WO2020239076A1 - Pyridazinone derivatives as thyroxine receptor-β agonists and application thereof - Google Patents

Pyridazinone derivatives as thyroxine receptor-β agonists and application thereof Download PDF

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Publication number
WO2020239076A1
WO2020239076A1 PCT/CN2020/093284 CN2020093284W WO2020239076A1 WO 2020239076 A1 WO2020239076 A1 WO 2020239076A1 CN 2020093284 W CN2020093284 W CN 2020093284W WO 2020239076 A1 WO2020239076 A1 WO 2020239076A1
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compound
add
reaction
alkyl
independently selected
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PCT/CN2020/093284
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French (fr)
Chinese (zh)
Inventor
于涛
张盛彬
吴成德
李婕
黎健
陈曙辉
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南京明德新药研发有限公司
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Priority to CN202080051869.2A priority Critical patent/CN114174282A/en
Publication of WO2020239076A1 publication Critical patent/WO2020239076A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/501—Pyridazines; Hydrogenated pyridazines not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/14—Drugs for disorders of the endocrine system of the thyroid hormones, e.g. T3, T4
    • A61P5/16—Drugs for disorders of the endocrine system of the thyroid hormones, e.g. T3, T4 for decreasing, blocking or antagonising the activity of the thyroid hormones
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
    • C07D237/02—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings
    • C07D237/06—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D237/10—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D237/14—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to a series of pyridazinone derivatives as thyroxine receptor-beta agonists, and their application in preparing medicines for diseases related to thyroxine receptor-beta agonists. Specifically, it relates to a compound represented by formula (I) or a pharmaceutically acceptable salt thereof.
  • Thyroid hormones play a very important role in the human body, including controlling the body's overall metabolism, protein synthesis, fat metabolism, neuron and bone growth, and regulating the function of the heart and kidneys. It is secreted by the thyroid. The hypothalamus and pituitary gland strictly regulate the secretion of thyroid hormone through the classic negative feedback mechanism of thyroid stimulating hormone releasing hormone and thyroid stimulating hormone. In recent years, the incidence of obesity and its complications, diabetes, metabolic syndrome, atherosclerosis and non-alcoholic steatohepatitis has been on the rise. Therefore, people hope to develop thyroid hormone and its analogues for clinical treatment.
  • Thyroid hormones perform transcriptional regulation by binding to two highly homologous receptors, which are thyroid receptor alpha (THR ⁇ ) and thyroid receptor beta (THR ⁇ ).
  • THR ⁇ is mainly distributed in the brain, heart and skeletal muscle, which can control heart rate; THR ⁇ is mainly distributed in the liver and brain, which can lower cholesterol and increase the metabolic rate (Curr Atheroscler Rep(2016)18(3):14; PNAS(2003), 100 (17), 10067-10072).
  • THR ⁇ thyroid receptor alpha
  • THR ⁇ thyroid receptor beta
  • the present invention provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof,
  • T 1 is selected from NR a ;
  • T 2 is selected from C, CH and N;
  • T 3 is selected from CR b and N;
  • T 4 is selected from CR c and O;
  • R a is selected from H and C 1-3 alkyl
  • R b and R c are each independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, C 1-3 alkyl and C 1-3 alkoxy, the C 1-3 alkyl and C 1- 3 alkoxy group optionally substituted with 1, 2 or 3 R <
  • R c is selected from H or CN
  • R 1 , R 2 and the atoms connected to them together form a C 3-8 cycloalkenyl group or a 3-8 membered heterocycloalkenyl group
  • the C 3-8 cycloalkenyl group And 3-8 membered heterocycloalkenyl groups are optionally substituted with 1, 2 or 3 R e ;
  • R c is selected from F, Cl, Br, I, OH, NH 2 and C 1-3 alkyl and C 1-3 alkoxy optionally substituted by 1, 2 or 3 R
  • R 1 and R 2 are independently selected from H and C 1-6 alkyl optionally substituted by 1, 2 or 3 R d , or R 1 , R 2 and the atoms connected to them together form a C 3-8 cycloalkenyl Or a 3-8 membered heterocycloalkenyl group, the C 3-8 cycloalkenyl group and 3-8 membered heterocycloalkenyl group are optionally substituted by 1, 2 or 3 R e ;
  • R 3 and R 4 are each independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, and C 1-3 alkyl optionally substituted with 1, 2 or 3 R f ;
  • R d, R e and R f are each independently selected from H, F, Cl, Br, I, OH, NH 2, CN and C 1-3 alkyl;
  • Each R is independently selected from H, F, Cl, Br, I, OH, NH 2 , CN and C 1-3 alkyl;
  • the 3-8 membered heterocycloalkenyl group includes 1, 2, 3 or 4 heteroatoms or heteroatom groups independently selected from -NH-, -O-, -S- and N.
  • the present invention provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof,
  • T 1 is selected from NR a ;
  • T 2 is selected from C, CH and N;
  • T 3 is selected from CR b and N;
  • T 4 is selected from CR c and O;
  • R a is selected from H and C 1-3 alkyl
  • R b and R c are each independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, C 1-3 alkyl and C 1-3 alkoxy, the C 1-3 alkyl and C 1- 3 alkoxy group optionally substituted with 1, 2 or 3 R <
  • R c is selected from H or CN
  • R 1 , R 2 and the atoms connected to them together form a C 3-8 cycloalkenyl group or a 3-8 membered heterocycloalkenyl group
  • the C 3-8 cycloalkenyl group And 3-8 membered heterocycloalkenyl groups are optionally substituted with 1, 2 or 3 R e ;
  • R c is selected from F, Cl, Br, I, OH, NH 2 and C 1-3 alkyl and C 1-3 alkoxy optionally substituted by 1, 2 or 3 R
  • R 1 and R 2 are independently selected from H and C 1-6 alkyl optionally substituted by 1, 2 or 3 R d , or R 1 , R 2 and the atoms connected to them together form a thienyl group, C 3-8 Cycloalkenyl or 3-8 membered heterocycloalkenyl, the C 3-8 cycloalkenyl and 3-8 membered heterocycloalkenyl are optionally substituted with 1, 2 or 3 R e ;
  • R 3 and R 4 are each independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, and C 1-3 alkyl optionally substituted with 1, 2 or 3 R f ;
  • R d, R e and R f are each independently selected from H, F, Cl, Br, I, OH, NH 2, CN and C 1-3 alkyl;
  • Each R is independently selected from H, F, Cl, Br, I, OH, NH 2 , CN and C 1-3 alkyl;
  • the 3-8 membered heterocycloalkenyl group contains 1, 2, 3 or 4 heteroatoms or heteroatom groups independently selected from -NH-, -O-, -S- and N.
  • the present invention provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof,
  • T 1 is NR a ;
  • T 2 is selected from C, CH and N;
  • T 3 is selected from CR b and N;
  • T 4 is selected from CR c and O;
  • R a is selected from H and C 1-3 alkyl
  • R b and R c are each independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, C 1-3 alkyl and C 1-3 alkoxy, the C 1-3 alkyl and C 1- 3 alkoxy group optionally substituted with 1, 2 or 3 R <
  • R c is selected from F, Cl, Br, I, OH, NH 2 and C 1-3 alkyl and C 1-3 alkoxy optionally substituted by 1, 2 or 3 R
  • R 1 and R 2 is each independently selected from H and C 1-6 alkyl optionally substituted with 1, 2 or 3 R d , or R 1 , R 2 and the atoms connected to them together form a thienyl group, C 3- 8 cycloalkenyl or 3-8 membered heterocycloalkenyl, the thienyl, C 3-8 cycloalkenyl and 3-8 membered heterocycloalkenyl are optionally substituted by 1, 2 or 3 R e ;
  • R c is selected from H or CN
  • R 1 , R 2 and the atoms connected to them together form a C 3-8 cycloalkenyl group or a 3-8 membered heterocycloalkenyl group, the C 3-8 cycloalkenyl group and The 3-8 membered heterocycloalkenyl is optionally substituted with 1, 2 or 3 R e ;
  • R 3 and R 4 are each independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, and C 1-3 alkyl optionally substituted with 1, 2 or 3 R f ;
  • R d, R e and R f are each independently selected from H, F, Cl, Br, I, OH, NH 2, CN, C 1-3 alkyl group and a C 1-3 alkoxy group;
  • Each R is independently selected from H, F, Cl, Br, I, OH, NH 2 , CN and C 1-3 alkyl;
  • the 3-8 membered heterocycloalkenyl group includes 1, 2, 3 or 4 heteroatoms or heteroatom groups independently selected from -NH-, -O-, -S- and N.
  • the present invention provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof,
  • T 1 is NR a ;
  • T 2 is selected from C, CH and N;
  • T 3 is selected from CR b and N;
  • T 4 is selected from CR c and O;
  • R a is selected from H and C 1-3 alkyl
  • R b and R c are each independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, C 1-3 alkyl and C 1-3 alkoxy, the C 1-3 alkyl and C 1- 3 alkoxy group optionally substituted with 1, 2 or 3 R <
  • R c is selected from F, Cl, Br, I, OH, NH 2 and C 1-3 alkyl and C 1-3 alkoxy optionally substituted by 1, 2 or 3 R
  • R 1 and R 2 is each independently selected from H and C 1-6 alkyl optionally substituted with 1, 2 or 3 R d , or R 1 , R 2 and the atoms connected to them together form a thienyl group, C 3- 8 cycloalkenyl or 3-8 membered heterocycloalkenyl, the thienyl, C 3-8 cycloalkenyl and 3-8 membered heterocycloalkenyl are optionally substituted by 1, 2 or 3 R e ;
  • R c is selected from H and CN
  • R 1 , R 2 and the atoms connected to them together form a C 6-8 cycloalkenyl group or a 3-8 membered heterocycloalkenyl group, and the C 6-8 cycloalkenyl group and The 3-8 membered heterocycloalkenyl is optionally substituted with 1, 2 or 3 R e ;
  • R 3 and R 4 are each independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, and C 1-3 alkyl optionally substituted with 1, 2 or 3 R f ;
  • R d and R e are each independently selected from H, F, Cl, Br, I, OH, NH 2, CN, OCD 3, C 1-3 alkyl, C 1-3 alkoxy and -OC 3-5 Cycloalkyl
  • R f is independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, C 1-3 alkyl and C 1-3 alkoxy;
  • Each R is independently selected from H, F, Cl, Br, I, OH, NH 2 , CN and C 1-3 alkyl;
  • the 3-8 membered heterocycloalkenyl group contains 1, 2, 3 or 4 heteroatoms or heteroatom groups independently selected from -NH-, -O-, -S- and N.
  • the present invention provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof,
  • T 1 is NR a ;
  • T 2 is selected from C, CH and N;
  • T 3 is selected from CR b and N;
  • T 4 is selected from CR c and O;
  • R a is selected from H and C 1-3 alkyl
  • R b and R c are each independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, C 1-3 alkyl and C 1-3 alkoxy, the C 1-3 alkyl and C 1- 3 alkoxy group optionally substituted with 1, 2 or 3 R <
  • R c is selected from F, Cl, Br, I, OH, NH 2 and C 1-3 alkyl and C 1-3 alkoxy optionally substituted by 1, 2 or 3 R
  • R 1 and R 2 is each independently selected from H and C 1-6 alkyl optionally substituted with 1, 2 or 3 R d , or R 1 , R 2 and the atoms connected to them together form a thienyl group, C 3- 8 cycloalkenyl or 3-8 membered heterocycloalkenyl, the thienyl, C 3-8 cycloalkenyl and 3-8 membered heterocycloalkenyl are optionally substituted by 1, 2 or 3 R e ;
  • R c is selected from H and CN
  • R 1 , R 2 and the atoms connected to them together form a thienyl group, a C 6-8 cycloalkenyl group or a 3-8 membered heterocycloalkenyl group
  • the thienyl group, C 6 -8 cycloalkenyl and 3-8 membered heterocycloalkenyl are optionally substituted with 1, 2 or 3 R e ;
  • R 3 and R 4 are each independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, and C 1-3 alkyl optionally substituted with 1, 2 or 3 R f ;
  • R d and R e are each independently selected from H, F, Cl, Br, I, OH, NH 2, CN, OCD 3, C 1-3 alkyl, OCH 3, OCH 2 CH 3 , OCH (CH 3) 2 and -OC 3-5 cycloalkyl;
  • R f is independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, C 1-3 alkyl and C 1-3 alkoxy;
  • Each R is independently selected from H, F, Cl, Br, I, OH, NH 2 , CN and C 1-3 alkyl;
  • the 3-8 membered heterocycloalkenyl group includes 1, 2, 3 or 4 heteroatoms or heteroatom groups independently selected from -NH-, -O-, -S- and N.
  • the present invention provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof,
  • T 1 is NR a ;
  • T 2 is selected from C, CH and N;
  • T 3 is selected from CR b and N;
  • T 4 is selected from CR c and O;
  • R a is selected from H and C 1-3 alkyl
  • R b and R c are each independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, C 1-3 alkyl and C 1-3 alkoxy, the C 1-3 alkyl and C 1- 3 alkoxy group optionally substituted with 1, 2 or 3 R <
  • R c is selected from F, Cl, Br, I, OH, NH 2 and C 1-3 alkyl and C 1-3 alkoxy optionally substituted by 1, 2 or 3 R
  • R 1 and R 2 is each independently selected from H and C 1-6 alkyl optionally substituted with 1, 2 or 3 R d , or R 1 , R 2 and the atoms connected to them together form a thienyl group, C 3- 8 cycloalkenyl or 3-8 membered heterocycloalkenyl, the thienyl, C 3-8 cycloalkenyl and 3-8 membered heterocycloalkenyl are optionally substituted by 1, 2 or 3 R e ;
  • R c is selected from H and CN
  • R 1 , R 2 and the atoms connected to them together form a thienyl group, a C 6-8 cycloalkenyl group or a 3-8 membered heterocycloalkenyl group
  • the thienyl group, C 6 -8 cycloalkenyl and 3-8 membered heterocycloalkenyl are optionally substituted with 1, 2 or 3 R e ;
  • R 3 and R 4 are each independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, and C 1-3 alkyl optionally substituted with 1, 2 or 3 R f ;
  • R d and R e are each independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, C 1-3 alkyl, C 1-3 alkoxy and -OC 3-5 cycloalkyl , The C 1-3 alkyl group, C 1-3 alkoxy group and -OC 3-5 cycloalkyl group are optionally substituted with 1, 2 or 3 R';
  • R f is independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, C 1-3 alkyl and C 1-3 alkoxy;
  • Each R is independently selected from H, F, Cl, Br, I, OH, NH 2 , CN and C 1-3 alkyl;
  • Each R' is independently selected from D, F, Cl, Br and I;
  • the 3-8 membered heterocycloalkenyl group contains 1, 2, 3 or 4 heteroatoms or heteroatom groups independently selected from -NH-, -O-, -S- and N.
  • the above-mentioned compound or a pharmaceutically acceptable salt thereof is selected from
  • T 2 is selected from C and N;
  • T 4 is selected from CR c and O;
  • R c is selected from F, Cl, Br, I, OH, NH 2 , C 1-3 alkyl and C 1-3 alkoxy, the C 1-3 alkyl and C 1-3 alkoxy optionally Replaced by 1, 2 or 3 R;
  • R 1 and R 2 are each independently selected from H and C 1-6 alkyl optionally substituted by 1, 2 or 3 R d , or R 1 , R 2 and the atoms connected to them together form C 3- 8 cycloalkenyl or 3-8 membered heterocycloalkenyl, the C 3-8 cycloalkenyl and 3-8 membered heterocycloalkenyl are optionally substituted by 1, 2 or 3 R e ;
  • R 3 and R 4 are each independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, and C 1-3 alkyl optionally substituted with 1, 2 or 3 R f ;
  • R d, R e and R f are each independently selected from H, F, Cl, Br, I, OH, NH 2, CN and C 1-3 alkyl;
  • Each R is independently selected from H, F, Cl, Br, I, OH, NH 2 , CN and C 1-3 alkyl;
  • the 3-8 membered heterocycloalkenyl group contains 1, 2, 3 or 4 heteroatoms or heteroatom groups independently selected from -NH-, -O-, -S- and N.
  • the above-mentioned compound or a pharmaceutically acceptable salt thereof is selected from
  • T 2 is selected from C and N;
  • T 4 is selected from CR c and O;
  • R c is selected from F, Cl, Br, I, OH, NH 2 , C 1-3 alkyl and C 1-3 alkoxy, the C 1-3 alkyl and C 1-3 alkoxy optionally Replaced by 1, 2 or 3 R;
  • R 1 and R 2 are each independently selected from H and C 1-6 alkyl optionally substituted by 1, 2 or 3 R d , or R 1 , R 2 and the atoms connected to them together form a thienyl group, C 3-8 cycloalkenyl or 3-8 membered heterocycloalkenyl, the C 3-8 cycloalkenyl and 3-8 membered heterocycloalkenyl are optionally substituted by 1, 2 or 3 R e ;
  • R 3 and R 4 are each independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, and C 1-3 alkyl optionally substituted with 1, 2 or 3 R f ;
  • R d, R e and R f are each independently selected from H, F, Cl, Br, I, OH, NH 2, CN and C 1-3 alkyl;
  • Each R is independently selected from H, F, Cl, Br, I, OH, NH 2 , CN and C 1-3 alkyl;
  • the 3-8 membered heterocycloalkenyl group includes 1, 2, 3 or 4 heteroatoms or heteroatom groups independently selected from -NH-, -O-, -S- and N.
  • the above-mentioned compound or a pharmaceutically acceptable salt thereof is selected from
  • T 2 is selected from C and N;
  • T 4 is selected from CR c and O;
  • R c is selected from F, Cl, Br, I, OH, NH 2 , C 1-3 alkyl and C 1-3 alkoxy, the C 1-3 alkyl and C 1-3 alkoxy optionally Replaced by 1, 2 or 3 R;
  • R 1 and R 2 are each independently selected from H and C 1-6 alkyl optionally substituted by 1, 2 or 3 R d , or R 1 , R 2 and the atoms connected to them together form a thienyl group, C 3-8 cycloalkenyl or 3-8 membered heterocycloalkenyl, the thienyl, C 3-8 cycloalkenyl and 3-8 membered heterocycloalkenyl are optionally substituted by 1, 2 or 3 R e ;
  • R 3 and R 4 are each independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, and C 1-3 alkyl optionally substituted with 1, 2 or 3 R f ;
  • R d, R e and R f are each independently selected from H, F, Cl, Br, I, OH, NH 2, CN, C 1-3 alkyl group and a C 1-3 alkoxy group;
  • Each R is independently selected from H, F, Cl, Br, I, OH, NH 2 , CN and C 1-3 alkyl;
  • the 3-8 membered heterocycloalkenyl group contains 1, 2, 3 or 4 heteroatoms or heteroatom groups independently selected from -NH-, -O-, -S- and N.
  • the above-mentioned compound or a pharmaceutically acceptable salt thereof is selected from
  • T 2 is selected from C and N;
  • T 4 is selected from CR c and O;
  • R c is selected from F, Cl, Br, I, OH, NH 2 , C 1-3 alkyl and C 1-3 alkoxy, the C 1-3 alkyl and C 1-3 alkoxy optionally Replaced by 1, 2 or 3 R;
  • R 1 and R 2 are each independently selected from H and C 1-6 alkyl optionally substituted by 1, 2 or 3 R d , or R 1 , R 2 and the atoms connected to them together form a thienyl group, C 3-8 cycloalkenyl or 3-8 membered heterocycloalkenyl, the thienyl, C 3-8 cycloalkenyl and 3-8 membered heterocycloalkenyl are optionally substituted by 1, 2 or 3 R e ;
  • R 3 and R 4 are each independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, and C 1-3 alkyl optionally substituted with 1, 2 or 3 R f ;
  • R d and R e are each independently selected from H, F, Cl, Br, I, OH, NH 2, CN, OCD 3, C 1-3 alkyl, C 1-3 alkoxy and -OC 3-5 Cycloalkyl
  • R f is independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, C 1-3 alkyl and C 1-3 alkoxy;
  • Each R is independently selected from H, F, Cl, Br, I, OH, NH 2 , CN and C 1-3 alkyl;
  • the 3-8 membered heterocycloalkenyl group includes 1, 2, 3 or 4 heteroatoms or heteroatom groups independently selected from -NH-, -O-, -S- and N.
  • the above-mentioned compound or a pharmaceutically acceptable salt thereof is selected from
  • T 2 is selected from C and N;
  • T 4 is selected from CR c and O;
  • R c is selected from F, Cl, Br, I, OH, NH 2 , C 1-3 alkyl and C 1-3 alkoxy, the C 1-3 alkyl and C 1-3 alkoxy optionally Replaced by 1, 2 or 3 R;
  • R 1 and R 2 are each independently selected from H and C 1-6 alkyl optionally substituted by 1, 2 or 3 R d , or R 1 , R 2 and the atoms connected to them together form a thienyl group, C 3-8 cycloalkenyl or 3-8 membered heterocycloalkenyl, the thienyl, C 3-8 cycloalkenyl and 3-8 membered heterocycloalkenyl are optionally substituted by 1, 2 or 3 R e ;
  • R 3 and R 4 are each independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, and C 1-3 alkyl optionally substituted with 1, 2 or 3 R f ;
  • R d and R e are each independently selected from H, F, Cl, Br, I, OH, NH 2, CN, OCD 3, C 1-3 alkyl, OCH 3, OCH 2 CH 3 , OCH (CH 3) 2 and -OC 3-5 cycloalkyl;
  • R f is independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, C 1-3 alkyl and C 1-3 alkoxy;
  • Each R is independently selected from H, F, Cl, Br, I, OH, NH 2 , CN and C 1-3 alkyl;
  • the 3-8 membered heterocycloalkenyl group contains 1, 2, 3 or 4 heteroatoms or heteroatom groups independently selected from -NH-, -O-, -S- and N.
  • the above-mentioned compound or a pharmaceutically acceptable salt thereof is selected from
  • T 2 is selected from C and N;
  • T 4 is selected from CR c and O;
  • R c is selected from F, Cl, Br, I, OH, NH 2 , C 1-3 alkyl and C 1-3 alkoxy, the C 1-3 alkyl and C 1-3 alkoxy optionally Replaced by 1, 2 or 3 R;
  • R 1 and R 2 are each independently selected from H and C 1-6 alkyl optionally substituted by 1, 2 or 3 R d , or R 1 , R 2 and the atoms connected to them together form a thienyl group, C 3-8 cycloalkenyl or 3-8 membered heterocycloalkenyl, the thienyl, C 3-8 cycloalkenyl and 3-8 membered heterocycloalkenyl are optionally substituted by 1, 2 or 3 R e ;
  • R 3 and R 4 are each independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, and C 1-3 alkyl optionally substituted with 1, 2 or 3 R f ;
  • R d and R e are each independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, C 1-3 alkyl, C 1-3 alkoxy and -OC 3-5 cycloalkyl , The C 1-3 alkyl group, C 1-3 alkoxy group and -OC 3-5 cycloalkyl group are optionally substituted with 1, 2 or 3 R';
  • R f is independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, C 1-3 alkyl and C 1-3 alkoxy;
  • Each R is independently selected from H, F, Cl, Br, I, OH, NH 2 , CN and C 1-3 alkyl;
  • Each R' is independently selected from D, F, Cl, Br and I;
  • the 3-8 membered heterocycloalkenyl group contains 1, 2, 3 or 4 heteroatoms or heteroatom groups independently selected from -NH-, -O-, -S- and N.
  • the above-mentioned compound or a pharmaceutically acceptable salt thereof is selected from
  • R c is selected from H and CN
  • R 1 , R 2 and the atoms connected to them together form a C 3-8 cycloalkenyl group and a 3-8 membered heterocycloalkenyl group, the C 3-8 cycloalkenyl group and a 3-8 membered heterocycloalkenyl group are optionally substituted with 1, 2, or 3 R e;
  • R 3 and R 4 are each independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, and C 1-3 alkyl optionally substituted with 1, 2 or 3 R f ;
  • R e and R f are each independently selected from H, F, Cl, Br, I, OH, NH 2 , CN and C 1-3 alkyl;
  • the 3-8 membered heterocycloalkenyl group contains 1, 2, 3 or 4 heteroatoms or heteroatom groups independently selected from -NH-, -O-, -S- and N.
  • the above-mentioned compound or a pharmaceutically acceptable salt thereof is selected from
  • R c is selected from H and CN
  • R 1 , R 2 and the atoms connected to them together form a thienyl group, a C 3-8 cycloalkenyl group, and a 3-8 membered heterocycloalkenyl group, the C 3-8 cycloalkenyl group and a 3-8 membered heterocycloalkenyl group group optionally substituted with 1, 2, or 3 R e;
  • R 3 and R 4 are each independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, and C 1-3 alkyl optionally substituted with 1, 2 or 3 R f ;
  • R e and R f are each independently selected from H, F, Cl, Br, I, OH, NH 2 , CN and C 1-3 alkyl;
  • the 3-8 membered heterocycloalkenyl group includes 1, 2, 3 or 4 heteroatoms or heteroatom groups independently selected from -NH-, -O-, -S- and N.
  • the above-mentioned compound or a pharmaceutically acceptable salt thereof is selected from
  • R c is selected from H and CN
  • R 1 , R 2 and the atoms connected to them together form a thienyl group, a C 3-8 cycloalkenyl group and a 3-8 membered heterocycloalkenyl group, the thienyl group, a C 3-8 cycloalkenyl group and a 3-8 membered group optionally substituted heterocyclenyl, 2, or 3 R e;
  • R 3 and R 4 are each independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, and C 1-3 alkyl optionally substituted with 1, 2 or 3 R f ;
  • R e and R f are each independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, C 1-3 alkyl and C 1-3 alkoxy;
  • the 3-8 membered heterocycloalkenyl group includes 1, 2, 3 or 4 heteroatoms or heteroatom groups independently selected from -NH-, -O-, -S- and N.
  • the above-mentioned compound or a pharmaceutically acceptable salt thereof is selected from
  • R c is selected from H and CN
  • R 1 , R 2 and the atoms connected to them together form a thienyl group, a C 6-8 cycloalkenyl group and a 3-8 membered heterocycloalkenyl group, the thienyl group, a C 6-8 cycloalkenyl group and a 3-8 membered group optionally substituted heterocyclenyl, 2, or 3 R e;
  • R 3 and R 4 are each independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, and C 1-3 alkyl optionally substituted with 1, 2 or 3 R f ;
  • R e is independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, OCD 3 , C 1-3 alkyl, C 1-3 alkoxy and -OC 3-5 cycloalkyl ;
  • R f is independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, C 1-3 alkyl and C 1-3 alkoxy;
  • the 3-8 membered heterocycloalkenyl group includes 1, 2, 3 or 4 heteroatoms or heteroatom groups independently selected from -NH-, -O-, -S- and N.
  • the above-mentioned compound or a pharmaceutically acceptable salt thereof is selected from
  • R c is selected from H and CN
  • R 1 , R 2 and the atoms connected to them together form a thienyl group, a C 6-8 cycloalkenyl group and a 3-8 membered heterocycloalkenyl group, the thienyl group, a C 6-8 cycloalkenyl group and a 3-8 membered group optionally substituted heterocyclenyl, 2, or 3 R e;
  • R 3 and R 4 are each independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, and C 1-3 alkyl optionally substituted with 1, 2 or 3 R f ;
  • R e are independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, OCD 3 , C 1-3 alkyl, OCH 3 , OCH 2 CH 3 , OCH(CH 3 ) 2 and- OC 3-5 cycloalkyl;
  • R f is independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, C 1-3 alkyl and C 1-3 alkoxy;
  • the 3-8 membered heterocycloalkenyl group includes 1, 2, 3 or 4 heteroatoms or heteroatom groups independently selected from -NH-, -O-, -S- and N.
  • the above-mentioned compound or a pharmaceutically acceptable salt thereof is selected from
  • R c is selected from H and CN
  • R 1 , R 2 and the atoms connected to them together form a thienyl group, a C 6-8 cycloalkenyl group and a 3-8 membered heterocycloalkenyl group, the thienyl group, a C 6-8 cycloalkenyl group and a 3-8 membered group optionally substituted heterocyclenyl, 2, or 3 R e;
  • R 3 and R 4 are each independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, and C 1-3 alkyl optionally substituted with 1, 2 or 3 R f ;
  • R e is each independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, C 1-3 alkyl, C 1-3 alkoxy and -OC 3-5 cycloalkyl, said C 1-3 alkyl, C 1-3 alkoxy and -OC 3-5 cycloalkyl are optionally substituted with 1, 2 or 3 R';
  • R f is independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, C 1-3 alkyl and C 1-3 alkoxy;
  • Each R' is independently selected from D, F, Cl, Br and I;
  • the 3-8 membered heterocycloalkenyl group contains 1, 2, 3 or 4 heteroatoms or heteroatom groups independently selected from -NH-, -O-, -S- and N.
  • the above-mentioned T 2 is selected from N, and when T 3 is selected from N, the connection between T 2 and T 3 Is a single bond; when T 4 is selected from CR c , the connection between T 3 and T 4 Is a double bond; when T 4 is selected from O, the connection between T 3 and T 4 It is a single key.
  • R b and R c are independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, CH 3 , CH 2 CH 3 and The CH 3 , CH 2 CH 3 and Optionally substituted by 1, 2 or 3 R, other variables are as defined in the present invention.
  • R b and R c are independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, CH 3 , CH 2 F, CHF 2 , CF 3 , CH 2 CH 3 , Other variables are as defined in the present invention.
  • R b and R c are independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, CH 3 , CH 2 F, CHF 2 , CF 3 , CH 2 CH 3 , CF 2 CH 3 , Other variables are as defined in the present invention.
  • R b and R c are independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, CH 3 , CH 2 F, CH 2 CN, CHF 2 , CF 3 , CH 2 CH 3 , CF 2 CH 3 , Other variables are as defined in the present invention.
  • the aforementioned R c is selected from F, Cl, Br, I, OH, NH 2 , CH 3 , CH 2 F, CHF 2 , CF 3 , CH 2 CH 3 , Other variables are as defined in the present invention.
  • the aforementioned R c is selected from F, Cl, Br, I, OH, NH 2 , CH 3 , CH 2 F, CHF 2 , CF 3 , CH 2 CH 3 , CF 2 CH 3 , Other variables are as defined in the present invention.
  • R c is selected from F, Cl, Br, I, OH, NH 2 , CH 3 , CH 2 F, CHF 2 , CH 2 CN, CF 3 , CH 2 CH 3 , CF 2 CH 3 .
  • Other variables are as defined in the present invention.
  • R 1 and R 2 are independently selected from H, CH 3 , CH 2 CH 3 , CH(CH 3 ) 2 and C(CH 3 ) 3 , and other variables are as defined in the present invention.
  • the above-mentioned R 1 , R 2 and the atoms connected to them together form a cyclohexenyl group, a bicyclo[2.2.1]hept-2-enyl group, 1,2,3,4-tetrahydropyridine Group, bicyclo[4.1.0]hept-3-enyl, 3,6-dihydro-2H-pyranyl and 7-oxabicyclo[2.2.1]hept-2-enyl, the cyclohexyl Alkenyl, bicyclo[2.2.1]hept-2-enyl, 1,2,3,4-tetrahydropyridyl, bicyclo[4.1.0]hept-3-enyl, 3,6-dihydro-2H - pyranyl and 7-oxabicyclo [2.2.1] hept-2-en-yl optionally substituted with 1, 2, or 3 R e, the other variables are as defined in the present invention.
  • the above-mentioned R 1 , R 2 and the atoms connected to them together form a cyclopentenyl, cyclohexenyl, bicyclo[2.2.1]hept-2-enyl, 1,2,3, 4-tetrahydropyridyl, bicyclo[4.1.0]hept-3-enyl, 3,6-dihydro-2H-pyranyl, 7-oxabicyclo[2.2.1]hept-2-enyl , Thienyl, 3,4-dihydro-2H-pyranyl and bicyclo[4.1.0]hept-2-enyl, the cyclopentenyl, cyclohexenyl, bicyclo[2.2.1]hept- 2-alkenyl, 1,2,3,4-tetrahydropyridyl, bicyclo[4.1.0]hept-3-enyl, 3,6-dihydro-2H-pyranyl, 7-oxabicyclo [2.2.1]Hept-2-
  • the above-mentioned R 1 , R 2 and the atoms connected to them together form a cyclohexenyl group, a bicyclo[2.2.1]hept-2-enyl group, 1,2,3,4-tetrahydropyridine Group, bicyclo[4.1.0]hept-3-enyl, 3,6-dihydro-2H-pyranyl, 7-oxabicyclo[2.2.1]hept-2-enyl, thienyl, 3 ,4-Dihydro-2H-pyranyl and bicyclo[4.1.0]hept-2-enyl, the cyclohexenyl, bicyclo[2.2.1]hept-2-enyl, 1,2,3 ,4-Tetrahydropyridyl, bicyclo[4.1.0]hept-3-enyl, 3,6-dihydro-2H-pyranyl, 7-oxabicyclo[2.2.1]hept-2-ene Group, thien
  • R 3 and R 4 are each independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, CH 3 and CH 2 CH 3 , said CH 3 and CH 2 CH 3 is optionally substituted with 1, 2 or 3 R f , and other variables are as defined in the present invention.
  • R 3 and R 4 are each independently selected from F, Cl, Br, I, OH, and NH 2 .
  • R 3 and R 4 are independently selected from F, Cl, Br, I, OH, and NH 2 , and other variables are as defined in the present invention.
  • R 3 and R 4 are independently selected from F, Cl, Br, I, OH, NH 2 and CF 3 , and other variables are as defined in the present invention.
  • the above-mentioned compound or a pharmaceutically acceptable salt thereof is selected from
  • Z 1 and Z 2 are each independently selected from CH(R e ), O and N(R e );
  • Z 3 is selected from CH 2 and O;
  • Z 4 is selected from O
  • Z 5 is selected from C(R e ) and N;
  • Z 6 is selected from N(R e ) and O;
  • R c is selected from H and CN
  • R 3, R 4 and R e are as defined in the present invention.
  • the above-mentioned compound or a pharmaceutically acceptable salt thereof is selected from
  • R 1 , R 2 , R 3 , R 4 and R c are as defined in the present invention.
  • the present invention also provides a compound represented by the following formula or a pharmaceutically acceptable salt thereof,
  • the above-mentioned compound or a pharmaceutically acceptable salt thereof is selected from:
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of the above-mentioned compound or a pharmaceutically acceptable salt thereof as an active ingredient and a pharmaceutically acceptable carrier.
  • the above-mentioned compound or a pharmaceutically acceptable salt thereof or the above-mentioned composition is used in the preparation of thyroxine receptor- ⁇ agonist related drugs.
  • the above application is characterized in that the thyroxine receptor- ⁇ agonist-related drug is a drug for the treatment of non-alcoholic steatohepatitis.
  • pharmaceutically acceptable salt refers to a salt of the compound of the present invention, which is prepared from a compound with specific substituents discovered in the present invention and a relatively non-toxic acid or base.
  • the base addition salt can be obtained by contacting the neutral form of the compound with a sufficient amount of base in a pure solution or a suitable inert solvent.
  • Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic ammonia or magnesium salts or similar salts.
  • the acid addition salt can be obtained by contacting the neutral form of the compound with a sufficient amount of acid in a pure solution or a suitable inert solvent.
  • Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts including, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, hydrogen carbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, Hydrogen sulfate, hydroiodic acid, phosphorous acid, etc.; and organic acid salts, the organic acid includes such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, Similar acids such as fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid and methanesulfonic acid; also include salts of amino acids (such as arginine, etc.) , And salts of organic acids such as glucuronic acid. Certain specific compounds of the present invention contain basic and acidic
  • the pharmaceutically acceptable salt of the present invention can be synthesized from the parent compound containing acid or base by conventional chemical methods. Generally, such salts are prepared by reacting these compounds in free acid or base form with a stoichiometric amount of appropriate base or acid in water or an organic solvent or a mixture of both.
  • the compounds provided by the present invention also exist in prodrug forms.
  • the prodrugs of the compounds described herein easily undergo chemical changes under physiological conditions to transform into the compounds of the invention.
  • prodrugs can be converted to the compounds of the present invention by chemical or biochemical methods in the in vivo environment.
  • Certain compounds of the present invention may exist in unsolvated or solvated forms, including hydrated forms.
  • the solvated form is equivalent to the unsolvated form, and both are included in the scope of the present invention.
  • the compounds of the present invention may exist in specific geometric or stereoisomeric forms.
  • the present invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers Conformers, (D)-isomers, (L)-isomers, and their racemic mixtures and other mixtures, such as enantiomers or diastereomeric enriched mixtures, all of these mixtures belong to Within the scope of the present invention.
  • Additional asymmetric carbon atoms may be present in substituents such as alkyl. All these isomers and their mixtures are included in the scope of the present invention.
  • enantiomer or “optical isomer” refers to stereoisomers that are mirror images of each other.
  • cis-trans isomer or “geometric isomer” is caused by the inability to rotate freely because of double bonds or single bonds of ring-forming carbon atoms.
  • diastereomer refers to a stereoisomer in which a molecule has two or more chiral centers and the relationship between the molecules is non-mirror-image relationship.
  • wedge-shaped solid line keys And wedge-shaped dashed key Represents the absolute configuration of a solid center, with a straight solid line key And straight dashed key Indicates the relative configuration of the three-dimensional center, using wavy lines Represents a wedge-shaped solid line key Or wedge-shaped dotted key Or use wavy lines Represents a straight solid line key And straight dashed key
  • the compound of the present invention may be specific.
  • tautomer or “tautomeric form” means that at room temperature, the isomers of different functional groups are in dynamic equilibrium and can be transformed into each other quickly. If tautomers are possible (such as in solution), the chemical equilibrium of tautomers can be reached.
  • proton tautomers also called prototropic tautomers
  • proton migration such as keto-enol isomerization and imine-ene Amine isomerization.
  • Valence isomers include some recombination of bonding electrons for mutual transformation.
  • keto-enol tautomerization is the tautomerism between two tautomers of pentane-2,4-dione and 4-hydroxypent-3-en-2-one.
  • the terms “enriched in one isomer”, “enriched in isomers”, “enriched in one enantiomer” or “enriched in enantiomers” refer to one of the isomers or pairs of
  • the content of the enantiomer is less than 100%, and the content of the isomer or enantiomer is greater than or equal to 60%, or greater than or equal to 70%, or greater than or equal to 80%, or greater than or equal to 90%, or greater than or equal to 95%, or 96% or greater, or 97% or greater, or 98% or greater, or 99% or greater, or 99.5% or greater, or 99.6% or greater, or 99.7% or greater, or 99.8% or greater, or greater than or equal 99.9%.
  • the term “isomer excess” or “enantiomeric excess” refers to the difference between the relative percentages of two isomers or two enantiomers. For example, if the content of one isomer or enantiomer is 90%, and the content of the other isomer or enantiomer is 10%, the isomer or enantiomer excess (ee value) is 80% .
  • optically active (R)- and (S)-isomers and D and L isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If you want to obtain an enantiomer of a compound of the present invention, it can be prepared by asymmetric synthesis or derivatization with chiral auxiliary agents, in which the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide pure The desired enantiomer.
  • the molecule when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), it forms a diastereomeric salt with a suitable optically active acid or base, and then passes through a conventional method known in the art The diastereoisomers are resolved, and then the pure enantiomers are recovered.
  • the separation of enantiomers and diastereomers is usually accomplished through the use of chromatography, which employs a chiral stationary phase and is optionally combined with chemical derivatization (for example, the formation of amino groups from amines). Formate).
  • the compounds of the present invention may contain unnatural proportions of atomic isotopes on one or more of the atoms constituting the compound.
  • compounds can be labeled with radioisotopes, such as tritium ( 3 H), iodine-125 ( 125 I), or C-14 ( 14 C).
  • deuterated drugs can be formed by replacing hydrogen with heavy hydrogen. The bond formed by deuterium and carbon is stronger than the bond formed by ordinary hydrogen and carbon. Compared with undeuterated drugs, deuterated drugs have reduced toxic side effects and increased drug stability. , Enhance the efficacy, extend the biological half-life of drugs and other advantages. All changes in the isotopic composition of the compounds of the present invention, whether radioactive or not, are included in the scope of the present invention.
  • substituted means that any one or more hydrogen atoms on a specific atom are replaced by substituents, and can include deuterium and hydrogen variants, as long as the valence of the specific atom is normal and the substituted compound is stable of.
  • oxygen it means that two hydrogen atoms are replaced. Oxygen substitution will not occur on aromatic groups.
  • optionally substituted means that it can be substituted or unsubstituted. Unless otherwise specified, the type and number of substituents can be arbitrary on the basis that they can be chemically realized.
  • any variable such as R
  • its definition in each case is independent.
  • the group may optionally be substituted with up to two Rs, and R has independent options in each case.
  • combinations of substituents and/or variants thereof are only permitted if such combinations result in stable compounds.
  • linking group When the number of a linking group is 0, such as -(CRR) 0 -, it means that the linking group is a single bond.
  • substituents When a substituent is vacant, it means that the substituent is absent. For example, when X in AX is vacant, it means that the structure is actually A.
  • substituents do not indicate which atom is connected to the substituted group, such substituents can be bonded via any atom.
  • a pyridyl group can pass through any one of the pyridine ring as a substituent. The carbon atom is attached to the substituted group.
  • the middle linking group L is -MW-, at this time -MW- can be formed by connecting ring A and ring B in the same direction as the reading order from left to right It can also be formed by connecting ring A and ring B in the direction opposite to the reading order from left to right Combinations of the linking groups, substituents, and/or variants thereof are only permitted if such combinations result in stable compounds.
  • C 1-6 alkyl is used to indicate a linear or branched saturated hydrocarbon group composed of 1 to 6 carbon atoms.
  • the C 1-6 alkyl group includes C 1-5 , C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-4 , C 6 and C 5 alkyl groups, etc.; it may Is monovalent (such as methyl), divalent (such as methylene) or multivalent (such as methine).
  • C 1-6 alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl) , S-butyl and t-butyl), pentyl (including n-pentyl, isopentyl and neopentyl), hexyl, etc.
  • C 1-3 alkyl is used to indicate a linear or branched saturated hydrocarbon group composed of 1 to 3 carbon atoms.
  • the C 1-3 alkyl group includes C 1-2 and C 2-3 alkyl groups, etc.; it can be monovalent (such as methyl), divalent (such as methylene) or multivalent (such as methine) .
  • Example C 1- 3 alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n- propyl and isopropyl) and the like.
  • C 1-3 alkoxy refers to those alkyl groups containing 1 to 3 carbon atoms attached to the rest of the molecule through an oxygen atom.
  • the C 1-3 alkoxy group includes C 1-2 , C 2-3 , C 3 and C 2 alkoxy groups and the like.
  • Examples of C 1-3 alkoxy include but are not limited to methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy) and the like.
  • C 3-8 cycloalkenyl means a partially unsaturated cyclic hydrocarbon group composed of 3 to 8 carbon atoms containing at least one carbon-carbon double bond, which includes monocyclic and bicyclic rings System, where the bicyclic ring system includes spiro ring, fused ring and bridged ring, any ring of this system is non-aromatic.
  • the C 3-8 cycloalkenyl includes C 3-6 , C 3-5 , C 4-10 , C 4-8 , C 4-6 , C 4-5 , C 5-8 or C 5-6 ring Alkenyl, etc.; it can be monovalent, divalent or multivalent.
  • C 3-8 cycloalkenyl examples include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl and the like.
  • C 6-8 cycloalkenyl means a partially unsaturated cyclic hydrocarbon group composed of 6 to 8 carbon atoms containing at least one carbon-carbon double bond, including monocyclic and bicyclic rings System, where the bicyclic ring system includes spiro ring, fused ring and bridged ring, any ring of this system is non-aromatic.
  • the C 6-8 cycloalkenyl group includes a C 6-7 or C 6-8 cycloalkenyl group, etc.; it may be monovalent, divalent or multivalent. Examples of C 6-8 cycloalkenyl include, but are not limited to, cyclohexenyl, cycloheptenyl, cyclooctenyl, and the like.
  • the term "3-8 membered heterocycloalkenyl" by itself or in combination with other terms means a partially unsaturated cyclic group consisting of 3 to 8 ring atoms containing at least one carbon-carbon double bond , Its 1, 2, 3 or 4 ring atoms are heteroatoms independently selected from O, S and N, and the rest are carbon atoms, wherein the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms can optionally be Oxidation (ie NO and S(O) p , p is 1 or 2). It includes monocyclic, bicyclic and tricyclic ring systems. The bicyclic and tricyclic ring systems include spiro, fused and bridged rings.
  • any ring in this system is non-aromatic.
  • a heteroatom may occupy the connection position of the heterocycloalkenyl group with the rest of the molecule.
  • the 3-8 membered heterocycloalkenyl group includes 3-6 membered, 3-5 membered, 4-6 membered, 4-5 membered, 5-6 membered, 4-membered, 5-membered, and 6-membered heterocycloalkenyl group.
  • Examples of 3-8 membered heterocycloalkenyl include but are not limited to
  • the term "3-8 membered heterocycloalkyl" by itself or in combination with other terms means a saturated cyclic group consisting of 3 to 8 ring atoms, with 1, 2, 3 or 4 ring atoms Are heteroatoms independently selected from O, S and N, and the rest are carbon atoms, wherein nitrogen atoms are optionally quaternized, and nitrogen and sulfur heteroatoms can be optionally oxidized (ie, NO and S(O) p , p Is 1 or 2). It includes monocyclic and bicyclic ring systems, where the bicyclic ring system includes spiro, fused, and bridged rings.
  • a heteroatom may occupy the connection position of the heterocycloalkyl group with the rest of the molecule.
  • the 3-8 membered heterocycloalkyl group includes 3-6 membered, 3-5 membered, 4-6 membered, 5-6 membered, 4-membered, 5-membered and 6-membered heterocycloalkyl group.
  • 3-8 membered heterocycloalkyl groups include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothienyl ( Including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2- Piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), Dioxanyl, dithiazyl, isoxazolidinyl, isothiazolidin
  • C n-n+m or C n -C n+m includes any specific case of n to n+m carbons, for example, C 1-12 includes C 1 , C 2 , C 3 , C 4, C 5, C 6, C 7, C 8, C 9, C 10, C 11, and C 12, also including any one of n + m to n ranges, for example C 1- 3 comprises a C 1-12 , C 1-6 , C 1-9 , C 3-6 , C 3-9 , C 3-12 , C 6-9 , C 6-12 , and C 9-12, etc.; in the same way, from n to n +m means the number of atoms in the ring is n to n+m, for example, 3-12 membered ring includes 3-membered ring, 4-membered ring, 5-membered ring, 6-membered ring, 7-membered ring, 8-membered ring, 9-membered ring , 10-membered ring, 11-member
  • leaving group refers to a functional group or atom that can be replaced by another functional group or atom through a substitution reaction (for example, an affinity substitution reaction).
  • representative leaving groups include triflate; chlorine, bromine, iodine; sulfonate groups, such as mesylate, tosylate, p-bromobenzenesulfonate, p-toluenesulfonic acid Esters, etc.; acyloxy groups such as acetoxy, trifluoroacetoxy and the like.
  • protecting group includes, but is not limited to, "amino protecting group", “hydroxy protecting group” or “thiol protecting group”.
  • amino protecting group refers to a protecting group suitable for preventing side reactions at the amino nitrogen position.
  • Representative amino protecting groups include, but are not limited to: formyl; acyl, such as alkanoyl (such as acetyl, trichloroacetyl or trifluoroacetyl); alkoxycarbonyl, such as tert-butoxycarbonyl (Boc) ; Arylmethyloxycarbonyl, such as benzyloxycarbonyl (Cbz) and 9-fluorenylmethyloxycarbonyl (Fmoc); arylmethyl, such as benzyl (Bn), trityl (Tr), 1,1-di -(4'-Methoxyphenyl)methyl; silyl groups, such as trimethylsilyl (TMS) and tert-butyldi
  • hydroxy protecting group refers to a protecting group suitable for preventing side reactions of the hydroxyl group.
  • Representative hydroxy protecting groups include but are not limited to: alkyl groups, such as methyl, ethyl, and tert-butyl; acyl groups, such as alkanoyl groups (such as acetyl); arylmethyl groups, such as benzyl (Bn), p-methyl Oxybenzyl (PMB), 9-fluorenylmethyl (Fm) and diphenylmethyl (diphenylmethyl, DPM); silyl groups such as trimethylsilyl (TMS) and tert-butyl Dimethylsilyl (TBS) and so on.
  • alkyl groups such as methyl, ethyl, and tert-butyl
  • acyl groups such as alkanoyl groups (such as acetyl)
  • arylmethyl groups such as benzyl (Bn), p-methyl Oxybenzyl (P
  • the structure of the compound of the present invention can be confirmed by conventional methods well known to those skilled in the art. If the present invention relates to the absolute configuration of the compound, the absolute configuration can be confirmed by conventional technical means in the art.
  • SXRD single crystal X-ray diffraction
  • the cultured single crystal is collected with a Bruker D8 venture diffractometer to collect diffraction intensity data
  • the light source is CuK ⁇ radiation
  • the scanning method After scanning and collecting relevant data, the direct method (Shelxs97) is further used to analyze the crystal structure to confirm the absolute configuration.
  • the compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, the embodiments formed by combining them with other chemical synthesis methods, and those well known to those skilled in the art Equivalent alternatives, preferred implementations include but are not limited to the embodiments of the present invention.
  • the solvent used in the present invention is commercially available.
  • the present invention uses the following abbreviations: aq stands for water; HATU stands for O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate ; EDC stands for N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride; m-CPBA stands for 3-chloroperoxybenzoic acid; eq stands for equivalent, equivalent amount; CDI stands for Carbonyl diimidazole; DCM stands for dichloromethane; PE stands for petroleum ether; DIAD stands for diisopropyl azodicarboxylate; DMF stands for N,N-dimethylformamide; DMSO stands for dimethyl sulfoxide; EtOAc stands for ethyl acetate Esters; EtOH stands for ethanol; MeOH stands for methanol; CB
  • the compound of the present invention has significant THR ⁇ / ⁇ activity and THR ⁇ selectivity. It has no inhibitory effect on CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4-M or weakly inhibits some of them, and shows high protein binding rate in human plasma.
  • the compound of the present invention has higher exposure and better oral bioavailability.
  • reaction solution was diluted with water (10mL) and ethyl acetate (20mL), separated, the aqueous phase was extracted with ethyl acetate (10mL*2), the organic phases were combined, and then washed with saturated brine (10mL*2), It was dried with anhydrous sodium sulfate, filtered to remove the desiccant, and the solvent was removed under reduced pressure to obtain the crude product.
  • MS-ESI m/z 326.1 [M+H] + , 328.1 [M+H+2] + .
  • WX001-8 (0.09g, 275.92 ⁇ mol) to the pre-dried reaction flask, then dissolve it with AcOH (2mL), then add hydrochloric acid (83.68mg, 849.22 ⁇ mol, 82.04 ⁇ L, 37% purity) to reduce the reaction system to At 5°C, add sodium nitrite (20.94mg, 303.52 ⁇ mol) in H 2 O (1mL) solution, stir and react at 5°C for 0.5 hours, and add WX001-9 (47.39mg, 303.52 ⁇ mol) after the raw material has been reacted. Stir at °C for 15 minutes.
  • reaction solution was cooled to room temperature, then poured into water (500mL), added with methyl tert-butyl ether (500mL*3) for extraction, combined all the organic phases, the organic phase was saturated with sodium chloride solution ( 500mL*2) Wash, dry with anhydrous sodium sulfate, filter, and concentrate to obtain a crude product.
  • reaction solution was directly concentrated under reduced pressure, the concentrate was adjusted to pH 7-8 with saturated sodium bicarbonate solution (50mL), the aqueous phase was extracted with ethyl acetate (50mL*3), the organic phases were combined, and washed with saturated brine (30mL*2), collect the organic phase, dry with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain a crude product.
  • WX004-1 (10g, 64.08mmol, 6.54mL, 1eq)
  • WX004-2 (5.84g, 64.08mmol, 1eq)
  • ethanol 140mL
  • 1 H NMR 400MHz, DMSO-d 6 ) ⁇ 12.99 (s, 1H), 12.45 (s, 1H).
  • MS-ESI m/z 182.0 [M+H] + .
  • reaction solution was quenched with water (40mL), the aqueous phase was extracted with ethyl acetate (40mL*3), the organic phases were combined, washed with saturated brine (40mL*2), the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and reduced pressure Concentrate to obtain a crude product.
  • reaction solution was quenched with water (50mL), the aqueous phase was extracted with ethyl acetate (50mL*3), the organic phases were combined, washed with saturated brine (50mL*2), the organic phase was collected, and dried over anhydrous sodium sulfate. Filter and concentrate under reduced pressure to obtain a crude product.
  • WX002-4 (6.92g, 28.61mmol) to the pre-dried reaction flask, then dissolve it with N,N-dimethylacetamide (31mL), then add potassium tert-butoxide (3.85g, 34.33mmol) and heat The reaction was stirred at 100°C for 1 hour, and then a solution of WX001-3 (6.1 g, 30.04 mmol) and N,N-dimethylacetamide (15.5 mL) was added, and the reaction was stirred at 130°C for 64 hours.
  • the reaction system was cooled to room temperature (20°C), diluted with water (150 mL) and ethyl acetate (100 mL), separated and collected the organic phase, the aqueous phase was extracted with ethyl acetate (100 mL*2), and the organic phases were combined Then, it was washed with saturated brine (200 mL*4), dried over anhydrous sodium sulfate, filtered to remove the desiccant, and the filtrate was concentrated under reduced pressure to obtain a residue.
  • reaction solution was quenched with 2M hydrochloric acid solution (20mL), the aqueous phase was extracted with methyl tert-butyl ether (30mL*3), the organic phases were combined, washed with saturated brine (30mL*3), and the organic phase was collected. It was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain compound WX006-6.
  • reaction solution was directly concentrated under reduced pressure, the concentrated solution was added to ice water (50mL), the pH was adjusted to 7-8 with sodium bicarbonate solid, the aqueous phase was extracted with ethyl acetate (50mL*3), the organic phases were combined and saturated Wash with brine (50 mL*2), collect the organic phase, dry with anhydrous sodium sulfate, filter and concentrate under reduced pressure to obtain a crude product.
  • reaction solution was cooled to room temperature, adjusted to pH 7-8 with 2N hydrochloric acid solution (20mL), the aqueous phase was extracted with ethyl acetate (30mL*3), washed with saturated brine, dried with anhydrous sodium sulfate, filtered, and reduced Press and concentrate to obtain a crude product.
  • MS-ESI m/z 358.0 [M+H] + .
  • the crude product was separated by high performance liquid chromatography (column: Waters Xbridge BEH C18 100*30mm*10 ⁇ m; mobile phase: [Water (10mM ammonium bicarbonate)) -Acetonitrile]; Acetonitrile%: 25%-45%, 10 minutes) to obtain WX006-9A.
  • NOE 400MHz, deuterated chloroform detects the correlation between the methyl hydrogen (1.34) on the six-membered methyl ring and the hydrogen (8.69) on the pyridazine ring, which proves that the structure of WX006-9 is correct.
  • WX008-4 (1g, 2.56mmol, 1eq), WX004-9 (2.37g, 5.13mmol, 2eq), 1,2-dichloroethane (30mL), copper acetate (931.10mg, 5.13mmol, 2eq), Pyridine (405.49mg, 5.13mmol, 413.76 ⁇ L, 2eq) was added to the reaction flask, and then reacted at 60°C for 12 hours. After the reaction was completed, the reaction solution was filtered, the filter cake was washed with 15 mL of 1,2-dichloroethane, and the filtrate was spin-dried to obtain a crude product.
  • Retention time 2.36 minutes (Instrument: Thar analytical SFC; Column: S, S_whelk_01 3.5 ⁇ m, 0.46cm id x 5cm L; Mobile phase: Mobile phase: A: food grade supercritical carbon dioxide; B: methanol (0.05% isopropylamine, Volume ratio); Gradient: B content increased from 5% to 50% in 4 minutes; Flow rate: 4.0 mL/min; Column temperature: 35°C; Detection wavelength: 220 nm; System back pressure: 100 bar).
  • WX011-9 (250.00mg, 652.35 ⁇ mol, 1eq) was added to the pre-dried reaction flask, ethanol (2mL) and 2M hydrochloric acid (2mL) were added, the reaction solution was heated to 80°C and stirred for 12 hours.
  • reaction solution After the reaction is completed, slowly add the reaction solution to room temperature water (200 mL), then neutralize the pH of the reaction solution to about 7 with saturated sodium bicarbonate solution, add dichloromethane (200 mL) to dilute, and separate and collect the organic phase.
  • the aqueous phase was extracted with dichloromethane (200mL*2), the organic phases were combined, washed with saturated brine (200mL*2), dried over anhydrous sodium sulfate, filtered to remove the desiccant, and the solvent was removed under reduced pressure to obtain the crude product WX012-6 .
  • WX013-3 (2g, 9.51mmol, 1eq), tetrahydrofuran (10mL), water (3mL), methanol (3mL), sodium hydroxide (951.29mg, 23.78mmol, 2.5eq) were added to the reaction flask, and then 25 React for 12 hours at °C. After the reaction is completed, add hydrochloric acid to the reaction solution to adjust the pH to 5, then spin dry, soak in methanol, filter and spin dry to obtain WX013-4. MS-ESI m/z: 181.0 [MH] + .
  • WX013-7 (0.165g, 767.16 ⁇ mol, 1eq)
  • WX001-4 (341.42mg, 1.92mmol, 2.5eq)
  • N,N-dimethylacetamide (5mL)
  • cesium carbonate (624.89mg, 1.92mmol, 2.5eq) was added to the reaction flask, and then reacted at 130°C for 4 hours.
  • WX013-8 (0.135g, 378.54 ⁇ mol, 1eq), acetic acid (3mL), and sodium acetate (77.63mg, 946.35 ⁇ mol, 2.5eq) were added to the reaction flask, and then reacted at 110°C for 12 hours. After the completion of the reaction, the reaction solution was spin-dried to obtain a crude product. The crude product was dissolved in ethyl acetate (30 mL). The pH of the solution was adjusted to 7-8 with sodium carbonate solution. The organic phase was separated and the organic phase was spin-dried to obtain WX013-9. MS-ESI m/z: 380.0 [M+H] + , 382.0 [M+H+2] + .
  • WX013-9 (0.13g, 341.90 ⁇ mol, 1eq)
  • ethanol 5mL
  • hydrochloric acid 12M, 142.46 ⁇ L, 5eq
  • WX013-12 was separated by supercritical chromatography (column: DAICEL CHIRALCEL OJ (250mm*30mm, 10 ⁇ m); mobile phase: [0.1% ammonia methanol]; methanol%: 25%-25%, 15min) to obtain WX013 and WX014.
  • Retention time 2.15 minutes (Instrument: CAS-TJ-ANA-SFC-A (Waters SFC-MS); Column: Chiralcel OJ-3 3 ⁇ m, 0.46cm id x 10cm L; Mobile phase: A: food-grade supercritical carbon dioxide ; B: methanol (0.05% diethylamine, volume ratio); gradient: the content of B increases from 10% to 40% within 5 minutes of the content of A; flow rate: 4.0 mL/min; column temperature: 35°C; detection wavelength : 220nm; system back pressure: 100bar).
  • Retention time 2.32 minutes (Instrument: CAS-TJ-ANA-SFC-A (Waters SFC-MS); Column: Chiralcel OJ-3 3 ⁇ m, 0.46cm id x 10cm L; Mobile phase: A: food-grade supercritical carbon dioxide ; B: methanol (0.05% diethylamine, volume ratio); gradient: the content of B increases from 10% to 40% within 5 minutes of the content of A; flow rate: 4.0mL/min; column temperature: 35°C; detection wavelength : 220nm; system back pressure: 100bar).
  • reaction solution was stirred at -20°C for 15 minutes, and then at -10°C for 5 minutes.
  • tetrahydrofuran 50mL
  • dimethyl disulfide 11.76g, 124.83mmol, 11.20mL, 1.05eq
  • the temperature was raised to 25°C and stirred for 2 hours.
  • the reaction solution was added to a saturated ammonium chloride aqueous solution (100 mL), and then extracted with methyl tert-butyl ether (200 mL*2). The organic phase was washed with saturated brine (50 mL*2).
  • WX015-3 (2.35g, 11.46mmol, 1eq) to the pre-dried reaction flask, then dissolve it with dimethyl sulfoxide (90mL), then add WX001-4 (3.06g, 17.19mmol, 1.5eq), carbonic acid Potassium (6.34g, 45.84mmol, 4eq), nitrogen pumping three times, adding cuprous iodide (1.31g, 6.88mmol, 0.6eq), nitrogen pumping again three times, raising to 90°C under nitrogen protection and stirring for reaction 17 hour.
  • WX015-4 and WX015-4A were hydrogenated under Pd/C and hydrogen conditions, and the chlorine at the ortho position of the nitrogen atom of each pyridazine ring was replaced by a hydrogen atom, and the structure was further judged by two-dimensional nuclear magnetism.
  • reaction solution was quenched with water (30mL), extracted with ethyl acetate (50mL*2), the combined organic phases were washed with saturated sodium bicarbonate (60mL), the organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure
  • WX015-10 (40.00mg, 55.98 ⁇ mol, 1eq) to the pre-dried library bottle, then dissolve it with acetonitrile (1.6mL), place it at 0°C and stir, then slowly add ceric ammonium nitrate (92.07mg, 167.95 ⁇ mol, 83.70 ⁇ L, 3eq) and water (0.8mL) mixed solution, then raised to 25°C and stirred for 2 hours.
  • the filter cake was concentrated under reduced pressure with an oil pump to obtain a crude product, which was separated by high performance liquid chromatography (column: Luna Omega 5u Polar C18 100A; mobile phase: [water (0.04% hydrochloric acid)-acetonitrile]; acetonitrile%: 28% -58%, 7min) to obtain WX016-5.
  • WX013-1 50g, 351.84mmol, 1eq
  • xylene 400mL
  • sulfolane 207.86g, 1.76mol, 5eq
  • the reaction solution was spin-dried to obtain a crude product.
  • WX017-1 (4.4g, 22.43mmol, 1eq) to the pre-dried reaction flask, then dissolve it with tetrahydrofuran (44mL), then add sodium iodide (1.68g, 11.21mmol, 0.5eq), trifluoromethyl trifluoromethyl Methyl silicon (7.97g, 56.07mmol, 2.5eq), slowly increase to 65°C and stir for 4 hours, add trifluoromethyl trimethylsilyl (7.97g, 56.07mmol, 2.5eq) at 65°C Continue to stir and react for 15 hours.
  • reaction solution was spin-dried with a water pump at 45°C, and then dissolved in dichloromethane (100mL), washed with water (100mL), 0.1N sodium thiosulfate (100mL), and saturated brine (100mL) in turn Then, it was concentrated under reduced pressure with a water pump at 45°C to obtain the crude product.
  • 1 HNMR 400MHz, deuterated chloroform
  • WX017-2 (3.59g, 14.58mmol, 1eq) to the pre-dried reaction flask, then dissolve it with methanol (17mL), then add sodium hydroxide solution (5.83g, 14.58mmol, 17mL, 10% purity, 1eq) The reaction was stirred at room temperature (25°C) for 14 hours. After the reaction is completed, the pH of the reaction solution is neutralized to about 6 with 1N hydrochloric acid, and directly concentrated under reduced pressure to obtain WX017-3.
  • WX017-3 (3.18g, 14.58mmol, 1eq) was added to the pre-dried reaction flask, and then dissolved with trifluoroacetic anhydride (32mL), and the reaction was stirred at room temperature (25°C) for 14 hours. After the completion of the reaction, the reaction solution was concentrated under reduced pressure with a water pump at 45°C to obtain WX017-4.
  • WX017-6 300mg, 1.19mmol, 1eq
  • WX017-7 365.58mg, 1.31mmol, 1.1eq
  • toluene 10mL
  • potassium phosphate 507.30mg, 2.39mmol, 2eq
  • 2-di-tert-butylphosphine-2',4',6'-triisopropylbiphenyl 101.48mg, 238.99 ⁇ mol, 0.2eq
  • palladium acetate 53.65mg, 238.99 ⁇ mol, 0.2eq
  • WX018-1 (5.2g, 13.71mmol, 1eq), tert-butanol (20mL), water (70mL) and acetonitrile (20mL) were added to the reaction flask, the temperature was reduced to 0°C after the nitrogen was changed, and then osmium tetroxide ( 348.43mg, 1.37mmol, 71.11 ⁇ L, 0.1eq) and sodium periodate (5.86g, 27.41mmol, 1.52mL, 2eq), the mixed solution reacted at 25°C for 3 hours.
  • osmium tetroxide 348.43mg, 1.37mmol, 71.11 ⁇ L, 0.1eq
  • sodium periodate 5.86g, 27.41mmol, 1.52mL, 2eq
  • WX018-8 (100mg, 194.12 ⁇ mol, 1eq), water (0.5mL) and dimethyl sulfoxide (1mL) were added to the pre-dried reaction flask, the nitrogen was pumped three times, and the temperature was raised to 50°C and stirred for 24 hours. After the reaction is completed, the reaction solution is directly filtered, and the filtrate is separated and purified by high performance liquid chromatography (condition: Column: Welch Xtimate C18 150*25mm*5 ⁇ m; mobile phase: [water (0.04% hydrochloric acid)-acetonitrile]; acetonitrile%: 30%-45%, 10 minutes) to obtain WX019-1.
  • reaction solution was carefully added to ice water (300mL) to quench, and then extracted with ethyl acetate (100mL*3), the organic phase was washed with saturated ammonium chloride solution (100mL*2), anhydrous sodium sulfate Dry, filter, and concentrate under reduced pressure to obtain a crude product.
  • WX020-2 (55g, 233.70mmol, 1eq) in a dry 1L round bottom flask, then add absolute ethanol (550mL) and methyl iodide (49.76g, 350.55mmol, 21.82mL, 1.5eq), stir and react at 80°C 1.5 hours. After the completion of the reaction, the reaction solution was concentrated to dryness, and then tetrahydrofuran (100 mL) was added for beating to obtain WX020-3.
  • absolute ethanol 550mL
  • methyl iodide 49.76g, 350.55mmol, 21.82mL, 1.5eq
  • reaction solution was diluted with water (50mL), separated, the organic phase was collected, the aqueous phase was extracted with dichloromethane (50mL*2), the organic phases were combined, and washed with saturated brine (50mL*2), anhydrous Dry over sodium sulfate, filter, and concentrate under reduced pressure to obtain a crude product.
  • the crude product is used on a high performance liquid chromatography column (column: Welch Xtimate C18 150*25mm*5 ⁇ m; mobile phase: [water (0.04% hydrochloric acid) )-Acetonitrile]; Acetonitrile%: 30%-50%, 10 minutes) to obtain WX021-3A.
  • NOE 400MHz, deuterated dimethyl sulfoxide shows that the hydrogen on the methoxy group (3.43) is correlated with H 1 (8.94), which proves that the structure of WX021-3 is correct.
  • WX021-7 is separated by supercritical chromatography (column: DAICEL CHIRALPAK AD (250mm*30mm, 10 ⁇ m); mobile phase: [carbon dioxide-isopropanol, 0.1% ammonia]; isopropanol%: 53%-53%, 7 Min]
  • DAICEL CHIRALPAK AD 250mm*30mm, 10 ⁇ m
  • mobile phase [carbon dioxide-isopropanol, 0.1% ammonia]
  • isopropanol% 53%-53%, 7 Min
  • Retention time 1.46 minutes (Instrument: Waters UPCC with PDA detactor; Column: Chiralpak AD-3, 50 ⁇ 4.6mm, ID, 3 ⁇ m; Mobile phase: A: food grade supercritical carbon dioxide; B: isopropanol (0.1% Diethylamine, volume ratio); Gradient: B content increased from 5% to 50% in 1.2 minutes and maintained for 1 minute, and then increased from 50% to 5% in 0.8 minutes; Flow rate: 3.4mL/min; Column temperature: 35°C; detection wavelength: 220nm; system back pressure: 100bar).
  • Retention time 1.71 minutes (Instrument: Waters UPCC with PDA detactor; Column: Chiralpak AD-3, 50 ⁇ 4.6mm, ID, 3 ⁇ m; Mobile phase: A: food grade supercritical carbon dioxide; B: isopropanol (0.1% Diethylamine, volume ratio); Gradient: B content increased from 5% to 50% in 1.2 minutes and maintained for 1 minute, and then increased from 50% to 5% in 0.8 minutes; Flow rate: 3.4mL/min; Column temperature: 35°C; detection wavelength: 220nm; system back pressure: 100bar).
  • WX007-1 (1.66g, 10.97mmol, 0.5eq) to the pre-dried reaction flask, then dissolve it with toluene (40mL), then add WX023-4 (4g, 21.94mmol, 1eq), then heat to 60°C and stir React for 1 hour.
  • the reaction system was cooled to room temperature (25°C), diluted with water (50mL) and ethyl acetate (50mL), separated into the organic phase, the aqueous phase was extracted with ethyl acetate (10mL*2), and the organic phases were combined , Washed with saturated brine (50mL*2), dried with anhydrous sodium sulfate, filtered to remove the desiccant, and concentrated under reduced pressure to obtain the crude product.
  • WX023-6 and WX023-7 were hydrogenated by Pd/C, the chlorine at the ortho position of the nitrogen atom of each pyridazine ring was replaced by a hydrogen atom, and the structure was judged by two-dimensional nuclear magnetism.
  • WX023-6 1 HNMR (400MHz, deuterated chloroform) ⁇ 7.46 (s, 2H), 6.66 (br s, 1H), 3.07-2.94 (m, 1H), 2.41-2.49 (m, 1H), 2.37- 2.24 (m, 2H), 1.92-1.75 (m, 2H), 1.52 (s, 9H), 1.34-1.28 (m, 1H), 1.07-1.00 (m, 1H).
  • WX023-7 1 HNMR (400MHz, deuterated chloroform) ⁇ 7.43 (s, 2H), 6.68 (br s, 1H), 3.22-3.10 (m, 1H), 2.37-2.24 (m, 3H), 1.84– 1.94 (m, 1H), 1.83-1.72 (m, 1H), 1.51 (s, 9H), 1.31-1.26 (m, 1H), 1.09-1.00 (m, 1H).
  • WX023-6A 1 H NMR (400MHz, deuterated methanol) ⁇ 8.91(s,1H), 7.71-7.79(m,1H),7.44-7.37(m,1H),7.32-7.28(m,1H), 2.99-2.89 (m, 1H), 2.70-2.59 (m, 2H), 2.44-2.35 (m, 1H), 2.20-2.12 (m, 1H), 1.83-1.71 (m, 1H), 1.59-1.55 (m ,1H),1.53(s,9H),1.49-1.41(m,1H).
  • Retention time 1.478 minutes (Instrument: Waters UPCC with PDA detactor; Column: Chiralpak AS-3, 50*4.6mm, ID, 3 ⁇ m; Mobile phase: A: food grade supercritical carbon dioxide; B: methanol (0.05% diethyl Amine, volume ratio); Gradient: B content increased from 5% to 50% in 1.2 minutes, 50% maintained for 1 minute, and then decreased from 50% to 5% in 0.8 minutes; Flow rate: 3.4 mL/min; Column Temperature: 35°C; Detection wavelength: 220nm; System back pressure: 100bar).
  • Retention time 1.696 minutes (Instrument: Waters UPCC with PDA detactor; Column: Chiralpak AS-3, 50*4.6mm, ID, 3 ⁇ m; Mobile phase: A: food grade supercritical carbon dioxide; B: methanol (0.05% diethyl Amine, volume ratio); Gradient: B content increased from 5% to 50% in 1.2 minutes, 50% maintained for 1 minute, and then decreased from 50% to 5% in 0.8 minutes; Flow rate: 3.4 mL/min; Column Temperature: 35°C; Detection wavelength: 220nm; System back pressure: 100bar).
  • REGIS(s, s) WHELK-O1 250mm*30mm, id.10 ⁇
  • mobile phase A carbon dioxide B methanol (0.1% ammonia)
  • gradient: methanol% 55 % Isocratic elution mode; flow rate: 80g/min; column temperature: 40°C; system back pressure: 100bar
  • Retention time 2.182 minutes (Instrument: Waters Acquity UPC 2 ; Column: (S, S)-WHELK-O1, 3.5 ⁇ m, 0.46cm id x 5cm L; Mobile phase: A: food grade supercritical carbon dioxide; B: methanol (0.05% diethylamine, volume ratio); Gradient: B content increased from 5% to 50% in 1.2 minutes, 50% maintained for 1 minute, and then decreased from 50% to 5% in 0.8 minutes; Flow rate: 3.4 mL/min; column temperature: 35°C; detection wavelength: 220nm; system back pressure: 1800psi).
  • Retention time 2.507 minutes (Instrument: Waters Acquity UPC 2 ; Column: (S, S)-WHELK-O1, 3.5 ⁇ m, 0.46cm id x 5cm L; Mobile phase: A: food grade supercritical carbon dioxide; B: methanol (0.05% diethylamine, volume ratio); Gradient: B content increased from 5% to 50% in 1.2 minutes, 50% maintained for 1 minute, and then decreased from 50% to 5% in 0.8 minutes; Flow rate: 3.4 mL/min; column temperature: 35°C; detection wavelength: 220nm; system back pressure: 1800psi).
  • reaction liquid system was lowered to room temperature (25°C), and then neutralized to about 7 with saturated sodium bicarbonate solution, diluted with ethyl acetate (10 mL), separated, the organic phase was used, and the aqueous phase was acetic acid Ethyl (10mL*2) was extracted, the organic phases were combined, washed with saturated brine (20mL*2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure with a water pump at 45°C to obtain WX027-5.
  • WX027-6 (0.045g, 121.42 ⁇ mol, 1eq) to a 40mL library bottle, add acetic acid (2mL) and concentrated hydrochloric acid (12M, 31.16 ⁇ L, 3.08eq), cool to 5°C, add sodium nitrite (9.22 mg, 133.56 ⁇ mol, 1.1 eq) in water (1 mL), then stirred at 5°C for 0.5 hours, added WX001-9 (20.85 mg, 133.56 ⁇ mol, 1.1 eq), and stirred at 5°C for 0.5 hours.
  • WX027-7 (0.03g, 55.79 ⁇ mol, 1eq) to a 40mL throwing library bottle, add N,N-dimethylacetamide (2mL) to dissolve the substrate, add potassium acetate (6.02mg, 61.37 ⁇ mol, 1.1 eq), heated to 115°C and stirred for 3 hours. After completion of the reaction, the reaction solution was filtered and separated by high performance liquid chromatography (column: Phenomenex Luna C18 100*30mm*5 ⁇ m; mobile phase: [water (0.04% hydrochloric acid)-acetonitrile]; acetonitrile%: 35%-55% , 9min) purified to obtain WX027.
  • WX028-3 (0.4g, 1.11mmol, 1eq) to a 40mL throwing library bottle, add glacial acetic acid (4mL) and hydrochloric acid (12M, 285.40 ⁇ L, 3.08eq), cool to 5°C, add sodium nitrite (84.40 mg, 1.22mmol, 1.1eq) in water (2mL), then stirred at 5°C for 0.5 hours, added WX001-9 (190.98mg, 1.22mmol, 1.1eq), and stirred at 5°C for 0.5 hours.
  • WX028-4 (0.25g, 474.52 ⁇ mol, 1eq) to a 40mL throwing library bottle, add N,N-dimethylacetamide (2mL) to dissolve the substrate, add potassium acetate (51.23mg, 521.97 ⁇ mol, 1.1 eq), heated to 115°C and stirred for 1 hour. After the reaction is completed, the reaction solution is directly filtered, and the filtrate is subjected to high performance liquid chromatography (column: Phenomenex luna C18 80*40mm*3 ⁇ m; mobile phase: [water (0.04% hydrochloric acid)-acetonitrile]; acetonitrile%: 37%-57% , 7min) purified to obtain WX028.

Abstract

Pyridazinone derivatives as thyroxine receptor-β agonists, and application thereof in preparing medicines for diseases related to thyroxine receptor-β agonists. Specifically disclosed is a compound represented by formula (I), or a pharmaceutically acceptable salt thereof.

Description

作为甲状腺素受体-β激动剂的哒嗪酮类衍生物及其应用Pyridazinone derivatives as thyroxine receptor-β agonist and application thereof
本申请主张如下优先权：This application claims the following priority:
CN201910459299.X，申请日2019-05-29；CN201910459299.X, application date 2019-05-29;
CN201910741177.X，申请日2019-08-12；CN201910741177.X, application date 2019-08-12;
CN201911130068.0，申请日2019-11-18；CN201911130068.0, application date 2019-11-18;
CN202010076525.9，申请日2020-01-23；CN202010076525.9, application date 2020-01-23;
CN202010188909.X，申请日2020-03-17；CN202010188909.X, application date 2020-03-17;
CN202010409420.0，申请日2020-05-14。CN202010409420.0, application date 2020-05-14.
技术领域Technical field
本发明涉及一系列作为甲状腺素受体-β激动剂的哒嗪酮类衍生物，及其在制备甲状腺素受体-β激动剂相关疾病的药物中的应用。具体涉及式(I)所示化合物或其药学上可接受的盐。The present invention relates to a series of pyridazinone derivatives as thyroxine receptor-beta agonists, and their application in preparing medicines for diseases related to thyroxine receptor-beta agonists. Specifically, it relates to a compound represented by formula (I) or a pharmaceutically acceptable salt thereof.
背景技术Background technique
甲状腺激素在人体内有非常重要的作用，包括控制人体整体代谢、蛋白合成、脂肪代谢、神经元和骨骼生长，以及调节心脏和肾脏功能。它由甲状腺分泌。下丘脑和垂体通过分泌促甲状腺激素释放激素和促甲状腺激素的经典负反馈机制严格调控甲状腺分泌甲状腺素。近年来，肥胖及其并发症，糖尿病，代谢综合症，动脉粥样硬化以及非酒精性脂肪肝炎的发病率成上升趋势。因此，人们希望开发甲状腺激素及其类似物用于临床治疗。Thyroid hormones play a very important role in the human body, including controlling the body's overall metabolism, protein synthesis, fat metabolism, neuron and bone growth, and regulating the function of the heart and kidneys. It is secreted by the thyroid. The hypothalamus and pituitary gland strictly regulate the secretion of thyroid hormone through the classic negative feedback mechanism of thyroid stimulating hormone releasing hormone and thyroid stimulating hormone. In recent years, the incidence of obesity and its complications, diabetes, metabolic syndrome, atherosclerosis and non-alcoholic steatohepatitis has been on the rise. Therefore, people hope to develop thyroid hormone and its analogues for clinical treatment.
甲状腺激素通过结合两个高度同源的受体行使转录调节功能，它们是甲状腺受体α(THRα)和甲状腺受体β(THRβ)。THRα主要分布在大脑、心脏和骨骼肌，能够控制心率；THRβ主要分布在肝脏和大脑，可以降低胆固醇，提高代谢速率(Curr Atheroscler Rep(2016)18(3):14；PNAS(2003),100(17),10067-10072)。人们在开发甲状腺激素及其类似物成药过程中，发现了心脏和骨骼的副作用，阻碍了进一步的临床开发。研究发现，该副作用可能是甲状腺激素类似物与THRα结合导致的(J.Med.Chem.(2014),57,3912-3923)。因此，开发肝脏组织分布特异性和甲状腺激素受体亚型选择性高的甲状腺激素类似物具有重大的临床价值。Thyroid hormones perform transcriptional regulation by binding to two highly homologous receptors, which are thyroid receptor alpha (THRα) and thyroid receptor beta (THRβ). THRα is mainly distributed in the brain, heart and skeletal muscle, which can control heart rate; THRβ is mainly distributed in the liver and brain, which can lower cholesterol and increase the metabolic rate (Curr Atheroscler Rep(2016)18(3):14; PNAS(2003), 100 (17), 10067-10072). During the development of thyroid hormones and their analogues, side effects of the heart and bones were discovered, which hindered further clinical development. Studies have found that this side effect may be caused by the combination of thyroid hormone analogues and THRα (J. Med. Chem. (2014), 57, 3912-3923). Therefore, the development of thyroid hormone analogs with specific liver tissue distribution and high thyroid hormone receptor subtype selectivity has great clinical value.
基于文献(J.Med.Chem.2014,57,3912-3923)报道，THRβ激动剂MGL-3196结构如下：Based on the report (J.Med.Chem.2014,57,3912-3923), the structure of the THRβ agonist MGL-3196 is as follows:
Figure PCTCN2020093284-appb-000001
Figure PCTCN2020093284-appb-000001
发明内容Summary of the invention
本发明提供了式(I)所示化合物或其药学上可接受的盐，The present invention provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof,
Figure PCTCN2020093284-appb-000002
Figure PCTCN2020093284-appb-000002
其中，among them,
Figure PCTCN2020093284-appb-000003
选自单键和双键；
Figure PCTCN2020093284-appb-000003
Selected from single bond and double bond;
T 1选自NR a； T 1 is selected from NR a ;
T 2选自C、CH和N； T 2 is selected from C, CH and N;
T 3选自CR b和N； T 3 is selected from CR b and N;
T 4选自CR c和O； T 4 is selected from CR c and O;
R a选自H和C 1-3烷基； R a is selected from H and C 1-3 alkyl;
R b和R c分别独立地选自H、F、Cl、Br、I、OH、NH 2、CN、C 1-3烷基和C 1-3烷氧基，所述C 1-3烷基和C 1- 3烷氧基任选被1、2或3个R取代； R b and R c are each independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, C 1-3 alkyl and C 1-3 alkoxy, the C 1-3 alkyl and C 1- 3 alkoxy group optionally substituted with 1, 2 or 3 R <
且当R c选自H或CN时，R 1、R 2和与它们相连的原子共同构成C 3-8环烯基或3-8元杂环烯基，所述C 3-8环烯基和3-8元杂环烯基任选被1、2或3个R e取代； And when R c is selected from H or CN, R 1 , R 2 and the atoms connected to them together form a C 3-8 cycloalkenyl group or a 3-8 membered heterocycloalkenyl group, the C 3-8 cycloalkenyl group And 3-8 membered heterocycloalkenyl groups are optionally substituted with 1, 2 or 3 R e ;
当R c选自F、Cl、Br、I、OH、NH 2和任选被1、2或3个R取代的C 1-3烷基和C 1-3烷氧基时，R 1和R 2分别独立地选自H和任选被1、2或3个R d取代的C 1-6烷基，或者，R 1、R 2和与它们相连的原子共同构成C 3-8环烯基或3-8元杂环烯基，所述C 3-8环烯基和3-8元杂环烯基任选被1、2或3个R e取代； When R c is selected from F, Cl, Br, I, OH, NH 2 and C 1-3 alkyl and C 1-3 alkoxy optionally substituted by 1, 2 or 3 R, R 1 and R 2 are independently selected from H and C 1-6 alkyl optionally substituted by 1, 2 or 3 R d , or R 1 , R 2 and the atoms connected to them together form a C 3-8 cycloalkenyl Or a 3-8 membered heterocycloalkenyl group, the C 3-8 cycloalkenyl group and 3-8 membered heterocycloalkenyl group are optionally substituted by 1, 2 or 3 R e ;
R 3和R 4分别独立地选自H、F、Cl、Br、I、OH、NH 2、CN和任选被1、2或3个R f取代的C 1-3烷基； R 3 and R 4 are each independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, and C 1-3 alkyl optionally substituted with 1, 2 or 3 R f ;
R d、R e和R f分别独立地选自H、F、Cl、Br、I、OH、NH 2、CN和C 1-3烷基； R d, R e and R f are each independently selected from H, F, Cl, Br, I, OH, NH 2, CN and C 1-3 alkyl;
各R分别独立地选自H、F、Cl、Br、I、OH、NH 2、CN和C 1-3烷基； Each R is independently selected from H, F, Cl, Br, I, OH, NH 2 , CN and C 1-3 alkyl;
所述3-8元杂环烯基包含1、2、3或4个独立选自-NH-、-O-、-S-和N的杂原子或杂原子团。The 3-8 membered heterocycloalkenyl group includes 1, 2, 3 or 4 heteroatoms or heteroatom groups independently selected from -NH-, -O-, -S- and N.
本发明提供了式(I)所示化合物或其药学上可接受的盐，The present invention provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof,
Figure PCTCN2020093284-appb-000004
Figure PCTCN2020093284-appb-000004
其中，among them,
Figure PCTCN2020093284-appb-000005
选自单键和双键；
Figure PCTCN2020093284-appb-000005
Selected from single bond and double bond;
T 1选自NR a； T 1 is selected from NR a ;
T 2选自C、CH和N； T 2 is selected from C, CH and N;
T 3选自CR b和N； T 3 is selected from CR b and N;
T 4选自CR c和O； T 4 is selected from CR c and O;
R a选自H和C 1-3烷基； R a is selected from H and C 1-3 alkyl;
R b和R c分别独立地选自H、F、Cl、Br、I、OH、NH 2、CN、C 1-3烷基和C 1-3烷氧基，所述C 1-3烷基和C 1- 3烷氧基任选被1、2或3个R取代； R b and R c are each independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, C 1-3 alkyl and C 1-3 alkoxy, the C 1-3 alkyl and C 1- 3 alkoxy group optionally substituted with 1, 2 or 3 R <
且当R c选自H或CN时，R 1、R 2和与它们相连的原子共同构成C 3-8环烯基或3-8元杂环烯基，所述C 3-8环烯基和3-8元杂环烯基任选被1、2或3个R e取代； And when R c is selected from H or CN, R 1 , R 2 and the atoms connected to them together form a C 3-8 cycloalkenyl group or a 3-8 membered heterocycloalkenyl group, the C 3-8 cycloalkenyl group And 3-8 membered heterocycloalkenyl groups are optionally substituted with 1, 2 or 3 R e ;
当R c选自F、Cl、Br、I、OH、NH 2和任选被1、2或3个R取代的C 1-3烷基和C 1-3烷氧基时，R 1和R 2分别独立地选自H和任选被1、2或3个R d取代的C 1-6烷基，或者，R 1、R 2和与它们相连的原子共同构成噻吩基、C 3-8环烯基或3-8元杂环烯基，所述C 3-8环烯基和3-8元杂环烯基任选被1、2或3个R e取代； When R c is selected from F, Cl, Br, I, OH, NH 2 and C 1-3 alkyl and C 1-3 alkoxy optionally substituted by 1, 2 or 3 R, R 1 and R 2 are independently selected from H and C 1-6 alkyl optionally substituted by 1, 2 or 3 R d , or R 1 , R 2 and the atoms connected to them together form a thienyl group, C 3-8 Cycloalkenyl or 3-8 membered heterocycloalkenyl, the C 3-8 cycloalkenyl and 3-8 membered heterocycloalkenyl are optionally substituted with 1, 2 or 3 R e ;
R 3和R 4分别独立地选自H、F、Cl、Br、I、OH、NH 2、CN和任选被1、2或3个R f取代的C 1-3烷基； R 3 and R 4 are each independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, and C 1-3 alkyl optionally substituted with 1, 2 or 3 R f ;
R d、R e和R f分别独立地选自H、F、Cl、Br、I、OH、NH 2、CN和C 1-3烷基； R d, R e and R f are each independently selected from H, F, Cl, Br, I, OH, NH 2, CN and C 1-3 alkyl;
各R分别独立地选自H、F、Cl、Br、I、OH、NH 2、CN和C 1-3烷基； Each R is independently selected from H, F, Cl, Br, I, OH, NH 2 , CN and C 1-3 alkyl;
所述3-8元杂环烯基包含1、2、3或4个独立选自-NH-、-O-、-S-和N的杂原子或杂原子团。The 3-8 membered heterocycloalkenyl group contains 1, 2, 3 or 4 heteroatoms or heteroatom groups independently selected from -NH-, -O-, -S- and N.
本发明提供了式(I)所示化合物或其药学上可接受的盐，The present invention provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof,
Figure PCTCN2020093284-appb-000006
Figure PCTCN2020093284-appb-000006
其中，among them,
Figure PCTCN2020093284-appb-000007
选自单键和双键；
Figure PCTCN2020093284-appb-000007
Selected from single bond and double bond;
T 1为NR a； T 1 is NR a ;
T 2选自C、CH和N； T 2 is selected from C, CH and N;
T 3选自CR b和N； T 3 is selected from CR b and N;
T 4选自CR c和O； T 4 is selected from CR c and O;
R a选自H和C 1-3烷基； R a is selected from H and C 1-3 alkyl;
R b和R c分别独立地选自H、F、Cl、Br、I、OH、NH 2、CN、C 1-3烷基和C 1-3烷氧基，所述C 1-3烷基和C 1- 3烷氧基任选被1、2或3个R取代； R b and R c are each independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, C 1-3 alkyl and C 1-3 alkoxy, the C 1-3 alkyl and C 1- 3 alkoxy group optionally substituted with 1, 2 or 3 R <
且当R c选自F、Cl、Br、I、OH、NH 2和任选被1、2或3个R取代的C 1-3烷基和C 1-3烷氧基时，R 1和R 2分别独立地选自H和任选被1、2或3个R d取代的C 1-6烷基，或者，R 1、R 2和与它们相连的原子共同构成噻吩基、C 3-8环烯基或3-8元杂环烯基，所述噻吩基、C 3-8环烯基和3-8元杂环烯基任选被1、2或3个R e取代； And when R c is selected from F, Cl, Br, I, OH, NH 2 and C 1-3 alkyl and C 1-3 alkoxy optionally substituted by 1, 2 or 3 R, R 1 and R 2 is each independently selected from H and C 1-6 alkyl optionally substituted with 1, 2 or 3 R d , or R 1 , R 2 and the atoms connected to them together form a thienyl group, C 3- 8 cycloalkenyl or 3-8 membered heterocycloalkenyl, the thienyl, C 3-8 cycloalkenyl and 3-8 membered heterocycloalkenyl are optionally substituted by 1, 2 or 3 R e ;
当R c选自H或CN时，R 1、R 2和与它们相连的原子共同构成C 3-8环烯基或3-8元杂环烯基，所述C 3-8环烯基和3-8元杂环烯基任选被1、2或3个R e取代； When R c is selected from H or CN, R 1 , R 2 and the atoms connected to them together form a C 3-8 cycloalkenyl group or a 3-8 membered heterocycloalkenyl group, the C 3-8 cycloalkenyl group and The 3-8 membered heterocycloalkenyl is optionally substituted with 1, 2 or 3 R e ;
R 3和R 4分别独立地选自H、F、Cl、Br、I、OH、NH 2、CN和任选被1、2或3个R f取代的C 1-3烷基； R 3 and R 4 are each independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, and C 1-3 alkyl optionally substituted with 1, 2 or 3 R f ;
R d、R e和R f分别独立地选自H、F、Cl、Br、I、OH、NH 2、CN、C 1-3烷基和C 1-3烷氧基； R d, R e and R f are each independently selected from H, F, Cl, Br, I, OH, NH 2, CN, C 1-3 alkyl group and a C 1-3 alkoxy group;
各R分别独立地选自H、F、Cl、Br、I、OH、NH 2、CN和C 1-3烷基； Each R is independently selected from H, F, Cl, Br, I, OH, NH 2 , CN and C 1-3 alkyl;
所述3-8元杂环烯基包含1、2、3或4个独立选自-NH-、-O-、-S-和N的杂原子或杂原子团。The 3-8 membered heterocycloalkenyl group includes 1, 2, 3 or 4 heteroatoms or heteroatom groups independently selected from -NH-, -O-, -S- and N.
本发明提供了式(I)所示化合物或其药学上可接受的盐，The present invention provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof,
Figure PCTCN2020093284-appb-000008
Figure PCTCN2020093284-appb-000008
其中，among them,
Figure PCTCN2020093284-appb-000009
选自单键和双键；
Figure PCTCN2020093284-appb-000009
Selected from single bond and double bond;
T 1为NR a； T 1 is NR a ;
T 2选自C、CH和N； T 2 is selected from C, CH and N;
T 3选自CR b和N； T 3 is selected from CR b and N;
T 4选自CR c和O； T 4 is selected from CR c and O;
R a选自H和C 1-3烷基； R a is selected from H and C 1-3 alkyl;
R b和R c分别独立地选自H、F、Cl、Br、I、OH、NH 2、CN、C 1-3烷基和C 1-3烷氧基，所述C 1-3烷基和C 1- 3烷氧基任选被1、2或3个R取代； R b and R c are each independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, C 1-3 alkyl and C 1-3 alkoxy, the C 1-3 alkyl and C 1- 3 alkoxy group optionally substituted with 1, 2 or 3 R <
且当R c选自F、Cl、Br、I、OH、NH 2和任选被1、2或3个R取代的C 1-3烷基和C 1-3烷氧基时，R 1和R 2分别独立地选自H和任选被1、2或3个R d取代的C 1-6烷基，或者，R 1、R 2和与它们相连的原子共同构成噻吩基、C 3-8环烯基或3-8元杂环烯基，所述噻吩基、C 3-8环烯基和3-8元杂环烯基任选被1、2或3个R e取代； And when R c is selected from F, Cl, Br, I, OH, NH 2 and C 1-3 alkyl and C 1-3 alkoxy optionally substituted by 1, 2 or 3 R, R 1 and R 2 is each independently selected from H and C 1-6 alkyl optionally substituted with 1, 2 or 3 R d , or R 1 , R 2 and the atoms connected to them together form a thienyl group, C 3- 8 cycloalkenyl or 3-8 membered heterocycloalkenyl, the thienyl, C 3-8 cycloalkenyl and 3-8 membered heterocycloalkenyl are optionally substituted by 1, 2 or 3 R e ;
当R c选自H和CN时，R 1、R 2和与它们相连的原子共同构成C 6-8环烯基或3-8元杂环烯基，所述C 6-8环烯基和3-8元杂环烯基任选被1、2或3个R e取代； When R c is selected from H and CN, R 1 , R 2 and the atoms connected to them together form a C 6-8 cycloalkenyl group or a 3-8 membered heterocycloalkenyl group, and the C 6-8 cycloalkenyl group and The 3-8 membered heterocycloalkenyl is optionally substituted with 1, 2 or 3 R e ;
R 3和R 4分别独立地选自H、F、Cl、Br、I、OH、NH 2、CN和任选被1、2或3个R f取代的C 1-3烷基； R 3 and R 4 are each independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, and C 1-3 alkyl optionally substituted with 1, 2 or 3 R f ;
R d和R e分别独立地选自H、F、Cl、Br、I、OH、NH 2、CN、OCD 3、C 1-3烷基、C 1-3烷氧基和-O-C 3-5环烷基； R d and R e are each independently selected from H, F, Cl, Br, I, OH, NH 2, CN, OCD 3, C 1-3 alkyl, C 1-3 alkoxy and -OC 3-5 Cycloalkyl
R f独立地选自H、F、Cl、Br、I、OH、NH 2、CN、C 1-3烷基和C 1-3烷氧基； R f is independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, C 1-3 alkyl and C 1-3 alkoxy;
各R分别独立地选自H、F、Cl、Br、I、OH、NH 2、CN和C 1-3烷基； Each R is independently selected from H, F, Cl, Br, I, OH, NH 2 , CN and C 1-3 alkyl;
所述3-8元杂环烯基包含1、2、3或4个独立选自-NH-、-O-、-S-和N的杂原子或杂原子团。The 3-8 membered heterocycloalkenyl group contains 1, 2, 3 or 4 heteroatoms or heteroatom groups independently selected from -NH-, -O-, -S- and N.
本发明提供了式(I)所示化合物或其药学上可接受的盐，The present invention provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof,
Figure PCTCN2020093284-appb-000010
Figure PCTCN2020093284-appb-000010
其中，among them,
Figure PCTCN2020093284-appb-000011
选自单键和双键；
Figure PCTCN2020093284-appb-000011
Selected from single bond and double bond;
T 1为NR a； T 1 is NR a ;
T 2选自C、CH和N； T 2 is selected from C, CH and N;
T 3选自CR b和N； T 3 is selected from CR b and N;
T 4选自CR c和O； T 4 is selected from CR c and O;
R a选自H和C 1-3烷基； R a is selected from H and C 1-3 alkyl;
R b和R c分别独立地选自H、F、Cl、Br、I、OH、NH 2、CN、C 1-3烷基和C 1-3烷氧基，所述C 1-3烷基和C 1- 3烷氧基任选被1、2或3个R取代； R b and R c are each independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, C 1-3 alkyl and C 1-3 alkoxy, the C 1-3 alkyl and C 1- 3 alkoxy group optionally substituted with 1, 2 or 3 R <
且当R c选自F、Cl、Br、I、OH、NH 2和任选被1、2或3个R取代的C 1-3烷基和C 1-3烷氧基时，R 1和R 2分别独立地选自H和任选被1、2或3个R d取代的C 1-6烷基，或者，R 1、R 2和与它们相连的原子共同构成噻吩基、C 3-8环烯基或3-8元杂环烯基，所述噻吩基、C 3-8环烯基和3-8元杂环烯基任选被1、2或3个R e取代； And when R c is selected from F, Cl, Br, I, OH, NH 2 and C 1-3 alkyl and C 1-3 alkoxy optionally substituted by 1, 2 or 3 R, R 1 and R 2 is each independently selected from H and C 1-6 alkyl optionally substituted with 1, 2 or 3 R d , or R 1 , R 2 and the atoms connected to them together form a thienyl group, C 3- 8 cycloalkenyl or 3-8 membered heterocycloalkenyl, the thienyl, C 3-8 cycloalkenyl and 3-8 membered heterocycloalkenyl are optionally substituted by 1, 2 or 3 R e ;
当R c选自H和CN时，R 1、R 2和与它们相连的原子共同构成噻吩基、C 6-8环烯基或3-8元杂环烯基，所述噻吩基、C 6-8环烯基和3-8元杂环烯基任选被1、2或3个R e取代； When R c is selected from H and CN, R 1 , R 2 and the atoms connected to them together form a thienyl group, a C 6-8 cycloalkenyl group or a 3-8 membered heterocycloalkenyl group, and the thienyl group, C 6 -8 cycloalkenyl and 3-8 membered heterocycloalkenyl are optionally substituted with 1, 2 or 3 R e ;
R 3和R 4分别独立地选自H、F、Cl、Br、I、OH、NH 2、CN和任选被1、2或3个R f取代的C 1-3烷基； R 3 and R 4 are each independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, and C 1-3 alkyl optionally substituted with 1, 2 or 3 R f ;
R d和R e分别独立地选自H、F、Cl、Br、I、OH、NH 2、CN、OCD 3、C 1-3烷基、OCH 3、OCH 2CH 3、OCH(CH 3) 2和-O-C 3-5环烷基； R d and R e are each independently selected from H, F, Cl, Br, I, OH, NH 2, CN, OCD 3, C 1-3 alkyl, OCH 3, OCH 2 CH 3 , OCH (CH 3) 2 and -OC 3-5 cycloalkyl;
R f独立地选自H、F、Cl、Br、I、OH、NH 2、CN、C 1-3烷基和C 1-3烷氧基； R f is independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, C 1-3 alkyl and C 1-3 alkoxy;
各R分别独立地选自H、F、Cl、Br、I、OH、NH 2、CN和C 1-3烷基； Each R is independently selected from H, F, Cl, Br, I, OH, NH 2 , CN and C 1-3 alkyl;
所述3-8元杂环烯基包含1、2、3或4个独立选自-NH-、-O-、-S-和N的杂原子或杂原子团。The 3-8 membered heterocycloalkenyl group includes 1, 2, 3 or 4 heteroatoms or heteroatom groups independently selected from -NH-, -O-, -S- and N.
本发明提供了式(I)所示化合物或其药学上可接受的盐，The present invention provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof,
Figure PCTCN2020093284-appb-000012
Figure PCTCN2020093284-appb-000012
其中，among them,
Figure PCTCN2020093284-appb-000013
选自单键和双键；
Figure PCTCN2020093284-appb-000013
Selected from single bond and double bond;
T 1为NR a； T 1 is NR a ;
T 2选自C、CH和N； T 2 is selected from C, CH and N;
T 3选自CR b和N； T 3 is selected from CR b and N;
T 4选自CR c和O； T 4 is selected from CR c and O;
R a选自H和C 1-3烷基； R a is selected from H and C 1-3 alkyl;
R b和R c分别独立地选自H、F、Cl、Br、I、OH、NH 2、CN、C 1-3烷基和C 1-3烷氧基，所述C 1-3烷基和C 1- 3烷氧基任选被1、2或3个R取代； R b and R c are each independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, C 1-3 alkyl and C 1-3 alkoxy, the C 1-3 alkyl and C 1- 3 alkoxy group optionally substituted with 1, 2 or 3 R <
且当R c选自F、Cl、Br、I、OH、NH 2和任选被1、2或3个R取代的C 1-3烷基和C 1-3烷氧基时，R 1和R 2分别独立地选自H和任选被1、2或3个R d取代的C 1-6烷基，或者，R 1、R 2和与它们相连的原子共同构成噻吩基、C 3-8环烯基或3-8元杂环烯基，所述噻吩基、C 3-8环烯基和3-8元杂环烯基任选被1、2或3个R e取代； And when R c is selected from F, Cl, Br, I, OH, NH 2 and C 1-3 alkyl and C 1-3 alkoxy optionally substituted by 1, 2 or 3 R, R 1 and R 2 is each independently selected from H and C 1-6 alkyl optionally substituted with 1, 2 or 3 R d , or R 1 , R 2 and the atoms connected to them together form a thienyl group, C 3- 8 cycloalkenyl or 3-8 membered heterocycloalkenyl, the thienyl, C 3-8 cycloalkenyl and 3-8 membered heterocycloalkenyl are optionally substituted by 1, 2 or 3 R e ;
当R c选自H和CN时，R 1、R 2和与它们相连的原子共同构成噻吩基、C 6-8环烯基或3-8元杂环烯基，所述噻吩基、C 6-8环烯基和3-8元杂环烯基任选被1、2或3个R e取代； When R c is selected from H and CN, R 1 , R 2 and the atoms connected to them together form a thienyl group, a C 6-8 cycloalkenyl group or a 3-8 membered heterocycloalkenyl group, and the thienyl group, C 6 -8 cycloalkenyl and 3-8 membered heterocycloalkenyl are optionally substituted with 1, 2 or 3 R e ;
R 3和R 4分别独立地选自H、F、Cl、Br、I、OH、NH 2、CN和任选被1、2或3个R f取代的C 1-3烷基； R 3 and R 4 are each independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, and C 1-3 alkyl optionally substituted with 1, 2 or 3 R f ;
R d和R e分别独立地选自H、F、Cl、Br、I、OH、NH 2、CN、C 1-3烷基、C 1-3烷氧基和-O-C 3-5环烷基，所述C 1-3烷基、C 1-3烷氧基和-O-C 3-5环烷基任选被1、2或3个R’取代； R d and R e are each independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, C 1-3 alkyl, C 1-3 alkoxy and -OC 3-5 cycloalkyl , The C 1-3 alkyl group, C 1-3 alkoxy group and -OC 3-5 cycloalkyl group are optionally substituted with 1, 2 or 3 R';
R f独立地选自H、F、Cl、Br、I、OH、NH 2、CN、C 1-3烷基和C 1-3烷氧基； R f is independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, C 1-3 alkyl and C 1-3 alkoxy;
各R分别独立地选自H、F、Cl、Br、I、OH、NH 2、CN和C 1-3烷基； Each R is independently selected from H, F, Cl, Br, I, OH, NH 2 , CN and C 1-3 alkyl;
各R’分别独立地选自D、F、Cl、Br和I；Each R'is independently selected from D, F, Cl, Br and I;
所述3-8元杂环烯基包含1、2、3或4个独立选自-NH-、-O-、-S-和N的杂原子或杂原子团。The 3-8 membered heterocycloalkenyl group contains 1, 2, 3 or 4 heteroatoms or heteroatom groups independently selected from -NH-, -O-, -S- and N.
本发明的一些方案中，上述化合物或其药学上可接受的盐，其选自In some aspects of the present invention, the above-mentioned compound or a pharmaceutically acceptable salt thereof is selected from
Figure PCTCN2020093284-appb-000014
Figure PCTCN2020093284-appb-000014
其中，among them,
Figure PCTCN2020093284-appb-000015
选自单键和双键；
Figure PCTCN2020093284-appb-000015
Selected from single bond and double bond;
T 2选自C和N； T 2 is selected from C and N;
T 4选自CR c和O； T 4 is selected from CR c and O;
R c选自F、Cl、Br、I、OH、NH 2、C 1-3烷基和C 1-3烷氧基，所述C 1-3烷基和C 1-3烷氧基任选被1、2或3个R取代； R c is selected from F, Cl, Br, I, OH, NH 2 , C 1-3 alkyl and C 1-3 alkoxy, the C 1-3 alkyl and C 1-3 alkoxy optionally Replaced by 1, 2 or 3 R;
R 1和R 2分别独立地选自H和任选被1、2或3个R d取代的C 1-6烷基，或者，R 1、R 2和与它们相连的原子共同构成C 3-8环烯基或3-8元杂环烯基，所述C 3-8环烯基和3-8元杂环烯基任选被1、2或3个R e取代； R 1 and R 2 are each independently selected from H and C 1-6 alkyl optionally substituted by 1, 2 or 3 R d , or R 1 , R 2 and the atoms connected to them together form C 3- 8 cycloalkenyl or 3-8 membered heterocycloalkenyl, the C 3-8 cycloalkenyl and 3-8 membered heterocycloalkenyl are optionally substituted by 1, 2 or 3 R e ;
R 3和R 4分别独立地选自H、F、Cl、Br、I、OH、NH 2、CN和任选被1、2或3个R f取代的C 1-3烷基； R 3 and R 4 are each independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, and C 1-3 alkyl optionally substituted with 1, 2 or 3 R f ;
R d、R e和R f分别独立地选自H、F、Cl、Br、I、OH、NH 2、CN和C 1-3烷基； R d, R e and R f are each independently selected from H, F, Cl, Br, I, OH, NH 2, CN and C 1-3 alkyl;
各R分别独立地选自H、F、Cl、Br、I、OH、NH 2、CN和C 1-3烷基； Each R is independently selected from H, F, Cl, Br, I, OH, NH 2 , CN and C 1-3 alkyl;
所述3-8元杂环烯基包含1、2、3或4个独立选自-NH-、-O-、-S-和N的杂原子或杂原子团。The 3-8 membered heterocycloalkenyl group contains 1, 2, 3 or 4 heteroatoms or heteroatom groups independently selected from -NH-, -O-, -S- and N.
本发明的一些方案中，上述化合物或其药学上可接受的盐，其选自In some aspects of the present invention, the above-mentioned compound or a pharmaceutically acceptable salt thereof is selected from
Figure PCTCN2020093284-appb-000016
Figure PCTCN2020093284-appb-000016
其中，among them,
Figure PCTCN2020093284-appb-000017
选自单键和双键；
Figure PCTCN2020093284-appb-000017
Selected from single bond and double bond;
T 2选自C和N； T 2 is selected from C and N;
T 4选自CR c和O； T 4 is selected from CR c and O;
R c选自F、Cl、Br、I、OH、NH 2、C 1-3烷基和C 1-3烷氧基，所述C 1-3烷基和C 1-3烷氧基任选被1、2或3个R取代； R c is selected from F, Cl, Br, I, OH, NH 2 , C 1-3 alkyl and C 1-3 alkoxy, the C 1-3 alkyl and C 1-3 alkoxy optionally Replaced by 1, 2 or 3 R;
R 1和R 2分别独立地选自H和任选被1、2或3个R d取代的C 1-6烷基，或者，R 1、R 2和与它们相连的原子共同构成噻吩基、C 3-8环烯基或3-8元杂环烯基，所述C 3-8环烯基和3-8元杂环烯基任选被1、2或3个R e取代； R 1 and R 2 are each independently selected from H and C 1-6 alkyl optionally substituted by 1, 2 or 3 R d , or R 1 , R 2 and the atoms connected to them together form a thienyl group, C 3-8 cycloalkenyl or 3-8 membered heterocycloalkenyl, the C 3-8 cycloalkenyl and 3-8 membered heterocycloalkenyl are optionally substituted by 1, 2 or 3 R e ;
R 3和R 4分别独立地选自H、F、Cl、Br、I、OH、NH 2、CN和任选被1、2或3个R f取代的C 1-3烷基； R 3 and R 4 are each independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, and C 1-3 alkyl optionally substituted with 1, 2 or 3 R f ;
R d、R e和R f分别独立地选自H、F、Cl、Br、I、OH、NH 2、CN和C 1-3烷基； R d, R e and R f are each independently selected from H, F, Cl, Br, I, OH, NH 2, CN and C 1-3 alkyl;
各R分别独立地选自H、F、Cl、Br、I、OH、NH 2、CN和C 1-3烷基； Each R is independently selected from H, F, Cl, Br, I, OH, NH 2 , CN and C 1-3 alkyl;
所述3-8元杂环烯基包含1、2、3或4个独立选自-NH-、-O-、-S-和N的杂原子或杂原子团。The 3-8 membered heterocycloalkenyl group includes 1, 2, 3 or 4 heteroatoms or heteroatom groups independently selected from -NH-, -O-, -S- and N.
本发明的一些方案中，上述化合物或其药学上可接受的盐，其选自In some aspects of the present invention, the above-mentioned compound or a pharmaceutically acceptable salt thereof is selected from
Figure PCTCN2020093284-appb-000018
Figure PCTCN2020093284-appb-000018
其中，among them,
Figure PCTCN2020093284-appb-000019
选自单键和双键；
Figure PCTCN2020093284-appb-000019
Selected from single bond and double bond;
T 2选自C和N； T 2 is selected from C and N;
T 4选自CR c和O； T 4 is selected from CR c and O;
R c选自F、Cl、Br、I、OH、NH 2、C 1-3烷基和C 1-3烷氧基，所述C 1-3烷基和C 1-3烷氧基任选被1、2或3个R取代； R c is selected from F, Cl, Br, I, OH, NH 2 , C 1-3 alkyl and C 1-3 alkoxy, the C 1-3 alkyl and C 1-3 alkoxy optionally Replaced by 1, 2 or 3 R;
R 1和R 2分别独立地选自H和任选被1、2或3个R d取代的C 1-6烷基，或者，R 1、R 2和与它们相连的原子共同构成噻吩基、C 3-8环烯基或3-8元杂环烯基，所述噻吩基、C 3-8环烯基和3-8元杂环烯基任选被1、2或3个R e取代； R 1 and R 2 are each independently selected from H and C 1-6 alkyl optionally substituted by 1, 2 or 3 R d , or R 1 , R 2 and the atoms connected to them together form a thienyl group, C 3-8 cycloalkenyl or 3-8 membered heterocycloalkenyl, the thienyl, C 3-8 cycloalkenyl and 3-8 membered heterocycloalkenyl are optionally substituted by 1, 2 or 3 R e ；
R 3和R 4分别独立地选自H、F、Cl、Br、I、OH、NH 2、CN和任选被1、2或3个R f取代的C 1-3烷基； R 3 and R 4 are each independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, and C 1-3 alkyl optionally substituted with 1, 2 or 3 R f ;
R d、R e和R f分别独立地选自H、F、Cl、Br、I、OH、NH 2、CN、C 1-3烷基和C 1-3烷氧基； R d, R e and R f are each independently selected from H, F, Cl, Br, I, OH, NH 2, CN, C 1-3 alkyl group and a C 1-3 alkoxy group;
各R分别独立地选自H、F、Cl、Br、I、OH、NH 2、CN和C 1-3烷基； Each R is independently selected from H, F, Cl, Br, I, OH, NH 2 , CN and C 1-3 alkyl;
所述3-8元杂环烯基包含1、2、3或4个独立选自-NH-、-O-、-S-和N的杂原子或杂原子团。The 3-8 membered heterocycloalkenyl group contains 1, 2, 3 or 4 heteroatoms or heteroatom groups independently selected from -NH-, -O-, -S- and N.
本发明的一些方案中，上述化合物或其药学上可接受的盐，其选自In some aspects of the present invention, the above-mentioned compound or a pharmaceutically acceptable salt thereof is selected from
Figure PCTCN2020093284-appb-000020
Figure PCTCN2020093284-appb-000020
其中，among them,
Figure PCTCN2020093284-appb-000021
选自单键和双键；
Figure PCTCN2020093284-appb-000021
Selected from single bond and double bond;
T 2选自C和N； T 2 is selected from C and N;
T 4选自CR c和O； T 4 is selected from CR c and O;
R c选自F、Cl、Br、I、OH、NH 2、C 1-3烷基和C 1-3烷氧基，所述C 1-3烷基和C 1-3烷氧基任选被1、2或3个R取代； R c is selected from F, Cl, Br, I, OH, NH 2 , C 1-3 alkyl and C 1-3 alkoxy, the C 1-3 alkyl and C 1-3 alkoxy optionally Replaced by 1, 2 or 3 R;
R 1和R 2分别独立地选自H和任选被1、2或3个R d取代的C 1-6烷基，或者，R 1、R 2和与它们相连的原子共同构成噻吩基、C 3-8环烯基或3-8元杂环烯基，所述噻吩基、C 3-8环烯基和3-8元杂环烯基任选被1、2或3个R e取代； R 1 and R 2 are each independently selected from H and C 1-6 alkyl optionally substituted by 1, 2 or 3 R d , or R 1 , R 2 and the atoms connected to them together form a thienyl group, C 3-8 cycloalkenyl or 3-8 membered heterocycloalkenyl, the thienyl, C 3-8 cycloalkenyl and 3-8 membered heterocycloalkenyl are optionally substituted by 1, 2 or 3 R e ；
R 3和R 4分别独立地选自H、F、Cl、Br、I、OH、NH 2、CN和任选被1、2或3个R f取代的C 1-3烷基； R 3 and R 4 are each independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, and C 1-3 alkyl optionally substituted with 1, 2 or 3 R f ;
R d和R e分别独立地选自H、F、Cl、Br、I、OH、NH 2、CN、OCD 3、C 1-3烷基、C 1-3烷氧基和-O-C 3-5环烷基； R d and R e are each independently selected from H, F, Cl, Br, I, OH, NH 2, CN, OCD 3, C 1-3 alkyl, C 1-3 alkoxy and -OC 3-5 Cycloalkyl
R f独立地选自H、F、Cl、Br、I、OH、NH 2、CN、C 1-3烷基和C 1-3烷氧基； R f is independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, C 1-3 alkyl and C 1-3 alkoxy;
各R分别独立地选自H、F、Cl、Br、I、OH、NH 2、CN和C 1-3烷基； Each R is independently selected from H, F, Cl, Br, I, OH, NH 2 , CN and C 1-3 alkyl;
所述3-8元杂环烯基包含1、2、3或4个独立选自-NH-、-O-、-S-和N的杂原子或杂原子团。The 3-8 membered heterocycloalkenyl group includes 1, 2, 3 or 4 heteroatoms or heteroatom groups independently selected from -NH-, -O-, -S- and N.
本发明的一些方案中，上述化合物或其药学上可接受的盐，其选自In some aspects of the present invention, the above-mentioned compound or a pharmaceutically acceptable salt thereof is selected from
Figure PCTCN2020093284-appb-000022
Figure PCTCN2020093284-appb-000022
其中，among them,
Figure PCTCN2020093284-appb-000023
选自单键和双键；
Figure PCTCN2020093284-appb-000023
Selected from single bond and double bond;
T 2选自C和N； T 2 is selected from C and N;
T 4选自CR c和O； T 4 is selected from CR c and O;
R c选自F、Cl、Br、I、OH、NH 2、C 1-3烷基和C 1-3烷氧基，所述C 1-3烷基和C 1-3烷氧基任选被1、2或3个R取代； R c is selected from F, Cl, Br, I, OH, NH 2 , C 1-3 alkyl and C 1-3 alkoxy, the C 1-3 alkyl and C 1-3 alkoxy optionally Replaced by 1, 2 or 3 R;
R 1和R 2分别独立地选自H和任选被1、2或3个R d取代的C 1-6烷基，或者，R 1、R 2和与它们相连的原子共同构成噻吩基、C 3-8环烯基或3-8元杂环烯基，所述噻吩基、C 3-8环烯基和3-8元杂环烯基任选被1、2或3个R e取代； R 1 and R 2 are each independently selected from H and C 1-6 alkyl optionally substituted by 1, 2 or 3 R d , or R 1 , R 2 and the atoms connected to them together form a thienyl group, C 3-8 cycloalkenyl or 3-8 membered heterocycloalkenyl, the thienyl, C 3-8 cycloalkenyl and 3-8 membered heterocycloalkenyl are optionally substituted by 1, 2 or 3 R e ；
R 3和R 4分别独立地选自H、F、Cl、Br、I、OH、NH 2、CN和任选被1、2或3个R f取代的C 1-3烷基； R 3 and R 4 are each independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, and C 1-3 alkyl optionally substituted with 1, 2 or 3 R f ;
R d和R e分别独立地选自H、F、Cl、Br、I、OH、NH 2、CN、OCD 3、C 1-3烷基、OCH 3、OCH 2CH 3、OCH(CH 3) 2和-O-C 3-5环烷基； R d and R e are each independently selected from H, F, Cl, Br, I, OH, NH 2, CN, OCD 3, C 1-3 alkyl, OCH 3, OCH 2 CH 3 , OCH (CH 3) 2 and -OC 3-5 cycloalkyl;
R f独立地选自H、F、Cl、Br、I、OH、NH 2、CN、C 1-3烷基和C 1-3烷氧基； R f is independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, C 1-3 alkyl and C 1-3 alkoxy;
各R分别独立地选自H、F、Cl、Br、I、OH、NH 2、CN和C 1-3烷基； Each R is independently selected from H, F, Cl, Br, I, OH, NH 2 , CN and C 1-3 alkyl;
所述3-8元杂环烯基包含1、2、3或4个独立选自-NH-、-O-、-S-和N的杂原子或杂原子团。The 3-8 membered heterocycloalkenyl group contains 1, 2, 3 or 4 heteroatoms or heteroatom groups independently selected from -NH-, -O-, -S- and N.
本发明的一些方案中，上述化合物或其药学上可接受的盐，其选自In some aspects of the present invention, the above-mentioned compound or a pharmaceutically acceptable salt thereof is selected from
Figure PCTCN2020093284-appb-000024
Figure PCTCN2020093284-appb-000024
其中，among them,
Figure PCTCN2020093284-appb-000025
选自单键和双键；
Figure PCTCN2020093284-appb-000025
Selected from single bond and double bond;
T 2选自C和N； T 2 is selected from C and N;
T 4选自CR c和O； T 4 is selected from CR c and O;
R c选自F、Cl、Br、I、OH、NH 2、C 1-3烷基和C 1-3烷氧基，所述C 1-3烷基和C 1-3烷氧基任选被1、2或3个R取代； R c is selected from F, Cl, Br, I, OH, NH 2 , C 1-3 alkyl and C 1-3 alkoxy, the C 1-3 alkyl and C 1-3 alkoxy optionally Replaced by 1, 2 or 3 R;
R 1和R 2分别独立地选自H和任选被1、2或3个R d取代的C 1-6烷基，或者，R 1、R 2和与它们相连的原子共同构成噻吩基、C 3-8环烯基或3-8元杂环烯基，所述噻吩基、C 3-8环烯基和3-8元杂环烯基任选被1、2或3个R e取代； R 1 and R 2 are each independently selected from H and C 1-6 alkyl optionally substituted by 1, 2 or 3 R d , or R 1 , R 2 and the atoms connected to them together form a thienyl group, C 3-8 cycloalkenyl or 3-8 membered heterocycloalkenyl, the thienyl, C 3-8 cycloalkenyl and 3-8 membered heterocycloalkenyl are optionally substituted by 1, 2 or 3 R e ；
R 3和R 4分别独立地选自H、F、Cl、Br、I、OH、NH 2、CN和任选被1、2或3个R f取代的C 1-3烷基； R 3 and R 4 are each independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, and C 1-3 alkyl optionally substituted with 1, 2 or 3 R f ;
R d和R e分别独立地选自H、F、Cl、Br、I、OH、NH 2、CN、C 1-3烷基、C 1-3烷氧基和-O-C 3-5环烷基，所述C 1-3烷基、C 1-3烷氧基和-O-C 3-5环烷基任选被1、2或3个R’取代； R d and R e are each independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, C 1-3 alkyl, C 1-3 alkoxy and -OC 3-5 cycloalkyl , The C 1-3 alkyl group, C 1-3 alkoxy group and -OC 3-5 cycloalkyl group are optionally substituted with 1, 2 or 3 R';
R f独立地选自H、F、Cl、Br、I、OH、NH 2、CN、C 1-3烷基和C 1-3烷氧基； R f is independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, C 1-3 alkyl and C 1-3 alkoxy;
各R分别独立地选自H、F、Cl、Br、I、OH、NH 2、CN和C 1-3烷基； Each R is independently selected from H, F, Cl, Br, I, OH, NH 2 , CN and C 1-3 alkyl;
各R’分别独立地选自D、F、Cl、Br和I；Each R'is independently selected from D, F, Cl, Br and I;
所述3-8元杂环烯基包含1、2、3或4个独立选自-NH-、-O-、-S-和N的杂原子或杂原子团。The 3-8 membered heterocycloalkenyl group contains 1, 2, 3 or 4 heteroatoms or heteroatom groups independently selected from -NH-, -O-, -S- and N.
本发明的一些方案中，上述化合物或其药学上可接受的盐，其选自In some aspects of the present invention, the above-mentioned compound or a pharmaceutically acceptable salt thereof is selected from
Figure PCTCN2020093284-appb-000026
Figure PCTCN2020093284-appb-000026
其中，among them,
R c选自H和CN； R c is selected from H and CN;
R 1、R 2和与它们相连的原子共同构成C 3-8环烯基和3-8元杂环烯基，所述C 3-8环烯基和3-8元杂环烯基任选被1、2或3个R e取代； R 1 , R 2 and the atoms connected to them together form a C 3-8 cycloalkenyl group and a 3-8 membered heterocycloalkenyl group, the C 3-8 cycloalkenyl group and a 3-8 membered heterocycloalkenyl group are optionally substituted with 1, 2, or 3 R e;
R 3和R 4分别独立地选自H、F、Cl、Br、I、OH、NH 2、CN和任选被1、2或3个R f取代的C 1-3烷基； R 3 and R 4 are each independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, and C 1-3 alkyl optionally substituted with 1, 2 or 3 R f ;
R e和R f分别独立地选自H、F、Cl、Br、I、OH、NH 2、CN和C 1-3烷基； R e and R f are each independently selected from H, F, Cl, Br, I, OH, NH 2 , CN and C 1-3 alkyl;
所述3-8元杂环烯基包含1、2、3或4个独立选自-NH-、-O-、-S-和N的杂原子或杂原子团。The 3-8 membered heterocycloalkenyl group contains 1, 2, 3 or 4 heteroatoms or heteroatom groups independently selected from -NH-, -O-, -S- and N.
本发明的一些方案中，上述化合物或其药学上可接受的盐，其选自In some aspects of the present invention, the above-mentioned compound or a pharmaceutically acceptable salt thereof is selected from
Figure PCTCN2020093284-appb-000027
Figure PCTCN2020093284-appb-000027
其中，among them,
R c选自H和CN； R c is selected from H and CN;
R 1、R 2和与它们相连的原子共同构成噻吩基、C 3-8环烯基和3-8元杂环烯基，所述C 3-8环烯基和3-8元杂环烯基任选被1、2或3个R e取代； R 1 , R 2 and the atoms connected to them together form a thienyl group, a C 3-8 cycloalkenyl group, and a 3-8 membered heterocycloalkenyl group, the C 3-8 cycloalkenyl group and a 3-8 membered heterocycloalkenyl group group optionally substituted with 1, 2, or 3 R e;
R 3和R 4分别独立地选自H、F、Cl、Br、I、OH、NH 2、CN和任选被1、2或3个R f取代的C 1-3烷基； R 3 and R 4 are each independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, and C 1-3 alkyl optionally substituted with 1, 2 or 3 R f ;
R e和R f分别独立地选自H、F、Cl、Br、I、OH、NH 2、CN和C 1-3烷基； R e and R f are each independently selected from H, F, Cl, Br, I, OH, NH 2 , CN and C 1-3 alkyl;
所述3-8元杂环烯基包含1、2、3或4个独立选自-NH-、-O-、-S-和N的杂原子或杂原子团。The 3-8 membered heterocycloalkenyl group includes 1, 2, 3 or 4 heteroatoms or heteroatom groups independently selected from -NH-, -O-, -S- and N.
本发明的一些方案中，上述化合物或其药学上可接受的盐，其选自In some aspects of the present invention, the above-mentioned compound or a pharmaceutically acceptable salt thereof is selected from
Figure PCTCN2020093284-appb-000028
Figure PCTCN2020093284-appb-000028
其中，among them,
R c选自H和CN； R c is selected from H and CN;
R 1、R 2和与它们相连的原子共同构成噻吩基、C 3-8环烯基和3-8元杂环烯基，所述噻吩基、C 3-8环烯基和3-8元杂环烯基任选被1、2或3个R e取代； R 1 , R 2 and the atoms connected to them together form a thienyl group, a C 3-8 cycloalkenyl group and a 3-8 membered heterocycloalkenyl group, the thienyl group, a C 3-8 cycloalkenyl group and a 3-8 membered group optionally substituted heterocyclenyl, 2, or 3 R e;
R 3和R 4分别独立地选自H、F、Cl、Br、I、OH、NH 2、CN和任选被1、2或3个R f取代的C 1-3烷基； R 3 and R 4 are each independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, and C 1-3 alkyl optionally substituted with 1, 2 or 3 R f ;
R e和R f分别独立地选自H、F、Cl、Br、I、OH、NH 2、CN、C 1-3烷基和C 1-3烷氧基； R e and R f are each independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, C 1-3 alkyl and C 1-3 alkoxy;
所述3-8元杂环烯基包含1、2、3或4个独立选自-NH-、-O-、-S-和N的杂原子或杂原子团。The 3-8 membered heterocycloalkenyl group includes 1, 2, 3 or 4 heteroatoms or heteroatom groups independently selected from -NH-, -O-, -S- and N.
本发明的一些方案中，上述化合物或其药学上可接受的盐，其选自In some aspects of the present invention, the above-mentioned compound or a pharmaceutically acceptable salt thereof is selected from
Figure PCTCN2020093284-appb-000029
Figure PCTCN2020093284-appb-000029
其中，among them,
R c选自H和CN； R c is selected from H and CN;
R 1、R 2和与它们相连的原子共同构成噻吩基、C 6-8环烯基和3-8元杂环烯基，所述噻吩基、C 6-8环烯基和3-8元杂环烯基任选被1、2或3个R e取代； R 1 , R 2 and the atoms connected to them together form a thienyl group, a C 6-8 cycloalkenyl group and a 3-8 membered heterocycloalkenyl group, the thienyl group, a C 6-8 cycloalkenyl group and a 3-8 membered group optionally substituted heterocyclenyl, 2, or 3 R e;
R 3和R 4分别独立地选自H、F、Cl、Br、I、OH、NH 2、CN和任选被1、2或3个R f取代的C 1-3烷基； R 3 and R 4 are each independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, and C 1-3 alkyl optionally substituted with 1, 2 or 3 R f ;
R e分别独立地选自H、F、Cl、Br、I、OH、NH 2、CN、OCD 3、C 1-3烷基、C 1-3烷氧基和-O-C 3-5环烷基； R e is independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, OCD 3 , C 1-3 alkyl, C 1-3 alkoxy and -OC 3-5 cycloalkyl ；
R f独立地选自H、F、Cl、Br、I、OH、NH 2、CN、C 1-3烷基和C 1-3烷氧基； R f is independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, C 1-3 alkyl and C 1-3 alkoxy;
所述3-8元杂环烯基包含1、2、3或4个独立选自-NH-、-O-、-S-和N的杂原子或杂原子团。The 3-8 membered heterocycloalkenyl group includes 1, 2, 3 or 4 heteroatoms or heteroatom groups independently selected from -NH-, -O-, -S- and N.
本发明的一些方案中，上述化合物或其药学上可接受的盐，其选自In some aspects of the present invention, the above-mentioned compound or a pharmaceutically acceptable salt thereof is selected from
Figure PCTCN2020093284-appb-000030
Figure PCTCN2020093284-appb-000030
其中，among them,
R c选自H和CN； R c is selected from H and CN;
R 1、R 2和与它们相连的原子共同构成噻吩基、C 6-8环烯基和3-8元杂环烯基，所述噻吩基、C 6-8环烯基和3-8元杂环烯基任选被1、2或3个R e取代； R 1 , R 2 and the atoms connected to them together form a thienyl group, a C 6-8 cycloalkenyl group and a 3-8 membered heterocycloalkenyl group, the thienyl group, a C 6-8 cycloalkenyl group and a 3-8 membered group optionally substituted heterocyclenyl, 2, or 3 R e;
R 3和R 4分别独立地选自H、F、Cl、Br、I、OH、NH 2、CN和任选被1、2或3个R f取代的C 1-3烷基； R 3 and R 4 are each independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, and C 1-3 alkyl optionally substituted with 1, 2 or 3 R f ;
R e分别独立地选自H、F、Cl、Br、I、OH、NH 2、CN、OCD 3、C 1-3烷基、OCH 3、OCH 2CH 3、OCH(CH 3) 2和-O-C 3-5环烷基； R e are independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, OCD 3 , C 1-3 alkyl, OCH 3 , OCH 2 CH 3 , OCH(CH 3 ) 2 and- OC 3-5 cycloalkyl;
R f独立地选自H、F、Cl、Br、I、OH、NH 2、CN、C 1-3烷基和C 1-3烷氧基； R f is independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, C 1-3 alkyl and C 1-3 alkoxy;
所述3-8元杂环烯基包含1、2、3或4个独立选自-NH-、-O-、-S-和N的杂原子或杂原子团。The 3-8 membered heterocycloalkenyl group includes 1, 2, 3 or 4 heteroatoms or heteroatom groups independently selected from -NH-, -O-, -S- and N.
本发明的一些方案中，上述化合物或其药学上可接受的盐，其选自In some aspects of the present invention, the above-mentioned compound or a pharmaceutically acceptable salt thereof is selected from
Figure PCTCN2020093284-appb-000031
Figure PCTCN2020093284-appb-000031
其中，among them,
R c选自H和CN； R c is selected from H and CN;
R 1、R 2和与它们相连的原子共同构成噻吩基、C 6-8环烯基和3-8元杂环烯基，所述噻吩基、C 6-8环烯基和3-8元杂环烯基任选被1、2或3个R e取代； R 1 , R 2 and the atoms connected to them together form a thienyl group, a C 6-8 cycloalkenyl group and a 3-8 membered heterocycloalkenyl group, the thienyl group, a C 6-8 cycloalkenyl group and a 3-8 membered group optionally substituted heterocyclenyl, 2, or 3 R e;
R 3和R 4分别独立地选自H、F、Cl、Br、I、OH、NH 2、CN和任选被1、2或3个R f取代的C 1-3烷基； R 3 and R 4 are each independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, and C 1-3 alkyl optionally substituted with 1, 2 or 3 R f ;
R e分别独立地选自H、F、Cl、Br、I、OH、NH 2、CN、C 1-3烷基、C 1-3烷氧基和-O-C 3-5环烷基，所述C 1-3烷基、C 1-3烷氧基和-O-C 3-5环烷基任选被1、2或3个R’取代； R e is each independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, C 1-3 alkyl, C 1-3 alkoxy and -OC 3-5 cycloalkyl, said C 1-3 alkyl, C 1-3 alkoxy and -OC 3-5 cycloalkyl are optionally substituted with 1, 2 or 3 R';
R f独立地选自H、F、Cl、Br、I、OH、NH 2、CN、C 1-3烷基和C 1-3烷氧基； R f is independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, C 1-3 alkyl and C 1-3 alkoxy;
各R’分别独立地选自D、F、Cl、Br和I；Each R'is independently selected from D, F, Cl, Br and I;
所述3-8元杂环烯基包含1、2、3或4个独立选自-NH-、-O-、-S-和N的杂原子或杂原子团。The 3-8 membered heterocycloalkenyl group contains 1, 2, 3 or 4 heteroatoms or heteroatom groups independently selected from -NH-, -O-, -S- and N.
本发明的一些方案中，上述T 2选自N，T 3选自N时，T 2和T 3之间连接的
Figure PCTCN2020093284-appb-000032
为单键；T 4选自CR c时，T 3和T 4之间连接的
Figure PCTCN2020093284-appb-000033
为双键；T 4选自O时，T 3和T 4之间连接的
Figure PCTCN2020093284-appb-000034
为单键。 In some aspects of the present invention, the above-mentioned T 2 is selected from N, and when T 3 is selected from N, the connection between T 2 and T 3
Figure PCTCN2020093284-appb-000032
Is a single bond; when T 4 is selected from CR c , the connection between T 3 and T 4
Figure PCTCN2020093284-appb-000033
Is a double bond; when T 4 is selected from O, the connection between T 3 and T 4
Figure PCTCN2020093284-appb-000034
It is a single key.
本发明的一些方案中，上述R b和R c分别独立地选自H、F、Cl、Br、I、OH、NH 2、CN、CH 3、CH 2CH 3和
Figure PCTCN2020093284-appb-000035
所述CH 3、CH 2CH 3和
Figure PCTCN2020093284-appb-000036
任选被1、2或3个R取代，其他变量如本发明所定义。 In some aspects of the present invention, the above-mentioned R b and R c are independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, CH 3 , CH 2 CH 3 and
Figure PCTCN2020093284-appb-000035
The CH 3 , CH 2 CH 3 and
Figure PCTCN2020093284-appb-000036
Optionally substituted by 1, 2 or 3 R, other variables are as defined in the present invention.
本发明的一些方案中，上述R b和R c分别独立地选自H、F、Cl、Br、I、OH、NH 2、CN、CH 3、CH 2F、CHF 2、CF 3、CH 2CH 3、
Figure PCTCN2020093284-appb-000037
其他变量如本发明所定义。 In some aspects of the present invention, the above-mentioned R b and R c are independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, CH 3 , CH 2 F, CHF 2 , CF 3 , CH 2 CH 3 ,
Figure PCTCN2020093284-appb-000037
Other variables are as defined in the present invention.
本发明的一些方案中，上述R b和R c分别独立地选自H、F、Cl、Br、I、OH、NH 2、CN、CH 3、CH 2F、CHF 2、CF 3、CH 2CH 3、CF 2CH 3、
Figure PCTCN2020093284-appb-000038
其他变量如本发明所定义。 In some aspects of the present invention, the above-mentioned R b and R c are independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, CH 3 , CH 2 F, CHF 2 , CF 3 , CH 2 CH 3 , CF 2 CH 3 ,
Figure PCTCN2020093284-appb-000038
Other variables are as defined in the present invention.
本发明的一些方案中，上述R b和R c分别独立地选自H、F、Cl、Br、I、OH、NH 2、CN、CH 3、CH 2F、CH 2CN、CHF 2、CF 3、CH 2CH 3、CF 2CH 3、
Figure PCTCN2020093284-appb-000039
其他变量如本发明所定义。 In some aspects of the present invention, the above-mentioned R b and R c are independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, CH 3 , CH 2 F, CH 2 CN, CHF 2 , CF 3 , CH 2 CH 3 , CF 2 CH 3 ,
Figure PCTCN2020093284-appb-000039
Other variables are as defined in the present invention.
本发明的一些方案中，上述R c选自F、Cl、Br、I、OH、NH 2、CH 3、CH 2F、CHF 2、CF 3、CH 2CH 3、
Figure PCTCN2020093284-appb-000040
其他变量如本发明所定义。 In some aspects of the present invention, the aforementioned R c is selected from F, Cl, Br, I, OH, NH 2 , CH 3 , CH 2 F, CHF 2 , CF 3 , CH 2 CH 3 ,
Figure PCTCN2020093284-appb-000040
Other variables are as defined in the present invention.
本发明的一些方案中，上述R c选自F、Cl、Br、I、OH、NH 2、CH 3、CH 2F、CHF 2、CF 3、CH 2CH 3、CF 2CH 3、
Figure PCTCN2020093284-appb-000041
其他变量如本发明所定义。 In some aspects of the present invention, the aforementioned R c is selected from F, Cl, Br, I, OH, NH 2 , CH 3 , CH 2 F, CHF 2 , CF 3 , CH 2 CH 3 , CF 2 CH 3 ,
Figure PCTCN2020093284-appb-000041
Other variables are as defined in the present invention.
本发明的一些方案中，上述R c选自F、Cl、Br、I、OH、NH 2、CH 3、CH 2F、CHF 2、CH 2CN、CF 3、CH 2CH 3、CF 2CH 3、
Figure PCTCN2020093284-appb-000042
其他变量如本发明所定义。 In some aspects of the present invention, the above R c is selected from F, Cl, Br, I, OH, NH 2 , CH 3 , CH 2 F, CHF 2 , CH 2 CN, CF 3 , CH 2 CH 3 , CF 2 CH 3 .
Figure PCTCN2020093284-appb-000042
Other variables are as defined in the present invention.
本发明的一些方案中，上述R 1和R 2分别独立地选自H、CH 3、CH 2CH 3、CH(CH 3) 2和C(CH 3) 3，其他变量如本发明所定义。 In some aspects of the present invention, the above R 1 and R 2 are independently selected from H, CH 3 , CH 2 CH 3 , CH(CH 3 ) 2 and C(CH 3 ) 3 , and other variables are as defined in the present invention.
本发明的一些方案中，上述R 1、R 2和与它们相连的原子共同构成环己烯基、双环[2.2.1]庚-2-烯基、1,2,3,4-四氢吡啶基、双环[4.1.0]庚-3-烯基、3,6-二氢-2H-吡喃基和7-氧杂二环[2.2.1]庚-2-烯基，所述环己烯基、双环[2.2.1]庚-2-烯基、1,2,3,4-四氢吡啶基、双环[4.1.0]庚-3-烯基、3,6-二氢-2H-吡喃基和7-氧杂二环[2.2.1]庚-2-烯基任选被1、2或3个R e取代，其他变量如本发明所定义。 In some embodiments of the present invention, the above-mentioned R 1 , R 2 and the atoms connected to them together form a cyclohexenyl group, a bicyclo[2.2.1]hept-2-enyl group, 1,2,3,4-tetrahydropyridine Group, bicyclo[4.1.0]hept-3-enyl, 3,6-dihydro-2H-pyranyl and 7-oxabicyclo[2.2.1]hept-2-enyl, the cyclohexyl Alkenyl, bicyclo[2.2.1]hept-2-enyl, 1,2,3,4-tetrahydropyridyl, bicyclo[4.1.0]hept-3-enyl, 3,6-dihydro-2H - pyranyl and 7-oxabicyclo [2.2.1] hept-2-en-yl optionally substituted with 1, 2, or 3 R e, the other variables are as defined in the present invention.
本发明的一些方案中，上述R 1、R 2和与它们相连的原子共同构成环戊烯基、环己烯基、双环[2.2.1]庚-2-烯基、1,2,3,4-四氢吡啶基、双环[4.1.0]庚-3-烯基、3,6-二氢-2H-吡喃基、7-氧杂二环[2.2.1]庚-2-烯基和噻吩基，所述环戊烯基、环己烯基、双环[2.2.1]庚-2-烯基、1,2,3,4-四氢吡啶基、双环[4.1.0]庚-3-烯基、3,6-二氢-2H-吡喃基、7-氧杂二环[2.2.1]庚-2-烯基和噻吩基任选被1、2或3个R e取代，其他变量如本发明所定义。 In some aspects of the present invention, the above-mentioned R 1 , R 2 and the atoms connected to them together form a cyclopentenyl, cyclohexenyl, bicyclo[2.2.1]hept-2-enyl, 1,2,3, 4-tetrahydropyridyl, bicyclo[4.1.0]hept-3-enyl, 3,6-dihydro-2H-pyranyl, 7-oxabicyclo[2.2.1]hept-2-enyl And thienyl, the cyclopentenyl, cyclohexenyl, bicyclo[2.2.1]hept-2-enyl, 1,2,3,4-tetrahydropyridyl, bicyclo[4.1.0]hept- 3-alkenyl, 3,6-dihydro-2H-pyranyl, 7-oxabicyclo[2.2.1]hept-2-enyl and thienyl are optionally substituted with 1, 2 or 3 R e , Other variables are as defined in the present invention.
本发明的一些方案中，上述R 1、R 2和与它们相连的原子共同构成环戊烯基、环己烯基、双环[2.2.1]庚-2-烯基、1,2,3,4-四氢吡啶基、双环[4.1.0]庚-3-烯基、3,6-二氢-2H-吡喃基、7-氧杂二环[2.2.1]庚-2-烯基、噻吩基、3,4-二氢-2H-吡喃基和双环[4.1.0]庚-2-烯基，所述环戊烯基、环己烯基、双环[2.2.1]庚-2-烯基、1,2,3,4-四氢吡啶基、双环[4.1.0]庚-3-烯基、3,6-二氢-2H-吡喃基、7-氧杂二环[2.2.1]庚-2-烯基、噻吩基、3,4-二氢-2H-吡喃基和双环[4.1.0]庚-2-烯基任选被1、2或3个R e取代，其他变量如本发明所定义。 In some aspects of the present invention, the above-mentioned R 1 , R 2 and the atoms connected to them together form a cyclopentenyl, cyclohexenyl, bicyclo[2.2.1]hept-2-enyl, 1,2,3, 4-tetrahydropyridyl, bicyclo[4.1.0]hept-3-enyl, 3,6-dihydro-2H-pyranyl, 7-oxabicyclo[2.2.1]hept-2-enyl , Thienyl, 3,4-dihydro-2H-pyranyl and bicyclo[4.1.0]hept-2-enyl, the cyclopentenyl, cyclohexenyl, bicyclo[2.2.1]hept- 2-alkenyl, 1,2,3,4-tetrahydropyridyl, bicyclo[4.1.0]hept-3-enyl, 3,6-dihydro-2H-pyranyl, 7-oxabicyclo [2.2.1]Hept-2-enyl, thienyl, 3,4-dihydro-2H-pyranyl and bicyclo[4.1.0]hept-2-enyl are optionally substituted by 1, 2 or 3 R Replace with e , and other variables are as defined in the present invention.
本发明的一些方案中，上述R 1、R 2和与它们相连的原子共同构成环己烯基、双环[2.2.1]庚-2-烯基、1,2,3,4-四氢吡啶基、双环[4.1.0]庚-3-烯基、3,6-二氢-2H-吡喃基、7-氧杂二环[2.2.1]庚-2-烯基、噻吩基、3,4-二氢-2H-吡喃基和双环[4.1.0]庚-2-烯基，所述环己烯基、双环[2.2.1]庚-2-烯基、1,2,3,4-四氢吡啶基、双环[4.1.0]庚-3-烯基、3,6-二氢-2H-吡喃基、7-氧杂二环[2.2.1]庚-2-烯基、噻吩基、3,4-二氢-2H-吡喃基和双环[4.1.0]庚-2-烯基任选被1、2或3个R e取代，其他变量如本发明所定义。 In some embodiments of the present invention, the above-mentioned R 1 , R 2 and the atoms connected to them together form a cyclohexenyl group, a bicyclo[2.2.1]hept-2-enyl group, 1,2,3,4-tetrahydropyridine Group, bicyclo[4.1.0]hept-3-enyl, 3,6-dihydro-2H-pyranyl, 7-oxabicyclo[2.2.1]hept-2-enyl, thienyl, 3 ,4-Dihydro-2H-pyranyl and bicyclo[4.1.0]hept-2-enyl, the cyclohexenyl, bicyclo[2.2.1]hept-2-enyl, 1,2,3 ,4-Tetrahydropyridyl, bicyclo[4.1.0]hept-3-enyl, 3,6-dihydro-2H-pyranyl, 7-oxabicyclo[2.2.1]hept-2-ene Group, thienyl group, 3,4-dihydro-2H-pyranyl group and bicyclo[4.1.0]hept-2-enyl group are optionally substituted with 1, 2 or 3 R e , and other variables are as defined in the present invention .
本发明的一些方案中，上述结构单元
Figure PCTCN2020093284-appb-000043
选自
Figure PCTCN2020093284-appb-000044
Figure PCTCN2020093284-appb-000045
其他变量如本发明所定义。 In some aspects of the present invention, the above-mentioned structural unit
Figure PCTCN2020093284-appb-000043
Selected from
Figure PCTCN2020093284-appb-000044
Figure PCTCN2020093284-appb-000045
Other variables are as defined in the present invention.
本发明的一些方案中，上述结构单元
Figure PCTCN2020093284-appb-000046
选自
Figure PCTCN2020093284-appb-000047
Figure PCTCN2020093284-appb-000048
其他变量如本发明所定义。 In some aspects of the present invention, the above-mentioned structural unit
Figure PCTCN2020093284-appb-000046
Selected from
Figure PCTCN2020093284-appb-000047
Figure PCTCN2020093284-appb-000048
Other variables are as defined in the present invention.
本发明的一些方案中，上述结构单元
Figure PCTCN2020093284-appb-000049
选自
Figure PCTCN2020093284-appb-000050
Figure PCTCN2020093284-appb-000051
其他变量如本发明所定义。 In some aspects of the present invention, the above-mentioned structural unit
Figure PCTCN2020093284-appb-000049
Selected from
Figure PCTCN2020093284-appb-000050
Figure PCTCN2020093284-appb-000051
Other variables are as defined in the present invention.
本发明的一些方案中，上述结构单元
Figure PCTCN2020093284-appb-000052
选自
Figure PCTCN2020093284-appb-000053
Figure PCTCN2020093284-appb-000054
Figure PCTCN2020093284-appb-000055
其他变量如本发明所定义。 In some aspects of the present invention, the above-mentioned structural unit
Figure PCTCN2020093284-appb-000052
Selected from
Figure PCTCN2020093284-appb-000053
Figure PCTCN2020093284-appb-000054
Figure PCTCN2020093284-appb-000055
Other variables are as defined in the present invention.
本发明的一些方案中，上述结构单元
Figure PCTCN2020093284-appb-000056
选自
Figure PCTCN2020093284-appb-000057
Figure PCTCN2020093284-appb-000058
Figure PCTCN2020093284-appb-000059
其他变量如本发明所定义。 In some aspects of the present invention, the above-mentioned structural unit
Figure PCTCN2020093284-appb-000056
Selected from
Figure PCTCN2020093284-appb-000057
Figure PCTCN2020093284-appb-000058
Figure PCTCN2020093284-appb-000059
Other variables are as defined in the present invention.
本发明的一些方案中，上述结构单元
Figure PCTCN2020093284-appb-000060
选自
Figure PCTCN2020093284-appb-000061
Figure PCTCN2020093284-appb-000062
其他变量如本发明所定义。 In some aspects of the present invention, the above-mentioned structural unit
Figure PCTCN2020093284-appb-000060
Selected from
Figure PCTCN2020093284-appb-000061
Figure PCTCN2020093284-appb-000062
Other variables are as defined in the present invention.
本发明的一些方案中，上述结构单元
Figure PCTCN2020093284-appb-000063
选自
Figure PCTCN2020093284-appb-000064
Figure PCTCN2020093284-appb-000065
其他变量如本发明所定义。 In some aspects of the present invention, the above-mentioned structural unit
Figure PCTCN2020093284-appb-000063
Selected from
Figure PCTCN2020093284-appb-000064
Figure PCTCN2020093284-appb-000065
Other variables are as defined in the present invention.
本发明的一些方案中，上述结构单元
Figure PCTCN2020093284-appb-000066
选自
Figure PCTCN2020093284-appb-000067
Figure PCTCN2020093284-appb-000068
其他变量如本发明所定义。 In some aspects of the present invention, the above-mentioned structural unit
Figure PCTCN2020093284-appb-000066
Selected from
Figure PCTCN2020093284-appb-000067
Figure PCTCN2020093284-appb-000068
Other variables are as defined in the present invention.
本发明的一些方案中，上述结构单元
Figure PCTCN2020093284-appb-000069
选自
Figure PCTCN2020093284-appb-000070
Figure PCTCN2020093284-appb-000071
其他变量如本发明所定义。 In some aspects of the present invention, the above-mentioned structural unit
Figure PCTCN2020093284-appb-000069
Selected from
Figure PCTCN2020093284-appb-000070
Figure PCTCN2020093284-appb-000071
Other variables are as defined in the present invention.
本发明的一些方案中，上述结构单元
Figure PCTCN2020093284-appb-000072
选自
Figure PCTCN2020093284-appb-000073
Figure PCTCN2020093284-appb-000074
Figure PCTCN2020093284-appb-000075
其他变量如本发明所定义。 In some aspects of the present invention, the above-mentioned structural unit
Figure PCTCN2020093284-appb-000072
Selected from
Figure PCTCN2020093284-appb-000073
Figure PCTCN2020093284-appb-000074
Figure PCTCN2020093284-appb-000075
Other variables are as defined in the present invention.
本发明的一些方案中，上述结构单元
Figure PCTCN2020093284-appb-000076
选自
Figure PCTCN2020093284-appb-000077
Figure PCTCN2020093284-appb-000078
其他变量如本发明所定义。 In some aspects of the present invention, the above-mentioned structural unit
Figure PCTCN2020093284-appb-000076
Selected from
Figure PCTCN2020093284-appb-000077
Figure PCTCN2020093284-appb-000078
Other variables are as defined in the present invention.
本发明的一些方案中，上述结构单元
Figure PCTCN2020093284-appb-000079
选自
Figure PCTCN2020093284-appb-000080
Figure PCTCN2020093284-appb-000081
Figure PCTCN2020093284-appb-000082
Figure PCTCN2020093284-appb-000083
其他变量如本发明所定义。 In some aspects of the present invention, the above-mentioned structural unit
Figure PCTCN2020093284-appb-000079
Selected from
Figure PCTCN2020093284-appb-000080
Figure PCTCN2020093284-appb-000081
Figure PCTCN2020093284-appb-000082
Figure PCTCN2020093284-appb-000083
Other variables are as defined in the present invention.
本发明的一些方案中，上述结构单元
Figure PCTCN2020093284-appb-000084
选自
Figure PCTCN2020093284-appb-000085
Figure PCTCN2020093284-appb-000086
Figure PCTCN2020093284-appb-000087
其他变量如本发明所定义。 In some aspects of the present invention, the above-mentioned structural unit
Figure PCTCN2020093284-appb-000084
Selected from
Figure PCTCN2020093284-appb-000085
Figure PCTCN2020093284-appb-000086
Figure PCTCN2020093284-appb-000087
Other variables are as defined in the present invention.
本发明的一些方案中，上述R 3和R 4分别独立地选自H、F、Cl、Br、I、OH、NH 2、CN、CH 3和CH 2CH 3，所述CH 3和CH 2CH 3任选被1、2或3个R f取代，其他变量如本发明所定义。 In some aspects of the present invention, the above-mentioned R 3 and R 4 are each independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, CH 3 and CH 2 CH 3 , said CH 3 and CH 2 CH 3 is optionally substituted with 1, 2 or 3 R f , and other variables are as defined in the present invention.
本发明的一些方案中，上述R 3和R 4分别独立地选自F、Cl、Br、I、OH和NH 2。 In some aspects of the present invention, the aforementioned R 3 and R 4 are each independently selected from F, Cl, Br, I, OH, and NH 2 .
本发明的一些方案中，上述R 3和R 4分别独立地选自F、Cl、Br、I、OH和NH 2，其他变量如本发明所定义。 In some aspects of the present invention, the aforementioned R 3 and R 4 are independently selected from F, Cl, Br, I, OH, and NH 2 , and other variables are as defined in the present invention.
本发明的一些方案中，上述R 3和R 4分别独立地选自F、Cl、Br、I、OH、NH 2和CF 3，其他变量如本发明所定义。 In some aspects of the present invention, the aforementioned R 3 and R 4 are independently selected from F, Cl, Br, I, OH, NH 2 and CF 3 , and other variables are as defined in the present invention.
本发明的一些方案中，上述结构单元
Figure PCTCN2020093284-appb-000088
选自
Figure PCTCN2020093284-appb-000089
其他变量如本发明所定义。 In some aspects of the present invention, the above-mentioned structural unit
Figure PCTCN2020093284-appb-000088
Selected from
Figure PCTCN2020093284-appb-000089
Other variables are as defined in the present invention.
本发明的一些方案中，上述结构单元
Figure PCTCN2020093284-appb-000090
选自
Figure PCTCN2020093284-appb-000091
Figure PCTCN2020093284-appb-000092
其他变量如本发明所定义。 In some aspects of the present invention, the above-mentioned structural unit
Figure PCTCN2020093284-appb-000090
Selected from
Figure PCTCN2020093284-appb-000091
Figure PCTCN2020093284-appb-000092
Other variables are as defined in the present invention.
本发明的一些方案中，上述结构单元
Figure PCTCN2020093284-appb-000093
选自
Figure PCTCN2020093284-appb-000094
Figure PCTCN2020093284-appb-000095
其他变量如本发明所定义。 In some aspects of the present invention, the above-mentioned structural unit
Figure PCTCN2020093284-appb-000093
Selected from
Figure PCTCN2020093284-appb-000094
Figure PCTCN2020093284-appb-000095
Other variables are as defined in the present invention.
本发明的一些方案中，上述结构单元
Figure PCTCN2020093284-appb-000096
选自
Figure PCTCN2020093284-appb-000097
Figure PCTCN2020093284-appb-000098
其他变量如本发明所定义。 In some aspects of the present invention, the above-mentioned structural unit
Figure PCTCN2020093284-appb-000096
Selected from
Figure PCTCN2020093284-appb-000097
Figure PCTCN2020093284-appb-000098
Other variables are as defined in the present invention.
本发明还有一些方案是由上述各变量任意组合而来。There are also some schemes of the present invention that come from any combination of the above-mentioned variables.
本发明的一些方案中，上述化合物或其药学上可接受的盐，其选自In some aspects of the present invention, the above-mentioned compound or a pharmaceutically acceptable salt thereof is selected from
Figure PCTCN2020093284-appb-000099
Figure PCTCN2020093284-appb-000099
其中，among them,
Z 1和Z 2分别独立地选自CH(R e)、O和N(R e)； Z 1 and Z 2 are each independently selected from CH(R e ), O and N(R e );
Z 3选自CH 2和O； Z 3 is selected from CH 2 and O;
Z 4选自O； Z 4 is selected from O;
Z 5选自C(R e)和N； Z 5 is selected from C(R e ) and N;
Z 6选自N(R e)和O； Z 6 is selected from N(R e ) and O;
R c选自H和CN； R c is selected from H and CN;
R 3、R 4和R e如本发明所定义。 R 3, R 4 and R e are as defined in the present invention.
本发明的一些方案中，上述化合物或其药学上可接受的盐，其选自In some aspects of the present invention, the above-mentioned compound or a pharmaceutically acceptable salt thereof is selected from
Figure PCTCN2020093284-appb-000100
Figure PCTCN2020093284-appb-000100
其中，among them,
R 1、R 2、R 3、R 4和R c如本发明所定义。 R 1 , R 2 , R 3 , R 4 and R c are as defined in the present invention.
本发明还提供了下式所示化合物或其药学上可接受的盐，The present invention also provides a compound represented by the following formula or a pharmaceutically acceptable salt thereof,
Figure PCTCN2020093284-appb-000101
Figure PCTCN2020093284-appb-000101
Figure PCTCN2020093284-appb-000102
Figure PCTCN2020093284-appb-000102
本发明的一些方案中，上述化合物或其药学上可接受的盐，其选自：In some aspects of the present invention, the above-mentioned compound or a pharmaceutically acceptable salt thereof is selected from:
Figure PCTCN2020093284-appb-000103
Figure PCTCN2020093284-appb-000103
本发明还提供了一种药物组合物，包括作为活性成分的治疗有效量的根据上述的化合物或其药学上可接受的盐以及药学上可接受的载体。The present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of the above-mentioned compound or a pharmaceutically acceptable salt thereof as an active ingredient and a pharmaceutically acceptable carrier.
本发明的一些方案中，上述化合物或其药学上可接受的盐或者上述的组合物在制备甲状腺素受体-β激动剂相关药物上的应用。In some aspects of the present invention, the above-mentioned compound or a pharmaceutically acceptable salt thereof or the above-mentioned composition is used in the preparation of thyroxine receptor-β agonist related drugs.
本发明的一些方案中，上述的应用，其特征在于，所述甲状腺素受体-β激动剂相关药物是用于治疗非酒精性脂肪肝炎的药物。In some aspects of the present invention, the above application is characterized in that the thyroxine receptor-β agonist-related drug is a drug for the treatment of non-alcoholic steatohepatitis.
定义和说明Definition and description
除非另有说明，本文所用的下列术语和短语旨在具有下列含义。一个特定的术语或短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。这里所采用的术语“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。Unless otherwise stated, the following terms and phrases used herein are intended to have the following meanings. A specific term or phrase should not be considered uncertain or unclear without a special definition, but should be understood in its ordinary meaning. When a trade name appears in this article, it is meant to refer to its corresponding commodity or its active ingredient. The term "pharmaceutically acceptable" as used here refers to those compounds, materials, compositions and/or dosage forms that are within the scope of reliable medical judgment and are suitable for use in contact with human and animal tissues , Without excessive toxicity, irritation, allergic reactions or other problems or complications, commensurate with a reasonable benefit/risk ratio.
术语“药学上可接受的盐”是指本发明化合物的盐，由本发明发现的具有特定取代基的化合物与相对无毒的酸或碱制备。当本发明的化合物中含有相对酸性的功能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的碱与这类化合物的中性形式接触的方式获得碱加成盐。药学上可接受的碱加成盐包括钠、钾、钙、铵、有机氨或镁盐或类似的盐。当本发明的化合物中含有相对碱性的官能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的酸与这类化合物的中性形式接触的方式获得酸加成盐。药学上可接受的酸加成盐的实例包括无机酸盐，所述无机酸包括例如盐酸、氢溴酸、硝酸、碳酸，碳酸氢根，磷酸、磷酸一氢根、磷酸二氢根、硫酸、硫酸氢根、氢碘酸、亚磷酸等；以及有机酸盐，所述有机酸包括如乙酸、丙酸、异丁酸、马来酸、丙二酸、苯甲酸、琥珀酸、辛二酸、反丁烯二酸、乳酸、扁桃酸、邻苯二甲酸、苯磺酸、对甲苯磺酸、柠檬酸、酒石酸和甲磺酸等类似的酸；还包括氨基酸(如精氨酸等)的盐，以及如葡糖醛酸等有机酸的盐。本发明的某些特定的化合物含有碱性和酸性的官能团，从而可以被转换成任一碱或酸加成盐。The term "pharmaceutically acceptable salt" refers to a salt of the compound of the present invention, which is prepared from a compound with specific substituents discovered in the present invention and a relatively non-toxic acid or base. When the compound of the present invention contains a relatively acidic functional group, the base addition salt can be obtained by contacting the neutral form of the compound with a sufficient amount of base in a pure solution or a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic ammonia or magnesium salts or similar salts. When the compound of the present invention contains a relatively basic functional group, the acid addition salt can be obtained by contacting the neutral form of the compound with a sufficient amount of acid in a pure solution or a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts including, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, hydrogen carbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, Hydrogen sulfate, hydroiodic acid, phosphorous acid, etc.; and organic acid salts, the organic acid includes such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, Similar acids such as fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid and methanesulfonic acid; also include salts of amino acids (such as arginine, etc.) , And salts of organic acids such as glucuronic acid. Certain specific compounds of the present invention contain basic and acidic functional groups, so they can be converted into any base or acid addition salt.
本发明的药学上可接受的盐可由含有酸根或碱基的母体化合物通过常规化学方法合成。一般情况下，这样的盐的制备方法是：在水或有机溶剂或两者的混合物中，经由游离酸或碱形式的这些化合物与化学计量的适当的碱或酸反应来制备。The pharmaceutically acceptable salt of the present invention can be synthesized from the parent compound containing acid or base by conventional chemical methods. Generally, such salts are prepared by reacting these compounds in free acid or base form with a stoichiometric amount of appropriate base or acid in water or an organic solvent or a mixture of both.
除了盐的形式，本发明所提供的化合物还存在前药形式。本文所描述的化合物的前药容易地在生理条件下发生化学变化从而转化成本发明的化合物。此外，前体药物可以在体内环境中通过化学或生化方法被转换到本发明的化合物。In addition to salt forms, the compounds provided by the present invention also exist in prodrug forms. The prodrugs of the compounds described herein easily undergo chemical changes under physiological conditions to transform into the compounds of the invention. In addition, prodrugs can be converted to the compounds of the present invention by chemical or biochemical methods in the in vivo environment.
本发明的某些化合物可以以非溶剂化形式或者溶剂化形式存在，包括水合物形式。一般而言，溶剂化形式与非溶剂化的形式相当，都包含在本发明的范围之内。Certain compounds of the present invention may exist in unsolvated or solvated forms, including hydrated forms. Generally speaking, the solvated form is equivalent to the unsolvated form, and both are included in the scope of the present invention.
本发明的化合物可以存在特定的几何或立体异构体形式。本发明设想所有的这类化合物，包括顺式和 反式异构体、(-)-和(+)-对对映体、(R)-和(S)-对映体、非对映异构体、(D)-异构体、(L)-异构体，及其外消旋混合物和其他混合物，例如对映异构体或非对映体富集的混合物，所有这些混合物都属于本发明的范围之内。烷基等取代基中可存在另外的不对称碳原子。所有这些异构体以及它们的混合物，均包括在本发明的范围之内。The compounds of the present invention may exist in specific geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers Conformers, (D)-isomers, (L)-isomers, and their racemic mixtures and other mixtures, such as enantiomers or diastereomeric enriched mixtures, all of these mixtures belong to Within the scope of the present invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl. All these isomers and their mixtures are included in the scope of the present invention.
除非另有说明，术语“对映异构体”或者“旋光异构体”是指互为镜像关系的立体异构体。Unless otherwise specified, the term "enantiomer" or "optical isomer" refers to stereoisomers that are mirror images of each other.
除非另有说明，术语“顺反异构体”或者“几何异构体”系由因双键或者成环碳原子单键不能自由旋转而引起。Unless otherwise specified, the term "cis-trans isomer" or "geometric isomer" is caused by the inability to rotate freely because of double bonds or single bonds of ring-forming carbon atoms.
除非另有说明，术语“非对映异构体”是指分子具有两个或多个手性中心，并且分子间为非镜像的关系的立体异构体。Unless otherwise specified, the term "diastereomer" refers to a stereoisomer in which a molecule has two or more chiral centers and the relationship between the molecules is non-mirror-image relationship.
除非另有说明，“(D)”或者“(+)”表示右旋，“(L)”或者“(-)”表示左旋，“(DL)”或者“(±)”表示外消旋。Unless otherwise specified, "(D)" or "(+)" means dextrorotation, "(L)" or "(-)" means levorotatory, and "(DL)" or "(±)" means racemic.
除非另有说明，用楔形实线键
Figure PCTCN2020093284-appb-000104
和楔形虚线键
Figure PCTCN2020093284-appb-000105
表示一个立体中心的绝对构型，用直形实线键
Figure PCTCN2020093284-appb-000106
和直形虚线键
Figure PCTCN2020093284-appb-000107
表示立体中心的相对构型，用波浪线
Figure PCTCN2020093284-appb-000108
表示楔形实线键
Figure PCTCN2020093284-appb-000109
或楔形虚线键
Figure PCTCN2020093284-appb-000110
或用波浪线
Figure PCTCN2020093284-appb-000111
表示直形实线键
Figure PCTCN2020093284-appb-000112
和直形虚线键
Figure PCTCN2020093284-appb-000113
Unless otherwise specified, use wedge-shaped solid line keys
Figure PCTCN2020093284-appb-000104
And wedge-shaped dashed key
Figure PCTCN2020093284-appb-000105
Represents the absolute configuration of a solid center, with a straight solid line key
Figure PCTCN2020093284-appb-000106
And straight dashed key
Figure PCTCN2020093284-appb-000107
Indicates the relative configuration of the three-dimensional center, using wavy lines
Figure PCTCN2020093284-appb-000108
Represents a wedge-shaped solid line key
Figure PCTCN2020093284-appb-000109
Or wedge-shaped dotted key
Figure PCTCN2020093284-appb-000110
Or use wavy lines
Figure PCTCN2020093284-appb-000111
Represents a straight solid line key
Figure PCTCN2020093284-appb-000112
And straight dashed key
Figure PCTCN2020093284-appb-000113
本发明的化合物可以存在特定的。除非另有说明，术语“互变异构体”或“互变异构体形式”是指在室温下，不同官能团异构体处于动态平衡，并能很快的相互转化。若互变异构体是可能的(如在溶液中)，则可以达到互变异构体的化学平衡。例如，质子互变异构体(proton tautomer)(也称质子转移互变异构体(prototropic tautomer))包括通过质子迁移来进行的互相转化，如酮-烯醇异构化和亚胺-烯胺异构化。价键异构体(valence tautomer)包括一些成键电子的重组来进行的相互转化。其中酮-烯醇互变异构化的具体实例是戊烷-2,4-二酮与4-羟基戊-3-烯-2-酮两个互变异构体之间的互变。The compound of the present invention may be specific. Unless otherwise specified, the term "tautomer" or "tautomeric form" means that at room temperature, the isomers of different functional groups are in dynamic equilibrium and can be transformed into each other quickly. If tautomers are possible (such as in solution), the chemical equilibrium of tautomers can be reached. For example, proton tautomers (also called prototropic tautomers) include interconversion through proton migration, such as keto-enol isomerization and imine-ene Amine isomerization. Valence isomers (valence tautomer) include some recombination of bonding electrons for mutual transformation. A specific example of keto-enol tautomerization is the tautomerism between two tautomers of pentane-2,4-dione and 4-hydroxypent-3-en-2-one.
除非另有说明，术语“富含一种异构体”、“异构体富集”、“富含一种对映体”或者“对映体富集”指其中一种异构体或对映体的含量小于100％，并且，该异构体或对映体的含量大于等于60％，或者大于等于70％，或者大于等于80％，或者大于等于90％，或者大于等于95％，或者大于等于96％，或者大于等于97％，或者大于等于98％，或者大于等于99％，或者大于等于99.5％，或者大于等于99.6％，或者大于等于99.7％，或者大于等于99.8％，或者大于等于99.9％。Unless otherwise specified, the terms "enriched in one isomer", "enriched in isomers", "enriched in one enantiomer" or "enriched in enantiomers" refer to one of the isomers or pairs of The content of the enantiomer is less than 100%, and the content of the isomer or enantiomer is greater than or equal to 60%, or greater than or equal to 70%, or greater than or equal to 80%, or greater than or equal to 90%, or greater than or equal to 95%, or 96% or greater, or 97% or greater, or 98% or greater, or 99% or greater, or 99.5% or greater, or 99.6% or greater, or 99.7% or greater, or 99.8% or greater, or greater than or equal 99.9%.
除非另有说明，术语“异构体过量”或“对映体过量”指两种异构体或两种对映体相对百分数之间的差值。例如，其中一种异构体或对映体的含量为90％，另一种异构体或对映体的含量为10％，则异构体或对映体过量(ee值)为80％。Unless otherwise stated, the term "isomer excess" or "enantiomeric excess" refers to the difference between the relative percentages of two isomers or two enantiomers. For example, if the content of one isomer or enantiomer is 90%, and the content of the other isomer or enantiomer is 10%, the isomer or enantiomer excess (ee value) is 80% .
可以通过的手性合成或手性试剂或者其他常规技术制备光学活性的(R)-和(S)-异构体以及D和L异构体。如果想得到本发明某化合物的一种对映体，可以通过不对称合成或者具有手性助剂的衍生作用来制备，其中将所得非对映体混合物分离，并且辅助基团裂开以提供纯的所需对映异构体。或者，当分子中含有碱 性官能团(如氨基)或酸性官能团(如羧基)时，与适当的光学活性的酸或碱形成非对映异构体的盐，然后通过本领域所公知的常规方法进行非对映异构体拆分，然后回收得到纯的对映体。此外，对映异构体和非对映异构体的分离通常是通过使用色谱法完成的，所述色谱法采用手性固定相，并任选地与化学衍生法相结合(例如由胺生成氨基甲酸盐)。The optically active (R)- and (S)-isomers and D and L isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If you want to obtain an enantiomer of a compound of the present invention, it can be prepared by asymmetric synthesis or derivatization with chiral auxiliary agents, in which the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide pure The desired enantiomer. Alternatively, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), it forms a diastereomeric salt with a suitable optically active acid or base, and then passes through a conventional method known in the art The diastereoisomers are resolved, and then the pure enantiomers are recovered. In addition, the separation of enantiomers and diastereomers is usually accomplished through the use of chromatography, which employs a chiral stationary phase and is optionally combined with chemical derivatization (for example, the formation of amino groups from amines). Formate).
本发明的化合物可以在一个或多个构成该化合物的原子上包含非天然比例的原子同位素。例如，可用放射性同位素标记化合物，比如氚( 3H)，碘-125( 125I)或C-14( 14C)。又例如，可用重氢取代氢形成氘代药物，氘与碳构成的键比普通氢与碳构成的键更坚固，相比于未氘化药物，氘代药物有降低毒副作用、增加药物稳定性、增强疗效、延长药物生物半衰期等优势。本发明的化合物的所有同位素组成的变换，无论放射性与否，都包括在本发明的范围之内。 The compounds of the present invention may contain unnatural proportions of atomic isotopes on one or more of the atoms constituting the compound. For example, compounds can be labeled with radioisotopes, such as tritium ( 3 H), iodine-125 ( 125 I), or C-14 ( 14 C). For another example, deuterated drugs can be formed by replacing hydrogen with heavy hydrogen. The bond formed by deuterium and carbon is stronger than the bond formed by ordinary hydrogen and carbon. Compared with undeuterated drugs, deuterated drugs have reduced toxic side effects and increased drug stability. , Enhance the efficacy, extend the biological half-life of drugs and other advantages. All changes in the isotopic composition of the compounds of the present invention, whether radioactive or not, are included in the scope of the present invention.
术语“任选”或“任选地”指的是随后描述的事件或状况可能但不是必需出现的，并且该描述包括其中所述事件或状况发生的情况以及所述事件或状况不发生的情况。The term "optional" or "optionally" refers to the event or condition described later that may but not necessarily occur, and the description includes the situation in which the event or condition occurs and the situation in which the event or condition does not occur .
术语“被取代的”是指特定原子上的任意一个或多个氢原子被取代基取代，可以包括重氢和氢的变体，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(即＝O)时，意味着两个氢原子被取代。氧取代不会发生在芳香基上。术语“任选被取代的”是指可以被取代，也可以不被取代，除非另有规定，取代基的种类和数目在化学上可以实现的基础上可以是任意的。The term "substituted" means that any one or more hydrogen atoms on a specific atom are replaced by substituents, and can include deuterium and hydrogen variants, as long as the valence of the specific atom is normal and the substituted compound is stable of. When the substituent is oxygen (ie =O), it means that two hydrogen atoms are replaced. Oxygen substitution will not occur on aromatic groups. The term "optionally substituted" means that it can be substituted or unsubstituted. Unless otherwise specified, the type and number of substituents can be arbitrary on the basis that they can be chemically realized.
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。因此，例如，如果一个基团被0-2个R所取代，则所述基团可以任选地至多被两个R所取代，并且每种情况下的R都有独立的选项。此外，取代基和/或其变体的组合只有在这样的组合会产生稳定的化合物的情况下才是被允许的。When any variable (such as R) occurs more than once in the composition or structure of a compound, its definition in each case is independent. Thus, for example, if a group is substituted with 0-2 Rs, the group may optionally be substituted with up to two Rs, and R has independent options in each case. In addition, combinations of substituents and/or variants thereof are only permitted if such combinations result in stable compounds.
当一个连接基团的数量为0时，比如-(CRR) 0-，表示该连接基团为单键。 When the number of a linking group is 0, such as -(CRR) 0 -, it means that the linking group is a single bond.
当其中一个变量选自单键时，表示其连接的两个基团直接相连，比如A-L-Z中L代表单键时表示该结构实际上是A-Z。When one of the variables is selected from a single bond, it means that the two groups connected are directly connected. For example, when L in A-L-Z represents a single bond, it means that the structure is actually A-Z.
当一个取代基为空缺时，表示该取代基是不存在的，比如A-X中X为空缺时表示该结构实际上是A。当所列举的取代基中没有指明其通过哪一个原子连接到被取代的基团上时，这种取代基可以通过其任何原子相键合，例如，吡啶基作为取代基可以通过吡啶环上任意一个碳原子连接到被取代的基团上。当所列举的连接基团没有指明其连接方向，其连接方向是任意的，例如，
Figure PCTCN2020093284-appb-000114
中连接基团L为-M-W-，此时-M-W-既可以按与从左往右的读取顺序相同的方向连接环A和环B构成
Figure PCTCN2020093284-appb-000115
也可以按照与从左往右的读取顺序相反的方向连接环A和环B构成
Figure PCTCN2020093284-appb-000116
所述连接基团、取代基和/或其变体的组合只有在这样的组合会产生稳定的化合物的情况下才是被允许的。 When a substituent is vacant, it means that the substituent is absent. For example, when X in AX is vacant, it means that the structure is actually A. When the listed substituents do not indicate which atom is connected to the substituted group, such substituents can be bonded via any atom. For example, a pyridyl group can pass through any one of the pyridine ring as a substituent. The carbon atom is attached to the substituted group. When the listed linking group does not indicate its connection direction, its connection direction is arbitrary, for example,
Figure PCTCN2020093284-appb-000114
The middle linking group L is -MW-, at this time -MW- can be formed by connecting ring A and ring B in the same direction as the reading order from left to right
Figure PCTCN2020093284-appb-000115
It can also be formed by connecting ring A and ring B in the direction opposite to the reading order from left to right
Figure PCTCN2020093284-appb-000116
Combinations of the linking groups, substituents, and/or variants thereof are only permitted if such combinations result in stable compounds.
除非另有规定，术语“C 1-6烷基”用于表示直链或支链的由1至6个碳原子组成的饱和碳氢基团。所述C 1-6烷基包括C 1-5、C 1-4、C 1-3、C 1-2、C 2-6、C 2-4、C 6和C 5烷基等；其可以是一价(如甲基)、二价(如亚甲基)或者多价(如次甲基)。C 1-6烷基的实例包括但不限于甲基(Me)、乙基(Et)、丙基(包括n-丙基和异丙基)、丁基(包括n-丁基，异丁基，s-丁基和t-丁基)、戊基(包括n-戊基，异戊基和新戊基)、己基等。 Unless otherwise specified, the term "C 1-6 alkyl" is used to indicate a linear or branched saturated hydrocarbon group composed of 1 to 6 carbon atoms. The C 1-6 alkyl group includes C 1-5 , C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-4 , C 6 and C 5 alkyl groups, etc.; it may Is monovalent (such as methyl), divalent (such as methylene) or multivalent (such as methine). Examples of C 1-6 alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl) , S-butyl and t-butyl), pentyl (including n-pentyl, isopentyl and neopentyl), hexyl, etc.
除非另有规定，术语“C 1-3烷基”用于表示直链或支链的由1至3个碳原子组成的饱和碳氢基团。所述C 1-3烷基包括C 1-2和C 2-3烷基等；其可以是一价(如甲基)、二价(如亚甲基)或者多价(如次甲基)。C 1- 3烷基的实例包括但不限于甲基(Me)、乙基(Et)、丙基(包括n-丙基和异丙基)等。 Unless otherwise specified, the term "C 1-3 alkyl" is used to indicate a linear or branched saturated hydrocarbon group composed of 1 to 3 carbon atoms. The C 1-3 alkyl group includes C 1-2 and C 2-3 alkyl groups, etc.; it can be monovalent (such as methyl), divalent (such as methylene) or multivalent (such as methine) . Example C 1- 3 alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n- propyl and isopropyl) and the like.
除非另有规定，术语“C 1-3烷氧基”表示通过一个氧原子连接到分子的其余部分的那些包含1至3个碳原子的烷基基团。所述C 1-3烷氧基包括C 1-2、C 2-3、C 3和C 2烷氧基等。C 1-3烷氧基的实例包括但不限于甲氧基、乙氧基、丙氧基(包括正丙氧基和异丙氧基)等。 Unless otherwise specified, the term "C 1-3 alkoxy" refers to those alkyl groups containing 1 to 3 carbon atoms attached to the rest of the molecule through an oxygen atom. The C 1-3 alkoxy group includes C 1-2 , C 2-3 , C 3 and C 2 alkoxy groups and the like. Examples of C 1-3 alkoxy include but are not limited to methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy) and the like.
除非另有规定，“C 3-8环烯基”表示包含至少一个碳-碳双键的由3至8个碳原子组成的部分不饱和的环状碳氢基团，其包括单环和双环体系，其中双环体系包括螺环、并环和桥环，此体系的任意环都是非芳香性的。所述C 3-8环烯基包括C 3-6、C 3-5、C 4-10、C 4-8、C 4-6、C 4-5、C 5-8或C 5-6环烯基等；其可以是一价、二价或者多价。C 3-8环烯基的实例包括但不限于，环丙烯基、环丁烯基、环戊烯基、环戊二烯基、环己烯基、环己二烯基等。 Unless otherwise specified, "C 3-8 cycloalkenyl" means a partially unsaturated cyclic hydrocarbon group composed of 3 to 8 carbon atoms containing at least one carbon-carbon double bond, which includes monocyclic and bicyclic rings System, where the bicyclic ring system includes spiro ring, fused ring and bridged ring, any ring of this system is non-aromatic. The C 3-8 cycloalkenyl includes C 3-6 , C 3-5 , C 4-10 , C 4-8 , C 4-6 , C 4-5 , C 5-8 or C 5-6 ring Alkenyl, etc.; it can be monovalent, divalent or multivalent. Examples of C 3-8 cycloalkenyl include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl and the like.
除非另有规定，“C 6-8环烯基”表示包含至少一个碳-碳双键的由6至8个碳原子组成的部分不饱和的环状碳氢基团，其包括单环和双环体系，其中双环体系包括螺环、并环和桥环，此体系的任意环都是非芳香性的。所述C 6-8环烯基包括C 6-7或C 6-8环烯基等；其可以是一价、二价或者多价。C 6-8环烯基的实例包括但不限于，环己烯基、环庚烯基、环辛烯基等。 Unless otherwise specified, "C 6-8 cycloalkenyl" means a partially unsaturated cyclic hydrocarbon group composed of 6 to 8 carbon atoms containing at least one carbon-carbon double bond, including monocyclic and bicyclic rings System, where the bicyclic ring system includes spiro ring, fused ring and bridged ring, any ring of this system is non-aromatic. The C 6-8 cycloalkenyl group includes a C 6-7 or C 6-8 cycloalkenyl group, etc.; it may be monovalent, divalent or multivalent. Examples of C 6-8 cycloalkenyl include, but are not limited to, cyclohexenyl, cycloheptenyl, cyclooctenyl, and the like.
除非另有规定，术语“3-8元杂环烯基”本身或者与其他术语联合分别表示包含至少一个碳-碳双键的由3至8个环原子组成的部分不饱和的环状基团，其1、2、3或4个环原子为独立选自O、S和N的杂原子，其余为碳原子，其中氮原子任选地被季铵化，氮和硫杂原子可任选被氧化(即NO和S(O) p，p是1或2)。其包括单环、双环和三环体系，其中双环和三环体系包括螺环、并环和桥环，此体系的任意环都是非芳香性的。此外，就该“3-8元杂环烯基”而言，杂原子可以占据杂环烯基与分子其余部分的连接位置。所述3-8元杂环烯基包括3-6元、3-5元、4-6元、4-5元、5-6元、4元、5元和6元杂环烯基等。3-8元杂环烯基的实例包括但不限于
Figure PCTCN2020093284-appb-000117
Unless otherwise specified, the term "3-8 membered heterocycloalkenyl" by itself or in combination with other terms means a partially unsaturated cyclic group consisting of 3 to 8 ring atoms containing at least one carbon-carbon double bond , Its 1, 2, 3 or 4 ring atoms are heteroatoms independently selected from O, S and N, and the rest are carbon atoms, wherein the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms can optionally be Oxidation (ie NO and S(O) p , p is 1 or 2). It includes monocyclic, bicyclic and tricyclic ring systems. The bicyclic and tricyclic ring systems include spiro, fused and bridged rings. Any ring in this system is non-aromatic. In addition, with regard to the "3-8 membered heterocycloalkenyl group", a heteroatom may occupy the connection position of the heterocycloalkenyl group with the rest of the molecule. The 3-8 membered heterocycloalkenyl group includes 3-6 membered, 3-5 membered, 4-6 membered, 4-5 membered, 5-6 membered, 4-membered, 5-membered, and 6-membered heterocycloalkenyl group. Examples of 3-8 membered heterocycloalkenyl include but are not limited to
Figure PCTCN2020093284-appb-000117
除非另有规定，术语“3-8元杂环烷基”本身或者与其他术语联合分别表示由3至8个环原子组成的饱和环状基团，其1、2、3或4个环原子为独立选自O、S和N的杂原子，其余为碳原子，其中氮原子任选地被季铵化，氮和硫杂原子可任选被氧化(即NO和S(O) p，p是1或2)。其包括单环和双环体系，其中双环体系包括螺环、并环和桥环。此外，就该“3-8元杂环烷基”而言，杂原子可以占据杂环烷基与分子其余部分的连接位置。所述3-8元杂环烷基包括3-6元、3-5元、4-6元、5-6元、4元、5元和6元杂环烷基等。3-8元杂环烷基的实例包括但不限于氮杂环丁基、氧杂环丁基、硫杂环丁基、吡咯烷基、吡唑烷基、咪唑烷基、四氢噻吩基(包括四氢噻吩-2-基和四氢噻吩-3-基等)、四氢呋喃基(包括四氢呋喃-2-基等)、四氢吡喃基、哌啶基(包括1-哌啶基、2-哌啶基和3-哌啶基等)、哌嗪基(包括1-哌嗪基和2-哌嗪基等)、吗啉基(包括3-吗啉基和4-吗啉基等)、二噁烷基、二噻烷基、异噁唑烷基、异噻唑烷基、1,2-噁嗪基、1,2-噻嗪基、六氢哒嗪基、高哌嗪基、高哌啶基或二氧杂环庚烷基等。 Unless otherwise specified, the term "3-8 membered heterocycloalkyl" by itself or in combination with other terms means a saturated cyclic group consisting of 3 to 8 ring atoms, with 1, 2, 3 or 4 ring atoms Are heteroatoms independently selected from O, S and N, and the rest are carbon atoms, wherein nitrogen atoms are optionally quaternized, and nitrogen and sulfur heteroatoms can be optionally oxidized (ie, NO and S(O) p , p Is 1 or 2). It includes monocyclic and bicyclic ring systems, where the bicyclic ring system includes spiro, fused, and bridged rings. In addition, with regard to the "3-8 membered heterocycloalkyl group", a heteroatom may occupy the connection position of the heterocycloalkyl group with the rest of the molecule. The 3-8 membered heterocycloalkyl group includes 3-6 membered, 3-5 membered, 4-6 membered, 5-6 membered, 4-membered, 5-membered and 6-membered heterocycloalkyl group. Examples of 3-8 membered heterocycloalkyl groups include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothienyl ( Including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2- Piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), Dioxanyl, dithiazyl, isoxazolidinyl, isothiazolidinyl, 1,2-oxazinyl, 1,2-thiazinyl, hexahydropyridazinyl, homopiperazinyl, homopiperidine Ridinyl or dioxepanyl and the like.
除非另有规定，C n-n+m或C n-C n+m包括n至n+m个碳的任何一种具体情况，例如C 1-12包括C 1、C 2、C 3、C 4、C 5、C 6、C 7、C 8、C 9、C 10、C 11、和C 12，也包括n至n+m中的任何一个范围，例如C 1-12包括C 1- 3、C 1-6、C 1-9、C 3-6、C 3-9、C 3-12、C 6-9、C 6-12、和C 9-12等；同理，n元至n+m元表示环上原子数为n至n+m个，例如3-12元环包括3元环、4元环、5元环、6元环、7元环、8元环、9元环、10元环、11元环、和12元环，也包括n至n+m中的任何一个范围，例如3-12元环包括3-6元环、3-9元环、5-6元环、5-7元环、6-7元环、6-8元环、和6-10元环等。 Unless otherwise specified, C n-n+m or C n -C n+m includes any specific case of n to n+m carbons, for example, C 1-12 includes C 1 , C 2 , C 3 , C 4, C 5, C 6, C 7, C 8, C 9, C 10, C 11, and C 12, also including any one of n + m to n ranges, for example C 1- 3 comprises a C 1-12 , C 1-6 , C 1-9 , C 3-6 , C 3-9 , C 3-12 , C 6-9 , C 6-12 , and C 9-12, etc.; in the same way, from n to n +m means the number of atoms in the ring is n to n+m, for example, 3-12 membered ring includes 3-membered ring, 4-membered ring, 5-membered ring, 6-membered ring, 7-membered ring, 8-membered ring, 9-membered ring , 10-membered ring, 11-membered ring, and 12-membered ring, including any range from n to n+m, for example, 3-12 membered ring includes 3-6 membered ring, 3-9 membered ring, 5-6 membered ring Ring, 5-7 membered ring, 6-7 membered ring, 6-8 membered ring, 6-10 membered ring, etc.
术语“离去基团”是指可以被另一种官能团或原子通过取代反应(例如亲和取代反应)所取代的官能团或原子。例如，代表性的离去基团包括三氟甲磺酸酯；氯、溴、碘；磺酸酯基，如甲磺酸酯、甲苯磺酸酯、对溴苯磺酸酯、对甲苯磺酸酯等；酰氧基，如乙酰氧基、三氟乙酰氧基等等。The term "leaving group" refers to a functional group or atom that can be replaced by another functional group or atom through a substitution reaction (for example, an affinity substitution reaction). For example, representative leaving groups include triflate; chlorine, bromine, iodine; sulfonate groups, such as mesylate, tosylate, p-bromobenzenesulfonate, p-toluenesulfonic acid Esters, etc.; acyloxy groups such as acetoxy, trifluoroacetoxy and the like.
术语“保护基”包括但不限于“氨基保护基”、“羟基保护基”或“巯基保护基”。术语“氨基保护基”是指适合用于阻止氨基氮位上副反应的保护基团。代表性的氨基保护基包括但不限于：甲酰基；酰基，例如链烷酰基(如乙酰基、三氯乙酰基或三氟乙酰基)；烷氧基羰基，如叔丁氧基羰基(Boc)；芳基甲氧羰基，如苄氧羰基(Cbz)和9-芴甲氧羰基(Fmoc)；芳基甲基，如苄基(Bn)、三苯甲基(Tr)、1,1-二-(4'-甲氧基苯基)甲基；甲硅烷基，如三甲基甲硅烷基(TMS)和叔丁基二甲基甲硅烷基(TBS)等等。术语“羟基保护基”是指适合用于阻止羟基副反应的保护基。代表性羟基保护基包括但不限于：烷基，如甲基、乙基和叔丁基；酰基，例如链烷酰基(如乙酰基)；芳基甲基，如苄基(Bn)，对甲氧基苄基(PMB)、9-芴基甲基(Fm)和二苯基甲基(二苯甲基，DPM)；甲硅烷基，如三甲基甲硅烷基(TMS)和叔丁基二甲基甲硅烷基(TBS)等等。The term "protecting group" includes, but is not limited to, "amino protecting group", "hydroxy protecting group" or "thiol protecting group". The term "amino protecting group" refers to a protecting group suitable for preventing side reactions at the amino nitrogen position. Representative amino protecting groups include, but are not limited to: formyl; acyl, such as alkanoyl (such as acetyl, trichloroacetyl or trifluoroacetyl); alkoxycarbonyl, such as tert-butoxycarbonyl (Boc) ; Arylmethyloxycarbonyl, such as benzyloxycarbonyl (Cbz) and 9-fluorenylmethyloxycarbonyl (Fmoc); arylmethyl, such as benzyl (Bn), trityl (Tr), 1,1-di -(4'-Methoxyphenyl)methyl; silyl groups, such as trimethylsilyl (TMS) and tert-butyldimethylsilyl (TBS) and so on. The term "hydroxy protecting group" refers to a protecting group suitable for preventing side reactions of the hydroxyl group. Representative hydroxy protecting groups include but are not limited to: alkyl groups, such as methyl, ethyl, and tert-butyl; acyl groups, such as alkanoyl groups (such as acetyl); arylmethyl groups, such as benzyl (Bn), p-methyl Oxybenzyl (PMB), 9-fluorenylmethyl (Fm) and diphenylmethyl (diphenylmethyl, DPM); silyl groups such as trimethylsilyl (TMS) and tert-butyl Dimethylsilyl (TBS) and so on.
本发明的化合物可以通过本领域技术人员所熟知的常规方法来确认结构，如果本发明涉及化合物的绝对构型，则该绝对构型可以通过本领域常规技术手段予以确证。例如单晶X射线衍射法(SXRD)，把培养出的单晶用Bruker D8 venture衍射仪收集衍射强度数据，光源为CuKα辐射，扫描方式：
Figure PCTCN2020093284-appb-000118
扫描，收集相关数据后，进一步采用直接法(Shelxs97)解析晶体结构，便可以确证绝对构型。 The structure of the compound of the present invention can be confirmed by conventional methods well known to those skilled in the art. If the present invention relates to the absolute configuration of the compound, the absolute configuration can be confirmed by conventional technical means in the art. For example, single crystal X-ray diffraction (SXRD), the cultured single crystal is collected with a Bruker D8 venture diffractometer to collect diffraction intensity data, the light source is CuKα radiation, and the scanning method:
Figure PCTCN2020093284-appb-000118
After scanning and collecting relevant data, the direct method (Shelxs97) is further used to analyze the crystal structure to confirm the absolute configuration.
本发明的化合物可以通过本领域技术人员所熟知的多种合成方法来制备，包括下面列举的具体实施方式、其与其他化学合成方法的结合所形成的实施方式以及本领域技术上人员所熟知的等同替换方式，优选的实施方式包括但不限于本发明的实施例。The compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, the embodiments formed by combining them with other chemical synthesis methods, and those well known to those skilled in the art Equivalent alternatives, preferred implementations include but are not limited to the embodiments of the present invention.
本发明所使用的溶剂可经市售获得。本发明采用下述缩略词：aq代表水；HATU代表O-(7-氮杂苯并三唑-1-基)-N,N,N',N'-四甲基脲六氟磷酸盐；EDC代表N-(3-二甲基氨基丙基)-N'-乙基碳二亚胺盐酸盐；m-CPBA代表3-氯过氧苯甲酸；eq代表当量、等量；CDI代表羰基二咪唑；DCM代表二氯甲烷；PE代表石油醚；DIAD代表偶氮二羧酸二异丙酯；DMF代表N,N-二甲基甲酰胺；DMSO代表二甲亚砜；EtOAc代表乙酸乙酯；EtOH代表乙醇；MeOH代表甲醇；CBz代表苄氧羰基，是一种胺保护基团；BOC代表叔丁氧羰基是一种胺保护基团；HOAc代表乙酸；NaCNBH 3代表氰基硼氢化钠；r.t.代表室温；O/N代表过夜；THF代表四氢呋喃；Boc 2O代表二-叔丁基二碳酸酯；T甲酸代表三氟乙酸；DIPEA代表二异丙基乙基胺；SOCl 2代表氯化亚砜；CS 2代表二硫化碳；TsOH代表对甲苯磺酸；NFSI代表N-氟-N-(苯磺酰基)苯磺酰胺；NCS代表1-氯吡咯烷-2,5-二酮；n-Bu 4NF代表氟化四丁基铵；iPrOH代表2-丙醇；mp代表熔点；LDA代表二异丙基胺基锂；LiHMDS代表六甲基二硅基胺基锂；Xantphos代表4,5-双二苯基膦-9,9-二甲基氧杂蒽；LiAlH 4代表四氢铝锂；Pd(dba) 2代表三(二亚苄基丙酮)二钯；Pd(dppf)Cl 2代表[1,1'-双(二苯基膦基)二茂铁]二氯化钯；DIEA代表N,N-二异丙基乙胺；Pd(PPh 3) 4代表四三苯基膦钯；IPA代表异丙醇；DEA代表二乙胺。 The solvent used in the present invention is commercially available. The present invention uses the following abbreviations: aq stands for water; HATU stands for O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate ; EDC stands for N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride; m-CPBA stands for 3-chloroperoxybenzoic acid; eq stands for equivalent, equivalent amount; CDI stands for Carbonyl diimidazole; DCM stands for dichloromethane; PE stands for petroleum ether; DIAD stands for diisopropyl azodicarboxylate; DMF stands for N,N-dimethylformamide; DMSO stands for dimethyl sulfoxide; EtOAc stands for ethyl acetate Esters; EtOH stands for ethanol; MeOH stands for methanol; CBz stands for benzyloxycarbonyl, which is an amine protecting group; BOC stands for tert-butoxycarbonyl which is an amine protecting group; HOAc stands for acetic acid; NaCNBH 3 stands for sodium cyanoborohydride ；Rt stands for room temperature; O/N stands for overnight; THF stands for tetrahydrofuran; Boc 2 O stands for di-tert-butyl dicarbonate; T formic acid stands for trifluoroacetic acid; DIPEA stands for diisopropylethylamine; SOCl 2 stands for chlorination Sulfoxide; CS 2 stands for carbon disulfide; TsOH stands for p-toluenesulfonic acid; NFSI stands for N-fluoro-N-(phenylsulfonyl)benzenesulfonamide; NCS stands for 1-chloropyrrolidine-2,5-dione; n-Bu 4 NF stands for tetrabutylammonium fluoride; iPrOH stands for 2-propanol; mp stands for melting point; LDA stands for lithium diisopropylamide; LiHMDS stands for lithium hexamethyldisilazide; Xantphos stands for 4,5-bis Diphenylphosphine-9,9-dimethylxanthene; LiAlH 4 stands for lithium aluminum tetrahydrogen; Pd(dba) 2 stands for tris(dibenzylideneacetone) two palladium; Pd(dppf)Cl 2 stands for [1 ,1'-bis(diphenylphosphino)ferrocene]palladium dichloride; DIEA stands for N,N-diisopropylethylamine; Pd(PPh 3 ) 4 stands for tetrakistriphenylphosphine palladium; IPA stands for Isopropanol; DEA stands for diethylamine.
化合物依据本领域常规命名原则或者使用
Figure PCTCN2020093284-appb-000119
软件命名，市售化合物采用供应商目录名称。 Compounds are based on conventional naming principles in the field or used
Figure PCTCN2020093284-appb-000119
The software is named, and the commercially available compounds use the supplier catalog name.
技术效果Technical effect
本发明化合物具有显著的THRα/β活性以及THRα选择性，对CYP1A2、CYP2C9、CYP2C19、CYP2D6和CYP3A4-M无抑制作用或对部分有微弱抑制，在人血浆中均表现出较高的蛋白结合率，本发明化合物具有较高的暴露量以及较好的口服生物利用度。The compound of the present invention has significant THRα/β activity and THRα selectivity. It has no inhibitory effect on CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4-M or weakly inhibits some of them, and shows high protein binding rate in human plasma. The compound of the present invention has higher exposure and better oral bioavailability.
具体实施方式Detailed ways
下面通过实施例对本发明进行详细描述，但并不意味着对本发明任何不利限制。本文已经详细地描述了本发明，其中也公开了其具体实施例方式，对本领域的技术人员而言，在不脱离本发明精神和范围的情况下针对本发明具体实施方式进行各种变化和改进将是显而易见的。The present invention will be described in detail through the following examples, but it is not meant to limit the present invention in any way. The present invention has been described in detail herein, and its specific embodiments are also disclosed. For those skilled in the art, various changes and improvements can be made to the specific embodiments of the present invention without departing from the spirit and scope of the present invention. It will be obvious.
实施例1Example 1
Figure PCTCN2020093284-appb-000120
Figure PCTCN2020093284-appb-000120
合成路线：synthetic route:
Figure PCTCN2020093284-appb-000121
Figure PCTCN2020093284-appb-000121
步骤1：化合物WX001-2的合成Step 1: Synthesis of compound WX001-2
在预先干燥的反应瓶中加入水合肼(3.29g,65.73mmol,3.19mL)，之后用AcOH(10mL)，H 2O(30mL)溶解，然后加入WX001-1(10g,65.73mmol)，升到100℃回流反应3小时。反应完成后，冷却至室温(25℃)，过滤，滤饼用水(20mL*3)洗涤之后用水泵在45℃旋干，再用甲苯(50mL)代一次，得到化合物WX001-2。 1H NMR(400MHz,DMSO-d 6)δ:11.27(br s,2H),2.34(br s,4H),1.64(br s,4H)。 Add hydrazine hydrate (3.29g, 65.73mmol, 3.19mL) to the pre-dried reaction flask, then dissolve it with AcOH (10mL), H 2 O (30mL), and then add WX001-1 (10g, 65.73mmol) to The reaction was refluxed at 100°C for 3 hours. After the completion of the reaction, it was cooled to room temperature (25°C), filtered, the filter cake was washed with water (20mL*3) and then spin-dried with a pump at 45°C, and replaced with toluene (50mL) once to obtain compound WX001-2. 1 H NMR (400MHz, DMSO-d 6 ) δ: 11.27 (br s, 2H), 2.34 (br s, 4H), 1.64 (br s, 4H).
步骤2：化合物WX001-3的合成Step 2: Synthesis of compound WX001-3
在预先干燥的反应瓶中加入WX001-2(9.16g,55.12mmol)，之后用三氯氧磷(45mL)溶解，然后升到110℃搅拌反应1小时。反应完成后，冷却至室温(25℃)，而后将反应液缓慢地加入到室温水(600mL)中，搅拌30分钟，过滤，滤饼减压浓缩得到化合物WX001-3。 1H NMR(400MHz,DMSO-d 6)δ:2.68(s,4H),1.77(s,4H)。 Add WX001-2 (9.16g, 55.12mmol) to the pre-dried reaction flask, then dissolve it with phosphorus oxychloride (45mL), then raise it to 110°C and stir for 1 hour. After the reaction was completed, it was cooled to room temperature (25° C.), and then the reaction solution was slowly added to room temperature water (600 mL), stirred for 30 minutes, filtered, and the filter cake was concentrated under reduced pressure to obtain compound WX001-3. 1 H NMR (400MHz, DMSO-d 6 ) δ: 2.68 (s, 4H), 1.77 (s, 4H).
步骤3：化合物WX001-5的合成Step 3: Synthesis of compound WX001-5
在预先干燥的反应瓶中加入WX001-3(6g,29.55mmol)，WX001-4(6.31g,35.46mmol)，之后用N,N-二甲基乙酰胺(30mL)溶解，然后加入碳酸铯(11.07g,33.98mmol)，65℃搅拌反应16小时。将反应体系降至室温(20℃)，补加WX001-4(1.05g,5.91mmol)，缓慢地升高至65℃搅拌反应4小时。反应完成后，冷却至室温(25℃)，加入乙酸乙酯(30mL)稀释反应液，之后通过铺有硅藻土的漏斗，滤饼由乙酸乙酯(3*30mL)洗涤后，滤液加水(100mL)稀释，分液，水相用乙酸乙酯(100mL*2)萃取，合并有机相，之后用饱和食盐水(200mL*4)洗涤，无水硫酸钠干燥，过滤除去干燥剂后，减压除去溶剂，得到粗品经自动过柱机分离(洗脱剂：石油醚：乙酸乙酯＝1:0至1:1)，得到化合物WX001-5。 1H NMR(400MHz, DMSO-d 6)δ6.70(s,2H),5.65(s,2H),2.71-2.65(m,4H),1.77-1.81(m,4H)。 Add WX001-3 (6g, 29.55mmol), WX001-4 (6.31g, 35.46mmol) into the pre-dried reaction flask, then dissolve it with N,N-dimethylacetamide (30mL), then add cesium carbonate ( 11.07g, 33.98mmol), the reaction was stirred at 65°C for 16 hours. The reaction system was lowered to room temperature (20° C.), WX001-4 (1.05 g, 5.91 mmol) was added, and the reaction system was slowly raised to 65° C. and stirred for 4 hours. After the reaction is complete, cool to room temperature (25°C), add ethyl acetate (30mL) to dilute the reaction solution, and then pass through a funnel spread with diatomaceous earth. After the filter cake is washed with ethyl acetate (3*30mL), the filtrate is added with water ( 100mL) was diluted and separated, the aqueous phase was extracted with ethyl acetate (100mL*2), the organic phases were combined, then washed with saturated brine (200mL*4), dried over anhydrous sodium sulfate, filtered to remove the desiccant, and then reduced pressure The solvent was removed, and the crude product obtained was separated by an automatic column passing machine (eluent: petroleum ether: ethyl acetate=1:0 to 1:1) to obtain compound WX001-5. 1 H NMR (400MHz, DMSO-d 6 ) δ 6.70 (s, 2H), 5.65 (s, 2H), 2.71-2.65 (m, 4H), 1.77-1.81 (m, 4H).
步骤4：化合物WX001-6的合成Step 4: Synthesis of compound WX001-6
在预先干燥的反应瓶中加入WX001-5(5g,14.51mmol)，苯甲酸酐(3.94g,17.41mmol,3.28mL)，之后用醋酸(50mL)溶解，升到70℃搅拌反应4.5小时。反应完成后，WX001-6的反应液直接用于下一步反应。MS-ESI m/z:447.9[M+H] +,449.9[M+H+2] +。 Add WX001-5 (5g, 14.51mmol), benzoic anhydride (3.94g, 17.41mmol, 3.28mL) to the pre-dried reaction flask, then dissolve it with acetic acid (50mL), raise to 70°C and stir for 4.5 hours. After the reaction is completed, the reaction solution of WX001-6 is directly used in the next reaction. MS-ESI m/z: 447.9 [M+H] + , 449.9 [M+H+2] + .
步骤5：化合物WX001-7的合成Step 5: Synthesis of compound WX001-7
向WX001-6(6.51g,14.51mmol)和醋酸(50mL)的溶液中，加入醋酸钠(2.38g,29.02mmol)，升到110℃搅拌反应15小时。反应完成后，冷却至室温(25℃)，加水(80mL)，发现有固体析出，不适合过滤，加入乙酸乙酯(100mL)稀释，分液，水相用乙酸乙酯(100mL*3)萃取，合并有机相，减压除去大部分溶剂，然后用碳酸氢钠固体淬灭醋酸，直到pH至7左右，加水(200mL)稀释，之后用乙酸乙酯(100mL*3)萃取，合并有机相，并用饱和食盐水(100mL*2)洗涤，无水硫酸钠干燥。过滤除去干燥剂后，减压除去溶剂。粗产品通过高效液相色谱分离分离(水(0.1％TFA)-乙腈)，用碳酸氢钠固体中和至pH至7左右，加乙酸乙酯(100mL)稀释，分液要有机相，水相用乙酸乙酯(100mL*2)萃取，合并有机相，并用饱和食盐水(100mL*2)洗涤，无水硫酸钠干燥，过滤除去干燥剂后，减压除去溶剂得到化合物WX001-7。MS-ESI m/z:430.1[M+H] +,432.0[M+H+2] +。 To the solution of WX001-6 (6.51 g, 14.51 mmol) and acetic acid (50 mL), sodium acetate (2.38 g, 29.02 mmol) was added, and the temperature was raised to 110° C. and the reaction was stirred for 15 hours. After the reaction is complete, cool to room temperature (25°C), add water (80 mL), and find solids precipitate out, which is not suitable for filtration, add ethyl acetate (100 mL) to dilute, separate the liquids, and extract the aqueous phase with ethyl acetate (100 mL*3) Combine the organic phases, remove most of the solvent under reduced pressure, and then quench the acetic acid with solid sodium bicarbonate until the pH is about 7, add water (200 mL) to dilute, and then extract with ethyl acetate (100 mL*3). Combine the organic phases. It was washed with saturated brine (100 mL*2) and dried with anhydrous sodium sulfate. After removing the desiccant by filtration, the solvent was removed under reduced pressure. The crude product was separated and separated by high performance liquid chromatography (water (0.1% TFA)-acetonitrile), neutralized with sodium bicarbonate solid to pH 7 or so, diluted with ethyl acetate (100mL), separated into organic phase and aqueous phase Extracted with ethyl acetate (100 mL*2), combined the organic phases, washed with saturated brine (100 mL*2), dried over anhydrous sodium sulfate, filtered to remove the desiccant, and removed the solvent under reduced pressure to obtain compound WX001-7. MS-ESI m/z: 430.1 [M+H] + , 432.0 [M+H+2] + .
步骤6：化合物WX001-8的合成Step 6: Synthesis of compound WX001-8
在预先干燥的反应瓶中加入WX001-7(0.5g,1.16mmol)，之后用THF(7.5mL)，H 2O(7.5mL)溶解，然后加入氢氧化钾(260.78mg,4.65mmol,4eq)，缓慢地升高至85℃搅拌反应18小时。将反应体系降至室温(20℃)，补加氢氧化钾(130.39mg,2.32mmol)，缓慢地升高至85℃搅拌反应6小时。反应完成后加水(10mL)和乙酸乙酯(20mL)稀释反应液，分液，水相用乙酸乙酯(10mL*2)萃取，合并有机相，之后用饱和食盐水(10mL*2)洗涤，并用无水硫酸钠干燥，过滤除去干燥剂后，减压除去溶剂得到粗品经薄层层析硅胶板(展开剂：石油醚：乙酸乙酯＝1:1)纯化得到化合物WX001-8粗品。MS-ESI m/z:326.1[M+H] +,328.1[M+H+2] +。 Add WX001-7 (0.5g, 1.16mmol) to the pre-dried reaction flask, then dissolve it with THF (7.5mL), H 2 O (7.5mL), and then add potassium hydroxide (260.78mg, 4.65mmol, 4eq) , Slowly raised to 85°C and stirred for 18 hours. The reaction system was lowered to room temperature (20°C), potassium hydroxide (130.39 mg, 2.32 mmol) was added, and the temperature was slowly raised to 85°C and the reaction was stirred for 6 hours. After the completion of the reaction, the reaction solution was diluted with water (10mL) and ethyl acetate (20mL), separated, the aqueous phase was extracted with ethyl acetate (10mL*2), the organic phases were combined, and then washed with saturated brine (10mL*2), It was dried with anhydrous sodium sulfate, filtered to remove the desiccant, and the solvent was removed under reduced pressure to obtain the crude product. The crude product was purified by thin-layer chromatography on silica gel plate (developing solvent: petroleum ether: ethyl acetate = 1:1) to obtain the crude product of compound WX001-8. MS-ESI m/z: 326.1 [M+H] + , 328.1 [M+H+2] + .
步骤7：化合物WX001-10的合成Step 7: Synthesis of compound WX001-10
在预先干燥的反应瓶中加入WX001-8(0.09g,275.92μmol)，之后用AcOH(2mL)溶解，然后加入盐酸(83.68mg,849.22μmol,82.04μL,37％纯度)，将反应体系降至5℃，加入亚硝酸钠(20.94mg,303.52μmol)的H 2O(1mL)溶液，在5℃下搅拌反应0.5小时，检测原料反应完后加入WX001-9(47.39mg,303.52μmol)，5℃搅拌15分钟。反应完成后，向反应体系中加入醋酸钠(0.1g)的水(0.5mL)溶液，发现有固体析出，过滤，滤液用饱和碳酸氢钠溶液中和滤液pH至7左右，加入二氯甲烷(20mL)稀释，分液，水相用二氯甲烷(20mL*2)萃取，合并有机相，并用无水硫酸钠干燥，过滤，过滤除去干燥剂后，减压除去溶剂得到化合物WX001-10。 Add WX001-8 (0.09g, 275.92μmol) to the pre-dried reaction flask, then dissolve it with AcOH (2mL), then add hydrochloric acid (83.68mg, 849.22μmol, 82.04μL, 37% purity) to reduce the reaction system to At 5°C, add sodium nitrite (20.94mg, 303.52μmol) in H 2 O (1mL) solution, stir and react at 5°C for 0.5 hours, and add WX001-9 (47.39mg, 303.52μmol) after the raw material has been reacted. Stir at °C for 15 minutes. After the reaction was completed, a solution of sodium acetate (0.1g) in water (0.5mL) was added to the reaction system, and solids were found to separate out, filtered, and the filtrate was neutralized with saturated sodium bicarbonate solution to neutralize the pH of the filtrate to about 7, and dichloromethane ( 20 mL) was diluted and separated, the aqueous phase was extracted with dichloromethane (20 mL*2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, filtered to remove the desiccant, and the solvent was removed under reduced pressure to obtain compound WX001-10.
步骤8：化合物WX001的合成Step 8: Synthesis of compound WX001
在预先干燥的反应瓶中加入WX001-10(0.066g,133.79μmol)，用N,N-二甲基乙酰胺(1mL)溶解，然后加入醋酸钾(19.70mg,200.69μmol)，缓慢地升高至115℃，搅拌反应2小时。反应完成后，反应液过滤后通过高效液相色谱分离(色谱柱:Waters Xbridge 150mm*25mm,5μm；流动相:[水(10mM NH 4HCO 3)-乙腈]；乙腈％:10％-40％,7min)分离得到目标化合物WX001。 1H NMR(400MHz，氘代甲醇)δ7.74(s,2H),2.77-2.79(m,2H),2.57-2.59(m,2H),1.87-1.88(m,4H)。。MS-ESI m/z:447.0[M+H] +,449.0[M+H+2] +。 Add WX001-10 (0.066g, 133.79μmol) to the pre-dried reaction flask, dissolve it with N,N-dimethylacetamide (1mL), then add potassium acetate (19.70mg, 200.69μmol), and slowly increase To 115°C, the reaction was stirred for 2 hours. After the reaction is completed, the reaction solution is filtered and separated by high performance liquid chromatography (column: Waters Xbridge 150mm*25mm, 5μm; mobile phase: [Water (10mM NH 4 HCO 3 )-acetonitrile]; acetonitrile%: 10%-40% , 7min) the target compound WX001 was isolated. 1 H NMR (400MHz, deuterated methanol) δ 7.74 (s, 2H), 2.77-2.79 (m, 2H), 2.57-2.59 (m, 2H), 1.87-1.88 (m, 4H). . MS-ESI m/z: 447.0 [M+H] + , 449.0 [M+H+2] + .
实施例2Example 2
Figure PCTCN2020093284-appb-000122
Figure PCTCN2020093284-appb-000122
合成路线：synthetic route:
Figure PCTCN2020093284-appb-000123
Figure PCTCN2020093284-appb-000123
步骤1：化合物WX002-3的合成Step 1: Synthesis of compound WX002-3
在预先干燥的三个反应瓶中分三批次加入WX002-1(33g,221.51mmol,1eq)和乙腈(32mL)，加入硝酸银 (18.81g,110.75mmol,0.5eq)和WX002-2(21.47g,243.66mmol,22.60mL,1.1eq)，25℃下加入环丁砜(197.51g,1.64mol,156.75mL,7.42eq)和水(363mL)的混合溶液，升温至55℃，加入浓硫酸(64.73g,659.96mmol,35.18mL,2.98eq)和水(111mL)，最后缓缓滴入过硫酸铵(50.55g,221.51mmol,48.14mL,1eq)和水(111mL)和混合液，70℃搅拌0.5小时，25℃下搅拌23.5小时。反应完成后，在0℃向反应液中缓慢滴加氨水(500mL)，调节pH至8，向反应液中加入水(1500mL)，将混合液经硅藻土过滤，滤饼经乙酸乙酯(1000mL)洗涤，收集滤液，滤液经乙酸乙酯萃取(100mL*3)，合并有机相，饱和食盐水洗涤(1000mL*2)，无水硫酸钠干燥，过滤，减压浓缩得粗产品。粗产品过硅胶色谱柱(石油醚：乙酸乙酯＝20:1转10:1转5:1转3:1)得到化合物WX002-3。 1H NMR(400MHz，氘代氯仿)δppm 1.31–1.32(d,J＝6.8Hz,6H)3.22-3.32(m,1H)7.38(s,1H)。MS-ESI m/z:191.1[M+H] +。 Add WX002-1 (33g, 221.51mmol, 1eq) and acetonitrile (32mL) into three pre-dried reaction flasks, add silver nitrate (18.81g, 110.75mmol, 0.5eq) and WX002-2 (21.47 g,243.66mmol, 22.60mL, 1.1eq), add a mixed solution of sulfolane (197.51g, 1.64mol, 156.75mL, 7.42eq) and water (363mL) at 25°C, warm to 55°C, add concentrated sulfuric acid (64.73g , 659.96mmol, 35.18mL, 2.98eq) and water (111mL), and finally slowly drop in ammonium persulfate (50.55g, 221.51mmol, 48.14mL, 1eq) and water (111mL) and the mixed solution, stirring at 70°C for 0.5 hours , Stir at 25°C for 23.5 hours. After the reaction is completed, slowly add ammonia water (500 mL) to the reaction solution at 0°C to adjust the pH to 8, add water (1500 mL) to the reaction solution, filter the mixture through Celite, and filter the filter cake with ethyl acetate ( 1000mL), the filtrate was collected, the filtrate was extracted with ethyl acetate (100mL*3), the organic phases were combined, washed with saturated brine (1000mL*2), dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was passed through a silica gel chromatography column (petroleum ether: ethyl acetate = 20:1 to 10:1 to 5:1 to 3:1) to obtain compound WX002-3. 1 H NMR (400MHz, deuterated chloroform) δ ppm 1.31-1.32 (d, J = 6.8 Hz, 6H) 3.22-3.32 (m, 1H) 7.38 (s, 1H). MS-ESI m/z: 191.1 [M+H] + .
步骤2：化合物WX002-5的合成Step 2: Synthesis of compound WX002-5
将WX002-4(60g,248.04mmol,1eq)溶解在N,N-二甲基乙酰胺(90mL)中，随后加入叔丁醇钾(33.40g,297.65mmol,1.2eq)，并加热到100℃搅拌1小时，然后加入WX002-3(49.76g,260.44mmol,1.05eq)的N,N-二甲基乙酰胺(30mL)溶液，并加热到130℃反应70小时。反应完成后，将反应液降到室温，然后倒入到水(500mL)中，加入甲基叔丁基醚(500mL*3)萃取，合并所有的有机相，有机相用饱和氯化钠溶液(500mL*2)洗涤，无水硫酸钠干燥，过滤，浓缩得到粗品。粗品用过柱机(石油醚：乙酸乙酯＝50:1到10:1)纯化，然后通过高效液相色谱分离(色谱柱:Phenomenex luna c18 250mm*100mm*10μm；流动相:[水(0.1％TFA)-乙腈]；乙腈％:70％-95％,20min)得到化合物WX002-5。MS-ESI m/z:397.0[M+H] +。 Dissolve WX002-4 (60g, 248.04mmol, 1eq) in N,N-dimethylacetamide (90mL), then add potassium tert-butoxide (33.40g, 297.65mmol, 1.2eq), and heat to 100°C After stirring for 1 hour, a solution of WX002-3 (49.76g, 260.44mmol, 1.05eq) in N,N-dimethylacetamide (30mL) was added and heated to 130°C for 70 hours. After the completion of the reaction, the reaction solution was cooled to room temperature, then poured into water (500mL), added with methyl tert-butyl ether (500mL*3) for extraction, combined all the organic phases, the organic phase was saturated with sodium chloride solution ( 500mL*2) Wash, dry with anhydrous sodium sulfate, filter, and concentrate to obtain a crude product. The crude product was purified by a column machine (petroleum ether: ethyl acetate = 50:1 to 10:1), and then separated by high performance liquid chromatography (column: Phenomenex luna c18 250mm*100mm*10μm; mobile phase: [水(0.1 %TFA)-acetonitrile]; Acetonitrile%: 70%-95%, 20min) to obtain compound WX002-5. MS-ESI m/z: 397.0 [M+H] + .
步骤3：化合物WX002-6的合成Step 3: Synthesis of compound WX002-6
在预先干燥的反应瓶中分别加入WX002-5(8g,20.18mmol,1eq)和冰乙酸(240mL)，加入醋酸钠(3.31g,40.35mmol,2eq)，置换氮气三次，在110℃下搅拌12小时。反应完成后，将反应液减压浓缩，倒入80mL水中，用固体碳酸氢钠调节溶液pH至7-8，然后加入乙酸乙酯和四氢呋喃的混合溶液萃取(乙酸乙酯：四氢呋喃＝3:1，200mL*3)，合并所有有机相，并用饱和食盐水(50mL*2)洗涤，无水硫酸钠干燥，过滤减压浓缩得到化合物WX002-6。MS-ESI m/z:378.9[M+H] +。 Add WX002-5 (8g, 20.18mmol, 1eq) and glacial acetic acid (240mL) into the pre-dried reaction flask, add sodium acetate (3.31g, 40.35mmol, 2eq), replace nitrogen for three times, and stir at 110℃ for 12 hour. After the completion of the reaction, the reaction solution was concentrated under reduced pressure, poured into 80 mL of water, the pH of the solution was adjusted to 7-8 with solid sodium bicarbonate, and then a mixed solution of ethyl acetate and tetrahydrofuran was added for extraction (ethyl acetate: tetrahydrofuran = 3:1 , 200mL*3), combine all organic phases, wash with saturated brine (50mL*2), dry with anhydrous sodium sulfate, filter and concentrate under reduced pressure to obtain compound WX002-6. MS-ESI m/z: 378.9 [M+H] + .
步骤4：化合物WX002-7的合成Step 4: Synthesis of compound WX002-7
在预先干燥的反应瓶中加入WX002-6(7.6g,20.10mmol,1eq)，碳酸钾(8.34g,60.31mmol,3eq)和N,N-二甲基甲酰胺(60mL)，最后加入对甲氧基苄氯(4.72g,30.15mmol,4.11mL,1.5eq)，置换氮气三次，25℃下搅拌16小时。反应完成后。向反应液中加入水(50mL)，乙酸乙酯萃取水相(30mL*3)，合并有机相，饱和食盐水洗涤(40mL*2)，收集有机相，无水硫酸钠干燥，过滤，减压浓缩得粗产品。粗产品经柱层析纯化(石油醚：乙酸乙酯＝20:1转10:1转5:1转3:1)得到化合物WX002-7。 1H NMR(400MHz，氘代氯仿)δ1.23-1.25(d,J＝6.8Hz,6H)3.17-3.27(m,1H)3.79(s,3H)4.95(s,2H)6.78-6.80(d,J＝8.8Hz,2H)7.01(s,1H)7.17-7.19(d,J＝8.8Hz,2H)7.55(s,2H)。MS-ESI m/z:499.1[M+H] +。 Add WX002-6 (7.6g, 20.10mmol, 1eq), potassium carbonate (8.34g, 60.31mmol, 3eq) and N,N-dimethylformamide (60mL) to the pre-dried reaction flask, and finally add p-formamide Oxybenzyl chloride (4.72g, 30.15mmol, 4.11mL, 1.5eq), replaced with nitrogen three times, and stirred at 25°C for 16 hours. After the reaction is complete. Water (50mL) was added to the reaction solution, the aqueous phase was extracted with ethyl acetate (30mL*3), the organic phases were combined, washed with saturated brine (40mL*2), the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and reduced pressure Concentrate to obtain a crude product. The crude product was purified by column chromatography (petroleum ether: ethyl acetate=20:1 to 10:1 to 5:1 to 3:1) to obtain compound WX002-7. 1 H NMR (400MHz, deuterated chloroform) δ1.23-1.25(d,J=6.8Hz,6H)3.17-3.27(m,1H)3.79(s,3H)4.95(s,2H)6.78-6.80(d , J=8.8 Hz, 2H) 7.01 (s, 1H) 7.17-7.19 (d, J=8.8 Hz, 2H) 7.55 (s, 2H). MS-ESI m/z: 499.1 [M+H] + .
步骤5：化合物WX002-9的合成Step 5: Synthesis of compound WX002-9
在预先干燥的反应瓶中加入WX002-7(100mg,197.88μmol,1eq)和乙腈(71mL)，加入三丁基(1-乙氧基乙烯)锡(WX002-8，10.29g,28.50mmol,9.62mL,2eq)，置换氮气三次，加入二氯双(三苯基膦)钯(1.50g,2.14mmol,0.15eq)和碘化亚铜(271.42mg,1.43mmol,0.1eq)，再次置换氮气三次，置于90℃下继续搅拌16小时。反应完成后。将反应液直接降温得到化合物WX002-9。MS-ESI m/z:489.2[M+H] +。 Add WX002-7 (100mg, 197.88μmol, 1eq) and acetonitrile (71mL) to the pre-dried reaction flask, add tributyl(1-ethoxyethylene)tin (WX002-8, 10.29g, 28.50mmol, 9.62 mL, 2eq), replace nitrogen three times, add dichlorobis(triphenylphosphine) palladium (1.50g, 2.14mmol, 0.15eq) and cuprous iodide (271.42mg, 1.43mmol, 0.1eq), replace nitrogen again three times , Placed at 90 ℃ and continue to stir for 16 hours. After the reaction is complete. The temperature of the reaction solution was directly lowered to obtain compound WX002-9. MS-ESI m/z: 489.2 [M+H] + .
步骤6：化合物WX002-10的合成Step 6: Synthesis of compound WX002-10
将盐酸(1M,42.73mL,3eq)加入到WX002-9(6.97g,14.24mmol,1eq)的反应液中，25℃搅拌4小时。反应完成后，将反应液用固体碳酸氢钠调节溶液的pH＝7-8，然后加入乙酸乙酯(200mL*3)萃取，合并所有的有机相，有机相用饱和氯化钠溶液(200mL*2)洗涤，无水硫酸钠干燥，过滤，浓缩得到粗品。粗产品经柱层析纯化(石油醚：乙酸乙酯＝1:0转20:1转10:1转5:1)得到化合物WX002-10。 1H NMR(400MHz氘代氯仿)δ1.24-1.26(d,J＝6.8Hz,6H)2.66(s,3H)3.20-3.27(m,1H)3.78(s,3H)4.93(s,2H)6.75-6.77(d,J＝8.8Hz,2H)7.04(s,1H)7.14-7.16(d,J＝8.8Hz,2H)7.97(s,2H)。MS-ESI m/z:461.1[M+H] +。 Hydrochloric acid (1M, 42.73mL, 3eq) was added to the reaction solution of WX002-9 (6.97g, 14.24mmol, 1eq) and stirred at 25°C for 4 hours. After the completion of the reaction, adjust the pH of the reaction solution to 7-8 with solid sodium bicarbonate, then add ethyl acetate (200mL*3) for extraction, combine all the organic phases, and use saturated sodium chloride solution (200mL*3) for the organic phase 2) Wash, dry with anhydrous sodium sulfate, filter, and concentrate to obtain a crude product. The crude product was purified by column chromatography (petroleum ether: ethyl acetate=1:0 to 20:1 to 10:1 to 5:1) to obtain compound WX002-10. 1 H NMR (400MHz deuterated chloroform) δ1.24-1.26(d,J=6.8Hz,6H)2.66(s,3H)3.20-3.27(m,1H)3.78(s,3H)4.93(s,2H) 6.75-6.77 (d, J=8.8 Hz, 2H) 7.04 (s, 1H) 7.14-7.16 (d, J=8.8 Hz, 2H) 7.97 (s, 2H). MS-ESI m/z: 461.1 [M+H] + .
步骤7：化合物WX002-11的合成Step 7: Synthesis of compound WX002-11
在预先干燥的反应瓶中加入WX002-10(5.5g,11.92mmol,1eq)和吡啶(55mL)，加入二氧化硒(2.65g,23.84mmol,2.59mL,2eq)，置换氮气三次，置于100℃下搅拌16小时。反应完成后，将反应液经2N盐酸溶液(约500mL)调节pH至2～3，乙酸乙酯萃取水相(400mL*3)，合并有机相，饱和食盐水洗涤(300mL*2)，收集有机相，无水硫酸钠干燥，过滤，减压浓缩得化合物WX002-11。MS-ESI m/z:491.2[M+H] +。 Add WX002-10 (5.5g, 11.92mmol, 1eq) and pyridine (55mL) to the pre-dried reaction flask, add selenium dioxide (2.65g, 23.84mmol, 2.59mL, 2eq), replace with nitrogen three times and place at 100 Stir for 16 hours at °C. After the completion of the reaction, adjust the pH of the reaction solution to 2～3 with 2N hydrochloric acid solution (about 500mL), extract the aqueous phase with ethyl acetate (400mL*3), combine the organic phases, wash with saturated brine (300mL*2), and collect the organic Phase, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound WX002-11. MS-ESI m/z: 491.2 [M+H] + .
步骤8：化合物WX002-12的合成Step 8: Synthesis of compound WX002-12
在预先干燥的反应瓶中加入WX002-11(6g,12.21mmol,1eq)和甲醇(60mL)，置换0℃下缓慢滴入氯化亚砜(2.91g,24.42mmol,1.77mL,2eq)，25℃继续搅拌0.5小时，升温至70℃搅拌15.5小时。反应完成后，将反应液直接减压浓缩，浓缩物经饱和碳酸氢钠溶液(50mL)调节pH至7～8，乙酸乙酯萃取水相(50mL*3)，合并有机相，饱和食盐水洗涤(30mL*2)，收集有机相，无水硫酸钠干燥，过滤，减压浓缩得粗产品。粗产品经薄层色谱柱层析纯化(石油醚：乙酸乙酯＝20:1转10:1转5:1转2:1)得到化合物WX002-12。 1H NMR(400MHz，氘代氯仿)δ1.24-1.26(d,J＝6.8Hz,6H)3.18-3.28(m,1H)3.78(s,3H)4.04(s,3H)4.93(s,2H)6.75-6.78(m,2H)7.04(m,1H)7.13-7.16(m,2H)8.13(s,2H)。MS-ESI m/z:505.1[M+H] +。 Add WX002-11 (6g, 12.21mmol, 1eq) and methanol (60mL) to the pre-dried reaction flask, and slowly drop thionyl chloride (2.91g, 24.42mmol, 1.77mL, 2eq) at 0℃, 25 Stirring was continued for 0.5 hour at °C, and the temperature was increased to 70 °C and stirred for 15.5 hours. After the completion of the reaction, the reaction solution was directly concentrated under reduced pressure, the concentrate was adjusted to pH 7-8 with saturated sodium bicarbonate solution (50mL), the aqueous phase was extracted with ethyl acetate (50mL*3), the organic phases were combined, and washed with saturated brine (30mL*2), collect the organic phase, dry with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain a crude product. The crude product was purified by thin layer chromatography column chromatography (petroleum ether: ethyl acetate = 20:1 to 10:1 to 5:1 to 2:1) to obtain compound WX002-12. 1 H NMR(400MHz, deuterated chloroform)δ1.24-1.26(d,J=6.8Hz,6H)3.18-3.28(m,1H)3.78(s,3H)4.04(s,3H)4.93(s,2H ) 6.75-6.78 (m, 2H) 7.04 (m, 1H) 7.13-7.16 (m, 2H) 8.13 (s, 2H). MS-ESI m/z: 505.1 [M+H] + .
步骤9：化合物WX002-13的合成Step 9: Synthesis of compound WX002-13
在预先干燥的反应瓶中加入WX002-12(100mg,197.88μmol,1eq)和甲醇(15mL)，置于-78℃下，通入氨气(33.70mg,1.98mmol,10eq)10分钟，升温至25℃继续搅拌15小时50分钟。反应完成后，将反应液减压浓缩得到化合物WX002-13。 1H NMR(400MHz，氘代氯仿)δ1.24-1.25(d,J＝6.8Hz,6H)3.24-3.27(d,J＝6.72Hz,1H)3.78(s,3H)4.93(s,2H)6.76-6.79(m,2H)7.01(s,1H)7.04-7.16(m,2H)8.46(s,2 H)。MS-ESI m/z:490.3[M+H] +。 Add WX002-12 (100mg, 197.88μmol, 1eq) and methanol (15mL) to the pre-dried reaction flask, place it at -78°C, add ammonia gas (33.70mg, 1.98mmol, 10eq) for 10 minutes, and heat to Stirring was continued for 15 hours and 50 minutes at 25°C. After the completion of the reaction, the reaction solution was concentrated under reduced pressure to obtain compound WX002-13. 1 H NMR (400MHz, deuterated chloroform) δ1.24-1.25(d,J=6.8Hz,6H)3.24-3.27(d,J=6.72Hz,1H)3.78(s,3H)4.93(s,2H) 6.76-6.79(m,2H)7.01(s,1H)7.04-7.16(m,2H)8.46(s,2H). MS-ESI m/z: 490.3 [M+H] + .
步骤10：化合物WX002-14的合成Step 10: Synthesis of compound WX002-14
在预先干燥的反应瓶中加入WX002-13(2.3g,4.69mmol,1eq)和二氯乙烷(50mL)，置换氮气三次，置于0℃下缓慢滴入草酰氯(773.98mg,6.10mmol,533.78μL,1.3eq)，25℃搅拌1小时，置于70℃继续搅拌15小时。反应完成后，将反应液直接减压浓缩得到得到化合物WX002-14。MS-ESI m/z:548.1[M+MeOH+H] +。 Add WX002-13 (2.3g, 4.69mmol, 1eq) and dichloroethane (50mL) to the pre-dried reaction flask, replace with nitrogen three times, and slowly drop oxalyl chloride (773.98mg, 6.10mmol, 533.78μL, 1.3eq), stirred at 25°C for 1 hour, placed at 70°C and continued stirring for 15 hours. After the completion of the reaction, the reaction solution was directly concentrated under reduced pressure to obtain compound WX002-14. MS-ESI m/z: 548.1 [M+MeOH+H] + .
步骤11：化合物WX002-15的合成Step 11: Synthesis of compound WX002-15
在预先干燥的反应瓶中加入WX002-14(2.4g,4.65mmol,1eq)和二氯甲烷(50mL)，加入乙醇(78.80g,1.71mol,100mL,367.99eq)，25℃下搅拌16小时。反应完成后，将反应液直接减压浓缩得到粗产品。粗产品经薄层色谱硅胶板纯化(石油醚：乙酸乙酯＝1:1)得到化合物WX002-15。 1H NMR(400MHz，氘代氯仿)δ1.24-1.26(d,J＝6.8Hz,6H)1.36(t,J＝7.13Hz,3H)3.21-2.27(m,1H)3.78(s,3H)4.30-4.35(m,2H)4.93(s,2H)6.77(d,J＝8.63Hz,2H)7.04(s,1H)7.13-7.15(d,J＝8.63Hz,2H)8.29(s,2H)。MS-ESI m/z:562.1[M+H] +。 WX002-14 (2.4g, 4.65mmol, 1eq) and dichloromethane (50mL) were added to the pre-dried reaction flask, ethanol (78.80g, 1.71mol, 100mL, 367.99eq) was added, and the mixture was stirred at 25°C for 16 hours. After the completion of the reaction, the reaction solution was directly concentrated under reduced pressure to obtain a crude product. The crude product was purified by thin-layer chromatography on a silica gel plate (petroleum ether: ethyl acetate=1:1) to obtain compound WX002-15. 1 H NMR (400MHz, deuterated chloroform) δ 1.24-1.26 (d, J = 6.8 Hz, 6H) 1.36 (t, J = 7.13 Hz, 3H) 3.21-2.27 (m, 1H) 3.78 (s, 3H) 4.30-4.35(m,2H)4.93(s,2H)6.77(d,J＝8.63Hz,2H)7.04(s,1H)7.13-7.15(d,J＝8.63Hz,2H)8.29(s,2H) . MS-ESI m/z: 562.1 [M+H] + .
步骤12：化合物WX002-16的合成Step 12: Synthesis of compound WX002-16
在预先干燥的反应瓶中加入WX002-15(750mg,1.33mmol,1eq)和冰乙酸(75mL)，加入盐酸羟胺(111.20mg,1.60mmol,1.2eq)，置换氮气三次，置于120℃搅拌16小时。补加盐酸羟胺(185.34mg,2.67mmol,2eq)，升温至125℃继续搅拌16小时。反应完成后，将反应液直接减压浓缩得粗产品。粗产品经薄层色谱硅胶板纯化(石油醚：乙酸乙酯＝0:1)得到化合物WX002-16。MS-ESI m/z:531.1[M+H] +。 Add WX002-15 (750mg, 1.33mmol, 1eq) and glacial acetic acid (75mL) to the pre-dried reaction flask, add hydroxylamine hydrochloride (111.20mg, 1.60mmol, 1.2eq), replace nitrogen for three times, place at 120℃ and stir for 16 hour. Additional hydroxylamine hydrochloride (185.34mg, 2.67mmol, 2eq) was added, and the temperature was raised to 125°C and stirring was continued for 16 hours. After the completion of the reaction, the reaction solution was directly concentrated under reduced pressure to obtain a crude product. The crude product was purified by thin-layer chromatography on silica gel plate (petroleum ether: ethyl acetate=0:1) to obtain compound WX002-16. MS-ESI m/z: 531.1 [M+H] + .
步骤13：化合物WX002的合成Step 13: Synthesis of compound WX002
在预先干燥的反应瓶中加入WX002-16(80mg,150.56μmol,1eq)和乙腈(8mL)，置换氮气三次，降温至0℃，缓慢加入硝酸铈铵(247.62mg,451.68μmol,225.11μL,3eq)和水(3.2mL)，缓慢升至室温25℃继续搅拌5小时。反应完成后，将反应液经乙酸乙酯萃取(15mL*3)，合并有机相，无水硫酸钠干燥，过滤，滤液减压浓缩得粗产品。粗产品经薄层色谱硅胶板纯化(二氯甲烷：甲醇＝5:1)得到产物粗品，产物粗品经高效液相色谱分离(色谱柱:Waters Xbridge BEH C18 100*25mm*5μm；流动相:[水(10mM NH 4HCO 3)-乙腈]；乙腈％:20％-50％,8min)得到化合物WX002。 1H NMR(400MHz，氘代甲醇)δ1.29-1.28(d,J＝6.88Hz,6H)3.20-3.13(m,1H)7.37(s,1H)8.01(s,2H)。MS-ESI m/z:411.0[M+H] +。 Add WX002-16 (80mg, 150.56μmol, 1eq) and acetonitrile (8mL) to the pre-dried reaction flask, replace with nitrogen three times, cool to 0℃, and slowly add ceric ammonium nitrate (247.62mg, 451.68μmol, 225.11μL, 3eq) ) And water (3.2mL), slowly rise to room temperature 25°C and continue stirring for 5 hours. After the completion of the reaction, the reaction solution was extracted with ethyl acetate (15 mL*3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by thin layer chromatography on silica gel plate (dichloromethane: methanol = 5:1) to obtain the crude product, which was separated by high performance liquid chromatography (column: Waters Xbridge BEH C18 100*25mm*5μm; mobile phase: [ Water (10mM NH 4 HCO 3 )-acetonitrile]; Acetonitrile%: 20%-50%, 8min) to obtain compound WX002. 1 H NMR (400MHz, deuterated methanol) δ 1.29-1.28 (d, J = 6.88 Hz, 6H) 3.20-3.13 (m, 1H) 7.37 (s, 1H) 8.01 (s, 2H). MS-ESI m/z: 411.0 [M+H] + .
实施例3Example 3
Figure PCTCN2020093284-appb-000124
Figure PCTCN2020093284-appb-000124
合成路线：synthetic route:
Figure PCTCN2020093284-appb-000125
Figure PCTCN2020093284-appb-000125
步骤1：化合物WX003-3的合成Step 1: Synthesis of compound WX003-3
向反应瓶中加入化合物WX003-1(2g，4.63mmol)，化合物WX003-2(1.43g，9.25mmol)，碳酸钾(1.92g，13.88mmol)，水(15mL)和1,4-二氧六环(45mL)，抽换氮气后搅拌20分钟，随后加入Pd(dppf)Cl 2(338.54mg，462.68μmol)，80℃下混合液反应6小时。反应完毕后，反应液用水(10mL)稀释，二氯甲烷(10mL x3)萃取，有机相用饱和食盐水(10mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩。粗品使用通过薄层层析硅胶板(石油醚：乙酸乙酯＝4:1)纯化。得到化合物WX003-3。 Add compound WX003-1 (2g, 4.63mmol), compound WX003-2 (1.43g, 9.25mmol), potassium carbonate (1.92g, 13.88mmol), water (15mL) and 1,4-dioxane to the reaction flask. The ring (45 mL) was replaced with nitrogen and stirred for 20 minutes, then Pd(dppf)Cl 2 (338.54 mg, 462.68 μmol) was added, and the mixture was reacted at 80° C. for 6 hours. After the completion of the reaction, the reaction solution was diluted with water (10 mL) and extracted with dichloromethane (10 mL x 3). The organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by thin layer chromatography on silica gel plate (petroleum ether: ethyl acetate = 4:1). Compound WX003-3 was obtained.
步骤2：化合物WX003-4的合成Step 2: Synthesis of compound WX003-4
向反应瓶中加入化合物WX003-3(1.0g，2.64mmol)，叔丁醇(20mL)，水(20mL)和乙腈(20mL)，抽换氮气后降温至0℃，随后加入高碘酸钠(1.13g，5.27mmol)和四氧化锇(67.01mg，263.57μmol)，25℃下混合液反应3小时。反应完毕后，反应液用硅藻土过滤，乙酸乙酯(20mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩。未进行进一步纯化，得到化合物WX003-4粗品，直接用于下一步。 1H NMR(400MHz,DMSO-d 6)δppm 9.73(s,1H),7.27-7.30(m,7H),6.91-6.95(m,2H),5.32(s,2H),5.14(s,2H),4.60(s,2H),3.74(s,3H)。 Compound WX003-3 (1.0g, 2.64mmol), tert-butanol (20mL), water (20mL) and acetonitrile (20mL) were added to the reaction flask, and the temperature was reduced to 0°C after exhausting nitrogen, then sodium periodate ( 1.13g, 5.27mmol) and osmium tetroxide (67.01mg, 263.57μmol), the mixed solution was reacted at 25°C for 3 hours. After the completion of the reaction, the reaction solution was filtered through Celite, washed with ethyl acetate (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Without further purification, the crude compound WX003-4 was obtained, which was used directly in the next step. 1 H NMR (400MHz, DMSO-d 6 ) δppm 9.73(s,1H), 7.27-7.30(m,7H), 6.91-6.95(m,2H), 5.32(s,2H), 5.14(s,2H) , 4.60 (s, 2H), 3.74 (s, 3H).
步骤3：化合物WX003-5的合成Step 3: Synthesis of compound WX003-5
向反应瓶中加入化合物WX003-4(500mg，1.31mmol)和二氯甲烷(20mL)，抽换氮气后降温至0℃，随后加入二乙胺基三氟化硫(422.65mg，2.62mmol)，在氮气保护下，25℃下混合液反应5小时。反应完毕后，将反应液倒入冰水(10mL)中，二氯甲烷(10mL*3)萃取，有机相用饱和食盐水(10mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩。粗品使用通过薄层层析硅胶板(石油醚：乙酸乙酯＝3:1)纯化得到化合物WX003-5。 1H NMR(400MHz，氘代氯仿)δ:7.27-7.32(m,7H),6.69-6.97(m,3H),5.31(s, 2H),5.04(s,2H),4.61(s,2H),3.74(s,3H)。 Compound WX003-4 (500mg, 1.31mmol) and dichloromethane (20mL) were added to the reaction flask, the temperature was reduced to 0°C after the nitrogen was exchanged, and then diethylaminosulfur trifluoride (422.65mg, 2.62mmol) was added, Under the protection of nitrogen, the mixture was reacted for 5 hours at 25°C. After the completion of the reaction, the reaction solution was poured into ice water (10 mL), extracted with dichloromethane (10 mL*3), the organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by thin-layer chromatography on silica gel plate (petroleum ether: ethyl acetate = 3:1) to obtain compound WX003-5. 1 H NMR (400MHz, deuterated chloroform) δ: 7.27-7.32 (m, 7H), 6.69-6.97 (m, 3H), 5.31 (s, 2H), 5.04 (s, 2H), 4.61 (s, 2H) ,3.74(s,3H).
步骤4：化合物WX003-6的合成Step 4: Synthesis of compound WX003-6
向反应瓶中加入化合物WX003-5(80mg，198.32μmol)和乙腈(1.4mL)，抽换氮气后降温至0℃，加入硝酸铈铵(326.18mg，594.97μmol)的水(0.6mL)溶液，27℃下混合液反应16小时。反应完毕后，将反应液直接旋干。粗品使用通过薄层层析硅胶板(石油醚：乙酸乙酯＝2:1)纯化得到化合物WX003-6。 1H NMR(400MHz，氘代氯仿)δ:13.00(s,1H),7.24-7.40(m,5H),6.61-7.00(t,J＝52.8Hz,1H),5.28(s,2H),4.61(s,2H)。 Add compound WX003-5 (80mg, 198.32μmol) and acetonitrile (1.4mL) to the reaction flask, and then cool to 0℃ after exhausting nitrogen. Add a solution of cerium ammonium nitrate (326.18mg, 594.97μmol) in water (0.6mL), The mixed solution was reacted for 16 hours at 27°C. After the reaction is completed, the reaction solution is directly spin-dried. The crude product was purified by thin-layer chromatography on a silica gel plate (petroleum ether: ethyl acetate = 2:1) to obtain compound WX003-6. 1 H NMR (400MHz, deuterated chloroform) δ: 13.00 (s, 1H), 7.24-7.40 (m, 5H), 6.61-7.00 (t, J = 52.8 Hz, 1H), 5.28 (s, 2H), 4.61 (s, 2H).
步骤5：化合物WX003-7的合成Step 5: Synthesis of compound WX003-7
向反应瓶中加入化合物WX003-6(53.14mg，114.75μmol)，化合物WX004-9(25mg，88.27μmol)，吡啶(17.45mg，220.67μmol)和1,2-二氯乙烷(1mL)，抽换氧气后加入醋酸铜(24.05mg，132.40μmol)，40℃下混合液反应16小时。反应完毕后，旋干反应液。粗品使用通过薄层层析硅胶板(石油醚：乙酸乙酯＝2:1)纯化，得到化合物WX003-7。MS-ESI m/z:700.1[M+H] +，702.1[M+H+2] +。 Add compound WX003-6 (53.14 mg, 114.75 μmol), compound WX004-9 (25 mg, 88.27 μmol), pyridine (17.45 mg, 220.67 μmol) and 1,2-dichloroethane (1 mL) into the reaction flask, and pump After changing the oxygen, copper acetate (24.05mg, 132.40μmol) was added, and the mixed solution was reacted at 40°C for 16 hours. After the reaction is complete, the reaction solution is spin-dried. The crude product was purified by thin layer chromatography on silica gel plate (petroleum ether: ethyl acetate = 2:1) to obtain compound WX003-7. MS-ESI m/z: 700.1 [M+H] + , 702.1 [M+H+2] + .
步骤6：化合物WX003-8的合成Step 6: Synthesis of compound WX003-8
向反应瓶中加入化合物WX003-7(30mg，42.83μmol)和乙腈(0.5mL)，抽换氮气后降温至0℃，缓慢滴入硝酸铈铵(70.43mg，128.49μmol)的水(0.25mL)溶液，25℃下混合液反应16小时。反应完毕后，反应液用水(5mL)稀释，二氯甲烷(10mL*3)萃取，有机相用饱和食盐水(2mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩。粗品使用通过薄层层析硅胶板(石油醚：乙酸乙酯＝1:1)纯化，得到化合物WX003-8。MS-ESI m/z:580.1[M+H] +，582.1[M+H+2] +。 Add compound WX003-7 (30mg, 42.83μmol) and acetonitrile (0.5mL) to the reaction flask, and then cool to 0°C after exhausting nitrogen. Slowly add ceric ammonium nitrate (70.43mg, 128.49μmol) water (0.25mL) The mixed solution was reacted at 25°C for 16 hours. After the completion of the reaction, the reaction solution was diluted with water (5 mL), extracted with dichloromethane (10 mL*3), the organic phase was washed with saturated brine (2 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by thin layer chromatography on silica gel plate (petroleum ether: ethyl acetate = 1:1) to obtain compound WX003-8. MS-ESI m/z: 580.1 [M+H] + , 582.1 [M+H+2] + .
步骤7：化合物WX003的合成Step 7: Synthesis of compound WX003
向反应瓶中加入化合物WX003-8(20mg，34.46μmol)和二氯甲烷(0.5mL)，抽换氮气后降温至0℃，随后加入三溴化硼(17.27mg，68.92μmol)，0℃下混合液反应20分钟。反应完毕后，反应液用水(2mL)稀释，过滤，二氯甲烷(10mL*3)萃取，有机相用饱和食盐水(2mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩。粗品经制备高效液相色谱(色谱柱:Luna C18 100mm*30mm,5μm；流动相:[水(0.225％FA)-乙腈]；乙腈％40％-90％,12min)纯化。得到目标化合物WX003。 1H NMR(400MHz，氘代二甲基亚砜)δ12.84(s,1H),12.21(s,1H),7.81(s,2H),7.44(s,1H),6.74-7.05(t,J＝52Hz,1H),3.02-3.08(m,1H),1.15-1.25(d,J＝6.8Hz,6H)。MS-ESI m/z:460.1[M+H] +，462.0[M+H+2] +。 Compound WX003-8 (20mg, 34.46μmol) and dichloromethane (0.5mL) were added to the reaction flask, the temperature was reduced to 0°C after exhausting nitrogen, and then boron tribromide (17.27mg, 68.92μmol) was added at 0°C The mixed solution reacted for 20 minutes. After the completion of the reaction, the reaction solution was diluted with water (2 mL), filtered, and extracted with dichloromethane (10 mL*3). The organic phase was washed with saturated brine (2 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by preparative high performance liquid chromatography (column: Luna C18 100mm*30mm, 5μm; mobile phase: [water (0.225% FA)-acetonitrile]; acetonitrile% 40%-90%, 12min). The target compound WX003 was obtained. 1 H NMR (400MHz, deuterated dimethyl sulfoxide) δ 12.84 (s, 1H), 12.21 (s, 1H), 7.81 (s, 2H), 7.44 (s, 1H), 6.74-7.05 (t, J = 52 Hz, 1H), 3.02-3.08 (m, 1H), 1.15-1.25 (d, J = 6.8 Hz, 6H). MS-ESI m/z: 460.1 [M+H] + , 462.0 [M+H+2] + .
实施例4Example 4
Figure PCTCN2020093284-appb-000126
Figure PCTCN2020093284-appb-000126
中间体WX004-9的合成Synthesis of intermediate WX004-9
Figure PCTCN2020093284-appb-000127
Figure PCTCN2020093284-appb-000127
合成路线：synthetic route:
Figure PCTCN2020093284-appb-000128
Figure PCTCN2020093284-appb-000128
步骤1：化合物WX004-12的合成Step 1: Synthesis of compound WX004-12
在预先干燥的反应瓶中加入双联频哪醇硼酸酯(6.35g,24.99mmol,1.5eq)，WX002-7(8.3g,16.66mmol,1eq)和二氧六环(83mL)，加入醋酸钾(3.27g,33.32mmol,2eq)，置换氮气三次，加入Pd(dppf)Cl 2(1.22g,1.67mmol,0.1eq)，再次置换氮气三次，置于70℃下搅拌16小时。反应完成后，将反应液经硅藻土过滤，滤液减压浓缩得到粗产品。粗产品经柱层析纯化(石油醚：乙酸乙酯＝20:1转10:1转5:1转3:1)得到化合物WX004-12。 1H NMR(400MHz，氘代氯仿)δ7.81(s,2H),7.16-7.23(m,2H),7.02(d,J＝0.86Hz,1H),6.75-6.81(m,2H),4.92(s,2H),3.78(s,3H),3.16-3.26(m,1H),1.38(s,12H),1.22-1.24(d,J＝6.97Hz,6H)。MS-ESI m/z:545.3[M+H] +。 Add double pinacol borate (6.35g, 24.99mmol, 1.5eq), WX002-7 (8.3g, 16.66mmol, 1eq) and dioxane (83mL) into the pre-dried reaction flask, add acetic acid Potassium (3.27g, 33.32mmol, 2eq), replaced with nitrogen three times, added Pd(dppf)Cl 2 (1.22g, 1.67mmol, 0.1eq), replaced with nitrogen again three times, and stirred at 70°C for 16 hours. After the completion of the reaction, the reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (petroleum ether: ethyl acetate=20:1 to 10:1 to 5:1 to 3:1) to obtain compound WX004-12. 1 H NMR (400MHz, deuterated chloroform) δ7.81 (s, 2H), 7.16-7.23 (m, 2H), 7.02 (d, J = 0.86Hz, 1H), 6.75-6.81 (m, 2H), 4.92 (s, 2H), 3.78 (s, 3H), 3.16-3.26 (m, 1H), 1.38 (s, 12H), 1.22-1.24 (d, J=6.97 Hz, 6H). MS-ESI m/z: 545.3 [M+H] + .
步骤2：化合物WX004-9的合成Step 2: Synthesis of compound WX004-9
在预先干燥的反应瓶中加入WX004-12(7.6g,13.94mmol,1eq)和丙酮(152mL)，H 2O(76mL)，加入高碘酸钠(2.98g,13.94mmol,772.35μL,1eq)，醋酸铵(7.74g,100.36mmol,7.2eq)，置换氮气三次，35℃下搅拌16小时。反应完成后，加入饱和硫代硫酸钠溶液(80mL)，用1M盐酸调节pH至5，过滤得到产物粗品。将反应粗产品冻干得到化合物WX004-9。 1H NMR(400MHz，氘代氯仿)δ7.81(s,2H),7.16-7.22(m,2H),7.04(s,1H),6.76-6.80(m,2H),4.93(s,2H),3.78(s,3H),3.18-3.27(m,1H),1.22-1.25(m,6H)。MS-ESI m/z:463.1[M+H] +。 In the pre-dried reaction flask, add WX004-12 (7.6g, 13.94mmol, 1eq), acetone (152mL), H 2 O (76mL), add sodium periodate (2.98g, 13.94mmol, 772.35μL, 1eq) , Ammonium acetate (7.74g, 100.36mmol, 7.2eq), replaced with nitrogen three times, and stirred at 35°C for 16 hours. After the reaction was completed, saturated sodium thiosulfate solution (80 mL) was added, the pH was adjusted to 5 with 1M hydrochloric acid, and the crude product was obtained by filtration. The crude reaction product was lyophilized to obtain compound WX004-9. 1 H NMR (400MHz, deuterated chloroform) δ7.81(s,2H),7.16-7.22(m,2H),7.04(s,1H),6.76-6.80(m,2H),4.93(s,2H) , 3.78 (s, 3H), 3.18-3.27 (m, 1H), 1.22-1.25 (m, 6H). MS-ESI m/z: 463.1 [M+H] + .
Figure PCTCN2020093284-appb-000129
Figure PCTCN2020093284-appb-000129
合成路线：synthetic route:
Figure PCTCN2020093284-appb-000130
Figure PCTCN2020093284-appb-000130
步骤1：化合物WX004-3的合成Step 1: Synthesis of compound WX004-3
在预先干燥的反应瓶中加入WX004-1(10g,64.08mmol,6.54mL,1eq)，WX004-2(5.84g,64.08mmol,1eq)和乙醇(140mL)，100℃反应16小时，旋干反应液加入水(140mL)，加入氢氧化钠(5.13g,128.16mmol,2eq)，100℃反应1小时。反应完成后，向反应液中加入乙酸乙酯(100mL*2)萃取，水相降温至0℃，加冰乙酸调pH至4，乙酸乙酯萃取(100mL*3)，有机相合并，饱和食盐水(100mL*2)洗涤，分出有机相，无水硫酸钠干燥，过滤，旋干得产物粗品。产物粗品经柱层析纯化(石油醚：乙酸乙酯＝20:1转10:1转5:1转2:1)得到化合物WX004-3。 1H NMR(400MHz,DMSO-d 6)δ14.01(s,1H)，13.66(s,1H)。MS-ESI m/z:197.9[M+H] +。 Add WX004-1 (10g, 64.08mmol, 6.54mL, 1eq), WX004-2 (5.84g, 64.08mmol, 1eq) and ethanol (140mL) to the pre-dried reaction flask, react at 100℃ for 16 hours, and spin to dry the reaction. Add water (140 mL) to the solution, add sodium hydroxide (5.13 g, 128.16 mmol, 2 eq), and react at 100° C. for 1 hour. After the reaction is completed, add ethyl acetate (100mL*2) to the reaction solution for extraction, cool the water phase to 0℃, add glacial acetic acid to adjust the pH to 4, extract with ethyl acetate (100mL*3), combine the organic phases, and saturated salt Wash with water (100 mL*2), separate the organic phase, dry with anhydrous sodium sulfate, filter, and spin dry to obtain the crude product. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 20:1 to 10:1 to 5:1 to 2:1) to obtain compound WX004-3. 1 H NMR (400MHz, DMSO-d 6 ) δ 14.01 (s, 1H), 13.66 (s, 1H). MS-ESI m/z: 197.9 [M+H] + .
步骤2：化合物WX004-4的合成Step 2: Synthesis of compound WX004-4
在预先干燥的反应瓶中加入WX004-3(5.6g,28.41mmol,1eq)和氢氧化钠(1M,85.22mL,3eq)，置换氮气三次，置于0℃，缓慢滴入过氧化氢溶液(16.10g,142.03mmol,13.65mL,30％纯度,5eq)，25℃下反应2小时。反应完成后，将反应液用1M的盐酸溶液(50mL)调节pH至3左右，(乙酸乙酯：四氢呋喃＝3:1)萃取水相(150mL*3)，合并有机相，饱和食盐水洗涤(150mL*2)，收集有机相，无水硫酸钠干燥，过滤，减压浓缩得化合物WX004-4。 1H NMR(400MHz,DMSO-d 6)δ12.99(s,1H)，12.45(s,1H)。MS-ESI m/z:182.0[M+H] +。 Add WX004-3 (5.6g, 28.41mmol, 1eq) and sodium hydroxide (1M, 85.22mL, 3eq) into the pre-dried reaction flask, replace with nitrogen three times, place it at 0℃, and slowly drop in hydrogen peroxide solution ( 16.10g, 142.03mmol, 13.65mL, 30% purity, 5eq), react at 25°C for 2 hours. After the completion of the reaction, the reaction solution was adjusted to pH 3 with 1M hydrochloric acid solution (50mL), (ethyl acetate:tetrahydrofuran=3:1) the aqueous phase (150mL*3) was extracted, the organic phases were combined and washed with saturated brine ( 150 mL*2), collect the organic phase, dry with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain compound WX004-4. 1 H NMR (400MHz, DMSO-d 6 ) δ 12.99 (s, 1H), 12.45 (s, 1H). MS-ESI m/z: 182.0 [M+H] + .
步骤3：化合物WX004-6的合成Step 3: Synthesis of compound WX004-6
在预先干燥的反应瓶中加入WX004-4(5.6g,30.93mmol,1eq)，WX004-5(6.29g,30.93mmol,7.64mL,1eq)和乙腈(120mL)，置换氮气三次，置于80℃下搅拌2小时。加入对甲氧基苄氯(5.81g,37.11mmol,5.05mL,1.2eq)和碘化钠(463.57mg,3.09mmol,0.1eq)，置换氮气三次，置于80℃下继续搅拌14小时。 反应完成后，将反应液直接减压浓缩得到粗产品。粗产品经柱层析纯化(石油醚：乙酸乙酯＝20:1转10:1转5:1转2:1)得到化合物WX004-6。 1H NMR(400MHz,DMSO-d 6)δ12.70(br,1H)，7.27-7.29(d,J＝8.68Hz,2H),6.91-6.93(d,J＝8.80Hz,2H),5.01(s,2H),3.74(s,3H)。MS-ESI m/z:300.2[M+H] +。 Add WX004-4 (5.6g, 30.93mmol, 1eq), WX004-5 (6.29g, 30.93mmol, 7.64mL, 1eq) and acetonitrile (120mL) into the pre-dried reaction flask, replace with nitrogen three times and place at 80℃ Stir for 2 hours. Add p-methoxybenzyl chloride (5.81g, 37.11mmol, 5.05mL, 1.2eq) and sodium iodide (463.57mg, 3.09mmol, 0.1eq), replace with nitrogen three times, and place at 80°C and continue stirring for 14 hours. After the completion of the reaction, the reaction solution was directly concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (petroleum ether: ethyl acetate=20:1 to 10:1 to 5:1 to 2:1) to obtain compound WX004-6. 1 H NMR (400MHz, DMSO-d 6 ) δ 12.70 (br, 1H), 7.27-7.29 (d, J = 8.68 Hz, 2H), 6.91-6.93 (d, J = 8.80 Hz, 2H), 5.01 ( s, 2H), 3.74 (s, 3H). MS-ESI m/z: 300.2 [M+H] + .
步骤4：化合物WX004-7的合成Step 4: Synthesis of compound WX004-7
在预先干燥的反应瓶中加入WX004-6(4.1g,13.61mmol,1eq)和N,N-二甲基甲酰胺(40mL)，抽换氮气后，0℃下缓慢加入钠氢(816.60mg,20.42mmol,60％纯度,1.5eq)，0℃搅拌0.5小时，加入苄基氯甲基醚(2.56g,16.33mmol,2.26mL,1.2eq)，25℃下搅拌3小时。将反应液用水淬灭(40mL)，乙酸乙酯萃取水相(40mL*3)，合并有机相，饱和食盐水洗涤(40mL*2)，收集有机相，无水硫酸钠干燥，过滤，减压浓缩得粗产品。粗产品经柱层析纯化(石油醚：乙酸乙酯＝20:1转10:1转5:1)得到化合物WX004-7。 1H NMR(400MHz,DMSO-d 6)δ7.28-7.32(m,7H),6.90-6.95(m,2H),5.31(s,2H),5.07(s,2H),4.62(s,2H),3.74(s,3H)。MS-ESI m/z:439.2[M+18] +。 Add WX004-6 (4.1g, 13.61mmol, 1eq) and N,N-dimethylformamide (40mL) to the pre-dried reaction flask, and after exhausting nitrogen, slowly add sodium hydrogen (816.60mg, 20.42mmol, 60% purity, 1.5eq), stirred at 0°C for 0.5 hours, added benzyl chloromethyl ether (2.56g, 16.33mmol, 2.26mL, 1.2eq), and stirred at 25°C for 3 hours. The reaction solution was quenched with water (40mL), the aqueous phase was extracted with ethyl acetate (40mL*3), the organic phases were combined, washed with saturated brine (40mL*2), the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and reduced pressure Concentrate to obtain a crude product. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 20:1 to 10:1 to 5:1) to obtain compound WX004-7. 1 H NMR (400MHz, DMSO-d 6 ) δ 7.28-7.32 (m, 7H), 6.90-6.95 (m, 2H), 5.31 (s, 2H), 5.07 (s, 2H), 4.62 (s, 2H) ), 3.74(s, 3H). MS-ESI m/z: 439.2 [M+18] + .
步骤5：化合物WX004-8的合成Step 5: Synthesis of compound WX004-8
在预先干燥的反应瓶中加入WX004-7(3.54g,8.40mmol,1eq)和乙腈(54mL)，置于0℃下，缓慢滴入硝酸铈铵(13.82g,25.20mmol,12.56mL,3eq)和水(27mL)的混合溶液，置换氮气三次，置于25℃下搅拌16小时。反应完成后，将反应液用水(50mL)淬灭，乙酸乙酯萃取水相(50mL*3)，合并有机相，饱和食盐水洗涤(50mL*2)，收集有机相，无水硫酸钠干燥，过滤，减压浓缩得粗产品。粗产品经柱层析纯化(石油醚：乙酸乙酯＝20:1转10:1转5:1转2:1)得到化合物WX004-8。 1H NMR(400MHz，氘代氯仿)δ9.89(s,1H)，7.29-7.39(m,5H)，5.49(s,2H)，4.74(s,2H)MS-ESI m/z:319.1[M+18] +。 Add WX004-7 (3.54g, 8.40mmol, 1eq) and acetonitrile (54mL) into the pre-dried reaction flask, place it at 0°C, and slowly drop in ceric ammonium nitrate (13.82g, 25.20mmol, 12.56mL, 3eq) The mixed solution with water (27 mL) was replaced with nitrogen three times, and the mixture was stirred at 25°C for 16 hours. After the completion of the reaction, the reaction solution was quenched with water (50mL), the aqueous phase was extracted with ethyl acetate (50mL*3), the organic phases were combined, washed with saturated brine (50mL*2), the organic phase was collected, and dried over anhydrous sodium sulfate. Filter and concentrate under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (petroleum ether: ethyl acetate=20:1 to 10:1 to 5:1 to 2:1) to obtain compound WX004-8. 1 H NMR (400MHz, deuterated chloroform) δ 9.89 (s, 1H), 7.29-7.39 (m, 5H), 5.49 (s, 2H), 4.74 (s, 2H) MS-ESI m/z: 319.1 [ M+18] + .
步骤6：化合物WX004-10的合成Step 6: Synthesis of compound WX004-10
在预先干燥的反应瓶中WX004-8(325.21mg,1.08mmol,1eq)，WX004-9(500mg,1.08mmol,1eq)和1,2-二氯乙烷(50mL)，加入吡啶(213.50mg,2.70mmol,217.86μL,2.5eq)和醋酸铜(294.15mg,1.62mmol,1.5eq)，氧气保护下，40℃搅拌12小时。反应完成后，将反应液经硅藻土过滤，滤液减压浓缩得到粗产品。粗产品经柱层析纯化(石油醚：乙酸乙酯＝20:1转10:1转5:1转2:1转1:1)得到化合物WX004-10。 1H NMR(400MHz，氘代氯仿)δppm 1.24–1.26(d,J＝6.85Hz,6H)3.19-3.29(m,1H)3.77(s,3H)4.79(s,2H)4.97(s,2H)5.61(s,2H)6.78–6.80(d,J＝8.56Hz,2H)7.04(s,1H)7.18–7.20(d,J＝8.44Hz,2H)7.31-7.40(m,5H)7.58(s,2H)。MS-ESI m/z:718.2[M+H] +。 In a pre-dried reaction flask, WX004-8 (325.21mg, 1.08mmol, 1eq), WX004-9 (500mg, 1.08mmol, 1eq) and 1,2-dichloroethane (50mL), add pyridine (213.50mg, 2.70mmol, 217.86μL, 2.5eq) and copper acetate (294.15mg, 1.62mmol, 1.5eq), under oxygen protection, stirring at 40°C for 12 hours. After the completion of the reaction, the reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (petroleum ether: ethyl acetate=20:1 to 10:1 to 5:1 to 2:1 to 1:1) to obtain compound WX004-10. 1 H NMR (400MHz, deuterated chloroform) δppm 1.24–1.26(d,J＝6.85Hz,6H) 3.19-3.29(m,1H)3.77(s,3H)4.79(s,2H)4.97(s,2H) 5.61(s,2H)6.78–6.80(d,J＝8.56Hz,2H)7.04(s,1H)7.18–7.20(d,J＝8.44Hz,2H)7.31-7.40(m,5H)7.58(s, 2H). MS-ESI m/z: 718.2 [M+H] + .
步骤7：化合物WX004-11的合成Step 7: Synthesis of compound WX004-11
在预先干燥的反应瓶中加入WX004-10(205mg,285.31μmol,1eq)和乙腈(20mL)，置于0℃下缓慢加入硝酸铈胺(469.25mg,855.94μmol,426.59μL,3eq)和水(8mL)的混合溶液，25℃搅拌16小时。反应完成后，将反应液用水(10mL)淬灭，乙酸乙酯萃取水相(20mL*3)，合并有机相，饱和食盐水洗涤(20mL*2)，收集有机相，无水硫酸钠干燥，过滤，减压浓缩得粗产品。粗产品经薄层色谱硅胶板纯化(石油醚：乙酸 乙酯＝1:1)得到化合物WX004-11。 1H NMR(400MHz，氘代氯仿)δppm 1.29-1.31(d,J＝6.85Hz,6H)，3.20-3.27(m,1H),4.78(s,2H),5.59(s,2H),7.15(s,1H),7.31-7.38(m,5H),7.55(s,2H),9.64(br s,1H)。MS-ESI m/z:598.1[M+H] +。 Add WX004-10 (205mg, 285.31μmol, 1eq) and acetonitrile (20mL) to the pre-dried reaction flask, and slowly add ceric amine nitrate (469.25mg, 855.94μmol, 426.59μL, 3eq) and water ( 8mL) was stirred at 25°C for 16 hours. After the completion of the reaction, the reaction solution was quenched with water (10 mL), the aqueous phase was extracted with ethyl acetate (20 mL*3), the organic phases were combined, washed with saturated brine (20 mL*2), the organic phase was collected, and dried over anhydrous sodium sulfate. Filter and concentrate under reduced pressure to obtain a crude product. The crude product was purified by thin layer chromatography on silica gel plate (petroleum ether: ethyl acetate = 1:1) to obtain compound WX004-11. 1 H NMR (400MHz, deuterated chloroform) δppm 1.29-1.31 (d, J = 6.85Hz, 6H), 3.20-3.27 (m, 1H), 4.78 (s, 2H), 5.59 (s, 2H), 7.15 ( s, 1H), 7.31-7.38 (m, 5H), 7.55 (s, 2H), 9.64 (br s, 1H). MS-ESI m/z: 598.1 [M+H] + .
步骤8：化合物WX004的合成Step 8: Synthesis of compound WX004
在预先干燥的反应瓶中加入WX004-11(140mg,233.97μmol,1eq)和二氯甲烷(14mL)，置于0℃下，缓慢滴入三溴化硼(117.23mg,467.95μmol,45.09μL,2eq)，0℃下搅拌15分钟。反应完成后，将反应液经饱和碳酸氢钠溶液(2mL)终止反应，乙酸乙酯萃取水相(5mL*3)，合并有机相，无水硫酸钠干燥，过滤减压浓缩得粗产品。粗产品经高效液相色谱分离(色谱柱:Waters Xbridge BEH C18 100*30mm*10μm；流动相:[水(10mM NH 4HCO 3)-乙腈]；乙腈％:30％-70％,8min)得到目标化合物WX004。 1H NMR(400MHz,氘代甲醇)δ1.28-1.30(d,J＝6.85Hz,6H)3.14-3019(m,1H)7.36(s,1H)7.75(s,2H)。MS-ESI m/z:478.0[M+H] +。 Add WX004-11 (140mg, 233.97μmol, 1eq) and dichloromethane (14mL) into the pre-dried reaction flask, place it at 0℃, and slowly drop in boron tribromide (117.23mg, 467.95μmol, 45.09μL, 2eq), stirring at 0°C for 15 minutes. After the completion of the reaction, the reaction solution was terminated with saturated sodium bicarbonate solution (2mL), the aqueous phase (5mL*3) was extracted with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a crude product. The crude product was separated by high performance liquid chromatography (column: Waters Xbridge BEH C18 100*30mm*10μm; mobile phase: [water (10mM NH 4 HCO 3 )-acetonitrile]; acetonitrile%: 30%-70%, 8min). Target compound WX004. 1 H NMR (400MHz, deuterated methanol) δ 1.28-1.30 (d, J = 6.85 Hz, 6H) 3.14-3019 (m, 1H) 7.36 (s, 1H) 7.75 (s, 2H). MS-ESI m/z: 478.0 [M+H] + .
实施例5Example 5
Figure PCTCN2020093284-appb-000131
Figure PCTCN2020093284-appb-000131
合成路线：synthetic route:
Figure PCTCN2020093284-appb-000132
Figure PCTCN2020093284-appb-000132
步骤1：化合物WX005-2的合成Step 1: Synthesis of compound WX005-2
在预先干燥的反应瓶中加入WX002-4(6.92g,28.61mmol)，之后用N,N-二甲基乙酰胺(31mL)溶解，然后加入叔丁醇钾(3.85g,34.33mmol)，加热到100℃搅拌反应1小时，然后加入WX001-3(6.1g,30.04mmol) 和N,N-二甲基乙酰胺(15.5mL)的溶液，加热到130℃搅拌反应64小时。反应完成后，将反应体系降至室温(20℃)，加水(150mL)和乙酸乙酯(100mL)稀释，分液收集有机相，水相用乙酸乙酯(100mL*2)萃取，合并有机相，之后用饱和食盐水(200mL*4)洗涤，无水硫酸钠干燥，过滤除去干燥剂后，滤液减压浓缩，得到残留物。加入甲基叔丁基醚(15mL)，搅拌10分钟，过滤，滤饼用甲基叔丁基醚(10mL*3)淋洗，滤饼旋干得到化合物WX005-2。 1H NMR(400MHz,DMSO-d 6)δ7.99(s,2H),2.77-2.79(m,2H),2.71-2.68(m,2H),1.81-1.84(m,4H)。 Add WX002-4 (6.92g, 28.61mmol) to the pre-dried reaction flask, then dissolve it with N,N-dimethylacetamide (31mL), then add potassium tert-butoxide (3.85g, 34.33mmol) and heat The reaction was stirred at 100°C for 1 hour, and then a solution of WX001-3 (6.1 g, 30.04 mmol) and N,N-dimethylacetamide (15.5 mL) was added, and the reaction was stirred at 130°C for 64 hours. After the completion of the reaction, the reaction system was cooled to room temperature (20°C), diluted with water (150 mL) and ethyl acetate (100 mL), separated and collected the organic phase, the aqueous phase was extracted with ethyl acetate (100 mL*2), and the organic phases were combined Then, it was washed with saturated brine (200 mL*4), dried over anhydrous sodium sulfate, filtered to remove the desiccant, and the filtrate was concentrated under reduced pressure to obtain a residue. Methyl tert-butyl ether (15 mL) was added, stirred for 10 minutes, filtered, the filter cake was rinsed with methyl tert-butyl ether (10 mL*3), and the filter cake was spin-dried to obtain compound WX005-2. 1 H NMR (400MHz, DMSO-d 6 ) δ 7.99 (s, 2H), 2.77-2.79 (m, 2H), 2.71-2.68 (m, 2H), 1.81-1.84 (m, 4H).
步骤2：化合物WX005-3的合成Step 2: Synthesis of compound WX005-3
在预先干燥的反应瓶中加入WX005-2(6.19g,15.15mmol)，用醋酸(62mL)溶解，然后加入醋酸钠(2.49g,30.31mmol)，缓慢地升高至110℃搅拌反应16小时。反应完成后，将反应体系降至室温(25℃)，之后用水泵将醋酸旋出大部分，之后加水(60mL)稀释，过滤，滤饼用乙酸乙酯(20mL*3)淋洗，旋干得到化合物WX005-3。 1H NMR(400MHz，氘代氯仿)δ11.08(s,1H),7.53(s,2H),2.70-2.77(m,2H),2.60-2.64(m,2H),1.88-1.82(m,4H)。 WX005-2 (6.19g, 15.15mmol) was added to the pre-dried reaction flask, dissolved with acetic acid (62mL), then sodium acetate (2.49g, 30.31mmol) was added, and the temperature was slowly raised to 110°C and stirred for 16 hours. After the reaction is completed, the reaction system is cooled to room temperature (25°C), and then most of the acetic acid is spun out with a water pump, and then diluted with water (60mL), filtered, the filter cake is rinsed with ethyl acetate (20mL*3) and spin-dried Compound WX005-3 was obtained. 1 H NMR (400MHz, deuterated chloroform) δ 11.08 (s, 1H), 7.53 (s, 2H), 2.70-2.77 (m, 2H), 2.60-2.64 (m, 2H), 1.88-1.82 (m, 4H).
步骤3：化合物WX005-4的合成Step 3: Synthesis of compound WX005-4
在预先干燥的反应瓶中加入WX005-3(4.4g,11.28mmol)，之后用N,N-二甲基甲酰胺(44mL)溶解，加入碳酸钾(4.68g,33.84mmol)，对甲氧基苄氯(2.65g,16.92mmol,2.30mL)，室温(20℃)搅拌反应16小时。反应完成后，加水(100mL)稀释，加乙酸乙酯(200mL)，分液收集有机相，水相用乙酸乙酯(100mL*3)萃取，合并有机相，之后用饱和食盐水(100mL*4)洗涤，无水硫酸钠干燥，过滤除去干燥剂后，减压除去溶剂，得到化合物WX005-4。1H NMR(400MHz,DMSO-d 6)δ7.96(s,2H),7.01-7.03(d,J＝8.4Hz,2H),6.77-6.80(d,J＝8.4Hz,2H),4.81(s,2H),3.71(s,3H),2.61(s,2H),2.44(s,2H),1.72(s,4H)。 Add WX005-3 (4.4g, 11.28mmol) to the pre-dried reaction flask, then dissolve it with N,N-dimethylformamide (44mL), add potassium carbonate (4.68g, 33.84mmol), p-methoxy Benzyl chloride (2.65g, 16.92mmol, 2.30mL) was stirred and reacted at room temperature (20°C) for 16 hours. After the reaction is complete, dilute with water (100mL), add ethyl acetate (200mL), separate and collect the organic phase, extract the aqueous phase with ethyl acetate (100mL*3), combine the organic phases, and then use saturated brine (100mL*4 ) Wash, dry with anhydrous sodium sulfate, filter to remove the desiccant, and remove the solvent under reduced pressure to obtain compound WX005-4. 1H NMR (400MHz, DMSO-d 6 ) δ 7.96 (s, 2H), 7.01-7.03 (d ,J=8.4Hz,2H),6.77-6.80(d,J=8.4Hz,2H),4.81(s,2H),3.71(s,3H),2.61(s,2H),2.44(s,2H) ,1.72(s,4H).
步骤4：化合物WX005-5的合成Step 4: Synthesis of compound WX005-5
在预先干燥的反应瓶中加入WX005-4(4.27g,8.37mmol)，双联频哪醇硼酸酯(3.19g,12.55mmol)和二氧六环(64mL)，醋酸钾(1.64g,16.74mmol,2eq)，置换氮气三次，加入Pd(dppf)Cl 2(612.38mg,836.92μmol)，再次置换氮气三次，置于70℃下搅拌16小时。反应完成后，将反应通过铺有硅藻土的漏斗，滤饼由二氯甲烷(50mL*3)洗涤后，将合并后的滤液减压浓缩，残余物再次溶于二氯甲烷(100mL)，依次用水(50mL*3)、饱和食盐水洗涤(50mL*3)，无水硫酸钠干燥，过滤除去干燥剂后，减压除去溶剂，所得残留物经层析柱分离(洗脱剂：石油醚：乙酸乙酯＝1:0至20:80)纯化得到化合物WX005-5。 1H NMR(400MHz,DMSO-d 6)δ7.72(s,2H),6.97-7.00(d,J＝8.4Hz,2H),6.77-6.81(d,J＝8.4Hz,2H),4.79(s,2H),3.71(s,3H),2.63(s,2H),2.44(s,2H),1.73(s,4H),1.32(s,12H)。 Add WX005-4 (4.27g, 8.37mmol), dual pinacol borate (3.19g, 12.55mmol), dioxane (64mL), potassium acetate (1.64g, 16.74) to the pre-dried reaction flask mmol, 2eq), replace with nitrogen three times, add Pd(dppf)Cl 2 (612.38 mg, 836.92 μmol), replace with nitrogen again three times, and stir at 70°C for 16 hours. After the completion of the reaction, the reaction was passed through a funnel paved with diatomaceous earth. After the filter cake was washed with dichloromethane (50mL*3), the combined filtrate was concentrated under reduced pressure, and the residue was dissolved in dichloromethane (100mL) again. Wash with water (50mL*3) and saturated brine (50mL*3) successively, dry with anhydrous sodium sulfate, filter to remove the desiccant, remove the solvent under reduced pressure, and separate the resulting residue on a chromatography column (eluent: petroleum ether : Ethyl acetate=1:0 to 20:80) to obtain compound WX005-5. 1 H NMR(400MHz, DMSO-d 6 )δ7.72(s,2H), 6.97-7.00(d,J=8.4Hz,2H), 6.77-6.81(d,J=8.4Hz,2H), 4.79( s, 2H), 3.71 (s, 3H), 2.63 (s, 2H), 2.44 (s, 2H), 1.73 (s, 4H), 1.32 (s, 12H).
步骤5：化合物WX005-6的合成Step 5: Synthesis of compound WX005-6
在预先干燥的反应瓶中加入WX005-5(1.2g,2.15mmol)，之后用丙酮(24mL)，水(12mL)溶解，然后加入高碘酸钠(460.58mg,2.15mmol,119.32μL)，醋酸铵(1.20g,15.50mmol)，氮气置换三次，35℃下搅拌反应 16小时。反应完成后，将反应体系降至室温(20℃)，加入饱和的亚硫酸钠溶液50mL，搅拌20分钟，用淀粉碘化钾试纸检测没有变橙蓝色，用1N的盐酸中和pH至5左右，发现有固体析出，用水泵在45℃减压浓缩除去丙酮，发现固体变多，过滤，滤饼旋干得到化合物WX005-6。 1H NMR(400MHz,DMSO-d 6)δ8.51(s,2H),7.90(s,2H),6.98-7.01(d,J＝8.8Hz,2H),6.75-6.81(d,J＝8.8Hz,2H),4.79(s,2H),3.70(s,3H),2.63(s,2H),2.44(s,2H),1.73-1.76(m,4H)。 Add WX005-5 (1.2g, 2.15mmol) to the pre-dried reaction flask, then dissolve it with acetone (24mL), water (12mL), and then add sodium periodate (460.58mg, 2.15mmol, 119.32μL), acetic acid Ammonium (1.20g, 15.50mmol), replaced with nitrogen three times, stirred at 35°C for 16 hours. After the completion of the reaction, the reaction system was reduced to room temperature (20°C), 50 mL of saturated sodium sulfite solution was added, and stirred for 20 minutes. The starch potassium iodide test paper was used to detect that it did not turn orange and blue. The pH was neutralized to about 5 with 1N hydrochloric acid. The solid precipitated, and the acetone was removed by concentrating under reduced pressure with a water pump at 45°C. It was found that the solid became more, filtered, and the filter cake was spin-dried to obtain compound WX005-6. 1 H NMR(400MHz,DMSO-d 6 )δ8.51(s,2H),7.90(s,2H),6.98-7.01(d,J=8.8Hz,2H),6.75-6.81(d,J=8.8 Hz, 2H), 4.79 (s, 2H), 3.70 (s, 3H), 2.63 (s, 2H), 2.44 (s, 2H), 1.73-1.76 (m, 4H).
步骤6：化合物WX005-7的合成Step 6: Synthesis of compound WX005-7
在预先干燥的反应瓶中加入WX003-6(0.1g,353.07μmol)，WX005-6(218.08mg,458.99μmol,)，之后用二氯乙烷(5mL)溶解，然后加入醋酸铜(96.19mg,529.60μmol)，吡啶(69.82mg,882.67μmol,71.24μL)，加料完全后，于40℃在氧气环境下(15psi)搅拌反应15小时。反应完成后，加水(15mL)和乙酸乙酯(15mL)稀释，分液收集有机相，水相用乙酸乙酯(15mL*2)萃取，合并有机相，之后用饱和食盐水(10mL*2)洗涤，并用无水硫酸钠干燥，过滤除去干燥剂后，减压除去溶剂，所得残留物通过薄层层析硅胶板(石油醚：乙酸乙酯＝1:1)纯化得到化合物WX005-7。MS-ESI m/z:712.2[M+H] +,714.1[M+H+2] +。 Add WX003-6 (0.1g, 353.07μmol), WX005-6 (218.08mg, 458.99μmol,) to the pre-dried reaction flask, then dissolve with dichloroethane (5mL), and then add copper acetate (96.19mg, 529.60μmol), pyridine (69.82mg, 882.67μmol, 71.24μL), after the addition is complete, the reaction was stirred at 40°C in an oxygen environment (15psi) for 15 hours. After the reaction is complete, dilute with water (15mL) and ethyl acetate (15mL), separate and collect the organic phase, extract the aqueous phase with ethyl acetate (15mL*2), combine the organic phases, and then use saturated brine (10mL*2) It was washed and dried with anhydrous sodium sulfate, filtered to remove the desiccant, and the solvent was removed under reduced pressure. The obtained residue was purified by thin-layer chromatography on a silica gel plate (petroleum ether: ethyl acetate = 1:1) to obtain compound WX005-7. MS-ESI m/z: 712.2 [M+H] + , 714.1 [M+H+2] + .
步骤7：化合物WX005-8的合成Step 7: Synthesis of compound WX005-8
在预先干燥的反应瓶中加入WX005-7(0.22g,308.76μmol)，之后用乙腈(7mL)溶解，将反应体系将至0℃，然后加入硝酸铈铵(507.81mg,926.28μmol,461.64μL)的水(3mL)溶液，缓慢地升高至室温(25℃)搅拌反应2小时。反应完成后，加水(10mL)和乙酸乙酯(10mL)稀释，分液要有机相，水相用乙酸乙酯(10mL*2)萃取，合并有机相，并用饱和食盐水(10mL*2)洗涤，无水硫酸钠干燥，过滤除去干燥剂后，减压除去溶剂，所得残留物经薄层层析硅胶板(石油醚：乙酸乙酯＝1:1)纯化得到化合物WX005-8。MS-ESI m/z:592.2[M+H] +,594.1[M+H+2] +。 Add WX005-7 (0.22g, 308.76μmol) to the pre-dried reaction flask, then dissolve it with acetonitrile (7mL), bring the reaction system to 0°C, and then add ceric ammonium nitrate (507.81mg, 926.28μmol, 461.64μL) The water (3 mL) solution of the solution was slowly raised to room temperature (25° C.) and the reaction was stirred for 2 hours. After the reaction is complete, dilute with water (10mL) and ethyl acetate (10mL), separate the organic phase, extract the aqueous phase with ethyl acetate (10mL*2), combine the organic phases, and wash with saturated brine (10mL*2) , Dried over anhydrous sodium sulfate, filtered to remove the desiccant, and removed the solvent under reduced pressure. The residue obtained was purified by thin layer chromatography on silica gel plate (petroleum ether: ethyl acetate = 1:1) to obtain compound WX005-8. MS-ESI m/z: 592.2 [M+H] + , 594.1 [M+H+2] + .
步骤8：化合物WX005的合成Step 8: Synthesis of compound WX005
在预先干燥的反应瓶中加入WX005-8(0.081g,136.74μmol)，之后二氯甲烷(2.4mL)溶解，将反应体系降至0℃，加入三溴化硼(68.51mg,273.47μmol,26.35μL)，0℃搅拌反应0.5小时。反应完成后，用饱和的碳酸氢钠溶液中和反应液pH至7左右，加入乙酸乙酯(5mL)稀释，分液要有机相，水相用乙酸乙酯(5mL*2)萃取，合并有机相，并用饱和食盐水(5mL*2)洗涤，无水硫酸钠干燥，过滤，过滤除去干燥剂后，减压除去溶剂，所得残留物经高效液相色谱分离(色谱柱:Phenomenex Luna C18 200*40mm*10μm；流动相:[水(0.2％FA)-乙腈]；乙腈％:30％-70％,10min)分离得到目标化合物WX005。 1H NMR(400MHz,DMSO-d 6)δ12.85(br s,1H),12.07(s,1H),7.80(s,2H),6.76-7.05(t,J＝52.4Hz,1H),2.66-2.67(m,2H),2.43-2.45(m,2H),1.75-1.78(m,4H)。MS-ESI m/z:472.1[M+H] +,474.0[M+H+2] +。 Add WX005-8 (0.081g, 136.74μmol) to the pre-dried reaction flask, then dissolve dichloromethane (2.4mL), reduce the reaction system to 0℃, and add boron tribromide (68.51mg, 273.47μmol, 26.35). μL), the reaction was stirred at 0°C for 0.5 hours. After the reaction is complete, neutralize the pH of the reaction solution to about 7 with saturated sodium bicarbonate solution, add ethyl acetate (5mL) to dilute, separate the organic phase, extract the aqueous phase with ethyl acetate (5mL*2), and combine the organic Phase, washed with saturated brine (5mL*2), dried with anhydrous sodium sulfate, filtered, filtered to remove the desiccant, and then removed the solvent under reduced pressure. The resulting residue was separated by high performance liquid chromatography (column: Phenomenex Luna C18 200* 40mm*10μm; mobile phase: [water (0.2% FA)-acetonitrile]; acetonitrile%: 30%-70%, 10 min) to obtain the target compound WX005. 1 H NMR (400MHz, DMSO-d 6 ) δ 12.85 (br s, 1H), 12.07 (s, 1H), 7.80 (s, 2H), 6.76-7.05 (t, J = 52.4 Hz, 1H), 2.66 -2.67 (m, 2H), 2.43-2.45 (m, 2H), 1.75-1.78 (m, 4H). MS-ESI m/z: 472.1 [M+H] + , 474.0 [M+H+2] + .
实施例6Example 6
Figure PCTCN2020093284-appb-000133
Figure PCTCN2020093284-appb-000133
合成路线：synthetic route:
Figure PCTCN2020093284-appb-000134
Figure PCTCN2020093284-appb-000134
步骤1：化合物WX006-3的合成Step 1: Synthesis of compound WX006-3
在预先干燥的反应瓶中加入钠氢(22.18g,554.52mmol,60％纯度,3.11eq)和四氢呋喃(200mL)，置换氮气三次，缓慢滴入WX006-2(40.15g,445.75mmol,37.53mL,2.5eq)，置于80℃下搅拌1.5小时，降温至25℃，缓慢滴入WX006-1(20g,178.30mmol,21.65mL,1eq)和四氢呋喃(200mL)的混合溶液，70℃下继续搅拌4小时。反应完毕后，将反应瓶缓慢倒入冰水浴(100mL)中，缓慢加入2M盐酸溶液(200mL)调节pH至5～6，滴加浓盐酸(10mL)调节pH至1，甲基叔丁基醚萃取水相(300mL*3)，合并有机相，饱和食盐水洗涤(300mL*2)，过滤减压浓缩得粗产品。粗产品过硅胶色谱柱(石油醚：乙酸乙酯＝1:0转80:1转50:1)纯化得到化合物WX006-3。 1H NMR(400MHz，氘代氯仿)δppm 1.18–1.20(d,J＝7.13Hz,3H)1.38-1.45(m,1H)1.47-1.55(m,1H)1.65-1.74(m,1H)1.78-1.87(m,1H)2.19-2.26(m,2H)2.40-2.51(m,1H)3.76(s,3H)。MS-ESI m/z:171.1[M+H] +。 Add sodium hydrogen (22.18g, 554.52mmol, 60% purity, 3.11eq) and tetrahydrofuran (200mL) into the pre-dried reaction flask, replace nitrogen for three times, and slowly drip WX006-2 (40.15g, 445.75mmol, 37.53mL, 2.5eq), placed at 80℃ and stirred for 1.5 hours, cooled to 25℃, slowly dripped into the mixed solution of WX006-1 (20g, 178.30mmol, 21.65mL, 1eq) and tetrahydrofuran (200mL), and continued stirring at 70℃4 hour. After the reaction is complete, slowly pour the reaction flask into an ice-water bath (100mL), slowly add 2M hydrochloric acid solution (200mL) to adjust the pH to 5-6, add dropwise concentrated hydrochloric acid (10mL) to adjust the pH to 1, methyl tert-butyl ether The aqueous phase (300 mL*3) was extracted, the organic phases were combined, washed with saturated brine (300 mL*2), filtered and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel chromatography column (petroleum ether: ethyl acetate=1:0 to 80:1 to 50:1) to obtain compound WX006-3. 1 H NMR (400MHz, deuterated chloroform) δppm 1.18–1.20(d,J=7.13Hz,3H)1.38-1.45(m,1H)1.47-1.55(m,1H)1.65-1.74(m,1H)1.78- 1.87 (m, 1H) 2.19-2.26 (m, 2H) 2.40-2.51 (m, 1H) 3.76 (s, 3H). MS-ESI m/z: 171.1 [M+H] + .
步骤2：化合物WX006-4的合成Step 2: Synthesis of compound WX006-4
在预先干燥的两个反应瓶中分别加入乙醚(260mL)，缓慢加入钠氢(15.28g,381.89mmol,60％纯度,5eq)，置于0℃下，缓慢滴入WX006-3(13g,76.38mmol,1eq)和乙醚(195mL)的混合溶液，置换氮气三次。反应完毕后，将反应液缓慢加入到搅拌着的冰水(500mL)中，二氯甲烷萃取水相(600mL*3)，合并有机 相，饱和食盐水洗涤(500mL*2)，收集有机相，无水硫酸钠干燥，过滤，减压浓缩得粗产品。粗产品过硅胶色谱柱(石油醚：乙酸乙酯＝1:0转50:1转20:1转10:1)纯化得到化合物WX006-4。 1H NMR(400MHz，氘代氯仿)δppm 1.20–1.22(d,J＝7.00Hz,3H)1.46-1.54(m,1H)1.58-1.78(m,2H)1.91-2.01(m,1H)2.39-2.49(m,1H)2.50-2.67(m,2H)3.81(s,3H)。MS-ESI m/z:303.0[M+H] +。 Add ether (260mL) to the two pre-dried reaction flasks, slowly add sodium hydrogen (15.28g, 381.89mmol, 60% purity, 5eq), place at 0℃, and slowly drop WX006-3 (13g, 76.38) mmol, 1 eq) and diethyl ether (195mL) mixed solution, replaced with nitrogen three times. After the reaction is completed, slowly add the reaction solution to stirring ice water (500mL), extract the aqueous phase (600mL*3) with dichloromethane, combine the organic phases, wash with saturated brine (500mL*2), collect the organic phase, Dry with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain a crude product. The crude product was purified by silica gel chromatography column (petroleum ether: ethyl acetate=1:0 to 50:1 to 20:1 to 10:1) to obtain compound WX006-4. 1 H NMR (400MHz, deuterated chloroform) δppm 1.20-1.22(d,J=7.00Hz,3H)1.46-1.54(m,1H)1.58-1.78(m,2H)1.91-2.01(m,1H)2.39- 2.49 (m, 1H) 2.50-2.67 (m, 2H) 3.81 (s, 3H). MS-ESI m/z: 303.0 [M+H] + .
步骤3：化合物WX006-6的合成Step 3: Synthesis of compound WX006-6
在预先干燥的反应瓶中加入WX006-4(2g,6.62mmol,1eq)和干燥过的N,N-二甲基甲酰胺(40mL)，加入分子筛(50mg)，加入甲酸钠(1.35g,19.85mmol,1.07mL,3eq)，加入无水氯化锂(841.52mg,19.85mmol,406.53μL,3eq)，置换氮气三次，置于0℃下依次缓慢滴入WX006-5(1.35g,13.23mmol,1.24mL,2eq)和二异丙基乙胺(1.71g,13.23mmol,2.31mL,2eq)，升温至25℃，加入醋酸钯(148.55mg,661.67μmol,0.1eq)，再次置换氮气三次，置于25℃下继续搅拌16小时。反应完毕后，将反应液用2M盐酸溶液淬灭(20mL)，甲基叔丁基醚萃取水相(30mL*3)，合并有机相，饱和食盐水洗涤(30mL*3)，收集有机相，无水硫酸钠干燥，过滤减压浓缩得到化合物WX006-6。MS-ESI m/z:167.1[M+H] +。 Add WX006-4 (2g, 6.62mmol, 1eq) and dried N,N-dimethylformamide (40mL) to the pre-dried reaction flask, add molecular sieve (50mg), add sodium formate (1.35g, 19.85mmol) , 1.07mL, 3eq), add anhydrous lithium chloride (841.52mg, 19.85mmol, 406.53μL, 3eq), replace nitrogen three times, place at 0℃ and slowly drop WX006-5 (1.35g, 13.23mmol, 1.24 mL, 2eq) and diisopropylethylamine (1.71g, 13.23mmol, 2.31mL, 2eq), heated to 25℃, added palladium acetate (148.55mg, 661.67μmol, 0.1eq), replaced the nitrogen again three times, placed Stirring was continued for 16 hours at 25°C. After the reaction, the reaction solution was quenched with 2M hydrochloric acid solution (20mL), the aqueous phase was extracted with methyl tert-butyl ether (30mL*3), the organic phases were combined, washed with saturated brine (30mL*3), and the organic phase was collected. It was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain compound WX006-6. MS-ESI m/z: 167.1 [M+H] + .
步骤4：化合物WX006-7的合成Step 4: Synthesis of compound WX006-7
在预先干燥的反应瓶中加入WX006-6(1.1g,6.62mmol,1eq)和冰乙酸(20mL)，加入水合肼(338.14mg,6.62mmol,328.29μL,98％纯度,1eq)和水(2mL)，置换氮气三次，置于100℃下搅拌16小时。反应完毕后，将反应液直接减压浓缩得到粗产品。将粗产品用甲基叔丁基醚(10mL)打浆得到化合物WX006-7。 1H NMR(400MHz,DMSO-d 6)δppm 1.11–1.13(d,J＝7.00Hz,3H)1.58-1.72(m,4H)1.85-1.88(m,1H)2.14-2.25(m,1H)2.77–2.78(br d,J＝4.13Hz,1H)9.67(br s,2H)。MS-ESI m/z:181.1[M+H] +。 In the pre-dried reaction flask, add WX006-6 (1.1g, 6.62mmol, 1eq) and glacial acetic acid (20mL), add hydrazine hydrate (338.14mg, 6.62mmol, 328.29μL, 98% purity, 1eq) and water (2mL ), replace with nitrogen three times, and stir at 100°C for 16 hours. After the completion of the reaction, the reaction solution was directly concentrated under reduced pressure to obtain a crude product. The crude product was slurried with methyl tert-butyl ether (10 mL) to obtain compound WX006-7. 1 H NMR (400MHz, DMSO-d 6 ) δppm 1.11-1.13(d,J＝7.00Hz,3H)1.58-1.72(m,4H)1.85-1.88(m,1H)2.14-2.25(m,1H)2.77 -2.78 (br d, J = 4.13 Hz, 1H) 9.67 (br s, 2H). MS-ESI m/z: 181.1 [M+H] + .
步骤5：化合物WX006-8的合成Step 5: Synthesis of compound WX006-8
在预先干燥的反应瓶中加入WX006-7(1.13g,6.27mmol,1eq)和三氯氧磷(26.64g,173.71mmol,16.14mL,27.70eq)，置换氮气三次，置于100℃搅拌3小时。反应完毕后，将反应液直接减压浓缩，浓缩液加入冰水(50mL)，经碳酸氢钠固体调节pH至7～8，乙酸乙酯萃取水相(50mL*3)，合并有机相，饱和食盐水洗涤(50mL*2)，收集有机相，无水硫酸钠干燥，过滤减压浓缩得粗产品。粗产品经柱层析纯化(石油醚：乙酸乙酯＝1:0转20:1转10:1转5:1)纯化得到化合物WX006-8。 1H NMR(400MHz，氘代氯仿)δppm 1.31–1.32(d,J＝7.00Hz,3H)1.72-1.81(m,1H)1.85-2.03(m,3H)2.53-2.66(m,1H)2.91(dd,J＝19.26,5.50Hz,1H)3.19(t,J＝6.38Hz,1H)。MS-ESI m/z:217.1[M+H] +。 Add WX006-7 (1.13g, 6.27mmol, 1eq) and phosphorus oxychloride (26.64g, 173.71mmol, 16.14mL, 27.70eq) into the pre-dried reaction flask, replace with nitrogen three times, and place at 100℃ and stir for 3 hours . After the completion of the reaction, the reaction solution was directly concentrated under reduced pressure, the concentrated solution was added to ice water (50mL), the pH was adjusted to 7-8 with sodium bicarbonate solid, the aqueous phase was extracted with ethyl acetate (50mL*3), the organic phases were combined and saturated Wash with brine (50 mL*2), collect the organic phase, dry with anhydrous sodium sulfate, filter and concentrate under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (petroleum ether: ethyl acetate=1:0 to 20:1 to 10:1 to 5:1) to obtain compound WX006-8. 1 H NMR (400MHz, deuterated chloroform) δppm 1.31–1.32 (d, J = 7.00 Hz, 3H) 1.72-1.81 (m, 1H) 1.85-2.03 (m, 3H) 2.53-2.66 (m, 1H) 2.91 ( dd, J = 19.26, 5.50 Hz, 1H) 3.19 (t, J = 6.38 Hz, 1H). MS-ESI m/z: 217.1 [M+H] + .
步骤6：化合物WX006-9的合成Step 6: Synthesis of compound WX006-9
在预先干燥的反应瓶中加入WX001-4(983.99mg,5.53mmol,1.5eq)和二甲基亚砜(16mL)，加入WX006-8(800mg,3.69mmol,1eq)和碳酸钾(2.04g,14.74mmol,4eq)，置换氮气三次，加入碘化亚铜(421.09mg,2.21mmol,0.6eq)，再次置换氮气三次，置于90℃下搅拌16小时。反应完毕后，反应液降温至室温，用2N盐酸溶液(20mL)调节pH至7～8，乙酸乙酯萃取水相(30mL*3)，饱和食盐水洗涤， 无水硫酸钠干燥，过滤，减压浓缩得粗产品。粗产品经剥层色谱柱层析纯化(石油醚：乙酸乙酯＝1:0转20:1转10:1转5:1)纯化得到固体产物，固体产物经甲基叔丁基醚打浆，收集滤液，滤液减压浓缩得到化合物WX006-9。MS-ESI m/z:358.0[M+H] +。 Add WX001-4 (983.99mg, 5.53mmol, 1.5eq) and dimethyl sulfoxide (16mL) to the pre-dried reaction flask, add WX006-8 (800mg, 3.69mmol, 1eq) and potassium carbonate (2.04g, 14.74mmol, 4eq), replaced with nitrogen three times, added cuprous iodide (421.09mg, 2.21mmol, 0.6eq), replaced with nitrogen again three times, placed at 90°C and stirred for 16 hours. After the reaction, the reaction solution was cooled to room temperature, adjusted to pH 7-8 with 2N hydrochloric acid solution (20mL), the aqueous phase was extracted with ethyl acetate (30mL*3), washed with saturated brine, dried with anhydrous sodium sulfate, filtered, and reduced Press and concentrate to obtain a crude product. The crude product was purified by stripping chromatography column chromatography (petroleum ether: ethyl acetate=1:0 to 20:1 to 10:1 to 5:1) to obtain a solid product, which was slurried with methyl tert-butyl ether. The filtrate was collected, and the filtrate was concentrated under reduced pressure to obtain compound WX006-9. MS-ESI m/z: 358.0 [M+H] + .
WX006-9结构鉴定：WX006-9 structure identification:
Figure PCTCN2020093284-appb-000135
Figure PCTCN2020093284-appb-000135
在预先干燥的反应瓶中加入WX006-9(0.1g,278.82μmol,1eq)和甲醇(1mL)，加入湿钯碳(0.1g,139.41μmol,10％纯度,0.5eq)，置换氢气三次，在氢气球(15psi)的压力下，置于25℃下搅拌2小时。反应完毕后。将反应液经硅藻土过滤，滤液减压浓缩得到粗产品，粗产品经高效液相色谱分离(色谱柱:Waters Xbridge BEH C18 100*30mm*10μm；流动相:[水(10mM碳酸氢铵)-乙腈]；乙腈％:25％-45％,10分钟)纯化得到WX006-9A。NOE(400MHz,氘代氯仿)检测甲基六元环上甲基的氢(1.34)与哒嗪环上的氢(8.69)有相关性，证明WX006-9结构正确。 1HNMR(400MHz,氘代氯仿)δ8.69(s,1H),6.99(d,J＝8.6Hz,2H),6.66-6.77(d,J＝8.6Hz,2H),3.61(br s,2H),2.91(d,J＝6.50Hz,1H),2.74(d,J＝4.00Hz,2H),1.91-2.01(m,2H),1.79-1.89(m,1H),1.61-1.65(m,1H),1.34(d,J＝7.13Hz,3H)。 Add WX006-9 (0.1g, 278.82μmol, 1eq) and methanol (1mL) to the pre-dried reaction flask, add wet palladium on carbon (0.1g, 139.41μmol, 10% purity, 0.5eq), and replace hydrogen three times. Under the pressure of a hydrogen balloon (15 psi), the mixture was stirred at 25°C for 2 hours. After the reaction is complete. The reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated by high performance liquid chromatography (column: Waters Xbridge BEH C18 100*30mm*10μm; mobile phase: [Water (10mM ammonium bicarbonate)) -Acetonitrile]; Acetonitrile%: 25%-45%, 10 minutes) to obtain WX006-9A. NOE (400MHz, deuterated chloroform) detects the correlation between the methyl hydrogen (1.34) on the six-membered methyl ring and the hydrogen (8.69) on the pyridazine ring, which proves that the structure of WX006-9 is correct. 1 HNMR (400MHz, deuterated chloroform)δ8.69(s,1H), 6.99(d,J=8.6Hz,2H),6.66-6.77(d,J=8.6Hz,2H),3.61(br s,2H ), 2.91 (d, J = 6.50 Hz, 1H), 2.74 (d, J = 4.00 Hz, 2H), 1.91-2.01 (m, 2H), 1.79-1.89 (m, 1H), 1.61-1.65 (m, 1H), 1.34 (d, J = 7.13 Hz, 3H).
步骤7：化合物WX006-10的合成Step 7: Synthesis of compound WX006-10
在预先干燥的反应瓶中加入WX006-9(500mg,1.39mmol,1eq)和冰乙酸(20mL)，加入乙酸钠(228.73mg,2.79mmol,2eq)，置于110℃搅拌16小时。反应完毕后，将反应液减压浓缩，倒入到水(30mL)中，用固体碳酸氢钠调节溶液的pH＝7-8，然后用(乙酸乙酯：四氢呋喃＝3:1，40mL*3)萃取，合并所有的有机相，有机相用饱和氯化钠溶液(30mL*2)洗涤，无水硫酸钠干燥，倾倒，浓缩得到化合物WX006-10。MS-ESI m/z:382.1[M+H] +。 WX006-9 (500 mg, 1.39 mmol, 1 eq) and glacial acetic acid (20 mL) were added to the pre-dried reaction flask, sodium acetate (228.73 mg, 2.79 mmol, 2 eq) was added, and the mixture was stirred at 110°C for 16 hours. After the completion of the reaction, the reaction solution was concentrated under reduced pressure, poured into water (30mL), the pH of the solution was adjusted to 7-8 with solid sodium bicarbonate, and then (ethyl acetate: tetrahydrofuran=3:1, 40mL*3 ) Extract, combine all the organic phases, wash the organic phase with saturated sodium chloride solution (30 mL*2), dry with anhydrous sodium sulfate, pour, and concentrate to obtain compound WX006-10. MS-ESI m/z: 382.1 [M+H] + .
步骤8：化合物WX006-11的合成Step 8: Synthesis of compound WX006-11
在预先干燥的反应瓶中加入WX006-10(532mg,1.39mmol,1eq)和乙醇(11mL)，加入稀盐酸(2M,10.44mL,15eq)，置换氮气三次，置于90℃下搅拌16小时。反应完毕后，将反应液直接减压浓缩，浓缩物用固体碳酸氢钠调节pH至7～8，(乙酸乙酯：四氢呋喃＝3:1，40mL*3)萃取水相，合并有机相，饱和食盐水洗涤，过滤，减压浓缩得粗产品。粗产品经柱层析纯化(石油醚：乙酸乙酯＝1:0转20:1转10:1转5:1转2:1转1:1)得到化合物WX006-11。 1H NMR(400MHz,DMSO-d 6)δppm 1.15–1.17(d,J＝7.00Hz,3H)1.63-1.82(m,4H)2.63-2.72(m,1H)2.83-2.92(m,1H)3.32(s,1H)5.60(s,2H)6.65(s,2H)11.95(s,1H)。MS-ESI m/z:340.1[M+H] +。 Add WX006-10 (532mg, 1.39mmol, 1eq) and ethanol (11mL) to the pre-dried reaction flask, add dilute hydrochloric acid (2M, 10.44mL, 15eq), replace nitrogen for three times, and place at 90°C and stir for 16 hours. After the completion of the reaction, the reaction solution was directly concentrated under reduced pressure, the concentrate was adjusted to pH 7-8 with solid sodium bicarbonate, (ethyl acetate:tetrahydrofuran=3:1, 40mL*3) the aqueous phase was extracted, and the organic phases were combined and saturated Wash with brine, filter, and concentrate under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (petroleum ether: ethyl acetate=1:0 to 20:1 to 10:1 to 5:1 to 2:1 to 1:1) to obtain compound WX006-11. 1 H NMR (400MHz, DMSO-d 6 ) δppm 1.15-1.17(d,J=7.00Hz,3H)1.63-1.82(m,4H)2.63-2.72(m,1H)2.83-2.92(m,1H)3.32 (s, 1H) 5.60 (s, 2H) 6.65 (s, 2H) 11.95 (s, 1H). MS-ESI m/z: 340.1 [M+H] + .
步骤9：化合物WX006-12的合成Step 9: Synthesis of compound WX006-12
在预先干燥的反应瓶中加入WX006-11(330mg,970.01μmol,1eq)和冰乙酸(2mL)，浓盐酸(12M,249.78 μL,3.09eq)，置于0℃下缓慢加入亚硝酸钠(70.94mg,1.03mmol,1.06eq)和水(2mL)的混合溶液，0℃下搅拌0.5小时。0℃下加入WX001-9(166.60mg,1.07mmol,1.1eq)，0℃下搅拌1.5小时。反应完毕后，将反应液用醋酸钠(3eq)的水溶液(3mL)淬灭，有大量固体生成，过滤得到化合物WX006-12。MS-ESI m/z:507.1[M+H] +。 Add WX006-11 (330mg, 970.01μmol, 1eq), glacial acetic acid (2mL), concentrated hydrochloric acid (12M, 249.78 μL, 3.09eq) into the pre-dried reaction flask, and slowly add sodium nitrite (70.94) at 0℃. mg, 1.03mmol, 1.06eq) and water (2mL) mixed solution, stirred at 0°C for 0.5 hours. WX001-9 (166.60mg, 1.07mmol, 1.1eq) was added at 0°C, and stirred at 0°C for 1.5 hours. After the reaction was completed, the reaction solution was quenched with an aqueous solution (3 mL) of sodium acetate (3eq), a large amount of solid was formed, and compound WX006-12 was obtained by filtration. MS-ESI m/z: 507.1 [M+H] + .
步骤10：化合物WX006的合成Step 10: Synthesis of compound WX006
在预先干燥的反应瓶中加入WX006-12(400mg,788.45μmol,1eq)和N,N-二甲基乙酰胺(5mL)，加入乙酸钾(85.12mg,867.29μmol,1.1eq)，置换氮气三次，置于115℃下搅拌2小时。反应完毕后，将反应液加入水(30mL)，有大量固体生成，过滤得到产物粗品。粗产品经高效液相色谱分离(色谱柱:Phenomenex luna C 18 250*50mm*10μm；流动相:[水(0.05％HCl)-乙腈]；乙腈％：45％-75％,10min)得到目标化合物WX006。 1H NMR(400MHz,DMSO-d 6)δppm 1.17–1.19(d,J＝6.8Hz,3H)1.66-1.83(m,4H)2.56–2.58(m,1H)2.68-2.79(m,1H)2.90(s,1H)7.78(s,2H)12.06(s,1H)13.27(s,1H)。MS-ESI m/z:461.0[M+H] +。 Add WX006-12 (400mg, 788.45μmol, 1eq) and N,N-dimethylacetamide (5mL) to the pre-dried reaction flask, add potassium acetate (85.12mg, 867.29μmol, 1.1eq), and replace nitrogen three times , Placed at 115 ℃ and stirred for 2 hours. After the reaction was completed, the reaction solution was added to water (30 mL), a large amount of solid was formed, and the crude product was obtained by filtration. The crude product was separated by high performance liquid chromatography (column: Phenomenex luna C 18 250*50mm*10μm; mobile phase: [water (0.05% HCl)-acetonitrile]; acetonitrile%: 45%-75%, 10min) to obtain the target compound WX006. 1 H NMR (400MHz, DMSO-d 6 ) δppm 1.17–1.19(d,J=6.8Hz,3H)1.66-1.83(m,4H)2.56–2.58(m,1H)2.68-2.79(m,1H)2.90 (s, 1H) 7.78 (s, 2H) 12.06 (s, 1H) 13.27 (s, 1H). MS-ESI m/z: 461.0 [M+H] + .
实施例8Example 8
Figure PCTCN2020093284-appb-000136
Figure PCTCN2020093284-appb-000136
合成路线：synthetic route:
Figure PCTCN2020093284-appb-000137
Figure PCTCN2020093284-appb-000137
步骤1：化合物WX008-2的合成Step 1: Synthesis of compound WX008-2
将WX008-1(5g,26.05mmol,1eq)，乙腈(50mL)，N,O-双三甲硅基乙酰胺(10.60g,52.09mmol,12.88mL,2eq)加到反应瓶中，氮气置换三次，而后在在80℃下反应2小时，随后加入碘化钠(3.90g,26.05mmol,1eq)，对甲氧基苄氯(4.89g,31.25mmol,4.26mL,1.2eq)，并在80℃下反应14小时，反应完后，过滤，滤液旋干得粗品，粗品经硅胶柱(洗脱剂：石油醚：乙酸乙酯＝0:1至3:1)纯化得到化合物WX008-2。MS m/z:309.8[M-H] +,311.8[M-H+2] +。 Add WX008-1 (5g, 26.05mmol, 1eq), acetonitrile (50mL), N,O-bistrimethylsilylacetamide (10.60g, 52.09mmol, 12.88mL, 2eq) into the reaction flask and replace with nitrogen three times. Then react at 80℃ for 2 hours, then add sodium iodide (3.90g, 26.05mmol, 1eq), p-methoxybenzyl chloride (4.89g, 31.25mmol, 4.26mL, 1.2eq), and at 80℃ The reaction was carried out for 14 hours. After the reaction was completed, it was filtered and the filtrate was spin-dried to obtain a crude product. The crude product was purified on a silica gel column (eluent: petroleum ether: ethyl acetate=0:1 to 3:1) to obtain compound WX008-2. MS m/z: 309.8 [MH] + , 311.8 [M-H+2] + .
步骤2：化合物WX008-3的合成Step 2: Synthesis of compound WX008-3
将WX008-2(3g,9.61mmol,1eq)，N,N-二甲基甲酰胺(20mL)加到反应器中，而后在0℃下加入钠氢(576.65mg,14.42mmol,60％纯度,1.5eq)，搅拌0.5小时，而后加入苄基氯甲醚(1.81g,11.53mmol,1.60mL,1.2eq)，并逐渐升温至20℃下反应11.5小时。反应完后，将反应液滴加到30mL冰水中，而后加入甲基叔丁基醚(50mL*3)萃取，合并有机相，有机相旋干得粗品。粗品经硅胶柱(洗脱剂：乙酸乙酯:石油醚＝3:1)纯化得化合物WX008-3。Add WX008-2 (3g, 9.61mmol, 1eq), N,N-dimethylformamide (20mL) to the reactor, and then add sodium hydrogen (576.65mg, 14.42mmol, 60% purity at 0°C, 1.5eq), stirred for 0.5 hours, then benzyl chloromethyl ether (1.81g, 11.53mmol, 1.60mL, 1.2eq) was added, and the temperature was gradually raised to 20°C for 11.5 hours of reaction. After the reaction, the reaction solution was added dropwise to 30 mL of ice water, and then methyl tert-butyl ether (50 mL*3) was added for extraction, the organic phases were combined, and the organic phase was spin-dried to obtain a crude product. The crude product was purified by silica gel column (eluent: ethyl acetate: petroleum ether = 3:1) to obtain compound WX008-3.
步骤3：化合物WX008-4的合成Step 3: Synthesis of compound WX008-4
将WX008-3(3.3g,7.63mmol,1eq)，乙腈(30mL)加到反应瓶中，而后降温至0℃，滴加硝酸铈铵(12.56g,22.90mmol,11.41mL,3eq)的水(10mL)溶液，并逐渐升温至20℃反应12小时。反应完成后，反应液旋干得粗品，粗品用乙酸乙酯50mL溶解，加饱和食盐水(50mL)洗涤，有机相旋干。粗品用甲基叔丁基醚(10mL)打浆纯化，得到化合物WX008-4。MS m/z:310.0[M-H] +,312.0[M-H+2] +。 Add WX008-3 (3.3g, 7.63mmol, 1eq), acetonitrile (30mL) to the reaction flask, then cool to 0°C, dropwise add ceric ammonium nitrate (12.56g, 22.90mmol, 11.41mL, 3eq) of water ( 10mL) solution, and gradually heated to 20°C to react for 12 hours. After the completion of the reaction, the reaction solution was spin-dried to obtain a crude product, which was dissolved in 50 mL of ethyl acetate, washed with saturated brine (50 mL), and the organic phase was spin-dried. The crude product was slurried and purified with methyl tert-butyl ether (10 mL) to obtain compound WX008-4. MS m/z: 310.0 [MH] + , 312.0 [M-H+2] + .
步骤4：化合物WX008-5的合成Step 4: Synthesis of compound WX008-5
将WX008-4(1g,2.56mmol,1eq)，WX004-9(2.37g,5.13mmol,2eq)，1,2-二氯乙烷(30mL)，醋酸铜(931.10mg,5.13mmol,2eq)，吡啶(405.49mg,5.13mmol,413.76μL,2eq)加到反应瓶中，而后在60℃下反应12小时。反应完成后，将反应液过滤，滤饼用15mL 1,2-二氯乙烷冲洗，而后滤液旋干得粗品。粗品经薄层色谱硅胶板(乙酸乙酯：石油醚＝3:1)纯化得到化合物WX008-5。MS m/z:728.1[M+H] +,730.0[M+H+2] +。 WX008-4 (1g, 2.56mmol, 1eq), WX004-9 (2.37g, 5.13mmol, 2eq), 1,2-dichloroethane (30mL), copper acetate (931.10mg, 5.13mmol, 2eq), Pyridine (405.49mg, 5.13mmol, 413.76μL, 2eq) was added to the reaction flask, and then reacted at 60°C for 12 hours. After the reaction was completed, the reaction solution was filtered, the filter cake was washed with 15 mL of 1,2-dichloroethane, and the filtrate was spin-dried to obtain a crude product. The crude product was purified by thin-layer chromatography on silica gel plate (ethyl acetate: petroleum ether = 3:1) to obtain compound WX008-5. MS m/z: 728.1 [M+H] + , 730.0 [M+H+2] + .
步骤5：化合物WX008-6的合成Step 5: Synthesis of compound WX008-6
将WX008-5(0.48g,658.07μmol,1eq)，乙腈(5mL)加到反应瓶中，降温至0℃，而后加入硝酸铈铵(1.08g,1.97mmol,983.92μL,3eq)的水(2.5mL)溶液，逐渐升温至20℃反应12小时。将反应液旋干得粗品，粗品经薄层色谱硅胶板(乙酸乙酯：石油醚＝1:1)纯化得到化合物WX008-6。MS m/z:608.0[M+H] +,610.0[M+H+2] +。 Add WX008-5 (0.48g, 658.07μmol, 1eq), acetonitrile (5mL) to the reaction flask, cool to 0℃, and then add ceric ammonium nitrate (1.08g, 1.97mmol, 983.92μL, 3eq) in water (2.5 mL) The solution was gradually heated to 20°C and reacted for 12 hours. The reaction solution was spin-dried to obtain a crude product, which was purified by thin-layer chromatography on a silica gel plate (ethyl acetate: petroleum ether = 1:1) to obtain compound WX008-6. MS m/z: 608.0 [M+H] + , 610.0 [M+H+2] + .
步骤6：化合物WX008-7的合成Step 6: Synthesis of compound WX008-7
在将WX008-6(0.2g,328.27μmol,1eq)，二氯甲烷(5mL)加到反应瓶中，而后降温至0℃，滴加三溴化硼(246.72mg,984.81μmol,94.89μL,3eq)，逐渐升温至20℃反应0.5小时。将反应液缓慢滴加到饱和碳酸氢钠溶液中淬灭，而后加入乙酸乙酯(50mL*2)萃取，有机相旋干得到化合物WX008-7。 1H NMR(400MHz，氘代甲醇)δ7.78(s,2H)，7.39(s,1H),3.14-3.17(m,1H),1.29(s,3H),1.31(s,3H)。MS m/z:487.9[M+H] +, 489.9[M+H+2] +。 After adding WX008-6 (0.2g, 328.27μmol, 1eq), dichloromethane (5mL) to the reaction flask, then cooling to 0℃, adding boron tribromide (246.72mg, 984.81μmol, 94.89μL, 3eq) ), gradually increase the temperature to 20°C and react for 0.5 hours. The reaction solution was slowly added dropwise to saturated sodium bicarbonate solution for quenching, and then ethyl acetate (50 mL*2) was added for extraction, and the organic phase was spin-dried to obtain compound WX008-7. 1 H NMR (400MHz, deuterated methanol) δ 7.78 (s, 2H), 7.39 (s, 1H), 3.14 to 3.17 (m, 1H), 1.29 (s, 3H), 1.31 (s, 3H). MS m/z: 487.9 [M+H] + , 489.9 [M+H+2] + .
步骤7：化合物WX008的合成Step 7: Synthesis of compound WX008
将WX008-7(0.08g,163.56μmol,1eq)，甲醇(5mL)，甲醇钠(26.51mg,490.69μmol,3eq)加到反应瓶中，在60℃下反应12小时。将反应液旋干得粗品，粗品经高效液相色谱分离(色谱柱:Phenomenex Luna C18 150*30mm*5μm；流动相:[水(0.04％HCl)-乙腈]；乙腈％:35％-60％,10min)纯化得到目标化合物WX008。 1H NMR(400MHz,DMSO-d 6)δ:ppm 1.21(d,J＝6.88Hz,6H),3.01-3.11(m,1H),3.86(s,3H),7.45(s,1H),7.87(s,2H),12.23(s,1H),12.52(s,1H)。MS m/z:440.1[M+H] +,442.1[M+H+2] +。 WX008-7 (0.08g, 163.56μmol, 1eq), methanol (5mL), and sodium methoxide (26.51mg, 490.69μmol, 3eq) were added to the reaction flask and reacted at 60°C for 12 hours. The reaction solution was spin-dried to obtain a crude product, which was separated by high performance liquid chromatography (column: Phenomenex Luna C18 150*30mm*5μm; mobile phase: [water (0.04% HCl)-acetonitrile]; acetonitrile%: 35%-60% , 10min) purification to obtain the target compound WX008. 1 H NMR (400MHz, DMSO-d 6 ) δ: ppm 1.21 (d, J = 6.88 Hz, 6H), 3.01-3.11 (m, 1H), 3.86 (s, 3H), 7.45 (s, 1H), 7.87 (s, 2H), 12.23 (s, 1H), 12.52 (s, 1H). MS m/z: 440.1 [M+H] + , 442.1 [M+H+2] + .
实施例9Example 9
Figure PCTCN2020093284-appb-000138
Figure PCTCN2020093284-appb-000138
合成路线：synthetic route:
Figure PCTCN2020093284-appb-000139
Figure PCTCN2020093284-appb-000139
步骤1：化合物WX009的合成Step 1: Synthesis of compound WX009
在预先干燥的反应瓶中加入WX006(790mg,1.71mmol,1eq)，超临界色谱分离(色谱柱：(s,s)WHELK-O1(250mm*30mm,5μm)；流动相:[中性-甲醇]；甲醇％:55％-55％,10分钟)得到粗产品，粗产品再次经超临界色谱分离(色谱柱:(s,s)WHELK-O1(250mm*30mm,5μm)；流动相:[0.1％氨水甲醇]；甲醇％:50％-50％,15min)得到WX009。 1H NMR(400MHz,DMSO-d 6)δ:ppm 1.17–1.19(d,J＝7.00Hz,3H),1.67-1.82(m,4H),2.58(s,1H),2.69-2.78(m,1H),2.90(s,1H),7.77(s,2H),12.04(s,1H)。MS m/z:461.0[M+H] +。保留时间2.36分钟(仪器:Thar analytical SFC；色谱柱:S,S_whelk_01 3.5μm,0.46cm id x 5cm L；流动相:流动相：A:食品级超临界二氧化碳；B:甲醇(0.05％异丙胺，体积比)；梯度：B含量在4分钟内从5％升高到50％；流速:4.0mL/min；柱温：35℃；检测波长：220nm；系统背压:100bar)。 Add WX006 (790mg, 1.71mmol, 1eq) to the pre-dried reaction flask, supercritical chromatography (column: (s, s) WHELK-O1 (250mm*30mm, 5μm)); mobile phase: [neutral-methanol ]; Methanol%: 55%-55%, 10 minutes) to obtain the crude product, the crude product was separated again by supercritical chromatography (column: (s, s) WHELK-O1 (250mm*30mm, 5μm); mobile phase: [ 0.1% ammonia methanol]; methanol%: 50%-50%, 15min) to obtain WX009. 1 H NMR (400MHz, DMSO-d 6 ) δ: ppm 1.17–1.19 (d, J = 7.00 Hz, 3H), 1.67-1.82 (m, 4H), 2.58 (s, 1H), 2.69-2.78 (m, 1H), 2.90 (s, 1H), 7.77 (s, 2H), 12.04 (s, 1H). MS m/z: 461.0 [M+H] + . Retention time 2.36 minutes (Instrument: Thar analytical SFC; Column: S, S_whelk_01 3.5μm, 0.46cm id x 5cm L; Mobile phase: Mobile phase: A: food grade supercritical carbon dioxide; B: methanol (0.05% isopropylamine, Volume ratio); Gradient: B content increased from 5% to 50% in 4 minutes; Flow rate: 4.0 mL/min; Column temperature: 35°C; Detection wavelength: 220 nm; System back pressure: 100 bar).
实施例11Example 11
Figure PCTCN2020093284-appb-000140
Figure PCTCN2020093284-appb-000140
合成路线：synthetic route:
Figure PCTCN2020093284-appb-000141
Figure PCTCN2020093284-appb-000141
步骤1：化合物WX011-2的合成Step 1: Synthesis of compound WX011-2
在预先干燥的三口瓶中加入WX011-1(15g,151.32mmol,1eq)和四氢呋喃(200mL)，置换氮气三次，干冰乙醇降温至-65℃时，缓慢加入正丁基锂(2M,83.22mL,1.1eq)，保持-65℃，搅拌30分钟，随后在-65℃下。加入碘甲烷(22.55g,158.88mmol,9.89mL,1.05eq)，加料完成后撤掉冰浴，缓慢升至室温，并室温(18-20℃)搅拌2小时。反应完成后，向反应中加入100mL水和乙酸乙酯(100mL*3)萃取，合并有机相，并用饱和食盐水(100mL*2)洗涤，分液后，有机相用无水硫酸钠干燥，过滤除去干燥剂后，减压旋干得到了WX011-2。 1HNMR(400MHz,氘代氯仿)δ3.24-3.27(t,J＝4.8Hz,2H),2.92(s,3H),2.34-2.37(t,J＝6.4Hz,2H),1.76-1.80(m,4H)。 Add WX011-1 (15g, 151.32mmol, 1eq) and tetrahydrofuran (200mL) to a pre-dried three-necked flask, replace nitrogen for three times, and when the dry ice ethanol is cooled to -65℃, slowly add n-butyllithium (2M, 83.22mL, 1.1eq), keep at -65°C, stir for 30 minutes, and then at -65°C. Add methyl iodide (22.55g, 158.88mmol, 9.89mL, 1.05eq), remove the ice bath after the addition is complete, slowly warm to room temperature, and stir at room temperature (18-20°C) for 2 hours. After the reaction is complete, add 100 mL of water and ethyl acetate (100 mL*3) to the reaction for extraction, combine the organic phases, and wash with saturated brine (100 mL*2). After separation, the organic phase is dried with anhydrous sodium sulfate and filtered After removing the desiccant, it was spin-dried under reduced pressure to obtain WX011-2. 1 HNMR (400MHz, deuterated chloroform) δ3.24-3.27(t,J=4.8Hz,2H), 2.92(s,3H),2.34-2.37(t,J=6.4Hz,2H), 1.76-1.80( m,4H).
步骤2：化合物WX011-3的合成Step 2: Synthesis of compound WX011-3
在预先干燥的单口瓶中加入WX011-2(14.5g,128.14mmol,1eq)和甲苯(200mL)，加入劳森试剂(51.83g,128.14mmol,1eq)，升温至80℃搅拌2小时。反应完成后，向反应液中加入200mL水，加乙酸乙酯(200mL*3)萃取，合并有机相，用200mL饱和食盐水洗涤，分液后，有机相用无水硫酸钠干燥，过滤，滤液减压旋干得到粗品。粗品用自动过柱机纯化，梯度淋洗：石油醚：乙酸乙酯＝10:1至5:1至1:1，得到WX011-3。 1H NMR(400MHz,氘代氯仿)δ3.83-3.88(t,J＝7.2Hz,2H),3.46(s,3H),2.98-3.01(t,J＝6Hz,2H),1.88-1.91(m,2H),1.71-1.74(m,2H)。 WX011-2 (14.5g, 128.14mmol, 1eq) and toluene (200mL) were added to the pre-dried single-necked flask, Lawson reagent (51.83g, 128.14mmol, 1eq) was added, and the temperature was raised to 80°C and stirred for 2 hours. After the reaction is complete, add 200 mL of water to the reaction solution, add ethyl acetate (200 mL*3) for extraction, combine the organic phases, wash with 200 mL of saturated brine, separate the organic phase, dry the organic phase with anhydrous sodium sulfate, filter, and filter the filtrate The crude product was obtained by rotary drying under reduced pressure. The crude product is purified by an automatic column machine, and gradient elution: petroleum ether: ethyl acetate = 10:1 to 5:1 to 1:1 to obtain WX011-3. 1 H NMR (400MHz, deuterated chloroform) δ3.83-3.88 (t, J = 7.2Hz, 2H), 3.46 (s, 3H), 2.98-3.01 (t, J = 6Hz, 2H), 1.88-1.91 ( m, 2H), 1.71-1.74 (m, 2H).
步骤3：化合物WX011-4的合成Step 3: Synthesis of compound WX011-4
在预先干燥的单口瓶中加入WX011-3(15g,116.08mmol,1eq)和乙醇(200mL)，加入碘甲烷(24.71g,174.12mmol,10.84mL,1.5eq)，加料完成后，将反应液升温至80℃搅拌1小时。反应完成后，将反应液直接减压旋干，向旋干剩余物中加入100mL四氢呋喃，室温搅拌10分钟，有固体析出，过滤，滤饼用20 mL四氢呋喃洗涤，将滤饼减压旋干得到WX011-4。 1H NMR(400MHz,氘代二甲基亚砜)δ3.75-3.78(t,J＝5.6Hz,2H),3.41(s,3H),3.03-3.06(m，2H),2.77(s,3H),1.76-1.85(m,4H)。 Add WX011-3 (15g, 116.08mmol, 1eq) and ethanol (200mL) to a pre-dried single-neck bottle, add methyl iodide (24.71g, 174.12mmol, 10.84mL, 1.5eq), after the addition is complete, the reaction solution is heated Stir at 80°C for 1 hour. After the completion of the reaction, the reaction solution was directly spin-dried under reduced pressure, 100mL of tetrahydrofuran was added to the spin-dried residue, stirred at room temperature for 10 minutes, a solid precipitated out, filtered, the filter cake was washed with 20 mL of tetrahydrofuran, the filter cake was spin-dried under reduced pressure to obtain WX011-4. 1 H NMR (400MHz, deuterated dimethyl sulfoxide) δ3.75-3.78 (t, J = 5.6Hz, 2H), 3.41 (s, 3H), 3.03-3.06 (m, 2H), 2.77 (s, 3H), 1.76-1.85 (m, 4H).
步骤4：化合物WX011-6的合成Step 4: Synthesis of compound WX011-6
在预先干燥的单口瓶中加入WX011-4(10g,68.84mmol,1eq,HI)和四氢呋喃(100mL)，加入叔丁醇钾(11.59g,103.26mmol,1.5eq)，室温(25℃)搅拌10分钟，过滤，滤液减压旋干，加入甲苯(10mL)，过滤，另外准备一个预先干燥的三口瓶，加入WX007-1(6.23g,41.30mmol,0.6eq)和甲苯(80mL)，氮气置换三次，降温至0℃，滴入刚刚过滤的甲苯溶液，控制温度保持0℃，滴加完成后升温至25℃搅拌40分钟。反应完成后，反应液加入100mL水，加入乙酸乙酯(100mL*4)萃取，合并有机相，用饱和食盐水(200mL)洗涤，分液后，有机相用无水硫酸钠干燥，过滤，滤液减压旋干，粗品用自动过柱机纯化，梯度淋洗：石油醚：乙酸乙酯＝10％至20％至30％，得到WX011-6。 1H NMR(400MHz,氘代氯仿)δ3.25-3.30(m,5H),2.73-2.76(t，J＝6.4Hz,2H),1.95-2.01(m,2H)。 Add WX011-4 (10g, 68.84mmol, 1eq, HI) and tetrahydrofuran (100mL) to a pre-dried single-mouth flask, add potassium tert-butoxide (11.59g, 103.26mmol, 1.5eq), and stir at room temperature (25°C) for 10 After 5 minutes, filter, the filtrate is spin-dried under reduced pressure, add toluene (10mL), filter, and prepare a pre-dried three-neck flask, add WX007-1 (6.23g, 41.30mmol, 0.6eq) and toluene (80mL), replace with nitrogen three times , Lower the temperature to 0°C, drop in the toluene solution just filtered, control the temperature to maintain 0°C, after the dropwise addition is completed, raise the temperature to 25°C and stir for 40 minutes. After the reaction is complete, add 100 mL of water to the reaction solution, add ethyl acetate (100 mL*4) for extraction, combine the organic phases, wash with saturated brine (200 mL), separate the organic phase, dry the organic phase with anhydrous sodium sulfate, filter, and filter the filtrate The product was spin-dried under reduced pressure, and the crude product was purified by an automatic column machine. Gradient elution: petroleum ether: ethyl acetate = 10% to 20% to 30% to obtain WX011-6. 1 H NMR (400MHz, deuterated chloroform) δ 3.25-3.30 (m, 5H), 2.73-2.76 (t, J=6.4 Hz, 2H), 1.95-2.01 (m, 2H).
步骤5：化合物WX011-8的合成Step 5: Synthesis of compound WX011-8
在预先干燥的反应瓶中加入WX011-6(0.6g,2.75mmol,1eq)和WX001-4(734.65mg,4.13mmol,1.5eq)，加入二甲基亚砜(10mL)和碳酸钾(1.52g,11.00mmol,4eq)，鼓入氮气，加入碘化亚铜(314.39mg,1.65mmol,0.6eq)，将反应液升温至90℃，搅拌16小时。反应完成后，向反应液中加入10mL水，加入乙酸乙酯萃取(10mL*3)，合并有机相，用饱和食盐水(20mL)洗涤，分液后，有机相用无水硫酸钠干燥，过滤，滤液减压旋干，粗品用自动过柱机纯化，梯度淋洗：石油醚：乙酸乙酯＝20％，得到WX011-8。 1H NMR(400MHz,氘代二甲基亚砜)δ6.69(s,2H),5.64(s,2H),3.33-3.02(m,5H),2.65-2.61(m,2H),1.96-1.87(m,2H)。 Add WX011-6 (0.6g, 2.75mmol, 1eq) and WX001-4 (734.65mg, 4.13mmol, 1.5eq) into the pre-dried reaction flask, add dimethyl sulfoxide (10mL) and potassium carbonate (1.52g) , 11.00mmol, 4eq), bubbling with nitrogen, adding cuprous iodide (314.39mg, 1.65mmol, 0.6eq), heating the reaction solution to 90°C and stirring for 16 hours. After the reaction is complete, add 10 mL of water to the reaction solution, add ethyl acetate for extraction (10 mL*3), combine the organic phases, wash with saturated brine (20 mL), separate the organic phases, dry the organic phase with anhydrous sodium sulfate, and filter The filtrate was spin-dried under reduced pressure, and the crude product was purified with an automatic column machine. Gradient elution: petroleum ether: ethyl acetate = 20% to obtain WX011-8. 1 H NMR (400MHz, deuterated dimethyl sulfoxide) δ 6.69 (s, 2H), 5.64 (s, 2H), 3.33-3.02 (m, 5H), 2.65-2.61 (m, 2H), 1.96 1.87 (m, 2H).
WX011-8结构鉴定：WX011-8 structure identification:
Figure PCTCN2020093284-appb-000142
Figure PCTCN2020093284-appb-000142
将WX011-8(0.05g,139.03μmol,1eq)和甲醇(10mL)加入到50mL单口瓶中，加入湿钯碳(0.01g,139.03μmol,10％纯度,1eq)，置换氢气三次，然后在氢气球(15psi)的压力下20℃反应2小时。反应完成后，反应液直接用硅藻土过滤，滤液减压旋干得到粗品，粗品用高效液相色谱柱(条件：色谱柱:Phenomenex Luna C18 150*30mm*5μm；流动相:[水(0.04％盐酸)-乙腈]；乙腈％:20％-45％,10分钟)纯化，冻干，得到WX011-8A。NOE(400MHz,氘代二甲基亚砜)显示N-甲基哌啶环上(2.74-2.77)位置处的氢与吡嗪环上(8.62)位置的氢有相关性，证明WX011-8结构正确。 1HNMR(400MHz,氘代二甲基亚砜)δ1.93-1.96(m,2H)，2.74-2.77(m,2H)，3.60-3.65(m,5H)，6.74(s,2H)，8.62(s,1H)。 Add WX011-8 (0.05g, 139.03μmol, 1eq) and methanol (10mL) into a 50mL single-neck flask, add wet palladium on carbon (0.01g, 139.03μmol, 10% purity, 1eq), replace the hydrogen three times, and then The reaction was carried out at 20°C for 2 hours under the pressure of the ball (15 psi). After the completion of the reaction, the reaction solution was directly filtered with diatomaceous earth, and the filtrate was spin-dried under reduced pressure to obtain the crude product. The crude product was used on a high performance liquid chromatography column (condition: column: Phenomenex Luna C18 150*30mm*5μm; mobile phase: [水(0.04) % Hydrochloric acid)-acetonitrile]; acetonitrile%: 20%-45%, 10 minutes) purified and lyophilized to obtain WX011-8A. NOE (400MHz, deuterated dimethyl sulfoxide) shows that the hydrogen at the (2.74-2.77) position on the N-methylpiperidine ring is related to the hydrogen at the (8.62) position on the pyrazine ring, proving the structure of WX011-8 correct. 1 HNMR (400MHz, deuterated dimethyl sulfoxide) δ1.93-1.96 (m, 2H), 2.74-2.77 (m, 2H), 3.60-3.65 (m, 5H), 6.74 (s, 2H), 8.62 (s,1H).
步骤6：化合物WX011-9的合成Step 6: Synthesis of compound WX011-9
在预先干燥的反应瓶中加入WX011-8(300.00mg,834.17μmol,1eq)，加入冰乙酸(5mL)和乙酸钠(684.30mg,8.34mmol,10eq)，将反应液升温至120℃，搅拌12小时。反应完成后，将反应液中的冰乙酸减压旋掉，旋蒸剩余物中加入10mL水，加入碳酸氢钠调节pH＝7后，加入乙酸乙酯(10mL*4)萃取，合并有机相，用饱和食盐水(10mL)洗涤，分液后，有机相用无水硫酸钠干燥，过滤，滤液减压旋干得到WX011-9。 1H NMR(400MHz,氘代二甲基亚砜)δ7.78(s,2H),3.17(s,3H),2.34-2.36(m,4H),2.07(s,3H),1.80-1.83(m,2H)。 Add WX011-8 (300.00mg, 834.17μmol, 1eq) to the pre-dried reaction flask, add glacial acetic acid (5mL) and sodium acetate (684.30mg, 8.34mmol, 10eq), heat the reaction solution to 120°C and stir for 12 hour. After the completion of the reaction, the glacial acetic acid in the reaction solution was spun off under reduced pressure, 10 mL of water was added to the rotary evaporation residue, sodium bicarbonate was added to adjust the pH=7, ethyl acetate (10 mL*4) was added for extraction, and the organic phases were combined. It was washed with saturated brine (10 mL) and separated, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried under reduced pressure to obtain WX011-9. 1 H NMR (400MHz, deuterated dimethyl sulfoxide) δ 7.78 (s, 2H), 3.17 (s, 3H), 2.34-2.36 (m, 4H), 2.07 (s, 3H), 1.80-1.83 ( m,2H).
步骤7：化合物WX011-10的合成Step 7: Synthesis of compound WX011-10
在预先干燥的反应瓶中加入WX011-9(250.00mg,652.35μmol,1eq)，加入乙醇(2mL)和2M盐酸(2mL)，反应液升温至80℃搅拌12小时。反应完成后，向反应液中加入饱和碳酸氢钠水溶液调节pH＝7，加入乙酸乙酯(10mL*3)萃取，合并有机相，减压旋干，粗品用1mL甲醇溶解后，过滤，滤液通过高效液相色谱(色谱柱:Phenomenex luna C18 250*50mm*10μm；流动相:[水(0.05％HCl)-乙腈]；乙腈％:20％-50％,10分钟)分离得到目标化合物WX011-10。 1HNMR(400MHz,氘代二甲基亚砜)δ11.56(s,1H),6.78(s,2H),3.16-3.20(m,5H),2.35-2.38(m,2H),1.78-1.81(m,2H)。 WX011-9 (250.00mg, 652.35μmol, 1eq) was added to the pre-dried reaction flask, ethanol (2mL) and 2M hydrochloric acid (2mL) were added, the reaction solution was heated to 80°C and stirred for 12 hours. After the reaction is complete, add saturated sodium bicarbonate aqueous solution to the reaction solution to adjust pH=7, add ethyl acetate (10mL*3) for extraction, combine the organic phases, spin dry under reduced pressure, the crude product is dissolved in 1mL methanol, filtered, and the filtrate is passed through High performance liquid chromatography (column: Phenomenex luna C18 250*50mm*10μm; mobile phase: [water (0.05% HCl)-acetonitrile]; acetonitrile%: 20%-50%, 10 minutes) to obtain the target compound WX011-10 . 1 HNMR (400MHz, deuterated dimethyl sulfoxide) δ 11.56 (s, 1H), 6.78 (s, 2H), 3.16-3.20 (m, 5H), 2.35-2.38 (m, 2H), 1.78-1.81 (m, 2H).
步骤8：化合物WX011-12的合成Step 8: Synthesis of compound WX011-12
在预先干燥的反应瓶中加入WX011-10(0.2g,586.18μmol,1eq)加入到预先干燥的投库瓶中，加入冰乙酸(2mL)和盐酸(177.91mg,1.81mmol,174.42μL,37％纯度,3.08eq)，降温至5℃，将亚硝酸钠(44.49mg,644.80μmol,1.1eq)溶于水(1mL)中，滴入反应体系，然后在5℃下搅拌0.5小时，加入WX001-9(100.68mg,644.80μmol,1.1eq)，在5℃下搅拌0.5小时。反应完成后，向反应液中加入饱和的醋酸钠水溶液(5mL)，有固体析出，过滤，滤饼用2mL水洗涤，将滤饼减压旋干得到WX011-12。 1H NMR(400MHz,氘代二甲基亚砜)δ12.10(s,1H),11.54(s,1H),10.81(s,1H),7.96(s,2H),4.22-4.17(m,2H),3.19(m,5H),2.49-2.38(m,2H),1.82-1.81(m,2H),1.28-1.24(t,J＝7.2Hz,3H)。 Add WX011-10 (0.2g, 586.18μmol, 1eq) to the pre-dried reaction flask, add glacial acetic acid (2mL) and hydrochloric acid (177.91mg, 1.81mmol, 174.42μL, 37% Purity, 3.08eq), cool to 5℃, dissolve sodium nitrite (44.49mg, 644.80μmol, 1.1eq) in water (1mL), drop into the reaction system, then stir at 5℃ for 0.5 hours, add WX001- 9 (100.68mg, 644.80μmol, 1.1eq), stirred at 5°C for 0.5 hours. After the reaction was completed, a saturated aqueous sodium acetate solution (5 mL) was added to the reaction solution, and solids were precipitated out, filtered, the filter cake was washed with 2 mL of water, and the filter cake was spin-dried under reduced pressure to obtain WX011-12. 1 H NMR (400MHz, deuterated dimethyl sulfoxide) δ 12.10 (s, 1H), 11.54 (s, 1H), 10.81 (s, 1H), 7.96 (s, 2H), 4.22-4.17 (m, 2H), 3.19 (m, 5H), 2.49-2.38 (m, 2H), 1.82-1.81 (m, 2H), 1.28-1.24 (t, J=7.2 Hz, 3H).
步骤8：化合物WX011的合成Step 8: Synthesis of compound WX011
在预先干燥的反应瓶中加入WX011-12(200.00mg,402.15μmol,1eq)，加入N,N-二甲基乙酰胺(2mL)，将底物溶解，加入乙酸钾(39.47mg,402.15μmol,1eq)，升温至115℃搅拌1小时。反应完成后，将反应液直接过滤，滤液通过高效液相色谱(色谱柱:Welch Xtimate C18 150*25mm*5μm；流动相:[水(0.04％HCl)-乙腈]；乙腈％:40％-70％,10分钟)分离得到目标化合物WX011。 1H NMR(400MHz,氘代二甲基亚砜)δ13.27(s,1H),11.57(s,1H),7.78(s,2H),3.27-3.22(m,5H),2.41-2.36(t,J＝6Hz,2H),1.84-1.81(m,2H)。MS-ESI m/z:462.0[M+H] +,464.0[M+H+2] +。 Add WX011-12 (200.00mg, 402.15μmol, 1eq) into the pre-dried reaction flask, add N,N-dimethylacetamide (2mL), dissolve the substrate, and add potassium acetate (39.47mg, 402.15μmol, 1eq), heated to 115°C and stirred for 1 hour. After the completion of the reaction, the reaction solution was directly filtered, and the filtrate was passed through high performance liquid chromatography (column: Welch Xtimate C18 150*25mm*5μm; mobile phase: [water (0.04% HCl)-acetonitrile]; acetonitrile%: 40%-70 %, 10 minutes) to obtain the target compound WX011. 1 H NMR (400MHz, deuterated dimethyl sulfoxide) δ 13.27 (s, 1H), 11.57 (s, 1H), 7.78 (s, 2H), 3.27-3.22 (m, 5H), 2.41-2.36 ( t, J = 6 Hz, 2H), 1.84-1.81 (m, 2H). MS-ESI m/z: 462.0 [M+H] + , 464.0 [M+H+2] + .
实施例12Example 12
Figure PCTCN2020093284-appb-000143
Figure PCTCN2020093284-appb-000143
合成路线：synthetic route:
Figure PCTCN2020093284-appb-000144
Figure PCTCN2020093284-appb-000144
步骤1：化合物WX012-4的合成Step 1: Synthesis of compound WX012-4
在预先干燥的反应瓶中加入WX008-3(4.66g,10.78mmol,1eq)，之后用乙腈(93mL)溶解，然后加入三叔丁基-1-乙氧基乙烯(7.79g,21.56mmol,7.28mL,2eq)，氮气抽换三次，加入双三苯基磷二氯化钯(1.14g,1.62mmol,0.15eq)，碘化亚铜(205.31mg,1.08mmol,0.1eq)，氮气再次抽换三次，缓慢的升高至90℃搅拌反应15小时。反应完成后，WX012-4的反应液直接用于下一步反应。Add WX008-3 (4.66g, 10.78mmol, 1eq) to the pre-dried reaction flask, then dissolve it with acetonitrile (93mL), then add tri-tert-butyl-1-ethoxyethylene (7.79g, 21.56mmol, 7.28) mL, 2eq), nitrogen pumping three times, adding bistriphenylphosphonium dichloride (1.14g, 1.62mmol, 0.15eq), cuprous iodide (205.31mg, 1.08mmol, 0.1eq), nitrogen pumping again Three times, slowly raising to 90°C and stirring for 15 hours. After the reaction is completed, the reaction solution of WX012-4 is directly used in the next reaction.
步骤2：化合物WX012-5的合成Step 2: Synthesis of compound WX012-5
将盐酸(6M,30mL,16.68eq)加入到WX012-4(4.57g,10.79mmol,1eq)的乙腈(93mL)溶液中，室温(25℃)搅拌反应30分钟。反应完成后，加入饱和的氟化钾溶液200mL，之后再加乙酸乙酯(100mL)稀释，分液收集有机相，水相用乙酸乙酯(100mL*2)萃取，合并有机相，并用饱和食盐水(100mL*2)洗涤，无水硫酸钠干燥，过滤除去干燥剂后，减压除去溶剂得到粗产品。粗产品通过自动过柱机分离(梯度淋洗：石油醚:乙酸乙酯＝1:0至3:7)，纯化得到WX012-5。 1H NMR(400MHz,氘代氯仿)δ7.33-7.29(d,J＝8.8Hz,2H),7.26-7.22(m,2H),7.19-7.15(m,3H),6.84-6.81(d,J＝8.8Hz,2H),5.39(s,2H),5.03(s,2H),4.61(s,2H),3.74(s,3H),2.43(s,3H)。MS-ESI m/z:396.1[M+H] +。 Hydrochloric acid (6M, 30 mL, 16.68 eq) was added to a solution of WX012-4 (4.57 g, 10.79 mmol, 1 eq) in acetonitrile (93 mL), and the reaction was stirred at room temperature (25° C.) for 30 minutes. After the reaction is complete, add 200 mL of saturated potassium fluoride solution, then add ethyl acetate (100 mL) to dilute, separate and collect the organic phase, extract the aqueous phase with ethyl acetate (100 mL*2), combine the organic phases, and use saturated salt Wash with water (100 mL*2), dry with anhydrous sodium sulfate, filter to remove the desiccant, and remove the solvent under reduced pressure to obtain a crude product. The crude product was separated by an automatic column passing machine (gradient elution: petroleum ether: ethyl acetate=1:0 to 3:7), and purified to obtain WX012-5. 1 H NMR (400MHz, deuterated chloroform) δ7.33-7.29 (d, J = 8.8Hz, 2H), 7.26-7.22 (m, 2H), 7.19-7.15 (m, 3H), 6.84-6.81 (d, J=8.8 Hz, 2H), 5.39 (s, 2H), 5.03 (s, 2H), 4.61 (s, 2H), 3.74 (s, 3H), 2.43 (s, 3H). MS-ESI m/z: 396.1 [M+H] + .
步骤3：化合物WX012-6的合成Step 3: Synthesis of compound WX012-6
在预先干燥的反应瓶中加入WX012-5(4g,10.12mmol,1eq)，之后用二氯甲烷(80mL)溶解，将反应体系降至0℃，然后加入二乙胺基三氟化硫(8.15g,50.58mmol,6.68mL,5eq)，缓慢的升高至室温(25℃)搅拌反 应2小时，将反应体系降至0℃，补加二乙胺基三氟化硫(8.15g,50.58mmol,6.68mL,5eq)，缓慢的升高至室温(25℃)搅拌反应17小时。反应完成后，将反应液缓慢的加入到室温水(200mL)中，之后用饱和的碳酸氢钠溶液中和反应液pH至7左右，加入二氯甲烷(200mL)稀释，分液收集有机相，水相用二氯甲烷(200mL*2)萃取，合并有机相，并用饱和食盐水(200mL*2)洗涤，无水硫酸钠干燥，过滤除去干燥剂后，减压除去溶剂得到粗产品WX012-6。Add WX012-5 (4g, 10.12mmol, 1eq) into the pre-dried reaction flask, then dissolve it with dichloromethane (80mL), reduce the reaction system to 0℃, and then add diethylaminosulfur trifluoride (8.15 g, 50.58mmol, 6.68mL, 5eq), slowly increase to room temperature (25°C) and stir for 2 hours, lower the reaction system to 0°C, add diethylaminosulfur trifluoride (8.15g, 50.58mmol , 6.68mL, 5eq), slowly raised to room temperature (25°C) and stirred for 17 hours. After the reaction is completed, slowly add the reaction solution to room temperature water (200 mL), then neutralize the pH of the reaction solution to about 7 with saturated sodium bicarbonate solution, add dichloromethane (200 mL) to dilute, and separate and collect the organic phase. The aqueous phase was extracted with dichloromethane (200mL*2), the organic phases were combined, washed with saturated brine (200mL*2), dried over anhydrous sodium sulfate, filtered to remove the desiccant, and the solvent was removed under reduced pressure to obtain the crude product WX012-6 .
步骤4：化合物WX012-7的合成Step 4: Synthesis of compound WX012-7
在预先干燥的反应瓶中加入WX012-6(3.46g,8.29mmol,1eq)，之后用乙腈(73mL)溶解，将反应体系将至0℃，然后加入硝酸铈铵(13.63g,24.87mmol,12.39mL,3eq)的水(31mL)溶液，缓慢的升高至室温(25℃)搅拌反应2小时。加水(100mL)和乙酸乙酯(100mL)稀释，分液收集有机相，水相用乙酸乙酯(100mL*2)萃取，合并有机相，并用饱和食盐水(100mL*2)洗涤无水硫酸钠干燥，过滤除去干燥剂后，减压除去溶剂得到粗产品。粗产品通过自动过柱机分离(梯度淋洗：石油醚：乙酸乙酯＝1:0至16:84)，纯化得到WX012-7。 1H NMR(400MHz,氘代二甲基亚砜)δ12.92(s,1H),7.41-7.18(m,5H),5.29(s,2H),4.62(s,2H),1.98–1.84(t,J＝19.2Hz,3H)。 Add WX012-6 (3.46g, 8.29mmol, 1eq) to the pre-dried reaction flask, then dissolve it with acetonitrile (73mL), bring the reaction system to 0°C, and then add ceric ammonium nitrate (13.63g, 24.87mmol, 12.39) mL, 3eq) in water (31 mL), slowly rise to room temperature (25°C) and stir for 2 hours. Dilute with water (100mL) and ethyl acetate (100mL), separate and collect the organic phase, extract the aqueous phase with ethyl acetate (100mL*2), combine the organic phases, and wash the anhydrous sodium sulfate with saturated brine (100mL*2) After drying and filtering to remove the desiccant, the solvent was removed under reduced pressure to obtain a crude product. The crude product was separated by automatic column passing machine (gradient elution: petroleum ether: ethyl acetate=1:0 to 16:84), and purified to obtain WX012-7. 1 H NMR (400MHz, deuterated dimethyl sulfoxide) δ 12.92 (s, 1H), 7.41-7.18 (m, 5H), 5.29 (s, 2H), 4.62 (s, 2H), 1.98-1.84 ( t, J = 19.2 Hz, 3H).
步骤5：化合物WX012-8的合成Step 5: Synthesis of compound WX012-8
在预先干燥的反应瓶中加入WX012-7(328.46mg,1.10mmol,1.05eq)，WX005-6(0.5g,1.05mmol,1eq)，之后用二氯乙烷(25mL)溶解，然后加入醋酸铜(286.71mg,1.58mmol,1.5eq)，吡啶(208.10mg,2.63mmol,212.35μL,2.5eq)，加料完全后，于40℃在氧气15psi条件下搅拌反应12小时。反应完成后，加水(50mL)和二氯甲烷(50mL)稀释，分液收集有机相，水相用二氯甲烷(50mL*2)萃取，合并有机相，并用饱和食盐水(50mL*2)洗涤，无水硫酸钠干燥，过滤除去干燥剂后，减压除去溶剂得到粗产品。粗产品通过自动过柱机分离(梯度淋洗：石油醚:乙酸乙酯＝1:0至20:80)，纯化得到WX012-8。 1H NMR(400MHz,氘代二甲基亚砜)δ7.82(s,2H),7.36-7.34(m,2H),7.32-7.27(m,1H),7.06-7.00(m,3H),6.83-6.77(m,3H),5.41(s,2H),4.84(s,2H),4.69(s,2H),3.69(s,3H),2.67-2.64(m,2H),2.47-2.45(m,2H),2.06-1.95(t,J＝19.2Hz,3H),1.75-1.71(d,J＝5.1Hz,4H)。 Add WX012-7 (328.46mg, 1.10mmol, 1.05eq), WX005-6 (0.5g, 1.05mmol, 1eq) into the pre-dried reaction flask, then dissolve with dichloroethane (25mL), then add copper acetate (286.71mg, 1.58mmol, 1.5eq), pyridine (208.10mg, 2.63mmol, 212.35μL, 2.5eq). After the addition is complete, the reaction is stirred at 40°C under oxygen 15psi for 12 hours. After the reaction is complete, dilute with water (50mL) and dichloromethane (50mL), separate and collect the organic phase, extract the aqueous phase with dichloromethane (50mL*2), combine the organic phases, and wash with saturated brine (50mL*2) , Dried with anhydrous sodium sulfate, filtered to remove the desiccant, and removed the solvent under reduced pressure to obtain a crude product. The crude product is separated by an automatic column passing machine (gradient elution: petroleum ether: ethyl acetate=1:0 to 20:80), and purified to obtain WX012-8. 1 H NMR (400MHz, deuterated dimethyl sulfoxide) δ 7.82 (s, 2H), 7.36-7.34 (m, 2H), 7.32-7.27 (m, 1H), 7.06-7.00 (m, 3H), 6.83-6.77(m,3H), 5.41(s, 2H), 4.84(s, 2H), 4.69(s, 2H), 3.69(s, 3H), 2.67-2.64(m, 2H), 2.47-2.45( m, 2H), 2.06-1.95 (t, J=19.2 Hz, 3H), 1.75-1.71 (d, J=5.1 Hz, 4H)
步骤6：化合物WX012-9的合成Step 6: Synthesis of compound WX012-9
在预先干燥的反应瓶中加入WX012-8(0.43g,591.84μmol,1eq)，之后用乙腈(14mL)溶解，将反应体系将至0℃，然后加入硝酸铈铵(973.37mg,1.78mmol,884.88μL,3eq)的水(6mL)溶液，缓慢的升高至室温(25℃)搅拌反应1小时。反应完成后，加水(20mL)和乙酸乙酯(20mL)稀释，分液收集有机相，水相用乙酸乙酯(20*3mL)萃取，合并有机相，并用饱和食盐水(20mL*2)洗涤，无水硫酸钠干燥，过滤除去干燥剂后，减压除去溶剂得到粗产品。粗产品通过薄层层析硅胶板(石油醚:乙酸乙酯＝1:1)，纯化得到WX012-9。MS-ESI m/z:606.1[M+H] +,608.0[M+H+2] +。 Add WX012-8 (0.43g, 591.84μmol, 1eq) to the pre-dried reaction flask, then dissolve it with acetonitrile (14mL), bring the reaction system to 0°C, and then add cerium ammonium nitrate (973.37mg, 1.78mmol, 884.88) μL, 3eq) of water (6mL) solution, slowly raised to room temperature (25°C) and stirred for 1 hour. After the reaction is completed, dilute with water (20mL) and ethyl acetate (20mL), separate and collect the organic phase, extract the aqueous phase with ethyl acetate (20*3mL), combine the organic phases, and wash with saturated brine (20mL*2) , Dried with anhydrous sodium sulfate, filtered to remove the desiccant, and removed the solvent under reduced pressure to obtain a crude product. The crude product was purified by thin layer chromatography on silica gel plate (petroleum ether: ethyl acetate = 1:1) to obtain WX012-9. MS-ESI m/z: 606.1 [M+H] + , 608.0 [M+H+2] + .
步骤7：化合物WX012的合成Step 7: Synthesis of compound WX012
在预先干燥的反应瓶中加入WX012-9(0.12g,197.89μmol,1eq)，之后二氯甲烷(1.2mL)溶解，将反应体系降至0℃，加入三溴化硼(99.15mg,395.78μmol,38.13μL,2eq)，0℃搅拌反应0.5小时，补加三溴化硼(99.15mg,395.78μmol,38.13μL,2eq)，反应完成后，0℃下用饱和的碳酸氢钠溶液中和反应液pH至7左右，加入二氯甲烷(3mL)稀释，分液要有机相，水相用二氯甲烷(3mL*2)萃取，合并有机相，无水硫酸钠干燥，过滤除去干燥剂后，减压除去溶剂得到粗产品。粗产品通过高效液相色谱分离(色谱柱:Welch Xtimate C18 150*25mm*5μm；流动相:[水(0.04％HCl)-乙腈]；乙腈％:35％-55％,10min)，纯化得到WX012。 1H NMR(400MHz,氘代二甲基亚砜)δ12.78(s,1H),12.06(s,1H),7.81(s,2H),2.68-2.64(m,2H),2.45-2.42(m,2H),2.02-1.89(t,J＝19.2Hz,3H),1.81-1.69(m,4H)。MS-ESI m/z:486.0[M+H] +,488.0[M+H+2] +。 Add WX012-9 (0.12g, 197.89μmol, 1eq) to the pre-dried reaction flask, then dissolve dichloromethane (1.2mL), reduce the reaction system to 0°C, add boron tribromide (99.15mg, 395.78μmol) , 38.13μL, 2eq), stir and react at 0℃ for 0.5 hours, add boron tribromide (99.15mg, 395.78μmol, 38.13μL, 2eq), after the reaction is completed, neutralize the reaction with saturated sodium bicarbonate solution at 0℃ The pH of the solution is about 7, add dichloromethane (3mL) to dilute, separate the organic phase, and extract the aqueous phase with dichloromethane (3mL*2), combine the organic phases, dry with anhydrous sodium sulfate, filter to remove the desiccant, The solvent was removed under reduced pressure to obtain a crude product. The crude product was separated by high performance liquid chromatography (column: Welch Xtimate C18 150*25mm*5μm; mobile phase: [water (0.04%HCl)-acetonitrile]; acetonitrile%: 35%-55%, 10min), and purified to obtain WX012 . 1 H NMR (400MHz, deuterated dimethyl sulfoxide) δ 12.78 (s, 1H), 12.06 (s, 1H), 7.81 (s, 2H), 2.68-2.64 (m, 2H), 2.45-2.42 ( m, 2H), 2.02-1.89 (t, J=19.2 Hz, 3H), 1.81-1.69 (m, 4H). MS-ESI m/z: 486.0 [M+H] + , 488.0 [M+H+2] + .
实施例13Example 13
Figure PCTCN2020093284-appb-000145
Figure PCTCN2020093284-appb-000145
合成路线：synthetic route:
Figure PCTCN2020093284-appb-000146
Figure PCTCN2020093284-appb-000146
步骤1：化合物WX013-2的合成Step 1: Synthesis of compound WX013-2
将WX013-1(25g,175.92mmol,1eq)加到反应瓶中，加热到100℃，而后加入环戊二烯(69.77g,527.76 mmol,3eq)，并将温度升至180℃下反应2小时。反应完成后，将反应液用油泵真空浓缩，粗品用(甲基叔丁基醚:正己烷＝1:3，共120mL)打浆纯化，过滤，滤液旋干得WX013-2。 1H NMR(400MHz,氘代二甲基亚砜)δ2.00-2.06(m,1H)2.16-2.22(m,1H)3.71(s,6H)3.89-3.93(m,2H)6.97(t,J＝1.88Hz,2H)。 Add WX013-1 (25g, 175.92mmol, 1eq) to the reaction flask, heat to 100°C, then add cyclopentadiene (69.77g, 527.76 mmol, 3eq), and raise the temperature to 180°C for 2 hours . After the completion of the reaction, the reaction solution was concentrated in a vacuum with an oil pump, and the crude product was slurried and purified with (methyl tert-butyl ether: n-hexane=1:3, 120 mL in total), filtered, and the filtrate was spin-dried to obtain WX013-2. 1 H NMR (400MHz, deuterated dimethyl sulfoxide) δ2.00-2.06(m,1H)2.16-2.22(m,1H)3.71(s,6H)3.89-3.93(m,2H)6.97(t, J=1.88Hz, 2H).
步骤2：化合物WX013-3的合成Step 2: Synthesis of compound WX013-3
将WX013-2(4.5g,21.61mmol,1eq)，四氢呋喃(20mL)，钯碳(0.4g,10％纯度)加到反应瓶中，氢气置换三次，而后在25℃，氢气压力15psi下反应5分钟。反应完成后将反应液加硅藻土过滤，滤液旋干得WX013-3。 1H NMR(400MHz,氘代二甲基亚砜)δ1.14-1.20(m,3H)1.32-1.40(m,1H)1.80-1.87(m,2H)3.23(s,2H)3.70(s,6H)，MS-ESI m/z:211.1[M+H] +。 Add WX013-2 (4.5g, 21.61mmol, 1eq), tetrahydrofuran (20mL), palladium on carbon (0.4g, 10% purity) to the reaction flask, replace with hydrogen three times, and then react at 25°C and hydrogen pressure 15psi. minute. After the reaction is completed, the reaction solution is filtered with celite, and the filtrate is spin-dried to obtain WX013-3. 1 H NMR (400MHz, deuterated dimethyl sulfoxide) δ1.14-1.20(m,3H)1.32-1.40(m,1H)1.80-1.87(m,2H)3.23(s,2H)3.70(s, 6H), MS-ESI m/z: 211.1 [M+H] + .
步骤3：化合物WX013-4的合成Step 3: Synthesis of compound WX013-4
将WX013-3(2g,9.51mmol,1eq)，四氢呋喃(10mL)，水(3mL)，甲醇(3mL)，氢氧化钠(951.29mg,23.78mmol,2.5eq)加到反应瓶中，而后在25℃下反应12小时。反应完成后，将反应液加盐酸调节pH至5，然后旋干，用甲醇浸泡，过滤旋干得WX013-4。MS-ESI m/z:181.0[M-H] +。 WX013-3 (2g, 9.51mmol, 1eq), tetrahydrofuran (10mL), water (3mL), methanol (3mL), sodium hydroxide (951.29mg, 23.78mmol, 2.5eq) were added to the reaction flask, and then 25 React for 12 hours at °C. After the reaction is completed, add hydrochloric acid to the reaction solution to adjust the pH to 5, then spin dry, soak in methanol, filter and spin dry to obtain WX013-4. MS-ESI m/z: 181.0 [MH] + .
步骤4：化合物WX013-5的合成Step 4: Synthesis of compound WX013-5
将WX013-4(1.5g,8.23mmol,1eq)，三氟乙酸酐(15mL)加到反应瓶中，然后在65℃下反应12小时。反应完成后，将反应液旋干得WX013-5。MS-ESI m/z:165.1[M+H] +。 WX013-4 (1.5g, 8.23mmol, 1eq), trifluoroacetic anhydride (15mL) were added to the reaction flask, and then reacted at 65°C for 12 hours. After the completion of the reaction, the reaction solution was spin-dried to obtain WX013-5. MS-ESI m/z: 165.1 [M+H] + .
步骤5：化合物WX013-6的合成Step 5: Synthesis of compound WX013-6
将WX013-5(1.25g,7.61mmol,1eq)，醋酸(10mL)，水(5mL)加到反应瓶中，而后在搅拌状态下加入水合肼(972.42mg,19.04mmol,944.10μL,98％纯度2.5eq)，并在100℃下反应12小时。反应完成后，将反应液直接旋干得粗品。粗品用甲基叔丁基醚(20mL)打浆纯化得WX013-6。MS-ESI m/z:179.1[M+H] +。 Add WX013-5 (1.25g, 7.61mmol, 1eq), acetic acid (10mL), water (5mL) to the reaction flask, and then add hydrazine hydrate (972.42mg, 19.04mmol, 944.10μL, 98% purity) under stirring 2.5eq) and react at 100°C for 12 hours. After the reaction is completed, the reaction solution is directly spin-dried to obtain a crude product. The crude product was slurried and purified with methyl tert-butyl ether (20 mL) to obtain WX013-6. MS-ESI m/z: 179.1 [M+H] + .
步骤6：化合物WX013-7的合成Step 6: Synthesis of compound WX013-7
将WX013-6(1g,5.61mmol,1eq)，三氯氧磷(10mL)加到反应瓶中，而后在100℃下反应4小时。反应完毕后，将反应液滴加到30mL温水中淬灭反应，而后加碳酸氢钠固体调节pH至7左右，而后加入乙酸乙酯(30mL*3)萃取，合并有机相，有机相旋干得粗品。粗品经硅胶柱(石油醚:乙酸乙酯＝3:1,至1:1梯度淋洗)纯化得WX013-7。 1HNMR(400MHz,氘代二甲基亚砜)δ1.15-1.17(m,2H)1.63-1.66(m,1H)1.86-1.95(m,1H)2.02-2.14(m,2H)3.52-3.66(m,2H)。MS-ESI m/z:215.0[M+H] +,217.0[M+H+2] +。 WX013-6 (1g, 5.61mmol, 1eq), phosphorus oxychloride (10mL) were added to the reaction flask, and then reacted at 100°C for 4 hours. After the completion of the reaction, the reaction solution was added dropwise to 30mL warm water to quench the reaction, and then sodium bicarbonate was added to adjust the pH to about 7, then ethyl acetate (30mL*3) was added for extraction, the organic phases were combined, and the organic phases were spin-dried to obtain Crude. The crude product was purified by silica gel column (petroleum ether: ethyl acetate = 3:1, to 1:1 gradient elution) to obtain WX013-7. 1 HNMR (400MHz, deuterated dimethyl sulfoxide) δ1.15-1.17(m,2H)1.63-1.66(m,1H)1.86-1.95(m,1H)2.02-2.14(m,2H)3.52-3.66 (m, 2H). MS-ESI m/z: 215.0 [M+H] + , 217.0 [M+H+2] + .
步骤7：化合物WX013-8的合成Step 7: Synthesis of compound WX013-8
将WX013-7(0.165g,767.16μmol,1eq)，WX001-4(341.42mg,1.92mmol,2.5eq)，N,N-二甲基乙酰胺(5mL)，碳酸铯(624.89mg,1.92mmol,2.5eq)加到反应瓶中，而后在130℃下反应4小时。反应完成后，将反应液过滤，滤液中加入乙酸乙酯(50mL)而后用饱和食盐水(100mL*3)洗涤，有机相旋干得粗品，粗品经高效液相色谱分离(色谱柱:Phenomenex Luna C18 150*30mm*5μm；流动相:[水(0.04％盐酸)-乙腈]；乙腈％:55％-85％,10分钟)纯化得到WX013-8。MS-ESI m/z:355.9[M+H] +,357.9[M+H+2] +。 WX013-7 (0.165g, 767.16μmol, 1eq), WX001-4 (341.42mg, 1.92mmol, 2.5eq), N,N-dimethylacetamide (5mL), cesium carbonate (624.89mg, 1.92mmol, 2.5eq) was added to the reaction flask, and then reacted at 130°C for 4 hours. After the completion of the reaction, the reaction solution was filtered, ethyl acetate (50mL) was added to the filtrate and then washed with saturated brine (100mL*3), the organic phase was spin-dried to obtain the crude product, and the crude product was separated by high performance liquid chromatography (column: Phenomenex Luna C18 150*30mm*5μm; mobile phase: [water (0.04% hydrochloric acid)-acetonitrile]; acetonitrile%: 55%-85%, 10 minutes) to obtain WX013-8. MS-ESI m/z: 355.9 [M+H] + , 357.9 [M+H+2] + .
步骤8：化合物WX013-9的合成Step 8: Synthesis of compound WX013-9
将WX013-8(0.135g,378.54μmol,1eq)，醋酸(3mL)，醋酸钠(77.63mg,946.35μmol,2.5eq)加到反应瓶中，而后在110℃下反应12小时。反应完成后，将反应液旋干得粗品，粗品用乙酸乙酯(30mL)溶解，用碳酸钠溶液调节溶液的pH＝7～8，分出有机相，有机相旋干得WX013-9。MS-ESI m/z:380.0[M+H] +,382.0[M+H+2] +。 WX013-8 (0.135g, 378.54μmol, 1eq), acetic acid (3mL), and sodium acetate (77.63mg, 946.35μmol, 2.5eq) were added to the reaction flask, and then reacted at 110°C for 12 hours. After the completion of the reaction, the reaction solution was spin-dried to obtain a crude product. The crude product was dissolved in ethyl acetate (30 mL). The pH of the solution was adjusted to 7-8 with sodium carbonate solution. The organic phase was separated and the organic phase was spin-dried to obtain WX013-9. MS-ESI m/z: 380.0 [M+H] + , 382.0 [M+H+2] + .
步骤9：化合物WX013-10的合成Step 9: Synthesis of compound WX013-10
将WX013-9(0.13g,341.90μmol,1eq)，乙醇(5mL)，盐酸(12M,142.46μL,5eq)加到反应中，而后在100℃下反应12小时。反应完成后将反应液旋干得WX0012-11。 1HNMR(400MHz,氘代二甲基亚砜)δ1.05-1.14(m,1H)1.20-1.22(m,1H)1.53-1.56(m,1H)1.77-1.79(d,J＝8.88Hz,1H)1.98-2.12(m,2H)3.51(s,1H)3.61(s,1H)5.68(s,2H)6.72(s,2H)12.07(s,1H)。MS-ESI m/z:338.0[M+H] +,340.0[M+H+2] +。 WX013-9 (0.13g, 341.90μmol, 1eq), ethanol (5mL), and hydrochloric acid (12M, 142.46μL, 5eq) were added to the reaction, and then reacted at 100°C for 12 hours. After the reaction is completed, the reaction solution is spin-dried to obtain WX0012-11. 1 HNMR (400MHz, deuterated dimethyl sulfoxide) δ1.05-1.14(m,1H)1.20-1.22(m,1H)1.53-1.56(m,1H)1.77-1.79(d,J=8.88Hz, 1H)1.98-2.12(m,2H)3.51(s,1H)3.61(s,1H)5.68(s,2H)6.72(s,2H)12.07(s,1H). MS-ESI m/z: 338.0 [M+H] + , 340.0 [M+H+2] + .
步骤10：化合物WX013-11的合成Step 10: Synthesis of compound WX013-11
将WX013-10(0.05g,147.85μmol,1eq)，醋酸(1.5mL)，盐酸(1mL)加到反应瓶中，而后在0℃下滴加亚硝酸钠(13.26mg,192.20μmol,1.3eq)的水(1mL)溶液，并在0℃下反应0.5小时，然后加入WX001-9(26.55mg,170.02μmol,1.15eq)，并在0℃下反应1.5小时。反应完毕后，加入乙酸钠固体约200mg，有固体析出，然后过滤，滤饼旋干得WX013-11。 1HNMR(400MHz,氘代二甲基亚砜)δ1.03-1.18(m,2H)1.25-1.27(m,3H)1.52-1.54(m,1H)1.76-1.78(m,1H)1.97-2.07(m,2H)3.31-3.33(m,2H)3.49(s,1H)3.61(s,1H)4.16-4.20(m,2H)7.81(s,2H)11.94-12.13(m,2H)。MS-ESI m/z:505.1[M+H] +,507.1[M+H+2] +。 Add WX013-10 (0.05g, 147.85μmol, 1eq), acetic acid (1.5mL), and hydrochloric acid (1mL) to the reaction flask, and then add sodium nitrite (13.26mg, 192.20μmol, 1.3eq) dropwise at 0°C And reacted at 0°C for 0.5 hours, and then added WX001-9 (26.55mg, 170.02μmol, 1.15eq) and reacted at 0°C for 1.5 hours. After the completion of the reaction, add about 200 mg of sodium acetate solid, and a solid precipitated, then filtered, and the filter cake was spin-dried to obtain WX013-11. 1 HNMR (400MHz, deuterated dimethyl sulfoxide) δ1.03-1.18(m,2H)1.25-1.27(m,3H)1.52-1.54(m,1H)1.76-1.78(m,1H)1.97-2.07 (m,2H)3.31-3.33(m,2H)3.49(s,1H)3.61(s,1H)4.16-4.20(m,2H)7.81(s,2H)11.94-12.13(m,2H). MS-ESI m/z: 505.1 [M+H] + , 507.1 [M+H+2] + .
步骤11：化合物WX013-12的合成Step 11: Synthesis of compound WX013-12
将WX013-11(0.085g,168.54μmol,1eq)，N,N-二甲基乙酰胺(1mL)，醋酸钾(82.71mg,842.72μmol,5eq)加到反应瓶中，而后在115℃下反应8小时。反应完成后，将反应液过滤。滤液经高效液相色谱分离(色谱柱:Phenomenex Luna C18 150*30mm*5μm；流动相:[水(0.04％盐酸)-乙腈]；乙腈％:40％-70％,10min)纯化得WX013-12。 1H NMR(400MHz,氘代二甲基亚砜)δ1.04-1.14(m,1H)1.20-1.30(m,1H)1.53-1.55(m,1H)1.78-1.81(m,1H)2.01-2.08(m,2H)3.50(s,1H)3.64(s,1H)7.80(s,2H)12.14(s,1H)13.31(s,1H)。MS-ESI m/z:459.0[M+H] +,461.0[M+H+2] +。 Add WX013-11 (0.085g, 168.54μmol, 1eq), N,N-dimethylacetamide (1mL), potassium acetate (82.71mg, 842.72μmol, 5eq) into the reaction flask, and then react at 115℃ 8 hours. After the completion of the reaction, the reaction solution was filtered. The filtrate was separated by high performance liquid chromatography (column: Phenomenex Luna C18 150*30mm*5μm; mobile phase: [water (0.04% hydrochloric acid)-acetonitrile]; acetonitrile%: 40%-70%, 10min) to obtain WX013-12 . 1 H NMR (400MHz, deuterated dimethyl sulfoxide) δ1.04-1.14(m,1H)1.20-1.30(m,1H)1.53-1.55(m,1H)1.78-1.81(m,1H)2.01- 2.08 (m, 2H) 3.50 (s, 1H) 3.64 (s, 1H) 7.80 (s, 2H) 12.14 (s, 1H) 13.31 (s, 1H). MS-ESI m/z: 459.0 [M+H] + , 461.0 [M+H+2] + .
步骤12：化合物WX013和WX014的合成Step 12: Synthesis of compounds WX013 and WX014
WX013-12经超临界色谱分离(色谱柱:DAICEL CHIRALCEL OJ(250mm*30mm,10μm)；流动相:[0.1％氨水甲醇]；甲醇％:25％-25％,15min)得到WX013和WX014。WX013-12 was separated by supercritical chromatography (column: DAICEL CHIRALCEL OJ (250mm*30mm, 10μm); mobile phase: [0.1% ammonia methanol]; methanol%: 25%-25%, 15min) to obtain WX013 and WX014.
WX013： 1H NMR(400MHz,氘代甲醇)δ1.18-1.26(m,1H),1.33-1.38(m,1H),1.63-1.66(d,J＝9.26Hz,1H),1.86-1.89(d,J＝9.26Hz,1H),2.02-2.20(m,2H),3.62-3.76(d,J＝29.2Hz,2H),7.75(s,2H)。MS-ESI m/z:459.0[M+H] +,461.0[M+H+2] +。保留时间:2.15分钟(仪器:CAS-TJ-ANA-SFC-A(Waters SFC-MS)；色谱柱:Chiralcel OJ-3 3μm,0.46cm id x 10cm L；流动相：A:食品级超临界二氧化碳；B:甲醇(0.05％二乙胺， 体积比)；梯度：B含量在A的含量5分钟内从10％升高到40％；流速:4.0mL/min；柱温：35℃；检测波长：220nm；系统背压:100bar)。 WX013: 1 H NMR (400MHz, deuterated methanol) δ 1.18-1.26 (m, 1H), 1.33-1.38 (m, 1H), 1.63-1.66 (d, J = 9.26 Hz, 1H), 1.86-1.89 ( d, J = 9.26 Hz, 1H), 2.02-2.20 (m, 2H), 3.62-3.76 (d, J = 29.2 Hz, 2H), 7.75 (s, 2H). MS-ESI m/z: 459.0 [M+H] + , 461.0 [M+H+2] + . Retention time: 2.15 minutes (Instrument: CAS-TJ-ANA-SFC-A (Waters SFC-MS); Column: Chiralcel OJ-3 3μm, 0.46cm id x 10cm L; Mobile phase: A: food-grade supercritical carbon dioxide ; B: methanol (0.05% diethylamine, volume ratio); gradient: the content of B increases from 10% to 40% within 5 minutes of the content of A; flow rate: 4.0 mL/min; column temperature: 35°C; detection wavelength : 220nm; system back pressure: 100bar).
WX014： 1H NMR(400MHz,氘代甲醇)δ1.18-1.26(m,1H),1.33-1.38(m,1H),1.63-1.66(d,J＝9.26Hz,1H),1.86-1.89(d,J＝9.26Hz,1H),2.02-2.20(m,2H),3.62-3.76(d,J＝29.2Hz,2H),7.75(s,2H)。MS-ESI m/z:459.0[M+H] +,461.0[M+H+2] +。保留时间：2.32分钟(仪器:CAS-TJ-ANA-SFC-A(Waters SFC-MS)；色谱柱:Chiralcel OJ-3 3μm,0.46cm id x 10cm L；流动相：A:食品级超临界二氧化碳；B:甲醇(0.05％二乙胺，体积比)；梯度：B含量在A的含量5分钟内从10％升高到40％；流速:4.0mL/min；柱温：35℃；检测波长：220nm；系统背压:100bar)。 WX014: 1 H NMR (400MHz, deuterated methanol) δ 1.18-1.26 (m, 1H), 1.33-1.38 (m, 1H), 1.63-1.66 (d, J = 9.26 Hz, 1H), 1.86-1.89 ( d, J = 9.26 Hz, 1H), 2.02-2.20 (m, 2H), 3.62-3.76 (d, J = 29.2 Hz, 2H), 7.75 (s, 2H). MS-ESI m/z: 459.0 [M+H] + , 461.0 [M+H+2] + . Retention time: 2.32 minutes (Instrument: CAS-TJ-ANA-SFC-A (Waters SFC-MS); Column: Chiralcel OJ-3 3μm, 0.46cm id x 10cm L; Mobile phase: A: food-grade supercritical carbon dioxide ; B: methanol (0.05% diethylamine, volume ratio); gradient: the content of B increases from 10% to 40% within 5 minutes of the content of A; flow rate: 4.0mL/min; column temperature: 35°C; detection wavelength : 220nm; system back pressure: 100bar).
实施例15Example 15
Figure PCTCN2020093284-appb-000147
Figure PCTCN2020093284-appb-000147
合成路线：synthetic route:
Figure PCTCN2020093284-appb-000148
Figure PCTCN2020093284-appb-000148
步骤1：化合物WX015-2的合成Step 1: Synthesis of compound WX015-2
将叔丁醇钾(14.67g,130.77mmol,1.1eq)和正己烷(40mL)加入到反应瓶中，然后将温度降到-30℃，将四甲基乙二胺(15.20g,130.77mmol,19.74mL,1.1eq)和正丁基锂(2.5M,52.31mL,1.1eq)分别加入到反应液中，随后将WX015-1(10g,118.88mmol,10.87mL,1eq)加入到反应液中，保持温度在-40℃，加料完毕后反应液在-20℃继续搅拌15分钟，然后在-10℃搅拌5分钟。加料完毕后，将四氢呋喃(50mL)加入到反应液中，并将温度降低到-50℃，然后将二硫化二甲基(11.76g,124.83mmol,11.20mL,1.05eq)一次性加入到反应液中，然后将温度升到25℃并搅拌2小时。反应完成后，将反应液加入到饱和氯化铵的水溶液中(100 mL)，然后用甲基叔丁基醚(200mL*2)萃取，有机相用饱和食盐水(50mL*2)洗，无水硫酸钠干燥，过滤，然后减压浓缩得到WX015-2。 1HNMR(400MHz,氘代氯仿)δ4.85-4.86(m,1H),4.00-4.026(m,2H),2.15(s,3H),1.99-2.03(m,2H),1.75-1.78(m,2H)。 Potassium tert-butoxide (14.67g, 130.77mmol, 1.1eq) and n-hexane (40mL) were added to the reaction flask, then the temperature was reduced to -30 ℃, tetramethylethylenediamine (15.20g, 130.77mmol, 19.74mL, 1.1eq) and n-butyllithium (2.5M, 52.31mL, 1.1eq) were added to the reaction solution, and then WX015-1 (10g, 118.88mmol, 10.87mL, 1eq) was added to the reaction solution, keeping The temperature was at -40°C. After the addition, the reaction solution was stirred at -20°C for 15 minutes, and then at -10°C for 5 minutes. After the addition is complete, add tetrahydrofuran (50mL) to the reaction solution, and lower the temperature to -50°C, then add dimethyl disulfide (11.76g, 124.83mmol, 11.20mL, 1.05eq) to the reaction solution at once Then, the temperature was raised to 25°C and stirred for 2 hours. After the reaction was completed, the reaction solution was added to a saturated ammonium chloride aqueous solution (100 mL), and then extracted with methyl tert-butyl ether (200 mL*2). The organic phase was washed with saturated brine (50 mL*2). It was dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain WX015-2. 1 HNMR (400MHz, deuterated chloroform) δ 4.85-4.86 (m, 1H), 4.00-4.026 (m, 2H), 2.15 (s, 3H), 1.99-2.03 (m, 2H), 1.75-1.78 (m ,2H).
步骤2：化合物WX015-3的合成Step 2: Synthesis of compound WX015-3
在预先干燥的反应瓶中加入WX007-1(3g,19.87mmol,1eq)和甲苯(30mL)，抽换氮气在0℃下搅拌，然后将WX015-2(3.62g,27.82mmol,1.4eq)溶解在甲苯(30mL)中，并滴加到上述反应体系中，0℃下继续搅拌10分钟，然后升至30℃搅拌20分钟。然后在50℃下加热反应5.5小时。反应完成后，用水泵在40℃下减压浓缩，加水60mL，再加乙酸乙酯(50mL*2)萃取，合并有机相，有机相再用饱和食盐水(70mL)洗涤，有机相用无水硫酸钠干燥，过滤，滤液用水泵在40℃下减压浓缩得到粗品，粗产品通过自动过柱机分离(梯度淋洗：石油醚:乙酸乙酯＝1:0至4:1)纯化得到化合物WX015-3。 1HNMR(400MHz,氘代氯仿)δ4.41-4.43(m,2H),2.75-2.78(m,2H),2.13-2.18(m,2H)。 Add WX007-1 (3g, 19.87mmol, 1eq) and toluene (30mL) into the pre-dried reaction flask, pump nitrogen and stir at 0℃, then dissolve WX015-2 (3.62g, 27.82mmol, 1.4eq) In toluene (30 mL), add dropwise to the above reaction system, continue stirring at 0°C for 10 minutes, and then raise to 30°C and stir for 20 minutes. Then the reaction was heated at 50°C for 5.5 hours. After the reaction is completed, concentrate with a water pump at 40°C under reduced pressure, add 60 mL of water, then add ethyl acetate (50 mL*2) for extraction, combine the organic phases, wash the organic phase with saturated brine (70 mL), and use anhydrous The filtrate was dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure with a water pump at 40°C to obtain a crude product. The crude product was separated by an automatic column machine (gradient elution: petroleum ether: ethyl acetate=1:0 to 4:1) and purified to obtain the compound WX015-3. 1 HNMR (400MHz, deuterated chloroform) δ4.41-4.43 (m, 2H), 2.75-2.78 (m, 2H), 2.13-2.18 (m, 2H).
步骤3：化合物WX015-4的合成Step 3: Synthesis of compound WX015-4
在预先干燥的反应瓶中加入WX015-3(2.35g,11.46mmol,1eq)，之后用二甲基亚砜(90mL)溶解，然后加入WX001-4(3.06g,17.19mmol,1.5eq)，碳酸钾(6.34g,45.84mmol,4eq)，氮气抽换三次，加入碘化亚铜(1.31g,6.88mmol,0.6eq)，氮气再次抽换三次，在氮气保护下升高到90℃搅拌反应17小时。反应完成后，反应液用硅藻土抽滤，滤液用饱和氯化铵(200mL)洗，加乙酸乙酯和石油醚的1:1混合液(150mL*5)萃取，合并有机相，有机相再用饱和食盐水(200mL)洗，无水硫酸钠干燥减压浓缩得粗品，粗品用快速过柱机分离纯化(梯度淋洗：石油醚:乙酸乙酯＝1:0至2:1)得到化合物WX015-4和WX015-4A。将WX015-4和WX015-4A分别在Pd/C，氢气条件下氢化，各自哒嗪环氮原子邻位的氯被氢原子取代，进一步通过二维核磁判断为所示结构。Add WX015-3 (2.35g, 11.46mmol, 1eq) to the pre-dried reaction flask, then dissolve it with dimethyl sulfoxide (90mL), then add WX001-4 (3.06g, 17.19mmol, 1.5eq), carbonic acid Potassium (6.34g, 45.84mmol, 4eq), nitrogen pumping three times, adding cuprous iodide (1.31g, 6.88mmol, 0.6eq), nitrogen pumping again three times, raising to 90℃ under nitrogen protection and stirring for reaction 17 hour. After the completion of the reaction, the reaction solution was filtered with Celite, the filtrate was washed with saturated ammonium chloride (200mL), and a 1:1 mixture of ethyl acetate and petroleum ether (150mL*5) was added for extraction, and the organic phases were combined. Then washed with saturated brine (200mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by a rapid column machine (gradient elution: petroleum ether: ethyl acetate=1:0 to 2:1). Compounds WX015-4 and WX015-4A. WX015-4 and WX015-4A were hydrogenated under Pd/C and hydrogen conditions, and the chlorine at the ortho position of the nitrogen atom of each pyridazine ring was replaced by a hydrogen atom, and the structure was further judged by two-dimensional nuclear magnetism.
步骤4：化合物WX015-5的合成Step 4: Synthesis of compound WX015-5
在预先干燥的反应瓶中加入WX015-4(470mg,1.36mmol,1eq)和溴化氢(8mL)，置于0℃下，加入亚硝酸钠(112.27mg,1.63mmol,1.2eq)和水(4mL)的混合溶液，0℃下搅拌0.5小时，将溴化亚铜(213.98mg,1.49mmol,45.43μL,1.1eq)，水(4mL)和溴化氢(8mL)的混合溶液缓慢滴加到上述体系中，自然升温至25℃继续搅拌15.5小时。反应完成后，反应液用水(30mL)淬灭，加乙酸乙酯萃取(50mL*2)，合并有机相再用饱和碳酸氢钠洗(60mL)，有机相用无水硫酸钠干燥，减压浓缩得粗品，粗品用自动过柱机分离纯化(梯度淋洗：石油醚:乙酸乙酯＝1:0至4:1)得到化合物WX015-5。Add WX015-4 (470mg, 1.36mmol, 1eq) and hydrogen bromide (8mL) to the pre-dried reaction flask, place it at 0°C, add sodium nitrite (112.27mg, 1.63mmol, 1.2eq) and water ( 4mL), stirred at 0°C for 0.5 hours, and the mixed solution of cuprous bromide (213.98mg, 1.49mmol, 45.43μL, 1.1eq), water (4mL) and hydrogen bromide (8mL) was slowly added dropwise to In the above system, the temperature was naturally raised to 25°C and stirring was continued for 15.5 hours. After the completion of the reaction, the reaction solution was quenched with water (30mL), extracted with ethyl acetate (50mL*2), the combined organic phases were washed with saturated sodium bicarbonate (60mL), the organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure The crude product was obtained, and the crude product was separated and purified by an automatic column passing machine (gradient elution: petroleum ether: ethyl acetate=1:0 to 4:1) to obtain compound WX015-5.
步骤5：化合物WX015-6的合成Step 5: Synthesis of compound WX015-6
在预先干燥的反应瓶中加入WX015-5(400mg,974.47μmol,1eq)，之后用冰乙酸(12mL)溶解，然后加入乙酸钠(159.88mg,1.95mmol,2eq)，110℃搅拌反应15小时。反应完成后，反应液加饱和碳酸氢钠调节pH＝7，用乙酸乙酯萃取(80mL*2)，有机相分别再用饱和碳酸氢钠洗(100mL)，饱和食盐水洗(100 mL)，有机相用无水硫酸钠干燥，减压浓缩得到粗品，粗品用乙酸乙酯和石油醚1:1的混合溶液(10mL)打浆得到化合物WX015-6。 1HNMR(400MHz,氘代氯仿)δ10.15(s,1H),7.55(s,2H),4.41-4.44(m,2H),2.76-2.79(m,2H),2.14-2.16(m,2H)。 WX015-5 (400mg, 974.47μmol, 1eq) was added to the pre-dried reaction flask, then dissolved with glacial acetic acid (12mL), and then sodium acetate (159.88mg, 1.95mmol, 2eq) was added, and the reaction was stirred at 110°C for 15 hours. After the completion of the reaction, the reaction solution was added with saturated sodium bicarbonate to adjust pH=7, extracted with ethyl acetate (80mL*2), and the organic phase was washed with saturated sodium bicarbonate (100mL), saturated brine (100mL), organic The phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude product. The crude product was slurried with a 1:1 mixed solution of ethyl acetate and petroleum ether (10 mL) to obtain compound WX015-6. 1 HNMR (400MHz, deuterated chloroform) δ 10.15 (s, 1H), 7.55 (s, 2H), 4.41-4.44 (m, 2H), 2.76-2.79 (m, 2H), 2.14-2.16 (m, 2H) ).
步骤6：化合物WX015-7的合成Step 6: Synthesis of compound WX015-7
在预先干燥的反应瓶中加入对甲氧基苄氯(221.71mg,1.42mmol,192.79μL,1.5eq)，碳酸钾(391.32mg,2.83mmol,3eq)和N,N-二甲基甲酰胺(9mL)，然后再加入WX015-6(370.00mg,943.80μmol,1eq)，抽换氮气，25℃下搅拌反应16小时。反应完成后,向反应液中加饱和氯化铵溶液(100mL)，用乙酸乙酯(80mL*2)萃取，合并有机相，有机相用饱和食盐水洗(100mL*4)，无水硫酸钠干燥，过滤，滤液用水泵40℃下减压浓缩得到粗品，上述粗品用自动过柱机分离纯化(梯度淋洗：石油醚:乙酸乙酯＝1:0至5:2)得到化合物WX015-7。Add p-methoxybenzyl chloride (221.71mg, 1.42mmol, 192.79μL, 1.5eq), potassium carbonate (391.32mg, 2.83mmol, 3eq) and N,N-dimethylformamide ( 9mL), and then add WX015-6 (370.00mg, 943.80μmol, 1eq), pump nitrogen, and stir the reaction at 25°C for 16 hours. After the reaction is complete, add saturated ammonium chloride solution (100mL) to the reaction solution, extract with ethyl acetate (80mL*2), combine the organic phases, wash the organic phases with saturated brine (100mL*4), and dry with anhydrous sodium sulfate , Filter, and concentrate the filtrate under reduced pressure with a water pump at 40°C to obtain a crude product. The crude product is separated and purified by an automatic column machine (gradient elution: petroleum ether: ethyl acetate=1:0 to 5:2) to obtain compound WX015-7.
步骤7：化合物WX015-8的合成Step 7: Synthesis of compound WX015-8
在预先干燥的反应瓶中加入WX015-7(170.00mg,331.91μmol,1eq)，加入二氧六环(5mL)使其溶解，然后加入双联频哪醇硼酸酯(126.43mg,497.87μmol,1.5eq)和乙酸钾(65.15mg,663.83μmol,2eq)，氮气置换3次，然后再加入1,1'-双(二苯基磷)二茂铁氯化钯(24.29mg,33.19μmol,0.1eq)，氮气再置换3次，升温至100℃反应2小时。反应完成后，反应液用硅藻土抽滤，滤液减压浓缩干，粗品用制备硅胶大板分离纯化(石油醚:乙酸乙酯＝4:5)得到化合物WX015-8。Add WX015-7 (170.00mg, 331.91μmol, 1eq) into the pre-dried reaction flask, add dioxane (5mL) to dissolve it, and then add double pinacol borate (126.43mg, 497.87μmol, 1.5eq) and potassium acetate (65.15mg, 663.83μmol, 2eq), replaced with nitrogen 3 times, and then added 1,1'-bis(diphenylphosphorus) ferrocene palladium chloride (24.29mg, 33.19μmol, 0.1 eq), nitrogen gas was replaced 3 times, and the temperature was raised to 100°C for 2 hours. After the completion of the reaction, the reaction solution was suction filtered with diatomaceous earth, the filtrate was concentrated to dryness under reduced pressure, and the crude product was separated and purified using a large silica gel preparation plate (petroleum ether: ethyl acetate = 4:5) to obtain compound WX015-8.
步骤8：化合物WX015-9的合成Step 8: Synthesis of compound WX015-9
在预先干燥的反应瓶中加入WX015-8(160mg,286.10μmol,1eq)，之后用丙酮(3mL)，水(1.5mL)溶解，然后加入高碘酸钠(61.19mg,286.10μmol,15.85μL,1eq)，醋酸铵(158.78mg,2.06mmol,7.2eq)，氮气置换三次，室温(25℃)搅拌反应15小时。反应完成后，反应液用水泵浓缩除去丙酮，再用油泵减压浓缩除去水得到粗品，粗品经高效液相色谱分离(色谱柱:Luna Omega 5u Polar C18 100A；流动相:[水(0.04％盐酸)-乙腈]；乙腈％:45％-65％,7分钟)得到化合物WX015-9。Add WX015-8 (160mg, 286.10μmol, 1eq) to the pre-dried reaction flask, then dissolve it with acetone (3mL), water (1.5mL), and then add sodium periodate (61.19mg, 286.10μmol, 15.85μL, 1eq), ammonium acetate (158.78mg, 2.06mmol, 7.2eq), replaced with nitrogen three times, and stirred at room temperature (25°C) for 15 hours. After the reaction is completed, the reaction solution is concentrated with a water pump to remove acetone, and then concentrated with an oil pump to remove water to obtain a crude product. The crude product is separated by high performance liquid chromatography (column: Luna Omega 5u Polar C18 100A; mobile phase: [water (0.04% hydrochloric acid) )-Acetonitrile]; Acetonitrile%: 45%-65%, 7 minutes) to obtain compound WX015-9.
步骤9：化合物WX015-10的合成Step 9: Synthesis of compound WX015-10
在预先干燥的反应瓶中加入WX003-6(31.17mg,110.04μmol,1.05eq)和WX015-9(50mg,104.80μmol,1eq)，之后用1,2-二氯乙烷(3mL)溶解，然后加入醋酸铜(28.55mg,157.20μmol,1.5eq)，吡啶(20.72mg,262.00μmol,21.15μL,2.5eq)，加料完全后，于40℃在氧气保护下搅拌反应12小时。反应完成后，反应液用1N盐酸溶液洗(30mL)再用乙酸乙酯萃取(30mL*2)，合并有机相再用饱和食盐水洗(40mL)，有机相干燥浓缩得粗品，粗品用制备硅胶大板分离纯化(石油醚:乙酸乙酯＝1:1)得到化合物WX015-10。 1HNMR(400MHz,氘代氯仿)δ7.51(s,2H),7.23-7.31(m,5H),7.08-7.10(m,2H),6.68-6.70(m,2H),6.44-6.57(t,J＝52.4Hz,1H),5.51(s,2H),4.88(s,2H),4.70(s,2H),4.29-4.31(m,2H),3.68(s,3H),2.62-2.66(m,2H),1.99-2.02(m,2H)。 Add WX003-6 (31.17mg, 110.04μmol, 1.05eq) and WX015-9 (50mg, 104.80μmol, 1eq) into the pre-dried reaction flask, then dissolve it with 1,2-dichloroethane (3mL), then Copper acetate (28.55mg, 157.20μmol, 1.5eq) and pyridine (20.72mg, 262.00μmol, 21.15μL, 2.5eq) were added. After the addition was complete, the reaction was stirred at 40°C under oxygen protection for 12 hours. After the completion of the reaction, the reaction solution was washed with 1N hydrochloric acid solution (30mL) and then extracted with ethyl acetate (30mL*2). The organic phases were combined and washed with saturated brine (40mL). The organic phase was dried and concentrated to obtain a crude product. The crude product was prepared with silica gel. Plate separation and purification (petroleum ether: ethyl acetate=1:1) to obtain compound WX015-10. 1 HNMR (400MHz, deuterated chloroform) δ 7.51 (s, 2H), 7.23-7.31 (m, 5H), 7.08-7.10 (m, 2H), 6.68-6.70 (m, 2H), 6.44-6.57 (t ,J=52.4Hz,1H),5.51(s,2H),4.88(s,2H),4.70(s,2H),4.29-4.31(m,2H),3.68(s,3H),2.62-2.66( m, 2H), 1.99-2.02 (m, 2H).
步骤10：化合物WX015-11的合成Step 10: Synthesis of compound WX015-11
在预先干燥的投库瓶中加入WX015-10(40.00mg,55.98μmol,1eq)，之后用乙腈(1.6mL)溶解，置于0℃下搅拌，然后缓慢滴加硝酸铈铵(92.07mg,167.95μmol,83.70μL,3eq)和水(0.8mL)的混合溶液，然后升至25℃搅拌2小时。反应完成后，反应液用水洗(20mL)，再用乙酸乙酯萃取(20mL*2)，合并有机相,再用饱和食盐水洗(30mL)，无水硫酸钠干燥，减压浓缩得粗品，粗品用制备薄层色谱硅胶板分离纯化(石油醚:乙酸乙酯＝3:5)得到化合物WX015-11。 1HNMR(400MHz,氘代氯仿)δ10.28(s,1H),7.48(s,2H),7.28-7.23(m,5H),6.65-6.39(t,J＝52.4Hz,1H),5.49(s,2H),4.69(s,2H),4.69-4.35(m,2H),2.65-2.61(m,2H),2.07-1.99(m,2H)。 Add WX015-10 (40.00mg, 55.98μmol, 1eq) to the pre-dried library bottle, then dissolve it with acetonitrile (1.6mL), place it at 0℃ and stir, then slowly add ceric ammonium nitrate (92.07mg, 167.95 μmol, 83.70μL, 3eq) and water (0.8mL) mixed solution, then raised to 25℃ and stirred for 2 hours. After the completion of the reaction, the reaction solution was washed with water (20mL), and then extracted with ethyl acetate (20mL*2), the organic phases were combined, washed with saturated brine (30mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. Separation and purification using preparative thin-layer chromatography silica gel plate (petroleum ether: ethyl acetate=3:5) gave compound WX015-11. 1 HNMR (400MHz, deuterated chloroform) δ 10.28 (s, 1H), 7.48 (s, 2H), 7.28-7.23 (m, 5H), 6.65-6.39 (t, J = 52.4 Hz, 1H), 5.49 ( s, 2H), 4.69 (s, 2H), 4.69-4.35 (m, 2H), 2.65-2.61 (m, 2H), 2.07-1.99 (m, 2H).
步骤11：化合物WX015的合成Step 11: Synthesis of compound WX015
在预先干燥的投库瓶中加入WX015-11(30mg,50.48μmol,1eq)，之后用二氯甲烷(0.5mL)溶解，氮气置换3次，置于0℃下搅拌，然后缓慢滴加三溴化硼(25.29mg,100.95μmol,9.73μL,2eq)和二氯甲烷(0.5mL)的混合溶液，然后在0℃搅拌反应0.5小时。反应完成后，反应液用饱和的碳酸氢钠溶液中和反应液pH至7左右，用乙酸乙酯(15mL*3)萃取，合并有机相，有机相减压浓缩得粗品，粗品经高效液相色谱分离(色谱柱:Luna Omega 5u Polar C18 100A；流动相:[水(0.04％盐酸)-乙腈]；乙腈％:27％-53％,7min)纯化得到化合物WX015。 1HNMR(400MHz,氘代二甲基亚砜)δ12.83(s,1H),12.10(s,1H),7.79(s,2H),6.90-6.77(t,J＝52.4Hz,1H),4.34-4.32(m,2H),2.67-2.66(m,2H),2.03-2.01(m,2H)。MS-ESI m/z:473.9[M+H]+,475.9[M+H+2] +。 Add WX015-11 (30mg, 50.48μmol, 1eq) to the pre-dried library bottle, then dissolve it with dichloromethane (0.5mL), replace with nitrogen 3 times, place it at 0℃ and stir, then slowly add tribromide dropwise A mixed solution of boron chloride (25.29mg, 100.95μmol, 9.73μL, 2eq) and dichloromethane (0.5mL) was then stirred at 0°C for 0.5 hours. After the reaction is completed, the reaction solution is neutralized with saturated sodium bicarbonate solution to pH 7 or so, extracted with ethyl acetate (15mL*3), the organic phases are combined, and the organic phases are concentrated under reduced pressure to obtain a crude product. The crude product is subjected to HPLC Chromatographic separation (column: Luna Omega 5u Polar C18 100A; mobile phase: [water (0.04% hydrochloric acid)-acetonitrile]; acetonitrile%: 27%-53%, 7 min) to obtain compound WX015. 1 HNMR (400MHz, deuterated dimethyl sulfoxide) δ 12.83 (s, 1H), 12.10 (s, 1H), 7.79 (s, 2H), 6.90-6.77 (t, J = 52.4 Hz, 1H), 4.34-4.32 (m, 2H), 2.67-2.66 (m, 2H), 2.03-2.01 (m, 2H). MS-ESI m/z: 473.9 [M+H]+, 475.9 [M+H+2] + .
实施例16Example 16
Figure PCTCN2020093284-appb-000149
Figure PCTCN2020093284-appb-000149
合成路线：synthetic route:
Figure PCTCN2020093284-appb-000150
Figure PCTCN2020093284-appb-000150
步骤1：化合物WX016-1的合成Step 1: Synthesis of compound WX016-1
在预先干燥的反应瓶中加入WX015-4A(440.00mg,1.27mmol,1eq)和氢溴酸(4mL)，置于0℃下，加入亚硝酸钠(175.18mg,2.54mmol,2eq)和水(2mL)的混合溶液，0℃下搅拌0.5小时，将上述反应液滴加到搅拌着的溴化亚铜(273.16mg,1.90mmol,58.00μL,1.5eq)，水(2mL)和氢溴酸(4mL)的混合溶液中，自然升温至25℃继续搅拌15.5小时。反应完毕后，向反应液加水(30mL)，然后用乙酸乙酯萃取(30mL*2)，合并有机相，有机相再用饱和碳酸氢钠洗(50mL*2)，饱和食盐水洗(50mL*2)，无水硫酸钠干燥，减压浓缩得WX016-1。 1HNMR(400MHz,氘代氯仿)δ7.43(s,2H),4.42-4.39(m,2H),2.74-2.71(m,2H),2.16-2.13(m,2H)。 Add WX015-4A (440.00mg, 1.27mmol, 1eq) and hydrobromic acid (4mL) to the pre-dried reaction flask, place it at 0°C, add sodium nitrite (175.18mg, 2.54mmol, 2eq) and water ( 2mL), stirred for 0.5 hours at 0 ℃, the above reaction solution was added dropwise to the stirring cuprous bromide (273.16mg, 1.90mmol, 58.00μL, 1.5eq), water (2mL) and hydrobromic acid ( In the mixed solution of 4mL), the temperature was naturally raised to 25°C and stirring was continued for 15.5 hours. After the completion of the reaction, add water (30mL) to the reaction solution, then extract with ethyl acetate (30mL*2), combine the organic phases, and wash the organic phases with saturated sodium bicarbonate (50mL*2) and saturated brine (50mL*2) ), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain WX016-1. 1 HNMR (400MHz, deuterated chloroform) δ7.43 (s, 2H), 4.42-4.39 (m, 2H), 2.74-2.71 (m, 2H), 2.16-2.13 (m, 2H).
步骤2：化合物WX016-2的合成Step 2: Synthesis of compound WX016-2
在预先干燥的反应瓶中加入WX016-1(520.00mg,1.27mmol,1eq)，之后用冰乙酸(12mL)溶解，然后加入乙酸钠(207.84mg,2.53mmol,2eq)，110℃搅拌反应15小时。反应完毕后，将反应液加饱和碳酸氢钠(50mL)，用乙酸乙酯萃取(100mL*2)，合并有机相，有机相用饱和碳酸氢钠洗(100mL)，饱和食盐水洗(100mL)，无水硫酸钠干燥，减压浓缩得到粗品，粗品用乙酸乙酯和石油醚1:1的混合溶液(10mL)打浆得到WX016-2。 1HNMR(400MHz,氘代氯仿)δ9.95(s,1H),7.46(s,2H),4.34-4.32(m,2H),2.56-2.53(m,2H),2.07-2.04(m,2H)。 Add WX016-1 (520.00mg, 1.27mmol, 1eq) to the pre-dried reaction flask, then dissolve it with glacial acetic acid (12mL), then add sodium acetate (207.84mg, 2.53mmol, 2eq), stir and react at 110°C for 15 hours . After the reaction, the reaction solution was added saturated sodium bicarbonate (50mL), extracted with ethyl acetate (100mL*2), the organic phases were combined, and the organic phases were washed with saturated sodium bicarbonate (100mL) and saturated brine (100mL). It was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude product. The crude product was slurried with a 1:1 mixed solution of ethyl acetate and petroleum ether (10 mL) to obtain WX016-2. 1 HNMR(400MHz, deuterated chloroform)δ9.95(s,1H),7.46(s,2H),4.34-4.32(m,2H),2.56-2.53(m,2H),2.07-2.04(m,2H) ).
步骤3：化合物WX016-3的合成Step 3: Synthesis of compound WX016-3
在预先干燥的反应瓶中加入WX016-2(520.00mg,1.33mmol,1eq)，N,N-二甲基甲酰胺(15mL)和碳酸钾(549.96mg,3.98mmol,3eq)，然后再加入对甲氧基苄氯(311.59mg,1.99mmol,270.95μL,1.5eq)，抽换氮气，25℃搅拌反应16小时。反应完毕后，反应液加饱和氯化铵溶液(70mL)，再加乙酸乙酯(70mL*2)萃取，合并有机相，有机相再用饱和食盐水洗(100mL*4)，无水硫酸钠干燥，过滤，滤液用水泵在40℃ 下减压浓缩得到粗品，粗品用自动过柱机分离纯化(梯度冲洗：石油醚:乙酸乙酯＝1:0至1:1)得到WX016-3。 1H NMR(400MHz,氘代氯仿)δ7.47(s,2H),7.08-7.06(m,2H),6.71-6.69(m,2H),4.83(s,2H),4.28-4.25(m,2H),3.71(s,3H),2.53(s,2H),2.01-1.98(m,2H)。 Add WX016-2 (520.00mg, 1.33mmol, 1eq), N,N-dimethylformamide (15mL) and potassium carbonate (549.96mg, 3.98mmol, 3eq) into the pre-dried reaction flask, and then add the right Methoxybenzyl chloride (311.59 mg, 1.99 mmol, 270.95 μL, 1.5 eq), pumped with nitrogen, stirred at 25° C. for 16 hours. After the reaction is complete, add saturated ammonium chloride solution (70mL) to the reaction solution, then add ethyl acetate (70mL*2) for extraction, combine the organic phases, wash the organic phases with saturated brine (100mL*4), and dry with anhydrous sodium sulfate , Filtered, and the filtrate was concentrated under reduced pressure with a water pump at 40°C to obtain a crude product. The crude product was separated and purified by an automatic column machine (gradient washing: petroleum ether: ethyl acetate = 1:0 to 1:1) to obtain WX016-3. 1 H NMR (400MHz, deuterated chloroform) δ7.47 (s, 2H), 7.08-7.06 (m, 2H), 6.71-6.69 (m, 2H), 4.83 (s, 2H), 4.28-4.25 (m, 2H), 3.71 (s, 3H), 2.53 (s, 2H), 2.01-1.98 (m, 2H).
步骤4：化合物WX016-4的合成Step 4: Synthesis of compound WX016-4
在预先干燥的反应瓶中加入WX016-3(550mg,1.07mmol,1eq)和二氧六环(11mL)，加入双联频哪醇硼酸酯(409.03mg,1.61mmol,1.5eq)和醋酸钾(210.77mg,2.15mmol,2eq)，置换氮气三次，加入1,1-双(二苯基膦)二茂铁二氯化钯(78.57mg,107.38μmol,0.1eq)，再次置换氮气三次，置于100℃下搅拌16小时。反应完毕后，将反应液经硅藻土过滤，滤液减压浓缩得到粗产品，粗产品经柱层析纯化(梯度淋洗：石油醚：乙酸乙酯＝10:1转5:1转1:1)得到WX016-4。 1HNMR(400MHz,氘代氯仿)δ1.38(s,12H)2.06(d,J＝7.46Hz,2H)2.57-2.63(m,2H)3.78(s,3H)4.32-4.36(d,J＝4.9Hz,2H)4.88(s,2H)6.76-6.67(d,J＝8.6Hz,2H)7.12-7.16(d,J＝8.4Hz,2H)7.81(s,2H)。MS-ESI m/z:559.2[M+H] +。 Add WX016-3 (550mg, 1.07mmol, 1eq) and dioxane (11mL) to the pre-dried reaction flask, add double pinacol borate (409.03mg, 1.61mmol, 1.5eq) and potassium acetate (210.77mg, 2.15mmol, 2eq), replace with nitrogen three times, add 1,1-bis(diphenylphosphine)ferrocene palladium dichloride (78.57mg, 107.38μmol, 0.1eq), replace with nitrogen again three times, set Stir at 100°C for 16 hours. After the completion of the reaction, the reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (gradient elution: petroleum ether: ethyl acetate = 10:1 to 5:1 to 1: 1) Obtain WX016-4. 1 HNMR (400MHz, deuterated chloroform) δ 1.38 (s, 12H) 2.06 (d, J = 7.46 Hz, 2H) 2.57-2.63 (m, 2H) 3.78 (s, 3H) 4.32-4.36 (d, J = 4.9 Hz, 2H) 4.88 (s, 2H) 6.76-6.67 (d, J = 8.6 Hz, 2H) 7.12-7.16 (d, J = 8.4 Hz, 2H) 7.81 (s, 2H). MS-ESI m/z: 559.2 [M+H] + .
步骤5：化合物WX016-5的合成Step 5: Synthesis of compound WX016-5
在预先干燥的反应器中加入WX016-4(600mg,1.07mmol,1eq)和丙酮(6mL)，水(2.5mL)，加入高碘酸钠(229.48mg,1.07mmol,59.45μL,1eq)，醋酸铵(595.42mg,7.72mmol,7.2eq)，置换氮气三次，35℃搅拌16小时。反应完毕后，将反应液中减压浓缩，剩余溶液加入饱和硫代硫酸钠溶液(20mL)，用1M盐酸调节pH至5，过滤收集滤饼。将滤饼用油泵减压浓缩得粗产品，粗产品经高效液相色谱分离(色谱柱:Luna Omega 5u Polar C18 100A；流动相:[水(0.04％盐酸)-乙腈]；乙腈％:28％-58％,7min)得到WX016-5。 1H NMR(400MHz,氘代二甲基亚砜)δ1.93-2.00(m,2H)2.42-2.45(t,J＝6.07Hz,2H)3.70(s,2H)4.30-4.35(m,2H)4.77(s,2H)6.77-6.79(d,J＝8.4Hz,2H)6.97-6.99(d,J＝8.4Hz,2H)7.89(s,2H)8.51(s,2H)。MS-ESI m/z:477.1[M+H] +。 In the pre-dried reactor, add WX016-4 (600mg, 1.07mmol, 1eq) and acetone (6mL), water (2.5mL), add sodium periodate (229.48mg, 1.07mmol, 59.45μL, 1eq), acetic acid Ammonium (595.42mg, 7.72mmol, 7.2eq), replaced with nitrogen three times, stirred at 35°C for 16 hours. After the completion of the reaction, the reaction solution was concentrated under reduced pressure, the remaining solution was added with saturated sodium thiosulfate solution (20 mL), the pH was adjusted to 5 with 1M hydrochloric acid, and the filter cake was collected by filtration. The filter cake was concentrated under reduced pressure with an oil pump to obtain a crude product, which was separated by high performance liquid chromatography (column: Luna Omega 5u Polar C18 100A; mobile phase: [water (0.04% hydrochloric acid)-acetonitrile]; acetonitrile%: 28% -58%, 7min) to obtain WX016-5. 1 H NMR (400MHz, deuterated dimethyl sulfoxide) δ1.93-2.00(m,2H)2.42-2.45(t,J=6.07Hz,2H)3.70(s,2H)4.30-4.35(m,2H ) 4.77 (s, 2H) 6.77-6.79 (d, J=8.4 Hz, 2H) 6.97-6.99 (d, J=8.4 Hz, 2H) 7.89 (s, 2H) 8.51 (s, 2H). MS-ESI m/z: 477.1 [M+H] + .
步骤6：化合物WX016-6的合成Step 6: Synthesis of compound WX016-6
在预先干燥的反应瓶中加入WX016-5(260mg,544.96μmol,1.1eq)和二氯乙烷(10mL)，加入WX003-6(140.32mg,495.42μmol,1eq)，然后依次加入醋酸铜(134.97mg,743.12μmol,1.5eq)和吡啶(97.97mg,1.24mmol,99.97μL,2.5eq)，置换氧气三次，置于40℃，15psi搅拌16小时。反应完毕后，将反应液用水(50mL)淬灭，乙酸乙酯萃取(50mL*3)，合并有机相，有机相用饱和食盐水洗(50mL*2)，无水硫酸钠干燥，过滤，减压浓缩得粗产品，粗产品经薄层色谱硅胶板纯化(石油醚：乙酸乙酯＝1:1)得到WX016-6。 1HNMR(400MHz,氘代氯仿)δ2.07-2.13(m,2H)2.60-2.65(m,2H)3.77(s,3H)4.34-4.37(m,2H)4.79(s,2H)4.93(s,2H)5.59(s,2H)6.51-6.74(t,J＝52.4Hz,1H)6.77-6.80(m,2H)7.15-7.17(m,2H)7.29-7.39(m,5H)7.61(s,2H)。MS-ESI m/z:714.1[M+H] +。 Add WX016-5 (260mg, 544.96μmol, 1.1eq) and dichloroethane (10mL) to the pre-dried reaction flask, add WX003-6 (140.32mg, 495.42μmol, 1eq), and then add copper acetate (134.97). mg, 743.12μmol, 1.5eq) and pyridine (97.97mg, 1.24mmol, 99.97μL, 2.5eq), replaced with oxygen three times, placed at 40°C and stirred at 15psi for 16 hours. After the completion of the reaction, the reaction solution was quenched with water (50mL), extracted with ethyl acetate (50mL*3), combined the organic phases, washed with saturated brine (50mL*2), dried over anhydrous sodium sulfate, filtered, and reduced pressure Concentrate to obtain a crude product, which is purified by thin layer chromatography on silica gel plate (petroleum ether: ethyl acetate = 1:1) to obtain WX016-6. 1 HNMR(400MHz, deuterated chloroform)δ2.07-2.13(m,2H)2.60-2.65(m,2H)3.77(s,3H)4.34-4.37(m,2H)4.79(s,2H)4.93(s ,2H)5.59(s,2H)6.51-6.74(t,J=52.4Hz,1H)6.77-6.80(m,2H)7.15-7.17(m,2H)7.29-7.39(m,5H)7.61(s, 2H). MS-ESI m/z: 714.1 [M+H] + .
步骤7：化合物WX016-7的合成Step 7: Synthesis of compound WX016-7
在预先干燥的反应瓶中加入WX016-6(120mg,167.95μmol,1eq)和乙腈(4mL)，置于0℃下缓慢滴入硝 酸铈铵(276.22mg,503.85μmol,251.11μL,3eq)和水(2mL)的混合溶液，缓慢升温至25℃继续搅拌2小时。反应完毕后，将反应液用水(50mL)淬灭，然后用乙酸乙酯萃取(55mL*3)，合并有机相，有机相用饱和食盐水洗(55mL*2)，无水硫酸钠干燥，过滤，减压浓缩得粗产品，粗产品经薄层色谱硅胶板纯化(石油醚：乙酸乙酯＝1:1)得到WX016-7。 1HNMR(400MHz,氘代氯仿)δ2.10-2.18(m,2H)2.63-2.66(t,J＝6.38Hz,2H)4.38-4.44(m,2H)4.77(s,2H)5.58(s,2H)6.44-6.77(t,J＝52.4Hz,1H)7.29-7.41(m,5H)7.58(s,2H)9.39(s,1H)。MS-ESI m/z:594.2[M+H] +。 Add WX016-6 (120mg, 167.95μmol, 1eq) and acetonitrile (4mL) into the pre-dried reaction flask, and slowly drop in cerium ammonium nitrate (276.22mg, 503.85μmol, 251.11μL, 3eq) and water at 0℃. (2mL) of the mixed solution, slowly heated to 25°C and continued stirring for 2 hours. After the completion of the reaction, the reaction solution was quenched with water (50 mL), and then extracted with ethyl acetate (55 mL*3). The organic phases were combined, washed with saturated brine (55 mL*2), dried with anhydrous sodium sulfate, filtered, Concentrate under reduced pressure to obtain a crude product. The crude product is purified by thin-layer chromatography on a silica gel plate (petroleum ether: ethyl acetate = 1:1) to obtain WX016-7. 1 HNMR(400MHz, deuterated chloroform)δ2.10-2.18(m,2H)2.63-2.66(t,J=6.38Hz,2H)4.38-4.44(m,2H)4.77(s,2H)5.58(s, 2H) 6.44-6.77 (t, J=52.4 Hz, 1H) 7.29-7.41 (m, 5H) 7.58 (s, 2H) 9.39 (s, 1H). MS-ESI m/z: 594.2 [M+H] + .
步骤8：化合物WX016的合成Step 8: Synthesis of compound WX016
在预先干燥的反应瓶中加入WX016-7(90mg,151.43μmol,1eq)和二氯甲烷(3mL)，置换氮气三次，置于0℃下，缓慢滴入三溴化硼(75.87mg,302.85μmol,29.18μL,2eq)，0℃下搅拌0.5小时。反应完毕后，用饱和的碳酸氢钠溶液调节反应液pH至7左右，加入乙酸乙酯(20mL)稀释，分液要有机相，水相用乙酸乙酯(20mL*2)萃取，合并有机相，并用饱和食盐水(20mL*2)洗，无水硫酸钠干燥，过滤，滤液用水泵40℃下减压浓缩得到粗产品，粗产品经高效液相色谱分离(色谱柱:Phenomenex Luna C18 200*40mm*10μm；流动相:[水(0.2％甲酸)-乙腈]；乙腈％:20％-50％,8min)得到WX016。 1HNMR(400MHz,氘代二甲基亚砜)δ1.95-2.06(m,2H)2.42-2.45(t,J＝6.32Hz,2H)4.35-4.37(t,J＝4.94Hz,2H)6.70-7.10(t,J＝52.4Hz,1H)7.81(s,2H)11.88(s,1H)12.85(s,1H)。MS-ESI m/z:474.0[M+H] +。 Add WX016-7 (90mg, 151.43μmol, 1eq) and dichloromethane (3mL) to the pre-dried reaction flask, replace with nitrogen three times, place at 0℃, and slowly drop in boron tribromide (75.87mg, 302.85μmol). , 29.18μL, 2eq), stirred at 0°C for 0.5 hours. After the reaction is complete, adjust the pH of the reaction solution to about 7 with saturated sodium bicarbonate solution, add ethyl acetate (20mL) to dilute, separate the organic phase, extract the aqueous phase with ethyl acetate (20mL*2), combine the organic phases , Washed with saturated brine (20mL*2), dried with anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure with a water pump at 40°C to obtain a crude product, which was separated by high performance liquid chromatography (column: Phenomenex Luna C18 200* 40mm*10μm; mobile phase: [water (0.2% formic acid)-acetonitrile]; acetonitrile%: 20%-50%, 8min) to obtain WX016. 1 HNMR (400MHz, deuterated dimethyl sulfoxide) δ1.95-2.06(m,2H)2.42-2.45(t,J=6.32Hz,2H)4.35-4.37(t,J=4.94Hz,2H) 6.70 -7.10 (t, J=52.4 Hz, 1H) 7.81 (s, 2H) 11.88 (s, 1H) 12.85 (s, 1H). MS-ESI m/z: 474.0 [M+H] + .
实施例17Example 17
Figure PCTCN2020093284-appb-000151
Figure PCTCN2020093284-appb-000151
合成路线：synthetic route:
Figure PCTCN2020093284-appb-000152
Figure PCTCN2020093284-appb-000152
步骤1：化合物WX017-1的合成Step 1: Synthesis of compound WX017-1
将WX013-1(50g,351.84mmol,1eq)，二甲苯(400mL)，环丁砜(207.86g,1.76mol,5eq)加到反应瓶中，然后在135℃下反应12小时。反应完毕后，将反应液旋干得粗品。粗品经硅胶柱(石油醚:乙酸乙酯＝3:1至1:1)梯度淋洗纯化得WX017-1。WX013-1 (50g, 351.84mmol, 1eq), xylene (400mL), and sulfolane (207.86g, 1.76mol, 5eq) were added to the reaction flask, and then reacted at 135°C for 12 hours. After the completion of the reaction, the reaction solution was spin-dried to obtain a crude product. The crude product was purified by gradient elution on a silica gel column (petroleum ether: ethyl acetate = 3:1 to 1:1) to obtain WX017-1.
步骤2：化合物WX017-2的合成Step 2: Synthesis of compound WX017-2
在预先干燥的反应瓶中加入WX017-1(4.4g,22.43mmol,1eq)，之后用四氢呋喃(44mL)溶解，然后加入碘化钠(1.68g,11.21mmol,0.5eq)，三氟甲基三甲基硅(7.97g,56.07mmol,2.5eq)，缓慢的升高至65℃搅拌反应4小时，补加三氟甲基三甲基硅(7.97g,56.07mmol,2.5eq)，在65℃下继续搅拌反应15小时。反应完毕后，将反应液用水泵在45℃下旋干，之后用二氯甲烷(100mL)溶解，依次用水(100mL)，0.1N的硫代硫酸钠(100mL)，饱和食盐水(100mL)洗，之后用水泵在45℃下减压浓缩得到粗品，粗产品通过自动过柱机分离(梯度淋洗：石油醚:乙酸乙酯＝1:0至9:1)纯化得到WX017-2。 1HNMR(400MHz,氘代氯仿)δ3.77(s,6H),2.77-2.53(m,4H),1.80-1.90(m,2H)。 Add WX017-1 (4.4g, 22.43mmol, 1eq) to the pre-dried reaction flask, then dissolve it with tetrahydrofuran (44mL), then add sodium iodide (1.68g, 11.21mmol, 0.5eq), trifluoromethyl trifluoromethyl Methyl silicon (7.97g, 56.07mmol, 2.5eq), slowly increase to 65°C and stir for 4 hours, add trifluoromethyl trimethylsilyl (7.97g, 56.07mmol, 2.5eq) at 65°C Continue to stir and react for 15 hours. After the reaction, the reaction solution was spin-dried with a water pump at 45°C, and then dissolved in dichloromethane (100mL), washed with water (100mL), 0.1N sodium thiosulfate (100mL), and saturated brine (100mL) in turn Then, it was concentrated under reduced pressure with a water pump at 45°C to obtain the crude product. The crude product was separated by an automatic column machine (gradient elution: petroleum ether: ethyl acetate=1:0 to 9:1) and purified to obtain WX017-2. 1 HNMR (400MHz, deuterated chloroform) δ 3.77 (s, 6H), 2.77-2.53 (m, 4H), 1.80-1.90 (m, 2H).
步骤3：化合物WX017-3的合成Step 3: Synthesis of compound WX017-3
在预先干燥的反应瓶中加入WX017-2(3.59g,14.58mmol,1eq)，之后用甲醇(17mL)溶解，然后加入氢氧 化钠溶液(5.83g,14.58mmol,17mL,10％纯度,1eq)，室温(25℃)搅拌反应14小时。反应完毕后，用1N的盐酸中和反应液pH至6左右，直接减压浓缩得到WX017-3。Add WX017-2 (3.59g, 14.58mmol, 1eq) to the pre-dried reaction flask, then dissolve it with methanol (17mL), then add sodium hydroxide solution (5.83g, 14.58mmol, 17mL, 10% purity, 1eq) The reaction was stirred at room temperature (25°C) for 14 hours. After the reaction is completed, the pH of the reaction solution is neutralized to about 6 with 1N hydrochloric acid, and directly concentrated under reduced pressure to obtain WX017-3.
步骤4：化合物WX017-4的合成Step 4: Synthesis of compound WX017-4
在预先干燥的反应瓶中加入WX017-3(3.18g,14.58mmol,1eq)，之后用三氟乙酸酐(32mL)溶解，室温(25℃)搅拌反应14小时。反应完毕后，将反应液用水泵在45℃下减压浓缩得到WX017-4。WX017-3 (3.18g, 14.58mmol, 1eq) was added to the pre-dried reaction flask, and then dissolved with trifluoroacetic anhydride (32mL), and the reaction was stirred at room temperature (25°C) for 14 hours. After the completion of the reaction, the reaction solution was concentrated under reduced pressure with a water pump at 45°C to obtain WX017-4.
步骤5：化合物WX017-5的合成Step 5: Synthesis of compound WX017-5
在预先干燥的反应瓶中加入WX017-4(2.92g,14.59mmol,1eq)，之后用醋酸(58mL)溶解，然后加入水合肼(1.03g,17.51mmol,1.00mL,1.2eq)，升到100℃搅拌反应3小时。反应完毕后，将反应液冷却至室温，用水泵在60℃下旋出大部分溶剂，之后加水(20mL)，有固体析出，过滤，收集滤饼，滤饼用油泵在45℃下旋干得到WX017-5。 1H NMR(400MHz,氘代二甲基亚砜)δ11.82(s,1H),11.01(s,1H),2.71-2.57(m,4H),2.08-2.17(m,2H)。 Add WX017-4 (2.92g, 14.59mmol, 1eq) to the pre-dried reaction flask, then dissolve it with acetic acid (58mL), then add hydrazine hydrate (1.03g, 17.51mmol, 1.00mL, 1.2eq), and increase to 100 The reaction was stirred at °C for 3 hours. After the reaction, the reaction solution was cooled to room temperature, and most of the solvent was spun off with a water pump at 60°C. Then, water (20mL) was added. A solid precipitated out. Filtered and collected the filter cake. The filter cake was spin-dried at 45°C with an oil pump. WX017-5. 1 H NMR (400MHz, deuterated dimethyl sulfoxide) δ 11.82 (s, 1H), 11.01 (s, 1H), 2.71-2.57 (m, 4H), 2.08-2.17 (m, 2H).
步骤6：化合物WX017-6的合成Step 6: Synthesis of compound WX017-6
在预先干燥的反应瓶中加入WX017-5(1.28g,5.98mmol,1eq)，之后用三氯氧磷(12mL)溶解，110℃搅拌反应2小时。反应完毕后，将反应体系降至室温，然后将其缓慢的加入到室温水(100mL)中，加入石油醚(50mL)稀释，分液要有机相，水相用石油醚(50mL*2)萃取，合并有机相，并用饱和食盐水(50mL*2)洗涤，无水硫酸钠干燥，过滤，滤液用水泵在45℃下减压浓缩得到粗品，粗品通过自动过柱机分离(梯度淋洗：石油醚:乙酸乙酯＝1:0至2:8)纯化得到WX017-6。 1HNMR(400MHz,氘代甲醇)δ3.24-3.01(m,4H),2.19-2.28(m,2H)。 WX017-5 (1.28g, 5.98mmol, 1eq) was added to the pre-dried reaction flask, and then dissolved with phosphorus oxychloride (12mL), and the reaction was stirred at 110°C for 2 hours. After the reaction is complete, the reaction system is cooled to room temperature, and then slowly added to room temperature water (100mL), added petroleum ether (50mL) to dilute, separated into organic phase, the water phase is extracted with petroleum ether (50mL*2) , The organic phases were combined, washed with saturated brine (50mL*2), dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure with a water pump at 45°C to obtain a crude product. The crude product was separated by an automatic column machine (gradient elution: petroleum Ether: ethyl acetate=1:0 to 2:8) to obtain WX017-6. 1 HNMR (400MHz, deuterated methanol) δ 3.24-3.01 (m, 4H), 2.19-2.28 (m, 2H).
步骤7：化合物WX017-8的合成Step 7: Synthesis of compound WX017-8
在预先干燥的反应瓶中加入WX017-6(300mg,1.19mmol,1eq)，WX017-7(365.58mg,1.31mmol,1.1eq)和甲苯(10mL)，加入磷酸钾(507.30mg,2.39mmol,2eq)，置换氮气三次，加入2-二叔丁基膦-2′,4′,6′-三异丙基联苯(101.48mg,238.99μmol,0.2eq)和醋酸钯(53.65mg,238.99μmol,0.2eq)，再次置换氮气三次，置于50℃下搅拌16小时，升温至100℃继续搅拌16小时。反应完毕后，将反应体系冷却至室温，向反应液中加入石油醚(30mL)，经硅藻土过滤，滤液减压浓缩得粗产品，粗产品经薄层色谱硅胶板纯化(石油醚：石油醚＝5:1)得到WX017-8。 1HNMR(400MHz,氘代氯仿)δ1.53(s,9H)2.12(d,J＝11.6Hz,2H)3.05(s,2H)3.19(s,2H)6.53(s,1H)7.47(s,2H)。MS-ESI m/z:492.0[M+H] +。 Add WX017-6 (300mg, 1.19mmol, 1eq), WX017-7 (365.58mg, 1.31mmol, 1.1eq) and toluene (10mL) into the pre-dried reaction flask, add potassium phosphate (507.30mg, 2.39mmol, 2eq) ), replace with nitrogen three times, add 2-di-tert-butylphosphine-2',4',6'-triisopropylbiphenyl (101.48mg, 238.99μmol, 0.2eq) and palladium acetate (53.65mg, 238.99μmol, 0.2eq), replaced with nitrogen again three times, placed at 50°C and stirred for 16 hours, heated to 100°C and continued stirring for 16 hours. After the completion of the reaction, the reaction system was cooled to room temperature, petroleum ether (30 mL) was added to the reaction solution, filtered through Celite, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by thin-layer chromatography on a silica gel plate (petroleum ether: petroleum ether). Ether = 5:1) to obtain WX017-8. 1 HNMR (400MHz, deuterated chloroform) δ 1.53 (s, 9H) 2.12 (d, J = 11.6 Hz, 2H) 3.05 (s, 2H) 3.19 (s, 2H) 6.53 (s, 1H) 7.47 (s, 2H). MS-ESI m/z: 492.0 [M+H] + .
步骤8：化合物WX017-9的合成Step 8: Synthesis of compound WX017-9
在预先干燥的反应瓶中加入WX017-8(120mg,243.54μmol,1eq)和醋酸(2mL)，加入醋酸钠(39.96mg,487.08μmol,2eq)，置换氮气三次，置于110℃搅拌16小时。反应完毕后，将反应液冷却至室温，减压浓缩得到WX017-9。MS-ESI m/z:416.0[M+H] +。 Add WX017-8 (120mg, 243.54μmol, 1eq) and acetic acid (2mL) to the pre-dried reaction flask, add sodium acetate (39.96mg, 487.08μmol, 2eq), replace nitrogen for three times, and place at 110°C and stir for 16 hours. After the completion of the reaction, the reaction solution was cooled to room temperature and concentrated under reduced pressure to obtain WX017-9. MS-ESI m/z: 416.0 [M+H] + .
步骤9：化合物WX017-10的合成Step 9: Synthesis of compound WX017-10
在预先干燥的反应瓶中加入WX017-9(100mg,240.27μmol,1eq)和乙醇(2mL)，加入HCl(2M,2mL,16.65eq)，置于90℃下搅拌16小时。反应完成后，将反应液中减压浓缩，然后用固体碳酸氢钠调节pH至7～8，乙酸乙酯萃取水相(15mL*3)，合并有机相，有机相用饱和食盐水洗涤(20mL*2)，无水硫酸钠干燥，过滤，减压浓缩得粗产品，粗产品经薄层色谱硅胶板纯化(石油醚：乙酸乙酯＝1:5)得到WX017-10。 1H NMR(400MHz,氘代氯仿)δ1.99-2.10(m,2H)2.92(s,2H)3.05(s,2H)6.68(s,2H)9.24(br s,1H)。MS-ESI m/z:374.9[M+H] +。 Add WX017-9 (100mg, 240.27μmol, 1eq) and ethanol (2mL) to the pre-dried reaction flask, add HCl (2M, 2mL, 16.65eq), and place at 90°C and stir for 16 hours. After the completion of the reaction, the reaction solution was concentrated under reduced pressure, and then the pH was adjusted to 7-8 with solid sodium bicarbonate, the aqueous phase was extracted with ethyl acetate (15mL*3), the organic phases were combined, and the organic phase was washed with saturated brine (20mL *2), dry with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain a crude product. The crude product is purified by thin layer chromatography on a silica gel plate (petroleum ether: ethyl acetate = 1:5) to obtain WX017-10. 1 H NMR (400MHz, deuterated chloroform) δ 1.99-2.10 (m, 2H) 2.92 (s, 2H) 3.05 (s, 2H) 6.68 (s, 2H) 9.24 (br s, 1H). MS-ESI m/z: 374.9 [M+H] + .
步骤10：化合物WX017-11的合成Step 10: Synthesis of compound WX017-11
在预先干燥的反应瓶中加入WX017-10(48mg,128.28μmol,1eq)和冰乙酸(1mL)，置于0℃下缓慢加入浓盐酸(12M,33.03μL,3.09eq)，缓慢加入亚硝酸钠(9.38mg,135.98μmol,1.06eq)和水(1mL)和混合溶液，置于0℃下搅拌1.5小时，然后加入WX001-9(22.03mg,141.11μmol,1.1eq)，在0℃下继续搅拌2.5小时。反应完毕后，将反应液在0℃下缓慢加入乙酸钠(3eq)和水(3mL)的混合溶液，有大量固体生成，过滤，收集滤饼，滤饼减压浓缩得到WX017-11。MS-ESI m/z:541.1[M+H] +,543.1[M+H+2] +。 Add WX017-10 (48mg, 128.28μmol, 1eq) and glacial acetic acid (1mL) to the pre-dried reaction flask, and slowly add concentrated hydrochloric acid (12M, 33.03μL, 3.09eq) at 0℃, and slowly add sodium nitrite (9.38mg, 135.98μmol, 1.06eq) and water (1mL) and mixed solution, placed at 0℃ and stirred for 1.5 hours, then add WX001-9 (22.03mg, 141.11μmol, 1.1eq), continue stirring at 0℃ 2.5 hours. After the reaction was completed, the reaction solution was slowly added to a mixed solution of sodium acetate (3eq) and water (3mL) at 0°C, a large amount of solids were formed, filtered, the filter cake was collected, and the filter cake was concentrated under reduced pressure to obtain WX017-11. MS-ESI m/z: 541.1 [M+H] +, 543.1 [M+H+2] + .
步骤11：化合物WX017的合成Step 11: Synthesis of compound WX017
在预先干燥的反应瓶中加入WX017-11(68mg,125.63μmol,1eq)和N,N-二甲基乙酰胺(1mL)，加入醋酸钾(14.18mg,144.47μmol,1.15eq)，置换氮气三次，置于115℃下搅拌6小时。反应完毕后，直接将反应液过滤，滤液经高效液相色谱分离(色谱柱:Phenomenex Luna C18 200*40mm*10μm；流动相:[水(0.2％甲酸)-乙腈]；乙腈％:25％-55％,8min)得到WX017。 1HNMR(400MHz,氘代甲醇)δ2.18-2.22(d,J＝13.4Hz,2H)2.89(s,2H)3.06-3.21(m,2H)7.77(s,2H)。MS-ESI m/z:495.0[M+H] +。 Add WX017-11 (68mg, 125.63μmol, 1eq) and N,N-dimethylacetamide (1mL) to the pre-dried reaction flask, add potassium acetate (14.18mg, 144.47μmol, 1.15eq), and replace with nitrogen three times , Placed at 115 ℃ and stirred for 6 hours. After the reaction, the reaction solution was directly filtered, and the filtrate was separated by high performance liquid chromatography (column: Phenomenex Luna C18 200*40mm*10μm; mobile phase: [water (0.2% formic acid)-acetonitrile]; acetonitrile%: 25%- 55%, 8min) to get WX017. 1 HNMR (400MHz, deuterated methanol) δ 2.18-2.22 (d, J=13.4 Hz, 2H) 2.89 (s, 2H) 3.06-3.21 (m, 2H) 7.77 (s, 2H). MS-ESI m/z: 495.0 [M+H] + .
实施例18Example 18
Figure PCTCN2020093284-appb-000153
Figure PCTCN2020093284-appb-000153
合成路线：synthetic route:
Figure PCTCN2020093284-appb-000154
Figure PCTCN2020093284-appb-000154
步骤1：化合物WX018-1的合成Step 1: Synthesis of compound WX018-1
将WX008-3(3g,6.94mmol,1eq)和乙烯基三正丁基锡(3.30g,10.41mmol,3.03mL,1.5eq)加入到50mL单口瓶中，加入1,4-二氧六环(30mL)，置换氮气三次，加入三苯基膦(546.09mg,2.08mmol,0.3eq)和醋酸钯(233.72mg,1.04mmol,0.15eq)，再置换氮气三次，反应液升温至80℃搅拌12小时。反应完成后，向反应液中加入20mL饱和氟化钾水溶液，室温搅拌1小时，过滤，滤液用乙酸乙酯(50mL*2)萃取，合并有机相直接减压浓缩得到WX018-1，没有进行纯化，产物易坏，直接用于下一步。Add WX008-3 (3g, 6.94mmol, 1eq) and vinyl tri-n-butyltin (3.30g, 10.41mmol, 3.03mL, 1.5eq) into a 50mL single-mouth bottle, add 1,4-dioxane (30mL) , Nitrogen was replaced three times, triphenylphosphine (546.09mg, 2.08mmol, 0.3eq) and palladium acetate (233.72mg, 1.04mmol, 0.15eq) were added, and nitrogen was replaced three times. The reaction solution was heated to 80°C and stirred for 12 hours. After the reaction is completed, add 20mL saturated potassium fluoride aqueous solution to the reaction solution, stir at room temperature for 1 hour, filter, and extract the filtrate with ethyl acetate (50mL*2). The combined organic phases are directly concentrated under reduced pressure to obtain WX018-1 without purification. , The product is easy to be damaged, directly used in the next step
步骤2：化合物WX018-2的合成Step 2: Synthesis of compound WX018-2
向反应瓶中加入WX018-1(5.2g,13.71mmol,1eq)，叔丁醇(20mL)，水(70mL)和乙腈(20mL)，抽换氮气后降温至0℃，随后加入四氧化锇(348.43mg,1.37mmol,71.11μL,0.1eq)和高碘酸钠(5.86g,27.41mmol,1.52mL,2eq)，25℃下混合液反应3小时。反应完成后，向反应液中加入饱和亚硫酸钠水溶液(30mL)，室温搅拌2小时，然后用乙酸乙酯(50mL*2)萃取，合并有机相，减压浓缩得到粗品，粗品用过柱机(洗脱剂极性，石油醚：乙酸乙酯＝20％-30％)纯化得到WX018-2。 1H NMR(400MHz,氘代氯仿)δ9.82(s,1H),7.40-7.42(d,J＝8.8Hz,2H),7.24-7.32(m,5H),6.90-6.92(d,J＝8.8Hz,2H),5.48(s,2H),5.16(s,2H),4.70(s,2H),3.82(s,3H)。 WX018-1 (5.2g, 13.71mmol, 1eq), tert-butanol (20mL), water (70mL) and acetonitrile (20mL) were added to the reaction flask, the temperature was reduced to 0°C after the nitrogen was changed, and then osmium tetroxide ( 348.43mg, 1.37mmol, 71.11μL, 0.1eq) and sodium periodate (5.86g, 27.41mmol, 1.52mL, 2eq), the mixed solution reacted at 25℃ for 3 hours. After the reaction is complete, add saturated sodium sulfite aqueous solution (30mL) to the reaction solution, stir at room temperature for 2 hours, then extract with ethyl acetate (50mL*2), combine the organic phases, concentrate under reduced pressure to obtain the crude product, and use the column machine (washing Removal polarity, petroleum ether: ethyl acetate = 20%-30%) and purified to obtain WX018-2. 1 H NMR (400MHz, deuterated chloroform) δ 9.82 (s, 1H), 7.40-7.42 (d, J = 8.8 Hz, 2H), 7.24-7.32 (m, 5H), 6.90-6.92 (d, J = 8.8Hz, 2H), 5.48 (s, 2H), 5.16 (s, 2H), 4.70 (s, 2H), 3.82 (s, 3H).
步骤3：化合物WX018-3的合成Step 3: Synthesis of compound WX018-3
将WX018-2(1.6g,4.20mmol,1eq)和1,2-二氯乙烷(20mL)加入到100mL三口瓶中，降温至0℃，加入醋酸硼氢化钠(1.38g,6.50mmol,1.55eq)，加料完成后，25℃下搅拌3小时。反应完成后。将反应液缓慢加入到饱和氯化铵水溶液(20mL)中，用乙酸乙酯(20mL*3)萃取，合并有机相，用无水硫酸钠干燥，过滤，减压浓缩得到粗品，粗品用快速硅胶柱纯化(洗脱剂极性，石油醚：乙酸乙酯＝10％-20％-30％)得 到WX018-3。 1H NMR(400MHz,氘代氯仿)δ7.27-7.38(m,7H),6.88-6.89(d,J＝6.4Hz,2H),5.47(s,2H),5.04(s,2H),4.69(s,2H),4.55(s,2H),3.81(s,3H)。 Add WX018-2 (1.6g, 4.20mmol, 1eq) and 1,2-dichloroethane (20mL) into a 100mL three-neck flask, cool to 0℃, add sodium acetate borohydride (1.38g, 6.50mmol, 1.55 eq), after the addition is complete, stir at 25°C for 3 hours. After the reaction is complete. The reaction solution was slowly added to a saturated aqueous ammonium chloride solution (20mL), extracted with ethyl acetate (20mL*3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. Column purification (polar eluent, petroleum ether: ethyl acetate = 10%-20%-30%) to obtain WX018-3. 1 H NMR (400MHz, deuterated chloroform) δ 7.27-7.38 (m, 7H), 6.88-6.89 (d, J = 6.4 Hz, 2H), 5.47 (s, 2H), 5.04 (s, 2H), 4.69 (s, 2H), 4.55 (s, 2H), 3.81 (s, 3H).
步骤4：化合物WX018-4的合成Step 4: Synthesis of compound WX018-4
将WX018-3(1.2g,3.13mmol,1eq)加入到40mL投库瓶中，加入1,2-二氯甲烷(20mL)，降温至0℃，加入二乙胺基三氟化硫(504.51mg,3.13mmol,413.53μL,1eq)，升至室温(27℃)搅拌3小时。反应完成后。向反应液中加入水(10mL)，用乙酸乙酯(10mL*3)萃取，合并有机相，有机相用无水硫酸钠干燥，过滤，减压浓缩得到粗品，粗用快速硅胶柱纯化(洗脱剂极性，石油醚：乙酸乙酯＝10％-20％-30％)得到WX018-4。 1H NMR(400MHz,氘代氯仿)δ7.18-7.30(m,7H),6.80-6.82(d,J＝8.8Hz,2H),5.39(s,2H),5.20(s,1H),5.08(s,1H),4.97(s,2H),4.61(s,2H),3.73(s,3H)。 Add WX018-3 (1.2g, 3.13mmol, 1eq) to a 40mL throwing bottle, add 1,2-dichloromethane (20mL), cool to 0℃, add diethylaminosulfur trifluoride (504.51mg , 3.13mmol, 413.53μL, 1eq), warm to room temperature (27°C) and stir for 3 hours. After the reaction is complete. Water (10mL) was added to the reaction solution, extracted with ethyl acetate (10mL*3), the organic phases were combined, the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by a flash silica gel column (washing Removal polarity, petroleum ether: ethyl acetate = 10%-20%-30%) to obtain WX018-4. 1 H NMR (400MHz, deuterated chloroform) δ7.18-7.30 (m, 7H), 6.80-6.82 (d, J = 8.8Hz, 2H), 5.39 (s, 2H), 5.20 (s, 1H), 5.08 (s, 1H), 4.97 (s, 2H), 4.61 (s, 2H), 3.73 (s, 3H).
步骤5：化合物WX018-5的合成Step 5: Synthesis of compound WX018-5
将WX018-4(0.5g,1.30mmol,1eq)和乙腈(10mL)加入到预先干燥的40mL投库瓶中，降温至0℃，将硝酸铈铵(1.42g,2.59mmol,1.29mL,2eq)溶于水(5mL)中，滴入反应液，滴加完成后，升至室温(25℃)搅拌3小时。反应完成后，将反应液直接减压浓缩得到粗品，粗品用快速硅胶柱纯化(洗脱剂极性，石油醚：乙酸乙酯＝10％-20％-30％)得到WX018-5。 1HNMR(400MHz,氘代氯仿)δ9.54(s,1H),7.31-7.38(m,5H),5.48(s,2H),5.32(s,1H),5.20(s,1H),4.73(s,2H)。 Add WX018-4 (0.5g, 1.30mmol, 1eq) and acetonitrile (10mL) to a pre-dried 40mL throwing library bottle, cool to 0℃, add cerium ammonium nitrate (1.42g, 2.59mmol, 1.29mL, 2eq) Dissolve in water (5 mL), add dropwise to the reaction solution, after the dropwise addition is completed, warm to room temperature (25°C) and stir for 3 hours. After the reaction is completed, the reaction solution is directly concentrated under reduced pressure to obtain the crude product, and the crude product is purified by a flash silica gel column (eluent polarity, petroleum ether: ethyl acetate = 10%-20%-30%) to obtain WX018-5. 1 HNMR (400MHz, deuterated chloroform) δ 9.54 (s, 1H), 7.31-7.38 (m, 5H), 5.48 (s, 2H), 5.32 (s, 1H), 5.20 (s, 1H), 4.73 ( s, 2H).
步骤6：化合物WX018-6的合成Step 6: Synthesis of compound WX018-6
将WX018-5(0.29g,1.09mmol,1eq)和WX005-6(675.33mg,1.42mmol,1.3eq)，1,2-二氯乙烷(2mL)加入到50mL单口瓶中抽换氧气三次，加入醋酸铜(297.88mg,1.64mmol,1.5eq)和吡啶(216.21mg,2.73mmol,220.62μL,2.5eq)，继续抽换氧气三次，升温至40℃搅拌12小时。反应完成后，反应液用硅藻土过滤，滤液减压旋干，粗品用快速硅胶柱纯化(洗脱剂极性，石油醚：乙酸乙酯＝10％-20％-30％)得到WX018-6。 1HNMR(400MHz,氘代氯仿)δ7.34-7.43(m,7H),7.24-7.26(d,J＝8.8Hz,2H),6.79-6.81(d,J＝8.8Hz,2H),5.63(s,2H),5.34-4.46(d,J＝46.4Hz,2H),4.98(s,2H),4.82(s,2H),3.79(s,3H),2.64-2.73(m,4H),1.65(s,4H)。 Add WX018-5 (0.29g, 1.09mmol, 1eq) and WX005-6 (675.33mg, 1.42mmol, 1.3eq), 1,2-dichloroethane (2mL) into a 50mL single-necked flask to pump oxygen three times, Add copper acetate (297.88mg, 1.64mmol, 1.5eq) and pyridine (216.21mg, 2.73mmol, 220.62μL, 2.5eq), continue to pump oxygen three times, and heat to 40°C and stir for 12 hours. After the completion of the reaction, the reaction solution was filtered with celite, the filtrate was spin-dried under reduced pressure, and the crude product was purified by a flash silica gel column (eluent polarity, petroleum ether: ethyl acetate = 10%-20%-30%) to obtain WX018- 6. 1 HNMR (400MHz, deuterated chloroform) δ7.34-7.43 (m, 7H), 7.24-7.26 (d, J = 8.8Hz, 2H), 6.79-6.81 (d, J = 8.8Hz, 2H), 5.63 ( s,2H),5.34-4.46(d,J=46.4Hz,2H),4.98(s,2H),4.82(s,2H),3.79(s,3H),2.64-2.73(m,4H),1.65 (s, 4H).
步骤7：化合物WX018-7的合成Step 7: Synthesis of compound WX018-7
将WX018-6(0.4g,575.92μmol,1eq)加入到50mL单口瓶中，加入乙腈(12mL)溶解，降温至0℃，将硝酸铈铵(947.20mg,1.73mmol,861.09μL,3eq)溶于水(4mL)中滴加到反应液中，保持温度0℃，滴加完成后，缓慢升至室温(25℃)搅拌3小时。反应完成后，向反应液中加入水(10mL)，加入乙酸乙酯(10mL*3)萃取，合并有机相，有机相用饱和食盐水(10mL)洗，无水硫酸钠干燥，过滤，减压旋干。粗品用薄层层析硅胶板(石油醚：乙酸乙酯＝1:1)纯化得到WX018-7。 1HNMR(400MHz,氘代氯仿)δ7.30-7.38(m,7H),5.58(s,2H),5.38(s,1H),5.27(s,1H),4.77(s,2H),2.64-2.74(m,4H),1.87(s,4H)。 Add WX018-6 (0.4g, 575.92μmol, 1eq) to a 50mL single-necked flask, add acetonitrile (12mL) to dissolve, cool to 0℃, and dissolve cerium ammonium nitrate (947.20mg, 1.73mmol, 861.09μL, 3eq) Water (4 mL) was added dropwise to the reaction solution, keeping the temperature at 0°C, after the addition was completed, slowly raising to room temperature (25°C) and stirring for 3 hours. After the completion of the reaction, water (10mL) was added to the reaction solution, ethyl acetate (10mL*3) was added for extraction, the organic phases were combined, and the organic phases were washed with saturated brine (10mL), dried over anhydrous sodium sulfate, filtered, and reduced pressure Spin dry. The crude product was purified by thin layer chromatography on silica gel plate (petroleum ether: ethyl acetate = 1:1) to obtain WX018-7. 1 HNMR (400MHz, deuterated chloroform) δ 7.30-7.38 (m, 7H), 5.58 (s, 2H), 5.38 (s, 1H), 5.27 (s, 1H), 4.77 (s, 2H), 2.64 2.74 (m, 4H), 1.87 (s, 4H).
步骤8：化合物WX018-8的合成Step 8: Synthesis of compound WX018-8
向反应瓶中加入WX018-7(0.18g,313.38μmol,1eq)和二氯甲烷(2mL)，抽换氮气后降温至0℃，随后加 入三溴化硼(157.02mg,626.76μmol,60.39μL,2eq)，0℃下混合液反应20分钟。反应完成后，将反应液倒入水(10mL)中淬灭，加入二氯甲烷(10mL*5)萃取，合并有机相，用饱和食盐水(20mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩得到WX018-8。Add WX018-7 (0.18g, 313.38μmol, 1eq) and dichloromethane (2mL) to the reaction flask, pump nitrogen and cool to 0℃, then add boron tribromide (157.02mg, 626.76μmol, 60.39μL, 2eq), the mixed solution was reacted at 0°C for 20 minutes. After the reaction was completed, the reaction solution was poured into water (10mL) for quenching, and dichloromethane (10mL*5) was added for extraction. The organic phases were combined, washed with saturated brine (20mL), dried with anhydrous sodium sulfate, filtered, and the filtrate Concentrate under reduced pressure to obtain WX018-8.
步骤9：化合物WX018的合成Step 9: Synthesis of compound WX018
将WX018-8(0.04g,77.65μmol,1eq)，碳酸钾(21.46mg,155.30μmol,2eq)，二氯甲烷(2mL)和水(2mL)加入到8mL拇指瓶中，抽换氮气三次，降温至0℃，加入四丁基溴化铵(375.47μg,1.16μmol,0.015eq)和三甲基氰硅烷(15.41mg,155.30μmol,19.43μL,2eq)，抽换氮气三次，升温至25℃，搅拌12小时。反应完成后，将反应液直接旋干，没有进行后处理，加入1mL二甲基亚砜溶解后，过滤，滤液用高效液相色谱法分离(条件：色谱柱:Luna Omega 5u Polar C18 100A；流动相:[水(0.04％盐酸)-乙腈]；乙腈％:33％-57％,7分钟)得到WX018。 1H NMR(400MHz,氘代二甲基亚砜)δ12.71(s,1H),12.05(s,1H),7.80(s,2H),4.05(s,2H),2.67(s,2H),2.44(s,2H),1.75-1.76(m,4H)。MS-ESI m/z:461.1[M+H] +,463.0[M+H+2] +。 Add WX018-8 (0.04g, 77.65μmol, 1eq), potassium carbonate (21.46mg, 155.30μmol, 2eq), dichloromethane (2mL) and water (2mL) into an 8mL thumb bottle, pump nitrogen for three times, and cool down To 0°C, add tetrabutylammonium bromide (375.47μg, 1.16μmol, 0.015eq) and trimethylsilyl cyanide (15.41mg, 155.30μmol, 19.43μL, 2eq), pump nitrogen for three times, and heat to 25°C, Stir for 12 hours. After the completion of the reaction, the reaction solution was spin-dried directly without post-treatment. After adding 1 mL of dimethyl sulfoxide to dissolve, filter, and separate the filtrate by high performance liquid chromatography (condition: column: Luna Omega 5u Polar C18 100A; mobile) Phase: [water (0.04% hydrochloric acid)-acetonitrile]; acetonitrile%: 33%-57%, 7 minutes) to obtain WX018. 1 H NMR (400MHz, deuterated dimethyl sulfoxide) δ 12.71 (s, 1H), 12.05 (s, 1H), 7.80 (s, 2H), 4.05 (s, 2H), 2.67 (s, 2H) , 2.44 (s, 2H), 1.75-1.76 (m, 4H). MS-ESI m/z: 461.1 [M+H] + , 463.0 [M+H+2] + .
实施例19Example 19
Figure PCTCN2020093284-appb-000155
Figure PCTCN2020093284-appb-000155
合成路线：synthetic route:
Figure PCTCN2020093284-appb-000156
Figure PCTCN2020093284-appb-000156
步骤1：化合物WX019-1的合成Step 1: Synthesis of compound WX019-1
将WX018-8(100mg,194.12μmol,1eq)，水(0.5mL)和二甲基亚砜(1mL)加入到预先干燥的反应瓶中，抽换氮气三次，升温至50℃，搅拌24小时。反应完成后，反应液直接过滤，滤液用高效液相色谱法分离纯化(条件：色谱柱:Welch Xtimate C18 150*25mm*5μm；流动相:[水(0.04％盐酸)-乙腈]；乙腈％:30％-45％,10分钟)得到WX019-1。WX018-8 (100mg, 194.12μmol, 1eq), water (0.5mL) and dimethyl sulfoxide (1mL) were added to the pre-dried reaction flask, the nitrogen was pumped three times, and the temperature was raised to 50°C and stirred for 24 hours. After the reaction is completed, the reaction solution is directly filtered, and the filtrate is separated and purified by high performance liquid chromatography (condition: Column: Welch Xtimate C18 150*25mm*5μm; mobile phase: [water (0.04% hydrochloric acid)-acetonitrile]; acetonitrile%: 30%-45%, 10 minutes) to obtain WX019-1.
步骤2：化合物WX019的合成Step 2: Synthesis of compound WX019
将WX019-1(0.02g,44.22μmol,1eq)加入到8mL的投库瓶中，加入二氯甲烷(2mL)，降温至0℃，加入二乙胺基三氟化硫(10.69mg,66.34μmol,8.76μL,1.5eq)，升温至27℃搅拌1小时。反应完成后，向反应液中加入水(10mL)，用乙酸乙酯(10mL*3)萃取，合并有机相，有机相用无水硫酸钠干燥，过滤， 减压浓缩得到粗品，粗品用高效液相色谱法分离纯化(条件：色谱柱:Phenomenex luna C18 80*40mm*3μm；流动相:[水(0.04％盐酸)-乙腈]；乙腈％:32％-56％,7分钟)得到WX019。 1HNMR(400MHz,氘代二甲基亚砜)δ12.69(s,1H),12.08(s,1H),7.82(s,2H),5.25-5.36(d,J＝46.8Hz,2H),2.67(s,2H),2.44(s,2H),1.77(s,4H)。MS-ESI m/z:454.0[M+H] +,456.0[M+H+2] +。 Add WX019-1 (0.02g, 44.22μmol, 1eq) to an 8mL library bottle, add dichloromethane (2mL), cool to 0℃, add diethylaminosulfur trifluoride (10.69mg, 66.34μmol , 8.76μL, 1.5eq), heated to 27°C and stirred for 1 hour. After the reaction is complete, add water (10mL) to the reaction solution, extract with ethyl acetate (10mL*3), combine the organic phases, dry the organic phase with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain a crude product. Separation and purification by phase chromatography (conditions: chromatographic column: Phenomenex luna C18 80*40mm*3μm; mobile phase: [water (0.04% hydrochloric acid)-acetonitrile]; acetonitrile%: 32%-56%, 7 minutes) to obtain WX019. 1 HNMR (400MHz, deuterated dimethyl sulfoxide) δ12.69 (s, 1H), 12.08 (s, 1H), 7.82 (s, 2H), 5.25-5.36 (d, J = 46.8 Hz, 2H), 2.67 (s, 2H), 2.44 (s, 2H), 1.77 (s, 4H). MS-ESI m/z: 454.0 [M+H] + , 456.0 [M+H+2] + .
实施例20Example 20
Figure PCTCN2020093284-appb-000157
Figure PCTCN2020093284-appb-000157
合成路线：synthetic route:
Figure PCTCN2020093284-appb-000158
Figure PCTCN2020093284-appb-000158
步骤1：化合物WX020-1的合成Step 1: Synthesis of compound WX020-1
在预先干燥的三口烧瓶中加入四氢呋喃(1500mL)和WX011-1(25g,252.19mmol,1eq)，然后0℃下加入氢化钠(13.11g,327.85mmol,60％纯度,1.3eq)搅拌1小时，加入对甲氧基苄氯(51.34g,327.85mmol,44.65mL,1.3eq)，继续搅拌1小时，然后升温到80℃搅拌12小时。反应完成后，将反应液小心地加入冰水(300mL)中淬灭，然后用乙酸乙酯(100mL*3)萃取，有机相用饱和氯化铵溶液(100mL*2)洗，无水硫酸钠干燥，过滤，减压浓缩得到粗品，粗产品然后经柱层析纯化(石油醚：乙酸乙酯＝3:1至1:1)得到WX020-1。 1H NMR(400MHz,氘代二甲基亚砜)δ7.18-7.15(m,2H)6.90-6.88(m,2H)4.42(s,2H)3.74(s,3H)3.14-3.13(m,2H)2.28-2.27(m,2H)1.66-1.70(m,4H)。 Add tetrahydrofuran (1500mL) and WX011-1 (25g, 252.19mmol, 1eq) in a pre-dried three-necked flask, then add sodium hydride (13.11g, 327.85mmol, 60% purity, 1.3eq) at 0°C and stir for 1 hour. Add p-methoxybenzyl chloride (51.34g, 327.85mmol, 44.65mL, 1.3eq), continue to stir for 1 hour, and then heat to 80°C and stir for 12 hours. After the reaction was completed, the reaction solution was carefully added to ice water (300mL) to quench, and then extracted with ethyl acetate (100mL*3), the organic phase was washed with saturated ammonium chloride solution (100mL*2), anhydrous sodium sulfate Dry, filter, and concentrate under reduced pressure to obtain a crude product. The crude product is then purified by column chromatography (petroleum ether: ethyl acetate = 3:1 to 1:1) to obtain WX020-1. 1 H NMR (400MHz, deuterated dimethyl sulfoxide) δ7.18-7.15(m,2H)6.90-6.88(m,2H)4.42(s,2H)3.74(s,3H)3.14-3.13(m, 2H) 2.28-2.27 (m, 2H) 1.66-1.70 (m, 4H).
步骤2：化合物WX020-2的合成Step 2: Synthesis of compound WX020-2
在干燥的1L圆底烧瓶中加入WX020-1(48g,218.90mmol,1eq)，然后加入甲苯(550mL)和劳森试剂(89.19g,218.90mmol,1eq)，80℃搅拌反应2小时。反应完成后，反应液直接减压浓缩干，然后经柱层析纯化(石油醚：乙酸乙酯＝3:1至1:1)得到WX020-2。 1H NMR(400MHz,氘代二甲基亚砜)δ7.24-7.19(m,2H)6.79-6.81(m,2H)5.19(s,2H)3.73(s,3H)3.26-3.25(m,2H)3.01-3.00(m,2H)1.66-1.75(m,4H)。 WX020-1 (48g, 218.90mmol, 1eq) was added to a dry 1L round bottom flask, and then toluene (550mL) and Lawson's reagent (89.19g, 218.90mmol, 1eq) were added, and the reaction was stirred at 80°C for 2 hours. After the completion of the reaction, the reaction solution was directly concentrated to dryness under reduced pressure, and then purified by column chromatography (petroleum ether: ethyl acetate=3:1 to 1:1) to obtain WX020-2. 1 H NMR (400MHz, deuterated dimethyl sulfoxide) δ7.24-7.19(m,2H)6.79-6.81(m,2H)5.19(s,2H)3.73(s,3H)3.26-3.25(m, 2H) 3.01-3.00 (m, 2H) 1.66-1.75 (m, 4H).
步骤3：化合物WX020-3的合成Step 3: Synthesis of compound WX020-3
在干燥的1L圆底烧瓶中加入WX020-2(55g,233.70mmol,1eq)，然后加入无水乙醇(550mL)和碘甲烷(49.76g,350.55mmol,21.82mL,1.5eq)，80℃搅拌反应1.5小时。反应完成后，反应液浓缩干，然后加入四氢呋喃(100mL)打浆，得到WX020-3。 1H NMR(400MHz,氘代二甲基亚砜)δ7.37-7.35(m,2H)7.01-6.98(m,2H)5.03(s,2H)3.78(s,3H)3.75-3.72(m,2H)3.18(s,2H)2.81(s,3H)1.84-1.82(m,4H)。 Add WX020-2 (55g, 233.70mmol, 1eq) in a dry 1L round bottom flask, then add absolute ethanol (550mL) and methyl iodide (49.76g, 350.55mmol, 21.82mL, 1.5eq), stir and react at 80℃ 1.5 hours. After the completion of the reaction, the reaction solution was concentrated to dryness, and then tetrahydrofuran (100 mL) was added for beating to obtain WX020-3. 1 H NMR (400MHz, deuterated dimethyl sulfoxide) δ7.37-7.35(m,2H)7.01-6.98(m,2H)5.03(s,2H)3.78(s,3H)3.75-3.72(m, 2H) 3.18 (s, 2H) 2.81 (s, 3H) 1.84-1.82 (m, 4H).
步骤4：化合物WX020-4的合成Step 4: Synthesis of compound WX020-4
将WX020-3(10g,26.36mmol,1eq)和四氢呋喃(100mL)加入到250mL单口瓶中，加入叔丁醇钾(4.44g,39.55mmol,1.5eq)，室温(25℃)，搅拌30分钟，过滤，滤液减压旋干，加入甲苯(50mL)，过滤，另外准备一个干燥的250mL三口瓶，加入WX007-1(1.99g,13.18mmol,0.5eq)和甲苯(30mL)，氮气置换三次，降温至0℃，滴入刚刚过滤的甲苯溶液，控制温度保持0℃，滴加完成后升温至25℃搅拌12小时。反应完成后，反应液加入水(100mL)，用乙酸乙酯(100mL*5)萃取，合并有机相，有机相用饱和食盐水(200mL)洗，无水硫酸钠干燥，过滤，减压浓缩得到粗品，粗品用快速硅胶柱分离纯化(洗脱剂极性，石油醚：乙酸乙酯＝10％-20％-30％)得到WX020-4。 1HNMR(400MHz,氘代氯仿)δ1.87-1.92(m,2H)2.75-2.78(m,2H)3.11-3.14(m,2H)3.83(s,3H)4.61(s,2H)6.91-6.93(d,J＝8.4Hz,2H)7.30-7.33(d,J＝8.8Hz,2H)。 Add WX020-3 (10g, 26.36mmol, 1eq) and tetrahydrofuran (100mL) into a 250mL single-neck flask, add potassium tert-butoxide (4.44g, 39.55mmol, 1.5eq) at room temperature (25°C), and stir for 30 minutes. Filter and spin dry the filtrate under reduced pressure, add toluene (50mL), filter, and prepare a dry 250mL three-necked flask, add WX007-1 (1.99g, 13.18mmol, 0.5eq) and toluene (30mL), replace with nitrogen three times, cool down When the temperature reaches 0°C, the toluene solution just filtered is added dropwise, the temperature is controlled to maintain 0°C, and after the dropwise addition is completed, the temperature is raised to 25°C and stirred for 12 hours. After the completion of the reaction, the reaction solution was added with water (100mL), extracted with ethyl acetate (100mL*5), combined the organic phases, washed with saturated brine (200mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain The crude product is separated and purified by a fast silica gel column (eluent polarity, petroleum ether: ethyl acetate = 10%-20%-30%) to obtain WX020-4. 1 HNMR (400MHz, deuterated chloroform) δ1.87-1.92(m,2H)2.75-2.78(m,2H)3.11-3.14(m,2H)3.83(s,3H)4.61(s,2H)6.91-6.93 (d, J=8.4 Hz, 2H) 7.30-7.33 (d, J=8.8 Hz, 2H).
步骤5：化合物WX020-5的合成Step 5: Synthesis of compound WX020-5
在预先干燥的反应瓶中加入WX020-4(3g,9.25mmol,1eq)和二氯甲烷(50mL)，置换氮气三次，缓慢滴入三氟乙酸(23.10g,202.59mmol,15.00mL,21.89eq)，25℃继续搅拌3小时。反应完毕后，将反应液减压浓缩，用饱和碳酸氢钠溶液调节pH至7～8，用乙酸乙酯(100mL*3)萃取，合并有机相，无水硫酸钠干燥(100mL*2)，收集有机相，无水硫酸钠干燥，过滤，减压浓缩得粗产品，粗产品经柱层析纯化(石油醚：乙酸乙酯＝10:1转5:1转2:1转1:1)得到WX020-5。 1H NMR(400MHz,氘代氯仿)δ1.98-2.05(m,2H)2.75-2.78(t,J＝6.4Hz,2H)3.48-3.51(m,2H)5.17(s,1H)。 Add WX020-4 (3g, 9.25mmol, 1eq) and dichloromethane (50mL) to the pre-dried reaction flask, replace nitrogen three times, and slowly drop in trifluoroacetic acid (23.10g, 202.59mmol, 15.00mL, 21.89eq) , And continue to stir at 25°C for 3 hours. After the reaction, the reaction solution was concentrated under reduced pressure, adjusted to pH 7-8 with saturated sodium bicarbonate solution, extracted with ethyl acetate (100mL*3), combined the organic phases, dried over anhydrous sodium sulfate (100mL*2), The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (petroleum ether: ethyl acetate = 10:1 to 5:1 to 2:1 to 1:1) Get WX020-5. 1 H NMR (400MHz, deuterated chloroform) δ 1.98-2.05 (m, 2H) 2.75-2.78 (t, J = 6.4 Hz, 2H) 3.48-3.51 (m, 2H) 5.17 (s, 1H).
步骤6：化合物WX020-6的合成Step 6: Synthesis of compound WX020-6
在预先干燥的反应瓶中WX020-5(500mg,2.45mmol,1eq)和二氯甲烷(10mL)，加入碳酸二叔丁酯(802.16mg,3.68mmol,844.38μL,1.5eq)和4-二甲氨基吡啶(598.70mg,4.90mmol,2eq)，置换氮气三次，置于25℃下搅拌16小时。反应完毕后，将反应液冷却至室温，加入二氯甲烷(30mL)和水(30mL)，分液，收集有机相，水相用二氯甲烷萃取(30mL*3)，合并有机相，有机相用饱和食盐水(50mL*3)洗，无水硫 酸钠干燥，过滤，减压浓缩得粗产品，粗产品经柱层析纯化(石油醚：乙酸乙酯＝10:1转5:1转2:1转1:1)得到WX020-6。MS-ESI m/z:304.1[M+H] +。 In the pre-dried reaction flask WX020-5 (500mg, 2.45mmol, 1eq) and dichloromethane (10mL), add di-tert-butyl carbonate (802.16mg, 3.68mmol, 844.38μL, 1.5eq) and 4-dimethyl Aminopyridine (598.70mg, 4.90mmol, 2eq), replaced with nitrogen three times, and stirred at 25°C for 16 hours. After the reaction is complete, cool the reaction solution to room temperature, add dichloromethane (30mL) and water (30mL), separate the layers, collect the organic phase, extract the aqueous phase with dichloromethane (30mL*3), combine the organic phases, and the organic phases Wash with saturated brine (50mL*3), dry with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain a crude product, which is purified by column chromatography (petroleum ether: ethyl acetate = 10:1 to 5:1 to 2 :1 to 1:1) to get WX020-6. MS-ESI m/z: 304.1 [M+H] + .
步骤7：化合物WX020-7的合成Step 7: Synthesis of compound WX020-7
在预先干燥的反应瓶中加入WX020-6(400mg,1.32mmol,1eq)，WX001-4(280.92mg,1.58mmol,1.2eq)和N,N-二甲基乙酰胺(4mL)，加入碳酸铯(535.59mg,1.64mmol,1.25eq)，置换氮气三次，置于65℃继续搅拌16小时。反应完毕后，将反应液冷却至室温，加入乙酸乙酯(250mL)和水(250mL)，分液，收集有机相，水相用乙酸乙酯萃取(250mL*3)，合并有机相，有机相用饱和食盐水(400mL*3)洗，无水硫酸钠干燥，过滤，减压浓缩得粗产品，粗产品经柱层析纯化(石油醚：乙酸乙酯＝10:1转5:1转2:1)得到WX020-7。MS-ESI m/z:445.0[M+H] +。 Add WX020-6 (400mg, 1.32mmol, 1eq), WX001-4 (280.92mg, 1.58mmol, 1.2eq) and N,N-dimethylacetamide (4mL) to the pre-dried reaction flask, add cesium carbonate (535.59mg, 1.64mmol, 1.25eq), replaced with nitrogen three times, placed at 65°C and continued stirring for 16 hours. After the reaction, the reaction solution was cooled to room temperature, ethyl acetate (250 mL) and water (250 mL) were added, the layers were separated, the organic phase was collected, the aqueous phase was extracted with ethyl acetate (250 mL*3), and the organic phases were combined. Wash with saturated brine (400mL*3), dry with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain a crude product. The crude product is purified by column chromatography (petroleum ether: ethyl acetate = 10:1 to 5:1 to 2 :1) Get WX020-7. MS-ESI m/z: 445.0 [M+H] + .
WX020-7结构鉴定：WX020-7 structure identification:
Figure PCTCN2020093284-appb-000159
Figure PCTCN2020093284-appb-000159
在预先干燥的反应瓶中加入WX20-7(160mg,358.96μmol,1eq)和氢溴酸(3mL)，置于0℃下，加入NaNO 2(29.72mg,430.76μmol,1.2eq)和水(1.5mL)的混合溶液，0℃下搅拌0.5小时，将上述反应液中滴加溴化亚铜(56.64mg,394.86μmol,12.03μL,1.1eq)和氢溴酸(3mL)的混合溶液，自然升温至25℃继续搅拌15.5小时。反应完毕后，用水(10mL)淬灭反应，二氯甲烷萃取水相(15mL*3)，合并有机相，饱和食盐水洗涤(15mL*2)，收集有机相，无水硫酸钠干燥，过滤，减压浓缩得粗产品，粗产品经薄层色谱硅胶板纯化(石油醚：乙酸乙酯＝2:1)得到WX020-7A。 Add WX20-7 (160mg, 358.96μmol, 1eq) and hydrobromic acid (3mL) to the pre-dried reaction flask, place it at 0℃, and add NaNO 2 (29.72mg, 430.76μmol, 1.2eq) and water (1.5 mL), stirred at 0°C for 0.5 hours. Add a mixture of cuprous bromide (56.64mg, 394.86μmol, 12.03μL, 1.1eq) and hydrobromic acid (3mL) dropwise to the above reaction solution, and heat up naturally Continue stirring for 15.5 hours at 25°C. After the reaction, the reaction was quenched with water (10mL), the aqueous phase was extracted with dichloromethane (15mL*3), the organic phases were combined, washed with saturated brine (15mL*2), the organic phase was collected, dried over anhydrous sodium sulfate, filtered, Concentrate under reduced pressure to obtain a crude product, which is purified by thin layer chromatography on silica gel plate (petroleum ether: ethyl acetate = 2:1) to obtain WX020-7A.
在预先干燥的反应瓶中加入WX020-7A(40.00mg,97.68μmol,1eq)和甲醇(3mL)，加入湿钯碳(20mg,976.82μmol,10％纯度,10eq)，置换氢气三次，置于氢气球(15psi)的压力下25℃反应1小时。反应完毕后。将反应液直接经硅藻土过滤，滤液减压浓缩得到粗产品。粗产品经高效液相色谱分离(色谱柱:Welch Xtimate C18 150*25mm*5μm；流动相:[水(0.04％盐酸)-乙腈]；乙腈％:30％-50％,10分钟)分离纯化得到WX020-7B，HMBC(400MHz,氘代氯仿)检测哒嗪环上与氧连接的碳(160)与氮六元环上的氢H 1(2.96)相关，证明WX020-7结构正确。 1H NMR(400MHz,氘代甲醇)δ8.46(s,1H),7.56(d,J＝8.13Hz,2H),7.32-7.41(m,1H),3.50-3.57(m,2H),2.96(m,2H),2.05(m,2H)。 Add WX020-7A (40.00mg, 97.68μmol, 1eq) and methanol (3mL) to the pre-dried reaction flask, add wet palladium on carbon (20mg, 976.82μmol, 10% purity, 10eq), replace the hydrogen three times, and place it in hydrogen The reaction was performed at 25°C for 1 hour under the pressure of the ball (15 psi). After the reaction is complete. The reaction solution was directly filtered through Celite, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by high performance liquid chromatography (column: Welch Xtimate C18 150*25mm*5μm; mobile phase: [water (0.04% hydrochloric acid)-acetonitrile]; acetonitrile%: 30%-50%, 10 minutes). WX020-7B, HMBC (400MHz, deuterated chloroform) detects that the carbon (160) connected to the oxygen on the pyridazine ring is related to the hydrogen H 1 (2.96) on the nitrogen six-membered ring, which proves that the structure of WX020-7 is correct. 1 H NMR (400MHz, deuterated methanol) δ8.46 (s, 1H), 7.56 (d, J = 8.13Hz, 2H), 7.32-7.41 (m, 1H), 3.50-3.57 (m, 2H), 2.96 (m, 2H), 2.05 (m, 2H).
步骤8：化合物WX020-8的合成Step 8: Synthesis of compound WX020-8
在预先干燥的反应瓶中加入WX020-7(150.00mg,336.53μmol,1eq)和冰乙酸(2mL)，加入乙酸钠(138.03mg,1.68mmol,5eq)，氮气置换三次，置于120℃下搅拌48小时。反应完毕后，将反应液冷却至室温，减压浓缩得到WX020-8。MS-ESI m/z:369.0[M+H] +。 Add WX020-7 (150.00mg, 336.53μmol, 1eq) and glacial acetic acid (2mL) to the pre-dried reaction flask, add sodium acetate (138.03mg, 1.68mmol, 5eq), replace with nitrogen three times, and stir at 120℃ 48 hours. After the completion of the reaction, the reaction solution was cooled to room temperature and concentrated under reduced pressure to obtain WX020-8. MS-ESI m/z: 369.0 [M+H] + .
步骤9：化合物WX020-9的合成Step 9: Synthesis of compound WX020-9
在预先干燥的反应瓶中加入WX020-8(120.00mg,325.03μmol,1eq)和乙醇(2mL)。加入稀盐酸(2M,2mL,12.31eq)，置换氮气三次，置于90℃下搅拌16小时。反应完毕后，将反应液冷却至室温，加入水(20mL)，用乙酸乙酯萃取(20mL*3)，合并有机相，有机相用饱和食盐水洗(30mL)，无水硫酸钠干燥，过滤，减压浓缩得粗产品，粗产品经薄层色谱硅胶板纯化(石油醚：乙酸乙酯＝0:1)得到WX020-9。MS-ESI m/z:327.0[M+H] +。 Add WX020-8 (120.00mg, 325.03μmol, 1eq) and ethanol (2mL) to the pre-dried reaction flask. Add dilute hydrochloric acid (2M, 2mL, 12.31eq), replace with nitrogen three times, and stir at 90°C for 16 hours. After the completion of the reaction, the reaction solution was cooled to room temperature, water (20mL) was added, extracted with ethyl acetate (20mL*3), the organic phases were combined, washed with saturated brine (30mL), dried with anhydrous sodium sulfate, filtered, Concentrate under reduced pressure to obtain a crude product, which is purified by thin layer chromatography on silica gel plate (petroleum ether: ethyl acetate = 0:1) to obtain WX020-9. MS-ESI m/z: 327.0 [M+H] + .
步骤10：化合物WX020-10的合成Step 10: Synthesis of compound WX020-10
在预先干燥的反应瓶中加入WX020-9(70.00mg,213.96μmol,1eq)和冰乙酸(1mL)，置于0℃下加入浓盐酸(12M,55.09μL,3.09eq)，缓慢加入亚硝酸钠(15.65mg,226.80μmol,1.06eq)的水(1mL)溶液，置于0℃下搅拌1.5小时，加入WX001-9(36.75mg,235.35μmol,1.1eq)，然后再0℃下继续搅拌2.5小时。反应完毕后，反应液在0℃下缓慢加入乙酸钠(3eq)和水(3mL)的混合溶液，有大量固体生成，过滤，收集滤饼，滤饼减压浓缩得到WX020-10。MS-ESI m/z:493.9[M+H] +。 Add WX020-9 (70.00mg, 213.96μmol, 1eq) and glacial acetic acid (1mL) into the pre-dried reaction flask, add concentrated hydrochloric acid (12M, 55.09μL, 3.09eq) at 0℃, and slowly add sodium nitrite (15.65mg, 226.80μmol, 1.06eq) in water (1mL), place it at 0℃ and stir for 1.5 hours, add WX001-9 (36.75mg, 235.35μmol, 1.1eq), and then continue stirring at 0℃ for 2.5 hours . After the reaction was completed, the reaction solution was slowly added to the mixed solution of sodium acetate (3eq) and water (3mL) at 0°C, a large amount of solid was formed, filtered, collected the filter cake, and concentrated under reduced pressure to obtain WX020-10. MS-ESI m/z: 493.9 [M+H] + .
步骤11：化合物WX020的合成Step 11: Synthesis of compound WX020
在预先干燥的反应瓶中加入WX020-10(100.00mg,202.31μmol,1eq)和N,N-二甲基乙酰胺(2mL)，加入醋酸钾(22.83mg,232.66μmol,1.15eq)，置换氮气三次，置于115℃继续搅拌6小时。反应完毕后，直接将反应液过滤，滤液经高效液相色谱分离(色谱柱:Welch Xtimate C18 150*25mm*5μm；流动相:[水(0.04％盐酸)-乙腈]；乙腈％:30％-50％,10min)得到WX020。 1H NMR(400MHz,氘代二甲基亚砜)δ1.83-1.86(m,2H)2.62-2.65(m,2H)3.37-3.40(m,2H)6.97(s,1H)7.73(s,2H)11.77(s,1H)13.25(s,1H)。MS-ESI m/z:448.0[M+H] +。 Add WX020-10 (100.00mg, 202.31μmol, 1eq) and N,N-dimethylacetamide (2mL) to the pre-dried reaction flask, add potassium acetate (22.83mg, 232.66μmol, 1.15eq), and replace the nitrogen Three times, keep stirring at 115°C for 6 hours. After the reaction, the reaction solution was directly filtered, and the filtrate was separated by high performance liquid chromatography (column: Welch Xtimate C18 150*25mm*5μm; mobile phase: [water (0.04% hydrochloric acid)-acetonitrile]; acetonitrile%: 30%- 50%, 10min) to obtain WX020. 1 H NMR (400MHz, deuterated dimethyl sulfoxide) δ1.83-1.86(m,2H)2.62-2.65(m,2H)3.37-3.40(m,2H)6.97(s,1H)7.73(s, 2H) 11.77 (s, 1H) 13.25 (s, 1H). MS-ESI m/z: 448.0 [M+H] + .
实施例21Example 21
Figure PCTCN2020093284-appb-000160
Figure PCTCN2020093284-appb-000160
合成路线：synthetic route:
Figure PCTCN2020093284-appb-000161
Figure PCTCN2020093284-appb-000161
步骤1：化合物WX021-1的合成Step 1: Synthesis of compound WX021-1
在预先干燥的反应瓶中加入WX001-3(10g,49.24mmol,1eq)和1.2-二氯乙烷(150mL)，加入溴代丁二酰亚胺(7.89g,44.32mmol,0.9eq)和偶氮二异丁腈(808.63mg,4.92mmol,0.1eq)，置换氮气三次，置于70℃的油浴下搅拌3小时。反应完成后，将反应液加水(50mL)稀释，分液，收集有机相，水相用二氯甲烷(50mL*2)萃取，合并有机相，并用饱和食盐水(50mL*2)洗，无水硫酸钠干燥，过滤，减压浓缩得粗产品，粗产品经柱层析纯化(石油醚：乙酸乙酯＝1:0转40:1转20:1)，用甲基叔丁基醚(10mL)打浆得到WX021-1。 1HNMR(400MHz,氘代氯仿)δ1.88-1.91(m,1H)2.06-2.10(m,2H)2.47-2.51(m,1H)2.76-2.78(m,1H)3.06-3.12(m,1H)5.25-5.44(m,1H)。 Add WX001-3 (10g, 49.24mmol, 1eq) and 1.2-dichloroethane (150mL) to the pre-dried reaction flask, add bromosuccinimide (7.89g, 44.32mmol, 0.9eq) and Nitrogen diisobutyronitrile (808.63 mg, 4.92 mmol, 0.1 eq), replaced with nitrogen three times, placed in an oil bath at 70° C. and stirred for 3 hours. After the completion of the reaction, the reaction solution was diluted with water (50mL), separated, the organic phase was collected, the aqueous phase was extracted with dichloromethane (50mL*2), the organic phases were combined, and washed with saturated brine (50mL*2), anhydrous Dry over sodium sulfate, filter, and concentrate under reduced pressure to obtain a crude product. The crude product is purified by column chromatography (petroleum ether: ethyl acetate=1:0 to 40:1 to 20:1), using methyl tert-butyl ether (10mL ) Beating to obtain WX021-1. 1 HNMR (400MHz, deuterated chloroform)δ 1.88-1.91(m,1H)2.06-2.10(m,2H)2.47-2.51(m,1H)2.76-2.78(m,1H)3.06-3.12(m,1H) ) 5.25-5.44 (m, 1H).
步骤2：化合物WX021-2的合成Step 2: Synthesis of compound WX021-2
将WX021-1(1.2g,4.26mmol,1eq)和甲醇(10mL)加入到反应瓶中，然后加入甲醇钠(574.79mg,10.64mmol,2.5eq)，加料完毕后，置换氮气三次，继续在25℃下搅拌8小时。反应完全后,将反应液减压浓缩，得到粗品，粗产品经柱层析纯化(梯度淋洗：石油醚：乙酸乙酯＝1:0转40:1转6:1)得到WX021-2。Add WX021-1 (1.2g, 4.26mmol, 1eq) and methanol (10mL) to the reaction flask, then add sodium methoxide (574.79mg, 10.64mmol, 2.5eq), after the addition is complete, replace the nitrogen three times, continue to 25 Stir for 8 hours at °C. After the completion of the reaction, the reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (gradient elution: petroleum ether: ethyl acetate=1:0 to 40:1 to 6:1) to obtain WX021-2.
步骤3：化合物WX021-3的合成Step 3: Synthesis of compound WX021-3
在预先干燥的反应瓶中加入WX021-2(2.1g,9.01mmol,1eq)和WX001-4(1.92g,10.81mmol,1.2eq)和N，N-二甲基乙酰胺(18mL)，然后用氮气置换三次，随后加入碳酸铯(4.40g,13.51mmol,1.5eq)，加料完毕后，然后继续在70℃下搅拌8小时。反应完全后，将反应液倒入到冰水(80mL)里，然后用稀盐酸2N调节溶液的pH＝5，用甲基叔丁基醚(100mL*3)萃取，饱和食盐水(30mL*5)洗，无水硫酸钠干燥，减压浓缩得到粗品，粗品用快速过柱机(石油醚：乙酸乙酯＝50:1到20：1到1:1)纯化得到粗品。然后用高效液相色谱法来分离纯化(纯化条件是：色谱柱:Phenomenex luna C18 250*50mm*10μm；流动相:[水 (0.1％三氟乙酸)-乙腈]；乙腈％:55％-55％,20分钟)得到WX021-3。1HNMR(400MHz,氘代氯仿)δ1.49-1.51(m,1H)1.85-1.89(m,2H)2.28-2.32(m,1H)2.53-2.56(m,1H)2.95-3.00(m,1H)3.52(s,3H)3.66(s,2H)4.31(s,1H)6.57(s,2H)。Add WX021-2 (2.1g, 9.01mmol, 1eq) and WX001-4 (1.92g, 10.81mmol, 1.2eq) and N,N-dimethylacetamide (18mL) to the pre-dried reaction flask, and then use Replace with nitrogen three times, then add cesium carbonate (4.40g, 13.51mmol, 1.5eq), after the addition is complete, then continue to stir at 70°C for 8 hours. After the reaction is complete, pour the reaction solution into ice water (80mL), then adjust the pH of the solution to 5 with dilute hydrochloric acid 2N, extract with methyl tert-butyl ether (100mL*3), and saturated brine (30mL*5) ) Washing, drying with anhydrous sodium sulfate, and concentrating under reduced pressure to obtain a crude product. The crude product is purified by a quick column machine (petroleum ether: ethyl acetate = 50:1 to 20:1 to 1:1) to obtain a crude product. Then use high performance liquid chromatography to separate and purify (purification conditions are: Column: Phenomenex Luna C18 250*50mm*10μm; mobile phase: [water (0.1% trifluoroacetic acid)-acetonitrile]; acetonitrile%: 55% -55 %, 20 minutes) to obtain WX021-3. 1HNMR (400MHz, deuterated chloroform) δ 1.49-1.51 (m, 1H) 1.85-1.89 (m, 2H) 2.28-2.32 (m, 1H) 2.53-2.56 (m, 1H) 2.95-3.00 (m, 1H) 3.52 (s, 3H) 3.66 (s, 2H) 4.31 (s, 1H) 6.57 (s, 2H).
WX021-3结构鉴定：WX021-3 structure identification:
Figure PCTCN2020093284-appb-000162
Figure PCTCN2020093284-appb-000162
将WX021-3(0.05g,133.46μmol,1eq)和甲醇(2mL)加入到50mL单口瓶中，加入湿钯碳(0.01g,133.46μmol,10％纯度,1eq)，置换氢气三次，然后在氢气球(15psi)的压力下20℃反应2小时。反应完成后，反应液直接用硅藻土过滤，滤液减压旋干得到粗品，粗品用高效液相色谱柱(色谱柱:Welch Xtimate C18 150*25mm*5μm；流动相:[水(0.04％盐酸)-乙腈]；乙腈％:30％-50％,10分钟)纯化，得到WX021-3A。NOE(400MHz,氘代二甲基亚砜)显示甲氧基(3.43)上的氢与H 1(8.94)有相关性，证明WX021-3结构正确。 1HNMR(400MHz,氘代二甲基亚砜)δ1.84-1.94(m,4H),2.69-2.82(m,2H),3.43(s,3H),4.42-4.44(m,1H),6.67(br s,2H),6.91(s,2H)，8.94(s,1H)。 Add WX021-3 (0.05g, 133.46μmol, 1eq) and methanol (2mL) into a 50mL single-neck flask, add wet palladium on carbon (0.01g, 133.46μmol, 10% purity, 1eq), replace the hydrogen three times, and then The reaction was performed at 20°C for 2 hours under the pressure of the ball (15 psi). After the reaction is completed, the reaction solution is directly filtered with diatomaceous earth, and the filtrate is spin-dried under reduced pressure to obtain the crude product. The crude product is used on a high performance liquid chromatography column (column: Welch Xtimate C18 150*25mm*5μm; mobile phase: [water (0.04% hydrochloric acid) )-Acetonitrile]; Acetonitrile%: 30%-50%, 10 minutes) to obtain WX021-3A. NOE (400MHz, deuterated dimethyl sulfoxide) shows that the hydrogen on the methoxy group (3.43) is correlated with H 1 (8.94), which proves that the structure of WX021-3 is correct. 1 HNMR (400MHz, deuterated dimethyl sulfoxide) δ 1.84-1.94 (m, 4H), 2.69-2.82 (m, 2H), 3.43 (s, 3H), 4.42-4.44 (m, 1H), 6.67 (br s, 2H), 6.91 (s, 2H), 8.94 (s, 1H).
步骤4：化合物WX021-4的合成Step 4: Synthesis of compound WX021-4
在预先干燥的反应瓶中加入WX021-3(600mg,1.60mmol,1eq)和乙酸钠(262.74mg,3.20mmol,2eq)和乙酸(12mL)，加料完毕后，然后继续在110℃下搅拌8小时。原料反应完全后，将反应液直接减压浓缩得到WX021-4。Add WX021-3 (600mg, 1.60mmol, 1eq), sodium acetate (262.74mg, 3.20mmol, 2eq) and acetic acid (12mL) into the pre-dried reaction flask. After the addition is complete, continue stirring at 110°C for 8 hours . After the reaction of the raw materials is complete, the reaction solution is directly concentrated under reduced pressure to obtain WX021-4.
步骤5：化合物WX021-5的合成Step 5: Synthesis of compound WX021-5
在预先干燥的反应瓶中加入WX021-4(1.60g,4.02mmol,1eq)和乙醇(10mL)和盐酸(10mL)，加料完毕后继续在90℃下搅拌8小时。反应完全后，将反应液减压浓缩，然后加入乙酸乙酯(20mL)和水(30mL)，用固体碳酸氢钠调节溶液的pH＝6-7，分出水相，水相用乙酸乙酯(20mL*2)萃取，合并有机相，有机相用饱和食盐水(20mL)洗，无水硫酸钠干燥，减压浓缩得到WX021-5。1HNMR(400MHz,氘代氯仿)δ1.45-1.48(m,1H)1.82-1.86(m,2H)2.20-2.21(m,1H)2.24-2.48(m,1H)2.85-2.86(m,1H)3.53(s,3H)4.42(s,1H)6.61(s,2H)9.96(s,1H)。Add WX021-4 (1.60g, 4.02mmol, 1eq), ethanol (10mL) and hydrochloric acid (10mL) into the pre-dried reaction flask, and continue stirring at 90°C for 8 hours after the addition is complete. After the reaction was completed, the reaction solution was concentrated under reduced pressure, then ethyl acetate (20mL) and water (30mL) were added, and the pH of the solution was adjusted to 6-7 with solid sodium bicarbonate. The aqueous phase was separated, and the aqueous phase was 20mL*2) extract, combine the organic phases, wash the organic phases with saturated brine (20mL), dry with anhydrous sodium sulfate, and concentrate under reduced pressure to obtain WX021-5. 1HNMR (400MHz, deuterated chloroform) δ1.45-1.48 (m ,1H)1.82-1.86(m,2H)2.20-2.21(m,1H)2.24-2.48(m,1H)2.85-2.86(m,1H)3.53(s,3H)4.42(s,1H)6.61(s ,2H)9.96(s,1H).
步骤6：化合物WX021-6的合成Step 6: Synthesis of compound WX021-6
在反应瓶中加入WX021-5(0.18g,505.33μmol,1eq)，水(4mL)，乙酸(2mL)和浓盐酸(12M,130.54μL,3.1eq)，加料完毕后在0℃下滴加亚硝酸钠(38.35mg,555.86μmol,1.1eq)的水(2mL)溶液，然后继续在0℃下搅拌1小时，然后加入WX001-9(86.79mg,555.86μmol,1.1eq)，加料完毕后在0℃下搅拌1小时。原料反应完全后，向反应液中加入饱和的乙酸钠溶液(10mL)，此时有大量的固体析出，然后用五孔漏斗过滤，收集滤饼，滤饼用油泵减压浓缩得到WX021-6。Add WX021-5 (0.18g, 505.33μmol, 1eq), water (4mL), acetic acid (2mL) and concentrated hydrochloric acid (12M, 130.54μL, 3.1eq) into the reaction flask. After the addition is complete, add the sub solution at 0°C. Sodium nitrate (38.35mg, 555.86μmol, 1.1eq) in water (2mL), then continue to stir at 0℃ for 1 hour, then add WX001-9 (86.79mg, 555.86μmol, 1.1eq), after the addition is completed Stir at °C for 1 hour. After the reaction of the raw materials is completed, a saturated sodium acetate solution (10 mL) is added to the reaction solution. At this time, a large amount of solid is precipitated, and then filtered with a five-hole funnel to collect the filter cake. The filter cake is concentrated under reduced pressure with an oil pump to obtain WX021-6.
步骤7：化合物WX021-7的合成Step 7: Synthesis of compound WX021-7
在预先干燥的反应瓶中加入WX021-6(0.19g,363.06μmol)和乙酸钾(71.26mg,726.13μmol,2eq)和N,N-二甲基乙酰胺(2mL)，加料完毕后继续在115℃下搅拌4小时。反应完全后，将反应液降到室温，然后过滤，滤液用制备高效液相色谱分离(色谱柱:Phenomenex Luna C18 100*30mm*5μm；流动相:[水(0.2％三氟乙酸)-乙腈]；乙腈％:35％-55％,9分钟)纯化得到WX021-7。Add WX021-6 (0.19g, 363.06μmol) and potassium acetate (71.26mg, 726.13μmol, 2eq) and N,N-dimethylacetamide (2mL) into the pre-dried reaction flask. After the addition, continue at 115 Stir for 4 hours at °C. After the reaction is complete, the reaction solution is cooled to room temperature, then filtered, and the filtrate is separated by preparative high performance liquid chromatography (column: Phenomenex Luna C18 100*30mm*5μm; mobile phase: [water (0.2% trifluoroacetic acid)-acetonitrile] ; Acetonitrile%: 35%-55%, 9 minutes) to obtain WX021-7.
步骤8：化合物WX021和WX022的合成Step 8: Synthesis of compounds WX021 and WX022
WX021-7经过超临界色谱分离(色谱柱:DAICEL CHIRALPAK AD(250mm*30mm,10μm)；流动相:[二氧化碳-异丙醇，0.1％氨水]；异丙醇％:53％-53％,7分钟]分离得到目标化合物WX021和WX022。WX021-7 is separated by supercritical chromatography (column: DAICEL CHIRALPAK AD (250mm*30mm, 10μm); mobile phase: [carbon dioxide-isopropanol, 0.1% ammonia]; isopropanol%: 53%-53%, 7 Min] The target compounds WX021 and WX022 were isolated.
WX021： 1HNMR(400MHz,氘代甲醇)δ1.56-1.61(m,1H),1.91-1.93(m,2H),2.29-2.33(d,J＝14.4Hz,1H),2.59-2.66(m,1H),2.92-2.97(d,J＝19.2Hz,1H),3.54(s,3H),4.43(s,1H),7.77(s,2H)。保留时间:1.46分钟(仪器:Waters UPCC with PDA detactor；色谱柱:Chiralpak AD-3,50×4.6mm,I.D.,3μm；流动相：A:食品级超临界二氧化碳；B:异丙醇(0.1％二乙胺，体积比)；梯度：B含量在1.2分钟内从5％升高到50％并保持1分钟，然后在0.8分钟内从50％升高到5％；流速:3.4mL/min；柱温：35℃；检测波长：220nm；系统背压:100bar)。 WX021: 1 HNMR (400MHz, deuterated methanol) δ1.56-1.61 (m, 1H), 1.91-1.93 (m, 2H), 2.29-2.33 (d, J = 14.4 Hz, 1H), 2.59-2.66 (m ,1H), 2.92-2.97(d, J=19.2Hz, 1H), 3.54(s, 3H), 4.43(s, 1H), 7.77(s, 2H). Retention time: 1.46 minutes (Instrument: Waters UPCC with PDA detactor; Column: Chiralpak AD-3, 50×4.6mm, ID, 3μm; Mobile phase: A: food grade supercritical carbon dioxide; B: isopropanol (0.1% Diethylamine, volume ratio); Gradient: B content increased from 5% to 50% in 1.2 minutes and maintained for 1 minute, and then increased from 50% to 5% in 0.8 minutes; Flow rate: 3.4mL/min; Column temperature: 35℃; detection wavelength: 220nm; system back pressure: 100bar).
WX022： 1HNMR(400MHz,氘代甲醇)δ1.56-1.61(m,1H),1.91-1.93(m,2H),2.29-2.33(d,J＝14.4Hz,1H),2.59-2.66(m,1H),2.92-2.97(d,J＝19.2Hz,1H),3.54(s,3H),4.43(s,1H),7.77(s,2H)。保留时间:1.71分钟(仪器:Waters UPCC with PDA detactor；色谱柱:Chiralpak AD-3,50×4.6mm,I.D.,3μm；流动相：A:食品级超临界二氧化碳；B:异丙醇(0.1％二乙胺，体积比)；梯度：B含量在1.2分钟内从5％升高到50％并保持1分钟，然后在0.8分钟内从50％升高到5％；流速:3.4mL/min；柱温：35℃；检测波长：220nm；系统背压:100bar)。 WX022: 1 HNMR (400MHz, deuterated methanol) δ1.56-1.61 (m, 1H), 1.91-1.93 (m, 2H), 2.29-2.33 (d, J = 14.4 Hz, 1H), 2.59-2.66 (m ,1H), 2.92-2.97(d, J=19.2Hz, 1H), 3.54(s, 3H), 4.43(s, 1H), 7.77(s, 2H). Retention time: 1.71 minutes (Instrument: Waters UPCC with PDA detactor; Column: Chiralpak AD-3, 50×4.6mm, ID, 3μm; Mobile phase: A: food grade supercritical carbon dioxide; B: isopropanol (0.1% Diethylamine, volume ratio); Gradient: B content increased from 5% to 50% in 1.2 minutes and maintained for 1 minute, and then increased from 50% to 5% in 0.8 minutes; Flow rate: 3.4mL/min; Column temperature: 35℃; detection wavelength: 220nm; system back pressure: 100bar).
实施例23Example 23
Figure PCTCN2020093284-appb-000163
Figure PCTCN2020093284-appb-000163
合成路线：synthetic route:
Figure PCTCN2020093284-appb-000164
Figure PCTCN2020093284-appb-000164
步骤1：化合物WX023-3的合成Step 1: Synthesis of compound WX023-3
在预先干燥的反应瓶中加入二甲基亚砜(50mL)，之后加入钠氢(2.29g,57.22mmol,60％纯度,1.1eq)，然后缓慢的加入WX023-2(12.59g,57.22mmol,1.1eq)，室温(20℃)下搅拌反应1小时，然后加入WX023-1(5g,52.01mmol,5.04mL,1eq)的二甲基亚砜(10mL)溶液，之后缓慢升高至50℃搅拌反应2小时。反应完成后，加水(200mL)和石油醚(100mL)稀释，分液要有机相，水相用石油醚(100mL*2)萃取，合并有机相，无水硫酸钠干燥，过滤，减压浓缩得到WX023-3。 1H NMR(400MHz,氘代氯仿)δ2.15–2.30(m,1H),1.85-1.90(m,1H),1.71-1.62(m,2H),1.60-1.52(m,1H),1.20-1.13(m,2H),1.06-1.00(m,1H),0.85-0.74(m,2H)。 Add dimethyl sulfoxide (50mL) to the pre-dried reaction flask, then add sodium hydrogen (2.29g, 57.22mmol, 60% purity, 1.1eq), and then slowly add WX023-2 (12.59g, 57.22mmol, 1.1eq), the reaction was stirred at room temperature (20℃) for 1 hour, then WX023-1 (5g, 52.01mmol, 5.04mL, 1eq) in dimethyl sulfoxide (10mL) solution was added, and then slowly increased to 50℃ and stirred React for 2 hours. After the reaction is complete, add water (200mL) and petroleum ether (100mL) to dilute, separate the organic phase, extract the aqueous phase with petroleum ether (100mL*2), combine the organic phases, dry with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain WX023-3. 1 H NMR (400MHz, deuterated chloroform) δ 2.15-2.30 (m, 1H), 1.85-1.90 (m, 1H), 1.71-1.62 (m, 2H), 1.60-1.52 (m, 1H), 1.20- 1.13 (m, 2H), 1.06-1.00 (m, 1H), 0.85-0.74 (m, 2H).
步骤2：化合物WX023-4的合成Step 2: Synthesis of compound WX023-4
在预先干燥的反应瓶中加入WX023-3(2.5g,22.70mmol,1eq)，之后用四氢呋喃(37.5mL)溶解，将反应体系降至-78℃，加入二异丙基氨基锂(2M,14.18mL,1.25eq)，-78℃搅拌反应0.5小时，然后加入三甲基氯硅烷(2.96g,27.23mmol,3.46mL,1.2eq)，缓慢的升高至室温(25℃)搅拌反应1小时。反应完成后，将其缓慢的加入到冰水(50mL)中，之后加入乙酸乙酯(50mL)稀释，分液要有机相，水相用乙酸乙酯(50mL*2)萃取，合并有机相，并用饱和食盐水(50mL*2)洗，无水硫酸钠干燥，过滤除去干燥剂后， 减压浓缩得到WX023-4。Add WX023-3 (2.5g, 22.70mmol, 1eq) to the pre-dried reaction flask, then dissolve it with tetrahydrofuran (37.5mL), reduce the reaction system to -78°C, add lithium diisopropylamide (2M, 14.18) mL, 1.25eq), stirred and reacted at -78°C for 0.5 hours, then added trimethylchlorosilane (2.96g, 27.23mmol, 3.46mL, 1.2eq), slowly raised to room temperature (25°C) and stirred for 1 hour. After the reaction is completed, slowly add it to ice water (50mL), then add ethyl acetate (50mL) to dilute, separate the organic phase, extract the aqueous phase with ethyl acetate (50mL*2), combine the organic phases, It was washed with saturated brine (50 mL*2), dried over anhydrous sodium sulfate, filtered to remove the desiccant, and concentrated under reduced pressure to obtain WX023-4.
步骤3：化合物WX023-5的合成Step 3: Synthesis of compound WX023-5
在预先干燥的反应瓶中加入WX007-1(1.66g,10.97mmol,0.5eq)，之后用甲苯(40mL)溶解，然后加入WX023-4(4g,21.94mmol,1eq)，然后加热到60℃搅拌反应1小时。反应完成后，将反应体系降至室温(25℃)，加水(50mL)和乙酸乙酯(50mL)稀释，分液要有机相，水相用乙酸乙酯(10mL*2)萃取，合并有机相，并用饱和食盐水(50mL*2)洗涤，无水硫酸钠干燥，过滤除去干燥剂后，减压浓缩得到粗产物，粗产品通过自动过柱机分离(梯度淋洗：PE:EA＝1:0至80:20)纯化得到WX023-5。 1HNMR(400MHz,氘代氯仿)δ3.08-2.95(m,1H),2.38-2.19(m,3H),1.97-1.85(m,1H),1.76-1.69(m,1H),1.36-1.26(m,1H),1.04-0.97(m,1H)。 Add WX007-1 (1.66g, 10.97mmol, 0.5eq) to the pre-dried reaction flask, then dissolve it with toluene (40mL), then add WX023-4 (4g, 21.94mmol, 1eq), then heat to 60℃ and stir React for 1 hour. After the completion of the reaction, the reaction system was cooled to room temperature (25°C), diluted with water (50mL) and ethyl acetate (50mL), separated into the organic phase, the aqueous phase was extracted with ethyl acetate (10mL*2), and the organic phases were combined , Washed with saturated brine (50mL*2), dried with anhydrous sodium sulfate, filtered to remove the desiccant, and concentrated under reduced pressure to obtain the crude product. The crude product was separated by an automatic column machine (gradient elution: PE:EA = 1: 0 to 80:20) Purify to obtain WX023-5. 1 HNMR (400MHz, deuterated chloroform) δ3.08-2.95 (m, 1H), 2.38-2.19 (m, 3H), 1.97-1.85 (m, 1H), 1.76-1.69 (m, 1H), 1.36-1.26 (m, 1H), 1.04-0.97 (m, 1H).
步骤4：化合物WX023-6和WX023-7的合成Step 4: Synthesis of compounds WX023-6 and WX023-7
在预先干燥的反应瓶中加入WX023-5(1.00g,4.65mmol,1eq)，WX017-7(1.42g,5.12mmol,1.1eq)和甲苯(25mL)，加入磷酸钾(1.97g,9.30mmol,2eq)，置换氮气三次，然后加入2-二叔丁基膦-2’,4’,6’-三异丙基联苯(394.87mg,930.00μmol,0.2eq)和醋酸钯(208.77mg,930.00μmol,0.2eq)，再次置换氮气三次，置于50℃下搅拌16小时。而后升高至100℃搅拌反应16小时。反应完成后，加水(100mL)和乙酸乙酯(100mL)稀释，有不溶物，通过垫有硅藻土的漏斗过滤，滤液分液要有机相，水相用乙酸乙酯(100mL*2)萃取，合并有机相，并用饱和食盐水(100mL*2)洗涤，无水硫酸钠干燥，过滤除去干燥剂后，减压浓缩得到粗产物，粗产品通过自动过柱机分离(梯度淋洗：PE:EA＝1:0至10:90)纯化得到WX023-6和WX023-7的混合物。之后通过高效液相色谱柱分离(色谱柱:Phenomenex luna C18 250*50mm*10μm；流动相:[水(0.05％盐酸)-乙腈]；乙腈％:65％-95％,10min)纯化得到WX023-6和WX023-7。WX023-6和WX023-7分别经过Pd/C氢化后，各自哒嗪环氮原子邻位的氯被氢原子取代，进一步通过二维核磁判断为所示结构。WX023-6： 1HNMR(400MHz,氘代氯仿)δ7.46(s,2H),6.66(br s,1H),3.07-2.94(m,1H),2.41-2.49(m,1H),2.37-2.24(m,2H),1.92-1.75(m,2H),1.52(s,9H),1.34-1.28(m,1H),1.07-1.00(m,1H)。WX023-7： 1HNMR(400MHz,氘代氯仿)δ7.43(s,2H),6.68(br s,1H),3.22-3.10(m,1H),2.37-2.24(m,3H),1.84–1.94(m,1H),1.83-1.72(m,1H),1.51(s,9H),1.31-1.26(m,1H),1.09-1.00(m,1H)。 Add WX023-5 (1.00g, 4.65mmol, 1eq), WX017-7 (1.42g, 5.12mmol, 1.1eq) and toluene (25mL) into the pre-dried reaction flask, add potassium phosphate (1.97g, 9.30mmol, 2eq), replace with nitrogen three times, then add 2-di-tert-butylphosphine-2',4',6'-triisopropylbiphenyl (394.87mg, 930.00μmol, 0.2eq) and palladium acetate (208.77mg, 930.00 μmol, 0.2eq), replaced with nitrogen again three times, and stirred at 50°C for 16 hours. Then the temperature was raised to 100°C and the reaction was stirred for 16 hours. After the reaction is complete, add water (100mL) and ethyl acetate (100mL) to dilute, there are insoluble materials, filter through a funnel pad with diatomaceous earth, the filtrate is separated into the organic phase, and the aqueous phase is extracted with ethyl acetate (100mL*2) , The organic phases were combined, washed with saturated brine (100mL*2), dried with anhydrous sodium sulfate, filtered to remove the desiccant, and concentrated under reduced pressure to obtain the crude product. The crude product was separated by an automatic column machine (gradient elution: PE: EA=1:0 to 10:90) to obtain a mixture of WX023-6 and WX023-7. Then it was separated by high performance liquid chromatography column (chromatographic column: Phenomenex luna C18 250*50mm*10μm; mobile phase: [water (0.05% hydrochloric acid)-acetonitrile]; acetonitrile%: 65%-95%, 10min) to obtain WX023- 6 and WX023-7. After WX023-6 and WX023-7 were hydrogenated by Pd/C, the chlorine at the ortho position of the nitrogen atom of each pyridazine ring was replaced by a hydrogen atom, and the structure was judged by two-dimensional nuclear magnetism. WX023-6: 1 HNMR (400MHz, deuterated chloroform) δ7.46 (s, 2H), 6.66 (br s, 1H), 3.07-2.94 (m, 1H), 2.41-2.49 (m, 1H), 2.37- 2.24 (m, 2H), 1.92-1.75 (m, 2H), 1.52 (s, 9H), 1.34-1.28 (m, 1H), 1.07-1.00 (m, 1H). WX023-7: 1 HNMR (400MHz, deuterated chloroform) δ7.43 (s, 2H), 6.68 (br s, 1H), 3.22-3.10 (m, 1H), 2.37-2.24 (m, 3H), 1.84– 1.94 (m, 1H), 1.83-1.72 (m, 1H), 1.51 (s, 9H), 1.31-1.26 (m, 1H), 1.09-1.00 (m, 1H).
WX023-6结构鉴定：WX023-6 structure identification:
Figure PCTCN2020093284-appb-000165
Figure PCTCN2020093284-appb-000165
在预先干燥的反应瓶中加入WX023-6(25.00mg,54.73μmol,1eq)，之后用甲醇(1mL)溶解，氢气抽换三 次，加入Pd/C(20mg,10％纯度)，氢气再次抽换三次，置于氢气球(15psi)的压力下20℃反应2小时。反应完成后，将反应液过滤，减压浓缩得到粗产品。粗产品通过高效液相色谱分离(色谱柱:Phenomenex luna C18 80*40mm*3μm；流动相:[水(0.04％盐酸)-乙腈]；乙腈％:46％-72％,7min)得到WX023-6A。NOE(400MHz,氘代甲醇)检测H 1氢和H 2氢有相关，证明WX023-6结构正确。WX023-6A： 1H NMR(400MHz,氘代甲醇)δ8.91(s,1H),7.71-7.79(m,1H),7.44-7.37(m,1H),7.32-7.28(m,1H),2.99-2.89(m,1H),2.70-2.59(m,2H),2.44-2.35(m,1H),2.20-2.12(m,1H),1.83-1.71(m,1H),1.59-1.55(m,1H),1.53(s,9H),1.49-1.41(m,1H)。 Add WX023-6 (25.00mg, 54.73μmol, 1eq) to the pre-dried reaction flask, then dissolve it with methanol (1mL), pump hydrogen three times, add Pd/C (20mg, 10% purity), pump hydrogen again Three times, the reaction was carried out at 20°C for 2 hours under the pressure of a hydrogen balloon (15 psi). After the reaction is completed, the reaction solution is filtered and concentrated under reduced pressure to obtain a crude product. The crude product was separated by high performance liquid chromatography (column: Phenomenex luna C18 80*40mm*3μm; mobile phase: [water (0.04% hydrochloric acid)-acetonitrile]; acetonitrile%: 46%-72%, 7min) to obtain WX023-6A . NOE (400MHz, deuterated methanol) detected correlation between H 1 hydrogen and H 2 hydrogen, which proved that the structure of WX023-6 is correct. WX023-6A: 1 H NMR (400MHz, deuterated methanol) δ8.91(s,1H), 7.71-7.79(m,1H),7.44-7.37(m,1H),7.32-7.28(m,1H), 2.99-2.89 (m, 1H), 2.70-2.59 (m, 2H), 2.44-2.35 (m, 1H), 2.20-2.12 (m, 1H), 1.83-1.71 (m, 1H), 1.59-1.55 (m ,1H),1.53(s,9H),1.49-1.41(m,1H).
WX023-7结构鉴定：WX023-7 structure identification:
Figure PCTCN2020093284-appb-000166
Figure PCTCN2020093284-appb-000166
在预先干燥的反应瓶中加入WX023-7(50.00mg,109.47μmol,1eq)，之后用甲醇(2mL)溶解，氢气抽换三次，加入湿Pd/C(20mg,10％纯度)，氢气再次抽换三次，置于氢气球(15psi)的压力下20℃反应2小时。反应完成后，将反应液过滤，滤液减压浓缩得到粗产品。粗产品通过高效液相色谱分离(色谱柱:Welch Xtimate C18 150*25mm*5μm；流动相:[水(0.04％盐酸)-乙腈]；乙腈％:50％-80％,8min)，得到WX023-7A。NOE(400MHz,氘代甲醇)检测H 1氢和H 2氢有相关，证明WX023-7结构正确。WX023-7A  1H NMR(400MHz,氘代甲醇)δ9.07(s,1H),7.61(s,2H),3.26-3.14(m,1H),2.54-2.36(m,2H),2.25-2.17(m,1H),2.04-1.96(m,1H),1.82-1.71(m,1H),1.53(s,9H),1.38-1.27(m,1H),1.27-1.19(m,1H)。 Add WX023-7 (50.00mg, 109.47μmol, 1eq) to the pre-dried reaction flask, then dissolve it with methanol (2mL), pump hydrogen three times, add wet Pd/C (20mg, 10% purity), pump hydrogen again It was changed three times and reacted for 2 hours at 20°C under the pressure of a hydrogen balloon (15 psi). After the completion of the reaction, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated by high performance liquid chromatography (column: Welch Xtimate C18 150*25mm*5μm; mobile phase: [water (0.04% hydrochloric acid)-acetonitrile]; acetonitrile%: 50%-80%, 8min) to obtain WX023- 7A. NOE (400MHz, deuterated methanol) detects the correlation between H 1 hydrogen and H 2 hydrogen, which proves that the structure of WX023-7 is correct. WX023-7A 1 H NMR (400MHz, deuterated methanol) δ9.07 (s, 1H), 7.61 (s, 2H), 3.26 3.14 (m, 1H), 2.54-2.36 (m, 2H), 2.25-2.17 (m, 1H), 2.04-1.96 (m, 1H), 1.82-1.71 (m, 1H), 1.53 (s, 9H), 1.38-1.27 (m, 1H), 1.27-1.19 (m, 1H).
步骤5：化合物WX023-8的合成Step 5: Synthesis of compound WX023-8
在预先干燥的反应瓶中加入WX023-6(0.097g,212.37μmol,1eq)，之后用醋酸(1mL)溶解，然后加入醋酸钠(34.84mg,424.74μmol,2eq)，缓慢的升高至110℃搅拌反应12小时。反应完成后，将反应液冷却至室温，用饱和的碳酸氢钠溶液调节反应液pH至7左右，加入乙酸乙酯(20mL)稀释，分液要有机相，水相用乙酸乙酯(20mL*2)萃取，合并有机相，并用饱和食盐水(20mL*2)洗涤，无水硫酸钠干燥，过滤，减压浓缩得到目标化合物WX023-8。Add WX023-6 (0.097g, 212.37μmol, 1eq) to the pre-dried reaction flask, then dissolve it with acetic acid (1mL), then add sodium acetate (34.84mg, 424.74μmol, 2eq), and slowly increase to 110℃ The reaction was stirred for 12 hours. After the reaction is complete, cool the reaction solution to room temperature, adjust the pH of the reaction solution to about 7 with saturated sodium bicarbonate solution, add ethyl acetate (20mL) to dilute, separate the organic phase, and use ethyl acetate (20mL* 2) Extract, combine the organic phases, wash with saturated brine (20 mL*2), dry with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain the target compound WX023-8.
步骤6：化合物WX023-9的合成Step 6: Synthesis of compound WX023-9
在预先干燥的反应瓶中加入WX023-8(80.00mg,210.40μmol,1eq)，之后用乙醇(1.2mL)溶解，然后加入盐酸(2M,1.26mL,11.95eq)，缓慢的升高至95℃搅拌反应15小时。反应完成后，将反应液用水泵在50℃旋出乙醇，用饱和的碳酸氢钠溶液调节反应液pH至7左右，加入乙酸乙酯(20mL)稀释，分液要有机相，水相用乙酸乙酯(20mL*2)萃取，合并有机相，并用无水硫酸钠干燥，过滤除去干燥剂后，减压浓 缩得到WX023-9。Add WX023-8 (80.00mg, 210.40μmol, 1eq) to the pre-dried reaction flask, then dissolve it with ethanol (1.2mL), then add hydrochloric acid (2M, 1.26mL, 11.95eq), and slowly increase to 95℃ The reaction was stirred for 15 hours. After the reaction is complete, spin out the ethanol from the reaction solution at 50°C with a water pump, adjust the pH of the reaction solution to about 7 with saturated sodium bicarbonate solution, add ethyl acetate (20mL) for dilution, separate the organic phase, and use acetic acid for the aqueous phase Ethyl (20mL*2) was extracted, the organic phases were combined, and dried over anhydrous sodium sulfate, filtered to remove the desiccant, and concentrated under reduced pressure to obtain WX023-9.
步骤7：化合物WX023-10的合成Step 7: Synthesis of compound WX023-10
在预先干燥的反应瓶中加入WX023-9(70.00mg,206.99μmol,1eq)，之后用醋酸(1mL)溶解，然后加入盐酸(62.82mg,637.52μmol,61.59μL,37％纯度,3.08eq)，将反应体系降至5℃，加入亚硝酸钠(15.71mg,227.68μmol,1.1eq)的水(0.5mL)溶液，在5℃下搅拌反应0.5小时，检测原料反应完后加入WX001-9(35.55mg,227.68μmol,1.1eq)，然后继续在5℃下搅拌0.5小时。反应完成后，向反应液中加醋酸钠(51mg)的水(1.5mL)溶液，发现有固体析出，再加水(10mL)，过滤，收集滤饼，滤饼用水(10mL*3)洗涤，滤饼旋干得到WX023-10。Add WX023-9 (70.00mg, 206.99μmol, 1eq) to the pre-dried reaction flask, then dissolve it with acetic acid (1mL), then add hydrochloric acid (62.82mg, 637.52μmol, 61.59μL, 37% purity, 3.08eq), The reaction system was reduced to 5°C, sodium nitrite (15.71mg, 227.68μmol, 1.1eq) in water (0.5mL) was added, and the reaction was stirred at 5°C for 0.5 hours. After the reaction of the raw materials was detected, WX001-9(35.55) mg, 227.68μmol, 1.1eq), and then continue to stir at 5°C for 0.5 hours. After the reaction is completed, add sodium acetate (51mg) in water (1.5mL) to the reaction solution, and it is found that a solid precipitates, then add water (10mL), filter, collect the filter cake, wash the filter cake with water (10mL*3), filter The cake was spin-dried to obtain WX023-10.
步骤8：化合物WX023-11的合成Step 8: Synthesis of compound WX023-11
在预先干燥的反应瓶中加入WX023-10(73.00mg,144.47μmol,1eq)，之后用N,N-二甲基乙酰胺(0.5mL)溶解，然后加入醋酸钾(21.27mg,216.70μmol,1.5eq)，在115℃下搅拌反应2小时。反应完成后，反应液过滤后通过高效液相色谱分离(色谱柱:Phenomenex luna C18 80*40mm*3μm；流动相:[水(0.04％盐酸)-乙腈]；乙腈％:35％-55％,7min)纯化得到WX023-11。Add WX023-10 (73.00mg, 144.47μmol, 1eq) to the pre-dried reaction flask, then dissolve it with N,N-dimethylacetamide (0.5mL), and then add potassium acetate (21.27mg, 216.70μmol, 1.5 eq), the reaction was stirred at 115°C for 2 hours. After the reaction is completed, the reaction solution is filtered and separated by high performance liquid chromatography (column: Phenomenex Luna C18 80*40mm*3μm; mobile phase: [water (0.04% hydrochloric acid)-acetonitrile]; acetonitrile%: 35%-55%, 7min) Purify to obtain WX023-11.
步骤8：化合物WX023和WX024的合成Step 8: Synthesis of compounds WX023 and WX024
WX023-11通过超临界色谱分离(色谱柱:Chiralpak AS,250*30mm i.d.10μm；流动相:A二氧化碳B甲醇(0.1％氨水)；Gradient:甲醇％＝50％等度洗脱模式；流速:70g/min；柱温:35℃；系统背压:150bar)得到WX023和WX024。WX023-11 is separated by supercritical chromatography (column: Chiralpak AS, 250*30mm id10μm; mobile phase: A carbon dioxide B methanol (0.1% ammonia); Gradient: methanol% = 50% isocratic elution mode; flow rate: 70g /min; column temperature: 35°C; system back pressure: 150 bar) to obtain WX023 and WX024.
WX023： 1H NMR(400MHz,氘代甲醇)δ7.75(s,2H),2.90-2.97(m,1H),2.26-2.34(m,2H),1.99-2.11(m,1H),1.85-1.92(m,1H),1.64-1.73(m,1H),1.27–1.32(m,1H),1.10-1.15(m,1H)。MS-ESI m/z:459.1[M+H] +,461.1[M+H+2] +。保留时间:1.478分钟(仪器:Waters UPCC with PDA detactor；色谱柱:Chiralpak AS-3,50*4.6mm,I.D.,3μm；流动相：A:食品级超临界二氧化碳；B:甲醇(0.05％二乙胺，体积比)；梯度：B含量在1.2分钟内从5％升高到50％，50％维持1分钟，然后在0.8分钟内从50％降到5％；流速:3.4mL/min；柱温：35℃；检测波长：220nm；系统背压:100bar)。 WX023: 1 H NMR (400MHz, deuterated methanol) δ 7.75 (s, 2H), 2.90-2.97 (m, 1H), 2.26-2.34 (m, 2H), 1.99-2.11 (m, 1H), 1.85 1.92(m,1H), 1.64-1.73(m,1H), 1.27–1.32(m,1H), 1.10-1.15(m,1H). MS-ESI m/z: 459.1 [M+H] + , 461.1 [M+H+2] + . Retention time: 1.478 minutes (Instrument: Waters UPCC with PDA detactor; Column: Chiralpak AS-3, 50*4.6mm, ID, 3μm; Mobile phase: A: food grade supercritical carbon dioxide; B: methanol (0.05% diethyl Amine, volume ratio); Gradient: B content increased from 5% to 50% in 1.2 minutes, 50% maintained for 1 minute, and then decreased from 50% to 5% in 0.8 minutes; Flow rate: 3.4 mL/min; Column Temperature: 35℃; Detection wavelength: 220nm; System back pressure: 100bar).
WX024： 1H NMR(400MHz,氘代甲醇)δ7.75(s,2H),2.90-2.96(m,1H),2.27-2.32(m,2H),1.99–2.05(m,1H),1.85-1.92(m,1H),1.68-1.70(m,1H),1.32–1.27(m,1H),1.10-1.14(m,1H)。MS-ESI m/z:459.1[M+H] +,461.1[M+H+2] +。保留时间:1.696分钟(仪器:Waters UPCC with PDA detactor；色谱柱:Chiralpak AS-3,50*4.6mm,I.D.,3μm；流动相：A:食品级超临界二氧化碳；B:甲醇(0.05％二乙胺，体积比)；梯度：B含量在1.2分钟内从5％升高到50％，50％维持1分钟，然后在0.8分钟内从50％降到5％；流速:3.4mL/min；柱温：35℃；检测波长：220nm；系统背压:100bar)。 WX024: 1 H NMR (400MHz, deuterated methanol) δ 7.75 (s, 2H), 2.90-2.96 (m, 1H), 2.27-2.32 (m, 2H), 1.99-2.05 (m, 1H), 1.85 1.92 (m, 1H), 1.68-1.70 (m, 1H), 1.32-1.27 (m, 1H), 1.10-1.14 (m, 1H). MS-ESI m/z: 459.1 [M+H] + , 461.1 [M+H+2] + . Retention time: 1.696 minutes (Instrument: Waters UPCC with PDA detactor; Column: Chiralpak AS-3, 50*4.6mm, ID, 3μm; Mobile phase: A: food grade supercritical carbon dioxide; B: methanol (0.05% diethyl Amine, volume ratio); Gradient: B content increased from 5% to 50% in 1.2 minutes, 50% maintained for 1 minute, and then decreased from 50% to 5% in 0.8 minutes; Flow rate: 3.4 mL/min; Column Temperature: 35℃; Detection wavelength: 220nm; System back pressure: 100bar).
实施例25Example 25
Figure PCTCN2020093284-appb-000167
Figure PCTCN2020093284-appb-000167
合成路线：synthetic route:
Figure PCTCN2020093284-appb-000168
Figure PCTCN2020093284-appb-000168
步骤1：化合物WX025-1的合成Step 1: Synthesis of compound WX025-1
在预先干燥的反应瓶中加入WX023-7(0.27g,591.13μmol,1eq)，之后用醋酸(4mL)溶解，然后加入醋酸钠(96.98mg,1.18mmol,2eq)，缓慢的升高至110℃搅拌反应12小时。反应完成后，将反应液冷却至室温，用饱和的碳酸氢钠溶液中和反应液pH至7左右，加入乙酸乙酯(20mL)稀释，分液要有机相，水相用乙酸乙酯(20mL*2)萃取，合并有机相，并用饱和食盐水(20mL*2)洗涤，无水硫酸钠干燥，过滤除去干燥剂后，减压浓缩得到目标化合物WX025-1。Add WX023-7 (0.27g, 591.13μmol, 1eq) to the pre-dried reaction flask, then dissolve it with acetic acid (4mL), then add sodium acetate (96.98mg, 1.18mmol, 2eq), and slowly increase to 110℃ The reaction was stirred for 12 hours. After the reaction is complete, cool the reaction solution to room temperature, neutralize the pH of the reaction solution to about 7 with saturated sodium bicarbonate solution, add ethyl acetate (20mL) for dilution, separate the organic phase, and use ethyl acetate (20mL for the aqueous phase) *2) Extract, combine the organic phases, wash with saturated brine (20 mL*2), dry with anhydrous sodium sulfate, filter to remove the desiccant, and concentrate under reduced pressure to obtain the target compound WX025-1.
步骤2：化合物WX025-2的合成Step 2: Synthesis of compound WX025-2
在预先干燥的反应瓶中加入WX025-1(0.22g,578.61μmol,1eq)，之后用乙醇(3.3mL)溶解，然后加入盐酸(2M,3.30mL,11.41eq)，缓慢的升高至95℃搅拌反应15小时。反应完成后，将反应液用水泵在50℃旋出乙醇，用饱和的碳酸氢钠溶液中和反应液pH至7左右，加入乙酸乙酯20mL稀释，分液收集有机相，水相用乙酸乙酯(20mL*2)萃取，合并有机相，并用无水硫酸钠干燥，过滤除去干燥剂后，减压浓缩得到WX025-2。Add WX025-1 (0.22g, 578.61μmol, 1eq) to the pre-dried reaction flask, then dissolve it with ethanol (3.3mL), then add hydrochloric acid (2M, 3.30mL, 11.41eq), and slowly increase to 95℃ The reaction was stirred for 15 hours. After the reaction is complete, spin out the ethanol from the reaction solution at 50°C with a water pump, neutralize the pH of the reaction solution to about 7 with saturated sodium bicarbonate solution, add 20 mL of ethyl acetate for dilution, separate and collect the organic phase, and use ethyl acetate for the aqueous phase. The ester (20 mL*2) was extracted, the organic phases were combined, and dried over anhydrous sodium sulfate, filtered to remove the desiccant, and concentrated under reduced pressure to obtain WX025-2.
步骤3：化合物WX025-3的合成Step 3: Synthesis of compound WX025-3
在预先干燥的反应瓶中加入WX025-2(130.00mg,384.40μmol,1eq)，之后用醋酸(6.5mL)溶解，然后加入盐酸(116.67mg,1.18mmol,114.38μL,37％纯度,3.08eq)，将反应体系降至5℃，加入亚硝酸钠(29.18mg,422.84μmol,1.1eq)的水(3.25mL)溶液，在5℃下搅拌反应0.5小时，检测原料反应完后加入WX001-9(66.02mg,422.84μmol,1.1eq)，5℃搅拌0.5小时。反应完成后，向反应液中加醋酸钠(100mg)的水(5mL)溶液，发现有固体析出，再加水(10mL)，过滤，收集滤饼，滤饼用水(10mL*3)洗涤，滤饼旋干得到WX025-3。Add WX025-2 (130.00mg, 384.40μmol, 1eq) to the pre-dried reaction flask, then dissolve it with acetic acid (6.5mL), then add hydrochloric acid (116.67mg, 1.18mmol, 114.38μL, 37% purity, 3.08eq) , The reaction system was reduced to 5℃, sodium nitrite (29.18mg, 422.84μmol, 1.1eq) in water (3.25mL) solution was added, and the reaction was stirred at 5℃ for 0.5 hours. After the reaction of the raw materials was detected, WX001-9( 66.02mg, 422.84μmol, 1.1eq), stirred at 5°C for 0.5 hours. After the reaction is complete, add a solution of sodium acetate (100mg) in water (5mL) to the reaction solution, and it is found that solids have precipitated, then add water (10mL), filter, collect the filter cake, wash the filter cake with water (10mL*3), filter cake Spin dry to get WX025-3.
步骤4：化合物WX025-4的合成Step 4: Synthesis of compound WX025-4
在预先干燥的反应瓶中加入WX025-3(114.00mg,225.60μmol,1eq)，之后用N,N-二甲基乙酰胺(1mL)溶解，然后加入醋酸钾(33.21mg,338.41μmol,1.5eq)，115℃下搅拌反应2小时。反应完成后，反应液过滤后通过高效液相色谱分离(色谱柱:Phenomenex luna C18 80*40mm*3μm；流动相:[水(0.04％盐酸)-乙腈]；乙腈％:35％-55％,7min)纯化得到WX025-4。Add WX025-3 (114.00mg, 225.60μmol, 1eq) to the pre-dried reaction flask, then dissolve it with N,N-dimethylacetamide (1mL), then add potassium acetate (33.21mg, 338.41μmol, 1.5eq) ), the reaction was stirred at 115°C for 2 hours. After the reaction is completed, the reaction solution is filtered and separated by high performance liquid chromatography (column: Phenomenex Luna C18 80*40mm*3μm; mobile phase: [water (0.04% hydrochloric acid)-acetonitrile]; acetonitrile%: 35%-55%, 7min) Purify to obtain WX025-4.
步骤4：化合物WX025和WX026的合成Step 4: Synthesis of compounds WX025 and WX026
WX025-4通过超临界色谱分离(色谱柱:REGIS(s,s)WHELK-O1(250mm*30mm,id.10μ)；流动相:A二氧化碳B甲醇(0.1％氨水)；梯度:甲醇％＝55％等度洗脱模式；流速:80g/min；柱温:40℃；系统背压:100bar)得到WX025和WX026。WX025-4 is separated by supercritical chromatography (column: REGIS(s, s) WHELK-O1 (250mm*30mm, id.10μ); mobile phase: A carbon dioxide B methanol (0.1% ammonia); gradient: methanol% = 55 % Isocratic elution mode; flow rate: 80g/min; column temperature: 40°C; system back pressure: 100bar) to obtain WX025 and WX026.
WX025： 1HNMR(400MHz,氘代二甲基亚砜)δ12.07(s,1H),7.76(s,2H),2.77–2.87(m,1H),2.32-2.25(m,1H),2.24-2.17(m,2H),1.73–1.80(m,1H),1.66-1.55(m,1H),1.17-1.09(m,1H),1.08-1.01(m,1H)。MS-ESI m/z:459.1[M+H] +,461.1[M+H+2] +。保留时间:2.182分钟(仪器:Waters Acquity UPC 2；色谱柱:(S,S)-WHELK-O1,3.5μm,0.46cm id x 5cm L；流动相：A:食品级超临界二氧化碳；B:甲醇(0.05％二乙胺，体积比)；梯度：B含量在1.2分钟内从5％升高到50％，50％维持1分钟，然后在0.8分钟内从50％降到5％；流速:3.4mL/min；柱温：35℃；检测波长：220nm；系统背压:1800psi)。 WX025: 1 HNMR (400MHz, deuterated dimethyl sulfoxide) δ 12.07 (s, 1H), 7.76 (s, 2H), 2.77-2.87 (m, 1H), 2.32-2.25 (m, 1H), 2.24 -2.17 (m, 2H), 1.73-1.80 (m, 1H), 1.66-1.55 (m, 1H), 1.17-1.09 (m, 1H), 1.08-1.01 (m, 1H). MS-ESI m/z: 459.1 [M+H] + , 461.1 [M+H+2] + . Retention time: 2.182 minutes (Instrument: Waters Acquity UPC 2 ; Column: (S, S)-WHELK-O1, 3.5μm, 0.46cm id x 5cm L; Mobile phase: A: food grade supercritical carbon dioxide; B: methanol (0.05% diethylamine, volume ratio); Gradient: B content increased from 5% to 50% in 1.2 minutes, 50% maintained for 1 minute, and then decreased from 50% to 5% in 0.8 minutes; Flow rate: 3.4 mL/min; column temperature: 35℃; detection wavelength: 220nm; system back pressure: 1800psi).
WX026： 1HNMR(400MHz,氘代二甲基亚砜)δ12.07(s,1H),7.76(s,2H),2.87-2.77(m,1H),2.32-2.25(m,1H),2.24-2.17(m,2H),1.73–1.80(m,1H),1.66–1.55(m,1H),1.15-1.09(m,1H),1.08–1.01(m,1H)。MS-ESI m/z:459.1[M+H] +,461.0[M+H+2] +。保留时间:2.507分钟(仪器:Waters Acquity UPC 2；色谱柱:(S,S)-WHELK-O1,3.5μm,0.46cm id x 5cm L；流动相：A:食品级超临界二氧化碳；B:甲醇(0.05％二乙胺，体积比)；梯度：B含量在1.2分钟内从5％升高到50％，50％维持1分钟，然后在0.8分钟内从50％降到5％；流速:3.4mL/min；柱温：35℃；检测波长：220nm；系统背压:1800psi)。 WX026: 1 HNMR (400MHz, deuterated dimethyl sulfoxide) δ 12.07 (s, 1H), 7.76 (s, 2H), 2.87-2.77 (m, 1H), 2.32-2.25 (m, 1H), 2.24 -2.17 (m, 2H), 1.73-1.80 (m, 1H), 1.66-1.55 (m, 1H), 1.15-1.09 (m, 1H), 1.08-1.01 (m, 1H). MS-ESI m/z: 459.1 [M+H] + , 461.0 [M+H+2] + . Retention time: 2.507 minutes (Instrument: Waters Acquity UPC 2 ; Column: (S, S)-WHELK-O1, 3.5μm, 0.46cm id x 5cm L; Mobile phase: A: food grade supercritical carbon dioxide; B: methanol (0.05% diethylamine, volume ratio); Gradient: B content increased from 5% to 50% in 1.2 minutes, 50% maintained for 1 minute, and then decreased from 50% to 5% in 0.8 minutes; Flow rate: 3.4 mL/min; column temperature: 35℃; detection wavelength: 220nm; system back pressure: 1800psi).
实施例27Example 27
Figure PCTCN2020093284-appb-000169
Figure PCTCN2020093284-appb-000169
合成路线：synthetic route:
Figure PCTCN2020093284-appb-000170
Figure PCTCN2020093284-appb-000170
步骤1：化合物WX027-2的合成Step 1: Synthesis of compound WX027-2
向反应瓶中加入WX027-1(10g,57.62mmol,1eq)和醋酸(100mL)，抽换氮气后加入液溴(20.26g,126.76mmol,6.53mL,2.2eq)，70℃下混合液反应2小时。反应完成后，反应液用水(1000mL)稀释，有固体析出，过滤，收集滤饼，滤饼用二氯甲烷(300mL)溶解，无水硫酸钠干燥，过滤，滤液浓缩得到WX027-2。 1HNMR(400MHz,氘代氯仿)δ8.38-8.39(d,J＝2.4Hz,1H),8.28-8.29(d,J＝2.4Hz,1H),6.47(s,1H)。 Add WX027-1 (10g, 57.62mmol, 1eq) and acetic acid (100mL) to the reaction flask, add liquid bromine (20.26g, 126.76mmol, 6.53mL, 2.2eq) after exhausting nitrogen, and react the mixture at 70°C for 2 hour. After the completion of the reaction, the reaction solution was diluted with water (1000 mL), and solid precipitated out, filtered, and the filter cake was collected. The filter cake was dissolved in dichloromethane (300 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain WX027-2. 1 HNMR (400MHz, deuterated chloroform) δ 8.38-8.39 (d, J = 2.4 Hz, 1H), 8.28-8.29 (d, J = 2.4 Hz, 1H), 6.47 (s, 1H).
步骤2：化合物WX027-3的合成Step 2: Synthesis of compound WX027-3
向反应瓶中加入WX027-2(5g,19.81mmol,1eq)，盐酸(12M,50.00mL,30.29eq)和乙醇(100mL)，抽换氮气后加入二水合氯化亚锡(17.88g,79.22mmol,4eq)，80℃下混合液反应3小时。反应完成后，先将反应液旋干，然后用饱和碳酸氢钠水溶液调pH至10，有固体析出，过滤，滤液用乙酸乙酯(50mL*3)萃取，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩得到WX027-3。 1HNMR(400MHz,氘代二甲基亚砜)δ8.70(s,1H),6.71-6.72(d,J＝2.6Hz,1H),6.59-6.60(d,J＝2.6Hz,1H),5.00(br s,2H)。 Add WX027-2 (5g, 19.81mmol, 1eq), hydrochloric acid (12M, 50.00mL, 30.29eq) and ethanol (100mL) to the reaction flask, and add stannous chloride dihydrate (17.88g, 79.22mmol). , 4eq), the mixed solution was reacted at 80°C for 3 hours. After the completion of the reaction, the reaction solution was spin-dried first, and then adjusted to pH 10 with a saturated aqueous sodium bicarbonate solution. A solid precipitated out. Filtered. The filtrate was extracted with ethyl acetate (50 mL*3), and the organic phase was dried with anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain WX027-3. 1 HNMR (400MHz, deuterated dimethyl sulfoxide) δ8.70 (s, 1H), 6.71-6.72 (d, J = 2.6Hz, 1H), 6.59-6.60 (d, J = 2.6Hz, 1H), 5.00 (br s, 2H).
步骤3：化合物WX027-4的合成Step 3: Synthesis of compound WX027-4
在预先干燥的反应瓶中加入WX027-3(657.32mg,2.95mmol,1.2eq)，WX001-3(0.5g,2.46mmol,1eq)，之后用二甲基亚砜(10mL)溶解，然后加入碳酸钾(510.44mg,3.69mmol,1.5eq)，氮气抽换3次，缓慢的升高至100℃搅拌反应15小时。反应完成后，将反应液冷却至室温(25℃)，通过垫有硅藻土的漏斗过滤，滤液用乙酸乙酯(20mL*3)洗涤，滤液加水(100mL)，分液要有机相，水相用乙酸乙酯(50mL*2)萃取，合并有机相，并用饱和食盐水(100mL*4)洗涤，无水硫酸钠干燥，过滤，滤液用水泵在45℃下减压浓缩得到粗品，粗产品通过自动过柱机分离(梯度淋洗：石油醚:乙酸乙酯＝1:0至1:1)，纯化得到 WX027-4。 1HNMR(400MHz,氘代二甲基亚砜)δ6.80-6.85(d,J＝2.4Hz,1H),6.67-6.72(d,J＝2.4Hz,1H),3.79(br s,2H),2.81-2.91(m,2H),2.66–2.77(m,2H),1.80-1.97(m,4H)。 Add WX027-3 (657.32mg, 2.95mmol, 1.2eq), WX001-3 (0.5g, 2.46mmol, 1eq) into the pre-dried reaction flask, then dissolve with dimethyl sulfoxide (10mL), then add carbonic acid Potassium (510.44mg, 3.69mmol, 1.5eq), nitrogen was pumped 3 times, and the temperature was slowly raised to 100°C and stirred for 15 hours. After the completion of the reaction, the reaction solution was cooled to room temperature (25°C), filtered through a funnel filled with diatomaceous earth, the filtrate was washed with ethyl acetate (20mL*3), water (100mL) was added to the filtrate, and the organic phase was separated into water. The phases were extracted with ethyl acetate (50mL*2), the organic phases were combined, washed with saturated brine (100mL*4), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure with a water pump at 45°C to obtain a crude product. Separated by an automatic column machine (gradient elution: petroleum ether: ethyl acetate=1:0 to 1:1), and purified to obtain WX027-4. 1 HNMR (400MHz, deuterated dimethyl sulfoxide) δ6.80-6.85(d,J=2.4Hz,1H), 6.67-6.72(d,J=2.4Hz,1H), 3.79(br s,2H) ,2.81-2.91(m,2H),2.66-2.77(m,2H),1.80-1.97(m,4H).
步骤4：化合物WX027-5的合成Step 4: Synthesis of compound WX027-5
在预先干燥的反应瓶中加入WX027-4(0.3g,771.06μmol,1eq)，之后用乙酸(3mL)溶解，然后加入乙酸钠(126.50mg,1.54mmol,2eq)，在110℃下搅拌反应14小时。反应完成后，将反应液体系降至室温(25℃)，之后用饱和的碳酸氢钠溶液中和至7左右，加入乙酸乙酯(10mL)稀释，分液，要有机相，水相用乙酸乙酯(10mL*2)萃取，合并有机相，并用饱和食盐水(20mL*2)洗涤，无水硫酸钠干燥，过滤，滤液用水泵在45℃下减压浓缩得到WX027-5。Add WX027-4 (0.3g, 771.06μmol, 1eq) to the pre-dried reaction flask, then dissolve it with acetic acid (3mL), then add sodium acetate (126.50mg, 1.54mmol, 2eq), and stir the reaction at 110℃14 hour. After the completion of the reaction, the reaction liquid system was lowered to room temperature (25°C), and then neutralized to about 7 with saturated sodium bicarbonate solution, diluted with ethyl acetate (10 mL), separated, the organic phase was used, and the aqueous phase was acetic acid Ethyl (10mL*2) was extracted, the organic phases were combined, washed with saturated brine (20mL*2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure with a water pump at 45°C to obtain WX027-5.
步骤5：化合物WX027-6的合成Step 5: Synthesis of compound WX027-6
将WX027-5(0.16g,387.72μmol,1eq)加入到40mL投库瓶中，加入乙醇(2mL)和2M稀盐酸(2mL)，置换氮气三次，升温至90℃搅拌12小时。反应完成后，向反应液中加入饱和碳酸氢钠水溶液调节pH＝7,加入乙酸乙酯(10mL*3)萃取，合并有机相，减压浓缩得到粗品，粗产品通过自动过柱机分离(梯度淋洗：石油醚:乙酸乙酯＝0:1)纯化得到WX027-6。WX027-5 (0.16g, 387.72μmol, 1eq) was added to a 40mL library bottle, ethanol (2mL) and 2M dilute hydrochloric acid (2mL) were added, nitrogen was replaced three times, and the temperature was raised to 90°C and stirred for 12 hours. After the reaction is completed, add saturated sodium bicarbonate aqueous solution to the reaction solution to adjust pH=7, add ethyl acetate (10mL*3) for extraction, combine the organic phases, concentrate under reduced pressure to obtain the crude product, and the crude product is separated by an automatic column machine (gradient Rinse: petroleum ether: ethyl acetate=0:1) Purify to obtain WX027-6.
步骤6：化合物WX027-7的合成Step 6: Synthesis of compound WX027-7
将WX027-6(0.045g,121.42μmol,1eq)加入到40mL投库瓶中，加乙酸(2mL)和浓盐酸(12M,31.16μL,3.08eq)，降温至5℃，加入亚硝酸钠(9.22mg,133.56μmol,1.1eq)的水(1mL)溶液，然后在5℃下搅拌0.5小时，加入WX001-9(20.85mg,133.56μmol,1.1eq)，在5℃下搅拌0.5小时。反应完成后，向反应液中加入10mL饱和乙酸钠水溶液，有大量固体析出，过滤，滤饼用2mL水洗涤，将滤饼减压浓缩得到WX027-7。Add WX027-6 (0.045g, 121.42μmol, 1eq) to a 40mL library bottle, add acetic acid (2mL) and concentrated hydrochloric acid (12M, 31.16μL, 3.08eq), cool to 5℃, add sodium nitrite (9.22 mg, 133.56 μmol, 1.1 eq) in water (1 mL), then stirred at 5°C for 0.5 hours, added WX001-9 (20.85 mg, 133.56 μmol, 1.1 eq), and stirred at 5°C for 0.5 hours. After the completion of the reaction, 10 mL of saturated sodium acetate aqueous solution was added to the reaction solution, a large amount of solids precipitated, filtered, the filter cake was washed with 2 mL of water, and the filter cake was concentrated under reduced pressure to obtain WX027-7.
步骤7：化合物WX027的合成Step 7: Synthesis of compound WX027
将WX027-7(0.03g,55.79μmol,1eq)加入到40mL投库瓶中，加入N,N-二甲基乙酰胺(2mL)将底物溶解，加入乙酸钾(6.02mg,61.37μmol,1.1eq)，升温至115℃搅拌3小时。反应完成后，将反应液过滤后通过高效液相色谱分离(色谱柱:Phenomenex Luna C18 100*30mm*5μm；流动相:[水(0.04％盐酸)-乙腈]；乙腈％:35％-55％,9min)纯化得到WX027。 1HNMR(400MHz,氘代二甲基亚砜)δ1.76-1.78(m,4H),2.45-2.46(m,2H),2.53-2.67(m,2H),7.81-7.82(d,J＝3.6Hz,1H),7.88(s,1H),12.08(s,1H),13.25(s,1H).。MS-ESI m/z:490.9[M+H] +,492.9[M+H+2] +。 Add WX027-7 (0.03g, 55.79μmol, 1eq) to a 40mL throwing library bottle, add N,N-dimethylacetamide (2mL) to dissolve the substrate, add potassium acetate (6.02mg, 61.37μmol, 1.1 eq), heated to 115°C and stirred for 3 hours. After completion of the reaction, the reaction solution was filtered and separated by high performance liquid chromatography (column: Phenomenex Luna C18 100*30mm*5μm; mobile phase: [water (0.04% hydrochloric acid)-acetonitrile]; acetonitrile%: 35%-55% , 9min) purified to obtain WX027. 1 HNMR (400MHz, deuterated dimethyl sulfoxide) δ1.76-1.78 (m, 4H), 2.45-2.46 (m, 2H), 2.53-2.67 (m, 2H), 7.81-7.82 (d, J= 3.6Hz, 1H), 7.88 (s, 1H), 12.08 (s, 1H), 13.25 (s, 1H). MS-ESI m/z: 490.9 [M+H] + , 492.9 [M+H+2] + .
实施例28Example 28
Figure PCTCN2020093284-appb-000171
Figure PCTCN2020093284-appb-000171
合成路线：synthetic route:
Figure PCTCN2020093284-appb-000172
Figure PCTCN2020093284-appb-000172
步骤1：化合物WX028-2的合成Step 1: Synthesis of compound WX028-2
将WX001-2(2g,12.04mmol,1eq)和WX028-1(3.13g,12.04mmol,1eq)加入到预先干燥的反应瓶中，加入N,N-二甲基乙酰胺(20mL)和碳酸铯(5.88g,18.05mmol,1.5eq)，鼓入氮气，将反应液加入到65℃油锅中，搅拌1小时。反应完成后，向反应液中加入10mL水，加入乙酸乙酯(10mL*3)萃取，合并有机相，有机相用饱和食盐水(10mL)洗涤，分液后有机相用无水硫酸钠干燥，过滤，滤液减压旋干得到粗品，粗品用自动过柱机(梯度淋洗：石油醚：乙酸乙酯＝10：1到5:1到3:1)纯化得到WX028-2。Add WX001-2 (2g, 12.04mmol, 1eq) and WX028-1 (3.13g, 12.04mmol, 1eq) to the pre-dried reaction flask, add N,N-dimethylacetamide (20mL) and cesium carbonate (5.88g, 18.05mmol, 1.5eq), bubbling in nitrogen, adding the reaction solution to an oil pan at 65°C and stirring for 1 hour. After the reaction is complete, add 10 mL of water to the reaction solution, add ethyl acetate (10 mL*3) for extraction, combine the organic phases, wash the organic phase with saturated brine (10 mL), separate the organic phase with anhydrous sodium sulfate and dry it. Filtration, the filtrate was spin-dried under reduced pressure to obtain a crude product, and the crude product was purified by an automatic column machine (gradient elution: petroleum ether: ethyl acetate = 10:1 to 5:1 to 3:1) to obtain WX028-2.
步骤2：化合物WX028-3的合成Step 2: Synthesis of compound WX028-3
将WX028-2(0.7g,1.80mmol,1eq)加入到40mL投库瓶中，加入乙醇(6mL)和盐酸(3mL)，加入二水合二氯化锡(2.03g,8.98mmol,5eq)，升温至80℃搅拌2小时。反应完成后，将反应液减压旋干，加入水(10mL)和乙酸乙酯(10mL)，将旋蒸剩余物溶解，加入饱和碳酸氢钠水溶液调节pH＝7-8，分液，水相用乙酸乙酯(10mL*3)萃取，合并有机相，用饱和食盐水(20mL)洗涤，分液后，有机相用无水硫酸钠干燥，过滤，减压旋干得到WX028-3。 1HNMR(400MHz,氘代二甲基亚砜)δ1.72-1.74(m,4H),2.39-2.42(m,2H),2.52-2.56(m,2H),5.79(s,2H),6.87-6.88(d,J＝2.8Hz,1H),6.94(s,1H),11.97(s,1H)。 Add WX028-2 (0.7g, 1.80mmol, 1eq) to a 40mL throwing library bottle, add ethanol (6mL) and hydrochloric acid (3mL), add tin dichloride dihydrate (2.03g, 8.98mmol, 5eq), heat up Stir at 80°C for 2 hours. After the completion of the reaction, the reaction solution was spin-dried under reduced pressure, water (10mL) and ethyl acetate (10mL) were added, the residue was dissolved by the rotary evaporation, and saturated sodium bicarbonate aqueous solution was added to adjust the pH=7-8, and the aqueous phase was separated. It was extracted with ethyl acetate (10 mL*3), the organic phases were combined, washed with saturated brine (20 mL), and separated, the organic phase was dried over anhydrous sodium sulfate, filtered, and spin-dried under reduced pressure to obtain WX028-3. 1 HNMR (400MHz, deuterated dimethyl sulfoxide) δ1.72-1.74 (m, 4H), 2.39-2.42 (m, 2H), 2.52-2.56 (m, 2H), 5.79 (s, 2H), 6.87 -6.88 (d, J=2.8 Hz, 1H), 6.94 (s, 1H), 11.97 (s, 1H).
步骤3：化合物WX028-4的合成Step 3: Synthesis of compound WX028-4
将WX028-3(0.4g,1.11mmol,1eq)加入到40mL投库瓶中，加冰乙酸(4mL)和盐酸(12M,285.40μL,3.08eq)，降温至5℃，加入亚硝酸钠(84.40mg,1.22mmol,1.1eq)的水(2mL)溶液，然后在5℃下搅拌0.5小时，加入WX001-9(190.98mg,1.22mmol,1.1eq)，在5℃下搅拌0.5小时。反应完成后，向反应液中加入10mL饱和乙酸钠水溶液，有大量固体析出，过滤，滤饼用2mL水洗涤，将滤饼减压旋干，得 到WX028-4。 1HNMR(400MHz,氘代二甲基亚砜)δ1.25-1.28(m,3H),1.74-1.77(s,4H),2.42-2.47(m,2H),2.51(m,2H),4.12-4.23(m,2H),8.01-8.02(d,J＝2Hz,1H),8.39(s,1H),10.84(s,2H),12.08(s,1H)。 Add WX028-3 (0.4g, 1.11mmol, 1eq) to a 40mL throwing library bottle, add glacial acetic acid (4mL) and hydrochloric acid (12M, 285.40μL, 3.08eq), cool to 5℃, add sodium nitrite (84.40 mg, 1.22mmol, 1.1eq) in water (2mL), then stirred at 5°C for 0.5 hours, added WX001-9 (190.98mg, 1.22mmol, 1.1eq), and stirred at 5°C for 0.5 hours. After the reaction was completed, 10 mL of saturated sodium acetate aqueous solution was added to the reaction solution, a large amount of solids precipitated out, filtered, the filter cake was washed with 2 mL of water, and the filter cake was spin-dried under reduced pressure to obtain WX028-4. 1 HNMR (400MHz, deuterated dimethyl sulfoxide) δ1.25-1.28 (m, 3H), 1.74-1.77 (s, 4H), 2.42-2.47 (m, 2H), 2.51 (m, 2H), 4.12 -4.23 (m, 2H), 8.01-8.02 (d, J = 2 Hz, 1H), 8.39 (s, 1H), 10.84 (s, 2H), 12.08 (s, 1H).
步骤4：化合物WX028的合成Step 4: Synthesis of compound WX028
将WX028-4(0.25g,474.52μmol,1eq)加入到40mL投库瓶中，加入N,N-二甲基乙酰胺(2mL)将底物溶解，加入乙酸钾(51.23mg,521.97μmol,1.1eq)，升温至115℃搅拌1小时。反应完成后，反应液直接过滤，滤液经高效液相色谱(色谱柱:Phenomenex luna C18 80*40mm*3μm；流动相:[水(0.04％盐酸)-乙腈]；乙腈％:37％-57％,7min)纯化得到WX028。 1HNMR(400MHz,氘代二甲基亚砜)δ1.75-1.77(m,4H),2.32-2.44(m,2H),2.63-2.67(m,2H),7.96-7.97(d,J＝2.4Hz,1H),8.11-8.12(d,J＝2.0Hz,1H),12.12(s,1H),13.31(s,1H)。MS-ESI m/z:481.1[M+H] +，483.1[M+H+2] +。 Add WX028-4 (0.25g, 474.52μmol, 1eq) to a 40mL throwing library bottle, add N,N-dimethylacetamide (2mL) to dissolve the substrate, add potassium acetate (51.23mg, 521.97μmol, 1.1 eq), heated to 115°C and stirred for 1 hour. After the reaction is completed, the reaction solution is directly filtered, and the filtrate is subjected to high performance liquid chromatography (column: Phenomenex luna C18 80*40mm*3μm; mobile phase: [water (0.04% hydrochloric acid)-acetonitrile]; acetonitrile%: 37%-57% , 7min) purified to obtain WX028. 1 HNMR (400MHz, deuterated dimethyl sulfoxide) δ1.75-1.77 (m, 4H), 2.32-2.44 (m, 2H), 2.63-2.67 (m, 2H), 7.96-7.97 (d, J = 2.4 Hz, 1H), 8.11-8.12 (d, J = 2.0 Hz, 1H), 12.12 (s, 1H), 13.31 (s, 1H). MS-ESI m/z: 481.1 [M+H] + , 483.1 [M+H+2] + .
实施例29Example 29
Figure PCTCN2020093284-appb-000173
Figure PCTCN2020093284-appb-000173
合成路线：synthetic route:
Figure PCTCN2020093284-appb-000174
Figure PCTCN2020093284-appb-000174
步骤1：化合物WX029-1的合成Step 1: Synthesis of compound WX029-1
将氘代甲醇(2.56g,70.93mmol,2.88mL,20eq)加入到预先干燥的反应瓶中，置换氮气三次，降温至0℃，加入氢化钠(354.62mg,8.87mmol,60％纯度,2.5eq)保持0℃搅拌0.5小时，另取一个干燥的反应瓶， 加入WX021-1(1g,3.55mmol,1eq)和四氢呋喃(1mL)，在0℃下，将上述反应液缓慢滴入，保持0℃搅拌1小时。反应完成后，将反应液倒入20mL水中，加入乙酸乙酯(20mL*3)萃取，合并有机相，用饱和食盐水(20mL)洗涤，分液后，有机相用无水硫酸钠干燥，过滤，将滤液减压旋干得粗品。粗品用过自动过柱机纯化(洗脱剂极性，石油醚：乙酸乙酯＝10％-20％)，得到WX029-1。 1HNMR(400MHz,氘代二甲基亚砜)δ4.39-4.40(m,1H),2.34-2.38(m,2H),1.92-1.94(m,2H),1.50-1.53(m,2H)。 Deuterated methanol (2.56g, 70.93mmol, 2.88mL, 20eq) was added to the pre-dried reaction flask, replaced with nitrogen three times, cooled to 0°C, added sodium hydride (354.62mg, 8.87mmol, 60% purity, 2.5eq ) Stir at 0℃ for 0.5 hours, take another dry reaction flask, add WX021-1 (1g, 3.55mmol, 1eq) and tetrahydrofuran (1mL), at 0℃, slowly drip the above reaction solution, keep 0℃ Stir for 1 hour. After the completion of the reaction, the reaction solution was poured into 20 mL of water, ethyl acetate (20 mL*3) was added for extraction, the organic phases were combined, washed with saturated brine (20 mL), and separated, the organic phase was dried with anhydrous sodium sulfate and filtered , The filtrate was spin-dried under reduced pressure to obtain a crude product. The crude product was purified by an automatic column machine (eluent polarity, petroleum ether: ethyl acetate = 10%-20%) to obtain WX029-1. 1 HNMR (400MHz, deuterated dimethyl sulfoxide) δ 4.39-4.40 (m, 1H), 2.34-2.38 (m, 2H), 1.92-1.94 (m, 2H), 1.50-1.53 (m, 2H) .
步骤2：化合物WX029-2的合成Step 2: Synthesis of compound WX029-2
将WX029-1(1.8g,7.62mmol,1eq)和WX001-4(2.71g,15.25mmol,2eq)加入到预先干燥的40mL投库瓶中，加入N,N-二甲基乙酰胺(20mL)和碳酸铯(4.97g,15.25mmol,2eq)，鼓入氮气，将反应液加入到70℃油锅中，搅拌8小时。反应完成后，向反应液中加入100mL水，加入乙酸乙酯(100mL*3)萃取,合并有机相，有机相用饱和食盐水(100mL)洗涤，无水硫酸钠干燥，过滤，减压旋干得粗品。粗品用快速硅胶柱纯化(洗脱剂极性：石油醚：乙酸乙酯＝10％至20％)，而后进一步通过高效液相色谱柱分离(色谱柱:Phenomenex luna C18(250*70mm,15μm)；流动相:[水(0.1％三氟乙酸)-乙腈]；乙腈％:50％-60％,20分钟)纯化得到WX029-2。 1HNMR(400MHz,氘代氯仿)δ6.91(s,2H),4.41(s,1H),3.07-3.12(m,1H),2.60-2.70(m,1H),2.39-2.43(m,1H),1.99(s,2H),1.61-1.64(m,1H)。 Add WX029-1 (1.8g, 7.62mmol, 1eq) and WX001-4 (2.71g, 15.25mmol, 2eq) into a pre-dried 40mL throwing library, add N,N-dimethylacetamide (20mL) And cesium carbonate (4.97g, 15.25mmol, 2eq), bubbling with nitrogen, adding the reaction solution to a 70°C oil pan, and stirring for 8 hours. After the reaction is complete, add 100 mL of water to the reaction solution, add ethyl acetate (100 mL*3) for extraction, combine the organic phases, wash the organic phases with saturated brine (100 mL), dry with anhydrous sodium sulfate, filter, and spin dry under reduced pressure Got crude. The crude product was purified by a flash silica gel column (eluent polarity: petroleum ether: ethyl acetate = 10% to 20%), and then further separated by a high performance liquid chromatography column (chromatographic column: Phenomenex luna C18 (250*70mm, 15μm) ; Mobile phase: [water (0.1% trifluoroacetic acid)-acetonitrile]; Acetonitrile%: 50%-60%, 20 minutes) to obtain WX029-2. 1 HNMR (400MHz, deuterated chloroform) δ 6.91 (s, 2H), 4.41 (s, 1H), 3.07-3.12 (m, 1H), 2.60-2.70 (m, 1H), 2.39-2.43 (m, 1H) ), 1.99 (s, 2H), 1.61-1.64 (m, 1H).
WX029-2结构鉴定：WX029-2 structure identification:
Figure PCTCN2020093284-appb-000175
Figure PCTCN2020093284-appb-000175
将WX029-2(0.05g,132.39μmol,1eq)和乙酸乙酯(10mL)加入到100mL单口瓶中，加入湿钯碳(0.05g,132.39μmol,10％纯度,1eq)，置换氢气三次，然后在氢气球(15psi)的压力下20℃反应2小时，反应完成后，反应液垫硅藻土过滤，将滤液减压旋干，粗品经高效液相色谱柱(色谱柱:Waters Xbridge BEH C18 100*25mm*5μm；流动相:[水(10mM碳酸氢铵)-乙腈]；乙腈％:1％-25％,10分钟)纯化，得到WX029-2A。NOE(400Hz，氘代氯仿)显示H1(4.178)与H2(7.849)有相关性，证明WX029-2结构正确。 1HNMR(400MHz,氘代氯仿)δ11.17(s,1H),7.85(s,1H),4.18-4.20(m,1H),2.55-2.67(m,2H),1.89-1.95(m,,2H),1.71-1.76(m,2H)。 Add WX029-2 (0.05g, 132.39μmol, 1eq) and ethyl acetate (10mL) into a 100mL single-neck flask, add wet palladium on carbon (0.05g, 132.39μmol, 10% purity, 1eq), replace hydrogen three times, and then React under the pressure of a hydrogen balloon (15psi) at 20°C for 2 hours. After the reaction is completed, the reaction liquid is filtered through Celite, the filtrate is spin-dried under reduced pressure, and the crude product is passed through an HPLC column (column: Waters Xbridge BEH C18 100 *25mm*5μm; mobile phase: [water (10mM ammonium bicarbonate)-acetonitrile]; acetonitrile%: 1%-25%, 10 minutes) to obtain WX029-2A. NOE (400Hz, deuterated chloroform) shows that H1 (4.178) is correlated with H2 (7.849), which proves that WX029-2 has a correct structure. 1 HNMR (400MHz, deuterated chloroform) δ 11.17 (s, 1H), 7.85 (s, 1H), 4.18-4.20 (m, 1H), 2.55-2.67 (m, 2H), 1.89-1.95 (m,, 2H), 1.71-1.76 (m, 2H).
步骤3：化合物WX029-3的合成Step 3: Synthesis of compound WX029-3
在预先干燥的反应瓶中加入WX029-2(0.4g,1.06mmol,1eq)和冰乙酸(2mL)，随后加入醋酸钠(260.64mg,3.18mmol,3eq)，加料完毕后110℃继续搅拌12小时。反应完成后，将反应液减压浓缩干，然后加入饱和碳酸氢钠溶液调节溶液的pH＝6-7，然后用乙酸乙酯(100mL*3)萃取，合并有机相，有机相用饱和 食盐水(100mL*2)洗，无水硫酸钠干燥，过滤，然后减压浓缩得到WX029-3。Add WX029-2 (0.4g, 1.06mmol, 1eq) and glacial acetic acid (2mL) to the pre-dried reaction flask, then add sodium acetate (260.64mg, 3.18mmol, 3eq), and continue stirring at 110°C for 12 hours after the addition is complete . After the completion of the reaction, the reaction solution was concentrated to dryness under reduced pressure, and then saturated sodium bicarbonate solution was added to adjust the pH of the solution to 6-7, and then extracted with ethyl acetate (100mL*3), the organic phases were combined, and the organic phase was saturated with brine (100mL*2) Wash, dry with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain WX029-3.
步骤4：化合物WX029-4的合成Step 4: Synthesis of compound WX029-4
将WX029-3(0.35g,872.26μmol,1eq)加入到40mL投库瓶中，加入2N盐酸(10mL)和乙醇(10mL)，升温至80℃搅拌4小时。反应完成后，向反应液中加入饱和碳酸氢钠水溶液调节pH＝7，加入乙酸乙酯(10mL*3)萃取，合并有机相，减压旋干，得到WX029-4。WX029-3 (0.35g, 872.26μmol, 1eq) was added to a 40mL library bottle, 2N hydrochloric acid (10mL) and ethanol (10mL) were added, and the temperature was raised to 80°C and stirred for 4 hours. After the completion of the reaction, saturated aqueous sodium bicarbonate solution was added to the reaction solution to adjust pH=7, ethyl acetate (10 mL*3) was added for extraction, the organic phases were combined, and spin-dried under reduced pressure to obtain WX029-4.
步骤5：化合物WX029-5的合成Step 5: Synthesis of compound WX029-5
将WX029-4(0.2g,556.76μmol,1eq)加入到40mL投库瓶中，加水(1mL)和盐酸(12M,142.90μL,3.08eq)，降温至5℃，加入亚硝酸钠(42.26mg,612.43μmol,1.1eq)的冰乙酸(2mL)溶液，然后在5℃下搅拌0.5小时，加入WX001-9(95.62mg,612.43μmol,1.1eq)，反应完成后，向反应液中加入10mL饱和乙酸钠水溶液，有大量固体析出，过滤，滤饼用10mL水洗涤，将滤饼减压旋干，得到WX029-5。Add WX029-4 (0.2g, 556.76μmol, 1eq) to a 40mL library bottle, add water (1mL) and hydrochloric acid (12M, 142.90μL, 3.08eq), cool to 5℃, add sodium nitrite (42.26mg, 612.43μmol, 1.1eq) in glacial acetic acid (2mL), then stirred at 5°C for 0.5 hours, WX001-9 (95.62mg, 612.43μmol, 1.1eq) was added, after the reaction was completed, 10mL saturated acetic acid was added to the reaction solution A large amount of solids precipitated in the sodium aqueous solution, filtered, the filter cake was washed with 10 mL of water, and the filter cake was spin-dried under reduced pressure to obtain WX029-5.
步骤6：化合物WX029-6的合成Step 6: Synthesis of compound WX029-6
将WX029-5(0.2g,379.98μmol,1eq)加入到40mL投库瓶中，加入N,N-二甲基乙酰胺(2mL)将底物溶解，加入醋酸钾(74.58mg,759.96μmol,2eq)，升温至115℃搅拌1小时。反应完成后，反应液直接过滤，滤液用高效液相色谱柱纯化(色谱柱:Waters Xbridge Prep OBD C18 150*40mm*10μm；流动相:[水(10mM碳酸氢铵)-乙腈]；乙腈％:25％-55％,8分钟)得到WX029-6。Add WX029-5 (0.2g, 379.98μmol, 1eq) to a 40mL throwing library bottle, add N,N-dimethylacetamide (2mL) to dissolve the substrate, add potassium acetate (74.58mg, 759.96μmol, 2eq ), heated to 115°C and stirred for 1 hour. After the reaction is completed, the reaction solution is directly filtered, and the filtrate is purified with a high performance liquid chromatography column (column: Waters Xbridge Prep OBD C18 150*40mm*10μm; mobile phase: [water (10mM ammonium bicarbonate)-acetonitrile]; acetonitrile%: 25%-55%, 8 minutes) to obtain WX029-6.
步骤7：化合物WX029和WX030的合成Step 7: Synthesis of compounds WX029 and WX030
WX029-6通过超临界色谱分离(仪器：Waters SFC150 AP preparative SFC；色谱柱:DAICEL CHIRALCEL OJ(250mm*30mm,10μm)；流动相:流动相:A二氧化碳B甲醇[中性]；梯度:甲醇％＝35％等度洗脱模式，10分钟；流速:70g/min；柱温:35℃；系统背压:150bar)得到WX029和WX030。WX029-6 is separated by supercritical chromatography (instrument: Waters SFC150 AP preparative SFC; Column: DAICEL CHIRALCEL OJ (250mm*30mm, 10μm); mobile phase: mobile phase: A carbon dioxide B methanol [neutral]; gradient: methanol% = 35% isocratic elution mode, 10 minutes; flow rate: 70g/min; column temperature: 35°C; system back pressure: 150bar) to obtain WX029 and WX030.
WX029： 1HNMR(400MHz,氘代甲醇)δ7.74-7.75(d,J＝4Hz,2H),4.40-4.42(m,1H),2.90-2.95(m,1H),2.64-2.89(m,1H),2.28-2.31(m,1H),1.90-1.94(m,2H)，1.55-1.57(m,1H)。MS-ESI m/z:480.2[M+H] +,482.2[M+H+2] +。保留时间:1.67分钟(仪器:Thar analytical SFC；色谱柱:Chiralpak AS-3 3μm,0.46cm id x 5cm L；流动相：A:食品级超临界二氧化碳；B:甲醇(0.05％异丙醇，体积比)；梯度：B含量在3分钟内从10％升高到40％，；流速:4.0mL/min；柱温：35℃；检测波长：220nm；系统背压:100bar)。 WX029: 1 HNMR (400MHz, deuterated methanol) δ7.74-7.75 (d, J = 4Hz, 2H), 4.40-4.42 (m, 1H), 2.90-2.95 (m, 1H), 2.64-2.89 (m, 1H), 2.28-2.31 (m, 1H), 1.90-1.94 (m, 2H), 1.55-1.57 (m, 1H). MS-ESI m/z: 480.2 [M+H] + , 482.2 [M+H+2] + . Retention time: 1.67 minutes (Instrument: Thar analytical SFC; Column: Chiralpak AS-3 3μm, 0.46cm id x 5cm L; Mobile phase: A: food-grade supercritical carbon dioxide; B: methanol (0.05% isopropanol, volume Gradient: B content increased from 10% to 40% within 3 minutes; flow rate: 4.0 mL/min; column temperature: 35° C.; detection wavelength: 220 nm; system back pressure: 100 bar).
WX030： 1H NMR(400MHz,氘代甲醇)δ7.72-7.73(d,J＝4Hz,2H),4.38-4.40(m,1H),2.88-2.93(m,1H),2.62-2.88(m,1H),2.26-2.87(m,1H),1.88-1.91(m,2H)，1.53-1.55(m,1H)。MS-ESI m/z:480.2[M+H]+,482.2[M+H+2] +。保留时间:1.63分钟(仪器:Thar analytical SFC；色谱柱:Chiralpak AS-3 3μm,0.46cm id x 5cm L；流动相：A:食品级超临界二氧化碳；B:甲醇(0.05异丙醇，体积比)；梯度：B含量在3分钟内从10％升高到40％，；流速:4.0mL/min；柱温：35℃；检测波长：220nm；系统背压:100bar)。 WX030: 1 H NMR (400MHz, deuterated methanol) δ7.72-7.73 (d, J = 4Hz, 2H), 4.38-4.40 (m, 1H), 2.88-2.93 (m, 1H), 2.62-2.88 (m , 1H), 2.26-2.87 (m, 1H), 1.88-1.91 (m, 2H), 1.53-1.55 (m, 1H). MS-ESI m/z: 480.2 [M+H]+, 482.2 [M+H+2] + . Retention time: 1.63 minutes (Instrument: Thar analytical SFC; Column: Chiralpak AS-3 3μm, 0.46cm id x 5cm L; Mobile phase: A: food grade supercritical carbon dioxide; B: methanol (0.05 isopropanol, volume ratio ); Gradient: B content increased from 10% to 40% within 3 minutes; flow rate: 4.0 mL/min; column temperature: 35° C.; detection wavelength: 220 nm; system back pressure: 100 bar).
实施例31Example 31
Figure PCTCN2020093284-appb-000176
Figure PCTCN2020093284-appb-000176
合成路线：synthetic route:
Figure PCTCN2020093284-appb-000177
Figure PCTCN2020093284-appb-000177
步骤1：化合物WX031-1的合成Step 1: Synthesis of compound WX031-1
在预先干燥的反应瓶中加入WX021-1(5g,17.73mmol,1eq)和乙醇(100mL)，置于0℃下，缓慢分批次加入乙醇钠(1.81g,26.60mmol,1.5eq)，置换氮气三次，0℃下搅拌1.5小时。反应完毕后，加水(20mL)稀释，分液，收集有机相，用2N盐酸调节pH至6左右，将体系中甲醇减压浓缩走，剩余溶液用二氯甲烷(20mL*2)萃取，合并有机相，并用饱和食盐水(30mL*2)洗涤，无水硫酸钠干燥，旋干得到粗产品。粗产品经柱层析纯化(石油醚：乙酸乙酯＝1:0转20:1转10:1转5:1转2:1)得到WX031-1。 1H NMR(400MHz,氘代氯仿)δ4.50(t,J＝2.57Hz,1H),3.64-3.87(m,2H),2.93(dd,J＝4.27,18.20Hz,1H),2.47-2.60(m,1H),2.34(dd,J＝2.95,14.49Hz,1H),1.93-2.06(m,2H),1.47-1.54(m,1H),1.23-1.28(m,3H)。MS-ESI m/z:247.0[M+H] +,249.0[M+H+2] +。 Add WX021-1 (5g, 17.73mmol, 1eq) and ethanol (100mL) to the pre-dried reaction flask, place it at 0℃, slowly add sodium ethoxide (1.81g, 26.60mmol, 1.5eq) in batches, and replace Nitrogen three times and stirring at 0°C for 1.5 hours. After the reaction is complete, dilute with water (20mL), separate the layers, collect the organic phase, adjust the pH to about 6 with 2N hydrochloric acid, concentrate the methanol in the system under reduced pressure, and extract the remaining solution with dichloromethane (20mL*2) and combine the organic Phase, washed with saturated brine (30mL*2), dried with anhydrous sodium sulfate, and spin-dried to obtain a crude product. The crude product was purified by column chromatography (petroleum ether: ethyl acetate=1:0 to 20:1 to 10:1 to 5:1 to 2:1) to obtain WX031-1. 1 H NMR (400MHz, deuterated chloroform) δ 4.50 (t, J = 2.57 Hz, 1H), 3.64-3.87 (m, 2H), 2.93 (dd, J = 4.27, 18.20 Hz, 1H), 2.47-2.60 (m, 1H), 2.34 (dd, J=2.95, 14.49 Hz, 1H), 1.93-2.06 (m, 2H), 1.47-1.54 (m, 1H), 1.23-1.28 (m, 3H). MS-ESI m/z: 247.0 [M+H] + , 249.0 [M+H+2] + .
步骤2：化合物WX031-2的合成Step 2: Synthesis of compound WX031-2
在预先干燥的反应瓶中加入WX031-1(2.7g,10.93mmol,1eq)，WX001-4(2.14g,12.02mmol,1.1eq)和DMF(30mL)，加入碳酸铯(4.27g,13.11mmol,1.2eq)，置换氮气三次，置于65℃下搅拌16小时。反应完毕后。将反应液经乙酸乙酯(200mL)稀释，硅藻土过滤，滤液经水(200mL)稀释，分液，用乙酸乙酯萃取水相(200mL*3)，合并有机相，饱和食盐水洗涤(300mL*3)，收集有机相，无水硫酸钠干燥，过滤，减压浓缩得粗产品。粗产品经柱层析纯化(石油醚：乙酸乙酯＝1:0转20:1转10:1转5:1转2:1转 1:1)得到粗品，粗品经高效液相色谱分离(色谱柱:Phenomenex luna C18 250*50mm*15μm；流动相:[水(0.1％三氟乙酸)-乙腈]；乙腈％:50％-70％,20min)得到WX031-2。 1H NMR(400MHz,氘代氯仿)δ6.70(s,2H),4.49(s,1H),4.09(s,2H),3.67-3.89(m,2H),3.06(dd,J＝4.82,19.32Hz,1H),2.62(m,1H),2.36(d,J＝14.01Hz,1H),1.89-2.05(m,2H),1.59(tt,J＝3.36,13.84Hz,1H),1.27-1.33(m,3H)。MS-ESI m/z:390.0[M+H] +,392.0[M+H+2] +。 Add WX031-1 (2.7g, 10.93mmol, 1eq), WX001-4 (2.14g, 12.02mmol, 1.1eq) and DMF (30mL) into the pre-dried reaction flask, add cesium carbonate (4.27g, 13.11mmol, 1.2eq), replaced with nitrogen three times, and stirred at 65°C for 16 hours. After the reaction is complete. The reaction solution was diluted with ethyl acetate (200mL), filtered through Celite, the filtrate was diluted with water (200mL), separated, the aqueous phase was extracted with ethyl acetate (200mL*3), the organic phases were combined, and washed with saturated brine ( 300mL*3), collect the organic phase, dry with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (petroleum ether: ethyl acetate=1:0 to 20:1 to 10:1 to 5:1 to 2:1 to 1:1) to obtain the crude product, which was separated by high performance liquid chromatography ( Chromatographic column: Phenomenex luna C18 250*50mm*15μm; mobile phase: [water (0.1% trifluoroacetic acid)-acetonitrile]; acetonitrile%: 50%-70%, 20min) to obtain WX031-2. 1 H NMR (400MHz, deuterated chloroform) δ 6.70 (s, 2H), 4.49 (s, 1H), 4.09 (s, 2H), 3.67-3.89 (m, 2H), 3.06 (dd, J = 4.82, 19.32Hz, 1H), 2.62 (m, 1H), 2.36 (d, J = 14.01Hz, 1H), 1.89-2.05 (m, 2H), 1.59 (tt, J = 3.36, 13.84 Hz, 1H), 1.27- 1.33 (m, 3H). MS-ESI m/z: 390.0 [M+H] + , 392.0 [M+H+2] + .
步骤3：化合物WX031-3的合成Step 3: Synthesis of compound WX031-3
在预先干燥的反应瓶中加入WX031-2(400mg,1.03mmol,1eq)和冰乙酸(8mL)，加入乙酸钠(168.84mg,2.06mmol,2eq)，置换氮气三次，置于120℃下搅拌16小时。反应完毕后。将反应液减压浓缩，倒入到水(10mL)中，用固体碳酸氢钠调节溶液的pH＝7-8，然后用(乙酸乙酯：四氢呋喃＝3:1，30mL*3)萃取，合并所有的有机相，有机相用饱和氯化钠溶液(30mL*2)洗涤，无水硫酸钠干燥，过滤，浓缩得到WX031-3。MS-ESI m/z:412.0[M+H] +,414.0[M+H+2] +。 Add WX031-2 (400mg, 1.03mmol, 1eq) and glacial acetic acid (8mL) to the pre-dried reaction flask, add sodium acetate (168.84mg, 2.06mmol, 2eq), replace with nitrogen three times, and place at 120℃ and stir for 16 hour. After the reaction is complete. The reaction solution was concentrated under reduced pressure, poured into water (10mL), the pH of the solution was adjusted to 7-8 with solid sodium bicarbonate, and then extracted with (ethyl acetate:tetrahydrofuran=3:1, 30mL*3) and combined All organic phases were washed with saturated sodium chloride solution (30mL*2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain WX031-3. MS-ESI m/z: 412.0 [M+H] + , 414.0 [M+H+2] + .
步骤4：化合物WX031-4的合成Step 4: Synthesis of compound WX031-4
在预先干燥的反应瓶中加入WX031-3(420mg,1.02mmol,1eq)和乙醇(6mL)。加入盐酸(2M,6mL,11.78eq)，置换氮气三次，置于90℃下搅拌3小时。反应完毕后，将反应液冷却至室温，加入水(20mL)，乙酸乙酯萃取水相(20mL*3)，合并有机相，饱和食盐水洗涤(30mL*1)，收集有机相，无水硫酸钠干燥，过滤，减压浓缩得WX031-4。MS-ESI m/z:370.0[M+H] +,372.0[M+H+2] +。 Add WX031-3 (420mg, 1.02mmol, 1eq) and ethanol (6mL) to the pre-dried reaction flask. Add hydrochloric acid (2M, 6mL, 11.78eq), replace with nitrogen three times, and stir at 90°C for 3 hours. After the reaction, the reaction solution was cooled to room temperature, water (20mL) was added, the aqueous phase was extracted with ethyl acetate (20mL*3), the organic phases were combined, washed with saturated brine (30mL*1), the organic phase was collected, and anhydrous sulfuric acid Dry with sodium, filter, and concentrate under reduced pressure to obtain WX031-4. MS-ESI m/z: 370.0 [M+H] + , 372.0 [M+H+2] + .
步骤5：化合物WX031-5的合成Step 5: Synthesis of compound WX031-5
在预先干燥的反应瓶中加入WX031-4(377mg,1.02mmol,1eq)和冰乙酸(5mL)，盐酸(12M,262.21μL,3.09eq)，0℃下缓慢滴入亚硝酸钠(74.48mg,1.08mmol,1.06eq)和水(5mL)的混合溶液，0℃搅拌0.5小时，0℃下加入WX001-9(158.99mg,1.02mmol,1eq)，0℃继续搅拌1.5小时。反应完毕后。将反应液用醋酸钠(3eq)的水溶液(9mL)淬灭，有大量固体生成，过滤得到WX031-5。MS-ESI m/z＝537.1[M+H] +,539.0[M+H+2] +。 Add WX031-4 (377mg, 1.02mmol, 1eq), glacial acetic acid (5mL), hydrochloric acid (12M, 262.21μL, 3.09eq) into the pre-dried reaction flask, and slowly drop sodium nitrite (74.48mg, A mixed solution of 1.08mmol, 1.06eq) and water (5mL) was stirred at 0°C for 0.5 hours, WX001-9 (158.99mg, 1.02mmol, 1eq) was added at 0°C, and stirring was continued for 1.5 hours at 0°C. After the reaction is complete. The reaction solution was quenched with an aqueous solution (9 mL) of sodium acetate (3eq), a large amount of solid was formed, and WX031-5 was obtained by filtration. MS-ESI m/z=537.1 [M+H] + , 539.0 [M+H+2] + .
步骤6：化合物WX031-6的合成Step 6: Synthesis of compound WX031-6
在预先干燥的反应瓶中加入WX031-5(547mg,1.02mmol,1eq)和N,N-二甲基乙酰胺(8mL)，加入乙酸钾(109.89mg,1.12mmol,1.1eq)，置换氮气三次，置于115℃下搅拌5小时。反应完毕后，将反应液直接过滤，滤液送高效液相色谱分离。经高效液相色谱分离(色谱柱:Phenomenex luna C18 250*50mm*10μm；流动相:[水(0.04％盐酸)-乙腈]；乙腈％:40％-60％,10min)得到WX031-6。 1H NMR(400MHz,氘代甲醇)δ7.75(s,2H),4.52(s,1H),3.71-3.85(m,2H),2.93(dd,J＝4.31,19.70Hz,1H),2.61(m,1H),2.22-2.32(m,1H),1.86-2.00(m,2H),1.52-1.63(m,1H),1.22(t,J＝7.00Hz,3H)。MS-ESI m/z＝491.0[M+H] +,493.0[M+H+2] +。经HMBC核磁检测，羰基碳C 1(156.29)与H 2(4.53)相关，证实为所示结构。 Add WX031-5 (547mg, 1.02mmol, 1eq) and N,N-dimethylacetamide (8mL) to the pre-dried reaction flask, add potassium acetate (109.89mg, 1.12mmol, 1.1eq), and replace with nitrogen three times , Placed at 115 ℃ and stirred for 5 hours. After the reaction is completed, the reaction solution is directly filtered, and the filtrate is sent to high performance liquid chromatography for separation. After separation by high performance liquid chromatography (chromatographic column: Phenomenex luna C18 250*50mm*10μm; mobile phase: [water (0.04% hydrochloric acid)-acetonitrile]; acetonitrile%: 40%-60%, 10min) to obtain WX031-6. 1 H NMR (400MHz, deuterated methanol) δ 7.75 (s, 2H), 4.52 (s, 1H), 3.71-3.85 (m, 2H), 2.93 (dd, J = 4.31, 19.70 Hz, 1H), 2.61 (m, 1H), 2.22-2.32 (m, 1H), 1.86-2.00 (m, 2H), 1.52-1.63 (m, 1H), 1.22 (t, J = 7.00 Hz, 3H). MS-ESI m/z=491.0 [M+H] + , 493.0 [M+H+2] + . After HMBC nuclear magnetic detection, the carbonyl carbon C 1 (156.29) is related to H 2 (4.53), which is confirmed to be the structure shown.
Figure PCTCN2020093284-appb-000178
Figure PCTCN2020093284-appb-000178
步骤7：化合物WX031和WX032的合成Step 7: Synthesis of compounds WX031 and WX032
在预先干燥的反应瓶中加入WX031-6(0.25g,508.87umol,1eq)。经超临界色谱分离(仪器:Waters SFC150 AP preparative SFC；色谱柱:DAICEL CHIRALCEL OJ(250mm*30mm,10um)；流动相:A二氧化碳B乙醇[中性]；梯度:乙醇％＝55％等度洗脱模式，10分钟；流速:65g/min；柱温:35℃；系统背压:150bar)得到WX031和WX032。Add WX031-6 (0.25g, 508.87umol, 1eq) to the pre-dried reaction flask. Separated by supercritical chromatography (instrument: Waters SFC150 AP preparative SFC; Column: DAICEL CHIRALCEL OJ (250mm*30mm, 10um); mobile phase: A carbon dioxide B ethanol [neutral]; gradient: ethanol% = 55% isocratic wash Mode-off, 10 minutes; flow rate: 65g/min; column temperature: 35°C; system back pressure: 150bar) to obtain WX031 and WX032.
WX031: 1H NMR(400MHz,氘代甲醇)δ7.75(s,2H),4.52(s,1H),3.71-3.85(m,2H),2.88-3.00(m,1H),2.54-2.68(m,1H),2.24-2.28(m,1H),1.91-1.97(m,2H),1.51-1.62(m,1H),1.22(t,J＝7.02Hz,3H)。保留时间:1.035分钟(仪器:Waters UPCC with PDA detactor；色谱柱:Chiralcel OJ-3,50×4.6mm,I.D.,3um；流动相：A:食品级超临界二氧化碳；B:乙醇(0.05％二乙胺，体积比)；梯度：B含量在1.2分钟内从5％升高到50％并保持1分钟，然后在0.8分钟内从50％降低到5％；流速:3.4mL/min；柱温：35℃；检测波长：220nm；系统背压:100bar)，MS-ESI m/z＝491.0[M+H] +,492.9[M+H+2] +。 WX031: 1 H NMR (400MHz, deuterated methanol) δ 7.75 (s, 2H), 4.52 (s, 1H), 3.71-3.85 (m, 2H), 2.88-3.00 (m, 1H), 2.54-2.68 ( m, 1H), 2.24-2.28 (m, 1H), 1.91-1.97 (m, 2H), 1.51-1.62 (m, 1H), 1.22 (t, J=7.02 Hz, 3H). Retention time: 1.035 minutes (Instrument: Waters UPCC with PDA detactor; Column: Chiralcel OJ-3, 50×4.6mm, ID, 3um; Mobile phase: A: food grade supercritical carbon dioxide; B: ethanol (0.05% diethyl) Amine, volume ratio); Gradient: B content increased from 5% to 50% in 1.2 minutes and maintained for 1 minute, and then decreased from 50% to 5% in 0.8 minutes; Flow rate: 3.4mL/min; Column temperature: 35°C; detection wavelength: 220nm; system backpressure: 100bar), MS-ESI m/z=491.0[M+H] + , 492.9[M+H+2] + .
WX032： 1H NMR(400MHz,氘代甲醇)δ7.75(s,2H),4.52(s,1H),3.71-3.85(m,2H),2.89-2.95(m,1H),2.56-2.66(m,1H),2.24-2.28(m,1H),1.89-2.00(m,2H),1.51-1.60(m,1H),1.21(t,J＝7.02Hz,3H)。保留时间:1.151分钟(仪器:Waters UPCC with PDA detactor；色谱柱:Chiralcel OJ-3,50×4.6mm,I.D.,3um；流动相：A:食品级超临界二氧化碳；B:乙醇(0.05％二乙胺，体积比)；梯度：B含量在1.2分钟内从5％升高到50％并保持1分钟，然后在0.8分钟内从50％降低到5％；流速:3.4mL/min；柱温：35℃；检测波长：220nm；系统背压:100bar)，MS-ESI m/z＝491.0[M+H] +,492.9[M+H+2] +。 WX032: 1 H NMR (400MHz, deuterated methanol) δ 7.75 (s, 2H), 4.52 (s, 1H), 3.71-3.85 (m, 2H), 2.89-2.95 (m, 1H), 2.56-2.66 ( m, 1H), 2.24-2.28 (m, 1H), 1.89-2.00 (m, 2H), 1.51-1.60 (m, 1H), 1.21 (t, J=7.02 Hz, 3H). Retention time: 1.151 minutes (Instrument: Waters UPCC with PDA detactor; Column: Chiralcel OJ-3, 50×4.6mm, ID, 3um; Mobile phase: A: food grade supercritical carbon dioxide; B: ethanol (0.05% diethyl) Amine, volume ratio); Gradient: B content increased from 5% to 50% in 1.2 minutes and maintained for 1 minute, and then decreased from 50% to 5% in 0.8 minutes; Flow rate: 3.4mL/min; Column temperature: 35°C; detection wavelength: 220nm; system backpressure: 100bar), MS-ESI m/z=491.0[M+H] + , 492.9[M+H+2] + .
实施例33Example 33
Figure PCTCN2020093284-appb-000179
Figure PCTCN2020093284-appb-000179
合成路线：synthetic route:
Figure PCTCN2020093284-appb-000180
Figure PCTCN2020093284-appb-000180
步骤1：化合物WX033-1的合成Step 1: Synthesis of compound WX033-1
在预先干燥的反应瓶里加入WX021-1(5g,17.73mmol,1eq)和异丙醇(50mL)，置换氮气置于90℃搅拌2小时。反应完毕后。将反应液冷却至25℃，加入固体碳酸氢钠调pH至6-7，然后减压浓缩得到固体，在固体中加入水(40mL)和乙酸乙酯(40mL)分液，收集有机相，水相用乙酸乙酯(3*40mL)萃取，合并有机相，依次用饱和食盐水(100mL)洗涤，无水硫酸钠干燥，过滤，减压浓缩得到粗品。粗品通过柱层析(梯度淋洗：石油醚：乙酸乙酯＝10：1至3:1至1:1)纯化得到WX033-1。 1HNMR(400MHz,氘代氯仿)δ1.17-1.36(m,6H)，1.43-1.60(m,2H)，1.98-2.16(m,1H)，2.33(dd,J＝14.32,2.81Hz,1H)，2.43-2.63(m,1H)，2.83-3.00(m,1H)，3.91-4.06(m,1H)，4.60-4.73(m,1H)。MS-ESI m/z:261.2[M+H] +,263.0[M+H+2] +。 Add WX021-1 (5g, 17.73mmol, 1eq) and isopropanol (50mL) into the pre-dried reaction flask, replace the nitrogen and place at 90℃ and stir for 2 hours. After the reaction is complete. The reaction solution was cooled to 25° C., solid sodium bicarbonate was added to adjust the pH to 6-7, and then concentrated under reduced pressure to obtain a solid. The solid was separated by adding water (40 mL) and ethyl acetate (40 mL), and the organic phase was collected. The phases were extracted with ethyl acetate (3*40 mL), the organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (gradient elution: petroleum ether: ethyl acetate = 10:1 to 3:1 to 1:1) to obtain WX033-1. 1 HNMR (400MHz, deuterated chloroform) δ1.17-1.36 (m, 6H), 1.43-1.60 (m, 2H), 1.98-2.16 (m, 1H), 2.33 (dd, J = 14.32, 2.81 Hz, 1H ), 2.43-2.63 (m, 1H), 2.83-3.00 (m, 1H), 3.91-4.06 (m, 1H), 4.60-4.73 (m, 1H). MS-ESI m/z: 261.2 [M+H] + , 263.0 [M+H+2] + .
步骤2：化合物WX033-2的合成Step 2: Synthesis of compound WX033-2
在预先干燥的反应瓶中加入WX033-1(1.5g,5.74mmol,1eq)，WX001-4(1.02g,5.74mmol,1eq)和二甲基亚砜(150mL)，再加入碳酸钾(3.18g,22.98mmol,4eq)，置换氮气三次，加入碘化亚铜(656.35mg,3.45mmol,0.6eq)，再次置换氮气，置于90℃中搅拌12小时。反应完毕后。将反应液冷却至25℃，加入水(300mL)稀释，通过硅藻土过滤，加入乙酸乙酯(300mL)分液，收集有机相，水相用乙酸乙酯(3*300mL)萃取，合并有机相，依次用饱和食盐水(3*1000mL)洗涤，无水硫酸钠干燥，过滤，减压浓缩得到粗品。粗品通过柱层析(梯度淋洗：石油醚:乙酸乙酯＝5:1至1:1)纯化，然后通过高效液相色谱(分离条件：色谱柱:Phenomenex Luna C18 200*40mm*10μm；流动相:[水(0.2％甲酸)-乙腈]；乙腈％:50％-90％,8分钟)纯化，得到WX033-2。 1H NMR(400MHz,氘代氯仿)δ1.30(dd,J＝18.39,6.25Hz,6H)，1.54-1.62(m,1H)， 1.94(s,1H)，2.01-2.14(m,1H)，2.29-2.41(m,1H)，2.59-2.68(m,1H)，3.06(dd,J＝19.45,5.44Hz,1H)，3.97-4.04(m,1H)，4.66(s,1H)，6.66(s,2H)。MS-ESI m/z:402.2[M+H] +,404.0[M+H+2] +。 Add WX033-1 (1.5g, 5.74mmol, 1eq), WX001-4 (1.02g, 5.74mmol, 1eq) and dimethyl sulfoxide (150mL) to the pre-dried reaction flask, then add potassium carbonate (3.18g , 22.98mmol, 4eq), replaced with nitrogen three times, added cuprous iodide (656.35mg, 3.45mmol, 0.6eq), replaced the nitrogen again, placed at 90°C and stirred for 12 hours. After the reaction is complete. The reaction solution was cooled to 25°C, diluted with water (300 mL), filtered through celite, and separated by adding ethyl acetate (300 mL), the organic phase was collected, the aqueous phase was extracted with ethyl acetate (3*300 mL), and the organic The phases were washed sequentially with saturated brine (3*1000 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (gradient elution: petroleum ether: ethyl acetate = 5:1 to 1:1), and then passed through high performance liquid chromatography (separation conditions: chromatographic column: Phenomenex Luna C18 200*40mm*10μm; mobile Phase: [water (0.2% formic acid)-acetonitrile]; acetonitrile%: 50%-90%, 8 minutes) to obtain WX033-2. 1 H NMR (400MHz, deuterated chloroform) δ 1.30 (dd, J = 18.39, 6.25 Hz, 6H), 1.54-1.62 (m, 1H), 1.94 (s, 1H), 2.01-2.14 (m, 1H) , 2.29-2.41(m,1H), 2.59-2.68(m,1H), 3.06(dd,J=19.45,5.44Hz,1H), 3.97-4.04(m,1H), 4.66(s,1H), 6.66 (s, 2H). MS-ESI m/z: 402.2 [M+H] + , 404.0 [M+H+2] + .
WX033-2结构鉴定：WX033-2 structure identification:
Figure PCTCN2020093284-appb-000181
Figure PCTCN2020093284-appb-000181
WX033-2经(HMBC)检测显示碳原子C 2(153)与氢H 1(4.66)相关，碳原子C 4(163)与氢H 2(2.59-2.68，3.06)相关，证实WX033-2结构正确。 WX033-2 (HMBC) test showed that carbon atom C 2 (153) is related to hydrogen H 1 (4.66), and carbon atom C 4 (163) is related to hydrogen H 2 (2.59-2.68, 3.06), confirming the structure of WX033-2 correct.
步骤3：化合物WX033-3的合成Step 3: Synthesis of compound WX033-3
在预先干燥的反应瓶里加入WX033-2(350mg,869.13μmol,1eq)，乙酸钠(142.60mg,1.74mmol,2eq)和冰乙酸(4mL)，置换氮气，置于110℃搅拌12小时。反应完毕后。将反应液冷却至25℃，直接减压浓缩得到WX033-3。MS-ESI m/z:462.2[M+H] +,464.0[M+H+2] +。 Add WX033-2 (350mg, 869.13μmol, 1eq), sodium acetate (142.60mg, 1.74mmol, 2eq) and glacial acetic acid (4mL) into the pre-dried reaction flask, replace the nitrogen, and place at 110°C and stir for 12 hours. After the reaction is complete. The reaction solution was cooled to 25°C and directly concentrated under reduced pressure to obtain WX033-3. MS-ESI m/z: 462.2 [M+H] + , 464.0 [M+H+2] + .
步骤4：化合物WX033-4的合成Step 4: Synthesis of compound WX033-4
在预先干燥的反应瓶里加入WX033-3(0.3g,703.74μmol,1eq)，盐酸(2M,7.04mL,20eq)和乙醇(3mL)，置换氮气，置于90℃搅拌12小时。反应完毕后。将反应液冷却至25℃，加水(15mL)稀释，加入固体碳酸氢钠调pH至6-7，加入乙酸乙酯(15mL)分液，收集有机相，水相用乙酸乙酯(3*15mL)萃取，合并有机相，依次用饱和食盐水(50mL)洗涤，无水硫酸钠干燥，过滤，减压浓缩得到粗品。反应无需纯化，直接用于下一步。得到WX033-4。MS-ESI m/z:384.2[M+H] +,386.0[M+H+2] +。 Add WX033-3 (0.3g, 703.74μmol, 1eq), hydrochloric acid (2M, 7.04mL, 20eq) and ethanol (3mL) into the pre-dried reaction flask, replace nitrogen, and place at 90°C and stir for 12 hours. After the reaction is complete. Cool the reaction solution to 25℃, dilute with water (15mL), add solid sodium bicarbonate to adjust the pH to 6-7, add ethyl acetate (15mL) for separation, collect the organic phase, and use ethyl acetate (3*15mL for the aqueous phase) ) Extract, combine the organic phases, sequentially wash with saturated brine (50 mL), dry with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain a crude product. The reaction does not need to be purified and used directly in the next step. Get WX033-4. MS-ESI m/z: 384.2 [M+H] + , 386.0 [M+H+2] + .
步骤5：化合物WX033-5的合成Step 5: Synthesis of compound WX033-5
在预先干燥的反应瓶中加入WX033-4(350mg,910.85μmol,1eq)，之后用冰乙酸(2mL)溶解，然后加入盐酸(276.45mg,2.81mmol,271.03μL,37％纯度,3.08eq)，将反应体系降至5℃，加入亚硝酸钠(69.13mg,1.00mmol,1.1eq)的水(1mL)溶液，在5℃下搅拌反应0.5小时，加入WX011-9(156.44mg,1.00mmol,1.1eq)，5℃搅拌0.5小时。反应完毕后，加入醋酸钠(82mg)和水(2mL)，发现有固体析出，过滤，收集滤饼，滤饼用水(10mL*3)洗涤，将滤饼旋干得到WX033-5。MS-ESI m/z＝551.3[M+H] +,553.0[M+H+2] +。 Add WX033-4 (350mg, 910.85μmol, 1eq) to the pre-dried reaction flask, then dissolve it with glacial acetic acid (2mL), then add hydrochloric acid (276.45mg, 2.81mmol, 271.03μL, 37% purity, 3.08eq), The reaction system was lowered to 5°C, sodium nitrite (69.13mg, 1.00mmol, 1.1eq) in water (1mL) was added, and the reaction was stirred at 5°C for 0.5 hours. WX011-9 (156.44mg, 1.00mmol, 1.1 eq), stirring at 5°C for 0.5 hours. After the reaction was completed, sodium acetate (82mg) and water (2mL) were added, and solids were found to separate out. Filter, collect the filter cake, wash the filter cake with water (10 mL*3), spin-dry the filter cake to obtain WX033-5. MS-ESI m/z=551.3 [M+H] + , 553.0 [M+H+2] + .
步骤6：化合物WX033-6的合成Step 6: Synthesis of compound WX033-6
在预先干燥的反应瓶中加入WX033-5(320mg,580.36μmol,1eq)，之后用N,N-二甲基乙酰胺(3mL)溶解，然后加入乙酸钾(85.44mg,870.55μmol,1.5eq)，置于115℃搅拌反应4小时。反应完毕后，将反应液冷却至25℃，直接过滤，将滤液送高效液相色谱。粗品通过高效液相色谱(色谱柱:3_Phenomenex Luna C18 75*30mm*3μm；流动相:[水(0.2％甲酸)-乙腈]；乙腈％:40％-70％,9分钟)纯化得到WX033-6。MS-ESI m/z＝505.2[M+H] +,507.0[M+H+2] +。 Add WX033-5 (320mg, 580.36μmol, 1eq) to the pre-dried reaction flask, then dissolve it with N,N-dimethylacetamide (3mL), then add potassium acetate (85.44mg, 870.55μmol, 1.5eq) , Placed at 115°C and stirred for 4 hours. After the reaction is completed, the reaction solution is cooled to 25°C, directly filtered, and the filtrate is sent to high performance liquid chromatography. The crude product was purified by high performance liquid chromatography (column: 3-Phenomenex Luna C18 75*30mm*3μm; mobile phase: [water (0.2% formic acid)-acetonitrile]; acetonitrile%: 40%-70%, 9 minutes) to obtain WX033-6 . MS-ESI m/z=505.2 [M+H] + , 507.0 [M+H+2] + .
步骤7：化合物WX033和WX034的合成Step 7: Synthesis of compounds WX033 and WX034
将7(0.1g,197.90μmol,1eq)进行超临界色谱分离。通过(仪器:Waters SFC150AP preparative SFC；色谱柱:DAICEL CHIRALPAK AD(250mm*30mm,10μm)；流动相:A二氧化碳B异丙醇[中性]；梯度:异丙醇％＝50％等度洗脱模式，30min；流速:80g/min；柱温:35℃；系统背压:150bar)进行超临界色谱分离得到WX033和WX034。The 7 (0.1g, 197.90μmol, 1eq) was separated by supercritical chromatography. Pass (instrument: Waters SFC150APpreparative SFC; Column: DAICEL CHIRALPAK AD (250mm*30mm, 10μm); mobile phase: A carbon dioxide B isopropanol [neutral]; gradient: isopropanol% = 50% isocratic elution Mode, 30min; Flow rate: 80g/min; Column temperature: 35℃; System back pressure: 150bar) WX033 and WX034 were obtained by supercritical chromatography.
WX033： 1H NMR(400MHz,氘代甲醇)δ1.23(dd,J＝6.00,3.88Hz,6H)，1.54-1.62(m,1H)，1.84-2.07(m,2H)，2.20(d,J＝12.38Hz,1H)，2.54-2.68(m,1H)，2.92(dd,J＝19.32,4.69Hz,1H)，4.05-4.11(m,1H)，4.64(s,1H)，7.75(s,2H)。保留时间:1.295分钟(仪器:Waters UPCC with PDA detactor；色谱柱:Chiralcel OJ-3,50×4.6mm,I.D.,3μm；流动相：A:食品级超临界二氧化碳；B:异丙醇(0.05％二乙胺，体积比)；梯度：B含量在1.2分钟内从5％升高到50％并保持1分钟，然后在0.8分钟内从50％降低到5％；流速:3.4mL/min；柱温：35℃；检测波长：220nm；系统背压:100bar)，MS-ESI m/z＝491.0[M+H] +,492.9[M+H+2] +。 WX033: 1 H NMR (400MHz, deuterated methanol) δ 1.23 (dd, J = 6.00, 3.88 Hz, 6H), 1.54-1.62 (m, 1H), 1.84-2.07 (m, 2H), 2.20 (d, J = 12.38 Hz, 1H), 2.54-2.68 (m, 1H), 2.92 (dd, J = 19.32, 4.69 Hz, 1H), 4.05-4.11 (m, 1H), 4.64 (s, 1H), 7.75 (s ,2H). Retention time: 1.295 minutes (Instrument: Waters UPCC with PDA detactor; Column: Chiralcel OJ-3, 50×4.6mm, ID, 3μm; Mobile phase: A: food grade supercritical carbon dioxide; B: isopropanol (0.05% Diethylamine, volume ratio); Gradient: B content increased from 5% to 50% in 1.2 minutes and maintained for 1 minute, then decreased from 50% to 5% in 0.8 minutes; Flow rate: 3.4mL/min; Column Temperature: 35°C; detection wavelength: 220nm; system back pressure: 100bar), MS-ESI m/z=491.0[M+H] + , 492.9[M+H+2] + .
WX034： 1H NMR(400MHz,氘代甲醇)δ1.23(dd,J＝6.00,4.00Hz,6H)，1.52-1.64(m,1H)，1.87-2.07(m,2H)，2.20(d,J＝13.63Hz,1H)，2.53-2.68(m,1H)，2.92(dd,J＝19.45,4.94Hz,1H)，4.05-4.11(m,1H)，4.64(s,1H)，7.75(s,2H)。保留时间:1.517分钟(仪器:Waters UPCC with PDA detactor；色谱柱:Chiralcel OJ-3,50×4.6mm,I.D.,3μm；流动相：A:食品级超临界二氧化碳；B:异丙醇(0.05％二乙胺，体积比)；梯度：B含量在1.2分钟内从5％升高到50％并保持1分钟，然后在0.8分钟内从50％降低到5％；流速:3.4mL/min；柱温：35℃；检测波长：220nm；系统背压:100bar)。MS-ESI m/z＝491.0[M+H] +,492.9[M+H+2] +。 WX034: 1 H NMR (400MHz, deuterated methanol) δ 1.23 (dd, J = 6.00, 4.00 Hz, 6H), 1.52-1.64 (m, 1H), 1.87-2.07 (m, 2H), 2.20 (d, J = 13.63 Hz, 1H), 2.53-2.68 (m, 1H), 2.92 (dd, J = 19.45, 4.94 Hz, 1H), 4.05-4.11 (m, 1H), 4.64 (s, 1H), 7.75 (s ,2H). Retention time: 1.517 minutes (Instrument: Waters UPCC with PDA detactor; Column: Chiralcel OJ-3, 50×4.6mm, ID, 3μm; Mobile phase: A: food grade supercritical carbon dioxide; B: isopropanol (0.05% Diethylamine, volume ratio); Gradient: B content increased from 5% to 50% in 1.2 minutes and maintained for 1 minute, then decreased from 50% to 5% in 0.8 minutes; Flow rate: 3.4mL/min; Column Temperature: 35℃; Detection wavelength: 220nm; System back pressure: 100bar). MS-ESI m/z=491.0 [M+H] + , 492.9 [M+H+2] + .
实施例35Example 35
Figure PCTCN2020093284-appb-000182
Figure PCTCN2020093284-appb-000182
合成路线：synthetic route:
Figure PCTCN2020093284-appb-000183
Figure PCTCN2020093284-appb-000183
步骤1：化合物WX035-1的合成Step 1: Synthesis of compound WX035-1
在预先干燥的反应瓶中加入WX021-5(287mg,805.72μmol,1eq)，之后用二氯甲烷(6mL)溶解，将反应体系冷却至0℃，然后加入三溴化硼(403.70mg,1.61mmol,155.27μL,2eq)，0℃搅拌反应1小时，升高至40℃搅拌反应12小时。反应完成后，将反应体系冷却至室温(25℃)，用饱和的碳酸氢钠中和反应液pH至中性，之后加入二氯甲烷(20mL)，四氢呋喃(10mL)，有机相溶解，分液要有机相，水相用乙酸乙酯(20mL*3)(加少量四氢呋喃助溶)萃取，合并有机相，并用饱和食盐水(20mL*2)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩得到WX035-1。Add WX021-5 (287mg, 805.72μmol, 1eq) to the pre-dried reaction flask, then dissolve it with dichloromethane (6mL), cool the reaction system to 0℃, and then add boron tribromide (403.70mg, 1.61mmol) , 155.27μL, 2eq), stirred at 0°C for 1 hour, raised to 40°C and stirred for 12 hours. After the completion of the reaction, the reaction system was cooled to room temperature (25°C), and the pH of the reaction solution was neutralized with saturated sodium bicarbonate, and then dichloromethane (20mL) and tetrahydrofuran (10mL) were added. The organic phase was dissolved and separated. For the organic phase, the aqueous phase was extracted with ethyl acetate (20mL*3) (adding a small amount of tetrahydrofuran for solubilization), the organic phases were combined, washed with saturated brine (20mL*2), dried over anhydrous sodium sulfate, filtered, and the filtrate was reduced in pressure Concentrate to obtain WX035-1.
步骤2：化合物WX035-3的合成Step 2: Synthesis of compound WX035-3
在预先干燥的反应瓶中加入WX035-2(140.22mg,2.41mmol,10mL,3eq)，将反应体系降至0℃，然后加入氢化钠(48.29mg,1.21mmol,60％纯度,1.5eq)，0℃搅拌反应10分钟，之后将该反应液缓慢加入到WX035-1(326mg,804.79μmol,1eq)的WX035-2(10mL)溶液中(滴加过程中会升温)，0℃搅拌反应30分钟。反应完成后，0℃下用1N的盐酸中和反应液pH至6左右，加水(30mL)和乙酸乙酯(30mL)，分液要有机相，水相用乙酸乙酯(30mL*2)萃取，合并有机相，并用饱和食盐水(30mL*2)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩得到WX035-3。Add WX035-2 (140.22mg, 2.41mmol, 10mL, 3eq) to the pre-dried reaction flask, reduce the reaction system to 0°C, and then add sodium hydride (48.29mg, 1.21mmol, 60% purity, 1.5eq), The reaction was stirred at 0°C for 10 minutes, and then the reaction solution was slowly added to the WX035-2 (10mL) solution of WX035-1 (326mg, 804.79μmol, 1eq) (the temperature would rise during the dropping), and the reaction was stirred at 0°C for 30 minutes . After the reaction is completed, neutralize the pH of the reaction solution to about 6 with 1N hydrochloric acid at 0℃, add water (30mL) and ethyl acetate (30mL), separate the organic phase, and extract the aqueous phase with ethyl acetate (30mL*2) , The organic phases were combined, washed with saturated brine (30 mL*2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain WX035-3.
步骤3：化合物WX035-4的合成Step 3: Synthesis of compound WX035-4
在预先干燥的反应瓶中加入WX035-3(300mg,784.85μmol,1eq)，之后用冰乙酸(6mL)溶解，然后加入盐酸(238.20mg,2.42mmol,233.53μL,37％纯度,3.08eq)，将反应体系降至5℃，加入亚硝酸钠(59.57mg,863.33μmol,1.1eq)的水(3mL)溶液，在5℃下搅拌反应0.5小时。加入WX001-9(134.80mg,863.33 μmol,1.1eq)，5℃搅拌0.5小时。反应完成后，0℃下加醋酸钠(200mg)的水(10mL)溶液，发现有固体析出，再加水(10mL)，固体变多，过滤，要滤饼，滤饼用水(5mL*2)洗涤，滤饼旋干得到WX035-4。Add WX035-3 (300mg, 784.85μmol, 1eq) to the pre-dried reaction flask, then dissolve it with glacial acetic acid (6mL), then add hydrochloric acid (238.20mg, 2.42mmol, 233.53μL, 37% purity, 3.08eq), The reaction system was lowered to 5°C, sodium nitrite (59.57mg, 863.33μmol, 1.1eq) in water (3mL) was added, and the reaction was stirred at 5°C for 0.5 hours. WX001-9 (134.80mg, 863.33 μmol, 1.1eq) was added and stirred at 5°C for 0.5 hour. After the reaction is complete, add a solution of sodium acetate (200mg) in water (10mL) at 0°C, and it is found that solids have precipitated, then add water (10mL), the solids will increase, filter, filter cake, filter cake with water (5mL*2) wash , The filter cake was spin-dried to obtain WX035-4.
步骤4：化合物WX035-5的合成Step 4: Synthesis of compound WX035-5
在预先干燥的反应瓶中加入WX035-4(430mg,782.73μmol,1eq)，之后用N,N-二甲基乙酰胺(4mL)溶解，然后加入醋酸钾(115.23mg,1.17mmol,1.5eq)，缓慢的升高至115℃搅拌反应1小时。补加醋酸钾(115.23mg,1.17mmol,1.5eq)，继续在115℃下搅拌反应0.5小时。反应完成后，反应液过滤，经高效液相色谱分离(分离条件：色谱柱:Welch Xtimate C18 150*25mm*5μm；流动相:[水(0.04％盐酸)-乙腈]；乙腈％:50％-60％,8分钟)得到WX035-5。Add WX035-4 (430mg, 782.73μmol, 1eq) to the pre-dried reaction flask, then dissolve it with N,N-dimethylacetamide (4mL), then add potassium acetate (115.23mg, 1.17mmol, 1.5eq) The temperature was slowly raised to 115°C and stirred for 1 hour. Potassium acetate (115.23mg, 1.17mmol, 1.5eq) was added, and the reaction was stirred at 115°C for 0.5 hours. After the reaction is completed, the reaction solution is filtered and separated by high performance liquid chromatography (Separation conditions: Column: Welch Xtimate C18 150*25mm*5μm; Mobile phase: [water (0.04% hydrochloric acid)-acetonitrile]; acetonitrile%: 50%- 60%, 8 minutes) to get WX035-5.
步骤5：化合物WX035和WX036的合成Step 5: Synthesis of compounds WX035 and WX036
WX035-5通过超临界色谱分离(仪器：Waters SFC150 AP preparative SFC，色谱柱:DAICEL CHIRALCEL OJ(250mm*30mm,10μm)，流动相:A二氧化碳B甲醇[中性]；梯度:甲醇％＝35％等度洗脱模式，15min，流速:70g/min；柱温:35℃；系统背压:150bar)得到WX035和WX036。WX035-5 is separated by supercritical chromatography (instrument: Waters SFC150 AP preparative SFC, column: DAICEL CHIRALCEL OJ (250mm*30mm, 10μm), mobile phase: A carbon dioxide B methanol [neutral]; gradient: methanol% = 35% Isocratic elution mode, 15min, flow rate: 70g/min; column temperature: 35℃; system back pressure: 150bar) to obtain WX035 and WX036.
WX035： 1HNMR(400MHz,氘代甲醇)δ7.75(s,2H),4.71s(m,1H),3.66-3.70(m,1H),2.90-2.95(m,1H),2.62-2.67(m,1H),2.36-2.40(m,1H),1.91-1.93(m,2H),1.60-1.61(m,1H),0.82-0.85(m,1H),0.65-0.66(m,1H),0.47-0.54(m,2H)。MS-ESI m/z:503.0[M+H] +,504.9[M+H+2] +。保留时间:1.143分钟(仪器:Waters UPCC with PDA detactor；色谱柱:Chiralpak AS-3,50*4.6mm,I.D.,3μm；流动相：A:食品级超临界二氧化碳；B:甲醇(0.05％二乙胺，体积比)；梯度：B含量在1.2分钟内从5％升高到50％，50％维持1分钟，然后在0.8分钟内从50％降到5％；流速:3.4mL/min；柱温：35℃；检测波长：220nm；系统背压:1800psi)。 WX035: 1 HNMR (400MHz, deuterated methanol) δ 7.75 (s, 2H), 4.71s (m, 1H), 3.66-3.70 (m, 1H), 2.90-2.95 (m, 1H), 2.62-2.67 ( m,1H),2.36-2.40(m,1H),1.91-1.93(m,2H),1.60-1.61(m,1H),0.82-0.85(m,1H),0.65-0.66(m,1H), 0.47-0.54 (m, 2H). MS-ESI m/z: 503.0 [M+H] + , 504.9 [M+H+2] + . Retention time: 1.143 minutes (Instrument: Waters UPCC with PDA detactor; Column: Chiralpak AS-3, 50*4.6mm, ID, 3μm; Mobile phase: A: food grade supercritical carbon dioxide; B: methanol (0.05% diethyl Amine, volume ratio); Gradient: B content increased from 5% to 50% in 1.2 minutes, 50% maintained for 1 minute, and then decreased from 50% to 5% in 0.8 minutes; Flow rate: 3.4 mL/min; Column Temperature: 35℃; detection wavelength: 220nm; system back pressure: 1800psi).
WX036： 1HNMR(400MHz,氘代甲醇)δ7.75(s,2H),4.75-4.67(m,1H),3.71-3.66(m,1H),2.98-2.87(m,1H),2.68-2.55(m,1H),2.44-2.32(m,1H),1.99-1.88(m,2H),1.66-1.54(m,1H),0.89-0.79(m,1H),0.71-0.61(m,1H),0.59-0.50(m,1H),0.50-0.40(m,1H)。MS-ESI m/z:503.0[M+H]+,504.9[M+H+2] +。保留时间:1.328分钟(仪器:Waters UPCC with PDA detactor；色谱柱:Chiralpak AS-3,50*4.6mm,I.D.,3μm；流动相：A:食品级超临界二氧化碳；B:甲醇(0.05％二乙胺，体积比)；梯度：B含量在1.2分钟内从5％升高到50％，50％维持1分钟，然后在0.8分钟内从50％降到5％；流速:3.4mL/min；柱温：35℃；检测波长：220nm；系统背压:1800psi)。 WX036: 1 HNMR (400MHz, deuterated methanol) δ 7.75 (s, 2H), 4.75-4.67 (m, 1H), 3.71-3.66 (m, 1H), 2.98-2.87 (m, 1H), 2.68-2.55 (m,1H),2.44-2.32(m,1H),1.99-1.88(m,2H),1.66-1.54(m,1H),0.89-0.79(m,1H),0.71-0.61(m,1H) ,0.59-0.50(m,1H),0.50-0.40(m,1H). MS-ESI m/z: 503.0 [M+H]+, 504.9 [M+H+2] + . Retention time: 1.328 minutes (Instrument: Waters UPCC with PDA detactor; Column: Chiralpak AS-3, 50*4.6mm, ID, 3μm; Mobile phase: A: food grade supercritical carbon dioxide; B: methanol (0.05% diethyl Amine, volume ratio); Gradient: B content increased from 5% to 50% in 1.2 minutes, 50% maintained for 1 minute, and then decreased from 50% to 5% in 0.8 minutes; Flow rate: 3.4 mL/min; Column Temperature: 35℃; detection wavelength: 220nm; system back pressure: 1800psi).
生物测试Biological test
实验一：核激素受体活性实验Experiment 1: Nuclear hormone receptor activity experiment
Figure PCTCN2020093284-appb-000184
NHR蛋白质相互作用(Pro)和核转位(NT)实验技术能以均匀非成像的形式监测核激素受体的激活程度，该实验使用了DiscoverX开发的名为酶片段互补(EFC)的技术。NHR Pro实验原理 是检测活化的全长NHR蛋白和含有一个或多个经典LXXLL相互作用基序的类固醇受体共活化肽(SRCP)结构域的核融合蛋白之间的蛋白蛋白相互作用。NHR被EFC检测系统的ProLinkTM组分标记，SRCP结构域与在细胞核中表达的酶受体组分(EA)融合。当被配体结合时，NHR将迁移到细胞核并募集SRCP结构域，由此发生互补，产生一单位的活性β-半乳糖苷酶(β-Gal)并产生化学发光信号。与此方法相关的益处包括减少化合物孵育时间，直接测量NHR靶标，使用全长人NHR序列，以及打破蛋白蛋白相互作用的限制挑选新类别化合物的能力。NHR NT实验监测NHR在细胞质和核区室之间的移动。该受体用我们的EFC分析系统的ProLabel TM成分标记，并且EA与核定位序列融合，限制EA向细胞核的表达。NHR迁移至细胞核导致与EA互补，产生活性β-Gal单位并产生化学发光信号。
Figure PCTCN2020093284-appb-000184
The NHR protein interaction (Pro) and nuclear translocation (NT) experimental technology can monitor the activation of nuclear hormone receptors in a uniform non-imaging form. The experiment uses a technology called Enzyme Fragment Complementation (EFC) developed by DiscoverX. The principle of the NHR Pro experiment is to detect the protein-protein interaction between the activated full-length NHR protein and the nuclear fusion protein containing one or more classic LXXLL interaction motifs of the steroid receptor co-activation peptide (SRCP) domain. NHR is labeled by the ProLinkTM component of the EFC detection system, and the SRCP domain is fused with the enzyme receptor component (EA) expressed in the nucleus. When bound by a ligand, NHR will migrate to the nucleus and recruit the SRCP domain, thereby complementing it, generating a unit of active β-galactosidase (β-Gal) and generating a chemiluminescent signal. The benefits associated with this method include reduced compound incubation time, direct measurement of NHR targets, use of full-length human NHR sequences, and the ability to break the limitations of protein-protein interactions to select new classes of compounds. The NHR NT experiment monitors the movement of NHR between the cytoplasm and the nuclear compartment. The receptor is labeled with the ProLabel TM component of our EFC analysis system, and the EA is fused with the nuclear localization sequence to limit the expression of EA to the nucleus. The migration of NHR to the nucleus results in complementation with EA, producing active β-Gal units and generating chemiluminescent signals.
实验设计：experimental design:
细胞处理Cell processing
1.根据标准程序，复苏并扩增PathHunter NHR细胞。1. Resuscitate and expand PathHunter NHR cells according to standard procedures.
2.将20μL细胞接种到白壁384微孔板中，在37℃下孵育适当的时间，然后再进行测试。测试培养基使用经木炭葡聚糖过滤的血清以降低激素水平。2. Inoculate 20μL of cells into a white-walled 384 microwell plate, incubate at 37°C for an appropriate time, and then perform the test. The test medium used charcoal dextran filtered serum to reduce hormone levels.
激动剂测试Agonist testing
1.对于激动剂试验，将细胞与化合物一起孵育以诱导反应。1. For the agonist test, incubate the cells with the compound to induce a response.
2.将化合物储存液用体系缓冲液稀释5倍。2. Dilute the compound stock solution 5 times with the system buffer.
3.将5μL稀释5倍的化合物加入到细胞中，并在37℃或室温下孵育3-16小时。溶媒终浓度为1％。3. Add 5 μL of the 5-fold diluted compound to the cells, and incubate at 37°C or room temperature for 3-16 hours. The final concentration of the solvent is 1%.
信号检测：Signal Detection:
1.加入12.5或15μL(50％v/v)PathHunter检测试剂，然后在室温下孵育1小时，即产生试验信号。1. Add 12.5 or 15 μL (50% v/v) PathHunter detection reagent, and then incubate at room temperature for 1 hour to generate a test signal.
2.用PerkinElmer的EnvisionTM读取微孔板中生成的化学发光信号。2. Use PerkinElmer's EnvisionTM to read the chemiluminescence signal generated in the microplate.
数据分析：data analysis:
1.使用CBIS数据分析软件(ChemInnovation，CA)分析化合物活性。1. Use CBIS data analysis software (ChemInnovation, CA) to analyze compound activity.
2.对于激动剂测试，使用以下公式计算活性百分比：2. For agonist testing, use the following formula to calculate the percentage of activity:
％活性＝100％×(测试样品的平均RLU-溶媒对照的平均RLU)/(对照配体平均最大RLU-溶媒对照的平均RLU)。% Activity=100%×(average RLU of test sample-average RLU of vehicle control)/(average maximum RLU of control ligand-average RLU of vehicle control).
表1各实施例化合物的THRα例和THRβ例活性Table 1 THRα and THRβ activities of each example compound
实施例Example 化合物Compound THRαEC 50(μM) THRαEC 50 (μM) THRβEC 50(μM) THRβEC 50 (μM) 选择性(THRα/THRβ)Selectivity (THRα/THRβ)
参比化合物Reference compound MGL-3196MGL-3196 4.184.18 2.92.9 1.41.4
11 WX001WX001 >100>100 2.462.46 >40.7>40.7
22 WX002WX002 0.760.76 1.751.75 0.40.4
33 WX003WX003 1.61.6 0.240.24 6.76.7
44 WX004WX004 7.457.45 2.132.13 3.53.5
55 WX005WX005 10.1110.11 0.490.49 20.620.6
66 WX006WX006 >100>100 12.1112.11 >8.3>8.3
88 WX008WX008 27.2327.23 9.949.94 2.72.7
99 WX009WX009 6.516.51 26.426.4 0.20.2
1111 WX011WX011 >100>100 4.74.7 >21.3>21.3
1212 WX012WX012 22.222.2 13.613.6 1.61.6
1313 WX013WX013 >100>100 5.025.02 >19.9>19.9
1313 WX014WX014 >100>100 3.793.79 >26.4>26.4
1515 WX015WX015 19.4619.46 2.682.68 7.27.2
1616 WX016WX016 20.9120.91 3.783.78 5.55.5
1717 WX017WX017 >100>100 3.973.97 >25.2>25.2
1818 WX018WX018 >100>100 21.7521.75 >4.6>4.6
1919 WX019WX019 3.273.27 0.0760.076 4343
2020 WX020WX020 >100>100 3.363.36 >29.8>29.8
21twenty one WX021WX021 >100>100 6.766.76 >14.8>14.8
21twenty one WX022WX022 >100>100 10.2710.27 >9.7>9.7
23twenty three WX023WX023 >100>100 1.581.58 >63.4>63.4
23twenty three WX024WX024 >100>100 5.135.13 >19.5>19.5
2525 WX025WX025 >100>100 4.254.25 >23.5>23.5
2525 WX026WX026 3.623.62 1.091.09 3.33.3
2727 WX027WX027 >100>100 1.31.3 >76.9>76.9
2828 WX028WX028 >100>100 1.31.3 >76.9>76.9
2929 WX029WX029 >100>100 37.3937.39 >2.7>2.7
2929 WX030WX030 >100>100 2.272.27 >44.1>44.1
3131 WX031WX031 >100>100 6.146.14 >16.3>16.3
3131 WX032WX032 7.617.61 1.351.35 5.65.6
3333 WX033WX033 >100>100 4.614.61 >21.7>21.7
3333 WX034WX034 35.8135.81 5.535.53 6.56.5
3535 WX035WX035 36.2636.26 11.2511.25 3.23.2
3535 WX036WX036 2.582.58 0.570.57 4.54.5
结论：本发明化合物具有显著的THRα/β活性，部分化合物THRα选择性优于MGL-3196。Conclusion: The compound of the present invention has significant THRα/β activity, and some compounds have better THRα selectivity than MGL-3196.
实验二：细胞色素P450同工酶抑制性研究Experiment 2: Study on the inhibition of cytochrome P450 isoenzymes
实验目的：测定受试化合物对人肝微粒体细胞色素P450同工酶(CYP1A2、CYP2C9、CYP2C19、CYP2D6和CYP3A4)活性的抑制作用。Experimental purpose: To determine the inhibitory effect of the test compound on the activity of human liver microsomal cytochrome P450 isoenzymes (CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4).
实验操作1：首先将受试化合物(10.0mM)进行稀释，制备工作液(100×最终浓度)，工作液浓度为1.00mM，同时准备P450同工酶(CYP1A2、CYP2C9、CYP2C19、CYP2D6和CYP3A4)各阳性抑制剂及其特异性底物混合物(5合1)的工作液；将保存在低于-60℃冰箱的人肝微粒体置于冰上解冻，待人肝微粒体全部溶解，用PB进行稀释，制备一定浓度工作液(0.253mg/mL)。先将20.0μL底物混合液加至反应板中(空白孔中加入20.0μL PB)，然后将158μL人肝微粒体工作液加入反应板中，将反应板置于冰上，待用；此时将2.00μL受试化合物(N＝2)及特异性抑制剂(N＝2)加入对应孔中，无抑制剂(受试化合物或阳性抑制剂)组加入对应的有机溶剂，受试化合物对照样品和阳性对照样品有机相均为1:9DMSO:MeOH；在37℃水浴预孵育10min后，将20.0μL辅酶因子(NADPH)溶液加入反应板中，置于37℃水浴孵育反应10min；加入400μL预冷的乙腈溶液(含200ng/mL Tolbutamide和Labetalol的内标)终止反应；将反应板置于摇床，振荡混匀10min；然后在4℃、4000rpm条件下离心20min；取200μL上清加至100μL水中，进行样品稀释；最后封板，振荡，摇匀，进行LC/MS/MS检测。实验结果如表2所示：Experimental operation 1: First, the test compound (10.0mM) was diluted to prepare a working solution (100×final concentration), the concentration of the working solution was 1.00mM, and the P450 isoenzymes (CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4) The working solution of each positive inhibitor and its specific substrate mixture (5 in 1); put the human liver microsomes stored in the refrigerator below -60℃ on ice to thaw, and when the human liver microsomes are completely dissolved, use PB Dilute, prepare a certain concentration of working solution (0.253mg/mL). First add 20.0μL of substrate mixture to the reaction plate (add 20.0μL of PB to the blank well), then add 158μL of human liver microsome working solution to the reaction plate, place the reaction plate on ice, and set aside; now Add 2.00 μL of test compound (N=2) and specific inhibitor (N=2) to the corresponding wells, add the corresponding organic solvent to the group without inhibitor (test compound or positive inhibitor), and test compound control sample The organic phase of the positive control sample and the positive control sample are both 1:9 DMSO:MeOH; after pre-incubating in a 37°C water bath for 10 minutes, add 20.0μL of coenzyme factor (NADPH) solution to the reaction plate and place it in a 37°C water bath to incubate the reaction for 10 minutes; add 400μL of pre-cooling Stop the reaction with acetonitrile solution (containing 200ng/mL Tolbutamide and Labetalol internal standard); place the reaction plate on a shaker, shake and mix for 10 min; then centrifuge at 4°C and 4000 rpm for 20 min; take 200 μL of supernatant and add to 100 μL of water , Perform sample dilution; finally seal the plate, shake, shake well, and perform LC/MS/MS detection. The experimental results are shown in Table 2:
表2受试化合物对人肝微粒体细胞色素P450同工酶活性的抑制作用结果Table 2 Results of inhibitory effects of test compounds on human liver microsomal cytochrome P450 isoenzyme activity
Figure PCTCN2020093284-appb-000185
Figure PCTCN2020093284-appb-000185
实验操作2：首先将受试化合物(10.0mM)进行梯度稀释，制备工作液(100×最终浓度)，且工作液浓度分别为：5.00,1.50,0.500,0.150,0.0500,0.0150,0.00500mM，同时准备P450同工酶(CYP1A2、CYP2C9、CYP2C19、CYP2D6和CYP3A4)各阳性抑制剂及其特异性底物混合物(5合1)的工作液；将保存在低于-60℃冰箱的人肝微粒体置于冰上解冻，待人肝微粒体全部溶解，用PB进行稀释，制备一定浓度工作液(0.253mg/mL)。先将20.0μL底物混合液加至反应板中(空白孔中加入20.0μL PB)，然后将158μL人肝微粒体工作液加入反应板中，将反应板置于冰上，待用；此时将2.00μL各个浓度的受试化合物(N＝1)及特异性抑制剂(N＝2)加入对应孔中，无抑制剂(受试化合物或阳性抑制剂)组加入对应的有机溶剂，作为对照组样品(受试化合物对照样品为1:1DMSO:MeOH，阳性对照样品均为1:9DMSO:MeOH)；在37℃水浴预孵育10min后，将20.0μL辅酶因子(NADPH)溶液加入反应板中，置于37℃水浴孵育反应10 min；加入400μL预冷的乙腈溶液(含200ng/mL Tolbutamide和Labetalol的内标)终止反应；将反应板置于摇床，振荡混匀10min；然后在4℃、4000rpm条件下离心20min；取200μL上清加至100μL水中，进行样品稀释；最后封板，振荡，摇匀，进行LC/MS/MS检测。实验结果如表3所示：Experimental operation 2: Firstly, the test compound (10.0mM) was diluted gradually to prepare a working solution (100×final concentration), and the concentration of the working solution were: 5.00, 1.50, 0.500, 0.150, 0.0500, 0.0150, 0.00500 mM, and Prepare the working solution of each positive inhibitor of P450 isoenzymes (CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4) and their specific substrate mixture (5 in 1); human liver microsomes stored in the refrigerator below -60℃ Thaw it on ice, and when the human liver microsomes are completely dissolved, dilute with PB to prepare a working solution of a certain concentration (0.253 mg/mL). First add 20.0μL of substrate mixture to the reaction plate (add 20.0μL of PB to the blank well), then add 158μL of human liver microsome working solution to the reaction plate, place the reaction plate on ice, and set aside; now Add 2.00 μL of each concentration of test compound (N=1) and specific inhibitor (N=2) to the corresponding wells, add the corresponding organic solvent to the group without inhibitor (test compound or positive inhibitor) as a control Group samples (the test compound control sample is 1:1DMSO:MeOH, and the positive control sample is 1:9DMSO:MeOH); after pre-incubation in a 37°C water bath for 10 minutes, 20.0μL of coenzyme factor (NADPH) solution is added to the reaction plate, Incubate the reaction in a 37°C water bath for 10 minutes; add 400μL of pre-cooled acetonitrile solution (containing 200ng/mL Tolbutamide and Labetalol internal standard) to terminate the reaction; place the reaction plate on a shaker, shake and mix for 10 minutes; then at 4°C, Centrifuge at 4000 rpm for 20 min; add 200 μL of supernatant to 100 μL of water to dilute the sample; finally, seal the plate, shake, shake, and perform LC/MS/MS detection. The experimental results are shown in Table 3:
表3.受试化合物对人肝微粒体细胞色素P450同工酶活性的抑制作用结果Table 3. Results of inhibitory effects of test compounds on human liver microsomal cytochrome P450 isoenzyme activity
Figure PCTCN2020093284-appb-000186
Figure PCTCN2020093284-appb-000186
实验结论：本发明化合物对CYP2C19、CYP2D6和CYP3A4均无抑制作用，对CYP1A2和CYP2C9有中等或弱抑制作用。Experimental conclusion: The compound of the present invention has no inhibitory effect on CYP2C19, CYP2D6 and CYP3A4, and has a moderate or weak inhibitory effect on CYP1A2 and CYP2C9.
实验三：血浆蛋白结合率研究Experiment 3: Study on plasma protein binding rate
实验目的：测定受试化合物在CD-1小鼠、SPRAGUE-DAWLEY大鼠、比格犬、食蟹猴和人血浆中的蛋白结合率Experimental purpose: To determine the protein binding rate of the test compound in CD-1 mice, SPRAGUE-DAWLEY rats, beagle dogs, cynomolgus monkeys and human plasma
实验操作：取CD-1小鼠、SPRAGUE-DAWLEY大鼠、比格犬、食蟹猴和人的空白血浆995μL，加入5μL受试化合物工作溶液(400μM)或华法林工作溶液(400μM)，使血浆样品中受试化合物与华法林终浓度均为2μM。将样品充分混合。有机相DMSO的终浓度为0.5％；移取50μL受试化合物和华法林血浆样品到样品接收板中(三个平行)，立即加入相应体积的对应空白血浆或缓冲液，使得每个样品孔的终体积为100μL，血浆：透析缓冲液的体积比为1:1，然后向这些样品中加入500μL终止液，此样品将作为T 0样品用于回收率测定。将T 0样品存储于2-8℃，等待与其它透析完的样品一起进行后续处理；将150μL受试化合物和华法林血浆样品加入到每个透析孔的给药端，在透析孔对应的接收端中加入150μL空白透析缓冲液。然后将透析板置于湿润的、5％CO 2的培养箱中，在37℃下、约100rpm振荡孵育4小时。透析结束后，移取50μL透析后的缓冲液样品和透析后的血浆样品到新的样品接收板。在样品中加入相应体积的对应空白血浆或缓冲液，使得每个样品孔的终体积为100μL，血浆：透析缓冲液的体积比为1:1。所有样品经过蛋白沉淀后进行LC/MS/MS分析，并通过公式：％未结合＝100*F/T,％结合率＝100-％未结合,％回收＝100*(F+T)/T 0计算蛋白结合率以及回收率(其中F是透析4h后透析液中化合物的峰面积比值；T是透析4h后血浆中化合物的峰面积比值；T 0是零时刻血浆样品中化合物的峰面积比值)。实验结果如表4所示： Experimental operation: Take 995μL of blank plasma from CD-1 mice, SPRAGUE-DAWLEY rats, beagle dogs, cynomolgus monkeys and humans, and add 5μL of the test compound working solution (400μM) or warfarin working solution (400μM), The final concentrations of the test compound and warfarin in the plasma sample were both 2 μM. Mix the sample thoroughly. The final concentration of DMSO in the organic phase is 0.5%; pipette 50μL of test compound and warfarin plasma samples into the sample receiving plate (three parallel), and immediately add the corresponding volume of blank plasma or buffer to make each sample well final volume of 100 L, plasma: dialysis buffer volume ratio of 1: 1, then these samples were added to 500μL stop solution, the sample was used as a sample recoveries were T 0. Store the T 0 sample at 2-8°C and wait for subsequent processing with other dialyzed samples; add 150 μL of test compound and warfarin plasma sample to the dosing end of each dialysis hole, in the corresponding dialysis hole Add 150μL of blank dialysis buffer to the receiving end. The dialysis plate was then placed in a humidified, 5% CO 2 incubator, and incubated at 37° C. with shaking at about 100 rpm for 4 hours. After dialysis, transfer 50 μL of the dialysis buffer sample and the dialysis plasma sample to a new sample receiving plate. Add a corresponding volume of corresponding blank plasma or buffer to the sample so that the final volume of each sample well is 100 μL, and the volume ratio of plasma:dialysis buffer is 1:1. All samples were analyzed by LC/MS/MS after protein precipitation, and passed the formula:% unbound=100*F/T,% binding rate=100-% unbound,% recovery=100*(F+T)/T 0 Calculate the protein binding rate and recovery rate (where F is the peak area ratio of the compound in the dialysate after 4 hours of dialysis; T is the peak area ratio of the compound in the plasma after 4 hours of dialysis; T 0 is the peak area ratio of the compound in the plasma sample at time zero ). The experimental results are shown in Table 4:
表4.受试化合物在CD-1小鼠、SPRAGUE-DAWLEY大鼠、比格犬、食蟹猴和人的血浆蛋白结合率Table 4. Plasma protein binding rates of test compounds in CD-1 mice, SPRAGUE-DAWLEY rats, beagle dogs, cynomolgus monkeys and humans
Figure PCTCN2020093284-appb-000187
Figure PCTCN2020093284-appb-000187
Figure PCTCN2020093284-appb-000188
Figure PCTCN2020093284-appb-000188
注：“/”表示未检测到。Note: "/" means not detected.
实验结论：本发明化合物在CD-1小鼠、SPRAGUE-DAWLEY大鼠、比格犬、食蟹猴和人血浆中均表现出较高的蛋白结合率。Experimental conclusion: The compound of the present invention shows a high protein binding rate in CD-1 mice, SPRAGUE-DAWLEY rats, beagle dogs, cynomolgus monkeys and human plasma.
实验四：体内药代动力学研究Experiment 4: In vivo pharmacokinetic study
C57BL/6小鼠口服及静脉注射本发明化合物的药代动力学研究Study on the pharmacokinetics of the compound of the present invention by oral and intravenous injection in C57BL/6 mice
受试化合物与2％N,N-二甲基甲酰胺/10％聚乙二醇400/44％0.1M磷酸盐缓冲液/44％的40％环糊精水溶液混合，涡旋并超声，制备得到1.5mg/mL澄清溶液。选取7至10周龄的C57BL/6雄性小鼠，静脉注射(IV)给予候选化合物溶液，剂量为3mg/kg。The test compound was mixed with 2% N,N-dimethylformamide/10% polyethylene glycol 400/44% 0.1M phosphate buffer/44% 40% cyclodextrin aqueous solution, vortexed and sonicated to prepare A clear solution of 1.5 mg/mL was obtained. C57BL/6 male mice aged 7 to 10 weeks were selected, and the candidate compound solution was administered intravenously (IV) at a dose of 3 mg/kg.
受试化合物与2％羟丙甲基纤维素/0.1％吐温80水溶液混合，涡旋并超声，制备得到1mg/mL均一混悬液备用。选取7至10周龄的C57BL/6雄性小鼠，口服(PO)给予候选化合物溶液，剂量为5mg/kg。The test compound was mixed with 2% hydroxypropylmethyl cellulose/0.1% Tween 80 aqueous solution, vortexed and sonicated to prepare a 1 mg/mL homogeneous suspension for later use. C57BL/6 male mice aged 7 to 10 weeks were selected and the candidate compound solution was administered orally (PO) at a dose of 5 mg/kg.
收集一定时间的全血，制备得到血浆，以LC-MS/MS方法分析药物浓度，并用Phoenix WinNonlin软件(美国Pharsight公司)计算药代参数。Collect whole blood for a certain period of time, prepare plasma, analyze the drug concentration by LC-MS/MS method, and use Phoenix WinNonlin software (Pharsight, USA) to calculate the pharmacokinetic parameters.
收集一定时间的全血，制备得到血浆，以LC-MS/MS方法分析药物浓度，并用Phoenix WinNonlin软件(美国Pharsight公司)计算药代参数。Collect whole blood for a certain period of time, prepare plasma, analyze the drug concentration by LC-MS/MS method, and use Phoenix WinNonlin software (Pharsight, USA) to calculate the pharmacokinetic parameters.
实验结果如表5所示：The experimental results are shown in Table 5:
表5.本发明化合物的药代动力学结果Table 5. Pharmacokinetic results of the compounds of the invention
Figure PCTCN2020093284-appb-000189
Figure PCTCN2020093284-appb-000189
Figure PCTCN2020093284-appb-000190
Figure PCTCN2020093284-appb-000190
注：IV：静脉注射；PO：口服；DNAUC＝AUC/给药剂量；N/A：不适用；结论：本发明化合物具有较高的暴露量以及较好的口服生物利用度。Note: IV: intravenous injection; PO: oral; DNAUC=AUC/dose; N/A: not applicable; Conclusion: The compound of the present invention has higher exposure and better oral bioavailability.

Claims (20)

  1. 式(I)所示化合物或其药学上可接受的盐，The compound represented by formula (I) or a pharmaceutically acceptable salt thereof,
    Figure PCTCN2020093284-appb-100001
    Figure PCTCN2020093284-appb-100001
    其中，among them,
    Figure PCTCN2020093284-appb-100002
    选自单键和双键；
    Figure PCTCN2020093284-appb-100002
    Selected from single bond and double bond;
    T 1为NR a； T 1 is NR a ;
    T 2选自C、CH和N； T 2 is selected from C, CH and N;
    T 3选自CR b和N； T 3 is selected from CR b and N;
    T 4选自CR c和O； T 4 is selected from CR c and O;
    R a选自H和C 1-3烷基； R a is selected from H and C 1-3 alkyl;
    R b和R c分别独立地选自H、F、Cl、Br、I、OH、NH 2、CN、C 1-3烷基和C 1-3烷氧基，所述C 1-3烷基和C 1- 3烷氧基任选被1、2或3个R取代； R b and R c are each independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, C 1-3 alkyl and C 1-3 alkoxy, the C 1-3 alkyl and C 1- 3 alkoxy group optionally substituted with 1, 2 or 3 R <
    且当R c选自F、Cl、Br、I、OH、NH 2和任选被1、2或3个R取代的C 1-3烷基和C 1-3烷氧基时，R 1和R 2分别独立地选自H和任选被1、2或3个R d取代的C 1-6烷基，或者，R 1、R 2和与它们相连的原子共同构成噻吩基、C 3-8环烯基或3-8元杂环烯基，所述噻吩基、C 3-8环烯基和3-8元杂环烯基任选被1、2或3个R e取代； And when R c is selected from F, Cl, Br, I, OH, NH 2 and C 1-3 alkyl and C 1-3 alkoxy optionally substituted by 1, 2 or 3 R, R 1 and R 2 is each independently selected from H and C 1-6 alkyl optionally substituted with 1, 2 or 3 R d , or R 1 , R 2 and the atoms connected to them together form a thienyl group, C 3- 8 cycloalkenyl or 3-8 membered heterocycloalkenyl, the thienyl, C 3-8 cycloalkenyl and 3-8 membered heterocycloalkenyl are optionally substituted by 1, 2 or 3 R e ;
    当R c选自H和CN时，R 1、R 2和与它们相连的原子共同构成噻吩基、C 6-8环烯基或3-8元杂环烯基，所述噻吩基、C 6-8环烯基和3-8元杂环烯基任选被1、2或3个R e取代； When R c is selected from H and CN, R 1 , R 2 and the atoms connected to them together form a thienyl group, a C 6-8 cycloalkenyl group or a 3-8 membered heterocycloalkenyl group, and the thienyl group, C 6 -8 cycloalkenyl and 3-8 membered heterocycloalkenyl are optionally substituted with 1, 2 or 3 R e ;
    R 3和R 4分别独立地选自H、F、Cl、Br、I、OH、NH 2、CN和任选被1、2或3个R f取代的C 1-3烷基； R 3 and R 4 are each independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, and C 1-3 alkyl optionally substituted with 1, 2 or 3 R f ;
    R d和R e分别独立地选自H、F、Cl、Br、I、OH、NH 2、CN、C 1-3烷基、C 1-3烷氧基和-O-C 3-5环烷基，所述C 1-3烷基、C 1-3烷氧基和-O-C 3-5环烷基任选被1、2或3个R’取代； R d and R e are each independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, C 1-3 alkyl, C 1-3 alkoxy and -OC 3-5 cycloalkyl , The C 1-3 alkyl group, C 1-3 alkoxy group and -OC 3-5 cycloalkyl group are optionally substituted with 1, 2 or 3 R';
    R f独立地选自H、F、Cl、Br、I、OH、NH 2、CN、C 1-3烷基和C 1-3烷氧基； R f is independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, C 1-3 alkyl and C 1-3 alkoxy;
    各R分别独立地选自H、F、Cl、Br、I、OH、NH 2、CN和C 1-3烷基； Each R is independently selected from H, F, Cl, Br, I, OH, NH 2 , CN and C 1-3 alkyl;
    各R’分别独立地选自D、F、Cl、Br和I；Each R'is independently selected from D, F, Cl, Br and I;
    所述3-8元杂环烯基包含1、2、3或4个独立选自-NH-、-O-、-S-和N的杂原子或杂原子团。The 3-8 membered heterocycloalkenyl group contains 1, 2, 3 or 4 heteroatoms or heteroatom groups independently selected from -NH-, -O-, -S- and N.
  2. 根据权利要求1所述化合物或其药学上可接受的盐，其选自The compound according to claim 1 or a pharmaceutically acceptable salt thereof, which is selected from
    Figure PCTCN2020093284-appb-100003
    Figure PCTCN2020093284-appb-100003
    其中，among them,
    Figure PCTCN2020093284-appb-100004
    选自单键和双键；
    Figure PCTCN2020093284-appb-100004
    Selected from single bond and double bond;
    T 2选自C和N； T 2 is selected from C and N;
    T 4选自CR c和O； T 4 is selected from CR c and O;
    R c选自F、Cl、Br、I、OH、NH 2、C 1-3烷基和C 1-3烷氧基，所述C 1-3烷基和C 1-3烷氧基任选被1、2或3个R取代； R c is selected from F, Cl, Br, I, OH, NH 2 , C 1-3 alkyl and C 1-3 alkoxy, the C 1-3 alkyl and C 1-3 alkoxy optionally Replaced by 1, 2 or 3 R;
    R 1和R 2分别独立地选自H和任选被1、2或3个R d取代的C 1-6烷基，或者，R 1、R 2和与它们相连的原子共同构成噻吩基、C 3-8环烯基或3-8元杂环烯基，所述噻吩基、C 3-8环烯基和3-8元杂环烯基任选被1、2或3个R e取代； R 1 and R 2 are each independently selected from H and C 1-6 alkyl optionally substituted by 1, 2 or 3 R d , or R 1 , R 2 and the atoms connected to them together form a thienyl group, C 3-8 cycloalkenyl or 3-8 membered heterocycloalkenyl, the thienyl, C 3-8 cycloalkenyl and 3-8 membered heterocycloalkenyl are optionally substituted by 1, 2 or 3 R e ；
    R 3和R 4分别独立地选自H、F、Cl、Br、I、OH、NH 2、CN和任选被1、2或3个R f取代的C 1-3烷基；R d和R e分别独立地选自H、F、Cl、Br、I、OH、NH 2、CN、C 1-3烷基、C 1-3烷氧基和-O-C 3-5环烷基，所述C 1-3烷基、C 1-3烷氧基和-O-C 3-5环烷基任选被1、2或3个R’取代； R 3 and R 4 are each independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, and C 1-3 alkyl optionally substituted with 1, 2 or 3 R f ; R d and R e is each independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, C 1-3 alkyl, C 1-3 alkoxy and -OC 3-5 cycloalkyl, said C 1-3 alkyl, C 1-3 alkoxy and -OC 3-5 cycloalkyl are optionally substituted with 1, 2 or 3 R';
    R f独立地选自H、F、Cl、Br、I、OH、NH 2、CN、C 1-3烷基和C 1-3烷氧基； R f is independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, C 1-3 alkyl and C 1-3 alkoxy;
    各R分别独立地选自H、F、Cl、Br、I、OH、NH 2、CN和C 1-3烷基； Each R is independently selected from H, F, Cl, Br, I, OH, NH 2 , CN and C 1-3 alkyl;
    各R’分别独立地选自D、F、Cl、Br和I；Each R'is independently selected from D, F, Cl, Br and I;
    所述3-8元杂环烯基包含1、2、3或4个独立选自-NH-、-O-、-S-和N的杂原子或杂原子团。The 3-8 membered heterocycloalkenyl group contains 1, 2, 3 or 4 heteroatoms or heteroatom groups independently selected from -NH-, -O-, -S- and N.
  3. 根据权利要求1所述化合物或其药学上可接受的盐，其选自The compound according to claim 1 or a pharmaceutically acceptable salt thereof, which is selected from
    Figure PCTCN2020093284-appb-100005
    Figure PCTCN2020093284-appb-100005
    其中，among them,
    R c选自H和CN； R c is selected from H and CN;
    R 1、R 2和与它们相连的原子共同构成噻吩基、C 6-8环烯基和3-8元杂环烯基，所述噻吩基、C 6-8环烯基和3-8元杂环烯基任选被1、2或3个R e取代； R 1 , R 2 and the atoms connected to them together form a thienyl group, a C 6-8 cycloalkenyl group and a 3-8 membered heterocycloalkenyl group, the thienyl group, a C 6-8 cycloalkenyl group and a 3-8 membered group optionally substituted heterocyclenyl, 2, or 3 R e;
    R 3和R 4分别独立地选自H、F、Cl、Br、I、OH、NH 2、CN和任选被1、2或3个R f取代的C 1-3烷基；R e分别独立地选自H、F、Cl、Br、I、OH、NH 2、CN、C 1-3烷基、C 1-3烷氧基和-O-C 3-5环烷基，所述C 1-3烷基、C 1-3烷氧基和-O-C 3-5环烷基任选被1、2或3个R’取代； R 3 and R 4 are each independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, and C 1-3 alkyl optionally substituted with 1, 2 or 3 R f ; R e respectively Are independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, C 1-3 alkyl, C 1-3 alkoxy and -OC 3-5 cycloalkyl, the C 1- 3 alkyl, C 1-3 alkoxy and -OC 3-5 cycloalkyl are optionally substituted with 1, 2 or 3 R';
    R f独立地选自H、F、Cl、Br、I、OH、NH 2、CN、C 1-3烷基和C 1-3烷氧基； R f is independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, C 1-3 alkyl and C 1-3 alkoxy;
    各R’分别独立地选自D、F、Cl、Br和I；Each R'is independently selected from D, F, Cl, Br and I;
    所述3-8元杂环烯基包含1、2、3或4个独立选自-NH-、-O-、-S-和N的杂原子或杂原子团。The 3-8 membered heterocycloalkenyl group contains 1, 2, 3 or 4 heteroatoms or heteroatom groups independently selected from -NH-, -O-, -S- and N.
  4. 根据权利要求1所述化合物或其药学上可接受的盐，其中，R b和R c分别独立地选自H、F、Cl、Br、I、OH、NH 2、CN、CH 3、CH 2F、CH 2CN、CHF 2、CF 3、CH 2CH 3、CF 2CH 3、
    Figure PCTCN2020093284-appb-100006
    The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein R b and R c are each independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, CH 3 , CH 2 F, CH 2 CN, CHF 2 , CF 3 , CH 2 CH 3 , CF 2 CH 3 ,
    Figure PCTCN2020093284-appb-100006
  5. 根据权利要求2所述化合物或其药学上可接受的盐，其中，R c选自F、Cl、Br、I、OH、NH 2、CH 3、CH 2F、CHF 2、CH 2CN、CF 3、CH 2CH 3、CF 2CH 3、
    Figure PCTCN2020093284-appb-100007
    The compound or a pharmaceutically acceptable salt thereof according to claim 2, wherein R c is selected from F, Cl, Br, I, OH, NH 2 , CH 3 , CH 2 F, CHF 2 , CH 2 CN, CF 3 , CH 2 CH 3 , CF 2 CH 3 ,
    Figure PCTCN2020093284-appb-100007
  6. 根据权利要求1、2、4或5任意一项所述化合物或其药学上可接受的盐，其中，R 1和R 2分别独立地选自H、CH 3、CH 2CH 3、CH(CH 3) 2和C(CH 3) 3。 The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1, 2, 4, or 5, wherein R 1 and R 2 are each independently selected from H, CH 3 , CH 2 CH 3 , CH (CH 3 ) 2 and C(CH 3 ) 3 .
  7. 根据权利要求1～5任意一项所述化合物或其药学上可接受的盐，其中，R 1、R 2和与它们相连的原子共同构成环己烯基、双环[2.2.1]庚-2-烯基、1,2,3,4-四氢吡啶基、双环[4.1.0]庚-3-烯基、3,6-二氢-2H-吡喃基、7-氧杂二环[2.2.1]庚-2-烯基、噻吩基、3,4-二氢-2H-吡喃基和双环[4.1.0]庚-2-烯基，所述环己烯基、双环[2.2.1]庚-2-烯基、1,2,3,4-四氢吡啶基、双环[4.1.0]庚-3-烯基、3,6-二氢-2H-吡喃基、7-氧杂二环[2.2.1]庚-2-烯基、噻吩基、3,4-二氢-2H-吡喃基和双环[4.1.0]庚-2-烯基任选被1、2或3个R e取代。 The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, wherein R 1 , R 2 and the atoms connected to them together form a cyclohexenyl group, a bicyclo[2.2.1]heptan-2 -Alkenyl, 1,2,3,4-tetrahydropyridyl, bicyclo[4.1.0]hept-3-enyl, 3,6-dihydro-2H-pyranyl, 7-oxabicyclo[ 2.2.1]hept-2-enyl, thienyl, 3,4-dihydro-2H-pyranyl and bicyclo[4.1.0]hept-2-enyl, the cyclohexenyl, bicyclo[2.2 .1]Hept-2-enyl, 1,2,3,4-tetrahydropyridyl, bicyclo[4.1.0]hept-3-enyl, 3,6-dihydro-2H-pyranyl, 7 -Oxabicyclo[2.2.1]hept-2-enyl, thienyl, 3,4-dihydro-2H-pyranyl and bicyclo[4.1.0]hept-2-enyl are optionally 1, 2 or 3 substituents R e.
  8. 根据权利要求7所述化合物或其药学上可接受的盐，其中，结构单元
    Figure PCTCN2020093284-appb-100008
    选自
    Figure PCTCN2020093284-appb-100009
    Figure PCTCN2020093284-appb-100010
    The compound or a pharmaceutically acceptable salt thereof according to claim 7, wherein the structural unit
    Figure PCTCN2020093284-appb-100008
    Selected from
    Figure PCTCN2020093284-appb-100009
    Figure PCTCN2020093284-appb-100010
  9. 根据权利要求8所述化合物或其药学上可接受的盐，其中，结构单元
    Figure PCTCN2020093284-appb-100011
    选自
    Figure PCTCN2020093284-appb-100012
    Figure PCTCN2020093284-appb-100013
    The compound or a pharmaceutically acceptable salt thereof according to claim 8, wherein the structural unit
    Figure PCTCN2020093284-appb-100011
    Selected from
    Figure PCTCN2020093284-appb-100012
    Figure PCTCN2020093284-appb-100013
  10. 根据权利要求1～5任意一项所述化合物或其药学上可接受的盐，其中，R 3和R 4分别独立地选自H、F、Cl、Br、I、OH、NH 2、CN、CH 3和CH 2CH 3，所述CH 3和CH 2CH 3任选被1、2或3个R f取代。 The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, wherein R 3 and R 4 are each independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, CH 3 and CH 2 CH 3 , the CH 3 and CH 2 CH 3 are optionally substituted with 1, 2 or 3 R f .
  11. 根据权利要求10所述化合物或其药学上可接受的盐，其中，R 3和R 4分别独立地选自F、Cl、Br、I、OH、NH 2和CF 3。 The compound or a pharmaceutically acceptable salt thereof according to claim 10, wherein R 3 and R 4 are each independently selected from F, Cl, Br, I, OH, NH 2 and CF 3 .
  12. 根据权利要求1所述化合物或其药学上可接受的盐，其中，结构单元
    Figure PCTCN2020093284-appb-100014
    选自
    Figure PCTCN2020093284-appb-100015
    Figure PCTCN2020093284-appb-100016
    The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein the structural unit
    Figure PCTCN2020093284-appb-100014
    Selected from
    Figure PCTCN2020093284-appb-100015
    Figure PCTCN2020093284-appb-100016
  13. 根据权利要求4或12所述化合物或其药学上可接受的盐，其中，结构单元
    Figure PCTCN2020093284-appb-100017
    选自
    Figure PCTCN2020093284-appb-100018
    Figure PCTCN2020093284-appb-100019
    The compound or a pharmaceutically acceptable salt thereof according to claim 4 or 12, wherein the structural unit
    Figure PCTCN2020093284-appb-100017
    Selected from
    Figure PCTCN2020093284-appb-100018
    Figure PCTCN2020093284-appb-100019
  14. 根据权利要求1、3、4、10或11任意一项所述化合物或其药学上可接受的盐，其化合物选自The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1, 3, 4, 10 or 11, wherein the compound is selected from
    Figure PCTCN2020093284-appb-100020
    Figure PCTCN2020093284-appb-100020
    其中，among them,
    Z 1和Z 2分别独立地选自CH(R e)、O和N(R e)； Z 1 and Z 2 are independently selected from CH(R e ), O and N(R e );
    Z 3选自CH 2和O； Z 3 is selected from CH 2 and O;
    Z 4选自O； Z 4 is selected from O;
    Z 5选自C(R e)和N； Z 5 is selected from C(R e ) and N;
    Z 6选自N(R e)和O； Z 6 is selected from N(R e ) and O;
    R c选自H和CN； R c is selected from H and CN;
    R 3、R 4和R e如权利要求1、3、4、10或11任意一项所定义。 R 3 , R 4 and R e are as defined in any one of claims 1 , 3 , 4 , 10 or 11.
  15. 根据权利要求1、2、5、10或11任意一项所述化合物或其药学上可接受的盐，其化合物选自The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1, 2, 5, 10 or 11, wherein the compound is selected from
    Figure PCTCN2020093284-appb-100021
    Figure PCTCN2020093284-appb-100021
    其中，among them,
    R 1、R 2、R 3、R 4和R c如权利要求1、2、5、10或11任意一项所定义。 R 1 , R 2 , R 3 , R 4 and R c are as defined in any one of claims 1 , 2 , 5 , 10 or 11.
  16. 下式所示化合物或其药学上可接受的盐，The compound represented by the following formula or a pharmaceutically acceptable salt thereof,
    Figure PCTCN2020093284-appb-100022
    Figure PCTCN2020093284-appb-100022
    Figure PCTCN2020093284-appb-100023
    Figure PCTCN2020093284-appb-100023
    Figure PCTCN2020093284-appb-100024
    Figure PCTCN2020093284-appb-100024
  17. 根据权利要求16所述化合物、其异构体或其药学上可接受的盐，其选自：The compound, its isomers, or pharmaceutically acceptable salts thereof according to claim 16, which are selected from:
    Figure PCTCN2020093284-appb-100025
    Figure PCTCN2020093284-appb-100025
    Figure PCTCN2020093284-appb-100026
    Figure PCTCN2020093284-appb-100026
  18. 一种药物组合物，包括作为活性成分的治疗有效量的根据权利要求1～17任意一项所述的化合物或其药学上可接受的盐以及药学上可接受的载体。A pharmaceutical composition comprising a therapeutically effective amount of the compound according to any one of claims 1 to 17 or a pharmaceutically acceptable salt thereof as an active ingredient and a pharmaceutically acceptable carrier.
  19. 根据权利要求1～17任意一项所述的化合物或其药学上可接受的盐或者根据权利要求18所述的组合物在制备甲状腺素受体-β激动剂相关药物上的应用。The use of the compound according to any one of claims 1-17, or a pharmaceutically acceptable salt thereof, or the composition according to claim 18 in the preparation of thyroxine receptor-β agonist related drugs.
  20. 根据权利要求19所述的应用，其特征在于，所述甲状腺素受体-β激动剂相关药物是用于治疗非酒精性脂肪肝炎的药物。The application according to claim 19, wherein the thyroxine receptor-β agonist-related drug is a drug for the treatment of non-alcoholic steatohepatitis.
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