WO2020239076A1 - DÉRIVÉS DE PYRIDAZINONE CONSTITUANT DES AGONISTES DU RÉCEPTEUR DE LA THYROXINE DE TYPE β ET LEUR UTILISATION - Google Patents

DÉRIVÉS DE PYRIDAZINONE CONSTITUANT DES AGONISTES DU RÉCEPTEUR DE LA THYROXINE DE TYPE β ET LEUR UTILISATION 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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English (en)
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/zh
Publication of WO2020239076A1 publication Critical patent/WO2020239076A1/fr

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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.

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Abstract

L'invention concerne des dérivés de pyridazinone constituant des agonistes du récepteur de la thyroxine de type β et leur utilisation dans la préparation de médicaments pour des maladies associées aux agonistes du récepteur de la thyroxine de type β. L'invention concerne en particulier un composé représenté par la formule (I), ou un sel pharmaceutiquement acceptable de celui-ci.
PCT/CN2020/093284 2019-05-29 2020-05-29 DÉRIVÉS DE PYRIDAZINONE CONSTITUANT DES AGONISTES DU RÉCEPTEUR DE LA THYROXINE DE TYPE β ET LEUR UTILISATION WO2020239076A1 (fr)

Priority Applications (1)

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CN202080051869.2A CN114174282A (zh) 2019-05-29 2020-05-29 作为甲状腺素受体-β激动剂的哒嗪酮类衍生物及其应用

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CN201910459299 2019-05-29
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CN201911130068 2019-11-18
CN202010076525.9 2020-01-23
CN202010076525 2020-01-23
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CN202010409420 2020-05-14

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WO2022099060A3 (fr) * 2020-11-06 2022-06-16 Aligos Therapeutics, Inc. Pyridazinones bicycliques et leurs procédés d'utilisation
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CN115073429A (zh) * 2021-03-15 2022-09-20 昆药集团股份有限公司 一种1，2，4-三嗪-3，5-二酮类化合物的盐型、晶型及其制备方法
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WO2023147779A1 (fr) * 2022-02-07 2023-08-10 四川海思科制药有限公司 Procédé de préparation d'un dérivé de pyridazinone, et intermédiaire de celui-ci

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