,3H),7.42(t,J＝7.9Hz,2H),7.24–7.13(m,3H),7.10(d,J＝8.3Hz,4H),7.03(dd,J＝8.4,2.2Hz,1H),6.96(d,J＝5.0Hz,1H),6.01(s,2H),5.07(dd,J＝13.3,5.1Hz,1H),4.38(d,J＝17.2Hz,1H),4.26(d,J＝17.1Hz,1H),4.05(t,J＝6.5Hz,2H),3.17(s,4H),3.04(t,J＝5.3Hz,4H),2.90(ddd,J＝17.1,13.6,5.4Hz,1H),2.68–2.55(m,2H),2.37(qd,J＝13.2,4.5Hz,1H),2.01–1.94(m,1H),1.90(t,J＝5.1Hz,4H),1.74(p,J＝6.8Hz,2H),1.42(t,J＝7.6Hz,2H),1.31(d,J＝20.6Hz,8H). 13C NMR(126MHz,DMSO-d 6)δ173.37,171.64,162.35,156.97,156.66,152.11,131.78,131.38,130.57,130.33,127.58,124.78,124.12,119.31,119.01,115.82,109.05,106.01,68.47,63.60,51.99,47.45,47.38,34.22,31.71,29.26,29.07,28.98,26.87,25.87,23.00. HRMS (ESI) m/z [M+H] + : 797.41249. 1 H NMR (500MHz,DMSO-d 6 )δ10.96(s,1H),7.66–7.54(m,3H),7.42(t,J=7.9Hz,2H),7.24–7.13(m,3H), 7.10(d,J=8.3Hz,4H),7.03(dd,J=8.4,2.2Hz,1H),6.96(d,J=5.0Hz,1H),6.01(s,2H),5.07(dd,J =13.3,5.1Hz,1H),4.38(d,J=17.2Hz,1H),4.26(d,J=17.1Hz,1H),4.05(t,J=6.5Hz,2H),3.17(s,4H ), 3.04(t, J＝5.3Hz, 4H), 2.90(ddd, J＝17.1, 13.6, 5.4Hz, 1H), 2.68–2.55(m, 2H), 2.37(qd, J＝13.2, 4.5Hz, 1H), 2.01–1.94(m, 1H), 1.90(t, J=5.1Hz, 4H), 1.74(p, J=6.8Hz, 2H), 1.42(t, J=7.6Hz, 2H), 1.31( d, J＝20.6Hz, 8H). 13 C NMR (126MHz, DMSO-d 6 ) δ173.37, 171.64, 162.35, 156.97, 156.66, 152.11, 131.78, 131.38, 130.57, 130.33, 127.58, 124.78, 1119.30, ,115.82,109.05,106.01,68.47,63.60,51.99,47.45,47.38,34.22,31.71,29.26,29.07,28.98,26.87,25.87,23.00.
实施例44 化合物44的制备The preparation of embodiment 44 compound 44
Figure PCTCN2022096512-appb-000155
Figure PCTCN2022096512-appb-000155
步骤1：中间体44b的制备Step 1: Preparation of Intermediate 44b
向反应瓶中依次加入中间体43c(1.5g)、1-Boc-3-氮杂环丁酮(2.453g)、MeOH(15mL)，搅拌下加入氰基硼氢化钠(1.081g)及冰乙酸(0.258g,0.246mL)，N 2保护下，室温搅拌过夜，反应完全，反应液旋蒸后残余物用DCM-MeOH(10:1，50mL×2)萃取，有机层合并后用饱和食盐水(50mL×1)洗涤，萃取液干燥过滤，滤液旋蒸后残余物用硅胶柱纯化(DCM-MeOH)得到中间体44b(1.07g)。 Add intermediate 43c (1.5g), 1-Boc-3-azetidinone (2.453g), MeOH (15mL) in turn to the reaction flask, and add sodium cyanoborohydride (1.081g) and glacial acetic acid under stirring (0.258g, 0.246mL), under the protection of N 2 , stirred overnight at room temperature, the reaction was complete, and the residue was extracted with DCM-MeOH (10:1, 50mL×2) after the reaction solution was rotary evaporated, and the organic layers were combined and saturated brine (50mL×1) was washed, the extract was dried and filtered, the filtrate was rotary evaporated, and the residue was purified by silica gel column (DCM-MeOH) to obtain intermediate 44b (1.07g).
MS(ESI,[M+H] +)m/z：582.5。 1H NMR(500MHz,DMSO-d 6)δ7.62–7.57(m,2H),7.45–7.39(m,2H),7.22–7.15(m,2H),7.13–7.06(m,4H),6.95(d,J＝4.9Hz,1H),6.01(s,2H),3.82(s,2H),3.57(d,J＝8.6Hz,2H),3.39(ddt,J＝8.7,6.8,3.3Hz,1H),3.04(dd,J＝6.8,4.0Hz,4H),1.87(t,J＝5.4Hz,4H),1.37(s,9H). MS (ESI, [M+H] + ) m/z: 582.5. 1 H NMR (500MHz,DMSO-d 6 )δ7.62–7.57(m,2H),7.45–7.39(m,2H),7.22–7.15(m,2H),7.13–7.06(m,4H),6.95 (d,J=4.9Hz,1H),6.01(s,2H),3.82(s,2H),3.57(d,J=8.6Hz,2H),3.39(ddt,J=8.7,6.8,3.3Hz, 1H), 3.04(dd, J=6.8, 4.0Hz, 4H), 1.87(t, J=5.4Hz, 4H), 1.37(s, 9H).
步骤2：中间体44c的制备Step 2: Preparation of intermediate 44c
向反应瓶中依次加入中间体44b(1.05g)、DCM(10mL)及MeOH(1.000mL)，搅拌下滴加盐酸二氧六环溶液(1.797g,12.32mL,49.3mmol)，N 2保护下室温搅拌1.5小时，反应完全，反应液旋蒸，残余物加饱和碳酸氢钠水溶液调至中性，用DCM-MeOH(10:1，50mL×2)萃取，有机层合并后用饱和食盐水(50mL×1)洗涤，萃取液干燥过滤，滤液旋干得到中间体44c(550mg)。 Intermediate 44b (1.05g), DCM (10mL) and MeOH (1.000mL) were added successively to the reaction flask, dioxane hydrochloride solution (1.797g, 12.32mL, 49.3mmol) was added dropwise under stirring, and under N 2 protection Stir at room temperature for 1.5 hours, the reaction is complete, the reaction solution is rotary evaporated, the residue is adjusted to neutrality by adding saturated aqueous sodium bicarbonate solution, extracted with DCM-MeOH (10:1, 50mL×2), the organic layers are combined and washed with saturated brine ( 50 mL×1) was washed, the extract was dried and filtered, and the filtrate was spin-dried to obtain intermediate 44c (550 mg).
MS(ESI,[M+H] +)m/z：482.3。 MS (ESI, [M+H] + ) m/z: 482.3.
步骤3：化合物44的制备Step 3: Preparation of Compound 44
向反应瓶中，依次加入中间体44c(120mg)、中间体13b(63.8mg)、DMSO(3mL)及N,N-二异丙基乙胺(124mg)，N 2保护下，90℃反应4小时，反应完全，反应液直接用C 18反相柱纯化(10nM乙酸铵水溶液-乙腈)洗脱，过柱液合并，DCM-MeOH(10:1)萃取后旋蒸干得到目标物44(62mg)。 Into the reaction flask, add intermediate 44c (120mg), intermediate 13b (63.8mg), DMSO (3mL) and N,N-diisopropylethylamine (124mg) in turn, under N 2 protection, react at 90°C 4 Hours, the reaction was complete, and the reaction solution was directly eluted with a C18 reverse-phase column (10nM ammonium acetate aqueous solution-acetonitrile), and the column liquid was combined, extracted with DCM-MeOH (10:1) and then evaporated to dryness to obtain the target object 44 (62mg ).
MS(ESI,[M+H] +)m/z：738.5。 1H NMR(500MHz,DMSO-d 6)δ11.14–10.98(m,1H),7.64(d,J＝8.3Hz,1H),7.61–7.56(m,2H),7.42(t,J＝8.0Hz,2H),7.22–7.15(m,2H),7.14–7.06(m,4H),6.95(d,J＝5.0Hz,1H),6.79(d,J＝2.1Hz,1H),6.65(dd,J＝8.4,2.2Hz,1H),6.00(s,2H),5.05(dd,J＝12.8,5.5Hz,1H),4.08–4.01(m,2H),3.83(dd,J＝8.9,4.3Hz,2H),3.67(tt,J＝7.0,4.3Hz,1H),3.37(td,J＝6.0,5.4,2.7Hz,1H),3.07(d,J＝12.4Hz,6H),2.88(ddd,J＝16.6,13.7,5.4Hz,1H),2.62–2.52(m,2H),2.05–1.82(m,6H). MS (ESI, [M+H] + ) m/z: 738.5. 1 H NMR (500MHz, DMSO-d 6 ) δ11.14–10.98(m,1H),7.64(d,J=8.3Hz,1H),7.61–7.56(m,2H),7.42(t,J=8.0 Hz,2H),7.22–7.15(m,2H),7.14–7.06(m,4H),6.95(d,J＝5.0Hz,1H),6.79(d,J＝2.1Hz,1H),6.65(dd ,J=8.4,2.2Hz,1H),6.00(s,2H),5.05(dd,J=12.8,5.5Hz,1H),4.08–4.01(m,2H),3.83(dd,J=8.9,4.3 Hz, 2H), 3.67(tt, J=7.0, 4.3Hz, 1H), 3.37(td, J=6.0, 5.4, 2.7Hz, 1H), 3.07(d, J=12.4Hz, 6H), 2.88(ddd ,J＝16.6,13.7,5.4Hz,1H),2.62–2.52(m,2H),2.05–1.82(m,6H).
实施例45 化合物45的制备The preparation of embodiment 45 compound 45
Figure PCTCN2022096512-appb-000156
Figure PCTCN2022096512-appb-000156
Figure PCTCN2022096512-appb-000157
Figure PCTCN2022096512-appb-000157
步骤1：中间体45b的制备Step 1: Preparation of intermediate 45b
向反应瓶中依次加入中间体44c(390mg)、1-Boc-3-氮杂环丁酮(245mg)及MeOH(10mL)，搅拌下加入氰基硼氢化钠(180mg)及冰乙酸(64.4mg,0.061mL,1.072mmol)，N 2保护下，室温搅拌过夜，反应完全，反应液旋蒸后残余物用DCM-MeOH(10:1，50mL×2)萃取，有机层合并后用饱和食盐水(50mL×1)洗涤，萃取液干燥过滤，滤液旋蒸后残余物用硅胶柱纯化(DCM-MeOH)得到中间体45b(252mg)。 Intermediate 44c (390mg), 1-Boc-3-azetidinone (245mg) and MeOH (10mL) were added sequentially to the reaction flask, and sodium cyanoborohydride (180mg) and glacial acetic acid (64.4mg , 0.061mL, 1.072mmol), under the protection of N 2 , stirred overnight at room temperature, the reaction was complete, the residue was extracted with DCM-MeOH (10:1, 50mL×2) after the reaction solution was rotary evaporated, and the organic layers were combined and then washed with saturated brine (50mL×1) was washed, the extract was dried and filtered, the filtrate was rotary evaporated, and the residue was purified by silica gel column (DCM-MeOH) to obtain intermediate 45b (252mg).
MS(ESI,[M+H] +)m/z：637.6。 MS (ESI, [M+H] + ) m/z: 637.6.
步骤2：中间体45c的制备Step 2: Preparation of Intermediate 45c
向反应瓶中依次加入中间体45b(240mg)、DCM(5mL)及MeOH(1mL)，缓慢滴加盐酸二氧六环溶液(390.1mg,2.67mL,10.70mmol)，滴完后N 2保护下室温搅拌过夜，反应完全，反应液旋蒸，残余物用饱和碳酸氢钠水溶液调至中性，用DCM-MeOH(10:1，50mL×2)萃取，有机层合并后用饱和食盐水(50mL×1)洗涤，萃取液干燥过滤，滤液旋干得到中间体45c(230mg)。 Add intermediate 45b (240mg), DCM (5mL) and MeOH (1mL) successively to the reaction flask, and slowly add dioxane hydrochloride solution (390.1mg, 2.67mL, 10.70mmol) dropwise, and after the dropwise addition, N 2 protection Stir at room temperature overnight, the reaction is complete, the reaction solution is rotary evaporated, the residue is adjusted to neutrality with saturated aqueous sodium bicarbonate, extracted with DCM-MeOH (10:1, 50mL×2), the organic layers are combined and washed with saturated brine (50mL ×1) washed, the extract was dried and filtered, and the filtrate was spin-dried to obtain intermediate 45c (230 mg).
MS(ESI,[M+H] +)m/z：537.5。 MS (ESI, [M+H] + ) m/z: 537.5.
步骤3：化合物45的制备Step 3: Preparation of compound 45
向反应瓶中依次加入中间体45c(190mg)、中间体13b(117mg)、DMSO(3mL)及N,N-二异丙基乙胺(229mg)，N 2保护下，90℃加热3小时，反应完全，反应液直接用C 18反相柱纯化(10nM乙酸铵水溶液-乙腈)洗脱，过柱液合并，DCM-MeOH(10:1)萃取后旋蒸干得到化合物45(75mg)。 Intermediate 45c (190mg), Intermediate 13b (117mg), DMSO (3mL) and N,N-diisopropylethylamine (229mg) were sequentially added to the reaction flask, and heated at 90°C for 3 hours under the protection of N2 . After the reaction was complete, the reaction solution was directly purified by a C 18 reverse phase column (10nM ammonium acetate aqueous solution-acetonitrile), and the column solution was combined, extracted with DCM-MeOH (10:1) and evaporated to dryness to obtain compound 45 (75 mg).
MS(ESI,[M+H] +)m/z：793.6。 1H NMR(500MHz,DMSO-d 6)δ11.07(s,1H),7.69–7.55(m,3H),7.48–7.39(m,2H),7.24–7.15(m,2H),7.15–7.06(m,4H),6.95(d,J＝4.9Hz,1H),6.78(d,J＝2.1Hz,1H),6.64(dd,J＝8.4,2.1Hz,1H),6.17–5.84(m,2H),5.05(dd,J＝12.8,5.4Hz,1H),4.03(dd,J＝8.8,6.9Hz,2H),3.77(dd,J＝8.9,4.3Hz,2H),3.59(tt,J＝6.9,4.3Hz,1H),3.41–3.34(m,1H),3.28(dt,J＝13.2,6.4Hz,3H),3.08–2.95(m,9H),2.88(ddd,J＝16.3,13.5,5.2Hz,1H),2.64–2.52(m,2H),2.01(ddq,J＝13.0,5.7,3.5,2.7Hz,1H),1.92–1.80(m,4H). MS (ESI, [M+H] + ) m/z: 793.6. 1 H NMR (500MHz,DMSO-d 6 )δ11.07(s,1H),7.69–7.55(m,3H),7.48–7.39(m,2H),7.24–7.15(m,2H),7.15–7.06 (m,4H),6.95(d,J=4.9Hz,1H),6.78(d,J=2.1Hz,1H),6.64(dd,J=8.4,2.1Hz,1H),6.17–5.84(m, 2H), 5.05(dd, J＝12.8, 5.4Hz, 1H), 4.03(dd, J＝8.8, 6.9Hz, 2H), 3.77(dd, J＝8.9, 4.3Hz, 2H), 3.59(tt, J =6.9,4.3Hz,1H),3.41–3.34(m,1H),3.28(dt,J=13.2,6.4Hz,3H),3.08–2.95(m,9H),2.88(ddd,J=16.3,13.5 ,5.2Hz,1H),2.64–2.52(m,2H),2.01(ddq,J＝13.0,5.7,3.5,2.7Hz,1H),1.92–1.80(m,4H).
实施例46 化合物46的制备The preparation of embodiment 46 compound 46
Figure PCTCN2022096512-appb-000158
Figure PCTCN2022096512-appb-000158
Figure PCTCN2022096512-appb-000159
Figure PCTCN2022096512-appb-000159
步骤1：中间体46b的制备Step 1: Preparation of Intermediate 46b
氮气保护下，在三口瓶中先后加入中间体46a(1.12g)、叔丁基-7-羟基-2-氮杂螺[3.5]壬烷-2-甲酸基酯(0.89g)、三苯基磷(1.94g)及四氢呋喃(150mL)，降温至0℃，滴加偶氮二甲酸二异丙酯(2.24g)，约15min滴加完毕，升温至25℃反应16h。反应完毕后，将反应液倒入200mL纯化水中，加入乙酸乙酯(200mL)萃取分层，有机相用饱和氯化钠水溶液(100mL)洗涤，浓缩有机相得粗品，过硅胶柱纯化(石油醚/乙酸乙酯)得中间体46b(5.26g)。Under nitrogen protection, intermediate 46a (1.12g), tert-butyl-7-hydroxy-2-azaspiro[3.5]nonane-2-carboxylate (0.89g), triphenyl Phosphorus (1.94g) and tetrahydrofuran (150mL) were cooled to 0°C, diisopropyl azodicarboxylate (2.24g) was added dropwise, and the addition was completed in about 15 minutes, and the temperature was raised to 25°C for 16 hours. After the reaction was completed, the reaction solution was poured into 200 mL of purified water, ethyl acetate (200 mL) was added for extraction and layering, the organic phase was washed with saturated aqueous sodium chloride solution (100 mL), and the organic phase was concentrated to obtain a crude product, which was purified by a silica gel column (petroleum ether /ethyl acetate) to obtain intermediate 46b (5.26g).
MS(ESI,[M+H] +)m/z：527.5。 MS (ESI, [M+H] + ) m/z: 527.5.
步骤2：中间体46c的制备Step 2: Preparation of intermediate 46c
向反应瓶中依次加入中间体46b(5.26g)、盐酸的二氧六环溶液(4M，40mL)，25℃搅拌反应48h。监控反应完全，反应液抽滤，滤饼用乙酸乙酯(150mL×3)洗涤，得到中间体46c(0.57g)。Intermediate 46b (5.26 g) and hydrochloric acid in dioxane (4M, 40 mL) were sequentially added to the reaction flask, and the reaction was stirred at 25° C. for 48 h. After monitoring the completion of the reaction, the reaction solution was filtered with suction, and the filter cake was washed with ethyl acetate (150 mL×3) to obtain intermediate 46c (0.57 g).
MS(ESI,[M+H] +)m/z：427.4。 1H NMR(500MHz,DMSO-d 6)δ8.23(s,1H),7.68–7.62(m,2H),7.46–7.40(m,2H),7.21–7.10(m,5H),7.03(d,J＝6.9Hz,1H),4.64(tt,J＝11.5,4.0Hz,1H),3.40(s,2H),3.27(s,2H),2.11(d,J＝13.0Hz,2H),1.94(qd,J＝13.0,3.5Hz,2H),1.84(dd,J＝13.3,3.9Hz,2H),1.59(td,J＝13.3,3.8Hz,2H). MS (ESI, [M+H] + ) m/z: 427.4. 1 H NMR (500MHz,DMSO-d 6 )δ8.23(s,1H),7.68–7.62(m,2H),7.46–7.40(m,2H),7.21–7.10(m,5H),7.03(d ,J=6.9Hz,1H),4.64(tt,J=11.5,4.0Hz,1H),3.40(s,2H),3.27(s,2H),2.11(d,J=13.0Hz,2H),1.94 (qd,J=13.0,3.5Hz,2H),1.84(dd,J=13.3,3.9Hz,2H),1.59(td,J=13.3,3.8Hz,2H).
步骤3：中间体46d的制备Step 3: Preparation of intermediate 46d
向单口瓶中依次加入中间体46c(500mg)、1-叔丁氧羰基-3-氮杂环丁酮(602mg)、乙酸(106mg)、氰基硼氢化钠(221mg)及甲醇(50mL)，常温搅拌反应2h，补加1-叔丁氧羰基-3-氮杂环丁酮(200mg)、乙酸(35mg)及氰基硼氢化钠(73mg)，常温反应16h，反应完全，将反应液倒入纯化水(50mL)中，加入二氯甲烷/甲醇＝10/1溶液(50mL)，萃取分层，有机相用饱和氯化钠水溶液洗涤，用无水硫酸钠干燥，浓缩有机相得粗品，过硅胶柱纯化得中间体46d(468mg)。Intermediate 46c (500 mg), 1-tert-butoxycarbonyl-3-azetidinone (602 mg), acetic acid (106 mg), sodium cyanoborohydride (221 mg) and methanol (50 mL) were sequentially added to a one-necked bottle, Stir the reaction at room temperature for 2 hours, add 1-tert-butoxycarbonyl-3-azetidinone (200 mg), acetic acid (35 mg) and sodium cyanoborohydride (73 mg), and react at room temperature for 16 hours. After the reaction is complete, pour the reaction solution into purified water (50 mL), added dichloromethane/methanol=10/1 solution (50 mL), extracted and separated, the organic phase was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and the organic phase was concentrated to obtain a crude product. Purified by silica gel column to obtain intermediate 46d (468mg).
MS(ESI,[M+H] +)m/z：582.5。 MS (ESI, [M+H] + ) m/z: 582.5.
步骤4：中间体46e的制备Step 4: Preparation of Intermediate 46e
向反应瓶中依次加入中间体46d(450mg)、盐酸二氧六环溶液(4M，10mL)、乙酸乙酯(10mL)，25℃搅拌反应3.5h。反应完全，反应液浓缩至干，加入纯化水(50mL)、二氯甲烷/甲醇＝10/1溶液(50mL)，搅拌状态下加入饱和碳酸氢钠水溶液(20mL)，萃取分层，有机相用饱和氯化钠水溶液洗涤，用无水硫酸钠干燥，浓缩得中间体46e(370mg)。Intermediate 46d (450mg), dioxane hydrochloride solution (4M, 10mL) and ethyl acetate (10mL) were sequentially added to the reaction flask, and the reaction was stirred at 25°C for 3.5h. The reaction was complete, the reaction solution was concentrated to dryness, purified water (50mL), dichloromethane/methanol=10/1 solution (50mL) was added, saturated aqueous sodium bicarbonate solution (20mL) was added under stirring, the layers were extracted, and the organic phase was used Wash with saturated aqueous sodium chloride, dry over anhydrous sodium sulfate, and concentrate to give intermediate 46e (370 mg).
MS(ESI,[M+H] +)m/z：482.4。 MS (ESI, [M+H] + ) m/z: 482.4.
步骤7：化合物46的制备Step 7: Preparation of Compound 46
向单口瓶中依次加入中间体46e(191mg)、中间体13b(219mg)、N,N-二异丙基乙胺(103mg)及二甲基亚砜(5mL)，80℃搅拌反应5h，反应完全，反应液通过120g C 18反相柱纯化得化合物46(46mg)。 Add intermediate 46e (191 mg), intermediate 13b (219 mg), N,N-diisopropylethylamine (103 mg) and dimethyl sulfoxide (5 mL) to the one-necked bottle in turn, stir at 80°C for 5 h, and react Completely, the reaction solution was purified by a 120 g C 18 reverse phase column to obtain compound 46 (46 mg).
HR-MS(ESI,[M+H] +)m/z：738.31431。 1H NMR(500MHz,DMSO-d 6)δ11.07(s,1H),8.23(s,1H),7.69–7.61(m,3H),7.48–7.39(m,2H),7.27–7.01(m,6H),6.79(d,J＝2.3Hz,1H),6.65(dd,J＝8.4,2.1Hz,1H),5.06(dd,J＝12.8,5.4Hz,1H),4.66(tt,J＝11.6,3.9Hz,1H),4.04(dd,J＝8.8,6.9Hz,2H),3.83(dd,J＝9.0,4.3Hz,2H),3.67(s,1H),3.12(s,2H),3.00(s,2H),2.88(ddd,J＝16.6,13.6,5.2Hz,1H),2.63–2.51(m,2H),2.48(d,J＝4.3Hz,1H),2.13–1.91(m,6H),1.89–1.82(m,2H). 13C NMR(126MHz,DMSO-d 6)δ173.27,170.57,167.96,167.64,158.61,157.46,156.84,155.90,155.36,153.96,143.19,134.29,130.59,130.52,128.64,125.27,124.22,119.49,119.38,117.20,114.66,104.97,97.87,60.65,55.39,55.11,53.80,49.19,34.97,34.80,31.46,28.81,22.69. HR-MS (ESI, [M+H] + ) m/z: 738.31431. 1 H NMR (500MHz,DMSO-d 6 )δ11.07(s,1H),8.23(s,1H),7.69–7.61(m,3H),7.48–7.39(m,2H),7.27–7.01(m ,6H),6.79(d,J=2.3Hz,1H),6.65(dd,J=8.4,2.1Hz,1H),5.06(dd,J=12.8,5.4Hz,1H),4.66(tt,J= 11.6,3.9Hz,1H),4.04(dd,J＝8.8,6.9Hz,2H),3.83(dd,J＝9.0,4.3Hz,2H),3.67(s,1H),3.12(s,2H), 3.00(s,2H),2.88(ddd,J=16.6,13.6,5.2Hz,1H),2.63–2.51(m,2H),2.48(d,J=4.3Hz,1H),2.13–1.91(m, 6H), 1.89–1.82(m,2H). 13 C NMR (126MHz, DMSO-d 6 ) .
实施例47:化合物47的制备Embodiment 47: the preparation of compound 47
Figure PCTCN2022096512-appb-000160
Figure PCTCN2022096512-appb-000160
步骤1：中间体47b的制备Step 1: Preparation of Intermediate 47b
向单口瓶中依次加入中间体46e(372mg)、1-叔丁氧羰基-3-氮杂环丁酮(661mg)、乙酸(70mg)、氰基硼氢化钠(291mg)及甲醇(50mL)，常温搅拌反应2h，补加1-叔丁氧羰基-3-氮杂环丁酮(132mg)、乙酸(23mg，0.39mmol)及氰基硼氢化钠(48mg)，常温反应16h，反应完全，将反应液倒入纯化水(50mL)中，加入二氯甲烷/甲醇＝10/1溶液(50mL)，萃取分层，有机相用饱和氯化钠水溶液洗涤，用无水硫酸钠干燥，浓缩有机相得粗品，过硅胶柱纯化得中间体47b(439mg)。Intermediate 46e (372 mg), 1-tert-butoxycarbonyl-3-azetidinone (661 mg), acetic acid (70 mg), sodium cyanoborohydride (291 mg) and methanol (50 mL) were sequentially added to a one-necked bottle, Stir the reaction at room temperature for 2 hours, add 1-tert-butoxycarbonyl-3-azetidinone (132 mg), acetic acid (23 mg, 0.39 mmol) and sodium cyanoborohydride (48 mg), and react at room temperature for 16 hours. Pour the reaction solution into purified water (50 mL), add dichloromethane/methanol=10/1 solution (50 mL), extract and separate layers, wash the organic phase with saturated aqueous sodium chloride solution, dry over anhydrous sodium sulfate, and concentrate the organic phase The crude product was obtained and purified by silica gel column to obtain intermediate 47b (439 mg).
MS(ESI,[M+H] +)m/z：637.5。 MS (ESI, [M+H] + ) m/z: 637.5.
步骤2：中间体47c的制备Step 2: Preparation of Intermediate 47c
向反应瓶中依次加入中间体47b(370mg)、盐酸二氧六环溶液(4M，1mL)及二氯甲烷(10mL)，25℃搅拌反应3.5h。反应完全，反应液浓缩至干，加入纯化水(50mL)、二氯甲烷/甲醇＝10/1溶液(50mL)，搅拌状态下加入饱和碳酸氢钠水溶液(20mL)，萃取分层，有机相用饱和氯化钠水溶液洗涤，用无水硫酸钠干燥，浓缩有机相得中间体47c(234mg)。Intermediate 47b (370 mg), dioxane hydrochloride solution (4M, 1 mL) and dichloromethane (10 mL) were sequentially added to the reaction flask, and the reaction was stirred at 25° C. for 3.5 h. The reaction was complete, the reaction solution was concentrated to dryness, purified water (50mL), dichloromethane/methanol=10/1 solution (50mL) was added, saturated aqueous sodium bicarbonate solution (20mL) was added under stirring, the layers were extracted, and the organic phase was used After washing with saturated aqueous sodium chloride, drying over anhydrous sodium sulfate, the organic phase was concentrated to obtain intermediate 47c (234 mg).
MS(ESI,[M+H] +)m/z：537.3。 1H NMR(500MHz,DMSO-d 6)δ8.23(s,1H),7.67–7.61(m,2H),7.47–7.38(m,2H),7.20–7.11(m,5H),7.10–6.38(m,2H),4.65(dp,J＝11.0,3.7Hz,1H),3.50–3.35(m,4H),3.22(dt,J＝34.6,6.4Hz,4H),3.03(s,2H),2.96–2.87(m,4H),2.04–1.91(m,4H),1.84(dd,J＝9.5,5.2Hz,2H),1.62(dt,J＝13.4,6.3Hz,2H). MS (ESI, [M+H] + ) m/z: 537.3. 1 H NMR (500MHz,DMSO-d 6 )δ8.23(s,1H),7.67–7.61(m,2H),7.47–7.38(m,2H),7.20–7.11(m,5H),7.10–6.38 (m,2H),4.65(dp,J=11.0,3.7Hz,1H),3.50–3.35(m,4H),3.22(dt,J=34.6,6.4Hz,4H),3.03(s,2H), 2.96–2.87(m,4H),2.04–1.91(m,4H),1.84(dd,J＝9.5,5.2Hz,2H),1.62(dt,J＝13.4,6.3Hz,2H).
步骤3：化合物47的制备Step 3: Preparation of Compound 47
向单口瓶中依次加入中间体47c(236mg)、中间体13b(243mg)、N,N-二异丙基乙胺(114mg)及二甲基亚砜(5mL)，80℃搅拌反应5h，反应完全，反应液通过120g C 18反相柱纯化得化合物47(140mg)。 Add intermediate 47c (236mg), intermediate 13b (243mg), N,N-diisopropylethylamine (114mg) and dimethyl sulfoxide (5mL) to the one-necked bottle in turn, stir at 80°C for 5h, and react Completely, the reaction solution was purified by a 120 g C 18 reverse phase column to obtain compound 47 (140 mg).
HR-MS(ESI,[M+H] +)m/z：793.35598。 1H NMR(500MHz,DMSO-d 6)δ11.07(s,1H),8.23(s,1H),7.66–7.62(m,3H),7.45–7.40(m,2H),7.21–7.07(m,6H),6.78(d,J＝2.2Hz,1H),6.64(dd,J＝8.4,2.1Hz,1H),5.05(dd,J＝12.8,5.4Hz,1H),4.65(tt,J＝11.5,3.7Hz,1H),4.03(dd,J＝8.8,6.8Hz,2H),3.78(dd,J＝8.9,4.3Hz,2H),3.60(tt,J＝7.0,4.3Hz,1H),3.27(t,J＝6.7Hz,2H),3.08(s,1H),3.05–2.80(m,6H),2.62–2.51(m,2H),2.06–1.89(m,6H),1.84(dd,J＝9.7,5.1Hz,2H),1.62(td,J＝13.3,3.8Hz,2H). 13C NMR(126MHz,DMSO-d 6)δ173.26,170.57,167.95,167.64,158.61,157.47,156.84,155.90,155.38,153.96,143.19,134.29,130.59,130.54,128.64,125.27,124.22,119.49,119.38,117.23,114.66,104.96,97.86,60.92,59.27,55.39,55.10,55.02,54.12,54.08,53.21,49.19,35.01,34.73,31.83,31.46,28.83,22.68. HR-MS (ESI, [M+H] + ) m/z: 793.35598. 1 H NMR (500MHz,DMSO-d 6 )δ11.07(s,1H),8.23(s,1H),7.66–7.62(m,3H),7.45–7.40(m,2H),7.21–7.07(m ,6H),6.78(d,J=2.2Hz,1H),6.64(dd,J=8.4,2.1Hz,1H),5.05(dd,J=12.8,5.4Hz,1H),4.65(tt,J= 11.5,3.7Hz,1H),4.03(dd,J＝8.8,6.8Hz,2H),3.78(dd,J＝8.9,4.3Hz,2H),3.60(tt,J＝7.0,4.3Hz,1H), 3.27(t,J＝6.7Hz,2H),3.08(s,1H),3.05–2.80(m,6H),2.62–2.51(m,2H),2.06–1.89(m,6H),1.84(dd, J＝9.7, 5.1Hz, 2H), 1.62 (td, J＝13.3, 3.8Hz, 2H). 13 C NMR (126MHz, DMSO-d 6 ) δ173.26, 170.57, 167.95, 167.64, 158.61, 157.47, 156.84, 155.90 ,155.38,153.96,143.19,134.29,130.59,130.54,128.64,125.27,124.22,119.49,119.38,117.23,114.66,104.96,97.86,60.92,59.27,55.39,55.10,55.02,54.12,54.08,53.21,49.19,35.01 ,34.73,31.83,31.46,28.83,22.68.
实施例48 化合物48的制备Example 48 Preparation of Compound 48
Figure PCTCN2022096512-appb-000161
Figure PCTCN2022096512-appb-000161
Figure PCTCN2022096512-appb-000162
Figure PCTCN2022096512-appb-000162
步骤1：化合物48的合成Step 1: Synthesis of compound 48
在单口瓶中，将化合物46e(150mg)和化合物31b(92mg)溶于二甲亚砜(4mL)中，加入N,N-二异丙基乙胺(121mg)，升温至90℃反应4小时。反应完毕后，反应液冷至室温，粗品经过反相纯化(洗脱剂：水/乙腈)得到化合物48(150mg)。In a single-necked bottle, dissolve compound 46e (150 mg) and compound 31b (92 mg) in dimethyl sulfoxide (4 mL), add N,N-diisopropylethylamine (121 mg), and heat up to 90 ° C for 4 hours . After the reaction was completed, the reaction liquid was cooled to room temperature, and the crude product was purified by reverse phase (eluent: water/acetonitrile) to obtain compound 48 (150 mg).
HRMS(ESI)m/z[M+H] +:756.30591。 1H NMR(500MHz,DMSO-d 6)δ11.09(s,1H),8.23(s,1H),7.70–7.63(m,2H),7.59(d,J＝11.1Hz,1H),7.48–7.37(m,2H),7.18(dd,J＝8.1,6.8Hz,1H),7.17–7.08(m,4H),6.91(d,J＝7.6Hz,1H),5.07(dd,J＝12.9,5.4Hz,1H),4.66(tt,J＝11.5,3.9Hz,1H),4.18(t,J＝7.9Hz,2H),3.96(t,J＝6.6Hz,2H),3.68–3.57(m,1H),3.13(s,2H),3.00(s,2H),2.88(ddd,J＝16.9,13.8,5.5Hz,1H),2.58(dt,J＝17.3,2.9Hz,1H),2.10–1.92(m,5H),1.92–1.80(m,2H),1.64(td,J＝13.3,3.7Hz,2H). 13C NMR(126MHz,DMSO-d 6)δ173.24,170.47,167.29,166.88,158.61,157.45,156.84,155.89,153.95,143.19,130.59,130.52,129.80,128.63,124.22,119.49,119.38,111.80,111.63,108.51,97.85,60.72,59.02,56.88,55.10,54.55,49.39,34.99,34.82,31.44,28.82,22.63. HRMS (ESI) m/z [M+H] + : 756.30591. 1 H NMR (500MHz,DMSO-d 6 )δ11.09(s,1H),8.23(s,1H),7.70–7.63(m,2H),7.59(d,J=11.1Hz,1H),7.48– 7.37(m,2H),7.18(dd,J=8.1,6.8Hz,1H),7.17–7.08(m,4H),6.91(d,J=7.6Hz,1H),5.07(dd,J=12.9, 5.4Hz, 1H), 4.66(tt, J＝11.5, 3.9Hz, 1H), 4.18(t, J＝7.9Hz, 2H), 3.96(t, J＝6.6Hz, 2H), 3.68–3.57(m, 1H), 3.13(s, 2H), 3.00(s, 2H), 2.88(ddd, J＝16.9, 13.8, 5.5Hz, 1H), 2.58(dt, J＝17.3, 2.9Hz, 1H), 2.10–1.92 (m,5H),1.92–1.80(m,2H),1.64(td,J＝13.3,3.7Hz,2H). 13 C NMR(126MHz,DMSO-d 6 )δ173.24,170.47,167.29,166.88,158.61, 157.45,156.84,155.89,153.95,143.19,130.59,130.52,129.80,128.63,124.22,119.49,119.38,111.80,111.63,108.51,97.85,60.72,59.02,56.88,55.10,54.55,49.39,34.99,34.82,31.44, 28.82, 22.63.
实施例49 化合物49的制备Example 49 Preparation of Compound 49
Figure PCTCN2022096512-appb-000163
Figure PCTCN2022096512-appb-000163
步骤1：化合物49的制备Step 1: Preparation of Compound 49
向微波管中加入中间体46e(0.05g)、中间体11c(0.062g)、Ruphos Pd G3(0.013g)、碳酸铯(0.101g)和DMF(3mL)，微波加热至110℃反应60分钟。反应液冷却至室温，加入DCM(50mL)和水(50mL)。有机相分离，用饱和氯化钠溶液(50mL)洗涤后用无水硫酸钠干燥，过滤，浓缩，浓缩物经硅胶柱层析分离纯化得到化合物49(0.021g)。Intermediate 46e (0.05g), intermediate 11c (0.062g), Ruphos Pd G3 (0.013g), cesium carbonate (0.101g) and DMF (3mL) were added to a microwave tube, heated to 110°C for 60 minutes by microwave. The reaction solution was cooled to room temperature, and DCM (50 mL) and water (50 mL) were added. The organic phase was separated, washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and the concentrate was separated and purified by silica gel column chromatography to obtain compound 49 (0.021 g).
MS(ESI,[M+H] +)m/z：724.4。 1H NMR(500MHz,DMSO-d 6)δ10.94(s,1H),8.23(s,1H),7.64(dd,J＝9.9,3.4Hz,2H),7.49(d,J＝8.1Hz,1H),7.43(t,J＝8.0Hz,2H),7.20–7.10(m,5H),6.52(s,1H),6.50–6.46(m,1H),5.03(dd,J＝13.2,5.2Hz,1H),4.71–4.60(m,1H),4.31(d,J＝16.8Hz,1H),4.18(d,J＝16.8Hz,1H),3.93(s,2H),3.72(s,2H),3.12(s,2H),3.00(s,2H),2.94–2.85(m,1H),2.58(d,J＝17.2Hz,1H),2.40–2.29(m,1H),2.05(d,J＝12.4Hz,2H),2.01–1.91(m,3H),1.85(d,J＝12.3Hz,2H),1.70–1.61(m,2H). MS (ESI, [M+H] + ) m/z: 724.4. 1 H NMR (500MHz, DMSO-d 6 )δ10.94(s, 1H), 8.23(s, 1H), 7.64(dd, J=9.9, 3.4Hz, 2H), 7.49(d, J=8.1Hz, 1H), 7.43(t, J＝8.0Hz, 2H), 7.20–7.10(m, 5H), 6.52(s, 1H), 6.50–6.46(m, 1H), 5.03(dd, J＝13.2, 5.2Hz ,1H),4.71–4.60(m,1H),4.31(d,J＝16.8Hz,1H),4.18(d,J＝16.8Hz,1H),3.93(s,2H),3.72(s,2H) ,3.12(s,2H),3.00(s,2H),2.94–2.85(m,1H),2.58(d,J＝17.2Hz,1H),2.40–2.29(m,1H),2.05(d,J ＝12.4Hz, 2H), 2.01–1.91(m, 3H), 1.85(d, J＝12.3Hz, 2H), 1.70–1.61(m, 2H).
实施例50 化合物50的制备The preparation of embodiment 50 compound 50
Figure PCTCN2022096512-appb-000164
Figure PCTCN2022096512-appb-000164
Figure PCTCN2022096512-appb-000165
Figure PCTCN2022096512-appb-000165
步骤1：化合物50的制备Step 1: Preparation of compound 50
向反应瓶中，依次加入中间体46c(170mg)、中间体36c(253mg)、DCM(30mL)及冰乙酸(22.26mg)，N 2保护下，将混合物室温搅拌20min。反应液中加入氰基硼氢化钠(69.9mg)，继续N 2保护下室温搅拌2小时，反应完全，反应液旋蒸后残余物用DCM-MeOH(20:1，30mL×2)萃取，有机层合并后用饱和食盐水(50mL×1)洗涤，萃取液干燥过滤，滤液旋蒸后残余物用硅胶柱纯化(DCM-MeOH)得到粗品(200mg)。粗品再用C 18反相柱纯化(10nM乙酸铵水溶液-乙腈)洗脱，过柱液合并，DCM-MeOH(10:1)萃取后旋蒸干得到化合物50(84mg)。 To the reaction flask, intermediate 46c (170 mg), intermediate 36c (253 mg), DCM (30 mL) and glacial acetic acid (22.26 mg) were sequentially added, and the mixture was stirred at room temperature for 20 min under N 2 protection. Sodium cyanoborohydride (69.9mg) was added to the reaction solution, and continued to stir at room temperature under N2 protection for 2 hours. The reaction was complete. After the reaction solution was rotary evaporated, the residue was extracted with DCM-MeOH (20:1, 30mL×2), organic The layers were combined and washed with saturated brine (50 mL×1), the extract was dried and filtered, and the filtrate was rotary evaporated, and the residue was purified by a silica gel column (DCM-MeOH) to obtain a crude product (200 mg). The crude product was purified by a C 18 reverse phase column (10 nM ammonium acetate aqueous solution-acetonitrile), and the column solution was combined, extracted with DCM-MeOH (10:1) and then evaporated to dryness to obtain compound 50 (84 mg).
MS(ESI,[M+H] +)m/z：752.4。 1H NMR(500MHz,DMSO-d 6)δ11.07(s,1H),8.23(s,1H),7.64(t,J＝8.4Hz,3H),7.46–7.40(m,2H),7.22–7.09(m,5H),6.77(d,J＝2.1Hz,1H),6.63(dd,J＝8.4,2.1Hz,1H),5.05(dd,J＝12.8,5.4Hz,1H),4.65(tt,J＝11.6,4.0Hz,1H),4.09(t,J＝7.9Hz,2H),3.75–3.65(m,2H),3.16–2.64(m,8H),2.62–2.51(m,3H),2.05–1.89(m,5H),1.84(d,J＝12.2Hz,2H),1.64(dt,J＝14.1,7.8Hz,2H). MS (ESI, [M+H] + ) m/z: 752.4. 1 H NMR (500MHz,DMSO-d 6 )δ11.07(s,1H),8.23(s,1H),7.64(t,J=8.4Hz,3H),7.46–7.40(m,2H),7.22– 7.09(m,5H),6.77(d,J=2.1Hz,1H),6.63(dd,J=8.4,2.1Hz,1H),5.05(dd,J=12.8,5.4Hz,1H),4.65(tt ,J=11.6,4.0Hz,1H),4.09(t,J=7.9Hz,2H),3.75–3.65(m,2H),3.16–2.64(m,8H),2.62–2.51(m,3H), 2.05–1.89(m,5H),1.84(d,J=12.2Hz,2H),1.64(dt,J=14.1,7.8Hz,2H).
实施例51 化合物51的制备Example 51 Preparation of Compound 51
Figure PCTCN2022096512-appb-000166
Figure PCTCN2022096512-appb-000166
步骤1：中间体51b-1和51b-2的制备Step 1: Preparation of intermediates 51b-1 and 51b-2
向单口瓶中依次加入中间体46c(1.0g)、1-叔丁氧羰基-3-吡咯烷酮(0.65g)、乙酸(0.21g)、氰基硼氢化钠(0.30g)及甲醇(20mL)，常温搅拌反应2h，反应完全，将反应液倒入纯化水(150mL)中，加入二氯甲烷/甲醇＝10/1溶液(150mL)，萃取分层，有机相用饱和氯化钠水溶液洗涤，用无水硫酸钠干燥，浓缩有机相得粗品，过硅胶柱纯化后，所得粗品51b经高压制备液相分离(CHIRALARTCellulose-SC色谱柱；乙醇：正己烷＝30:70)，先出峰的为S构型中间体51b-1(0.42g)，后出峰的为R构型中间体51b-2(0.38g)。Intermediate 46c (1.0g), 1-tert-butoxycarbonyl-3-pyrrolidone (0.65g), acetic acid (0.21g), sodium cyanoborohydride (0.30g) and methanol (20mL) were sequentially added to the one-necked bottle, Stir the reaction at room temperature for 2 hours, and the reaction is complete. Pour the reaction solution into purified water (150 mL), add dichloromethane/methanol=10/1 solution (150 mL), extract and separate layers, and wash the organic phase with saturated aqueous sodium chloride solution. Dry over anhydrous sodium sulfate, concentrate the organic phase to obtain the crude product, after purification by silica gel column, the obtained crude product 51b is separated by high-pressure preparative liquid phase (CHIRALARTCellulose-SC column; ethanol: n-hexane = 30:70), the first peak is S Configuration intermediate 51b-1 (0.42g), the last peak is R configuration intermediate 51b-2 (0.38g).
MS(ESI,[M+H] +)m/z：596.5。 MS (ESI, [M+H] + ) m/z: 596.5.
步骤2：中间体51c的制备Step 2: Preparation of intermediate 51c
向反应瓶中依次加入中间体51b-2(2.10g)、盐酸二氧六环溶液(4M，6mL)，25℃搅拌反应3.5h。反应完全，反应液浓缩至干，加入纯化水(50mL)、二氯甲烷/甲醇＝10/1溶液(50mL)，搅拌状态下加入饱和碳酸氢钠水溶液(50mL)，萃取分层，有机相用饱和氯化钠水溶液洗涤，用无水硫酸钠干燥，浓缩有机相得中间体51c(290mg)。Intermediate 51b-2 (2.10 g) and dioxane hydrochloride solution (4M, 6 mL) were successively added to the reaction flask, and the reaction was stirred at 25° C. for 3.5 h. The reaction was complete, the reaction solution was concentrated to dryness, purified water (50mL), dichloromethane/methanol = 10/1 solution (50mL) was added, and saturated aqueous sodium bicarbonate solution (50mL) was added under stirring, the layers were extracted, and the organic phase was used Wash with saturated aqueous sodium chloride, dry over anhydrous sodium sulfate, and concentrate the organic phase to obtain intermediate 51c (290 mg).
MS(ESI,[M+H] +)m/z：496.4。 MS (ESI, [M+H] + ) m/z: 496.4.
步骤3：化合物51的制备Step 3: Preparation of compound 51
向单口瓶中依次加入中间体51c(290mg)、中间体13b(242mg)、N,N-二异丙基乙胺(151mg)及二甲基亚砜(5mL)，80℃搅拌反应5h，反应完全，反应液通过120g C 18反相柱纯化得化合物51(142mg)。 Add intermediate 51c (290mg), intermediate 13b (242mg), N,N-diisopropylethylamine (151mg) and dimethyl sulfoxide (5mL) to the one-necked bottle in turn, stir at 80°C for 5h, and react Completely, the reaction solution was purified by a 120 g C 18 reverse phase column to obtain compound 51 (142 mg).
MS(ESI,[M+H] +)m/z：752.5。 1H NMR(500MHz,DMSO)δ11.08(s,1H),8.23(s,1H),7.64(dd,J＝8.8,2.9Hz,3H),7.44(t,J＝7.9Hz,2H),7.22–7.09(m,5H),6.91(d,J＝2.2Hz,1H),6.79(dd,J＝8.6,2.2Hz,1H),5.06(dd,J＝12.9,5.4Hz,1H),4.65(ddt,J＝11.7,8.4,4.0Hz,1H),3.50–3.39(m,3H),3.14(d,J＝45.0Hz,3H),3.05–2.83(m,3H),2.57(ddd,J＝21.9,10.2,6.2Hz,2H),2.05–1.90(m,6H),1.90–1.78(m,3H),1.72–1.54(m,2H). 13C NMR(126MHz,DMSO)δ173.29,170.63,168.18,167.71,158.61,157.46,156.85,155.90,153.95,152.31,143.20,134.49,130.60,130.52,128.64,125.41,124.22,119.50,119.38,115.71,106.00,97.84,61.68,55.04,49.15,46.91,35.21,34.31,31.47,28.78,22.73. MS (ESI, [M+H] + ) m/z: 752.5. 1 H NMR (500MHz, DMSO) δ11.08(s, 1H), 8.23(s, 1H), 7.64(dd, J=8.8, 2.9Hz, 3H), 7.44(t, J=7.9Hz, 2H), 7.22–7.09(m,5H),6.91(d,J=2.2Hz,1H),6.79(dd,J=8.6,2.2Hz,1H),5.06(dd,J=12.9,5.4Hz,1H),4.65 (ddt,J=11.7,8.4,4.0Hz,1H),3.50–3.39(m,3H),3.14(d,J=45.0Hz,3H),3.05–2.83(m,3H),2.57(ddd,J ＝21.9,10.2,6.2Hz,2H),2.05–1.90(m,6H),1.90–1.78(m,3H),1.72–1.54(m,2H). 13 C NMR(126MHz,DMSO)δ173.29,170.63, 168.18,167.71,158.61,157.46,156.85,155.90,153.95,152.31,143.20,134.49,130.60,130.52,128.64,125.41,124.22,119.50,119.38,115.71,106.00,97.84,61.68,55.04,49.15,46.91,35.21, 34.31, 31.47, 28.78, 22.73.
实施例52 化合物52的制备The preparation of embodiment 52 compound 52
Figure PCTCN2022096512-appb-000167
Figure PCTCN2022096512-appb-000167
步骤1：中间体52b的制备Step 1: Preparation of intermediate 52b
向反应瓶中依次加入中间体51b-1(2.10g)及盐酸二氧六环溶液(4M，6mL)，25℃搅拌反应3.5h。反应完全，反应液浓缩至干，加入纯化水(50mL)、二氯甲烷/甲醇＝10/1溶液(50mL)，搅拌状态下加入饱和碳酸氢钠水溶液(50mL)，萃取分层，有机相用饱和氯化钠水溶液洗涤，用无水硫酸钠干燥，浓缩有机相得52b(350mg)。Intermediate 51b-1 (2.10 g) and dioxane hydrochloride solution (4M, 6 mL) were successively added into the reaction flask, and the reaction was stirred at 25° C. for 3.5 h. The reaction was complete, the reaction solution was concentrated to dryness, purified water (50mL), dichloromethane/methanol = 10/1 solution (50mL) was added, and saturated aqueous sodium bicarbonate solution (50mL) was added under stirring, the layers were extracted, and the organic phase was used It was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and the organic phase was concentrated to give 52b (350 mg).
MS(ESI,[M+H] +)m/z：496.4。 MS (ESI, [M+H] + ) m/z: 496.4.
步骤3：化合物52的制备Step 3: Preparation of Compound 52
向单口瓶中依次加入52b(350mg)、中间体13b(293mg)、N,N-二异丙基乙胺(183mg)及二甲基亚砜(5mL)，80℃搅拌反应5h，反应完全，反应液通过120g C 18反相柱纯化得化合物52(180mg)。 Add 52b (350mg), intermediate 13b (293mg), N,N-diisopropylethylamine (183mg) and dimethyl sulfoxide (5mL) to the one-necked bottle in turn, stir and react at 80°C for 5h, and the reaction is complete. The reaction solution was purified by a 120 g C 18 reverse phase column to obtain compound 52 (180 mg).
MS(ESI,[M+H] +)m/z：752.5。1H NMR(500MHz,DMSO)δ11.08(s,1H),8.23(s,1H),7.64(dd,J＝8.5,3.8Hz,3H),7.44(t,J＝7.8Hz,2H),7.16(ddd,J＝23.6,14.9,7.7Hz,5H),6.94–6.87(m,1H),6.79(dd,J＝8.6,2.2Hz,1H),5.06(dd,J＝12.9,5.4Hz,1H),4.65(dq,J＝11.5,7.3,5.6Hz,1H),3.49–3.39(m,3H),3.23–3.07(m,3H),3.05–2.83(m,3H),2.63–2.51(m,2H),2.08–1.91(m,6H),1.91–1.78(m,3H),1.62(dt,J＝14.2,8.0Hz,2H). 13C NMR(126MHz,DMSO)δ173.29,170.63,168.18,167.71,158.60,157.46,156.84,155.90,153.95,152.32,143.20,134.49,130.60,130.52,128.64,125.41,124.22,119.50,119.38,115.99,115.70,105.99,97.84,63.24,61.69,55.05,49.15,46.92,35.23,34.32,31.47,28.79,22.73. MS (ESI, [M+H] + ) m/z: 752.5. 1H NMR (500MHz, DMSO) δ11.08 (s, 1H), 8.23 (s, 1H), 7.64 (dd, J = 8.5, 3.8Hz ,3H),7.44(t,J=7.8Hz,2H),7.16(ddd,J=23.6,14.9,7.7Hz,5H),6.94–6.87(m,1H),6.79(dd,J=8.6,2.2 Hz,1H),5.06(dd,J＝12.9,5.4Hz,1H),4.65(dq,J＝11.5,7.3,5.6Hz,1H),3.49–3.39(m,3H),3.23–3.07(m, 3H),3.05–2.83(m,3H),2.63–2.51(m,2H),2.08–1.91(m,6H),1.91–1.78(m,3H),1.62(dt,J＝14.2,8.0Hz, 2H). 13 C NMR(126MHz,DMSO)δ173.29,170.63,168.18,167.71,158.60,157.46,156.84,155.90,153.95,152.32,143.20,134.49,130.60,130.52,128.64,125.41,124.22,119.50,119.38,115.99 ,115.70,105.99,97.84,63.24,61.69,55.05,49.15,46.92,35.23,34.32,31.47,28.79,22.73.
实施例53：化合物53的制备Embodiment 53: Preparation of compound 53
Figure PCTCN2022096512-appb-000168
Figure PCTCN2022096512-appb-000168
Figure PCTCN2022096512-appb-000169
Figure PCTCN2022096512-appb-000169
步骤1：中间体53b的制备Step 1: Preparation of intermediate 53b
向单口瓶中依次加入4-羟基哌啶(0.439g)、中间体13b(1g)、NMP(10mL)及DIPEA(1.404g)，N 2保护下，将混合物加热至80℃反应6h。反应结束后，反应液中加入EA萃取，有机相用无水硫酸钠干燥，通过硅胶柱层析纯化(DCM/CH 3OH)得到0.98g中间体53b。 4-Hydroxypiperidine (0.439g), intermediate 13b (1g), NMP (10mL) and DIPEA (1.404g) were sequentially added to a one-necked flask, and the mixture was heated to 80°C for 6h under the protection of N 2 . After the reaction, EA was added to the reaction liquid for extraction, the organic phase was dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (DCM/CH 3 OH) to obtain 0.98 g of intermediate 53b.
MS(ESI,[M+H] +)m/z：358.1。 1H NMR(500MHz,DMSO-d 6)δ11.07(s,1H),7.65(d,J＝8.5Hz,1H),7.31(d,J＝2.4Hz,1H),7.23(dd,J＝8.7,2.4Hz,1H),5.07(dd,J＝12.8,5.4Hz,1H),4.75(d,J＝4.1Hz,1H),3.82(dt,J＝13.5,4.7Hz,2H),3.75(tt,J＝7.9,3.9Hz,1H),3.21(dd,J＝9.8,3.4Hz,1H),2.94–2.82(m,1H),2.62–2.46(m,2H),2.21–1.86(m,2H),1.81(ddt,J＝13.1,6.8,3.8Hz,2H),1.42(dtd,J＝12.8,8.9,3.7Hz,2H). MS (ESI, [M+H] + ) m/z: 358.1. 1 H NMR (500MHz, DMSO-d 6 ) δ11.07(s, 1H), 7.65(d, J=8.5Hz, 1H), 7.31(d, J=2.4Hz, 1H), 7.23(dd, J= 8.7,2.4Hz,1H),5.07(dd,J=12.8,5.4Hz,1H),4.75(d,J=4.1Hz,1H),3.82(dt,J=13.5,4.7Hz,2H),3.75( tt,J=7.9,3.9Hz,1H),3.21(dd,J=9.8,3.4Hz,1H),2.94–2.82(m,1H),2.62–2.46(m,2H),2.21–1.86(m, 2H), 1.81(ddt, J=13.1, 6.8, 3.8Hz, 2H), 1.42(dtd, J=12.8, 8.9, 3.7Hz, 2H).
步骤2：中间体53c的制备Step 2: Preparation of Intermediate 53c
向单口瓶中依次加入中间体53b(0.9g)及DCM(20mL)，室温搅拌下加入戴斯-马丁氧化剂(3.20g)，N 2保护下，继续室温反应1.5h。反应液抽滤，除去少量不溶物，滤饼用少量DCM洗涤，滤液和洗液合并后，搅拌下分批多次加入饱和亚硫酸钠水溶液，待无气泡产生后静置分层，分出有机层后，水层再用DCM萃取(50mL×1)，有机层合并后，有机层用无水硫酸钠搅拌干燥，过滤，滤液旋蒸，浓缩物通过硅胶柱层析纯化(DCM/CH 3OH)得到0.76g中间体53c。 Intermediate 53b (0.9g) and DCM (20mL) were sequentially added to a one-necked flask, and Dess-Martin oxidant (3.20g) was added under stirring at room temperature, and the reaction was continued at room temperature for 1.5h under N 2 protection. Suction filter the reaction solution to remove a small amount of insoluble matter, wash the filter cake with a small amount of DCM, combine the filtrate and washing liquid, add saturated sodium sulfite aqueous solution in batches under stirring, wait until no bubbles are generated, let it stand for stratification, and separate the organic layer , the aqueous layer was extracted with DCM (50mL×1), after the organic layers were combined, the organic layer was stirred and dried with anhydrous sodium sulfate, filtered, the filtrate was rotary evaporated, and the concentrate was purified by silica gel column chromatography (DCM/CH 3 OH) to obtain 0.76 g of intermediate 53c.
MS(ESI,[M+H] +)m/z：356.4。 MS (ESI, [M+H] + ) m/z: 356.4.
步骤3：化合物53的制备Step 3: Preparation of compound 53
向单口瓶中依次加入中间体53c(200mg)、中间体46c(288mg)及DCM(5mL)，室温搅拌下滴加醋酸(16.90mg)，将混合物加热至40℃反应2h，反应液降至0℃，加入三乙酰氧基硼氢化钠(239mg)，室温搅拌2h。反应结束后，反应液减压蒸除溶剂，加入3mL DMSO溶解后，以220g反相柱层析纯化(H 2O/CH 3CN)得到0.231g化合物53。 Add intermediate 53c (200mg), intermediate 46c (288mg) and DCM (5mL) to the single-necked bottle successively, add acetic acid (16.90mg) dropwise under stirring at room temperature, heat the mixture to 40°C for 2h, and the reaction solution drops to 0 °C, sodium triacetoxyborohydride (239mg) was added, and stirred at room temperature for 2h. After the reaction, the reaction liquid was evaporated to remove the solvent under reduced pressure, dissolved in 3 mL of DMSO, and purified by 220 g of reverse phase column chromatography (H 2 O/CH 3 CN) to obtain 0.231 g of compound 53.
MS(ESI,[M+H] +)m/z：766.5。 1H NMR(500MHz,DMSO-d 6)δ11.08(s,1H),8.23(s,1H),7.65(dd,J＝8.8,2.8Hz,3H),7.48–7.40(m,2H),7.33(s,1H),7.24(d,J＝8.8Hz,1H),7.19(t,J＝7.4Hz,1H),7.17–7.08(m,4H),5.07(dd,J＝12.8,5.4Hz,1H),4.66(tt,J＝11.7,3.9Hz,1H),3.89(s,2H),3.11(d,J＝26.1Hz,3H),2.89(ddd,J＝16.6,13.7,5.3Hz,2H),2.62–2.52(m,2H),2.33(s,1H),2.05–1.93(m,4H),1.85(d,J＝9.5Hz,2H),1.75(s,2H),1.69–1.57(m,2H),1.30–1.20(m,2H),0.84(tdt,J＝9.8,6.6,3.7Hz,1H). MS (ESI, [M+H] + ) m/z: 766.5. 1 H NMR (500MHz,DMSO-d 6 )δ11.08(s,1H),8.23(s,1H),7.65(dd,J＝8.8,2.8Hz,3H),7.48–7.40(m,2H), 7.33(s, 1H), 7.24(d, J=8.8Hz, 1H), 7.19(t, J=7.4Hz, 1H), 7.17–7.08(m, 4H), 5.07(dd, J=12.8, 5.4Hz ,1H),4.66(tt,J=11.7,3.9Hz,1H),3.89(s,2H),3.11(d,J=26.1Hz,3H),2.89(ddd,J=16.6,13.7,5.3Hz, 2H),2.62–2.52(m,2H),2.33(s,1H),2.05–1.93(m,4H),1.85(d,J＝9.5Hz,2H),1.75(s,2H),1.69–1.57 (m,2H),1.30–1.20(m,2H),0.84(tdt,J=9.8,6.6,3.7Hz,1H).
实施例54：化合物54的制备Embodiment 54: Preparation of compound 54
Figure PCTCN2022096512-appb-000170
Figure PCTCN2022096512-appb-000170
Figure PCTCN2022096512-appb-000171
Figure PCTCN2022096512-appb-000171
步骤1：中间体54b的制备Step 1: Preparation of intermediate 54b
在单口瓶中，0℃下，将硼氢化钠(1.91g)缓慢加入3-Boc-9-氧代-3-氮杂螺[5.5]十一烷54a(4.5g)的MeOH(30mL)搅拌液中，20分钟后加入完毕，混合物在0℃搅拌反应1h。将反应液中加入少量氯化铵水溶液淬灭反应后，加入1M HCl调pH＝7，加入DCM(100mL)和水(100mL)。有机相分离，分别用100mL饱和食盐水洗涤后用无水硫酸钠干燥，过滤，滤液通过减压蒸除溶剂，得到5.01g中间体54b。In a one-necked flask, sodium borohydride (1.91 g) was slowly added to 3-Boc-9-oxo-3-azaspiro[5.5]undecane 54a (4.5 g) in MeOH (30 mL) at 0 °C and stirred After 20 minutes, the addition was completed, and the mixture was stirred at 0°C for 1 h. After adding a small amount of ammonium chloride aqueous solution to the reaction solution to quench the reaction, 1M HCl was added to adjust the pH to 7, and DCM (100 mL) and water (100 mL) were added. The organic phase was separated, washed with 100 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to remove the solvent under reduced pressure to obtain 5.01 g of intermediate 54b.
1H NMR(500MHz,DMSO-d 6)δ3.41(tt,J＝9.4,2.9Hz,1H),3.26(t,J＝5.8Hz,4H),1.57(dd,J＝12.0,4.1Hz,4H),1.38(s,9H),1.36–1.32(m,2H),1.31–1.20(m,4H),1.15–1.04(m,2H). 1 H NMR (500MHz, DMSO-d 6 ) δ3.41(tt, J=9.4, 2.9Hz, 1H), 3.26(t, J=5.8Hz, 4H), 1.57(dd, J=12.0, 4.1Hz, 4H),1.38(s,9H),1.36–1.32(m,2H),1.31–1.20(m,4H),1.15–1.04(m,2H).
步骤2：中间体54c，中间体54d的制备Step 2: Preparation of intermediate 54c, intermediate 54d
向三口瓶中，N 2保护下，加入3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-4-胺(4.2g)、THF(100mL)、中间体54b(4.48g)、三苯基膦(10.90g)，降温至0℃，缓慢滴加双-2-甲氧乙基偶氮二羧酸酯(5.60g)，20min加毕，室温搅拌2h。反应结束后，将反应液倒入水(200mL)中，加入EA(200mL)，有机相分离，分别用300mL饱和食盐水洗涤后用无水硫酸钠干燥，过滤，滤液通过减压蒸除溶剂，得到7.0g中间体54c，MS(ESI,[M+H] +)m/z：815.4；及3.0g中间体54d，MS(ESI,[M+H] +)m/z：555.6。 Into the three-necked flask, under N2 protection, add 3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (4.2g), THF (100mL), Intermediate 54b (4.48g), triphenylphosphine (10.90g), lower the temperature to 0°C, slowly add bis-2-methoxyethyl azodicarboxylate (5.60g), dropwise for 20min, stir at room temperature 2h. After the reaction, the reaction solution was poured into water (200mL), EA (200mL) was added, the organic phase was separated, washed with 300mL saturated brine, dried with anhydrous sodium sulfate, filtered, and the filtrate was evaporated to remove the solvent under reduced pressure. 7.0 g of intermediate 54c, MS (ESI, [M+H] + ) m/z: 815.4; and 3.0 g of intermediate 54d, MS (ESI, [M+H] + ) m/z: 555.6 were obtained.
步骤3：中间体54e的制备Step 3: Preparation of Intermediate 54e
向单口瓶中，依次加入中间体54d(3.0g)、中间体54c(4.5g)、HCl(41.4mL,4M，1,4-二氧六环溶液)，室温反应5h，反应结束，向反应液中加入100mL EA，搅拌30min后，析出大量固体，过滤，滤饼加饱和碳酸氢钠溶液溶解调pH＝8-9，加入200mLDCM：CH 3OH(10：1)溶液萃取三次，有机相用饱和氯化钠水溶液洗涤后用无水硫酸钠干燥，过滤，滤液通过减压蒸除溶剂，得到4.5g中间体54e。 Into the one-necked bottle, sequentially add intermediate 54d (3.0g), intermediate 54c (4.5g), HCl (41.4mL, 4M, 1,4-dioxane solution), and react at room temperature for 5h. Add 100mL EA to the solution, stir for 30min, a large amount of solid precipitates, filter, add saturated sodium bicarbonate solution to dissolve the filter cake to adjust pH=8-9, add 200mL DCM:CH 3 OH (10:1) solution for extraction three times, and use After washing with saturated aqueous sodium chloride, it was dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to remove the solvent under reduced pressure to obtain 4.5 g of intermediate 54e.
MS(ESI,[M+H] +)m/z：455.3。 1H NMR(500MHz,DMSO-d 6)δ8.23(s,1H),7.68–7.63(m,2H),7.46–7.40(m,2H),7.21–7.16(m,1H),7.16–7.10(m,4H),4.64(tt,J＝11.9,4.3Hz,1H),3.43–3.24(m,1H),2.72–2.62(m,4H),2.23–2.08(m,2H),1.84(d,J＝13.3Hz,2H),1.73(dt,J＝13.3,4.0Hz,2H),1.53(t,J＝5.5Hz,2H),1.28(tt,J＝10.5,4.9Hz,4H). MS (ESI, [M+H] + ) m/z: 455.3. 1 H NMR (500MHz,DMSO-d 6 )δ8.23(s,1H),7.68–7.63(m,2H),7.46–7.40(m,2H),7.21–7.16(m,1H),7.16–7.10 (m,4H),4.64(tt,J＝11.9,4.3Hz,1H),3.43–3.24(m,1H),2.72–2.62(m,4H),2.23–2.08(m,2H),1.84(d , J=13.3Hz, 2H), 1.73(dt, J=13.3, 4.0Hz, 2H), 1.53(t, J=5.5Hz, 2H), 1.28(tt, J=10.5, 4.9Hz, 4H).
步骤4：中间体54f的制备Step 4: Preparation of intermediate 54f
向单口瓶中依次加入氮杂环丁烷-3-醇(0.439g)、中间体13b(1g)、NMP(10mL)及DIPEA(1.404g)，N 2保护下，将混合物加热至80℃反应6h。反应结束后，反应液中加入EA萃取，有机相用无水硫酸钠干燥，通过硅胶柱层析纯化(DCM/CH 3OH)得到0.98g中间体54f。 Add azetidin-3-ol (0.439g), intermediate 13b (1g), NMP (10mL) and DIPEA (1.404g) to a one-necked flask in sequence, and heat the mixture to 80°C under N2 protection 6h. After the reaction was completed, EA was added to the reaction solution for extraction, the organic phase was dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (DCM/CH 3 OH) to obtain 0.98 g of intermediate 54f.
MS(ESI,[M+H] +)m/z：330.2。 1H NMR(500MHz,DMSO-d6)δ11.06(s,1H),7.63(d,J＝8.3Hz,1H),6.79(d,J＝2.1Hz,1H),6.65(dd,J＝8.3,2.2Hz,1H),5.79(d,J＝6.3Hz,1H),5.05(dd,J＝12.8,5.4Hz,1H),4.63(qt,J＝6.4,4.5Hz,1H),3.17(d,J＝5.3Hz,4H),2.93–2.81(m,1H),2.63–2.51(m,2H),2.05–1.97(m,1H). MS (ESI, [M+H] + ) m/z: 330.2. 1 H NMR (500MHz, DMSO-d6) δ11.06(s, 1H), 7.63(d, J=8.3Hz, 1H), 6.79(d, J=2.1Hz, 1H), 6.65(dd, J=8.3 ,2.2Hz,1H),5.79(d,J=6.3Hz,1H),5.05(dd,J=12.8,5.4Hz,1H),4.63(qt,J=6.4,4.5Hz,1H),3.17(d ,J＝5.3Hz,4H),2.93–2.81(m,1H),2.63–2.51(m,2H),2.05–1.97(m,1H).
步骤5：中间体54g的制备Step 5: Preparation of Intermediate 54g
向单口瓶中依次加入中间体54f(0.9g)及DCM(20mL)，室温搅拌下加入戴斯马丁氧化剂(3.20g)，N 2保护下，继续室温反应1.5h。反应液抽滤，滤饼用少量DCM洗涤，滤液和洗液合并后，搅拌下分批多次加入饱和亚硫酸钠水溶液，待无气泡产生后静置分层，分出有机层后，水层再用DCM萃取(50mL×1)，有机层合并后，有机层用无水硫酸钠搅拌干燥，过滤，滤液旋蒸，浓缩物通过硅胶柱层析纯化(DCM/CH 3OH)得到0.760g中间体54g。 The intermediate 54f (0.9g) and DCM (20mL) were sequentially added to the one-necked flask, and the Dess Martin oxidant (3.20g) was added under stirring at room temperature, and the reaction was continued at room temperature for 1.5h under the protection of N 2 . The reaction solution was suction filtered, and the filter cake was washed with a small amount of DCM. After the filtrate and the washing liquid were combined, the saturated sodium sulfite aqueous solution was added in batches several times under stirring. DCM extraction (50mL×1), after the organic layers were combined, the organic layer was stirred and dried with anhydrous sodium sulfate, filtered, the filtrate was rotary evaporated, and the concentrate was purified by silica gel column chromatography (DCM/CH 3 OH) to obtain 0.760g intermediate 54g .
MS(ESI,[M+H] +)m/z：328.3。 MS (ESI, [M+H] + ) m/z: 328.3.
步骤6：化合物54的制备Step 6: Preparation of compound 54
向单口瓶中依次加入中间体54g(200mg)、中间体54e(417mg)、DCM(5mL)，室温搅拌下滴加醋酸 (18.35mg)，将混合物加热至40℃反应2h后，降温至0℃左右，加入三乙酰氧基硼氢化钠(259mg)，室温搅拌过夜，反应结束后，减压蒸除溶剂，加入3mL DMSO溶解后，以220g反相柱层析(H 2O/CH 3CN)得到0.11g化合物54。 Add intermediate 54g (200mg), intermediate 54e (417mg) and DCM (5mL) to the one-necked bottle in turn, add acetic acid (18.35mg) dropwise under stirring at room temperature, heat the mixture to 40°C for 2h, then cool down to 0°C Add sodium triacetoxyborohydride (259mg) and stir overnight at room temperature. After the reaction, evaporate the solvent under reduced pressure, add 3mL DMSO to dissolve, and perform 220g reverse-phase column chromatography (H 2 O/CH 3 CN) 0.11 g of compound 54 was obtained.
MS(ESI,[M+H] +)m/z：766.5。 1H NMR(500MHz,DMSO-d 6)δ11.08(s,1H),8.23(s,1H),7.68–7.62(m,3H),7.45–7.40(m,2H),7.22–7.10(m,5H),6.79(d,J＝2.1Hz,1H),6.65(dd,J＝8.4,2.1Hz,1H),5.06(dd,J＝12.7,5.5Hz,1H),4.66(td,J＝11.6,9.6,5.6Hz,1H),4.10(t,J＝7.6Hz,2H),3.83(dd,J＝8.6,5.1Hz,2H),3.31(s,1H),2.88(ddd,J＝16.5,13.6,5.3Hz,1H),2.57(dd,J＝17.7,13.0Hz,2H),2.34(s,4H),2.22–2.07(m,2H),2.06–1.96(m,1H),1.78(dd,J＝30.3,12.4Hz,4H),1.65(s,2H),1.46–1.36(m,2H),1.36–1.26(m,2H). MS (ESI, [M+H] + ) m/z: 766.5. 1 H NMR (500MHz,DMSO-d 6 )δ11.08(s,1H),8.23(s,1H),7.68–7.62(m,3H),7.45–7.40(m,2H),7.22–7.10(m ,5H),6.79(d,J=2.1Hz,1H),6.65(dd,J=8.4,2.1Hz,1H),5.06(dd,J=12.7,5.5Hz,1H),4.66(td,J= 11.6,9.6,5.6Hz,1H), 4.10(t,J=7.6Hz,2H),3.83(dd,J=8.6,5.1Hz,2H),3.31(s,1H),2.88(ddd,J=16.5 ,13.6,5.3Hz,1H),2.57(dd,J＝17.7,13.0Hz,2H),2.34(s,4H),2.22–2.07(m,2H),2.06–1.96(m,1H),1.78( dd,J＝30.3,12.4Hz,4H),1.65(s,2H),1.46–1.36(m,2H),1.36–1.26(m,2H).
实施例55：化合物55的制备Embodiment 55: Preparation of compound 55
Figure PCTCN2022096512-appb-000172
Figure PCTCN2022096512-appb-000172
步骤1：化合物55的制备Step 1: Preparation of compound 55
向反应瓶中依次加入中间体54e(200mg)、中间体53c(335mg)、DCM(30mL)及冰乙酸(26.4mg)，N 2保护下，将混合物室温搅拌60min。反应液中加入氰基硼氢化钠(111mg)，继续N 2保护下室温搅拌过夜，反应完全，反应液旋蒸后残余物用DCM-MeOH(20:1，30mL×2)萃取，有机层合并后用饱和食盐水(50mL×1)洗涤，萃取液干燥过滤，滤液旋蒸后，残余物用硅胶柱纯化(DCM-MeOH)得到粗品(110mg)。粗品用C 18反相柱纯化(10nM乙酸铵水溶液-乙腈)洗脱，过柱液合并，DCM-MeOH(10:1)萃取后旋蒸干得到化合物55(55mg)。 Intermediate 54e (200 mg), Intermediate 53c (335 mg), DCM (30 mL) and glacial acetic acid (26.4 mg) were sequentially added to the reaction flask, and the mixture was stirred at room temperature for 60 min under N 2 protection. Sodium cyanoborohydride (111 mg) was added to the reaction solution, and continued to stir overnight at room temperature under N2 protection. The reaction was complete. After the reaction solution was rotary evaporated, the residue was extracted with DCM-MeOH (20:1, 30mL×2), and the organic layers were combined. After washing with saturated brine (50mL×1), the extract was dried and filtered. After the filtrate was rotary evaporated, the residue was purified with silica gel column (DCM-MeOH) to obtain a crude product (110mg). The crude product was purified by a C 18 reverse phase column (10 nM ammonium acetate aqueous solution-acetonitrile), combined through the column, extracted with DCM-MeOH (10:1) and evaporated to dryness to obtain compound 55 (55 mg).
MS(ESI,[M+H] +)m/z：794.4。 1H NMR(500MHz,DMSO-d 6)δ11.08(s,1H),8.23(s,1H),7.65(dd,J＝8.7,2.1Hz,3H),7.43(t,J＝7.9Hz,2H),7.32(d,J＝2.3Hz,1H),7.24(dd,J＝8.7,2.3Hz,1H),7.15(ddd,J＝22.8,14.5,7.7Hz,5H),5.07(dd,J＝12.8,5.4Hz,1H),4.65(td,J＝11.8,5.7Hz,1H),4.06(dd,J＝18.4,13.4Hz,2H),3.00–2.83(m,3H),2.62–2.51(m,5H),2.19–2.06(m,2H),2.01(ddt,J＝13.6,6.1,3.9Hz,1H),1.89–1.82(m,2H),1.82–1.70(m,4H),1.62(s,2H),1.50(q,J＝12.3Hz,2H),1.41–1.21(m,5H). MS (ESI, [M+H] + ) m/z: 794.4. 1 H NMR (500MHz, DMSO-d 6 )δ11.08(s, 1H), 8.23(s, 1H), 7.65(dd, J=8.7, 2.1Hz, 3H), 7.43(t, J=7.9Hz, 2H),7.32(d,J=2.3Hz,1H),7.24(dd,J=8.7,2.3Hz,1H),7.15(ddd,J=22.8,14.5,7.7Hz,5H),5.07(dd,J =12.8,5.4Hz,1H),4.65(td,J=11.8,5.7Hz,1H),4.06(dd,J=18.4,13.4Hz,2H),3.00–2.83(m,3H),2.62–2.51( m,5H),2.19–2.06(m,2H),2.01(ddt,J＝13.6,6.1,3.9Hz,1H),1.89–1.82(m,2H),1.82–1.70(m,4H),1.62( s, 2H), 1.50(q, J=12.3Hz, 2H), 1.41–1.21(m, 5H).
实施例56：化合物56的制备Embodiment 56: Preparation of compound 56
Figure PCTCN2022096512-appb-000173
Figure PCTCN2022096512-appb-000173
步骤1：化合物56的合成Step 1: Synthesis of compound 56
向单口瓶中，将化合物28d(81mg)和化合物54e(100mg)溶于甲醇(5mL)中，加入氰基硼氢化钠(27.6mg)，加入1滴醋酸，室温反应2小时。反应完毕后，向体系中加入二氯甲烷(50mL)和水(50mL)。有机相分离，水相用二氯甲烷(50mL×2)萃取，合并有机相，用无水硫酸钠干燥，过滤，减压蒸除溶剂，粗品经过反相纯化(洗脱剂：水/乙腈)得到化合物56(50mg)。In a single-necked bottle, compound 28d (81 mg) and compound 54e (100 mg) were dissolved in methanol (5 mL), sodium cyanoborohydride (27.6 mg) was added, 1 drop of acetic acid was added, and the reaction was carried out at room temperature for 2 hours. After the reaction was complete, dichloromethane (50 mL) and water (50 mL) were added to the system. The organic phase was separated, the aqueous phase was extracted with dichloromethane (50mL×2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the solvent was evaporated under reduced pressure, and the crude product was purified by reverse phase (eluent: water/acetonitrile) Compound 56 (50 mg) was obtained.
HRMS(ESI)m/z[M+H] +:808.39385。 1H NMR(500MHz,DMSO-d 6)δ11.08(s,1H),8.23(s,1H),7.65(dd,J＝8.6,3.1Hz,3H),7.43(t,J＝7.9Hz,2H),7.30(d,J＝2.3Hz,1H),7.26–7.08(m,6H),5.06(dd,J＝12.8,5.4Hz,1H),4.65(td,J＝11.5,10.9,5.4Hz,1H),4.03(d,J＝12.7Hz,2H),2.96(t,J＝12.4Hz,2H),2.93–2.83(m,1H),2.63–2.52(m,2H),2.34(s,4H),2.14(h,J＝10.7Hz,4H),2.01(ddq,J＝8.4,5.9,3.3,2.6Hz,1H),1.88–1.70(m,7H),1.63(s,2H),1.39(s,2H),1.30(s,2H),1.14(d,J＝12.3Hz,2H). 13C NMR(126MHz, DMSO-d 6)δ173.28,170.59,168.11,167.44,158.61,157.46,156.84,155.88,155.49,153.94,143.14,134.52,130.60,130.54,128.67,125.47,124.22,119.50,119.38,118.04,108.19,97.89,56.36,49.20,47.72,31.46,30.34,30.15,27.11,22.67. HRMS (ESI) m/z [M+H] + : 808.39385. 1 H NMR (500MHz, DMSO-d 6 )δ11.08(s, 1H), 8.23(s, 1H), 7.65(dd, J=8.6, 3.1Hz, 3H), 7.43(t, J=7.9Hz, 2H), 7.30(d, J=2.3Hz, 1H), 7.26–7.08(m, 6H), 5.06(dd, J=12.8, 5.4Hz, 1H), 4.65(td, J=11.5, 10.9, 5.4Hz ,1H),4.03(d,J=12.7Hz,2H),2.96(t,J=12.4Hz,2H),2.93–2.83(m,1H),2.63–2.52(m,2H),2.34(s, 4H), 2.14(h, J=10.7Hz, 4H), 2.01(ddq, J=8.4, 5.9, 3.3, 2.6Hz, 1H), 1.88–1.70(m, 7H), 1.63(s, 2H), 1.39 (s,2H),1.30(s,2H),1.14(d,J＝12.3Hz,2H). 13 C NMR(126MHz, DMSO-d 6 )δ173.28,170.59,168.11,167.44,158.61,157.46,156.84, 155.88,155.49,153.94,143.14,134.52,130.60,130.54,128.67,125.47,124.22,119.50,119.38,118.04,108.19,97.89,56.36,49.20,47.72,31.46,30.34,30.15,27.11,22.67.
实施例57：化合物57的制备Embodiment 57: Preparation of compound 57
Figure PCTCN2022096512-appb-000174
Figure PCTCN2022096512-appb-000174
步骤1：中间体57b的制备Step 1: Preparation of intermediate 57b
向三口瓶中，N 2保护下，加入3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-4-胺(2g)、THF(30mL)、中间体57a(1.909g)、三苯基膦(5.19g)，降温至0℃，缓慢加入双-2-甲氧乙基偶氮二羧酸酯(2.67g)，加毕，室温搅拌2h。反应结束后，将反应液倒入水(100mL)中，加入EA(100mL)，有机相分离，分别用100mL饱和食盐水洗涤后用无水硫酸钠干燥，过滤，滤液通过减压蒸除溶剂，得到3.2g中间体57b。 Into the three-necked flask, under the protection of N2 , add 3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (2g), THF (30mL), intermediate Compound 57a (1.909g), triphenylphosphine (5.19g), cooled to 0°C, slowly added bis-2-methoxyethyl azodicarboxylate (2.67g), after addition, stirred at room temperature for 2h. After the reaction, the reaction solution was poured into water (100mL), EA (100mL) was added, the organic phase was separated, washed with 100mL saturated brine, dried with anhydrous sodium sulfate, filtered, and the filtrate was evaporated to remove the solvent under reduced pressure. 3.2 g of intermediate 57b were obtained.
MS(ESI,[M+H] +)m/z：787.6。 MS (ESI, [M+H] + ) m/z: 787.6.
步骤2：中间体57c的制备Step 2: Preparation of intermediate 57c
向单口瓶中依次加入中间体57b(3.2g)、HCl(30.5mL,4M，1,4-二氧六环溶液)，室温反应5h，反应结束，向反应液中加入100mL EA，搅拌30min后，析出大量固体，过滤，滤饼加饱和碳酸氢钠溶液，调pH＝8-9，加入200mL DCM：CH 3OH(10：1)溶液萃取三次，有机相用饱和氯化钠水溶液洗涤后用无水硫酸钠干燥，过滤，滤液通过减压蒸除溶剂，得到1.0g中间体57c。 Add intermediate 57b (3.2g) and HCl (30.5mL, 4M, 1,4-dioxane solution) to the one-necked flask in sequence, react at room temperature for 5h, and the reaction is complete, add 100mL EA to the reaction solution, and stir for 30min , precipitated a large amount of solids, filtered, added saturated sodium bicarbonate solution to the filter cake, adjusted pH = 8-9, added 200mL DCM:CH 3 OH (10:1) solution for extraction three times, washed the organic phase with saturated aqueous sodium chloride solution and used Dry over anhydrous sodium sulfate, filter, and evaporate the filtrate to remove the solvent under reduced pressure to obtain 1.0 g of intermediate 57c.
MS(ESI,[M+H] +)m/z：427.3。 MS (ESI, [M+H] + ) m/z: 427.3.
步骤3：中间体57d的制备Step 3: Preparation of intermediate 57d
向单口瓶中依次加入中间体57c(100mg)、1-Boc-3-氮杂环丁酮(48.2mg)、MeOH(5mL)及醋酸(84mg)，65℃反应1h后，降温至0℃，加入三乙酰氧基硼氢化钠(29.5mg)，常温搅拌过夜。反应结束后，反应液中加入硫代硫酸钠以淬灭反应，加入30mL DCM萃取反应，有机相通过饱和食盐水洗涤后用无水硫酸钠干燥，过滤，滤液蒸除溶剂后，残留物通过硅胶柱层析(DCM/CH 3OH)得到0.079g中间体57d。 Add intermediate 57c (100 mg), 1-Boc-3-azetidinone (48.2 mg), MeOH (5 mL) and acetic acid (84 mg) to the one-necked bottle in turn, react at 65 °C for 1 h, then cool to 0 °C, Sodium triacetoxyborohydride (29.5 mg) was added and stirred overnight at room temperature. After the reaction is over, add sodium thiosulfate to the reaction solution to quench the reaction, add 30mL DCM to extract the reaction, wash the organic phase with saturated brine, dry it with anhydrous sodium sulfate, filter, evaporate the filtrate to remove the solvent, and pass the residue through silica gel Column chromatography (DCM/ CH3OH ) afforded 0.079 g of intermediate 57d.
MS(ESI,[M+H] +)m/z：582.4。 MS (ESI, [M+H] + ) m/z: 582.4.
步骤4：中间体57e的制备Step 4: Preparation of Intermediate 57e
向单口瓶中依次加入中间体57d(80mg)、DCM(2mL)，缓慢滴入HCl(0.688mL,4M，1,4-二氧六环溶液)，将混合物室温反应1h。反应结束，将反应液加入饱和碳酸氢钠水溶液中并调pH＝8-9，加入DCM(200mL)和水(100mL)，有机相分离，用饱和氯化钠水溶液洗涤，有机相用无水硫酸钠干燥，过滤，滤液通过减压蒸除溶剂，得到0.02g中间体57e。Intermediate 57d (80 mg) and DCM (2 mL) were sequentially added to a one-necked flask, and HCl (0.688 mL, 4M, 1,4-dioxane solution) was slowly added dropwise, and the mixture was reacted at room temperature for 1 h. After the reaction was completed, the reaction solution was added to saturated aqueous sodium bicarbonate solution to adjust the pH to 8-9, DCM (200 mL) and water (100 mL) were added, the organic phase was separated, washed with saturated aqueous sodium chloride solution, and the organic phase was washed with anhydrous sulfuric acid It was dried over sodium, filtered, and the filtrate was evaporated under reduced pressure to obtain 0.02 g of intermediate 57e.
MS(ESI,[M+H] +)m/z：482.4。 MS (ESI, [M+H] + ) m/z: 482.4.
步骤5：化合物57的制备Step 5: Preparation of compound 57
向单口瓶中依次加入中间体57e(20mg)、中间体13b(22.94mg)、DMSO(5mL)及DIPEA(26.8mg)，N 2保护下，将混合物加热至90℃反应5h。反应液通过120g C 18反相柱纯化(1％醋酸铵水溶液/CH 3CN)得到0.012g化合物57。 Intermediate 57e (20 mg), Intermediate 13b (22.94 mg), DMSO (5 mL) and DIPEA (26.8 mg) were sequentially added to a one-necked flask, and the mixture was heated to 90° C. for 5 h under the protection of N 2 . The reaction solution was purified by a 120 g C 18 reverse phase column (1% aqueous ammonium acetate/CH 3 CN) to obtain 0.012 g of compound 57.
MS(ESI,[M+H] +)m/z：738.5。 1H NMR(500MHz,DMSO-d 6)δ11.08(s,1H),8.23(s,1H),7.67(dd,J＝16.4,8.2Hz,3H),7.44(t,J＝7.7Hz,2H),7.16(td,J＝18.0,16.2,7.7Hz,5H),6.79(s,1H),6.65(d,J＝8.4Hz, 1H),5.36(p,J＝8.3Hz,1H),5.06(dd,J＝12.8,5.5Hz,1H),4.11(t,J＝7.5Hz,2H),3.84(s,2H),2.88(ddd,J＝17.7,13.8,5.4Hz,1H),2.63–2.52(m,2H),2.46–2.36(m,4H),2.27(s,2H),2.05–1.97(m,1H),1.73(d,J＝29.1Hz,4H),1.24(d,J＝6.5Hz,2H). MS (ESI, [M+H] + ) m/z: 738.5. 1 H NMR (500MHz, DMSO-d 6 )δ11.08(s, 1H), 8.23(s, 1H), 7.67(dd, J=16.4, 8.2Hz, 3H), 7.44(t, J=7.7Hz, 2H), 7.16(td, J=18.0, 16.2, 7.7Hz, 5H), 6.79(s, 1H), 6.65(d, J=8.4Hz, 1H), 5.36(p, J=8.3Hz, 1H), 5.06(dd, J=12.8,5.5Hz,1H),4.11(t,J=7.5Hz,2H),3.84(s,2H),2.88(ddd,J=17.7,13.8,5.4Hz,1H),2.63 –2.52(m,2H),2.46–2.36(m,4H),2.27(s,2H),2.05–1.97(m,1H),1.73(d,J＝29.1Hz,4H),1.24(d,J =6.5Hz,2H).
实施例58:化合物58-1和58-2的制备Embodiment 58: the preparation of compound 58-1 and 58-2
Figure PCTCN2022096512-appb-000175
Figure PCTCN2022096512-appb-000175
步骤1：中间体58b的制备Step 1: Preparation of intermediate 58b
向反应瓶中依次加入中间体58a(1.8g)及THF(20mL)，反应液在冰水浴下加入硼氢化钠(0.806g)后，室温搅拌2hr，反应完全，反应液旋蒸后残余物用DCM(50mL×2)萃取，有机层合并后用饱和食盐水(50mL×1)洗涤，萃取液干燥过滤，滤液旋蒸干得到中间体58b(2.02g)。Add intermediate 58a (1.8g) and THF (20mL) in turn to the reaction flask, add sodium borohydride (0.806g) to the reaction solution under an ice-water bath, stir at room temperature for 2hr, the reaction is complete, and the residue after the reaction solution is rotary evaporated DCM (50mL×2) was extracted, the organic layers were combined and washed with saturated brine (50mL×1), the extract was dried and filtered, and the filtrate was rotary evaporated to dryness to obtain intermediate 58b (2.02g).
1H NMR(500MHz,DMSO-d 6)δ4.45(d,J＝4.6Hz,1H),3.44(s,1H),3.24(t,J＝7.0Hz,2H),3.05(d,J＝7.7Hz,1H),2.97(s,1H),1.70–1.47(m,6H),1.40–1.37(m,9H),1.30–1.17(m,4H). 1 H NMR (500MHz, DMSO-d 6 )δ4.45(d, J=4.6Hz, 1H), 3.44(s, 1H), 3.24(t, J=7.0Hz, 2H), 3.05(d, J= 7.7Hz,1H),2.97(s,1H),1.70–1.47(m,6H),1.40–1.37(m,9H),1.30–1.17(m,4H).
步骤2：中间体58c的制备Step 2: Preparation of intermediate 58c
向反应瓶中依次加入中间体58b(1.818g)、3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-4-胺(1.8g)、THF(90mL)及三苯基膦(4.67g)，0℃下，N 2保护下搅拌5min后，将DIAD(2.400g)缓慢滴入搅拌液中，10分钟后滴加完毕，混合物室温搅拌2小时，反应完全，反应液旋蒸后残余物用DCM(50mL×2)萃取，有机层合并后用饱和食盐水(50mL×1)洗涤，萃取液干燥过滤，滤液旋蒸后残余物用硅胶柱纯化(DCM-MeOH)得到中间体58c(1.23g)。 Intermediate 58b (1.818g), 3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (1.8g), THF ( 90mL) and triphenylphosphine (4.67g), stirred at 0°C for 5min under the protection of N 2 , then slowly added DIAD (2.400g) into the stirring solution, and the addition was completed after 10 minutes, and the mixture was stirred at room temperature for 2 hours. After the reaction was complete, the residue was extracted with DCM (50mL×2) after the reaction solution was rotary evaporated, the organic layers were combined and washed with saturated brine (50mL×1), the extract was dried and filtered, and the residue was purified with a silica gel column after the filtrate was rotary evaporated ( DCM-MeOH) afforded intermediate 58c (1.23 g).
步骤3：中间体58d-1和58d-2的制备Step 3: Preparation of intermediates 58d-1 and 58d-2
向反应瓶中依次加入中间体58c(1.2g)及盐酸二氧六环溶液(11.10mL,44.4mmol)，N 2保护下，室温搅拌过夜。反应完全，反应液旋蒸后残余物用DCM-MeOH(20:1，30mL×2)萃取，有机层合并后用饱和食盐水(50mL×1)洗涤，萃取液干燥过滤，滤液旋蒸后残余物用硅胶柱纯化(DCM/MeOH)得到中间体58d-1(357mg)及中间体58d-2(343mg)。 Intermediate 58c (1.2 g) and dioxane hydrochloride solution (11.10 mL, 44.4 mmol) were successively added to the reaction flask, and stirred overnight at room temperature under the protection of N 2 . After the reaction was complete, the residue was extracted with DCM-MeOH (20:1, 30mL×2) after the reaction solution was rotary evaporated, and the organic layers were combined and washed with saturated brine (50mL×1), the extract was dried and filtered, and the filtrate remained The material was purified by silica gel column (DCM/MeOH) to obtain intermediate 58d-1 (357 mg) and intermediate 58d-2 (343 mg).
MS(ESI,[M+H] +)m/z：441.3。 MS (ESI, [M+H] + ) m/z: 441.3.
步骤4：化合物58-1和58-2的制备Step 4: Preparation of Compounds 58-1 and 58-2
向反应瓶中依次加入中间体58d-1(240mg)、中间体54g(357mg)、DCM(20mL)及冰乙酸(32.7mg)。室温搅拌1小时后，加入氰基硼氢化钠(137mg)，室温反应过夜，反应完全，反应液在反应淬灭后旋蒸，残余物用C 18反相柱层析纯化(10nM乙酸铵水溶液-乙腈)洗脱，过柱液合并，萃取浓缩得到目标物58-1(150mg)。 Intermediate 58d-1 (240 mg), Intermediate 54g (357 mg), DCM (20 mL) and glacial acetic acid (32.7 mg) were sequentially added to the reaction flask. After stirring at room temperature for 1 hour, sodium cyanoborohydride (137 mg) was added and reacted overnight at room temperature. The reaction was complete . Acetonitrile) was eluted, the column solution was combined, extracted and concentrated to obtain the target compound 58-1 (150 mg).
MS(ESI,[M+H] +)m/z：752.5。 1H NMR(500MHz,DMSO-d 6)δ11.08(s,1H),8.24(s,1H),7.64(dd,J＝8.9,7.1Hz,3H),7.48–7.41(m,2H),7.19(td,J＝7.4,1.2Hz,1H),7.17–7.10(m,4H),6.78(d,J＝2.1Hz,1H),6.64(dd,J＝8.3,2.1Hz,1H),5.06(dd,J＝12.8,5.4Hz,1H),4.68(tt,J＝11.8,4.1Hz,1H),4.11(t,J＝7.8Hz,2H),3.93(dd,J＝8.9,4.7Hz,2H),3.52(p,J＝5.8Hz,1H),2.88(ddd,J＝16.6,13.6,5.3Hz,1H),2.58(dd,J＝14.1,4.7Hz,3H),2.53(d,J＝3.9Hz,2H),2.03–1.99(m,3H),1.86(dd,J＝13.0,3.9Hz,2H),1.79(d,J＝12.8Hz,2H),1.65–1.52(m,4H). 13C NMR(126MHz,DMSO-d 6)δ173.26,170.56,167.92,167.62,158.59, 157.44,156.85,155.91,155.39,153.93,143.20,134.28,130.59,130.56,128.65,125.27,124.21,119.51,119.36,117.16,114.59,104.92,97.86,59.70,56.00,55.28,53.23,49.25,49.16,41.07,37.06,31.45,29.72,22.68. MS (ESI, [M+H] + ) m/z: 752.5. 1 H NMR (500MHz,DMSO-d 6 )δ11.08(s,1H),8.24(s,1H),7.64(dd,J＝8.9,7.1Hz,3H),7.48–7.41(m,2H), 7.19 (td, J=7.4, 1.2Hz, 1H), 7.17–7.10 (m, 4H), 6.78 (d, J=2.1Hz, 1H), 6.64 (dd, J=8.3, 2.1Hz, 1H), 5.06 (dd, J=12.8,5.4Hz,1H),4.68(tt,J=11.8,4.1Hz,1H),4.11(t,J=7.8Hz,2H),3.93(dd,J=8.9,4.7Hz, 2H), 3.52(p, J=5.8Hz, 1H), 2.88(ddd, J=16.6, 13.6, 5.3Hz, 1H), 2.58(dd, J=14.1, 4.7Hz, 3H), 2.53(d, J ＝3.9Hz, 2H), 2.03–1.99(m, 3H), 1.86(dd, J＝13.0, 3.9Hz, 2H), 1.79(d, J＝12.8Hz, 2H), 1.65–1.52(m, 4H) . 13 C NMR(126MHz,DMSO-d 6 )δ173.26,170.56,167.92,167.62,158.59, 157.44,156.85,155.91,155.39,153.93,143.20,134.28,130.59,130.56,128.65,125.27,124.21,119.51,119.36, 117.16, 114.59, 104.92, 97.86, 59.70, 56.00, 55.28, 53.23, 49.25, 49.16, 41.07, 37.06, 31.45, 29.72, 22.68.
向反应瓶中依次加入中间体58d-2(200mg)、中间体54g(297mg)、DCM(20mL)及冰乙酸(27.3mg)。室温搅拌1小时后，加入氰基硼氢化钠(114mg)，室温反应过夜，反应完全，反应液在反应淬灭后旋蒸，残余物用C 18反相柱层析纯化(10nM乙酸铵水溶液-乙腈)洗脱，过柱液合并，萃取浓缩得到目标物58-2(140mg)。 Intermediate 58d-2 (200 mg), Intermediate 54g (297 mg), DCM (20 mL) and glacial acetic acid (27.3 mg) were sequentially added to the reaction flask. After stirring at room temperature for 1 hour, sodium cyanoborohydride (114 mg) was added and reacted at room temperature overnight. The reaction was complete . Acetonitrile) was eluted, the column solution was combined, extracted and concentrated to obtain the target compound 58-2 (140 mg).
MS(ESI,[M+H] +)m/z：752.5。 1H NMR(500MHz,DMSO-d 6)δ11.08(s,1H),8.23(s,1H),7.65(dd,J＝8.4,3.4Hz,3H),7.47–7.39(m,2H),7.22–7.17(m,1H),7.17–7.09(m,4H),6.79(d,J＝2.1Hz,1H),6.65(dd,J＝8.4,2.1Hz,1H),5.06(dd,J＝12.8,5.4Hz,1H),4.67(td,J＝11.6,10.7,4.9Hz,1H),4.10(t,J＝7.8Hz,2H),3.90(d,J＝6.6Hz,2H),3.46(s,1H),2.88(ddd,J＝16.7,13.6,5.3Hz,1H),2.66–2.53(m,4H),2.37(s,2H),2.13–1.95(m,3H),1.88–1.80(m,2H),1.74(d,J＝13.2Hz,4H),1.62–1.53(m,2H). 13C NMR(126MHz,DMSO-d 6)δ173.26,170.57,167.93,167.62,158.60,157.44,156.83,155.88,155.39,153.95,143.15,134.29,130.58,130.53,128.65,125.29,124.21,119.49,119.37,114.62,104.92,97.86,55.90,55.51,53.22,50.41,49.18,40.99,36.59,31.45,29.04,22.68. MS (ESI, [M+H] + ) m/z: 752.5. 1 H NMR (500MHz,DMSO-d 6 )δ11.08(s,1H),8.23(s,1H),7.65(dd,J＝8.4,3.4Hz,3H),7.47–7.39(m,2H), 7.22–7.17(m,1H),7.17–7.09(m,4H),6.79(d,J=2.1Hz,1H),6.65(dd,J=8.4,2.1Hz,1H),5.06(dd,J= 12.8, 5.4Hz, 1H), 4.67(td, J=11.6, 10.7, 4.9Hz, 1H), 4.10(t, J=7.8Hz, 2H), 3.90(d, J=6.6Hz, 2H), 3.46( s,1H),2.88(ddd,J＝16.7,13.6,5.3Hz,1H),2.66–2.53(m,4H),2.37(s,2H),2.13–1.95(m,3H),1.88–1.80( m,2H),1.74(d,J＝13.2Hz,4H),1.62–1.53(m,2H). 13 C NMR(126MHz,DMSO-d 6 )δ173.26,170.57,167.93,167.62,158.60,157.44,156.83 ,155.88,155.39,153.95,143.15,134.29,130.58,130.53,128.65,125.29,124.21,119.49,119.37,114.62,104.92,97.86,55.90,55.51,53.22,50.41,49.18,40.99,36.59,31.45,29.04,22.68 .
实施例59:化合物59的制备Embodiment 59: the preparation of compound 59
Figure PCTCN2022096512-appb-000176
Figure PCTCN2022096512-appb-000176
步骤1：中间体59b的制备Step 1: Preparation of Intermediate 59b
氮气保护下，在三口瓶中加入中间体59a(2.00g)及甲醇(50mL)，降温至0℃，缓慢加入硼氢化钠固体(0.50g)，约15min加完，升温至25℃反应2h。反应完毕后，将反应液倒入100mL纯化水中，加入乙酸乙酯(100mL)，萃取分层，有机相用饱和氯化钠水溶液(100mL)洗涤，浓缩有机相得粗品，过硅胶柱纯化(乙酸乙酯)得中间体59b(1.41g)。Under the protection of nitrogen, intermediate 59a (2.00 g) and methanol (50 mL) were added to a three-necked flask, the temperature was lowered to 0 °C, solid sodium borohydride (0.50 g) was slowly added, and the addition was completed in about 15 min, and the temperature was raised to 25 °C for 2 h. After the reaction was completed, the reaction solution was poured into 100 mL of purified water, ethyl acetate (100 mL) was added, the layers were extracted, the organic phase was washed with saturated aqueous sodium chloride solution (100 mL), and the organic phase was concentrated to obtain a crude product, which was purified by a silica gel column (acetic acid ethyl ester) to give intermediate 59b (1.41 g).
1H NMR(500MHz,DMSO-d 6)δ4.61(d,J＝4.4Hz,1H),4.07(pd,J＝6.5,4.4Hz,1H),3.43–3.37(m,2H),3.23–3.13(m,2H),2.05–1.91(m,2H),1.39(s,10H),1.29(dt,J＝12.8,6.3Hz,2H)。 1 H NMR (500MHz, DMSO-d 6 ) δ4.61 (d, J=4.4Hz, 1H), 4.07 (pd, J=6.5, 4.4Hz, 1H), 3.43–3.37 (m, 2H), 3.23– 3.13 (m, 2H), 2.05–1.91 (m, 2H), 1.39 (s, 10H), 1.29 (dt, J=12.8, 6.3Hz, 2H).
步骤2：中间体59c的制备Step 2: Preparation of intermediate 59c
氮气保护下，在三口瓶中先后加入3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-4-胺(1.80g)、中间体59b(1.35g)、三苯基磷(3.11g)及四氢呋喃(250mL)，降温至0℃，滴加偶氮二甲酸二异丙酯(3.60g)，约15min滴加完毕，升温至25℃反应16h。反应完毕后，将反应液倒入200mL纯化水中，加入乙酸乙酯(200mL)，萃取分层，有机相用饱和氯化钠水溶液(100mL)洗涤，浓缩有机相得粗品，过硅胶柱纯化(石油醚/乙酸乙酯)得中间体59c(4.63g)。Under nitrogen protection, 3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (1.80g), intermediate 59b (1.35g ), triphenylphosphine (3.11g) and tetrahydrofuran (250mL), the temperature was lowered to 0°C, and diisopropyl azodicarboxylate (3.60g) was added dropwise, and the addition was completed in about 15 minutes, and the temperature was raised to 25°C for 16h. After the reaction was completed, the reaction solution was poured into 200 mL of purified water, ethyl acetate (200 mL) was added, the layers were extracted, the organic phase was washed with a saturated aqueous sodium chloride solution (100 mL), and the organic phase was concentrated to obtain a crude product, which was purified by a silica gel column (petroleum ether/ethyl acetate) to give intermediate 59c (4.63 g).
MS(ESI,[M+H] +)m/z：513.4。 MS (ESI, [M+H] + ) m/z: 513.4.
步骤3：中间体59d的制备Step 3: Preparation of Intermediate 59d
向反应瓶中依次加入中间体59c(4.63g)及盐酸二氧六环溶液(4M，137mL)，25℃搅拌反应16h。反应完全，反应液浓缩至干，加入纯化水(150mL)、二氯甲烷/甲醇＝10/1溶液(550mL)，搅拌状态下加入饱和 碳酸氢钠水溶液(120mL)，萃取分层，有机相用饱和氯化钠水溶液洗涤，用无水硫酸钠干燥，浓缩有机相得中间体59d(1.68g)。Intermediate 59c (4.63 g) and dioxane hydrochloride solution (4M, 137 mL) were sequentially added to the reaction flask, and the reaction was stirred at 25° C. for 16 h. The reaction was complete, the reaction solution was concentrated to dryness, added purified water (150mL), dichloromethane/methanol=10/1 solution (550mL), added saturated aqueous sodium bicarbonate solution (120mL) while stirring, extracted and separated, and used the organic phase Wash with saturated aqueous sodium chloride, dry over anhydrous sodium sulfate, and concentrate the organic phase to obtain intermediate 59d (1.68 g).
MS(ESI,[M+H] +)m/z：413.3。 1H NMR(500MHz,DMSO-d 6)δ8.23(s,1H),7.69–7.63(m,2H),7.47–7.40(m,2H),7.22–7.10(m,5H),7.03(d,J＝8.2Hz,1H),5.35–5.25(m,1H),2.94(dd,J＝10.4,6.8Hz,2H),2.72(tt,J＝5.2,2.6Hz,2H),2.55(dd,J＝10.6,3.2Hz,2H),2.34(dt,J＝12.6,8.1Hz,2H),1.85(ddd,J＝12.9,6.6,2.3Hz,2H). MS (ESI, [M+H] + ) m/z: 413.3. 1 H NMR (500MHz,DMSO-d 6 )δ8.23(s,1H),7.69–7.63(m,2H),7.47–7.40(m,2H),7.22–7.10(m,5H),7.03(d ,J=8.2Hz,1H),5.35–5.25(m,1H),2.94(dd,J=10.4,6.8Hz,2H),2.72(tt,J=5.2,2.6Hz,2H),2.55(dd, J＝10.6, 3.2Hz, 2H), 2.34 (dt, J＝12.6, 8.1Hz, 2H), 1.85 (ddd, J＝12.9, 6.6, 2.3Hz, 2H).
步骤4：中间体59e的制备Step 4: Preparation of Intermediate 59e
向单口瓶中依次加入中间体59d(1.60g)、1-叔丁氧羰基-3-氮杂环丁酮(1.00g)、乙酸(0.35g)、氰基硼氢化钠(0.49g)及甲醇(50mL)，常温搅拌反应2h，补加1-叔丁氧羰基-3-氮杂环丁酮(0.66g)、乙酸(0.12g)及氰基硼氢化钠(0.24g)，常温反应16h，反应完全，将反应液倒入纯化水(150mL)中，加入二氯甲烷/甲醇＝10/1溶液(150mL)，萃取分层，有机相用饱和氯化钠水溶液洗涤，用无水硫酸钠干燥，浓缩有机相得粗品，过硅胶柱纯化得中间体59e(2.90g)。Add intermediate 59d (1.60g), 1-tert-butoxycarbonyl-3-azetidinone (1.00g), acetic acid (0.35g), sodium cyanoborohydride (0.49g) and methanol to the one-necked flask in sequence (50 mL), stirred at room temperature for 2 h, added 1-tert-butoxycarbonyl-3-azetidinone (0.66 g), acetic acid (0.12 g) and sodium cyanoborohydride (0.24 g), and reacted at room temperature for 16 h, After the reaction is complete, pour the reaction solution into purified water (150 mL), add dichloromethane/methanol=10/1 solution (150 mL), extract and separate layers, wash the organic phase with saturated aqueous sodium chloride, and dry over anhydrous sodium sulfate , the organic phase was concentrated to obtain a crude product, which was purified by a silica gel column to obtain intermediate 59e (2.90 g).
MS(ESI,[M+H] +)m/z：568.5。 MS (ESI, [M+H] + ) m/z: 568.5.
步骤5：中间体59f的制备Step 5: Preparation of Intermediate 59f
向反应瓶中依次加入中间体59e(2.9g)、盐酸二氧六环溶液(4M，13mL)及二氯甲烷(20mL)，25℃搅拌反应3.5h。反应完全，反应液浓缩至干，加入纯化水(150mL)、二氯甲烷/甲醇＝10/1溶液(150mL)，搅拌状态下加入饱和碳酸氢钠水溶液(50mL)，萃取分层，有机相用饱和氯化钠水溶液洗涤，用无水硫酸钠干燥，浓缩有机相得中间体59f(1.5g)。Intermediate 59e (2.9 g), dioxane hydrochloride solution (4M, 13 mL) and dichloromethane (20 mL) were sequentially added to the reaction flask, and the reaction was stirred at 25° C. for 3.5 h. The reaction was complete, the reaction solution was concentrated to dryness, purified water (150mL), dichloromethane/methanol=10/1 solution (150mL) was added, and saturated aqueous sodium bicarbonate solution (50mL) was added under stirring, the layers were extracted, and the organic phase was used Wash with saturated aqueous sodium chloride, dry over anhydrous sodium sulfate, and concentrate the organic phase to obtain intermediate 59f (1.5 g).
MS(ESI,[M+H] +)m/z：468.4。 1H NMR(500MHz,DMSO-d 6)δ8.25(s,1H),7.68–7.64(m,2H),7.46–7.41(m,2H),7.34–6.82(m,7H),5.42–5.32(m,1H),3.57–3.45(m,4H),3.28–3.21(m,1H),2.84–2.77(m,2H),2.44(t,J＝7.6Hz,2H),2.36(dq,J＝7.8,4.6Hz,4H),1.94–1.82(m,2H). MS (ESI, [M+H] + ) m/z: 468.4. 1 H NMR (500MHz,DMSO-d 6 )δ8.25(s,1H),7.68–7.64(m,2H),7.46–7.41(m,2H),7.34–6.82(m,7H),5.42–5.32 (m,1H),3.57–3.45(m,4H),3.28–3.21(m,1H),2.84–2.77(m,2H),2.44(t,J＝7.6Hz,2H),2.36(dq,J ＝7.8,4.6Hz,4H),1.94–1.82(m,2H).
步骤6：化合物59的制备Step 6: Preparation of Compound 59
向单口瓶中依次加入中间体59f(300mg)、中间体13b(266mg)、N,N-二异丙基乙胺(166mg)及二甲基亚砜(5mL)，80℃搅拌反应5h，反应完全，反应液通过120g C 18反相柱纯化得化合物59(200mg)。 Add intermediate 59f (300mg), intermediate 13b (266mg), N,N-diisopropylethylamine (166mg) and dimethyl sulfoxide (5mL) to the one-necked bottle successively, stir at 80°C for 5h, and react Completely, the reaction solution was purified by a 120 g C 18 reverse phase column to obtain compound 59 (200 mg).
HR-MS(ESI,[M+H] +)m/z：724.29818。 1H NMR(500MHz,DMSO-d 6)δ11.07(s,1H),8.23(s,1H),7.66(d,J＝8.3Hz,3H),7.46–7.40(m,2H),7.21–7.10(m,5H),6.81(d,J＝2.1Hz,1H),6.67(dd,J＝8.4,2.1Hz,1H),5.43–5.33(m,1H),5.06(dd,J＝12.8,5.4Hz,1H),4.12(q,J＝9.2,8.5Hz,2H),3.95(dd,J＝8.8,4.7Hz,2H),3.47(dq,J＝11.2,5.6Hz,1H),2.92–2.79(m,3H),2.64–2.52(m,4H),2.48(d,J＝2.7Hz,2H),2.37(dt,J＝11.7,7.8Hz,2H),2.06–1.88(m,3H). 13C NMR(126MHz,DMSO)δ173.29,170.59,167.95,167.65,158.59,157.49,156.79,155.95,155.43,154.37,143.21,134.32,130.60,130.49,128.62,125.32,124.24,119.45,119.42,117.26,114.68,104.97,97.92,58.37,57.52,55.98,52.95,49.19,38.93,31.46,22.69. HR-MS (ESI, [M+H] + ) m/z: 724.29818. 1 H NMR (500MHz,DMSO-d 6 )δ11.07(s,1H),8.23(s,1H),7.66(d,J＝8.3Hz,3H),7.46–7.40(m,2H),7.21– 7.10(m,5H),6.81(d,J=2.1Hz,1H),6.67(dd,J=8.4,2.1Hz,1H),5.43–5.33(m,1H),5.06(dd,J=12.8, 5.4Hz, 1H), 4.12(q, J=9.2, 8.5Hz, 2H), 3.95(dd, J=8.8, 4.7Hz, 2H), 3.47(dq, J=11.2, 5.6Hz, 1H), 2.92– 2.79(m,3H),2.64–2.52(m,4H),2.48(d,J=2.7Hz,2H),2.37(dt,J=11.7,7.8Hz,2H),2.06–1.88(m,3H) . 13 C NMR(126MHz,DMSO)δ173.29,170.59,167.95,167.65,158.59,157.49,156.79,155.95,155.43,154.37,143.21,134.32,130.60,130.49,128.62,125.32,124.24,119.45,119.42,117.26,114.68 ,104.97,97.92,58.37,57.52,55.98,52.95,49.19,38.93,31.46,22.69.
实施例60:化合物60的合成Embodiment 60: the synthesis of compound 60
Figure PCTCN2022096512-appb-000177
Figure PCTCN2022096512-appb-000177
步骤1：中间体60b的制备Step 1: Preparation of intermediate 60b
向单口瓶中依次加入中间体59f(0.9g)、1-叔丁氧羰基-3-氮杂环丁酮(0.49g)、乙酸(0.17g)、氰基 硼氢化钠(0.24g)及甲醇(50mL)，常温搅拌反应2h，补加1-叔丁氧羰基-3-氮杂环丁酮(0.33g)、乙酸(0.05g)及氰基硼氢化钠(0.120g)，常温反应16h，反应完全，将反应液倒入纯化水(150mL)中，加入二氯甲烷/甲醇＝10/1溶液(150mL)，萃取分层，有机相用饱和氯化钠水溶液洗涤，用无水硫酸钠干燥，浓缩有机相得粗品，过硅胶柱纯化得中间体60b(0.57g)。Add intermediate 59f (0.9g), 1-tert-butoxycarbonyl-3-azetidinone (0.49g), acetic acid (0.17g), sodium cyanoborohydride (0.24g) and methanol to a one-necked flask in sequence (50 mL), stirred at room temperature for 2 h, added 1-tert-butoxycarbonyl-3-azetidinone (0.33 g), acetic acid (0.05 g) and sodium cyanoborohydride (0.120 g), and reacted at room temperature for 16 h, After the reaction is complete, pour the reaction solution into purified water (150 mL), add dichloromethane/methanol=10/1 solution (150 mL), extract and separate layers, wash the organic phase with saturated aqueous sodium chloride, and dry over anhydrous sodium sulfate , the organic phase was concentrated to obtain a crude product, which was purified by a silica gel column to obtain intermediate 60b (0.57 g).
MS(ESI,[M+H] +)m/z：623.6。 MS (ESI, [M+H] + ) m/z: 623.6.
步骤2：中间体60c的制备Step 2: Preparation of intermediate 60c
向反应瓶中依次加入中间体60b(570mg)、盐酸二氧六环溶液(4M，7mL)及甲醇(20mL)，25℃搅拌反应3.5h。反应完全，反应液浓缩至干，加入纯化水(150mL)、二氯甲烷/甲醇＝10/1溶液(150mL)，搅拌状态下加入饱和碳酸氢钠水溶液(50mL)，萃取分层，有机相用饱和氯化钠水溶液洗涤，用无水硫酸钠干燥，浓缩有机相得中间体60c(210mg)。Intermediate 60b (570 mg), dioxane hydrochloride solution (4M, 7 mL) and methanol (20 mL) were sequentially added to the reaction flask, and the reaction was stirred at 25° C. for 3.5 h. The reaction was complete, the reaction solution was concentrated to dryness, purified water (150mL), dichloromethane/methanol=10/1 solution (150mL) was added, and saturated aqueous sodium bicarbonate solution (50mL) was added under stirring, the layers were extracted, and the organic phase was used Wash with saturated aqueous sodium chloride, dry over anhydrous sodium sulfate, and concentrate the organic phase to obtain intermediate 60c (210 mg).
MS(ESI,[M+H] +)m/z：523.5。 1H NMR(500MHz,DMSO-d 6)δ8.24(s,1H),7.68–7.62(m,2H),7.47–7.39(m,2H),7.22–7.09(m,5H),5.36(ddd,J＝15.5,8.9,6.5Hz,1H),3.57(s,6H),3.38(d,J＝9.6Hz,2H),3.31–3.23(m,2H),3.00(s,2H),2.79(s,2H),2.47(d,J＝7.1Hz,1H),2.39–2.28(m,4H),1.88(dd,J＝12.2,6.5Hz,2H). MS (ESI, [M+H] + ) m/z: 523.5. 1 H NMR (500MHz,DMSO-d 6 )δ8.24(s,1H),7.68–7.62(m,2H),7.47–7.39(m,2H),7.22–7.09(m,5H),5.36(ddd ,J=15.5,8.9,6.5Hz,1H),3.57(s,6H),3.38(d,J=9.6Hz,2H),3.31–3.23(m,2H),3.00(s,2H),2.79( s, 2H), 2.47(d, J=7.1Hz, 1H), 2.39–2.28(m, 4H), 1.88(dd, J=12.2, 6.5Hz, 2H).
步骤3：化合物60的制备Step 3: Preparation of Compound 60
向单口瓶中依次加入中间体60c(200mg)、中间体13b(159mg)、N,N-二异丙基乙胺(99mg)及二甲基亚砜(5mL)，80℃搅拌反应5h，反应完全，反应液通过120g C 18反相柱纯化得化合物60(260mg)。 Add intermediate 60c (200mg), intermediate 13b (159mg), N,N-diisopropylethylamine (99mg) and dimethyl sulfoxide (5mL) to the one-necked bottle successively, stir at 80°C for 5h, and react Completely, the reaction solution was purified by a 120 g C 18 reverse phase column to obtain compound 60 (260 mg).
HR-MS(ESI,[M+H] +)m/z：779.34052。 1H NMR(500MHz,DMSO-d 6)δ11.07(s,1H),8.25(s,1H),7.64(dd,J＝15.7,8.3Hz,3H),7.43(t,J＝7.8Hz,2H),7.16(ddd,J＝20.8,13.6,7.7Hz,5H),6.79(d,J＝2.1Hz,1H),6.66(dd,J＝8.4,2.2Hz,1H),5.38(t,J＝8.1Hz,1H),5.05(dd,J＝12.8,5.4Hz,1H),4.06(t,J＝7.8Hz,2H),3.82(dd,J＝9.0,4.3Hz,2H),3.65(p,J＝5.0Hz,1H),3.38(s,2H),3.07(s,3H),2.93–2.74(m,3H),2.63–2.53(m,2H),2.49(d,J＝6.4Hz,2H),2.35(dq,J＝11.8,7.6Hz,4H),2.00(ddt,J＝7.8,5.3,2.8Hz,1H),1.90(dd,J＝12.4,6.5Hz,2H). 13C NMR(126MHz,DMSO)δ173.30,170.59,167.95,167.65,158.60,157.51,156.78,155.97,155.38,154.39,143.23,134.30,130.61,130.50,128.62,125.27,124.26,119.44,117.24,114.69,104.96,97.95,58.69,57.37,55.38,54.91,54.80,54.06,53.27,49.18,38.75,31.45,22.68. HR-MS (ESI, [M+H] + ) m/z: 779.34052. 1 H NMR (500MHz, DMSO-d 6 )δ11.07(s, 1H), 8.25(s, 1H), 7.64(dd, J=15.7, 8.3Hz, 3H), 7.43(t, J=7.8Hz, 2H), 7.16(ddd, J＝20.8, 13.6, 7.7Hz, 5H), 6.79(d, J＝2.1Hz, 1H), 6.66(dd, J＝8.4, 2.2Hz, 1H), 5.38(t, J =8.1Hz, 1H), 5.05(dd, J=12.8, 5.4Hz, 1H), 4.06(t, J=7.8Hz, 2H), 3.82(dd, J=9.0, 4.3Hz, 2H), 3.65(p ,J=5.0Hz,1H),3.38(s,2H),3.07(s,3H),2.93–2.74(m,3H),2.63–2.53(m,2H),2.49(d,J=6.4Hz, 2H), 2.35(dq, J=11.8, 7.6Hz, 4H), 2.00(ddt, J=7.8, 5.3, 2.8Hz, 1H), 1.90(dd, J=12.4, 6.5Hz, 2H). 13 C NMR (126MHz,DMSO)δ173.30,170.59,167.95,167.65,158.60,157.51,156.78,155.97,155.38,154.39,143.23,134.30,130.61,130.50,128.62,125.27,124.26,119.44,117.24,114.69,104.96,97.95,58.69 ,57.37,55.38,54.91,54.80,54.06,53.27,49.18,38.75,31.45,22.68.
实施例61:化合物61的合成Embodiment 61: the synthesis of compound 61
Figure PCTCN2022096512-appb-000178
Figure PCTCN2022096512-appb-000178
用叔丁基-2-氧代-8-氮杂螺[4.5]癸烷-8-羧酸乙酯代替3-Boc-9-氧代-3-氮杂螺[5.5]十一烷作为原料，参照实施例54中第一步至第四步的操作步骤合成实施例61。Using ethyl tert-butyl-2-oxo-8-azaspiro[4.5]decane-8-carboxylate instead of 3-Boc-9-oxo-3-azaspiro[5.5]undecane as starting material , Synthesize Example 61 with reference to the operation steps from the first step to the fourth step in Example 54.
实施例62:化合物62的合成Embodiment 62: the synthesis of compound 62
Figure PCTCN2022096512-appb-000179
Figure PCTCN2022096512-appb-000179
用9-氧代-2-氮杂螺[叔丁基][5.5]十一烷-2-羧酸叔丁酯代替3-Boc-9-氧代-3-氮杂螺[5.5]十一烷作为原料，参照实施例54中第一步至第四步的操作步骤合成实施例62。Replace 3-Boc-9-oxo-3-azaspiro[5.5]undeca with tert-butyl 9-oxo-2-azaspiro[tert-butyl][5.5]undecane-2-carboxylate Using alkanes as raw materials, Example 62 was synthesized by referring to the first to fourth steps in Example 54.
实施例63:化合物63的合成Embodiment 63: the synthesis of compound 63
Figure PCTCN2022096512-appb-000180
Figure PCTCN2022096512-appb-000180
用6-羟基-2-氮杂螺[3.3]庚烷-2-甲酸叔丁酯代替7-羟基-2-氮杂螺[3.5]壬烷-2-羧酸叔丁酯作为原料，参照实施例46中第一步至第五步的操作步骤合成实施例63。Use tert-butyl 6-hydroxy-2-azaspiro[3.3]heptane-2-carboxylate instead of tert-butyl 7-hydroxy-2-azaspiro[3.5]nonane-2-carboxylate as raw material, refer to implementation Example 63 was synthesized by the operation procedure of the first step to the fifth step in Example 46.
实施例64:化合物64的合成Embodiment 64: the synthesis of compound 64
Figure PCTCN2022096512-appb-000181
Figure PCTCN2022096512-appb-000181
用6-羟基-2-氮杂螺[3.4]辛烷-2-甲酸叔丁酯代替7-羟基-2-氮杂螺[3.5]壬烷-2-羧酸叔丁酯作为原料，参照实施例46中第一步至第五步的操作步骤合成实施例64。Use 6-hydroxy-2-azaspiro[3.4]octane-2-carboxylic acid tert-butyl ester to replace 7-hydroxy-2-azaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester as raw material, refer to the implementation Example 64 was synthesized by the operation steps from the first step to the fifth step in Example 46.
实施例65:化合物65的合成Embodiment 65: the synthesis of compound 65
Figure PCTCN2022096512-appb-000182
Figure PCTCN2022096512-appb-000182
用6-氟-7-羟基-2-氮杂螺环[3.5]壬烷-2-羧酸叔丁酯代替7-羟基-2-氮杂螺[3.5]壬烷-2-羧酸叔丁酯作为原料，参照实施例46中第一步至第五步的操作步骤合成实施例65。Replace tert-butyl 7-hydroxy-2-azaspiro[3.5]nonane-2-carboxylate with tert-butyl 6-fluoro-7-hydroxy-2-azaspiro[3.5]nonane-2-carboxylate Using the ester as a raw material, Example 65 was synthesized by referring to the steps from the first step to the fifth step in Example 46.
实施例66:化合物66的合成Embodiment 66: the synthesis of compound 66
Figure PCTCN2022096512-appb-000183
Figure PCTCN2022096512-appb-000183
用1-氟-7-羟基-2-氮杂螺环[3.5]壬烷-2-羧酸叔丁酯代替7-羟基-2-氮杂螺[3.5]壬烷-2-羧酸叔丁酯作为原料，参照实施例46中第一步至第五步的操作步骤合成实施例66。Replace tert-butyl 7-hydroxy-2-azaspiro[3.5]nonane-2-carboxylate with tert-butyl 1-fluoro-7-hydroxy-2-azaspiro[3.5]nonane-2-carboxylate Esters were used as raw materials, and Example 66 was synthesized by referring to the steps from the first step to the fifth step in Example 46.
实施例67:化合物67的合成Embodiment 67: the synthesis of compound 67
Figure PCTCN2022096512-appb-000184
Figure PCTCN2022096512-appb-000184
用3-(5-溴-6-氟-1-氧异吲哚-2-基)哌啶-2,6-二酮代替3-(5-溴-1-氧异吲哚-2-基)哌啶-2,6-二酮作为原料，参照实施例49中第一步的操作步骤合成实施例67。Replace 3-(5-bromo-1-oxoisoindol-2-yl) with 3-(5-bromo-6-fluoro-1-oxoisoindol-2-yl)piperidine-2,6-dione ) piperidine-2,6-dione as a raw material, and Example 67 was synthesized by referring to the first step in Example 49.
或者，or,
Figure PCTCN2022096512-appb-000185
Figure PCTCN2022096512-appb-000185
步骤1：中间体67b的制备Step 1: Preparation of Intermediate 67b
向反应瓶中依次加入中间体67a(5g)、甲醇(50mL)、浓硫酸(2.5mL)，氮气保护下，回流反应4h。反应完毕，降至室温，将反应液倒入饱和碳酸氢钠溶液中，EA萃取，饱和氯化钠水溶液洗涤，无水硫酸钠干燥，过滤，浓缩，得到中间体67b(5.40g)Intermediate 67a (5 g), methanol (50 mL), and concentrated sulfuric acid (2.5 mL) were sequentially added to the reaction flask, and the mixture was refluxed for 4 h under nitrogen protection. After the reaction was completed, it was lowered to room temperature, and the reaction solution was poured into a saturated sodium bicarbonate solution, extracted with EA, washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain intermediate 67b (5.40g)
1H NMR(500MHz,DMSO-d6)δ7.83(dd,J＝11.4,8.5Hz,1H),7.48(dd,J＝11.8,7.9Hz,1H),3.83(s,3H),2.50(s,3H)。 1 H NMR (500MHz, DMSO-d6) δ7.83(dd, J=11.4,8.5Hz,1H),7.48(dd,J=11.8,7.9Hz,1H),3.83(s,3H),2.50(s ,3H).
步骤2：中间体67c的制备Step 2: Preparation of intermediate 67c
向反应瓶中依次加入中间体67b(5.30g)、N-溴代丁二酰亚胺(5.57g)、偶氮二异丁腈(0.47g)及四氯 化碳(100mL)，80℃反应5h，反应完毕，反应液冷至室温，加入水(100ml)，DCM萃取两次，每次100ml，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩，得中间体67c(5.98g)。Add intermediate 67b (5.30g), N-bromosuccinimide (5.57g), azobisisobutyronitrile (0.47g) and carbon tetrachloride (100mL) successively to the reaction flask, and react at 80°C 5h, the reaction was completed, the reaction solution was cooled to room temperature, water (100ml) was added, DCM was extracted twice, 100ml each time, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain intermediate 67c ( 5.98g).
1H NMR(500MHz,DMSO-d6)δ7.96–7.89(m,1H),7.81–7.76(m,1H),4.98(s,2H),3.88(s,3H). 1 H NMR (500MHz, DMSO-d6) δ7.96–7.89(m,1H), 7.81–7.76(m,1H), 4.98(s,2H), 3.88(s,3H).
步骤3：化合物67d的制备Step 3: Preparation of compound 67d
向反应瓶中依次加入中间体67c(5.20g)、3-氨基哌啶-2,6-二酮盐酸盐(3.55g)、三乙胺(5.96g)、DMSO(50ml)，85℃反应4h。反应完毕，冷却至室温，加入水(150mL)，抽滤，干燥，得到中间体67d(2.31g)。Add intermediate 67c (5.20g), 3-aminopiperidine-2,6-dione hydrochloride (3.55g), triethylamine (5.96g), DMSO (50ml) to the reaction flask in sequence, and react at 85°C 4h. After the reaction was completed, it was cooled to room temperature, water (150 mL) was added, suction filtered, and dried to obtain intermediate 67d (2.31 g).
MS(ESI,[M-H] -)m/z：279.1。 1H NMR(500MHz,DMSO-d6)δ11.01(s,1H),7.84–7.73(m,2H),5.11(dd,J＝13.4,5.1Hz,1H),4.49–4.28(m,2H),2.96–2.85(m,1H),2.65–2.56(m,1H),2.46–2.34(m,1H),2.06–1.97(m,1H). MS (ESI, [MH] - ) m/z: 279.1. 1 H NMR (500MHz, DMSO-d6) δ11.01(s, 1H), 7.84–7.73(m, 2H), 5.11(dd, J=13.4, 5.1Hz, 1H), 4.49–4.28(m, 2H) ,2.96–2.85(m,1H),2.65–2.56(m,1H),2.46–2.34(m,1H),2.06–1.97(m,1H).
步骤4：化合物67的制备Step 4: Preparation of compound 67
用46e代替47c，67d代替13b作为原料，参照实施例47中第三步的操作步骤合成实施例67。Using 46e instead of 47c and 67d instead of 13b as raw materials, Example 67 was synthesized by referring to the third step in Example 47.
MS(ESI,[M+H] +)m/z：742.5。 1H NMR(500MHz,DMSO-d6)δ10.94(s,1H),8.23(s,1H),7.67–7.61(m,2H),7.47–7.40(m,2H),7.35–7.29(m,1H),7.21–7.10(m,5H),6.67(d,J＝7.9Hz,1H),5.04(dd,J＝13.3,5.1Hz,1H),4.71–4.61(m,1H),4.34–4.15(m,2H),4.10–4.02(m,2H),3.86–3.78(m,2H),3.67–3.55(m,1H),3.12(s,2H),3.00(s,2H),2.94–2.84(m,1H),2.62–2.54(m,1H),2.42–2.29(m,1H),2.07–1.91(m,5H),1.89–1.81(m,2H),1.69–1.60(m,2H). MS (ESI, [M+H] + ) m/z: 742.5. 1 H NMR (500MHz,DMSO-d6)δ10.94(s,1H),8.23(s,1H),7.67–7.61(m,2H),7.47–7.40(m,2H),7.35–7.29(m, 1H),7.21–7.10(m,5H),6.67(d,J＝7.9Hz,1H),5.04(dd,J＝13.3,5.1Hz,1H),4.71–4.61(m,1H),4.34–4.15 (m,2H),4.10–4.02(m,2H),3.86–3.78(m,2H),3.67–3.55(m,1H),3.12(s,2H),3.00(s,2H),2.94–2.84 (m,1H),2.62–2.54(m,1H),2.42–2.29(m,1H),2.07–1.91(m,5H),1.89–1.81(m,2H),1.69–1.60(m,2H) .
实施例68:化合物68的合成Embodiment 68: the synthesis of compound 68
Figure PCTCN2022096512-appb-000186
Figure PCTCN2022096512-appb-000186
用中间体57c代替中间体46c作为原料，参照实施例53中第三步的操作步骤合成实施例68。Using intermediate 57c instead of intermediate 46c as a raw material, Example 68 was synthesized referring to the third step in Example 53.
实施例69:化合物69的合成Embodiment 69: the synthesis of compound 69
Figure PCTCN2022096512-appb-000187
Figure PCTCN2022096512-appb-000187
用6-羟基-3-氮杂双环[3.1.0]己烷-3-羧酸叔丁酯代替中间体59b作为原料，参照实施例59中第二步至第六步的操作步骤合成实施例69。Use tert-butyl 6-hydroxy-3-azabicyclo[3.1.0]hexane-3-carboxylate instead of intermediate 59b as a raw material, and refer to the second step to the sixth step in Example 59 to synthesize the example 69.
实施例70:化合物70的合成Embodiment 70: the synthesis of compound 70
Figure PCTCN2022096512-appb-000188
Figure PCTCN2022096512-appb-000188
用7-羟基八氢异喹啉-2(1H)-羧酸叔丁酯代替中间体59b作为原料，参照实施例59中第二步至第六步的操作步骤合成实施例70。Using tert-butyl 7-hydroxyoctahydroisoquinoline-2(1H)-carboxylate instead of intermediate 59b as a raw material, Example 70 was synthesized by referring to the second to sixth steps in Example 59.
实施例71:化合物71的合成Embodiment 71: the synthesis of compound 71
Figure PCTCN2022096512-appb-000189
Figure PCTCN2022096512-appb-000189
用6-羟基八氢异喹啉-2(1H)-羧酸叔丁酯代替中间体59b作为原料，参照实施例59中第二步至第六步的操作步骤合成实施例71。Using tert-butyl 6-hydroxyoctahydroisoquinoline-2(1H)-carboxylate instead of intermediate 59b as a raw material, Example 71 was synthesized referring to the second to sixth steps in Example 59.
实施例72:化合物72的合成Embodiment 72: the synthesis of compound 72
Figure PCTCN2022096512-appb-000190
Figure PCTCN2022096512-appb-000190
用5-羟基八氢-2H-异吲哚-2-羧酸叔丁酯代替中间体59b作为原料，参照实施例59中第二步至第六步的操作步骤合成实施例72。Using tert-butyl 5-hydroxyoctahydro-2H-isoindole-2-carboxylate instead of intermediate 59b as a raw material, Example 72 was synthesized by referring to the second to sixth steps in Example 59.
实施例73:化合物73的合成Embodiment 73: the synthesis of compound 73
Figure PCTCN2022096512-appb-000191
Figure PCTCN2022096512-appb-000191
用6-羟基-3-氮杂双环[3.2.0]庚烷-3-甲酸叔丁酯代替中间体59b作为原料，参照实施例59中第二步至第六步的操作步骤合成实施例73。Use tert-butyl 6-hydroxy-3-azabicyclo[3.2.0]heptane-3-carboxylate instead of intermediate 59b as a raw material, and synthesize Example 73 with reference to the second to sixth steps in Example 59 .
实施例74:化合物74的合成Embodiment 74: the synthesis of compound 74
Figure PCTCN2022096512-appb-000192
Figure PCTCN2022096512-appb-000192
用6-羟基六氢-1H-环戊二烯并[C]吡啶-2(3H)-羧酸叔丁酯代替中间体59b作为原料，参照实施例59中第二步至第六步的操作步骤合成实施例74。Use tert-butyl 6-hydroxyhexahydro-1H-cyclopentadieno[C]pyridine-2(3H)-carboxylate instead of intermediate 59b as a raw material, referring to the operation of the second step to the sixth step in Example 59 Step Synthesis of Example 74.
实施例75：化合物75的合成Embodiment 75: the synthesis of compound 75
Figure PCTCN2022096512-appb-000193
Figure PCTCN2022096512-appb-000193
步骤1：中间体75b的制备Step 1: Preparation of Intermediate 75b
向单口瓶中依次加入中间体46e(1.5g)、4-氟邻苯二甲酸二甲酯(0.58g)、DIPEA(0.63g)及DMSO (25mL)，80℃搅拌反应2h，反应完全，冷却至室温，将反应液倒入水(100mL)中，加入乙酸乙酯，萃取分层，有机相用饱和氯化钠水溶液洗涤，用无水硫酸钠干燥，浓缩有机相得粗品，过硅胶柱纯化后，得到中间体75b(1.02g)。Add intermediate 46e (1.5g), dimethyl 4-fluorophthalate (0.58g), DIPEA (0.63g) and DMSO (25mL) to the one-necked flask in turn, stir at 80°C for 2h, and cool to completion to room temperature, pour the reaction solution into water (100 mL), add ethyl acetate, extract and separate layers, wash the organic phase with saturated aqueous sodium chloride, dry over anhydrous sodium sulfate, concentrate the organic phase to obtain a crude product, and purify through a silica gel column Afterwards, intermediate 75b (1.02g) was obtained.
MS(ESI,[M+H]+)m/z：674.3。MS (ESI, [M+H]+) m/z: 674.3.
步骤2：中间体75c的制备Step 2: Preparation of Intermediate 75c
向反应瓶中依次加入中间体75b(1.02g)、1,4-二氧六环(15mL)、甲醇(15mL)及氢氧化钠溶液(5M,3.05mL)，70℃搅拌反应1h。反应完全，反应液浓缩，除去部分有机溶剂，冰浴降温下，滴加1M稀盐酸，有固体析出，抽滤，水洗，干燥，得到中间体75c(0.77g)。Intermediate 75b (1.02g), 1,4-dioxane (15mL), methanol (15mL) and sodium hydroxide solution (5M, 3.05mL) were sequentially added to the reaction flask, and the reaction was stirred at 70°C for 1h. After the reaction was complete, the reaction liquid was concentrated, part of the organic solvent was removed, 1M dilute hydrochloric acid was added dropwise in an ice bath, and a solid precipitated out, which was filtered by suction, washed with water, and dried to obtain intermediate 75c (0.77g).
MS(ESI,[M+H]+)m/z：646.3。MS (ESI, [M+H]+) m/z: 646.3.
步骤3：中间体75d的制备Step 3: Preparation of Intermediate 75d
向反应瓶中依次加入中间体75c(0.40g)、1-甲基吡唑(44.2mg)、DMF(2mL)及四甲基氯代脲六氟磷酸酯(0.12g)，室温搅拌反应1h。得到含有中间体75d的DMF溶液，直接用于下一步反应。Intermediate 75c (0.40 g), 1-methylpyrazole (44.2 mg), DMF (2 mL) and tetramethylchlorourea hexafluorophosphate (0.12 g) were sequentially added to the reaction flask, and the reaction was stirred at room temperature for 1 h. The obtained DMF solution containing intermediate 75d was directly used in the next reaction.
MS(ESI,[M+H]+)m/z：628.3。MS (ESI, [M+H]+) m/z: 628.3.
步骤4：中间体75e-1和75e-2的制备Step 4: Preparation of intermediates 75e-1 and 75e-2
向上述反应液中加入甲醇(6mL)，室温反应过夜，反应完毕。加入冰水，有固体析出，抽滤，水洗，真空干燥，得到中间体75e-1和75e-2的混合物(0.20g)。Methanol (6 mL) was added to the above reaction solution, and the reaction was carried out overnight at room temperature, and the reaction was completed. Ice water was added, solids precipitated out, suction filtered, washed with water, and dried in vacuo to obtain a mixture of intermediates 75e-1 and 75e-2 (0.20 g).
中间体75e-1和75e-2的混合物：MS(ESI,[M+H]+)m/z：660.3。Mixture of intermediates 75e-1 and 75e-2: MS (ESI, [M+H]+) m/z: 660.3.
步骤5：中间体75f-1和75f-2的制备Step 5: Preparation of intermediates 75f-1 and 75f-2
向反应瓶中依次加入75e-1和75e-2的混合物(0.20g)、HATU(0.16g)、DIPEA(0.07g)及DMF(2mL)，室温搅拌反应0.5h，加入(R)-3-氨基-哌啶-2,6-二酮盐酸盐(0.08g)，室温反应1h，反应完毕。加入冰水，抽滤，水洗滤饼，真空干燥，得到中间体75f-1和75f-2的混合物(0.23g)。Add the mixture of 75e-1 and 75e-2 (0.20g), HATU (0.16g), DIPEA (0.07g) and DMF (2mL) to the reaction flask in turn, stir at room temperature for 0.5h, add (R)-3- Amino-piperidine-2,6-dione hydrochloride (0.08g) was reacted at room temperature for 1 hour, and the reaction was completed. Add ice water, filter with suction, wash the filter cake with water, and dry in vacuo to obtain a mixture of intermediates 75f-1 and 75f-2 (0.23g).
中间体75f-1和75f-2的混合物：MS(ESI,[M+H]+)m/z：770.3。Mixture of intermediates 75f-1 and 75f-2: MS (ESI, [M+H]+) m/z: 770.3.
步骤6：化合物75的制备Step 6: Preparation of compound 75
向单口瓶中依次加入75f-1和75f-2的混合物(0.23g)、DIPEA(0.07g)及DCM(2mL)，室温反应过夜，反应完全，加入DMSO(2mL)，浓缩除去DCM，通过120g C 18反相柱纯化得化合物75(105mg，ee＝92.90％)。 Add the mixture of 75f-1 and 75f-2 (0.23g), DIPEA (0.07g) and DCM (2mL) to the single-necked bottle successively, react overnight at room temperature, the reaction is complete, add DMSO (2mL), concentrate to remove DCM, pass through 120g Compound 75 (105 mg, ee=92.90%) was purified by C 18 reverse phase column purification.
MS(ESI,[M+H]+)m/z：738.3。 1H NMR(500MHz,DMSO-d6)δ11.08(s,1H),8.23(s,1H),7.64(d,J＝8.4Hz,3H),7.47–7.40(m,2H),7.22–7.09(m,5H),6.79(d,J＝2.2Hz,1H),6.65(dd,J＝8.4,2.1Hz,1H),5.06(dd,J＝12.8,5.4Hz,1H),4.71–4.61(m,1H),4.04(t,J＝7.8Hz,2H),3.87–3.80(m,2H),3.70–3.63(m,1H),3.12(s,2H),2.99(s,2H),2.94–2.83(m,1H),2.62–2.52(m,2H),2.10–1.91(m,5H),1.89–1.81(m,2H),1.69–1.59(m,2H). MS (ESI, [M+H]+) m/z: 738.3. 1 H NMR (500MHz,DMSO-d6)δ11.08(s,1H),8.23(s,1H),7.64(d,J=8.4Hz,3H),7.47–7.40(m,2H),7.22–7.09 (m,5H),6.79(d,J=2.2Hz,1H),6.65(dd,J=8.4,2.1Hz,1H),5.06(dd,J=12.8,5.4Hz,1H),4.71–4.61( m,1H),4.04(t,J＝7.8Hz,2H),3.87–3.80(m,2H),3.70–3.63(m,1H),3.12(s,2H),2.99(s,2H),2.94 –2.83(m,1H),2.62–2.52(m,2H),2.10–1.91(m,5H),1.89–1.81(m,2H),1.69–1.59(m,2H).
实施例76 化合物76的合成The synthesis of embodiment 76 compound 76
Figure PCTCN2022096512-appb-000194
Figure PCTCN2022096512-appb-000194
用(S)-3-氨基-哌啶-2,6-二酮盐酸盐代替(R)-3-氨基-哌啶-2,6-二酮盐酸盐作为原料，参照实施例75中第三步至第六步的操作步骤合成实施例76(112mg,ee＝97.44％)。Use (S)-3-amino-piperidine-2,6-dione hydrochloride instead of (R)-3-amino-piperidine-2,6-dione hydrochloride as raw material, refer to Example 75 Example 76 (112 mg, ee=97.44%) was synthesized by the operation steps from the third step to the sixth step.
MS(ESI,[M+H]+)m/z：738.3。 1H NMR(500MHz,DMSO-d6)δ11.08(s,1H),8.23(s,1H),7.64(d,J＝8.2Hz,3H),7.47–7.40(m,2H),7.21–7.09(m,5H),6.79(d,J＝2.1Hz,1H),6.70–6.62(m,1H),5.06(dd,J＝12.8,5.4Hz,1H),4.71–4.61(m,1H),4.04(t,J＝7.8Hz,2H),3.91–3.79(m,2H),3.70–3.62(m,1H),3.12(s,2H),3.00(s,2H),2.94–2.83(m,1H),2.62–2.52(m,2H),2.08–1.92(m,5H),1.89–1.82(m,2H),1.69–1.60(m,2H). MS (ESI, [M+H]+) m/z: 738.3. 1 H NMR (500MHz, DMSO-d6) δ11.08(s,1H),8.23(s,1H),7.64(d,J=8.2Hz,3H),7.47–7.40(m,2H),7.21–7.09 (m,5H),6.79(d,J=2.1Hz,1H),6.70–6.62(m,1H),5.06(dd,J=12.8,5.4Hz,1H),4.71–4.61(m,1H), 4.04(t,J＝7.8Hz,2H),3.91–3.79(m,2H),3.70–3.62(m,1H),3.12(s,2H),3.00(s,2H),2.94–2.83(m, 1H),2.62–2.52(m,2H),2.08–1.92(m,5H),1.89–1.82(m,2H),1.69–1.60(m,2H).
实施例77 化合物77的制备The preparation of embodiment 77 compound 77
Figure PCTCN2022096512-appb-000195
Figure PCTCN2022096512-appb-000195
化合物49通过高效液相色谱法分离制备得到化合物77。制备条件如下：Compound 49 was separated and prepared by high performance liquid chromatography to obtain compound 77. The preparation conditions are as follows:
仪器及制备柱：采用YMC K-prep Lab100g高压制备色谱仪，制备柱型号CHIRALART Amylose-SA (30×250mm,5μm)。流动相体系：正己烷/乙醇:二氯甲烷(1:1)，等梯度洗脱：正己烷/乙醇:二氯甲烷(1:1)＝30/70。Instrument and preparative column: YMC K-prep Lab100g high-pressure preparative chromatograph is used, and the preparative column model is CHIRALART Amylose-SA (30×250mm, 5μm). Mobile phase system: n-hexane/ethanol:dichloromethane (1:1), isocratic elution: n-hexane/ethanol:dichloromethane (1:1)=30/70.
化合物77的分析方法：Analytical method of compound 77:
仪器：岛津LC-20AT高效液相色谱仪。色谱柱：CHIRALART Amylose-SA(4.6×250mm,5μm)。流动相A：正己烷。流动相B：乙醇:二氯甲烷(1:1)。洗脱程序：流动相A:B＝30:70，等度洗脱50min。Instrument: Shimadzu LC-20AT high performance liquid chromatography. Chromatographic column: CHIRALART Amylose-SA (4.6×250mm, 5μm). Mobile phase A: n-hexane. Mobile phase B: ethanol:dichloromethane (1:1). Elution procedure: mobile phase A:B=30:70, isocratic elution for 50min.
化合物77保留时间：7.158min。Compound 77 retention time: 7.158min.
HRMS(ESI)m/z[M+H] +:724.3371。 1H NMR(500MHz,DMSO-d 6)δ10.94(s,1H),8.23(s,1H),7.64(d,J＝8.1Hz,2H),7.49(d,J＝8.2Hz,1H),7.43(t,J＝7.7Hz,2H),7.15(ddd,J＝21.5,14.0,7.7Hz,5H),6.56–6.44(m,2H),5.03(dd,J＝13.3,5.2Hz,1H),4.66(tt,J＝11.1,4.1Hz,1H),4.30(d,J＝16.8Hz,1H),4.18(d,J＝16.8Hz,1H),3.93(t,J＝7.5Hz,2H),3.71(dt,J＝8.2,4.0Hz,2H),3.65(s,1H),3.15(d,J＝23.9Hz,2H),3.00(s,2H),2.90(ddd,J＝18.1,13.5,5.4Hz,1H),2.62–2.54(m,1H),2.35(qd,J＝13.1,4.4Hz,1H),2.03(t,J＝11.1Hz,2H),1.97(d,J＝13.0Hz,2H),1.89–1.79(m,2H),1.65(dt,J＝14.1,7.2Hz,2H). HRMS (ESI) m/z [M+H] + : 724.3371. 1 H NMR (500MHz,DMSO-d 6 )δ10.94(s,1H),8.23(s,1H),7.64(d,J=8.1Hz,2H),7.49(d,J=8.2Hz,1H) ,7.43(t,J=7.7Hz,2H),7.15(ddd,J=21.5,14.0,7.7Hz,5H),6.56–6.44(m,2H),5.03(dd,J=13.3,5.2Hz,1H ), 4.66(tt, J=11.1, 4.1Hz, 1H), 4.30(d, J=16.8Hz, 1H), 4.18(d, J=16.8Hz, 1H), 3.93(t, J=7.5Hz, 2H ),3.71(dt,J=8.2,4.0Hz,2H),3.65(s,1H),3.15(d,J=23.9Hz,2H),3.00(s,2H),2.90(ddd,J=18.1, 13.5,5.4Hz,1H),2.62–2.54(m,1H),2.35(qd,J=13.1,4.4Hz,1H),2.03(t,J=11.1Hz,2H),1.97(d,J=13.0 Hz, 2H), 1.89–1.79(m, 2H), 1.65(dt, J=14.1, 7.2Hz, 2H).
实施例78 化合物78的合成Synthesis of Example 78 Compound 78
Figure PCTCN2022096512-appb-000196
Figure PCTCN2022096512-appb-000196
步骤1：中间体78b的制备Step 1: Preparation of Intermediate 78b
向反应瓶中依次加入3-羟基氮杂环丁烷盐酸盐(6.42g)、化合物78a(7g)、碳酸钾(16.20g)及DMA(100mL)，氮气保护下，将混合物加热至80℃反应2.5h。反应液冷至室温，加入50mL乙酸乙酯和50mL水。有机相分离，分别用100mL饱和食盐水洗涤后用无水硫酸钠干燥，过滤，通过旋转蒸发仪减压蒸除溶剂，得到中间体78b(11.5g)。3-Hydroxyazetidine hydrochloride (6.42g), compound 78a (7g), potassium carbonate (16.20g) and DMA (100mL) were successively added to the reaction flask, and the mixture was heated to 80°C under nitrogen protection Reaction 2.5h. The reaction solution was cooled to room temperature, and 50 mL of ethyl acetate and 50 mL of water were added. The organic phase was separated, washed with 100 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure by a rotary evaporator to obtain intermediate 78b (11.5 g).
MS(ESI,[M+H] +)m/z：233.11。 1H NMR(500MHz,DMSO-d6)δ7.87(d,J＝8.8Hz,1H),6.87(d,J＝2.4Hz,1H),6.66(dd,J＝8.8,2.4Hz,1H),5.79(d,J＝6.4Hz,1H),4.61(dtd,J＝10.8,6.5,4.5Hz,1H),4.26–4.13(m,2H),3.82(s,3H),3.75–3.67(m,2H). MS (ESI, [M+H] + ) m/z: 233.11. 1 H NMR (500MHz, DMSO-d6) δ7.87 (d, J=8.8Hz, 1H), 6.87 (d, J=2.4Hz, 1H), 6.66 (dd, J=8.8, 2.4Hz, 1H), 5.79(d,J=6.4Hz,1H),4.61(dtd,J=10.8,6.5,4.5Hz,1H),4.26–4.13(m,2H),3.82(s,3H),3.75–3.67(m, 2H).
步骤2：中间体78c的制备Step 2: Preparation of intermediate 78c
向反应瓶中依次加入中间体78b(10g)、水(50mL)、吡啶(98g)及乙酸(52.5g)、亚磷酸氢钠(30.3g)、雷尼镍(3.31g)，氮气保护下，将混合物加热至80℃反应8h，补加雷尼镍(4.04g)，80℃过夜反应后再补加雷尼镍(4.04g)，80℃继续反应过夜后，监控原料反应完毕。反应液冷至室温，过滤除去Ni粉(注意不要抽干)，加入EA(500mL)和水(500mL)。有机相分离，分别用0.5M稀盐酸(500mL)洗涤三次，除去吡啶，再用200mL饱和碳酸氢钠洗涤，最后用200mL饱和食盐水洗涤后用无水硫酸钠干燥，过滤，通过旋转蒸发仪减压蒸除溶剂，得到中间体78c(5.12g)。Add intermediate 78b (10g), water (50mL), pyridine (98g) and acetic acid (52.5g), sodium hydrogen phosphite (30.3g), Raney nickel (3.31g) successively in the reaction flask, under nitrogen protection, The mixture was heated to 80° C. for 8 hours, and Raney nickel (4.04 g) was added. After the overnight reaction at 80° C., Raney nickel (4.04 g) was added again. After the reaction was continued at 80° C. overnight, the reaction of the raw materials was monitored to complete the reaction. The reaction solution was cooled to room temperature, and the Ni powder was removed by filtration (be careful not to drain it), and EA (500 mL) and water (500 mL) were added. The organic phase was separated, washed three times with 0.5M dilute hydrochloric acid (500mL), removed pyridine, washed with 200mL saturated sodium bicarbonate, finally washed with 200mL saturated brine, dried with anhydrous sodium sulfate, filtered, and reduced by rotary evaporator. The solvent was removed by autoclaving to afford intermediate 78c (5.12 g).
MS(ESI,[M-H] +)m/z：236.1。 1H NMR(500MHz,DMSO-d6)δ10.48(s,1H),7.83–7.78(m,1H),6.66–6.62(m,2H),5.76(d,J＝6.6Hz,1H),4.61(qd,J＝6.6,3.1Hz,1H),4.21(ddd,J＝8.0,6.6,1.2Hz,2H),3.82(s,3H),3.69(ddd,J＝8.4,4.6,1.2Hz,2H). MS (ESI, [MH] + ) m/z: 236.1. 1 H NMR(500MHz,DMSO-d6)δ10.48(s,1H),7.83–7.78(m,1H),6.66–6.62(m,2H),5.76(d,J=6.6Hz,1H),4.61 (qd,J=6.6,3.1Hz,1H),4.21(ddd,J=8.0,6.6,1.2Hz,2H),3.82(s,3H),3.69(ddd,J=8.4,4.6,1.2Hz,2H ).
步骤3：中间体78d的制备Step 3: Preparation of Intermediate 78d
向反应瓶中依次加入中间体78c(5g)、(S)-4,5-二氨基-5-氧代戊酸叔丁酯单盐酸盐(3.37g)、MeOH(100mL)及乙酸(1.50g)，降温至0℃后，加入氰基硼氢化钠(2.10g)，氮气保护下，将混合物室温反应过夜。反应完毕后，反应液通过硅胶柱层析纯化，通过旋转蒸发仪减压蒸除溶剂，得到中间体78d(3.79g)。Intermediate 78c (5 g), (S)-4,5-diamino-5-oxopentanoic acid tert-butyl ester monohydrochloride (3.37 g), MeOH (100 mL) and acetic acid (1.50 g), after cooling down to 0° C., sodium cyanoborohydride (2.10 g) was added, and the mixture was reacted overnight at room temperature under nitrogen protection. After the reaction was completed, the reaction solution was purified by silica gel column chromatography, and the solvent was evaporated under reduced pressure by a rotary evaporator to obtain intermediate 78d (3.79 g).
MS(ESI,[M+H] +)m/z：390.3。 1H NMR(500MHz,DMSO-d6)δ7.48(s,1H),7.45(d,J＝8.3Hz,1H),7.12(s,1H),6.53(d,J＝2.0Hz,1H),6.46(dd,J＝8.2,2.1Hz,1H),5.69(d,J＝6.4Hz,1H),4.66(d,J＝8.1Hz,1H),4.63–4.55(m,1H),4.50–4.25(m,2H),4.17–4.10(m,2H),3.59(ddd,J＝7.8,4.7,2.5Hz,2H),2.50(p,J＝ 1.8Hz,2H),2.15–2.09(m,2H),1.34(s,9H). MS (ESI, [M+H] + ) m/z: 390.3. 1 H NMR (500MHz, DMSO-d6) δ7.48(s, 1H), 7.45(d, J=8.3Hz, 1H), 7.12(s, 1H), 6.53(d, J=2.0Hz, 1H), 6.46(dd,J=8.2,2.1Hz,1H),5.69(d,J=6.4Hz,1H),4.66(d,J=8.1Hz,1H),4.63–4.55(m,1H),4.50–4.25 (m,2H),4.17–4.10(m,2H),3.59(ddd,J＝7.8,4.7,2.5Hz,2H),2.50(p,J＝1.8Hz,2H),2.15–2.09(m,2H ),1.34(s,9H).
步骤4：中间体78e的制备Step 4: Preparation of Intermediate 78e
向反应瓶中依次加入中间体78d(1.5g)、乙腈(40mL)、IBX氧化剂(3.24g)，氮气保护下，将混合物80℃反应4h。反应完毕后，过滤除去氧化剂后，滤饼用DCM洗涤三次，有机相通过硅胶柱层析纯化，得到中间体78e(0.267g)。Intermediate 78d (1.5 g), acetonitrile (40 mL) and IBX oxidant (3.24 g) were sequentially added to the reaction flask, and the mixture was reacted at 80° C. for 4 h under nitrogen protection. After the reaction was completed, the oxidant was removed by filtration, the filter cake was washed three times with DCM, and the organic phase was purified by silica gel column chromatography to obtain intermediate 78e (0.267 g).
1H NMR(500MHz,DMSO-d6)δ7.58–7.50(m,2H),7.14(s,1H),6.75(d,J＝2.1Hz,1H),6.67(dd,J＝8.3,2.2Hz,1H),4.79(s,4H),4.69(dd,J＝10.4,4.1Hz,1H),4.53(d,J＝17.2Hz,1H),4.36(d,J＝17.3Hz,1H),2.15–1.98(m,4H),1.34(s,9H). 1 H NMR (500MHz, DMSO-d6) δ7.58–7.50 (m, 2H), 7.14 (s, 1H), 6.75 (d, J=2.1Hz, 1H), 6.67 (dd, J=8.3, 2.2Hz ,1H),4.79(s,4H),4.69(dd,J=10.4,4.1Hz,1H),4.53(d,J=17.2Hz,1H),4.36(d,J=17.3Hz,1H),2.15 –1.98(m,4H),1.34(s,9H).
步骤5：中间体78f的制备Step 5: Preparation of intermediate 78f
向反应瓶中依次加入中间体78e(150mg)、DCM(10mL)、46c(183mg)、乙酸(11.62mg)，氮气保护下，将混合物40℃反应2h。反应瓶降至室温后，加入氰基硼氢化钠(73.0mg)，室温反应6h，反应液通过硅胶柱层析纯化，得到固体中间体78f(290mg)。Intermediate 78e (150mg), DCM (10mL), 46c (183mg), acetic acid (11.62mg) were sequentially added to the reaction flask, and the mixture was reacted at 40°C for 2h under nitrogen protection. After the reaction flask was lowered to room temperature, sodium cyanoborohydride (73.0 mg) was added and reacted at room temperature for 6 h. The reaction solution was purified by silica gel column chromatography to obtain solid intermediate 78f (290 mg).
MS(ESI,[M+H] +)m/z：798.4。 1H NMR(500MHz,DMSO-d6)δ8.23(s,1H),7.67–7.60(m,2H),7.49–7.39(m,4H),7.18(tt,J＝7.3,1.2Hz,1H),7.15–7.08(m,5H),6.52(d,J＝2.1Hz,1H),6.46(dd,J＝8.3,2.0Hz,1H),4.66(tt,J＝7.4,3.8Hz,2H),4.47(d,J＝17.2Hz,1H),4.30(d,J＝17.2Hz,1H),3.95–3.88(m,2H),3.69(dt,J＝8.3,4.3Hz,2H),3.63(s,1H),3.05(d,J＝60.7Hz,4H),2.12(d,J＝6.4Hz,2H),2.08(d,J＝6.5Hz,1H),2.06–1.91(m,5H),1.85(d,J＝11.9Hz,2H),1.69–1.60(m,2H),1.33(s,9H). MS (ESI, [M+H] + ) m/z: 798.4. 1 H NMR(500MHz,DMSO-d6)δ8.23(s,1H),7.67–7.60(m,2H),7.49–7.39(m,4H),7.18(tt,J＝7.3,1.2Hz,1H) ,7.15–7.08(m,5H),6.52(d,J＝2.1Hz,1H),6.46(dd,J＝8.3,2.0Hz,1H),4.66(tt,J＝7.4,3.8Hz,2H), 4.47(d, J=17.2Hz, 1H), 4.30(d, J=17.2Hz, 1H), 3.95–3.88(m, 2H), 3.69(dt, J=8.3, 4.3Hz, 2H), 3.63(s ,1H),3.05(d,J=60.7Hz,4H),2.12(d,J=6.4Hz,2H),2.08(d,J=6.5Hz,1H),2.06–1.91(m,5H),1.85 (d,J=11.9Hz,2H),1.69–1.60(m,2H),1.33(s,9H).
步骤6：化合物78的合成Step 6: Synthesis of Compound 78
向反应瓶中依次加入中间体78f(95mg)、MeCN(10mL)、苯磺酸(51.4mg)，氮气保护下，将混合物加热至85℃反应4h。反应液冷至室温，减压蒸除溶剂，通过反相柱层析纯化，得到化合物78(20mg)。Intermediate 78f (95 mg), MeCN (10 mL) and benzenesulfonic acid (51.4 mg) were sequentially added to the reaction flask, and the mixture was heated to 85° C. for 4 h under nitrogen protection. The reaction solution was cooled to room temperature, the solvent was evaporated under reduced pressure, and purified by reverse phase column chromatography to obtain compound 78 (20 mg).
MS(ESI,[M+H] +)m/z:724.4。 1H NMR(500MHz,DMSO-d6)δ10.94(s,1H),8.23(s,1H),7.71–7.61(m,2H),7.49(d,J＝8.3Hz,1H),7.46–7.40(m,2H),7.19(tt,J＝7.3,1.2Hz,1H),7.13(ddd,J＝14.1,7.5,1.6Hz,4H),6.52(d,J＝1.9Hz,1H),6.48(dd,J＝8.3,2.0Hz,1H),5.03(dd,J＝13.3,5.1Hz,1H),4.66(td,J＝11.2,5.7Hz,1H),4.30(d,J＝16.8Hz,1H),4.18(d,J＝16.9Hz,1H),3.96–3.88(m,2H),3.71(dt,J＝7.9,4.0Hz,2H),3.64(s,1H),3.12(s,2H),3.00(s,2H),2.94–2.83(m,1H),2.63–2.55(m,1H),2.35(qd,J＝13.3,4.5Hz,1H),2.08–2.01(m,2H),2.00–1.91(m,3H),1.85(d,J＝12.1Hz,2H),1.69–1.61(m,2H). MS (ESI, [M+H] + ) m/z: 724.4. 1 H NMR (500MHz, DMSO-d6) δ10.94(s,1H),8.23(s,1H),7.71–7.61(m,2H),7.49(d,J=8.3Hz,1H),7.46–7.40 (m,2H),7.19(tt,J=7.3,1.2Hz,1H),7.13(ddd,J=14.1,7.5,1.6Hz,4H),6.52(d,J=1.9Hz,1H),6.48( dd,J=8.3,2.0Hz,1H),5.03(dd,J=13.3,5.1Hz,1H),4.66(td,J=11.2,5.7Hz,1H),4.30(d,J=16.8Hz,1H ),4.18(d,J=16.9Hz,1H),3.96–3.88(m,2H),3.71(dt,J=7.9,4.0Hz,2H),3.64(s,1H),3.12(s,2H) ,3.00(s,2H),2.94–2.83(m,1H),2.63–2.55(m,1H),2.35(qd,J＝13.3,4.5Hz,1H),2.08–2.01(m,2H),2.00 –1.91(m,3H),1.85(d,J＝12.1Hz,2H),1.69–1.61(m,2H).
实施例78 化合物79的制备The preparation of embodiment 78 compound 79
Figure PCTCN2022096512-appb-000197
Figure PCTCN2022096512-appb-000197
化合物50通过高效液相色谱法分离制备得到化合物79。制备条件如下：Compound 50 was separated and prepared by high performance liquid chromatography to obtain compound 79. The preparation conditions are as follows:
仪器及制备柱：采用YMC K-prep Lab100g高压制备色谱仪，制备柱型号CHIRALART Amylose-SA(4.6×250mm,5μm)。流动相体系：正己烷/乙醇:二氯甲烷(2:1)，等梯度洗脱：正己烷/乙醇:二氯甲烷(2:1)＝40/60。Instrument and preparative column: YMC K-prep Lab100g high-pressure preparative chromatograph is used, and the preparative column model is CHIRALART Amylose-SA (4.6×250mm, 5μm). Mobile phase system: n-hexane/ethanol:dichloromethane (2:1), isocratic elution: n-hexane/ethanol:dichloromethane (2:1)=40/60.
化合物79的分析方法：Analytical method of compound 79:
仪器：Waters超高效合相色谱仪。色谱柱：CHIRALART Cellulose-SC(4.6向100mm,5.0μm)。流动相A：CO 2。流动相B：甲醇-乙腈(1:1)(含0.1％氨水)。洗脱程序：流动相A:B＝30:70。 Instrument: Waters ultra-high performance convergence chromatograph. Chromatographic column: CHIRALART Cellulose-SC (4.6 to 100 mm, 5.0 μm). Mobile phase A: CO2 . Mobile phase B: methanol-acetonitrile (1:1) (containing 0.1% ammonia). Elution procedure: mobile phase A:B=30:70.
化合物79保留时间：6.399min。Compound 79 retention time: 6.399min.
HRMS(ESI)m/z[M+H] +:752.3313。 1H NMR(500MHz,DMSO-d 6)δ11.07(s,1H),8.23(s,1H),7.63(t,J＝8.9Hz,3H),7.43(t,J＝7.8Hz,2H),7.16(ddd,J＝17.6,15.2,7.7Hz,5H),6.77(d,J＝2.1Hz,1H),6.63(dd,J＝8.4,2.1Hz,1H),5.05(dd,J＝12.8,5.5Hz,1H),4.64(ddt,J＝11.5,8.2,4.0Hz,1H),4.09(t,J＝8.0Hz,2H),3.69(dd,J＝8.4,5.0Hz,2H),3.07(s,1H),2.96(s,1H),2.88(ddd,J＝16.5,13.6,5.3Hz,2H),2.79–2.73(m,1H),2.70(s,1H),2.63–2.51(m,2H),2.00(dt,J＝16.4,8.5Hz,4H),1.93(dd,J＝12.5,3.3Hz,1H),1.84(dd,J＝10.9,5.7Hz,2H),1.67–1.58(m,2H). HRMS (ESI) m/z [M+H] + : 752.3313. 1 H NMR (500MHz,DMSO-d 6 )δ11.07(s,1H),8.23(s,1H),7.63(t,J=8.9Hz,3H),7.43(t,J=7.8Hz,2H) ,7.16(ddd,J=17.6,15.2,7.7Hz,5H),6.77(d,J=2.1Hz,1H),6.63(dd,J=8.4,2.1Hz,1H),5.05(dd,J=12.8 ,5.5Hz,1H),4.64(ddt,J=11.5,8.2,4.0Hz,1H),4.09(t,J=8.0Hz,2H),3.69(dd,J=8.4,5.0Hz,2H),3.07 (s,1H),2.96(s,1H),2.88(ddd,J＝16.5,13.6,5.3Hz,2H),2.79–2.73(m,1H),2.70(s,1H),2.63–2.51(m ,2H),2.00(dt,J=16.4,8.5Hz,4H),1.93(dd,J=12.5,3.3Hz,1H),1.84(dd,J=10.9,5.7Hz,2H),1.67–1.58( m,2H).
实施例80 化合物80的制备The preparation of embodiment 80 compound 80
Figure PCTCN2022096512-appb-000198
Figure PCTCN2022096512-appb-000198
Figure PCTCN2022096512-appb-000199
Figure PCTCN2022096512-appb-000199
步骤1：中间体80b的制备Step 1: Preparation of Intermediate 80b
向单口瓶中依次加入中间体80a(1.0g)、二氯甲烷(20mL)及戴斯马丁氧化剂(2.94g)，室温搅拌反应1h，反应完全，冰水浴降温，加入饱和亚硫酸钠溶液和饱和碳酸氢钠溶液淬灭反应，加入二氯甲烷，萃取分层，有机相用饱和氯化钠水溶液洗涤，无水硫酸钠干燥，浓缩有机相得粗品中间体80b(2.62g)，直接用于下一步。Add intermediate 80a (1.0g), dichloromethane (20mL) and Dess Martin oxidant (2.94g) to the one-necked bottle in turn, stir at room temperature for 1h, the reaction is complete, cool down in an ice-water bath, add saturated sodium sulfite solution and saturated bicarbonate The reaction was quenched with sodium solution, dichloromethane was added, the layers were extracted, the organic phase was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and the organic phase was concentrated to obtain the crude intermediate 80b (2.62 g), which was directly used in the next step.
步骤2：中间体80c的制备Step 2: Preparation of Intermediate 80c
向单口瓶中依次加入中间体46c(1.2g)、80b(2.23g)、乙酸(1滴)、氰基硼氢化钠(1.24g)及甲醇(20mL)，常温搅拌反应2h，反应完全，将反应液倒入纯化水(50mL)中，加入二氯甲烷/甲醇＝10/1溶液(100mL)，萃取分层，有机相用饱和氯化钠水溶液洗涤，无水硫酸钠干燥，浓缩有机相得粗品，过硅胶柱纯化得中间体80c(1.22g)。Add intermediates 46c (1.2g), 80b (2.23g), acetic acid (1 drop), sodium cyanoborohydride (1.24g) and methanol (20mL) to the one-necked bottle in turn, stir and react at room temperature for 2h, and the reaction is complete. Pour the reaction solution into purified water (50 mL), add dichloromethane/methanol = 10/1 solution (100 mL), extract and separate layers, wash the organic phase with saturated aqueous sodium chloride, dry over anhydrous sodium sulfate, and concentrate the organic phase to obtain The crude product was purified by silica gel column to obtain intermediate 80c (1.22g).
MS(ESI,[M+H] +)m/z：596.3。 MS (ESI, [M+H] + ) m/z: 596.3.
步骤3：中间体80d的制备Step 3: Preparation of Intermediate 80d
向反应瓶中依次加入中间体80c(1.22g)、盐酸二氧六环溶液(4M，30mL)、乙酸乙酯(20mL)，25℃搅拌反应3.5h。反应完全，反应液浓缩至干，加入纯化水(50mL)、二氯甲烷/甲醇＝10/1溶液(150mL)，搅拌状态下加入饱和碳酸氢钠水溶液(50mL)，萃取分层，有机相用饱和氯化钠水溶液洗涤，无水硫酸钠干燥，浓缩得中间体80d(0.84g)。The intermediate 80c (1.22g), dioxane hydrochloride solution (4M, 30mL) and ethyl acetate (20mL) were successively added to the reaction flask, and the reaction was stirred at 25°C for 3.5h. The reaction was complete, the reaction solution was concentrated to dryness, purified water (50mL), dichloromethane/methanol = 10/1 solution (150mL) was added, and saturated aqueous sodium bicarbonate solution (50mL) was added under stirring, the layers were extracted, and the organic phase was used Wash with saturated aqueous sodium chloride, dry over anhydrous sodium sulfate, and concentrate to give intermediate 80d (0.84g).
MS(ESI,[M+H] +)m/z：496.3。 MS (ESI, [M+H] + ) m/z: 496.3.
步骤4-9：化合物80的合成Step 4-9: Synthesis of Compound 80
用80d代替46e作为原料，参照实施例75中第一步至第六步的操作步骤合成实施例80(123mg,ee＝97.50％)。Using 80d instead of 46e as a raw material, Example 80 (123 mg, ee=97.50%) was synthesized by referring to the first to sixth steps in Example 75.
MS(ESI,[M+H]+)m/z：752.3。 1H NMR(500MHz,DMSO-d6)δ10.91(s,1H),8.06(s,1H),7.51–7.43(m,3H),7.30–7.23(m,2H),7.05–6.92(m,5H),6.60(s,1H),6.46(d,J＝8.3Hz,1H),4.89(dd,J＝12.7,5.4Hz,1H),4.53–4.43(m,1H),3.97–3.90(m,2H),3.65–3.47(m,2H),3.03–2.48(m,7H),2.45–2.35(m,2H),1.97–1.74(m,5H),1.71–1.65(m,2H),1.52–1.42(m,2H). MS (ESI, [M+H]+) m/z: 752.3. 1 H NMR (500MHz,DMSO-d6)δ10.91(s,1H),8.06(s,1H),7.51–7.43(m,3H),7.30–7.23(m,2H),7.05–6.92(m, 5H), 6.60(s, 1H), 6.46(d, J＝8.3Hz, 1H), 4.89(dd, J＝12.7, 5.4Hz, 1H), 4.53–4.43(m, 1H), 3.97–3.90(m ,2H),3.65–3.47(m,2H),3.03–2.48(m,7H),2.45–2.35(m,2H),1.97–1.74(m,5H),1.71–1.65(m,2H),1.52 –1.42(m,2H).
试验例1：化合物对OCI-LY10细胞BTK降解的作用Test Example 1: Effects of Compounds on BTK Degradation in OCI-LY10 Cells
采用Total-BTK Kits(cisbio，63ADK064PEH)试剂盒进行检测，用Blocking reagent stock solution(100X)和Lysis buffer stock solution(4X)配制4X Supplemented Lysis buffer。用Detection buffer、Total-BTK d2 antibody、Total-BTK Eu Cryptate antibody配制Premixed antibody solutions。Total-BTK Kits (cisbio, 63ADK064PEH) kit was used for detection, and 4X Supplemented Lysis buffer was prepared with Blocking reagent stock solution (100X) and Lysis buffer stock solution (4X). Prepare Premixed antibody solutions with Detection buffer, Total-BTK d2 antibody, and Total-BTK Eu Cryptate antibody.
取处于生长状态良好的OCI-LY10细胞，收集至离心管，调整细胞密度至4.17×10 6个/mL，接种于384孔板上(12μL/孔)，细胞培养箱中培养过夜，使用纳升加样仪进行化合物加样，使化合物终浓度为100nM-0.098nM，各浓度2个复孔，同时设置对照。细胞培养箱中继续培养24小时后，加入4μL/孔4X Supplemented Lysis buffer裂解细胞，室温振荡40分钟后，加入4μL/孔Premixed antibody solutions，室温 静置过夜，Envision酶标仪665nm/620nm处检测其荧光值，四参数分析，拟合量效曲线，计算Dmax(最大降解率)。实验结果见表1。 Take OCI-LY10 cells in a good growth state, collect them into centrifuge tubes, adjust the cell density to 4.17× 106 cells/mL, inoculate them on a 384-well plate (12 μL/well), and culture them overnight in a cell culture incubator, using nanoliter The sample adding instrument is used to add the compound, so that the final concentration of the compound is 100nM-0.098nM, and each concentration has 2 duplicate wells, and a control is set at the same time. After continuing to culture in the cell culture incubator for 24 hours, add 4 μL/well 4X Supplemented Lysis buffer to lyse the cells, shake at room temperature for 40 minutes, add 4 μL/well Premixed antibody solutions, let stand overnight at room temperature, and detect its concentration at 665nm/620nm with an Envision microplate reader. Fluorescence value, four-parameter analysis, fitting dose-effect curve, and calculating Dmax (maximum degradation rate). The experimental results are shown in Table 1.
表1 BTK降解活性结果Table 1 BTK degradation activity results
Figure PCTCN2022096512-appb-000200
Figure PCTCN2022096512-appb-000200
试验例2：体外细胞增殖抑制活性Test Example 2: In vitro cell proliferation inhibitory activity
2.1 OCI-LY10细胞增殖抑制活性测定2.1 Determination of OCI-LY10 cell proliferation inhibitory activity
取处于生长状态良好的OCI-LY10细胞，收集至离心管，调整细胞密度至1×10 5个/mL，接种于96孔板上(100μL/孔)，细胞培养箱中培养过夜，使用纳升加样仪进行化合物加样，使化合物终浓度为5000nM-0.31nM，各浓度2个复孔，同时设置对照。细胞培养箱中继续培养72小时后，加入10μL CCK-8(CK04，PP799)，细胞培养箱中孵育2.5小时后，Envision酶标仪450nm处检测其吸光值，四参数分析，拟合量效曲线，计算IC 50。实验结果见表2。 Take OCI-LY10 cells in a good growth state, collect them into centrifuge tubes, adjust the cell density to 1× 105 cells/mL, seed them on 96-well plates (100 μL/well), and culture them overnight in a cell culture incubator, using nanoliter The sample adding instrument is used to add the compound, so that the final concentration of the compound is 5000nM-0.31nM, and each concentration has 2 duplicate wells, and a control is set at the same time. After continuing to culture in the cell incubator for 72 hours, add 10 μL of CCK-8 (CK04, PP799), incubate in the cell incubator for 2.5 hours, detect its absorbance at 450 nm with an Envision microplate reader, analyze with four parameters, and fit the dose-effect curve , to calculate IC 50 . The experimental results are shown in Table 2.
2.2 TMD8-BTK(C481S)细胞增殖抑制活性测定2.2 Determination of TMD8-BTK (C481S) cell proliferation inhibitory activity
取处于生长状态良好的TMD8-BTK(C481S)细胞，收集至离心管，调整细胞密度至8×10 4个/mL，接种于96孔板上(100μL/孔)，细胞培养箱中培养过夜，使用纳升加样仪进行化合物加样，使化合物终浓度为5000nM-0.31nM，各浓度2个复孔，同时设置对照。细胞培养箱中继续培养72小时后，加入10μL CCK-8(CK04，PP799)，细胞培养箱中孵育4小时后，Envision酶标仪450nm处检测其吸光值，四参数分析，拟合量效曲线，计算IC 50。实验结果见表2。 Take TMD8-BTK (C481S) cells in a good growth state, collect them into centrifuge tubes, adjust the cell density to 8× 104 cells/mL, seed them on 96-well plates (100 μL/well), and culture them overnight in a cell culture incubator. The compound was added using a nanoliter sampler, so that the final concentration of the compound was 5000nM-0.31nM, and two replicate wells were prepared for each concentration, and a control was set at the same time. After continuing to culture in the cell incubator for 72 hours, add 10 μL of CCK-8 (CK04, PP799), incubate in the cell incubator for 4 hours, detect its absorbance at 450 nm with an Envision microplate reader, analyze with four parameters, and fit the dose-effect curve , to calculate IC 50 . The experimental results are shown in Table 2.
表2 细胞增殖抑制活性结果Table 2 Cell Proliferation Inhibitory Activity Results
Figure PCTCN2022096512-appb-000201
Figure PCTCN2022096512-appb-000201
注：“-”表示未测定Note: "-" means not determined
试验例3：体外激酶抑制与选择性Test Example 3: Kinase Inhibition and Selectivity in Vitro
3.1 BTK(WT)抑制活性3.1 BTK(WT) inhibitory activity
配制Assay Buffer，其成分为Hepes(Gibco，15630)：50mM、MgCl 2：10mM、DTT：2mM、EGTA：1mM、Tween 20：0.010％。用Assay Buffer配制BTK(WT)激酶(Life，PR5442A)、ATP(Sigma，A7699)和ULight-poly GT(PE，TRF0100-M)工作液。用Detection Buffer(PE，CR97-100)配制EDTA和Eu-labeled anti-phosphotyrosine(PT66)抗体(PE，AD0069)工作液。化合物组和对照组加入6μL相应浓度的BTK(WT)激酶(终浓度为0.003ng/μl)，同时空白组加入6μL Assay Buffer，然后纳升加样仪加入化合物，化合物浓度设置最高为1000nM，4倍稀释，7个浓度梯度，室温孵育30min，接着加入4μL ATP(终浓度为10μM)和ULight-poly GT混合物(终浓度为100nM)，室温孵育2h后，加入5μL EDTA(终浓度为10mM)终止反应，最后加入5μL抗体(终浓度为2nM)，室温孵育1h后，波长665/615nm下检测信号值，四参数分析，拟合量效曲线，计算IC 50。 Assay Buffer was prepared, and its components were Hepes (Gibco, 15630): 50 mM, MgCl 2 : 10 mM, DTT: 2 mM, EGTA: 1 mM, Tween 20: 0.010%. Assay Buffer was used to prepare BTK (WT) kinase (Life, PR5442A), ATP (Sigma, A7699) and ULight-poly GT (PE, TRF0100-M) working solutions. Use Detection Buffer (PE, CR97-100) to prepare EDTA and Eu-labeled anti-phosphotyrosine (PT66) antibody (PE, AD0069) working solution. Add 6 μL of BTK (WT) kinase at the corresponding concentration (final concentration: 0.003 ng/μl) to the compound group and the control group, and add 6 μL Assay Buffer to the blank group, and then add the compound to the nanoliter sampler. Doubling dilution, 7 concentration gradients, incubate at room temperature for 30min, then add 4μL of ATP (final concentration of 10μM) and ULight-poly GT mixture (final concentration of 100nM), after incubation at room temperature for 2h, add 5μL of EDTA (final concentration of 10mM) to stop For the reaction, 5 μL of antibody (final concentration: 2 nM) was added at the end, and after incubation at room temperature for 1 hour, the signal value was detected at a wavelength of 665/615 nm. Four-parameter analysis was performed to fit the dose-effect curve and calculate the IC 50 .
3.2 BTK(C481S)抑制活性3.2 BTK(C481S) inhibitory activity
配制Assay Buffer，其成分为Hepes(Gibco，15630)：50mM、MgCl 2：10mM、DTT：2mM、EGTA：1mM、Tween 20：0.010％。用Assay Buffer配制BTK(C481S)激酶(Carna Biosciences，08-547)、ATP(Sigma，A7699)和ULight-poly GT(PE，TRF0100-M)工作液。用Detection Buffer配制EDTA和Eu-labeled anti-phosphotyrosine(PT66)抗体(PE，AD0069)工作液。化合物组和对照组加入6μL相应浓度的BTK(C481S)激酶(终浓度为0.005ng/μl)，同时空白组加入6μL Assay Buffer，然后纳升加样仪加入化合物，化合物浓度设置最高为1000nM，4倍稀释，7个浓度梯度，室温孵育30min，接着加入4μL ATP(终浓度为10μM)和ULight-poly GT混合物(终浓度为100nM)，室温孵育2h后，加入5μL EDTA(终浓度为10mM)终止反应，最后加入5μL抗体(终浓度为2nM)，室温孵育1h后，波长665/615nm下检测信号值，四参数分析，拟合量效曲线，计算IC 50。 Assay Buffer was prepared, and its components were Hepes (Gibco, 15630): 50 mM, MgCl 2 : 10 mM, DTT: 2 mM, EGTA: 1 mM, Tween 20: 0.010%. Assay Buffer was used to prepare BTK (C481S) kinase (Carna Biosciences, 08-547), ATP (Sigma, A7699) and ULight-poly GT (PE, TRF0100-M) working solutions. Use Detection Buffer to prepare EDTA and Eu-labeled anti-phosphotyrosine (PT66) antibody (PE, AD0069) working solution. Add 6 μL of BTK (C481S) kinase at the corresponding concentration (final concentration: 0.005 ng/μl) to the compound group and the control group, and add 6 μL Assay Buffer to the blank group, and then add the compound to the nanoliter sampler. The compound concentration is set up to 1000 nM. Doubling dilution, 7 concentration gradients, incubate at room temperature for 30min, then add 4μL of ATP (final concentration of 10μM) and ULight-poly GT mixture (final concentration of 100nM), after incubation at room temperature for 2h, add 5μL of EDTA (final concentration of 10mM) to stop For the reaction, 5 μL of antibody (final concentration: 2 nM) was added at the end, and after incubation at room temperature for 1 hour, the signal value was detected at a wavelength of 665/615 nm. Four-parameter analysis was performed to fit the dose-effect curve and calculate the IC 50 .
3.3 EGFR抑制活性3.3 EGFR inhibitory activity
配制Assay Buffer，其成分为Hepes(Gibco，15630)：50mM、MgCl 2：10mM、DTT：2mM、EGTA：1mM、Tween 20：0.010％。用Assay Buffer配制EGFR激酶(Carna，08-115)、ATP(Sigma，A7699)和ULight-poly GT(PE，TRF0100-M)工作液。用Detection Buffer配制EDTA和Eu-labeled anti-phosphotyrosine(PT66)抗体(PE，AD0069)工作液。化合物组和对照组加入6μL相应浓度的EGFR激酶(终浓度为0.006ng/μl)，同时空白组加入6μL Assay Buffer，然后纳升加样仪加入化合物，化合物浓度设置最高为1000nM，4倍稀释，7个浓度梯度，室温孵育30min，接着加入4μL ATP(终浓度为5μM)和ULight-poly GT混合物(终浓度为100nM)，室温孵育2h后，加入5μL EDTA(终浓度为10mM)终止反应，最后加入5μL抗体(终浓度为2nM)，室温孵育1h后，波长665/615nm下检测信号值，四参数分析，拟合量效曲线，计算IC 50。 Assay Buffer was prepared, and its components were Hepes (Gibco, 15630): 50 mM, MgCl 2 : 10 mM, DTT: 2 mM, EGTA: 1 mM, Tween 20: 0.010%. Assay Buffer was used to prepare EGFR kinase (Carna, 08-115), ATP (Sigma, A7699) and ULight-poly GT (PE, TRF0100-M) working solutions. Use Detection Buffer to prepare EDTA and Eu-labeled anti-phosphotyrosine (PT66) antibody (PE, AD0069) working solution. Add 6 μL of corresponding concentration of EGFR kinase (final concentration is 0.006ng/μl) to the compound group and control group, and add 6 μL Assay Buffer to the blank group at the same time, then add the compound to the nanoliter sampler, the compound concentration is set up to 1000nM, 4-fold dilution, Seven concentration gradients were incubated at room temperature for 30 min, followed by adding 4 μL of ATP (final concentration of 5 μM) and ULight-poly GT mixture (final concentration of 100 nM), after incubation at room temperature for 2 h, adding 5 μL of EDTA (final concentration of 10 mM) to stop the reaction, and finally Add 5 μL of antibody (final concentration is 2nM), incubate at room temperature for 1 hour, detect signal value at wavelength 665/615nm, perform four-parameter analysis, fit dose-effect curve, and calculate IC 50 .
3.4 TEC抑制活性3.4 TEC inhibitory activity
配制Assay Buffer，其成分为Hepes(Gibco，15630)：50mM、MgCl 2：10mM、DTT：2mM、EGTA：1mM、Tween 20：0.010％。用Assay Buffer配制TEC激酶(Carna，08-115)、ATP(Sigma，A7699)和ULight-poly GT(PE，TRF0100-M)工作液。用Detection Buffer配制EDTA和Eu-labeled anti-phosphotyrosine(PT66)抗体(PE，AD0069)工作液。化合物组和对照组加入6μL相应浓度的TEC激酶(终浓度为0.01ng/μl)，同时空白组加入6μL Assay Buffer，然后纳升加样仪加入化合物，化合物浓度设置最高为1000nM，4倍稀释，7个浓度梯度，室温孵育30min，接着加入4μL ATP(终浓度为10μM)和ULight-poly GT混合物(终浓度为100nM)，室温孵育2h后，加入5μL EDTA(终浓度为10mM)终止反应，最后加入5μL抗体(终浓度为2nM)，室温孵育1h后，波长665/615nm下检测信号值，四参数分析，拟合量效曲线，计算IC 50。实验结果见表3。 Assay Buffer was prepared, and its components were Hepes (Gibco, 15630): 50 mM, MgCl 2 : 10 mM, DTT: 2 mM, EGTA: 1 mM, Tween 20: 0.010%. Assay Buffer was used to prepare TEC kinase (Carna, 08-115), ATP (Sigma, A7699) and ULight-poly GT (PE, TRF0100-M) working solutions. Use Detection Buffer to prepare EDTA and Eu-labeled anti-phosphotyrosine (PT66) antibody (PE, AD0069) working solution. Add 6 μL of corresponding concentration of TEC kinase (final concentration is 0.01ng/μl) to the compound group and the control group, and add 6 μL Assay Buffer to the blank group, and then add the compound to the nanoliter sampler. Seven concentration gradients were incubated at room temperature for 30 min, followed by adding 4 μL of ATP (final concentration of 10 μM) and ULight-poly GT mixture (final concentration of 100 nM), after incubation at room temperature for 2 h, adding 5 μL of EDTA (final concentration of 10 mM) to terminate the reaction, and finally Add 5 μL of antibody (final concentration is 2nM), incubate at room temperature for 1 hour, detect signal value at wavelength 665/615nm, perform four-parameter analysis, fit dose-effect curve, and calculate IC 50 . The experimental results are shown in Table 3.
表3 体外激酶抑制活性Table 3 In vitro kinase inhibitory activity
Figure PCTCN2022096512-appb-000202
Figure PCTCN2022096512-appb-000202
Figure PCTCN2022096512-appb-000203
Figure PCTCN2022096512-appb-000203
注：“-”表示未测定Note: "-" means not determined
试验例4：体外肝微位体代谢稳定性Test Example 4: Metabolic stability of liver microsomes in vitro
肝微粒体温孵样本按照如下制备：将PBS缓冲液(pH 7.4)、肝微粒体溶液(0.5mg/mL)、受试化合物及NADPH+MgCl 2溶液进行混合，于37℃及300rpm孵育1小时。0小时样本按照如下制备：将PBS缓冲液(pH 7.4)、肝微粒体溶液(0.5mg/mL)、及受试化合物进行混合。向各样本中加入含内标的乙腈溶液经蛋白沉淀制备上清液，用50％的乙腈水(v/v)稀释后用于LC/MS/MS测定。结果见表4。 Liver microsome warm-incubated samples were prepared as follows: PBS buffer (pH 7.4), liver microsome solution (0.5 mg/mL), test compound and NADPH+MgCl 2 solution were mixed, and incubated at 37°C and 300rpm for 1 hour. 0 hour samples were prepared as follows: PBS buffer (pH 7.4), liver microsome solution (0.5 mg/mL), and test compound were mixed. Acetonitrile solution containing internal standard was added to each sample to prepare supernatant by protein precipitation, which was diluted with 50% acetonitrile water (v/v) and used for LC/MS/MS determination. The results are shown in Table 4.
表4 体外肝微粒体代谢稳定性Table 4 Metabolic stability of liver microsomes in vitro
Figure PCTCN2022096512-appb-000204
Figure PCTCN2022096512-appb-000204
注：“-”表示未测定Note: "-" means not determined
试验例5:小鼠药代动力学Test example 5: mouse pharmacokinetics
ICR小鼠，体重18～22g，适应3～5天后，随机分组，每组9只，按10mg/kg剂量灌胃给予待测化合物的溶液。采血时间点为给药后15min、30min、1h、2h、3h、4h、6h、8h、10h、24h，于眼眶取血制备待测血浆样品。吸取20μL待测血浆样品和标准曲线样品，加入含内标的乙腈溶液经蛋白沉淀得到上清液，用50％的乙腈水(v/v)稀释后用于LC/MS/MS测定。采用非房室模型拟合，药代参数见表5。ICR mice, with a body weight of 18-22 g, were randomly divided into groups after 3-5 days of adaptation, with 9 mice in each group, and were intragastrically administered the solution of the compound to be tested at a dose of 10 mg/kg. The blood collection time points were 15min, 30min, 1h, 2h, 3h, 4h, 6h, 8h, 10h, and 24h after administration, and blood was collected from the orbit to prepare plasma samples to be tested. Aspirate 20 μL of the plasma sample to be tested and the standard curve sample, add an acetonitrile solution containing an internal standard to obtain a supernatant through protein precipitation, and dilute it with 50% acetonitrile water (v/v) for LC/MS/MS determination. The non-compartmental model was used for fitting, and the pharmacokinetic parameters are shown in Table 5.
表5 药代动力学研究结果Table 5 Pharmacokinetic study results
Figure PCTCN2022096512-appb-000205
Figure PCTCN2022096512-appb-000205
试验例6：体内药效研究Test Example 6: In Vivo Drug Efficacy Study
TMD-8小鼠皮下移植瘤，浓度1×10 8/ml*0.1ml/只，在无菌条件下，接种于NOD-SCID小鼠右侧腋窝下。皮下移植瘤接种后待肿瘤瘤体积长至100-300mm 3左右将动物分组： TMD-8 mice subcutaneously transplanted tumors at a concentration of 1×10 8 /ml*0.1ml per mouse, and inoculated them under the right axilla of NOD-SCID mice under sterile conditions. After inoculation of subcutaneous transplanted tumors, wait until the tumor volume grows to about 100-300 mm 3 and divide the animals into groups:
模型组：溶媒，6只小鼠；化合物50给予组：10mg/kg，qd，i.g.，6只小鼠。Model group: vehicle, 6 mice; Compound 50 administration group: 10 mg/kg, qd, i.g., 6 mice.
按4ml/kg的体积分别灌胃给予溶媒或待测化合物，每日1次，连续给药21天。每周测2-3次瘤体积，同时称鼠重，记录数据；每日观察动物表现。待全部给药结束后，第22天处死动物，剥瘤称重。The vehicle or the compound to be tested were intragastrically administered at a volume of 4 ml/kg, once a day, for 21 consecutive days. The tumor volume was measured 2-3 times a week, and the mice were weighed at the same time, and the data was recorded; the performance of the animals was observed daily. After all the administration was completed, the animals were sacrificed on the 22nd day, and the tumors were stripped and weighed.
使用下面公式计算肿瘤体积和抑瘤率：Tumor volume and tumor inhibition rate were calculated using the following formula:
肿瘤体积(TV)＝(长×宽 2)/2。 Tumor volume (TV)=(length×width 2 )/2.
抑瘤率(tumor growth inhibition,TGI)＝(1-治疗组瘤重量/模型组瘤重量)×100％。Tumor growth inhibition (TGI)=(1-Tumor weight in treatment group/Tumor weight in model group)×100%.
试验结果表明，本申请实施例的化合物可以在一定程度上抑制肿瘤体积的增加；在第22天的TGI在40％-90％之间。The test results show that the compound of the embodiment of the present application can inhibit the increase of tumor volume to a certain extent; the TGI on the 22nd day is between 40% and 90%.
实验例7：化合物对TMD8细胞内BTK蛋白降解动力学测试Experimental Example 7: Kinetic Test of Compounds on BTK Protein Degradation in TMD8 Cells
取处于生长状态良好的TMD8细胞，收集至离心管，调整细胞密度至4.17×10 6个/mL，接种于384孔板上(12μL/孔)，使用纳升加样仪进行化合物加样，使化合物终浓度为500nM-7.8nM，各浓度2个复孔，同时设置对照。细胞培养箱中分别继续培养6h、12h、23h、36h、48h后，加入4μL/孔裂解液(cisbio，63ADK064PEH)，室温振荡40分钟后，加入4μL/孔检测缓冲液配制的预先1：1体积混合的抗体(cisbio，63ADK064PEH)，离心混匀，室温静置过夜。Envision酶标仪665nm/620nm处检测其荧光值，计算降解率。 Take TMD8 cells in a good growth state, collect them into centrifuge tubes, adjust the cell density to 4.17× 106 cells/mL, inoculate them on 384-well plates (12 μL/well), and use a nanoliter sampler to add samples to make The final concentration of the compound is 500nM-7.8nM, each concentration has 2 duplicate wells, and a control is set at the same time. After continuing to culture in the cell incubator for 6h, 12h, 23h, 36h, and 48h, add 4μL/well lysate (cisbio, 63ADK064PEH), shake at room temperature for 40 minutes, add 4μL/well detection buffer prepared in advance 1:1 volume The mixed antibodies (cisbio, 63ADK064PEH) were centrifuged to mix well, and left to stand overnight at room temperature. The fluorescence value was detected at 665nm/620nm with Envision microplate reader, and the degradation rate was calculated.
结果如下：化合物浓度为500nM或125nM时，本申请实施例的化合物的23h后的降解率大于60％，更优的是大于90％；48h后的降解率大于80％，更优的是大于95％。The results are as follows: when the compound concentration is 500nM or 125nM, the degradation rate of the compound of the embodiment of the present application is greater than 60% after 23h, more preferably greater than 90%; the degradation rate after 48h is greater than 80%, more preferably greater than 95% %.
本领域技术人员将认识到，本公开的范围并不限于上文描述的各种具体实施方式和实施例，而是能够在不脱离本公开的精神和构思的情况下，进行各种修改、替换、或重新组合，这都落入了本公开的保护范围内。Those skilled in the art will appreciate that the scope of the present disclosure is not limited to the various specific implementations and examples described above, but various modifications and substitutions can be made without departing from the spirit and concept of the present disclosure. , or recombination, all fall within the protection scope of the present disclosure.

Claims (15)

  1. 式I化合物、其立体异构体或其药学上可接受的盐，A compound of formula I, its stereoisomer or a pharmaceutically acceptable salt thereof,
    Figure PCTCN2022096512-appb-100001
    Figure PCTCN2022096512-appb-100001
    其中，in,
    Figure PCTCN2022096512-appb-100002
    表示单键或者双键；
    Figure PCTCN2022096512-appb-100002
    Indicates a single bond or a double bond;
    L 1选自-O-或-NHCO-； L 1 is selected from -O- or -NHCO-;
    每个R 1各自独立地选自卤素、-CN、C 1-4烷氧基、或任选地被一个或多个卤素取代的C 1-4烷基； each R is independently selected from halogen, -CN, C 1-4 alkoxy, or C 1-4 alkyl optionally substituted with one or more halogens;
    每个R 2各自独立地选自卤素或C 1-4烷基； each R 2 is independently selected from halogen or C 1-4 alkyl;
    m和n分别独立地选自0、1、2、或3；m and n are independently selected from 0, 1, 2, or 3;
    X选自CH或N；X is selected from CH or N;
    X 1、X 2、或X 3分别独立地选自CH、C、或N； X 1 , X 2 , or X 3 are independently selected from CH, C, or N;
    X 4选自-CH 2-或-C(＝O)-； X 4 is selected from -CH 2 - or -C(=O)-;
    Cy选自任选地被一个或多个卤素或＝O取代的如下基团：7-12元螺环烷基、7-12元杂螺环烷基、6-12元并环烷基、或6-12元杂并环烷基；Cy is selected from the following groups optionally substituted by one or more halogens or =O: 7-12 membered spirocycloalkyl, 7-12 membered heterospirocycloalkyl, 6-12 membered and cycloalkyl, or 6-12 membered heterocycloalkyl;
    LNK基团选自-Ak 1-、-Ak 2-Cy 1-Cy 2-、或-Ak 2-Cy 1-； The LNK group is selected from -Ak 1 -, -Ak 2 -Cy 1 -Cy 2 -, or -Ak 2 -Cy 1 -;
    Ak 1选自键或-C 1-12烷基-，所述-C 1-12烷基-中的1个或者多个碳原子任选地被O或N原子替换； Ak is selected from a bond or -C 1-12 alkyl-, one or more carbon atoms in the -C 1-12 alkyl- are optionally replaced by O or N atoms;
    Ak 2选自键或-C 1-6烷基-； Ak 2 is selected from a bond or -C 1-6 alkyl-;
    Cy 1和Cy 2分别独立地选自3-12元环烷基或3-12元杂环烷基，所述环烷基或杂环烷基任选地被一个或者多个卤素取代； Cy 1 and Cy 2 are each independently selected from 3-12 membered cycloalkyl or 3-12 membered heterocycloalkyl, the cycloalkyl or heterocycloalkyl optionally substituted by one or more halogens;
    R 3选自氢、卤素、氨基、或C 1-4烷基。 R 3 is selected from hydrogen, halogen, amino, or C 1-4 alkyl.
  2. 根据权利要求1所述的式I化合物、其立体异构体或其药学上可接受的盐，其中每个R 1各自独立地选自氟、氯、-CN、C 1-3烷氧基、或任选地被一个或多个F或者氯或溴或碘取代的C 1-3烷基； The compound of formula I according to claim 1, its stereoisomer or pharmaceutically acceptable salt thereof, wherein each R is independently selected from fluorine, chlorine, -CN, C 1-3 alkoxy, or C 1-3 alkyl optionally substituted by one or more F or chlorine or bromine or iodine;
    或者，每个R 1各自独立地选自氟、氯、-CN、甲氧基、乙氧基、或任选地被一个或多个F或者氯取代的甲基； Alternatively, each R is independently selected from fluoro, chloro, -CN, methoxy, ethoxy, or methyl optionally substituted with one or more F or chloro;
    或者，每个R 1各自独立地选自氯或-CF 3。 Alternatively, each R 1 is independently selected from chlorine or -CF 3 .
  3. 根据权利要求1或2所述的式I化合物、其立体异构体或其药学上可接受的盐，其中每个R 2各自独立地选自氟、氯、溴、碘、或C 1-3烷基； A compound of formula I according to claim 1 or 2, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein each R is independently selected from fluorine, chlorine, bromine, iodine, or C 1-3 alkyl;
    或者，每个R 2各自独立地选自氟、氯、甲基、或乙基； Alternatively, each R is independently selected from fluoro, chloro, methyl, or ethyl;
    或者，R 2选自氟。 Alternatively, R2 is selected from fluorine.
  4. 根据权利要求1-3任一项所述的式I化合物、其立体异构体或其药学上可接受的盐，其中m选自0、1、或2；或者，m选自0或1；A compound of formula I according to any one of claims 1-3, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein m is selected from 0, 1, or 2; or, m is selected from 0 or 1;
    任选地，n选自0、1、或2；或者，n选自0或1。Optionally, n is selected from 0, 1, or 2; alternatively, n is selected from 0 or 1.
  5. 根据权利要求1-4任一项所述的式I化合物、其立体异构体或其药学上可接受的盐，其中X 1选自C或N； A compound of formula I according to any one of claims 1-4, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein X is selected from C or N;
    任选地，X 2选自C或N； Optionally, X is selected from C or N;
    任选地，X 3选自CH或N； Optionally, X is selected from CH or N;
    任选地，X 1选自C，X 2选自N，X 3选自CH；或者，X 1选自N，X 2选自C，X 3选自N。 Optionally, X1 is selected from C, X2 is selected from N, X3 is selected from CH; alternatively, X1 is selected from N, X2 is selected from C, X3 is selected from N.
  6. 根据权利要求1-5任一项所述的式I化合物、其立体异构体或其药学上可接受的盐，其中Cy选自任选地被一个或多个卤素或＝O取代的如下基团：7-12元螺二环烷基、7-12元杂螺二环烷基、6-12元并二环烷基或6-12元杂并二环烷基；The compound of formula I according to any one of claims 1-5, its stereoisomer or pharmaceutically acceptable salt thereof, wherein Cy is selected from the following groups optionally substituted by one or more halogen or =O Group: 7-12 membered spirobicycloalkyl, 7-12 membered heterospirobicycloalkyl, 6-12 membered heterobicycloalkyl or 6-12 membered heterobicycloalkyl;
    或者，Cy选自任选地被一个或多个卤素或＝O取代的如下基团：7-12元螺二环烷基、7-12元杂螺二环烷基、7-10元并二环烷基或6-10元杂并二环烷基；Alternatively, Cy is selected from the following groups optionally substituted by one or more halogens or =O: 7-12 membered spirobicycloalkyl, 7-12 membered heterospirobicycloalkyl, 7-10 membered anabicycloalkyl Cycloalkyl or 6-10 membered heterobicycloalkyl;
    或者，Cy选自任选地被一个或多个卤素或＝O取代的如下基团：7元、8元、9元、10元、11元或12元杂螺二环烷基，或6元、7元、8元、9元或10元杂并二环烷基；Alternatively, Cy is selected from the following groups optionally substituted with one or more halogens or =O: 7-, 8-, 9-, 10-, 11- or 12-membered heterospirobicycloalkyl, or 6-membered , 7-membered, 8-membered, 9-membered or 10-membered heterobicycloalkyl;
    或者，Cy选自任选地被1个氟原子或＝O取代的含有1-2个N原子的7-11元杂螺二环烷基，或含有 1-2个N原子或O原子的6-10元杂并二环烷基；Alternatively, Cy is selected from a 7-11 membered heterospirobicycloalkyl group containing 1-2 N atoms optionally substituted by 1 fluorine atom or =O, or a 6-membered group containing 1-2 N atoms or O atoms. -10-membered heterobicycloalkyl;
    或者，Cy选自任选地被一个或多个卤素或＝O取代的如下基团：二氮杂螺[3.5]壬烷、氮杂螺[3.5]壬烷、氮杂螺[5.5]十一烷、氮杂螺[3.3]庚烷、氮杂螺[3.4]辛烷、二氮杂螺[3.3]庚烷、氮杂螺[4.5]癸烷、二氮杂螺[4.5]癸烷、氮杂螺[5.5]十一烷、八氢环戊[c]吡咯、呋喃[3,4-b]吡咯、氮杂双环[3.1.0]己烷、氮杂双环[3.2.0]庚烷、八氢-1H-异吲哚、十氢异喹啉、或八氢-1H-环戊[c]吡啶；Alternatively, Cy is selected from the following groups optionally substituted with one or more halogens or =O: diazaspiro[3.5]nonane, azaspiro[3.5]nonane, azaspiro[5.5]undeca azaspiro[3.3]heptane, azaspiro[3.4]octane, diazaspiro[3.3]heptane, azaspiro[4.5]decane, diazaspiro[4.5]decane, nitrogen Heterospiro[5.5]undecane, octahydrocyclopenta[c]pyrrole, furo[3,4-b]pyrrole, azabicyclo[3.1.0]hexane, azabicyclo[3.2.0]heptane, Octahydro-1H-isoindole, decahydroisoquinoline, or octahydro-1H-cyclopenta[c]pyridine;
    或者，Cy选自任选地被一个或多个氟或＝O取代的如下基团：
    Figure PCTCN2022096512-appb-100003
    Figure PCTCN2022096512-appb-100004
    Alternatively, Cy is selected from the following groups optionally substituted with one or more fluorine or =O:
    Figure PCTCN2022096512-appb-100003
    Figure PCTCN2022096512-appb-100004
    或者，Cy选自
    Figure PCTCN2022096512-appb-100005
    Figure PCTCN2022096512-appb-100006
    Alternatively, Cy is selected from
    Figure PCTCN2022096512-appb-100005
    Figure PCTCN2022096512-appb-100006
  7. 根据权利要求1-6任一项所述的式I化合物、其立体异构体或其药学上可接受的盐，其中Ak 1选自键或-C 1-10烷基-，所述-C 1-10烷基-中的1个或者多个碳原子任选地被O或者N原子替换； A compound of formula I according to any one of claims 1-6, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein Ak is selected from a bond or -C 1-10 alkyl-, said -C One or more carbon atoms in 1-10 alkyl groups are optionally replaced by O or N atoms;
    或者，Ak 1选自键或-C 1-10烷基-，所述-C 1-10烷基-中的1-5个碳原子任选地被O或者N原子替换； Alternatively, Ak is selected from a bond or -C 1-10 alkyl-, and 1-5 carbon atoms in the -C 1-10 alkyl- are optionally replaced by O or N atoms;
    或者，Ak 1选自键、-C 1-9烷基-、-C 1-9烷基-O-、-C 1-9烷基-NH-、-C 1-5烷基-O-C 1-5烷基-O-、-C 1-3烷基-O-C 1-3烷基-O-C 1-3烷基-O-、或-C 1-3烷基-O-C 1-3烷基-O-C 1-3烷基-NH-； Alternatively, Ak 1 is selected from bond, -C 1-9 alkyl-, -C 1-9 alkyl-O-, -C 1-9 alkyl-NH-, -C 1-5 alkyl-OC 1- 5 Alkyl-O-, -C 1-3 Alkyl-OC 1-3 Alkyl-OC 1-3 Alkyl-O-, or -C 1-3 Alkyl-OC 1-3 Alkyl-OC 1 -3 Alkyl-NH-;
    或者，Ak 1选自键、-C 1-3烷基-、-C 8-9烷基-、-C 2-8烷基-O-、-C 2-8烷基-NH-、-C 2-4烷基-O-C 3-5烷基-O-、-C 1-2烷基-O-C 1-2烷基-O-C 1-2烷基-O-、或-C 1-2烷基-O-C 1-2烷基-O-C 1-2烷基-NH-； Alternatively, Ak is selected from bond, -C 1-3 alkyl-, -C 8-9 alkyl-, -C 2-8 alkyl-O- , -C 2-8 alkyl -NH-, -C 2-4 Alkyl-OC 3-5 Alkyl-O-, -C 1-2 Alkyl-OC 1-2 Alkyl-OC 1-2 Alkyl-O-, or -C 1-2 Alkyl- OC 1-2 alkyl-OC 1-2 alkyl-NH-;
    或者，Ak 1选自键、-CH 2-、-(CH 2) 2-、-(CH 2) 9-、-(CH 2) 2O-、-(CH 2) 3O-、-(CH 2) 4O-、-(CH 2) 5O-、-(CH 2) 8O-、-(CH 2) 4NH-、-(CH 2) 8NH-、-(CH 2) 2O(CH 2) 5O-、-(CH 2) 2O(CH 2) 3O-、-(CH 2) 3O(CH 2) 3O-、-(CH 2) 4O(CH 2) 4O-、-(CH 2) 2O(CH 2) 2O(CH 2) 2O-、或-(CH 2) 2O(CH 2) 2O(CH 2) 2NH-。 Alternatively, Ak 1 is selected from a bond, -CH 2 -, -(CH 2 ) 2 -, -(CH 2 ) 9 -, -(CH 2 ) 2 O-, -(CH 2 ) 3 O-, -(CH 2 ) 4 O-, -(CH 2 ) 5 O-, -(CH 2 ) 8 O-, -(CH 2 ) 4 NH-, -(CH 2 ) 8 NH-, -(CH 2 ) 2 O( CH 2 ) 5 O-, -(CH 2 ) 2 O(CH 2 ) 3 O-, -(CH 2 ) 3 O(CH 2 ) 3 O-, -(CH 2 ) 4 O(CH 2 ) 4 O -, -(CH 2 ) 2 O(CH 2 ) 2 O(CH 2 ) 2 O-, or -(CH 2 ) 2 O(CH 2 ) 2 O(CH 2 ) 2 NH-.
  8. 根据权利要求1-7任一项所述的式I化合物、其立体异构体或其药学上可接受的盐，其中Ak 2选自键或-C 1-4烷基-； A compound of formula I according to any one of claims 1-7, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein Ak is selected from a bond or -C 1-4 alkyl-;
    或者，Ak 2选自键或-C 1-3烷基-； Alternatively, Ak is selected from a bond or -C 1-3 alkyl-;
    或者，Ak 2选自键、-CH 2-、或-(CH 2) 2-； Alternatively, Ak 2 is selected from a bond, -CH 2 -, or -(CH 2 ) 2 -;
    或者，Ak 2选自键或-CH 2-。 Alternatively, Ak 2 is selected from a bond or -CH 2 -.
  9. 根据权利要求1-8任一项所述的式I化合物、其立体异构体或其药学上可接受的盐，其中Cy 1与Cy 2分别独立地选自3-10元环烷基或3-10元杂环烷基，所述环烷基或杂环烷基任选地被一个或者多个卤素取代； According to the compound of formula I described in any one of claims 1-8, its stereoisomer or pharmaceutically acceptable salt thereof, wherein Cy 1 and Cy 2 are independently selected from 3-10 membered cycloalkyl groups or 3 -10 membered heterocycloalkyl, said cycloalkyl or heterocycloalkyl is optionally substituted by one or more halogens;
    或者，Cy 1与Cy 2分别独立地选自3-8元环烷基或3-8元杂环烷基，所述环烷基或杂环烷基任选地被一个或者多个卤素取代； Alternatively, Cy 1 and Cy 2 are independently selected from 3-8 membered cycloalkyl or 3-8 membered heterocycloalkyl, which are optionally substituted by one or more halogens;
    或者，Cy 1与Cy 2分别独立地选自3-6元环烷基或3-6元杂环烷基，所述环烷基或杂环烷基任选地被一个或者多个卤素取代； Alternatively, Cy 1 and Cy 2 are independently selected from 3-6 membered cycloalkyl or 3-6 membered heterocycloalkyl, which are optionally substituted by one or more halogens;
    或者，Cy 1与Cy 2分别独立地选自4-6元环烷基或4-6元杂环烷基，所述环烷基或杂环烷基任选地被一个或者多个卤素取代； Alternatively, Cy 1 and Cy 2 are independently selected from 4-6 membered cycloalkyl or 4-6 membered heterocycloalkyl, which are optionally substituted by one or more halogens;
    或者，Cy 1与Cy 2分别独立地选自4-6元杂环烷基，所述杂环烷基任选地被一个或者多个卤素取代； Alternatively, Cy 1 and Cy 2 are independently selected from 4-6 membered heterocycloalkyl groups, which are optionally substituted by one or more halogens;
    或者，Cy 1和Cy 2分别独立地选自含有1-2个选自N或O或S原子的杂原子的4-6元杂环烷基； Alternatively, Cy 1 and Cy 2 are independently selected from 4-6 membered heterocycloalkyls containing 1-2 heteroatoms selected from N or O or S atoms;
    或者，Cy 1与Cy 2分别独立地选自氮杂环丁烷基、吡咯烷基、哌啶环基、哌嗪环基或氮杂双环[3.1.0]己烷基，所述氮杂环丁烷基、吡咯烷基、哌啶环基、哌嗪环基或氮杂双环[3.1.0]己烷基任选地被一个或者多个卤素取代； Alternatively, Cy 1 and Cy 2 are independently selected from azetidinyl group, pyrrolidinyl group, piperidine ring group, piperazine ring group or azabicyclo[3.1.0]hexyl group. Butyl group, pyrrolidinyl group, piperidine ring group, piperazine ring group or azabicyclo[3.1.0]hexyl group are optionally substituted by one or more halogens;
    或者，Cy 1与Cy 2分别独立地选自
    Figure PCTCN2022096512-appb-100007
    Figure PCTCN2022096512-appb-100008
    所述
    Figure PCTCN2022096512-appb-100009
    Figure PCTCN2022096512-appb-100010
    任选地被一个或者多个卤素取代；     Or, Cy 1 and Cy 2 are independently selected from
    Figure PCTCN2022096512-appb-100007
    Figure PCTCN2022096512-appb-100008
    said
    Figure PCTCN2022096512-appb-100009
    Figure PCTCN2022096512-appb-100010
    optionally substituted by one or more halogens;
    或者，Cy 1与Cy 2分别独立地选自
    Figure PCTCN2022096512-appb-100011
    Figure PCTCN2022096512-appb-100012
    Or, Cy 1 and Cy 2 are independently selected from
    Figure PCTCN2022096512-appb-100011
    Figure PCTCN2022096512-appb-100012
    任选地，Cy 2选自氮杂环丁烷基、吡咯烷基、或哌啶环基； Optionally, Cy 2 is selected from azetidinyl, pyrrolidinyl, or piperidine ring groups;
    或者，Cy 2选自氮杂环丁烷基； Alternatively, Cy 2 is selected from azetidinyl;
    或者，Cy 2选自
    Figure PCTCN2022096512-appb-100013
    Alternatively, Cy 2 is selected from
    Figure PCTCN2022096512-appb-100013
  10. 根据权利要求1-9任一项所述的式I化合物、其立体异构体或其药学上可接受的盐，其中-Ak 2-Cy 1-Cy 2-选自
    Figure PCTCN2022096512-appb-100014
    Figure PCTCN2022096512-appb-100015
    The compound of formula I according to any one of claims 1-9, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein -Ak 2 -Cy 1 -Cy 2 - is selected from
    Figure PCTCN2022096512-appb-100014
    Figure PCTCN2022096512-appb-100015
    任选地，-Ak 2-Cy 1-选自
    Figure PCTCN2022096512-appb-100016
    Figure PCTCN2022096512-appb-100017
    Optionally, -Ak 2 -Cy 1 -is selected from
    Figure PCTCN2022096512-appb-100016
    Figure PCTCN2022096512-appb-100017
    任选地，LNK选自键、-CH 2-、-(CH 2) 2-、-(CH 2) 9-、-(CH 2) 2O-、-(CH 2) 3O-、-(CH 2) 4O-、-(CH 2) 5O-、-(CH 2) 8O-、-(CH 2) 4NH-、-(CH 2) 8NH-、-(CH 2) 2O(CH 2) 5O-、-(CH 2) 2O(CH 2) 3O-、-(CH 2) 3O(CH 2) 3O-、-(CH 2) 4O-(CH 2) 4O-、-(CH 2) 2O(CH 2) 2O(CH 2) 2O-、-(CH 2) 2O(CH 2) 2O(CH 2) 2NH-、
    Figure PCTCN2022096512-appb-100018
    Figure PCTCN2022096512-appb-100019
    Optionally, LNK is selected from a bond, -CH 2 -, -(CH 2 ) 2 -, -(CH 2 ) 9 -, -(CH 2 ) 2 O-, -(CH 2 ) 3 O-, -( CH 2 ) 4 O-, -(CH 2 ) 5 O-, -(CH 2 ) 8 O-, -(CH 2 ) 4 NH-, -(CH 2 ) 8 NH-, -(CH 2 ) 2 O (CH 2 ) 5 O-, -(CH 2 ) 2 O(CH 2 ) 3 O-, -(CH 2 ) 3 O(CH 2 ) 3 O-, -(CH 2 ) 4 O-(CH 2 ) 4 O-, -(CH 2 ) 2 O(CH 2 ) 2 O(CH 2 ) 2 O-, -(CH 2 ) 2 O(CH 2 ) 2 O(CH 2 ) 2 NH-,
    Figure PCTCN2022096512-appb-100018
    Figure PCTCN2022096512-appb-100019
    和/或，
    Figure PCTCN2022096512-appb-100020
    选自-Cy-Ak 1-、-Cy-Ak 2-Cy 1-Cy 2-、或-Cy-Ak 2-Cy 1-；     and / or,
    Figure PCTCN2022096512-appb-100020
    selected from -Cy-Ak 1 -, -Cy-Ak 2 -Cy 1 -Cy 2 -, or -Cy-Ak 2 -Cy 1 -;
    任选地，
    Figure PCTCN2022096512-appb-100021
    选自-Cy-Ak 1-、-Cy-Cy 1-Cy 2-、-Cy-CH 2-Cy 1-、-Cy-(CH 2) 2-Cy 1-、或-Cy-Cy 1-；     optionally,
    Figure PCTCN2022096512-appb-100021
    selected from -Cy-Ak 1 -, -Cy-Cy 1 -Cy 2 -, -Cy-CH 2 -Cy 1 -, -Cy-(CH 2 ) 2 -Cy 1 -, or -Cy-Cy 1 -;
    任选地，
    Figure PCTCN2022096512-appb-100022
    选自
    Figure PCTCN2022096512-appb-100023
    Figure PCTCN2022096512-appb-100024
    optionally,
    Figure PCTCN2022096512-appb-100022
    selected from
    Figure PCTCN2022096512-appb-100023
    Figure PCTCN2022096512-appb-100024
    Figure PCTCN2022096512-appb-100025
    Figure PCTCN2022096512-appb-100025
    Figure PCTCN2022096512-appb-100026
    Figure PCTCN2022096512-appb-100026
  11. 根据权利要求1-10任一项所述的式I化合物、其立体异构体或其药学上可接受的盐，R 3选自氢、卤素、氨基、或C 1-3烷基；或者，R 3选自氢、氟、氯、溴、碘、或氨基；或者，R 3选自氢、氟、或氨基。 According to the compound of formula I described in any one of claims 1-10, its stereoisomer or pharmaceutically acceptable salt thereof, R is selected from hydrogen, halogen, amino, or C 1-3 alkyl; or, R is selected from hydrogen, fluorine, chlorine, bromine, iodine, or amino; alternatively, R is selected from hydrogen, fluorine, or amino.
  12. 根据权利要求1-11任一项所述的式I化合物、其立体异构体或其药学上可接受的盐，其选自式II化合物、式II-1化合物、式III化合物、式IV化合物、式III-1化合物、式V化合物、式VI化合物、式VII化合物、式VIII化合物、式V-1化合物或式VI-1化合物、其立体异构体或其药学上可接受的盐，According to the compound of formula I described in any one of claims 1-11, its stereoisomer or pharmaceutically acceptable salt thereof, it is selected from the compound of formula II, the compound of formula II-1, the compound of formula III, the compound of formula IV , a compound of formula III-1, a compound of formula V, a compound of formula VI, a compound of formula VII, a compound of formula VIII, a compound of formula V-1 or a compound of formula VI-1, a stereoisomer thereof or a pharmaceutically acceptable salt thereof,
    Figure PCTCN2022096512-appb-100027
    Figure PCTCN2022096512-appb-100027
    其中，X 5选自CH、CH 2或者N； Wherein, X 5 is selected from CH, CH 2 or N;
    Figure PCTCN2022096512-appb-100028
    Figure PCTCN2022096512-appb-100028
    Figure PCTCN2022096512-appb-100029
    Figure PCTCN2022096512-appb-100029
  13. 以下化合物、其立体异构体或其药学上可接受的盐：The following compounds, their stereoisomers or pharmaceutically acceptable salts thereof:
    Figure PCTCN2022096512-appb-100030
    Figure PCTCN2022096512-appb-100030
    Figure PCTCN2022096512-appb-100031
    Figure PCTCN2022096512-appb-100031
    Figure PCTCN2022096512-appb-100032
    Figure PCTCN2022096512-appb-100032
    Figure PCTCN2022096512-appb-100033
    Figure PCTCN2022096512-appb-100033
    Figure PCTCN2022096512-appb-100034
    Figure PCTCN2022096512-appb-100034
    Figure PCTCN2022096512-appb-100035
    Figure PCTCN2022096512-appb-100035
    Figure PCTCN2022096512-appb-100036
    Figure PCTCN2022096512-appb-100036
  14. 药物组合物，其包含权利要求1-13任一项所述化合物、其立体异构体或其药学上可接受的盐。A pharmaceutical composition comprising the compound of any one of claims 1-13, its stereoisomer or a pharmaceutically acceptable salt thereof.
  15. 用于预防或者治疗与BTK相关疾病的权利要求1-13任一项所述化合物、其立体异构体或其药学上可接受的盐、或权利要求14所述的药物组合物；任选地，所述BTK相关疾病选自自身免疫性疾病、炎症疾病或癌症。The compound of any one of claims 1-13, its stereoisomer or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 14 for preventing or treating diseases related to BTK; optionally , the BTK-related disease is selected from autoimmune disease, inflammatory disease or cancer.
PCT/CN2022/096512 2021-06-01 2022-06-01 Bruton's tyrosine kinase degrader containing fused-ring or spiro-ring WO2022253250A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN202280037318.XA CN117377675A (en) 2021-06-01 2022-06-01 Bruton's tyrosine kinase degradation agent containing parallel ring or spiro ring

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN202110607649 2021-06-01
CN202110607649.X 2021-06-01

Publications (1)

Publication Number Publication Date
WO2022253250A1 true WO2022253250A1 (en) 2022-12-08

Family

ID=84323919

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2022/096512 WO2022253250A1 (en) 2021-06-01 2022-06-01 Bruton's tyrosine kinase degrader containing fused-ring or spiro-ring

Country Status (2)

Country Link
CN (1) CN117377675A (en)
WO (1) WO2022253250A1 (en)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023072270A1 (en) * 2021-10-29 2023-05-04 百极弘烨(南通)医药科技有限公司 Protac compound, pharmaceutical composition comprising same, preparation method therefor, and use thereof
US11897862B2 (en) 2022-03-17 2024-02-13 Gilead Sciences, Inc. IKAROS zinc finger family degraders and uses thereof

Citations (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014152114A1 (en) * 2013-03-15 2014-09-25 Boehringer Ingelheim International Gmbh Heteroaromatic compounds as btk inhibitors
CN104080789A (en) * 2012-01-31 2014-10-01 南京奥昭生物科技有限公司 Cyclic molecules as bruton's tyrosine kinase inhibitors
CN105916859A (en) * 2014-02-03 2016-08-31 卡迪拉保健有限公司 Heterocyclic compounds
WO2017127371A1 (en) * 2016-01-21 2017-07-27 Sunnylife Pharma Inc. Bruton's tyrosine kinase inhibitors
WO2017156495A1 (en) * 2016-03-11 2017-09-14 Corvus Pharmaceuticals, Inc. Compounds and methods for modulating bruton's tyrosine kinase
WO2019127008A1 (en) * 2017-12-26 2019-07-04 清华大学 Compound for targeted degradation of btk and application thereof
CN110724143A (en) * 2019-10-09 2020-01-24 清华大学 Preparation of target BTK protein degradation compound and application of target BTK protein degradation compound in treatment of autoimmune system diseases and tumors
CN110845500A (en) * 2019-10-09 2020-02-28 清华大学 Application of target BTK degradation compound in treatment of autoimmune system diseases
CN112010858A (en) * 2019-05-31 2020-12-01 四川海思科制药有限公司 BTK inhibitor, preparation method and pharmaceutical application thereof
WO2020239103A1 (en) * 2019-05-31 2020-12-03 四川海思科制药有限公司 Btk inhibitor ring derivative, preparation method therefor and pharmaceutical application thereof
WO2020252397A1 (en) * 2019-06-12 2020-12-17 Baylor College Of Medicine Small molecule proteolysis-targeting chimeras and methods of use thereof
WO2021018018A1 (en) * 2019-07-26 2021-02-04 Beigene, Ltd. Degradation of bruton's tyrosine kinase (btk) by conjugation of btk inidbitors with e3 ligase ligand and methods of use
WO2022007824A1 (en) * 2020-07-07 2022-01-13 四川海思科制药有限公司 Compound having btk kinase degrading activity, and preparation method and pharmaceutical use therefor

Patent Citations (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104080789A (en) * 2012-01-31 2014-10-01 南京奥昭生物科技有限公司 Cyclic molecules as bruton's tyrosine kinase inhibitors
WO2014152114A1 (en) * 2013-03-15 2014-09-25 Boehringer Ingelheim International Gmbh Heteroaromatic compounds as btk inhibitors
CN105916859A (en) * 2014-02-03 2016-08-31 卡迪拉保健有限公司 Heterocyclic compounds
WO2017127371A1 (en) * 2016-01-21 2017-07-27 Sunnylife Pharma Inc. Bruton's tyrosine kinase inhibitors
WO2017156495A1 (en) * 2016-03-11 2017-09-14 Corvus Pharmaceuticals, Inc. Compounds and methods for modulating bruton's tyrosine kinase
WO2019127008A1 (en) * 2017-12-26 2019-07-04 清华大学 Compound for targeted degradation of btk and application thereof
WO2020239103A1 (en) * 2019-05-31 2020-12-03 四川海思科制药有限公司 Btk inhibitor ring derivative, preparation method therefor and pharmaceutical application thereof
CN112010858A (en) * 2019-05-31 2020-12-01 四川海思科制药有限公司 BTK inhibitor, preparation method and pharmaceutical application thereof
WO2020252397A1 (en) * 2019-06-12 2020-12-17 Baylor College Of Medicine Small molecule proteolysis-targeting chimeras and methods of use thereof
WO2021018018A1 (en) * 2019-07-26 2021-02-04 Beigene, Ltd. Degradation of bruton's tyrosine kinase (btk) by conjugation of btk inidbitors with e3 ligase ligand and methods of use
CN110845500A (en) * 2019-10-09 2020-02-28 清华大学 Application of target BTK degradation compound in treatment of autoimmune system diseases
CN110724143A (en) * 2019-10-09 2020-01-24 清华大学 Preparation of target BTK protein degradation compound and application of target BTK protein degradation compound in treatment of autoimmune system diseases and tumors
WO2022007824A1 (en) * 2020-07-07 2022-01-13 四川海思科制药有限公司 Compound having btk kinase degrading activity, and preparation method and pharmaceutical use therefor

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023072270A1 (en) * 2021-10-29 2023-05-04 百极弘烨(南通)医药科技有限公司 Protac compound, pharmaceutical composition comprising same, preparation method therefor, and use thereof
US11897862B2 (en) 2022-03-17 2024-02-13 Gilead Sciences, Inc. IKAROS zinc finger family degraders and uses thereof

Also Published As

Publication number Publication date
CN117377675A (en) 2024-01-09

Similar Documents

Publication Publication Date Title
CN113651814B (en) KRAS mutein inhibitors
CN101631778B (en) Cyclopenta [D] pyrimidines as AKT protein kinase inhibitors
WO2022253250A1 (en) Bruton's tyrosine kinase degrader containing fused-ring or spiro-ring
CN101578273B (en) Hydroxylated and methoxylated cyclopenta [d] pyrimidines as akt protein kinase inhibitors
CN113801114B (en) Fused bicyclic heteroaryl derivative, preparation method and application thereof in medicines
TWI794232B (en) Kinase inhibitors and uses thereof
TW200940542A (en) Pyrimidyl cyclopentanes as AKT protein kinase inhibitors
CN102858754A (en) RAF inhibitor compounds and methods of use thereof
WO2022247816A1 (en) Nitrogen-containing heterocyclic compound, preparation method therefor, and application thereof in medicines
TW202319055A (en) Annulated pyridazine compound
CN109867675B (en) Pyrrolopyrimidine derivative compound, pharmaceutical composition and application thereof
WO2022213980A1 (en) Tyk2 inhibitor and use thereof
WO2017071636A1 (en) Phthalazine ketone derivative, and preparation method and use thereof
CN112574278A (en) Heterocyclic compound as protein degradation agent and preparation method and medical application thereof
WO2023088406A1 (en) Fused imide derivative
WO2023041055A1 (en) Kif18a inhibitor
WO2022166741A1 (en) Macrocyclic compound containing benzoheterocycle and acting as egfr kinase inhibitor, and pharmaceutical composition and use thereof
WO2023280317A1 (en) Benzylamino tricyclic compound and use thereof
CN114685532A (en) Macrocyclic compound and medical application thereof
JP2019518032A (en) Bicyclic pyridine, pyrazine and pyrimidine derivatives as PI3K BETA inhibitors
WO2024061366A1 (en) Small molecule compound having phosphorylated aryl structure, and use thereof
WO2023143282A1 (en) Hydrazino group-containing compound
WO2024017358A1 (en) Macrocyclic compound, pharmaceutical composition thereof, and use thereof
WO2024012449A1 (en) Compound containing trifluoromethyl group
WO2023116763A1 (en) Pyridazine compound, and pharmaceutical composition and use thereof

Legal Events

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

Ref document number: 22815294

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE