WO2024099434A1 - 葫芦脲类化合物及其医药用途 - Google Patents

葫芦脲类化合物及其医药用途 Download PDF

Info

Publication number
WO2024099434A1
WO2024099434A1 PCT/CN2023/131007 CN2023131007W WO2024099434A1 WO 2024099434 A1 WO2024099434 A1 WO 2024099434A1 CN 2023131007 W CN2023131007 W CN 2023131007W WO 2024099434 A1 WO2024099434 A1 WO 2024099434A1
Authority
WO
WIPO (PCT)
Prior art keywords
formula
iii
pharmaceutically acceptable
acceptable salt
compound
Prior art date
Application number
PCT/CN2023/131007
Other languages
English (en)
French (fr)
Inventor
祝令建
任文明
邹洋
雷生辉
朱丹
黄建
Original Assignee
上海森辉医药有限公司
上海盛迪医药有限公司
江苏恒瑞医药股份有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 上海森辉医药有限公司, 上海盛迪医药有限公司, 江苏恒瑞医药股份有限公司 filed Critical 上海森辉医药有限公司
Publication of WO2024099434A1 publication Critical patent/WO2024099434A1/zh

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4188—1,3-Diazoles condensed with other heterocyclic ring systems, e.g. biotin, sorbinil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A61P21/02—Muscle relaxants, e.g. for tetanus or cramps
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P23/00—Anaesthetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/22—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains four or more hetero rings

Definitions

  • the present invention relates to the field of medicine, and in particular to cucurbituril compounds and their medical uses.
  • Muscle relaxants are one of the three basic elements of general anesthesia. While muscle relaxants meet the needs of endotracheal intubation and surgery, they also bring safety risks - residual muscle relaxants, which can cause subjective discomfort in patients and a series of pulmonary complications such as hypoxemia, reflux aspiration, etc. In order to reduce the incidence of residual muscle relaxants, measures such as the use of medium- and short-acting muscle relaxants, optimization of intraoperative muscle relaxant management, antagonism of muscle relaxant effects after surgery, and objective perioperative muscle relaxant monitoring have been taken to continuously make progress in this clinical problem of residual muscle relaxants.
  • Postoperative antagonistic muscle relaxant refers to the use of muscle relaxant antagonists to reverse the residual effects of non-depolarizing muscle relaxants.
  • muscle relaxant antagonists can be roughly divided into two categories: one is competitive muscle relaxant antagonists, including neostigmine as an acetylcholine inhibitor; the other is selective muscle relaxant antagonists, including sugammadex sodium as a steroid muscle relaxant antagonist, cysteine as a benzylisoquinoline muscle relaxant antagonist, etc.
  • Prior art WO2012051407A discloses a class of non-closed ring CB[n] type molecular containers with a cucurbituril structure, namely Calabadion2, which can efficiently bind to benzylisoquinoline and steroidal muscle relaxants, and prevent the binding of muscle relaxants to neuromuscular cholinergic receptors by covering the quaternary ammonium sites of benzylisoquinoline and steroidal muscle relaxants, thereby quickly reversing the muscle relaxant effect.
  • the present disclosure provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof,
  • R 1 is independently selected from C 2-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, -C(O) 2 R', R'-(O)-alkylene-, hydroxyl, NR'(R"), 3 to 7 membered cycloalkyl, 3 to 7 membered heterocyclyl; or two R 1s attached to adjacent carbon atoms together form a 3 to 10 membered cycloalkyl or 3 to 10 membered heterocyclyl; said R 1 is optionally substituted by one or more R 1A ;
  • R 2 is each independently selected from hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, -C(O) 2 R', R'-(O)-alkylene-, hydroxyl, NR'(R"), 3 to 7 membered cycloalkyl, 3 to 7 membered heterocyclyl; or two R 2 attached to adjacent carbon atoms together form a 3 to 10 membered cycloalkyl or 3 to 10 membered heterocyclyl; said R 2 is optionally substituted by one or more R 2A ;
  • Ring A is independently selected from a 5- to 12-membered aromatic group or a 5- to 12-membered heteroaryl group
  • R 3 is independently selected from halogen, C 1-6 alkyl, hydroxy, nitro, cyano, -C(O) 2 R', NR'(R"), R'-(O)-alkylene-, 3 to 7 membered cycloalkyl, 3 to 7 membered heterocyclyl or and at least one of them is , said R 3 is optionally substituted by one or more R 3A ;
  • R4 is A + is a monovalent or divalent cation
  • R 1A , R 2A , and R 3A are each independently selected from halogen, cyano, nitro, amino, C 1-6 alkyl, or C 1-6 alkoxy;
  • R' and R" are each independently selected from hydrogen, C1-6 alkyl, C1-6 hydroxyalkyl, C1-6 haloalkyl, 3 to 7 membered cycloalkyl, 3 to 7 membered heterocyclyl;
  • n are each independently selected from 1, 2, 3, 4 or 5;
  • p is each independently selected from 1, 2, 3, 4, 5 or 6.
  • the present disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the ring A is phenyl or naphthyl.
  • the present disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the ring A is naphthyl.
  • the compound of formula (I) or a pharmaceutically acceptable salt thereof provided by the present disclosure is a compound of formula (I-1) or a pharmaceutically acceptable salt thereof,
  • R 1 , R 2 , p, m and A + are as defined in the compound represented by formula (I).
  • the present disclosure provides a compound represented by formula (I), (I-1) or a pharmaceutically acceptable salt thereof, wherein two R 1s attached to adjacent carbon atoms together form a 3- to 10-membered cycloalkyl or a 3- to 10-membered heterocyclic group.
  • the present disclosure provides a compound of formula (I), (I-1) or a pharmaceutically acceptable salt thereof, wherein two R 1s attached to adjacent carbon atoms together form a 4- to 8-membered cycloalkyl or a 4- to 8-membered heterocyclic group.
  • the present disclosure provides a compound represented by formula (I), (I-1) or a pharmaceutically acceptable salt thereof, Wherein, two R1s connected to adjacent carbon atoms together form a 5- to 6-membered cycloalkyl group or a 5- to 6-membered heterocyclic group.
  • the present disclosure provides a compound represented by formula (I), (I-1) or a pharmaceutically acceptable salt thereof, wherein two R 1s attached to adjacent carbon atoms together form a 6-membered cycloalkyl group.
  • the present disclosure provides a compound of formula (I), (I-1) or a pharmaceutically acceptable salt thereof, wherein two R1s attached to adjacent carbon atoms together form a 5- to 6-membered heterocyclic group, wherein the heteroatom is nitrogen or oxygen.
  • the present disclosure provides a compound of formula (I), (I-1) or a pharmaceutically acceptable salt thereof, wherein two R 1s attached to adjacent carbon atoms together form a 5- to 6-membered heterocyclic group, wherein the heteroatom is oxygen.
  • the present disclosure provides a compound of formula (I) or (I-1) or a pharmaceutically acceptable salt thereof, wherein R 1 is independently a C 2-6 alkyl group.
  • the present disclosure provides a compound of formula (I) or (I-1) or a pharmaceutically acceptable salt thereof, wherein R 1 is independently ethyl.
  • the present disclosure provides a compound of formula (I) or (I-1) or a pharmaceutically acceptable salt thereof, wherein R 1 is independently a C 1-6 haloalkyl group.
  • the present disclosure provides a compound of formula (I) or (I-1) or a pharmaceutically acceptable salt thereof, wherein R 1 is independently a C 1-3 haloalkyl group.
  • the present disclosure provides a compound of formula (I) or (I-1) or a pharmaceutically acceptable salt thereof, wherein R 1 is independently one, two or three fluoro-substituted methyl groups.
  • the present disclosure provides compounds of formula (I) or (I-1) or pharmaceutically acceptable salts thereof, wherein R 1 is independently -C(O) 2 R', and R' and R" are independently selected from hydrogen, C 1-6 alkyl, and C 1-6 haloalkyl.
  • the present disclosure provides compounds of formula (I) or (I-1) or pharmaceutically acceptable salts thereof, wherein R 1 is independently -C(O) 2 R', and R' is selected from H or C 1-6 alkyl.
  • the present disclosure provides a compound of formula (I) or (I-1) or a pharmaceutically acceptable salt thereof, wherein each R 1 is independently -C(O) 2 R', and R' is selected from methyl or ethyl.
  • the present disclosure provides compounds represented by formula (I) or (I-1) or pharmaceutically acceptable salts thereof, wherein R 1 is independently C 1-6 hydroxyalkyl or C 1-6 alkyl-OC 1-6 alkylene-.
  • the present disclosure provides compounds represented by formula (I) or (I-1) or pharmaceutically acceptable salts thereof, wherein R 1 is independently C 1-3 hydroxyalkyl or C 1-3 alkyl-OC 1-3 alkylene-.
  • the present disclosure provides a compound represented by formula (I) or (I-1) or a pharmaceutically acceptable salt thereof, wherein R 1 is independently hydroxymethyl or methyl-O-methylene-.
  • the present disclosure provides compounds of formula (I) or (I-1) or pharmaceutically acceptable salts thereof, wherein R 1 is each independently R'-(O)-alkylene-, and R' is selected from C 1-6 alkyl, C 1-6 hydroxyalkyl, C 1-6 haloalkyl, 3 to 7 membered cycloalkyl, and 3 to 7 membered heterocyclyl.
  • the present disclosure provides a compound of formula (I) or (I-1) or a pharmaceutically acceptable salt thereof, wherein R 1 is independently R'-(O)-alkylene-, and R' is C 1-6 alkyl or C 1-6 haloalkyl.
  • the present disclosure provides a compound of formula (I) or (I-1) or a pharmaceutically acceptable salt thereof, wherein R 1 is independently R'-(O)-alkylene-, and R' is a C 1-3 alkyl.
  • the present disclosure provides a compound of formula (I), (I-1) or a pharmaceutically acceptable salt thereof, wherein R 2 is each independently hydrogen.
  • the present disclosure provides a compound of formula (I) or (I-1) or a pharmaceutically acceptable salt thereof, wherein A + is a monovalent cation, and the monovalent cation is selected from H + , Na + , K + , H 4 N + , Et 3 NH + , (HOCH 2 CH 2 ) 3 NH + or a cationic form of ethylenediamine, piperazine, or triphenylmethylaminomethane.
  • a + is a monovalent cation
  • the monovalent cation is selected from H + , Na + , K + , H 4 N + , Et 3 NH + , (HOCH 2 CH 2 ) 3 NH + or a cationic form of ethylenediamine, piperazine, or triphenylmethylaminomethane.
  • the present disclosure provides a compound represented by formula (I) or (I-1) or a pharmaceutically acceptable salt thereof, wherein A + is a monovalent cation selected from H + , Na + or K + .
  • the A + is a monovalent cation
  • the monovalent cation is Na + .
  • the present disclosure provides a compound represented by formula (I) or (I-1) or a pharmaceutically acceptable salt thereof, wherein A + is a divalent cation selected from Ca 2+ , Mg 2+ or Zn 2+ .
  • the present disclosure provides a compound represented by formula (I) or (I-1) or a pharmaceutically acceptable salt thereof, wherein p is independently selected from 2, 3 or 4.
  • the present disclosure provides a compound represented by formula (I) or (I-1) or a pharmaceutically acceptable salt thereof, wherein p is 3.
  • the present disclosure provides a compound of formula (I) or (I-1) or a pharmaceutically acceptable salt thereof, wherein m is independently selected from 2, 3 or 4.
  • the present disclosure provides a compound represented by formula (I) or (I-1) or a pharmaceutically acceptable salt thereof, wherein m is 2.
  • the present disclosure provides a compound represented by formula (I), (I-1) or a pharmaceutically acceptable salt thereof, wherein two R1s attached to adjacent carbon atoms together form a 5-membered cycloalkyl, a 6-membered cycloalkyl or a 7-membered cycloalkyl, for example
  • the present disclosure provides a compound represented by formula (I), (I-1) or a pharmaceutically acceptable salt thereof, wherein two R 1s attached to adjacent carbon atoms together form a 6-membered heterocycloalkyl group, for example
  • the present disclosure provides a compound represented by formula (I), (I-1) or a pharmaceutically acceptable salt thereof,
  • the two R1s attached to adjacent carbon atoms together form a 5-membered heterocycloalkyl group, for example
  • the compound represented by formula (I) or a pharmaceutically acceptable salt thereof provided by the present disclosure is a compound represented by formula (I-1-A), formula (I-1-B), formula (I-1-C), formula (I-1-D) or formula (I-1-E) or a pharmaceutically acceptable salt thereof,
  • X 3 is independently selected from O, S, NH;
  • d is each independently selected from 0, 1, 2, 3, 4, 5, 6, 7, 8;
  • e is each independently selected from 0, 1, 2, 3, 4, 5, 6, 7, 8;
  • f are each independently selected from 0, 1, 2;
  • g are each independently selected from 0, 1, 2;
  • R 1A and p are as defined above.
  • the present disclosure provides a compound of formula (I), formula (I-1), formula (I-1-A), formula (I-1-B), formula (I-1-C), formula (I-1-D) or formula (I-1-E) or a pharmaceutically acceptable salt thereof, wherein R 1A is each independently selected from halogen, cyano, amino, C 1-6 alkyl or C 1-6 alkoxy.
  • the present disclosure provides a compound of formula (I), formula (I-1), formula (I-1-A), formula (I-1-B), formula (I-1-C), formula (I-1-D) or formula (I-1-E) or a pharmaceutically acceptable salt thereof, wherein R 1A is each independently selected from halogen, C 1-6 alkyl or C 1-6 alkoxy.
  • the present disclosure provides compounds of formula (I), formula (I-1), formula (I-1-A), formula (I-1-B), formula (I-1-C), formula (I-1-D) or formula (I-1-E) or pharmaceutically acceptable salts thereof, wherein R 1A is each independently selected from fluorine, chlorine, methyl, ethyl, methoxy, and ethoxy.
  • the present disclosure provides a compound represented by formula (I), formula (I-1), formula (I-1-A), formula (I-1-B), formula (I-1-C), formula (I-1-D) or formula (I-1-E) or a pharmaceutically acceptable salt thereof, which is selected from:
  • Another aspect of the present disclosure provides a compound represented by formula (II) or a pharmaceutically acceptable salt thereof,
  • X 1 and X 2 are each independently selected from O, S, and -NH-, provided that X 1 and X 2 are not O at the same time;
  • R 5 is each independently selected from C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, -C(O) 2 R', R'-(O)-alkylene-, hydroxyl, NR'(R"), 3 to 7-membered cycloalkyl, 3 to 7-membered heterocyclyl; or two R 5 attached to adjacent carbon atoms together form a 3 to 10-membered cycloalkyl or 3 to 10-membered heterocyclyl; said R 5 is optionally substituted by one or more R 5A ;
  • R 6 is independently selected from hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, -C(O) 2 R', R'-(O)-alkylene-, hydroxyl, NR'(R"), 3 to 7 membered cycloalkyl, 3 to 7 membered heterocyclyl; or two R 6 attached to adjacent carbon atoms together form a 3 to 10 membered cycloalkyl or 3 to 10 membered heterocyclyl; said R 6 is optionally substituted by one or more R 6A ;
  • Ring B is selected from a 5- to 12-membered aromatic group or a 5- to 12-membered heteroaryl group
  • R 7 is independently selected from halogen, C 1-6 alkyl, hydroxy, nitro, cyano, -C(O) 2 R', NR'(R"), R'-(O)-alkylene-, 3 to 7 membered cycloalkyl, 3 to 7 membered heterocyclyl or and at least one of them is Said R 7 is optionally substituted by one or more R 7A ;
  • R 8 The A + is a monovalent or divalent cation
  • R 5A , R 6A , R 7A are each independently selected from halogen, cyano, nitro, amino, C 1-6 alkyl or C 1-6 alkoxy;
  • R' and R" are each independently selected from hydrogen, C1-6 alkyl, C1-6 hydroxyalkyl, C1-6 haloalkyl, 3 to 7 membered cycloalkyl, 3 to 7 membered heterocyclyl;
  • y and z are each independently selected from 1, 2, 3, 4 or 5;
  • w is selected from 1, 2, 3, 4, 5 or 6.
  • the present disclosure provides a compound of formula (II) or a pharmaceutically acceptable salt thereof, wherein ring B is selected from phenyl or naphthyl.
  • the present disclosure provides a compound of formula (II) or a pharmaceutically acceptable salt thereof, wherein ring B is naphthyl.
  • the compound of formula (II) or a pharmaceutically acceptable salt thereof provided by the present disclosure is a compound of formula (II-1) or a pharmaceutically acceptable salt thereof,
  • R 5 , R 6 , w, z, and A + are respectively defined as in the compound represented by formula (II).
  • the compound of formula (II) or a pharmaceutically acceptable salt thereof provided by the present disclosure is a compound of formula (II-2) or a pharmaceutically acceptable salt thereof,
  • R 5 , R 6 , w, z, and A + are respectively defined as in the compound represented by formula (II).
  • the compound of formula (II) or a pharmaceutically acceptable salt thereof provided by the present disclosure is a compound of formula (II-3) or a pharmaceutically acceptable salt thereof,
  • R 5 , R 6 , w, z, and A + are respectively defined as in the compound represented by formula (II).
  • the present disclosure provides compounds of formula (II), (II-1), (II-2), (II-3) or pharmaceutically acceptable salts thereof, wherein each R 5 is independently C 1-6 alkyl or C 1-6 haloalkyl.
  • the present disclosure provides compounds represented by formula (II), (II-1), (II-2), (II-3) or pharmaceutically acceptable salts thereof, wherein each R 5 is independently a C 1-3 alkyl group.
  • the present disclosure provides compounds represented by formula (II), (II-1), (II-2), (II-3) or pharmaceutically acceptable salts thereof, wherein each R 5 is independently methyl.
  • the present disclosure provides compounds represented by formula (II), (II-1), (II-2), (II-3) or pharmaceutically acceptable salts thereof, wherein each R 6 is independently hydrogen.
  • the present disclosure provides compounds of formula (II), (II-1), (II-2), (II-3) or pharmaceutically acceptable salts thereof, wherein A + is selected from a monovalent cation, and the monovalent cation is selected from H + , Na + , K + , H 4 N + , Et 3 NH + , (HOCH 2 CH 2 ) 3 NH + or a cationic form of ethylenediamine, piperazine, or triphenylmethylaminomethane.
  • a + is selected from a monovalent cation
  • the monovalent cation is selected from H + , Na + , K + , H 4 N + , Et 3 NH + , (HOCH 2 CH 2 ) 3 NH + or a cationic form of ethylenediamine, piperazine, or triphenylmethylaminomethane.
  • the present disclosure provides compounds represented by formula (II), (II-1), (II-2), (II-3) or pharmaceutically acceptable salts thereof, wherein A + is a monovalent cation selected from H + , Na + or K + .
  • the present disclosure provides compounds represented by formula (II), (II-1), (II-2), (II-3) or pharmaceutically acceptable salts thereof, wherein A + is a divalent cation selected from Ca2 + , Mg2 + or Zn2 + .
  • the present disclosure provides compounds represented by formula (II), (II-1), (II-2), (II-3) or pharmaceutically acceptable salts thereof, wherein w is independently selected from 2, 3 or 4.
  • the present disclosure provides compounds represented by formula (II), (II-1), (II-2), (II-3) or pharmaceutically acceptable salts thereof, wherein w is independently 3.
  • the present disclosure provides compounds represented by formula (II), (II-1), (II-2), (II-3) or pharmaceutically acceptable salts thereof, wherein z is independently selected from 2, 3 or 4.
  • the present disclosure provides compounds represented by formula (II), (II-1), (II-2), (II-3) or pharmaceutically acceptable salts thereof, wherein z is independently 2.
  • the compounds of formula (II), (II-1), (II-2), (II-3) or pharmaceutically acceptable salts thereof provided by the present disclosure are selected from:
  • Another aspect of the present disclosure provides a compound represented by formula (III) or a pharmaceutically acceptable salt thereof,
  • X C1 and X C2 are each independently selected from O, S, and -NH-;
  • R C2 is selected from hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, -C(O) 2 R', R'-(O)-alkylene-, hydroxyl, NR'(R"), 3 to 7 membered cycloalkyl, 3 to 7 membered heterocyclyl; or two R C2 attached to adjacent carbon atoms together form a 3 to 10 membered cycloalkyl or 3 to 10 membered heterocyclyl; said R C2 is optionally substituted by one or more halogen, cyano, nitro, amino, C 1-6 alkyl or C 1-6 alkoxy;
  • Ring C is selected from 6- to 18-membered aromatic groups or 5- to 18-membered heteroaryl groups;
  • R C3 are each independently
  • R C4 are each independently Carboxylic acid group, -carboxylate-cation, phosphate group, -phosphate-cation, sulfonic acid group, -sulfonate-cation;
  • L, L 1 , and L 2 are the same or different and are each independently an alkylene group or a heteroalkylene group, wherein the alkylene group or the heteroalkylene group is optionally substituted with one or more halogen, cyano, nitro, amino, C 1-6 alkyl or C 1-6 alkoxy groups;
  • R c is each independently selected from hydrogen, halogen, cyano, nitro, amino, C 1-6 alkyl or C 1-6 alkoxy;
  • Ra and Rb are the same or different and are each independently selected from a carboxylate group, a -carboxylate-cation, a phosphate group, a -phosphate-cation, a sulfonic acid group, and a -sulfonate-cation;
  • R', R" are each independently selected from hydrogen, C1-6 alkyl, C1-6 hydroxyalkyl, C1-6 haloalkyl, 3 to 7 membered cycloalkyl, 3 to 7 membered heterocyclyl;
  • x is selected from 1, 2, 3, 4 or 5;
  • v is each independently selected from 1, 2, 3, 4 or 5;
  • q is independently selected from 1, 2, 3, 4, 5 or 6.
  • the present disclosure provides a compound of formula (III) or a pharmaceutically acceptable salt thereof, wherein X C1 and X C2 are the same and selected from O, S, and -NH-. In certain embodiments, wherein X C1 and X C2 are both O.
  • the present disclosure provides a compound represented by formula (III) or a pharmaceutically acceptable salt thereof, wherein wherein L is each independently a C 1-6 alkylene group.
  • the present disclosure provides a compound of formula (III) or a pharmaceutically acceptable salt thereof, wherein ring C is selected from a benzene ring, a naphthalene ring or an anthracene ring, preferably a naphthalene ring or anthracene ring.
  • the compound of formula (III) or a pharmaceutically acceptable salt thereof provided by the present disclosure is selected from a compound of formula (III-A), formula (III-B), formula (III-C) or formula (III-D) or a pharmaceutically acceptable salt thereof,
  • R and D are each independently selected from a carboxylate group, a -carboxylate-cation, a phosphate group, and a -phosphate-cation;
  • R E are each independently selected from carboxylic acid, -carboxylate-cation, phosphate, -phosphate-cation, sulfonic acid, -sulfonate-cation;
  • r is selected from 1, 2, and 3;
  • RC2 , q, x, L1 , L2 , Ra , Rb and Rc are as defined above.
  • the present disclosure provides compounds of formula (III), (III-A), (III-B), (III-C) or (III-D) or pharmaceutically acceptable salts thereof, wherein L 1 and L 2 are the same or different and are each independently C 1-6 alkylene.
  • the present disclosure provides compounds of formula (III), formula (III-A), formula (III-B), formula (III-C) or formula (III-D) or pharmaceutically acceptable salts thereof, wherein R D is each independently selected from a carboxylic acid group, a -carboxylate-cation.
  • the present disclosure provides compounds of formula (III), formula (III-A), formula (III-B), formula (III-C) or formula (III-D) or pharmaceutically acceptable salts thereof, wherein RE is each independently selected from a carboxylic acid group, a -carboxylate-cation, a sulfonic acid group, and a -sulfonate-cation.
  • the present disclosure provides compounds of formula (III), formula (III-A), formula (III-B), formula (III-C) or formula (III-D) or pharmaceutically acceptable salts thereof, wherein Ra and Rb are the same or different and are independently selected from carboxylic acid, -carboxylate-cation, sulfonic acid, and -sulfonate-cation.
  • the compound of formula (III) or a pharmaceutically acceptable salt thereof provided by the present disclosure is selected from the compound of formula (III-A-1), formula (III-B-1), formula (III-B-2), formula (III-C-1), formula (III-C-2), formula (III-C-3), formula (III-D-1), formula (III-D-2) or formula (III-D-3) or a pharmaceutically acceptable salt thereof,
  • a are each independently selected from 1, 2, 3, and 4;
  • b is selected from 1, 2, 3, 4;
  • c is selected from 1, 2, 3, 4;
  • a 1 + or A 2 + are the same or different and are each independently selected from a monovalent cation or a divalent cation;
  • R C2 , q, x, and r are as defined above.
  • the present disclosure provides compounds of formula (III), formula (III-A), formula (III-B), formula (III-C), formula (III-D), formula (III-A-1), formula (III-B-1), formula (III-B-2), formula (III-C-1), formula (III-C-2), formula (III-C-3), formula (III-D-1), formula (III-D-2) or formula (III-D-3) or pharmaceutically acceptable salts thereof, wherein R C2 are each independently hydrogen.
  • the present disclosure provides a compound of formula (III), formula (III-A), formula (III-B), formula (III-C), formula (III-D), formula (III-A-1), formula (III-B-1), formula (III-B-2), formula (III-C-1), formula (III-C-2), formula (III-C-3), formula (III-D-1), formula (III-D-2) or formula (III-D-3) or a pharmaceutically acceptable salt thereof, wherein x is selected from 2, 3 or 4. In certain embodiments, x is selected from 2 and 3. In certain embodiments, x is 2.
  • the present disclosure provides formula (III-A), formula (III-B), formula (III-C), formula (III-D), formula (III-A-1), formula (III-B-1), formula (III-B-2), formula (III-C-1), formula (III-C-2), formula (III-C-3), A compound represented by formula (III-D-1), formula (III-D-2) or formula (III-D-3) or a pharmaceutically acceptable salt thereof, wherein q is independently selected from 2, 3 or 4. In certain embodiments, q is selected from 3 and 4. In certain embodiments, q is 3.
  • the present disclosure provides a compound of formula (III-A), formula (III-B), formula (III-C), formula (III-D), formula (III-A-1), formula (III-B-1), formula (III-B-2), formula (III-C-1), formula (III-C-2), formula (III-C-3), formula (III-D-1), formula (III-D-2) or formula (III-D-3) or a pharmaceutically acceptable salt thereof, wherein r is selected from 2 or 3. In certain embodiments, r is 2.
  • the present disclosure provides compounds of formula (III-A-1), formula (III-B-1), formula (III-B-2), formula (III-C-1), formula (III-C-2), formula (III-C-3), formula (III-D-1), formula (III-D-2) or formula (III-D-3) or pharmaceutically acceptable salts thereof, wherein a, b, c are the same or different and are independently selected from 1, 2 or 3, preferably, a, b, c are all 1.
  • the present disclosure provides compounds of formula (III-A-1), formula (III-B-1), formula (III-B-2), formula (III-C-1), formula (III-C-2), formula (III-C-3), formula (III-D-1), formula (III-D-2) or formula (III-D-3) or pharmaceutically acceptable salts thereof, wherein A 1 + and A 2 + are each independently a monovalent cation, and the monovalent cation is selected from H + , Na + , K + , H 4 N + , Et 3 NH + , (HOCH 2 CH 2 ) 3 NH + or a cationic form of ethylenediamine, piperazine, or triphenylmethylaminomethane. In certain embodiments, the monovalent cation is selected from H + , Na + or K + . In certain embodiments, the monovalent cation is Na + .
  • the present disclosure provides compounds of formula (III-A-1), formula (III-B-1), formula (III-B-2), formula (III-C-1), formula (III-C-2), formula (III-C-3), formula (III-D-1), formula (III-D-2) or formula (III-D-3) or pharmaceutically acceptable salts thereof, wherein A 1+ and A 2+ are each independently a divalent cation selected from Ca 2+ , Mg 2+ or Zn 2+ .
  • the present disclosure provides a compound represented by formula (III), formula (III-A), formula (III-B), formula (III-C), formula (III-D), formula (III-A-1), formula (III-B-1), formula (III-B-2), formula (III-C-1), formula (III-C-2), formula (III-C-3), formula (III-D-1), formula (III-D-2) or formula (III-D-3), or a pharmaceutically acceptable salt thereof, which is selected from:
  • Another aspect of the present disclosure provides a compound represented by formula (IV) or a pharmaceutically acceptable salt thereof,
  • X 4 is independently selected from O, S, NH;
  • X 5 is each independently selected from O, S, NH;
  • R 9A are each independently selected from hydrogen, halogen, cyano, nitro, amino, carboxyl, mercapto, C 1-6 alkyl or C 1-6 alkoxy, wherein the alkyl or alkoxy is optionally substituted with one or more halogen, cyano, nitro, amino, carboxyl or mercapto;
  • R 9B are each independently selected from hydrogen, halogen, cyano, nitro, amino, carboxyl, mercapto, C 1-6 alkyl or C 1-6 alkoxy, wherein the alkyl or alkoxy is optionally substituted with one or more halogen, cyano, nitro, amino, carboxyl or mercapto;
  • R 10 is independently selected from hydrogen, halogen, cyano, nitro, amino, carboxyl, mercapto, C 1-6 alkyl or C 1-6 alkoxy, wherein the alkyl or alkoxy is optionally substituted with one or more halogen, cyano, nitro, amino, carboxyl or mercapto;
  • h is each independently selected from 1, 2, 3, 4;
  • R 1A , d, e, f, g, and p are as defined above.
  • X 4 is simultaneously O. Alternatively, in some embodiments, X 4 is simultaneously S. Alternatively, in some embodiments, X 4 is simultaneously NH.
  • X 5 is simultaneously O. Alternatively, in some embodiments, X 5 is simultaneously S. Alternatively, in some embodiments, X 5 is simultaneously NH.
  • the compound of formula (IV) or a pharmaceutically acceptable salt thereof provided by the present disclosure is selected from a compound of formula (IV-A), formula (IV-B) or formula (IV-C) or a pharmaceutically acceptable salt thereof,
  • R 9A , R 9B , R 10 , h and p are as defined above.
  • R 9A is independently selected from hydrogen, C 1-6 alkyl or C 1-6 alkoxy. In certain specific embodiments, R 9A is independently selected from hydrogen, methyl, ethyl, methoxy, ethoxy.
  • R 9B is independently selected from hydrogen, C 1-6 alkyl or C 1-6 alkoxy. In certain specific embodiments, R 9B is independently selected from hydrogen, methyl, ethyl, methoxy, ethoxy.
  • each R 10 is independently selected from hydrogen, C 1-6 alkyl or C 1-6 alkoxy. In certain specific embodiments, each R 10 is independently selected from hydrogen, methyl, ethyl, methoxy, ethoxy.
  • the compound of formula (IV), formula (IV-A), formula (IV-B) or formula (IV-C) or a pharmaceutically acceptable salt thereof provided by the present disclosure is selected from:
  • Another aspect of the present disclosure provides a method for preparing a compound of formula (I-1) or a pharmaceutically acceptable salt thereof, comprising the steps of reacting a compound of formula (C) with a compound of formula (B) in an acidic environment,
  • Another aspect of the present disclosure provides a method for preparing a compound of formula (II-1) or a pharmaceutically acceptable salt thereof, comprising the steps of reacting a compound of formula (D) with a compound of formula (B) in an acidic environment,
  • the reagent for providing an acidic environment in the present disclosure may be an organic acid or an inorganic acid, such as trifluoroacetic acid.
  • the present disclosure provides a composition
  • a composition comprising a compound represented by formula (I), (I-1), (II), (II-1), (II-2), (II-3), formula (III), formula (III-A), formula (III-B), formula (III-C), formula (III-D), formula (III-A-1), formula (III-B-1), formula (III-B-2), formula (III-C-1), formula (III-C-2), formula (III-C-3), formula (III-D-1), formula (III-D-2) or formula (III-D-3) or a pharmaceutically acceptable salt thereof, an isotopic substitute and a pharmaceutically acceptable excipient.
  • the unit dose of the pharmaceutical composition is 0.001 mg-1000 mg.
  • the pharmaceutical composition contains 0.01-99.99% based on the total weight of the composition. In certain embodiments, the pharmaceutical composition contains 0.1-99.9% of the aforementioned compound or its pharmaceutically acceptable salt or its isotope substitute. In certain embodiments, the pharmaceutical composition contains 0.5%-99.5% of the aforementioned compound or its pharmaceutically acceptable salt or its isotope substitute. In certain embodiments, the pharmaceutical composition contains 1%-99% of the aforementioned compound or its pharmaceutically acceptable salt or its isotope substitute. In certain embodiments, the pharmaceutical composition contains 2%-98% of the aforementioned compound or its pharmaceutically acceptable salt or its isotope substitute.
  • the pharmaceutical composition contains 0.01%-99.99% of a pharmaceutically acceptable excipient based on the total weight of the composition. In certain embodiments, the pharmaceutical composition contains 0.1%-99.9% of a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition contains 0.5%-99.5% of a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition contains 1%-99% of a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition contains 2%-98% of a pharmaceutically acceptable excipient.
  • the present disclosure provides the use of the compounds represented by the above-mentioned formula (I), formula (I-1), formula (I-1-A), formula (I-1-B), formula (I-1-C), formula (I-1-D), formula (I-1-E), formula (II), formula (II-1), formula (II-2), formula (II-3), formula (III), formula (III-A), formula (III-B), formula (III-C), formula (III-D), formula (III-A-1), formula (III-B-1), formula (III-B-2), formula (III-C-1), formula (III-C-2), formula (III-C-3), formula (III-D-1), formula (III-D-2), formula (III-D-3), formula (IV), formula (IV-A), formula (IV-B) or formula (IV-C) or their pharmaceutically acceptable salts, isotope substitutes, and compositions in the preparation of drugs for treating or preventing diseases or conditions, wherein the diseases or conditions are selected from proliferative diseases, blood cancers,
  • the present disclosure provides a method for treating or preventing a disease or condition, wherein the disease or condition is selected from a proliferative disease, a blood cancer, a cardiovascular-related disease or an infectious disease, by administering to a patient a compound represented by the above-mentioned formula (I), formula (I-1), formula (I-1-A), formula (I-1-B), formula (I-1-C), formula (I-1-D), formula (I-1-E), formula (II), formula (II-1), formula (II-2), formula (II-3), formula (III), formula (III-A), formula (III-B), formula (III-C), formula (III-D), formula (III-A-1), formula (III-B-1), formula (III-B-2), formula (III-C-1), formula (III-C-2), formula (III-C-3), formula (III-D-1), formula (III-D-2), formula (III-D-3), formula (IV), formula (IV-A), formula (IV-B) or formula (IV-C
  • the present disclosure provides the use of the compounds represented by the above-mentioned formula (I), formula (I-1), formula (I-1-A), formula (I-1-B), formula (I-1-C), formula (I-1-D), formula (I-1-E), formula (II), formula (II-1), formula (II-2), formula (II-3), formula (III), formula (III-A), formula (III-B), formula (III-C), formula (III-D), formula (III-A-1), formula (III-B-1), formula (III-B-2), formula (III-C-1), formula (III-C-2), formula (III-C-3), formula (III-D-1), formula (III-D-2), formula (III-D-3), formula (IV), formula (IV-A), formula (IV-B) or formula (IV-C) or their pharmaceutically acceptable salts, isotope substitutes, and compositions in the preparation of drugs for reversing drug-induced neuromuscular blockade and/or anesthesia.
  • Another aspect of the present disclosure provides a method for reversing drug-induced neuromuscular blockade and/or anesthesia, wherein the patient is administered the above-mentioned formula (I), formula (I-1), formula (I-1-A), formula (I-1-B), formula (I-1-C), formula (I-1-D), formula (I-1-E), formula (II), formula (II-1), formula (II-2), formula (II-3), formula (III), formula (III-A), formula (III-A), formula (III-B), formula (I ...B), formula (III-C), formula (I-1-D), formula (I-1-E), formula (II), formula (II-1), formula (II-2), formula (II-3), formula (III), formula (III-A), formula (III-B), formula (III- A compound represented by formula (III-B), formula (III-C), formula (III-D), formula (III-A-1), formula (III-B-1), formula (III-B-2), formula (III-C-1), formula (
  • the proliferative diseases described in the present disclosure are selected from fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, pseudomyxoma peritoneum, lymphangioendothelial theca sarcoma, synovioma, synovial sarcoma, colon sarcoma, mesothelioma, mesothelioma, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, head and neck cancer, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinoma, cystic adenocarcinoma, medullary carcinoma, bronchial carcinoma, renal cell carcinoma , liver cancer, bile duct cancer,
  • the blood cancer described in the present disclosure is selected from the group consisting of leukemia, lymphoma and myeloma.
  • the present disclosure provides a compound represented by formula (I), formula (I-1), formula (I-1-A), formula (I-1-B), formula (I-1-C), formula (I-1-D), formula (I-1-E), formula (II), formula (II-1), formula (II-2), formula (II-3), formula (III), formula (III-A), formula (III-B), formula (III-C), formula (III-D), formula (III-A-1), formula (III-B-1), formula (III-B-2), formula (III-C-1), formula (III-C-2), formula (III-C-3), formula (III-D-1), formula (III-D-2), formula (III-D-3), formula (IV), formula (IV-A), formula (IV-B) or formula (IV-C) or its pharmaceutically acceptable salt, isotope substitution, or the use of the compound prepared by the aforementioned method as a drug.
  • the pharmaceutically acceptable salts of the compounds described in the present disclosure can be selected from inorganic salts or organic salts.
  • the inorganic salts include but are not limited to Na + , K + , Ca 2+ , Mg 2+ , and Zn 2+ ;
  • the organic salts include but are not limited to H 4 N + , Et 3 NH + , (HOCH 2 CH 2 ) 3 NH + or cationic forms of ethylenediamine, piperazine, and triphenylmethylaminomethane.
  • the compounds of the present disclosure may exist in specific geometric or stereoisomeric forms.
  • the present disclosure contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic mixtures and other mixtures thereof, such as mixtures enriched in enantiomers or diastereomers, all of which are within the scope of the present disclosure.
  • Additional asymmetric carbon atoms may be present in substituents such as alkyl. All of these isomers and their mixtures are included within the scope of the present disclosure.
  • the compounds of the present disclosure containing asymmetric carbon atoms can be isolated in optically pure form or in racemic form. Optically pure forms can be resolved from racemic mixtures or synthesized by using chiral raw materials or chiral reagents.
  • Optically active (R)- and (S)-isomers as well as D and L isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the present disclosure is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide the pure desired enantiomer.
  • a functional group such as an amino group
  • an acidic functional group such as a carboxyl group
  • a diastereoisomer salt is formed with an appropriate optically active acid or base, and then the diastereoisomers are separated by conventional methods known in the art, and then the pure enantiomers are recovered.
  • the separation of enantiomers and diastereomers is usually achieved by using chromatography, which uses a chiral stationary phase and is optionally combined with a chemical derivatization method (such as the formation of carbamates from amines).
  • the bond Indicates that the configuration is not specified, that is, if there are chiral isomers in the chemical structure, the bond Can be or include both Two configurations.
  • tautomer or “tautomeric form” refers to structural isomers of different energies that can interconvert via a low energy barrier.
  • proton tautomers also referred to as prototransfer tautomers
  • proton migration such as keto-enol and imine-enamine, lactam-lactim isomerization. Lactam-lactim equilibrium examples are between A and B as shown below.
  • the present disclosure also includes isotopically labeled compounds of the present disclosure that are identical to those described herein, but in which one or more atoms are replaced by atoms having an atomic mass or mass number different from that normally found in nature.
  • isotopes that can be incorporated into compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F, 123 I, 125 I, and 36 Cl , respectively.
  • deuterium when a position is specifically designated as deuterium (D), the position is understood to have deuterium (i.e., at least 10% deuterium incorporation) at least 1000 times greater than the natural abundance of deuterium (which is 0.015%).
  • the natural abundance of the compound in the example may be at least 1000 times greater than deuterium, at least 2000 times greater than deuterium, at least 3000 times greater than deuterium, at least 4000 times greater than deuterium, at least 5000 times greater than deuterium, at least 6000 times greater than deuterium or more.
  • the present disclosure also includes various deuterated forms of the formula (I) compound. Each available hydrogen atom connected to a carbon atom may be independently replaced by a deuterium atom.
  • deuterated forms of the formula (I) compound can synthesize deuterated forms of the formula (I) compound with reference to the relevant literature.
  • commercially available deuterated starting materials may be used, or they may be synthesized using conventional techniques using deuterated reagents, including but not limited to deuterated borane, trideuterated borane in tetrahydrofuran, deuterated lithium aluminum hydride, deuterated iodoethane and deuterated iodomethane, and the like.
  • “Pharmaceutical composition” means a mixture containing one or more compounds described herein or their physiologically pharmaceutically acceptable salts or prodrugs and other chemical components, as well as other components such as physiologically pharmaceutically acceptable carriers and excipients.
  • the purpose of a pharmaceutical composition is to facilitate administration to an organism, facilitate the absorption of the active ingredient, and thus exert biological activity.
  • “Pharmaceutically acceptable excipients” include, but are not limited to, any adjuvant, carrier, glidant, sweetener, diluent, preservative, dye/colorant, flavoring agent, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent, solvent or emulsifier approved by the U.S. Food and Drug Administration (FDA) for use by humans or domestic animals.
  • FDA U.S. Food and Drug Administration
  • an "effective amount” or “therapeutically effective amount” includes an amount sufficient to ameliorate or prevent the symptoms or conditions of a medical condition.
  • An effective amount also means an amount sufficient to allow or facilitate diagnosis.
  • the effective amount for a particular patient or veterinary subject may vary depending on factors such as the condition to be treated, the patient's overall health, the method, route and dosage of administration, and the severity of side effects.
  • An effective amount may be the maximum dose or dosing regimen that avoids significant side effects or toxic effects.
  • C1-6alkyl indicates that the alkyl group has 1 to 6 carbon atoms, and specifically may be an alkyl group having 1, 2, 3, 4, 5 or 6 carbon atoms.
  • alkyl refers to a non-branched or branched saturated hydrocarbon chain.
  • an alkyl group has 1 to 20 carbon atoms (i.e., C 1-20 alkyl), 1 to 8 carbon atoms (i.e., C 1-8 alkyl), 1 to 6 carbon atoms (i.e., C 1-6 alkyl), or 1 to 4 carbon atoms (i.e., C 1-4 alkyl).
  • alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and 3-methylpentyl.
  • butyl includes n-butyl (i.e., -( CH2 ) 3CH3 ), sec-butyl (i.e., -CH( CH3 ) CH2CH3 ), isobutyl ( i.e.
  • cycloalkyl or “carbocycle” refers to a saturated or partially unsaturated cyclic alkyl having a monocyclic or polycyclic ring (including fused, bridged and spirocyclic ring systems).
  • cycloalkyl includes cycloalkenyl (i.e., the cyclic group has at least one double bond).
  • the cyclic alkyl used herein has 3 to 20 ring carbon atoms (i.e., C 3-20 cycloalkyl), 3 to 12 ring carbon atoms (i.e., C 3-12 cycloalkyl), 3 to 10 ring carbon atoms (i.e., C 3-10 cycloalkyl), 3 to 8 ring carbon atoms (i.e., C 3-8 cycloalkyl), or 3 to 7 ring carbon atoms (i.e., C 3-7 cycloalkyl), or 3 to 6 ring carbon atoms (i.e., C 3-6 cycloalkyl).
  • cycloalkyl examples include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, cyclohexenyl, cyclohexadienyl.
  • the cycloalkyl ring may be fused to an aryl or heteroaryl ring, wherein the ring attached to the parent structure is a cycloalkyl, non-limiting examples of which include indanyl, tetrahydronaphthyl, benzocycloheptanyl, and the like.
  • heterocyclyl or “heterocycloalkyl” refers to a saturated or unsaturated cycloalkyl group having one or more ring heteroatoms independently selected from nitrogen, oxygen, sulfur and phosphorus.
  • heterocyclylalkane includes heterocycloalkenyl (i.e., a heterocyclyl having at least one double bond), bridged heterocyclyl, fused heterocyclyl and spiral-heterocyclyl.
  • the heterocyclyl group can be a monocyclic or polycyclic ring, wherein the polycyclic ring can be fused, bridged or spirocyclic.
  • any non-aromatic ring containing at least one heteroatom is considered to be a heterocyclyl group, regardless of connection (i.e., it can be combined by carbon atoms or heteroatoms).
  • heterocyclyl is intended to include any non-aromatic ring containing at least one heteroatom, which ring can be fused to an aryl or heteroaryl ring, regardless of connection to the rest of the molecule.
  • the heterocyclyl group has 3 to 20 ring atoms (i.e., 3 to 20-membered heterocyclyl), 3 to 12 ring atoms (i.e., 3 to 12-membered heterocyclyl), 3 to 10 ring atoms (i.e., 3 to 10-membered heterocyclyl), 3 to 8 ring atoms (i.e., 3 to 8-membered heterocyclyl), 3 to 7 ring atoms (i.e., 3 to 7-membered heterocyclyl), 3 to 6 ring atoms (i.e., 3 to 6-membered heterocyclyl); has 1 to 5 ring heteroatoms, 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom, and the ring heteroatoms are independently selected from nitrogen, sulfur, phosphorus or oxygen.
  • the ring heteroatoms are independently selected from nitrogen, sulfur, phosphorus or oxygen.
  • heterocyclic groups include pyrrolidinyl, imidazolidinyl, oxetanyl, dioxolanyl, azetidinyl, tetrahydrofuranyl, tetrahydrofuranyl, tetrahydrothiophenyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl.
  • heteroaryl refers to a heteroaromatic system containing 1 to 4 heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen.
  • the heteroaryl group is preferably 6 to 12 members, more preferably 5 or 6 members.
  • Non-limiting examples include: imidazolyl, furanyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, tetrazolyl, pyridinyl, pyrimidinyl, thiadiazole, pyrazine, etc.
  • the heteroaryl ring may be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring attached to the parent structure is a heteroaryl ring, non-limiting examples of which include:
  • alkoxy refers to the group “alkyl-O-,” wherein alkyl is as defined above. Examples of alkoxy include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and 1,2-dimethylbutoxy.
  • haloalkyl refers to an unbranched or branched alkyl group as defined above, wherein one or more hydrogen atoms are replaced by a halogen.
  • a residue when a residue is substituted with more than one halogen, it may be referred to by using a prefix corresponding to the number of halogen moieties attached.
  • Dihaloalkyl and trihaloalkyl refer to alkyl groups substituted with two or three halogen groups, which may be, but need not be, the same halogen. Examples of haloalkyl groups include difluoromethyl ( -CHF2 ) and trifluoromethyl ( -CF3 ).
  • haloalkoxy refers to an alkoxy group as defined above wherein one or more hydrogen atoms are replaced by a halogen.
  • hydroxyalkyl refers to an alkyl group substituted with one or more hydroxy groups, the alkyl group being as defined above.
  • a “monovalent group” refers to a compound that "formally” eliminates a monovalent atom or group.
  • a “subunit” refers to a compound that "formally” eliminates two monovalent or one divalent atoms or groups.
  • alkylene refers to the portion remaining after removing two hydrogen atoms from an alkane molecule, including straight and branched subgroups of 1 to 20 carbon atoms.
  • alkylene groups containing 1 to 6 carbon atoms include methylene ( -CH2- ), ethylene (such as -CH2CH2- or -CH( CH3 )-).
  • alkylene groups may be substituted or unsubstituted .
  • Alkylene groups used in any context herein are optionally substituted in the same manner as alkyl groups.
  • heteroalkylene refers to an alkylene group in which one or more -CH2- groups are replaced by heteroatoms selected from N, O and S; wherein the alkylene group is as defined above; the heteroalkylene group may be substituted or unsubstituted. Unless otherwise specified, the heteroalkylene group may be substituted or unsubstituted.
  • the heteroalkylene group used in any context herein is optionally substituted in the same manner as the alkyl group.
  • hydroxy refers to an -OH group.
  • halogen refers to fluorine, chlorine, bromine or iodine.
  • cyano refers to -CN.
  • nitro refers to -NO2 .
  • Substituted means that one or more hydrogen atoms, preferably up to 5, more preferably 1 to 3 hydrogen atoms in the group are replaced independently of each other by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and the skilled person can determine (by experiment or theory) possible or impossible substitutions without undue effort.
  • the structures of the compounds were determined by nuclear magnetic resonance (NMR) and/or mass spectrometry (MS). NMR shifts ( ⁇ ) are given in units of 10 -6 (ppm). NMR measurements were made using a Bruker AVANCE-400 NMR spectrometer. The reagents were deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), deuterated methanol (CD 3 OD), and the internal standard was tetramethylsilane (TMS).
  • DMSO-d 6 deuterated dimethyl sulfoxide
  • CDCl 3 deuterated chloroform
  • CD 3 OD deuterated methanol
  • TMS tetramethylsilane
  • MS was measured using Shimadzu 2010 Mass Spectrometer or Agilent 6110A MSD mass spectrometer.
  • Chiral HPLC analysis was performed using Chiralpak IC-3 100 ⁇ 4.6mm I.D., 3um, Chiralpak AD-3 150 ⁇ 4.6mm I.D., 3um, Chiralpak AD-3 50 ⁇ 4.6mm I.D., 3um, Chiralpak AS-3 150 ⁇ 4.6mm I.D., 3um, Chiralpak AS-3 100 ⁇ 4.6mm I.D., 3 ⁇ m, ChiralCel OD-3 150 ⁇ 4.6mm I.D., 3um, Chiralcel OD-3 100 ⁇ 4.6mm I.D., 3 ⁇ m, ChiralCel OJ-H 150 ⁇ 4.6mm I.D., 5um, Chiralcel OJ-3 150 ⁇ 4.6mm I.D., 3um columns;
  • the thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate.
  • the silica gel plate used in thin layer chromatography (TLC) adopts a specification of 0.15mm-0.2mm, and the specification used for thin layer chromatography separation and purification products is 0.4mm-0.5mm.
  • the chiral preparative column used was DAICEL CHIRALPAK IC (250mm*30mm, 10um) or Phenomenex-Amylose-1 (250mm*30mm, 5um).
  • the CombiFlash rapid preparation instrument uses Combiflash Rf150 (TELEDYNE ISCO).
  • the known starting materials disclosed in the present invention can be synthesized by methods known in the art, or can be purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc, Darui Chemicals and other companies.
  • the reactions can be carried out under an argon atmosphere or a nitrogen atmosphere.
  • Argon atmosphere or nitrogen atmosphere means that the reaction bottle is connected to an argon or nitrogen balloon with a capacity of about 1L.
  • Hydrogen atmosphere means that the reaction bottle is connected to a hydrogen balloon with a capacity of about 1L.
  • the pressurized hydrogenation reaction uses a Parr 3916EKX hydrogenator and a Clear Blue QL-500 hydrogen generator or a HC2-SS hydrogenator.
  • the hydrogenation reaction is usually carried out by evacuating the vacuum, filling with hydrogen, and repeating the operation three times.
  • Microwave reactions were performed using a CEM Discover-S 908860 microwave reactor.
  • the solution refers to an aqueous solution.
  • reaction temperature is room temperature, 20°C to 30°C.
  • the reaction progress in the embodiment is monitored by thin layer chromatography (TLC), the developing solvent used in the reaction, the system of column chromatography eluent used for purifying the compound and the developing solvent system of thin layer chromatography, the volume ratio of the solvent is adjusted according to the polarity of the compound, and a small amount of alkaline or acidic reagents such as triethylamine and acetic acid can be added for adjustment.
  • TLC thin layer chromatography
  • Step 1 Add urea (38.89 g, 647.46 mmol), 0.3 M dilute hydrochloric acid (80 mL) and 1,2-cyclohexanedione 2a (22.0 g, 196.20 mmol) to a 500 mL three-necked flask, heat to 50 ° C and stir for 16 hours. The reaction was cooled to room temperature, filtered, and the filter cake was rinsed with 100 mL of water and 100 mL of anhydrous ethanol, and dried to obtain compound 2b (light yellow body, 27.4 g, yield: 71%).
  • Step 2 Add compound 2b (27.4 g, 139.65 mmol), 140 mL 9 M hydrochloric acid and paraformaldehyde (20.9 g, 698.23 mmol) into a 1 L three-necked flask, stir the reaction solution at room temperature for 24 hours, add 500 mL of water to the reaction system, and continue stirring at room temperature for 16 hours. Filter the reaction solution, wash and dry to obtain compound 2c (white solid, 20.2 g, yield: 52%).
  • Step 3 Compound 2c (2.73 g, 9.73 mmol) was weighed into a dry three-necked flask and the argon atmosphere was replaced. Methanesulfonic acid (10 mL) was added to dissolve, compound 1a (1 g, 3.24 mmol, prepared by the known method "WO2012/051407A”) was added, and the mixture was stirred at room temperature for 24 hours. The reaction solution was slowly added to 100 mL of water (cooled in an ice-water bath), and the mixture was returned to room temperature after the addition. Filtered. Drying gave 1.77 g of crude product, which was heated and dissolved in TFA (4 mL), and then 16 mL of water was added, stirred, filtered, and vacuum dried to give compound 2d (1.21 g, yield: 44.9%).
  • Step 4 Compound 2d (1.06 g, 1.27 mmol) was weighed into a dry three-necked flask, argon was replaced, TFA (10 mL) was added to dissolve, and then compound 1b (1.42 g, 3.17 mmol, prepared by the known method "WO2012/051407A”) was added. After the addition, the reaction was heated to 60 ° C and stirred for 3 hours. TFA was evaporated under reduced pressure, 20 mL of ethanol was added to the obtained solid and heated under reflux for 2 hours, cooled to room temperature, and filtered.
  • the filter cake was washed with ethanol and dried, and the obtained solid was heated and dissolved with 10 mL of water, and then 30 mL of ethanol was added, filtered, and then the filter cake was purified by high performance liquid chromatography (chromatographic column: SharpSil-T, 30*150 mm, 5 ⁇ m; mobile phase: water phase and acetonitrile, gradient ratio: water phase 25%-42%), and finally salted with sodium hydroxide to obtain compound 2 (0.27 g, yield: 12.6%).
  • Step 1 Dissolve urea (12 g, 0.2 mol) in 0.3 M HCl (30 mL), add compound 3a (6.97 g, 0.061 mol) at room temperature, and then stir at room temperature for 24 hours; filter, wash, and dry to obtain the title product 3b (6.8 g, yield: 56.2%).
  • Step 2 The substrate 3b (3.4 g, 17.2 mmol) was weighed into a dry three-necked flask, and 2.54 g of paraformaldehyde and 9 M HCl (15 mL) were added. The mixture was stirred at room temperature for 24 hours. The reaction was continued to stir at room temperature for 24 hours, filtered, washed, and dried to obtain the title product 3c (2.1 g, yield: 43.2%).
  • Step 3 Dissolve compound 3c (2.75 g, 9.73 mmol) in methanesulfonic acid (10 mL), add compound 1a (1 g, 3.24 mmol) and stir at room temperature for 18 hours. Slowly add the reaction solution into 100 mL of water (cooled in an ice-water bath), and return to room temperature after the addition. Filter. Dry to obtain 1.67 g of crude product. Heat the above crude product and dissolve it in TFA (4 mL), then add 16 mL of water, stir, filter, and vacuum dry to obtain the title product 3d (off-white solid, 1.56 g, yield: 57.3%).
  • Step 4 3d (0.89 g, 1.06 mmol) was weighed into a dry three-necked flask, argon was replaced, TFA (10 mL) was added to dissolve, and then compound 1b (1.19 g, 2.66 mmol) was added. After the addition, the reaction was heated to 70 ° C and stirred for 3 hours. TFA was evaporated under reduced pressure, and 20 mL of ethanol was added to the obtained solid and heated under reflux for 2 hours, cooled to room temperature, filtered, and dried.
  • the obtained solid was heated and dissolved with 6.6 mL of water, and then 19.8 mL of Ethanol, filtered, washed, and the filter cake was purified by high performance liquid chromatography (chromatographic column: SharpSil-T, 30*150mm, 5 ⁇ m; mobile phase: water phase and acetonitrile, gradient ratio: water phase 25%-42%), and finally salified with sodium hydroxide to obtain the title product 3 (0.28 g, yield: 15.5%).
  • Step 1 Dissolve 1,4-dihydroxynaphthalene (1 g, 6.24 mmol) in 10% NaOH aqueous solution (8 mL), replace the atmosphere with nitrogen, and then add dropwise a solution of compound 11a (2.14 g, 15.6 mmol) in dioxane (12 mL). The reaction mixture was stirred at room temperature overnight. The reaction solution was dried by rotary evaporation and purified by reverse phase preparative method to obtain white solid compound 11b (0.8 g, yield: 26%).
  • Step 2 Compound 11b (520 mg, 1.09 mmol) was dissolved in TFA (10 mL), and then compound 2d (364 mg, 0.44 mmol) was added. After the addition, the reaction system was heated to 70 ° C and stirred for 2 hours.
  • TFA was evaporated under reduced pressure, and the obtained solid was purified by column (chromatographic column: SharpSil-T, 30 ⁇ 150 mm, 5 ⁇ m; mobile phase: water phase and acetonitrile, gradient ratio: water phase 25%-42%) to obtain 192 mg of white solid, which was dissolved in 2 mL of water, and then the pH value of the system was adjusted to 5-8 with 0.5 M sodium hydroxide aqueous solution, 10 mL of ethanol was added, the solid was precipitated, and filtered to obtain white solid compound 11 (120 mg, yield: 16.5%).
  • Step 1 Compound 12a (10.85 g, 51.6 mmol, prepared by the same preparation method as compound 2b in Example 1) was weighed into a dry three-necked flask, 7.75 g of paraformaldehyde and 9M HCl (45 mL) were added, and stirred at room temperature for 24 hours. 163 mL of water was added, and the reaction was stirred at room temperature for another 24 hours; filtered, the filter cake was washed with water (60 mL) and ethanol (60 mL), and dried to obtain 10.84 g of off-white solid compound 12b (yield: 71.4%).
  • Step 2 Compound 12b (2.00 g, 6.80 mmol) was weighed into a dry three-necked flask, argon was replaced, and methanesulfonic acid (7 mL) was added to dissolve; compound 1a (0.70 g, 2.27 mmol, prepared by the known method "WO2012/051407A2”) was added at room temperature (23 ° C). After stirring and reacting at room temperature for 18 hours, the reaction solution was slowly added to 70 mL of water (cooled in an ice-water bath), and the temperature was restored to room temperature after the addition. Filter, and wash the filter cake with a small amount of water. Dry to obtain 1.97 g of crude product.
  • Step 3 Compound 12c (1.00 g, 1.16 mmol) was weighed into a dry three-necked flask, argon was replaced, TFA (10 mL) was added to dissolve, and then compound 1b was added. After the addition, the reaction was heated to 60 ° C and stirred for 3 hours. TFA was evaporated under reduced pressure, 20 mL of ethanol was added to the obtained solid and heated under reflux for 2 hours, cooled to room temperature, and filtered. The filter cake was washed with ethanol and dried. The obtained solid was purified by high performance liquid chromatography (mobile phase: water phase and acetonitrile, gradient ratio: water phase 25%-42%), and finally salified with sodium hydroxide to obtain 0.12 g of white solid compound 12.
  • Step 1 Add DMSO (50mL) and KOH (8.75g, 156mmol) to a three-necked flask, ultrasonically mix the mixture to disperse KOH in DMSO, then replace the air with nitrogen, and stir at room temperature for one hour.
  • Compound 13a (5g, 31.25mmol) and compound 13b (24.3g, 125mmol) are slowly added to the reaction solution.
  • the reaction is heated to 60°C and stirred for 2 hours.
  • 200mL of water is added and extracted with dichloromethane (50mL ⁇ 3).
  • the combined organic phase is washed with saturated brine (100mL), dried, filtered, and the solvent is spun off.
  • Step 2 Compound 13c (3.50 g, 9.02 mmol) was weighed into a dry three-necked flask, nitrogen was replaced, TFA (20 mL) was added to dissolve, and then compound 2d (3.00 g, 3.61 mmol) and acetic anhydride (918 mg, 9.02 mmol) were added. After the addition, the reaction was heated to 70 ° C and stirred for 4 hours. TFA was evaporated under reduced pressure, and 50 mL of methyl tert-butyl ether was added to the obtained solid, heated to 50 ° C and stirred for half an hour, cooled to room temperature, and filtered. The filter cake was washed with methyl tert-butyl ether and dried to obtain 4.2 g of brown solid compound 13d.
  • Step 3 Add compound 13d (2.0 g, 1.27 mmol) to a 50 mL single-mouth bottle, add methanol and water (1:1, 30 mL), LiOH.H2O (534 mg, 12.7 mmol) to dissolve it. After the addition, heat the reaction to 80 ° C and stir for 3 hours. Distill off the solvent under reduced pressure, add ethanol and water (10:1, 20 mL) and stir at room temperature for half an hour, and filter. Wash the filter cake with ethanol and dry.
  • Step 1 Add compound E1 (25g, 96mmol) and anhydrous THF (70mL) into a three-necked flask, then replace the air with nitrogen, and then cool to -78°C with a dry ice acetone bath, then slowly drop DIBAL-H (135mL, 202mmol, 1.5M toluene), after the drop is complete, warm up to 0°C, and stir the reaction at 0°C for 45 minutes. Then drop HCl (1M, 500mL) at 0°C to quench the reaction, add 200mL of ethyl acetate, and extract with ethyl acetate (50mL ⁇ 3).
  • DIBAL-H 135mL, 202mmol, 1.5M toluene
  • Step 3 Compound E3 (5.0 g, 8.56 mmol) was weighed into a dry single-necked flask and the atmosphere was replaced with nitrogen. Add DMSO (60 mL) to dissolve, then add NaCN (4.2 g, 85.6 mmol). After the addition, heat the reaction to 75 ° C and stir for 1 hour. Pour the reaction solution into ice water, a large amount of solid precipitates, and filter. Add ethyl acetate to the obtained solid, stir at room temperature for half an hour, filter, and dry to obtain 2.33 g of white solid compound E (yield: 73.5%).
  • Step 5 Compound 14a (1.4 g, 2.50 mmol) was weighed into a dry three-necked flask, nitrogen was replaced, TFA (5 mL) was added to dissolve, and then compound 2d (520 mg, 0.625 mmol) and acetic anhydride (5 mL) were added. After the addition, the reaction was heated to 90 ° C and stirred for 4 hours. TFA was evaporated under reduced pressure, 50 mL of methyl tert-butyl ether was added to the obtained solid, heated to 50 ° C and stirred for half an hour, cooled to room temperature, and filtered. The filter cake was washed with methyl tert-butyl ether and dried to obtain 1.2 g of brown solid.
  • Step 6 Compound 14b (150 mg, 0.078 mmol) was weighed into a 25 mL single-mouth bottle, methanol and water (1:1, 10 mL) were added until it could not be dissolved, and then LiOH.H2O ( 534 mg, 12.7 mmol) was added. After the addition, the reaction was heated to 80°C and stirred for 3 hours. The reaction solution was purified by high performance liquid chromatography (mobile phase: water phase and acetonitrile, gradient ratio: water phase 25%-42%), and finally salified with sodium hydroxide to obtain 53 mg of white solid compound 14 (yield: 40%).
  • Step 1 Add compound E3 (2.25 g, 3.83 mmol) and sodium sulfite (4.91 g, 38.9 mmol) to a three-necked flask, replace the air with nitrogen, and then add 42 mL of isopropanol and 42 mL of water. Heat the reaction to 100 ° C and stir for 24 hours. The reaction is cooled to room temperature and concentrated to obtain a crude product. Then 83 mL of methanol is added, and the mixture is stirred for 1 hour. The solid is collected by filtration and sent to HPLC for preparation to obtain 1.62 g of white solid compound 15a (yield: 64%).
  • Step 2 Compound 15a (1.57 g, 2.37 mmol) was weighed into a dry three-necked flask, argon was replaced, TFA (15 mL) was added to dissolve, and then compound 2d (0.79 g, 0.95 mmol) was added. After the addition, the reaction was heated to 70 ° C and stirred for 3 hours. TFA was evaporated under reduced pressure, 40 mL of ethanol was added to the obtained solid and heated under reflux for 2 hours, cooled to room temperature, and filtered. The filter cake was washed with ethanol and dried.
  • the obtained solid was dissolved in 12 mL of water, and then the pH value of the system was adjusted to about 7 with 1M sodium hydroxide aqueous solution, 50 mL of ethanol was added, and the viscous material was precipitated, the supernatant was poured off, and the residue was spin-dried, and then purified by high performance liquid chromatography (mobile phase: water phase and acetonitrile, gradient ratio: water phase 25%-42%), and finally salified with sodium hydroxide to obtain 299 mg of white solid compound 15 (yield: 12%).
  • Step 2 Add compound 16a (800 mg, 2.14 mmol) and sodium sulfite (593 mg, 4.70 mmol) to a three-necked flask, replace the air with nitrogen, and then add 6 mL DMF and 6 mL water. Heat the reaction to 100 ° C and stir for 24 hours. The reaction solution is cooled to room temperature, filtered, and the filtrate is poured into 60 mL of acetone. A precipitate is precipitated and filtered to obtain 880 mg of a light yellow solid. The crude product is dissolved in 2 mL of water, and ethanol (10 mL) is slowly added dropwise. A large amount of solid precipitates. Filter, and the solid is drained to obtain 570 mg of white solid compound 16b (yield: 63%).
  • Step 3 Compound 16b (570 mg, 1.36 mmol) was weighed into a dry three-necked flask, argon was replaced, TFA/Ac 2 O (1:1, 10 mL) was added to dissolve, and then compound 2d (452 mg, 0.54 mmol) was added. After the addition, the reaction was heated to 70°C and stirred for 2 hours.
  • Step 1 Add zinc powder (3.720 g, 56.9 mmol) and acetic acid (20 ml) in a 100 mL three-necked flask, replace with nitrogen three times, then add compound 17a (0.980 g, 5.69 mmol) at once, and stir at room temperature for 5-10 minutes.
  • the central control shows that the reaction is complete, the reaction liquid is filtered, the filter cake is rinsed with 15 mL of acetic acid, the filtrate is concentrated under reduced pressure, the obtained solid is dissolved with 50 mL of ethyl acetate, washed with 20 ml of saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to obtain 0.982 g of compound 17b (yield: 99%, purity 95.8%).
  • Step 2 Sodium hydroxide (0.370 g, 9.24 mmol) and water (3.3 ml) were added to a 50 mL three-necked flask in sequence, and the nitrogen was replaced three times. After stirring and dissolving, compound 17b (0.7 g, 4.02 mmol) was added and cooled in an ice-water bath. Then a solution of 1,3-propane sultone (1.030 g, 9.24 mmol) in dioxane (8.4 ml) was added dropwise, and the mixture was returned to room temperature and stirred for 19 h. The central control showed that the raw material reaction was complete.
  • reaction solution was filtered, and the filter cake was rinsed with a mixed solvent of dioxane/water (5 mL/1 mL) and dioxane (5 mL) in sequence.
  • the filter cake was then concentrated with toluene (15 mL ⁇ 3) to obtain 0.830 g of compound 17c (yield: 44.6%, purity: 99.7%).
  • Step 3 Compound 17c (0.416 g, 0.9 mmol), TFA (6 mL) and compound 2d (0.3 g, 0.36 mmol) were added to a 50 mL single-mouth bottle, replaced with nitrogen three times, heated to 70 ° C in an oil bath, and reacted for 3 h. The central control showed that the reaction was complete, and the reaction was stopped. The reaction solution was cooled to room temperature, concentrated to obtain a solid, added 15 mL of ethanol and stirred for 10 min, filtered, and the filter cake was rinsed with ethanol (10 mL) to obtain 822 mg of crude compound 17d (yield: 35.7%, purity: 97.7%).
  • Step 4 Compound 17d (0.210 g, 0.128 mmol) and THF (4 mL) were added to a 100 mL single-mouth bottle in sequence, the pH of the solution was adjusted to 7 with 0.5 N sodium hydroxide aqueous solution, and then ethanol (12 mL) was added dropwise to precipitate solids. The filter cake was filtered and rinsed with ethanol (5 mL), and the resulting filter cake was lyophilized to obtain 0.153 g of compound 17 (yield: 69.2%, purity: 98.02%).
  • Step 1 Add 2 mL of tert-butyl alcohol to compound 18a (338 mg, 3.43 mmol, prepared by a known method, Journal of the American Chemical Society, 1996, vol. 118, #34, p. 7946–7968) and stir to dissolve. Then add N-methylmorpholine oxide (803.4 mg, 6.86 mmol) and potassium osmate dihydrate (25.3 mg, 68.6 ⁇ mol). After addition, react at room temperature for 16 hours. The central control shows that the reaction is complete.
  • Step 2 Add DMSO (12.22 g, 156.41 mmol) and DCM (310 mL) to a 500 mL three-necked reaction bottle, protect with nitrogen, cool to -60 ° C, add trifluoroacetic anhydride (29.15 g, 138.77 mmol) dropwise, and add the solution of compound 18b (5.1 g, 35.36 mmol) in DCM (15 mL) after 20 minutes of warming and stirring, add triethylamine (32.67 g, 322.86 mmol) after 1.5 hours of warming and stirring, and stir at -60 ° C for 1 hour and then warm to room temperature.
  • the central control shows that the reaction is complete, and 324 mL 10% hydrochloric acid is added to the reaction system, and the liquid is separated.
  • the aqueous phase is extracted with DCM (100 mL ⁇ 2), the organic phases are combined, dried over anhydrous sodium sulfate, and concentrated.
  • Step 3 Add urea (5.25 g, 87.35 mmol), 0.3 M dilute hydrochloric acid (13.4 mL) and compound 18c (3.71 g, 26.47 mmol) to a 100 mL reaction bottle, heat to 50 ° C and stir for 16 hours. The reaction was cooled to room temperature, filtered, and the filter cake was rinsed with 10 mL of water and 12 mL of anhydrous ethanol, and dried to obtain 2.34 g of compound 18d (yield: 39%).
  • Step 4 Add compound 18d (1.12 g, 5.0 mmol), 5 mL 9 M hydrochloric acid and paraformaldehyde (751 mg, 25.0 mmol) to a 50 mL reaction bottle, and stir the reaction solution at room temperature for 24 hours. Add 18 mL of water to the reaction system, continue stirring at room temperature for 22 hours, filter the reaction solution, rinse the filter cake with 5 mL of water and 5 mL of ethanol, and dry to obtain 0.54 g of compound 18e (yield: 35%).
  • Step 5 Compound 18e (0.54 g, 1.75 mmol) was weighed into a dry reaction bottle, argon was replaced, and methanesulfonic acid (1.8 mL) was added to dissolve. Compound 1a (0.18 g, 0.584 mmol) was added at room temperature and stirred for 24 hours. The reaction solution was slowly added to 18 mL of water (cooled in an ice-water bath), and after the addition, the mixture was returned to room temperature and stirred for 10 minutes.
  • Step 6 Compound 18f (502 mg, 0.565 mmol) was weighed into a dry three-necked flask, argon was replaced, trifluoroacetic acid (5 mL) was added to dissolve, and then compound 1b (637 mg, 1.42 mmol) was added. After the addition, the reaction was heated to 70°C and stirred for 3 hours. TFA was evaporated under reduced pressure, 7.5 mL of ethanol was added to the obtained solid and heated to reflux for 1 hour, cooled to room temperature, and filtered. The filter cake was washed with ethanol and dried.
  • the obtained solid was purified by high performance liquid chromatography (mobile phase: water and acetonitrile, gradient ratio: aqueous phase 25%-42%), and then salified with sodium hydroxide to obtain 0.12 g of compound 18 (yield: 12%).
  • Step 2 Add DMSO (9.82 g, 125.69 mmol) and DCM (200 mL) to a 500 mL three-necked reaction bottle, protect with nitrogen, cool to -60 ° C, add trifluoroacetic anhydride (24.24 g, 115.40 mmol) dropwise, add the solution in DCM (8 mL) of compound 19b (3 g, 23.04 mmol) after 20 minutes of warming and stirring, add triethylamine (26.50 g, 261.87 mmol) after 1.5 hours of warming and stirring, and stir at -60 ° C for 1 hour and then warm to room temperature.
  • DMSO 9.82 g, 125.69 mmol
  • DCM 200 mL
  • Step 3 Add urea (3.17 g, 52.78 mmol), 0.3 M dilute hydrochloric acid (7.24 mL) and compound 19c (2.01 g, 15.93 mmol) to a 100 mL reaction bottle, heat to 50 ° C and stir for 16 hours. The reaction was cooled to room temperature, filtered, and the filter cake was rinsed with 10 mL of water and 10 mL of anhydrous ethanol, and dried to obtain 1.52 g of compound 19d (yield: 45%).
  • Step 5 Compound 19e (66 mg, 0.21 mmol) was weighed into a dry three-necked flask, argon was replaced, methanesulfonic acid (0.5 mL) was added to dissolve, and compound 1a (189 mg, 0.64 mmol) was added at room temperature. After stirring at room temperature for 18 hours, the reaction solution was slowly added to 5 mL of water (cooled in an ice-water bath), and the temperature was restored to room temperature after the addition. Filter, wash the filter cake with a small amount of water, dissolve the dried crude product in TFA (0.26 mL), then add 1 mL of water, and stir at room temperature for 10 minutes. Filter, wash the filter cake with a small amount of water, and vacuum dry to obtain 185 mg of compound 19f (yield: 100%).
  • Step 6 Compound 19f (204 mg, 0.24 mmol) was weighed into a dry three-necked flask, argon was replaced, TFA (2 mL) was added to dissolve, and then compound 1b (266 mg, 0.59 mmol) was added. After the addition, the reaction was heated to 70°C and stirred for 3 hours, TFA was evaporated under reduced pressure, 3 mL of ethanol was added to the obtained solid, heated to reflux (80°C) for 40 min, cooled to room temperature, and filtered.
  • Test Example 1 Test on the effect of the disclosed compound on muscle relaxant antagonism
  • the compounds provided in the present disclosure were tested for their reversal effects on the muscle relaxant effect of the gastrocnemius muscle in a rat neuromuscular model, and the onset time, TOF and other indicators were evaluated, and compared with CB2 and neostigmine.
  • SPF grade SD male rats BL-420A biological function experimental system (main unit, stimulator, tension transducer), ventilator, electronic scale, surgical instruments, syringe, hair clipper, electronic scale, iron stand, foam board, ethyl formate, sodium chloride, CB2, compound 2, compound 3, cisatracurium, succinylcholine, neostigmine, sterile water, 95% alcohol.
  • the rats were randomly divided into CB2, compound 2, compound 3, and neostigmine groups, with 4 rats in each group (based on the actual number of rats in each group), and the administration volume was 2 mL/kg.
  • the sciatic nerve and gastrocnemius were separated, the sciatic nerve was stimulated, and the muscle tension signal was recorded by the tension transducer.
  • Mechanical ventilation was given through the endotracheal intubation and a small animal ventilator.
  • the drug was given: a muscle relaxant (cisatracurium) at a dose of 2 times the ED 90 (0.8 mg/kg) was given for the first time, at which time the muscle tension curve should decrease.
  • the antagonist (test substance and neostigmine) was injected 30-60s after the administration.
  • a muscle relaxant succinylcholine
  • ED 90 0.9 mg/kg
  • the experiment can be stopped when the muscle tension naturally recovers to more than 95%.
  • the muscle tension signal was continuously recorded, and the onset time and clinical efficacy were statistically analyzed. By comparing the muscle tension signal after administration, the muscle relaxation reversal effect of the antagonist was judged and compared.
  • the rats were weighed, and when the rats were emotionally stable, 25% urethane prepared with ethyl formate was injected intraperitoneally at 1 mL/100 g for anesthesia. After the pain reflex disappeared, the rats were fixed in a prone position on a foam board, and the buttocks and outer right thigh area were depilated.
  • a muscle relaxant succinylcholine
  • ED 90 dose an ED 90 dose
  • the biofunctional experimental system was used to calculate the onset time, secondary muscle relaxant onset time and other indicators, and the statistical standards are as follows.
  • TOF recovery 90% time the time when the T 4 /T 1 value of TOF train stimulation recovers to about 90% - antagonist administration time
  • compounds 2 and 3 can reach the efficacy level of neostigmine at 20 mg/kg, which is better than CB2.
  • Test Example 2 Test of the in vitro binding activity of the disclosed compounds on muscle relaxants
  • the in vitro binding activity of the disclosed compounds with muscle relaxants was tested by isothermal titration calorimetry (ITC) to evaluate the Kd value of the binding.
  • Isothermal titration calorimeter including computer host and supporting software
  • CB2 compound 2, compound 3, compound 7, compound 12, compound 13, compound 15, cisatracurium, and deionized water.
  • the Kd value of the binding of the test compound to cisatracurium is calculated by the thermal curve.
  • the cleaning procedure cleans the pipes, sample cell and titration needle and then proceeds to the next compound test.
  • Test Example 3 Test on the effect of the disclosed compound on muscle relaxant antagonism
  • the compounds provided in the present disclosure were tested for their reversal effects on the muscle relaxant effect of the gastrocnemius muscle in a rat neuromuscular model, and the onset time, TOF and other indicators were evaluated, and compared with CB2 and neostigmine.
  • SPF grade SD male rats BL-420A biological function experimental system (main unit, stimulator, tension transducer), ventilator, electronic scale, surgical instruments, syringe, hair clipper, electronic scale, iron stand, foam board, ethyl formate, sodium chloride, CB2, compound 2, compound 3, cisatracurium, succinylcholine, neostigmine, sterile water, 95% alcohol.
  • the rats were randomly divided into CB2, compound 2, compound 15, and neostigmine groups, with 5 rats in each group (based on the actual number of rats in each group), and the administration volume was 2 mL/kg.
  • the sciatic nerve and gastrocnemius were separated, the sciatic nerve was stimulated, and the muscle tension signal was recorded by the tension transducer.
  • Mechanical ventilation was given through the endotracheal intubation and a small animal ventilator.
  • the drug was given: a muscle relaxant (cisatracurium) at a dose of 2 times the ED 90 (0.8 mg/kg) was given for the first time, at which time the muscle tension curve should decrease.
  • the antagonist (test substance and neostigmine) was injected 30-60s after the administration.
  • a muscle relaxant succinylcholine
  • ED 90 0.9 mg/kg
  • the experiment can be stopped when the muscle tension naturally recovers to more than 95%.
  • the muscle tension signal was continuously recorded, and the onset time and clinical efficacy were statistically analyzed. By comparing the muscle tension signal after administration, the muscle relaxation reversal effect of the antagonist was judged and compared.
  • the rats were weighed, and when the rats were emotionally stable, 25% urethane prepared with ethyl formate was injected intraperitoneally at 1 mL/100 g for anesthesia. After the pain reflex disappeared, the rats were fixed in a prone position on a foam board, and the buttocks and outer right thigh area were depilated.
  • a muscle relaxant succinylcholine
  • ED 90 dose an ED 90 dose
  • the biofunctional experimental system was used to calculate the onset time, secondary muscle relaxant onset time and other indicators, and the statistical standards are as follows.
  • TOF recovery 90% time the time when the T 4 /T 1 value of TOF train stimulation recovers to about 90% - antagonist administration time
  • compounds 2 and 15 can reach the efficacy level of neostigmine at 20 mg/kg, which is better than CB2.
  • Test Example 4 Test of the in vitro binding activity of the disclosed compounds on muscle relaxants
  • the in vitro binding activity of the disclosed compounds with muscle relaxants was tested by isothermal titration calorimetry (ITC) to evaluate the Kd value of the binding.
  • Isothermal titration calorimeter including computer host and supporting software
  • CB2 compound 2, compound 11, compound 15, compound 16, cisatracurium, and deionized water.
  • Prepare the aqueous solution of cisatracurium and the aqueous solution of the test compound, cisatracurium: test compound 10:1 ⁇ 20:1.
  • the Kd value of the binding of the test compound to cisatracurium is calculated by the thermal curve.
  • the cleaning procedure cleans the pipes, sample cell and titration needle and then proceeds to the next compound test.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Epidemiology (AREA)
  • Pain & Pain Management (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Neurology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Anesthesiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

本公开涉及葫芦脲类化合物及其医药用途。具体地，本公开涉及式(I)所示的化合物及其可药用盐，各取代基定义见说明书，其制备方法及含有该化合物的药物组合物以及其作为治疗剂的用途，特别是在治疗或预防增殖性疾病、心血管相关疾病或血液癌中的用途，在逆转药物诱导的神经肌肉阻滞和/或麻醉中的用途。(I)

Description

葫芦脲类化合物及其医药用途 技术领域
本公开属于医药领域，具体涉及葫芦脲类化合物及其医药用途。
背景技术
肌松是全身麻醉中三大基本要素之一。肌松药在满足气管插管和手术需要的同时也带来了安全隐患——肌松残余，这会导致患者主观上不适感受以及低氧血症、反流误吸等一系列肺部并发症。了降低肌松残余发生率，往往通过使用中短效肌松药、优化术中肌松管理、术毕拮抗肌松药效应、围术期客观肌松监测等措施，使得肌松残余这一临床难题不断取得进展。
术毕拮抗肌松，是指通过采用肌松药拮抗剂，来逆转非去极化肌松药的残留作用。目前，常用的肌松药拮抗剂大致可分为两类：一类是竞争性肌松拮抗剂，包括作为乙酰胆碱抑制剂的新斯的明等；另一类是选择性肌松拮抗剂，包括作为甾类肌松药拮抗剂的舒更葡萄钠、作为苄异喹啉类肌松药拮抗剂的半胱氨酸等。
现有技术WO2012051407A公开了一类具有葫芦脲结构的非闭合环CB[n]型的分子容器，即Calabadion2，其可与苄异喹啉类和甾类肌松药高效结合，通过覆盖苄异喹啉类和甾类肌松药的季铵位点，以阻止肌松药与神经肌肉胆碱受体的结合，从而迅速实现逆转肌松作用。
发明内容
本公开提供一种式(I)所示的化合物或其可药用盐，
其中，
R1各自独立地选自C2-6烷基、C1-6卤代烷基、C1-6羟烷基、-C(O)2R'、R'-(O)-亚烷基-、羟基、NR'(R”)、3至7元环烷基、3至7元杂环基；或者连接在相邻碳原子上的两个R1一起形成3至10元的环烷基或3至10元的杂环基；所述R1任选被一个或多个R1A取代；
R2各自独立地选自氢、C1-6烷基、C1-6卤代烷基、C1-6羟烷基、-C(O)2R'、R'-(O)-亚烷基-、羟基、NR'(R”)、3至7元环烷基、3至7元杂环基；或者连接在相邻碳原子上的两个R2一起形成3至10元的环烷基或3至10元的杂环基；所述R2任选被一个或多个R2A取代；
环A各自独立地选自5至12元的芳香基或5至12元的杂芳基；
R3各自独立地选自卤素、C1-6烷基、羟基、硝基、氰基、-C(O)2R'、NR'(R”)、R'-(O)-亚烷基-、3至7元环烷基、3至7元杂环基或且至少有一个为，所述R3任选被一个或多个R3A取代；
R4为A+为一价或二价阳离子；
R1A、R2A、R3A各自独立地选自卤素、氰基、硝基、氨基、C1-6烷基或C1-6烷氧基；
R'和R”各自独立地选自氢、C1-6烷基、C1-6羟烷基、C1-6卤代烷基、3至7元环烷基、3至7元杂环基；
m和n各自独立地选自1、2、3、4或5；
p各自独立地选自1、2、3、4、5或6。
可选的实施方案中，本公开提供的式(I)所示的化合物或其可药用盐，其中，所述环A为苯基或萘基。
可选的实施方案中，本公开提供的式(I)所示的化合物或其可药用盐，其中，所述环A为萘基。
可选的实施方案中，本公开提供的式(I)所示的化合物或其可药用盐，其为式(I-1)所示化合物或其可药用盐，
其中，R1、R2、p、m和A+如式(I)所示的化合物中定义。
在一些实施方案中，本公开提供的式(I)、(I-1)所示的化合物或其可药用盐，其中，连接在相邻碳原子上的两个R1一起形成3至10元的环烷基或3至10元的杂环基。
在一些实施方案中，本公开提供的式(I)、(I-1)所示的化合物或其可药用盐，其中，连接在相邻碳原子上的两个R1一起形成4至8元的环烷基或4至8元的杂环基。
在一些实施方案中，本公开提供的式(I)、(I-1)所示的化合物或其可药用盐， 其中，连接在相邻碳原子上的两个R1一起形成5至6元的环烷基或5至6元的杂环基。
在一些实施方案中，本公开提供的式(I)、(I-1)所示的化合物或其可药用盐，其中，连接在相邻碳原子上的两个R1一起形成6元环烷基。
在一些实施方案中，本公开提供的式(I)、(I-1)所示的化合物或其可药用盐，其中，连接在相邻碳原子上的两个R1一起形成5至6元的杂环基，其中的杂原子为氮或氧。
在一些实施方案中，本公开提供的式(I)、(I-1)所示的化合物或其可药用盐，其中，连接在相邻碳原子上的两个R1一起形成5至6元的杂环基，其中的杂原子为氧。
在一些实施方案中，本公开提供的式(I)、(I-1)所示的化合物或其可药用盐，其中，R1各自独立地为C2-6烷基。
在一些实施方案中，本公开提供的式(I)、(I-1)所示的化合物或其可药用盐，其中，R1各自独立地为乙基。
在一些实施方案中，本公开提供的式(I)、(I-1)所示的化合物或其可药用盐，其中，R1各自独立地为C1-6卤代烷基。
在一些实施方案中，本公开提供的式(I)、(I-1)所示的化合物或其可药用盐，其中，R1各自独立地为C1-3卤代烷基。
在一些实施方案中，本公开提供的式(I)、(I-1)所示的化合物或其可药用盐，其中，R1各自独立地为一个或两个或三个氟取代的甲基。
在一些实施方案中，本公开提供的式(I)、(I-1)所示的化合物或其可药用盐，其中，R1各自独立地为-C(O)2R'，所述R'和R”各自独立地选自氢、C1-6烷基、C1-6卤代烷基。
在一些实施方案中，本公开提供的式(I)、(I-1)所示的化合物或其可药用盐，其中，R1各自独立地为-C(O)2R'，所述R'选自H或C1-6烷基。
在一些实施方案中，本公开提供的式(I)、(I-1)所示的化合物或其可药用盐，其中，R1各自独立地为-C(O)2R'，所述R'选自甲基或乙基。
在一些实施方案中，本公开提供的式(I)、(I-1)所示的化合物或其可药用盐，其中，R1各自独立地为C1-6羟烷基或C1-6烷基-O-C1-6亚烷基-。
在一些实施方案中，本公开提供的式(I)、(I-1)所示的化合物或其可药用盐，其中，R1各自独立地为C1-3羟烷基或C1-3烷基-O-C1-3亚烷基-。
在一些实施方案中，本公开提供的式(I)、(I-1)所示的化合物或其可药用盐，其中，R1各自独立地为羟甲基或甲基-O-亚甲基-。
在一些实施方案中，本公开提供的式(I)、(I-1)所示的化合物或其可药用盐，其中，R1各自独立地为R'-(O)-亚烷基-，所述R'选自C1-6烷基、C1-6羟烷基、C1-6卤代烷基、3至7元环烷基、3至7元杂环基。
在一些实施方案中，本公开提供的式(I)、(I-1)所示的化合物或其可药用盐，其中，R1各自独立地为R'-(O)-亚烷基-，所述R'为C1-6烷基或C1-6卤代烷基。
在一些实施方案中，本公开提供的式(I)、(I-1)所示的化合物或其可药用盐，其中，R1各自独立地为R'-(O)-亚烷基-，所述R'为C1-3烷基。
在一些实施方案中，本公开提供的式(I)、(I-1)所示的化合物或其可药用盐，其中，R2各自独立地为氢。
在一些实施方案中，本公开提供的式(I)、(I-1)所示的化合物或其可药用盐，所述A+为一价阳离子，所述一价阳离子选自H+、Na+、K+、H4N+、Et3NH+、(HOCH2CH2)3NH+或乙二胺、哌嗪、三苯基甲基氨基甲烷的阳离子形式。
在一些实施方案中，本公开提供的式(I)、(I-1)所示的化合物或其可药用盐，所述A+为一价阳离子，所述一价阳离子选自H+、Na+或K+。
在一些实施方案中，本公开提供的式(I)、(I-1)所示的化合物或其可药用盐，所述A+为一价阳离子，所述一价阳离子为Na+。
在一些实施方案中，本公开提供的式(I)、(I-1)所示的化合物或其可药用盐，所述A+为二价阳离子，所述二价阳离子选自Ca2+、Mg2+或Zn2+。
在一些实施方案中，本公开提供的式(I)、(I-1)所示的化合物或其可药用盐，其中，p各自独立地选自2、3或4。
在一些实施方案中，本公开提供的式(I)、(I-1)所示的化合物或其可药用盐，其中，p为3。
在一些实施方案中，本公开提供的式(I)、(I-1)所示的化合物或其可药用盐，其中，m各自独立地选自2、3或4。
在一些实施方案中，本公开提供的式(I)、(I-1)所示的化合物或其可药用盐，其中，m为2。
在一些实施方案中，本公开提供的式(I)、(I-1)所示的化合物或其可药用盐，其中连接在相邻碳原子上的两个R1一起形成5元环烷基、6元环烷基或7元环烷基，例如
在一些实施方案中，本公开提供的式(I)、(I-1)所示的化合物或其可药用盐，其中连接在相邻碳原子上的两个R1一起形成6元杂环烷基，例如
在一些实施方案中，本公开提供的式(I)、(I-1)所示的化合物或其可药用盐， 其中连接在相邻碳原子上的两个R1一起形成5元杂环烷基，例如
可选的实施方案中，本公开提供的式(I)所示的化合物或其可药用盐，其为式(I-1-A)、式(I-1-B)、式(I-1-C)、式(I-1-D)或式(I-1-E)所示化合物或其可药用盐，
其中，X3各自独立地选自O、S、NH；
d各自独立地选自0、1、2、3、4、5、6、7、8；
e各自独立地选自0、1、2、3、4、5、6、7、8；
f各自独立地选自0、1、2；
g各自独立地选自0、1、2；
R1A、p如前述中定义。
在一些实施方案中，本公开提供的式(I)、式(I-1)、式(I-1-A)、式(I-1-B)、式(I-1-C)、式(I-1-D)或式(I-1-E)所示的化合物或其可药用盐，其中R1A各自独立地选自卤素、氰基、氨基、C1-6烷基或C1-6烷氧基。
在一些实施方案中，本公开提供的式(I)、式(I-1)、式(I-1-A)、式(I-1-B)、式(I-1-C)、式(I-1-D)或式(I-1-E)所示的化合物或其可药用盐，其中R1A各自独立地选自卤素、C1-6烷基或C1-6烷氧基。
在一些实施方案中，本公开提供的式(I)、式(I-1)、式(I-1-A)、式(I-1-B)、式(I-1-C)、式(I-1-D)或式(I-1-E)所示的化合物或其可药用盐，其中R1A各自独立地选自氟、氯、甲基、乙基、甲氧基、乙氧基。
本公开提供的式(I)、式(I-1)、式(I-1-A)、式(I-1-B)、式(I-1-C)、式(I-1-D)或式(I-1-E)所示的化合物或其可药用盐，其选自：


本公开另一方面提供一种式(II)所示的化合物或其可药用盐，
其中，X1、X2各自独立地选自O、S、-NH-，条件是X1、X2不同时为O；
R5各自独立地选自C1-6烷基、C1-6卤代烷基、C1-6羟烷基、-C(O)2R'、R'-(O)-亚烷基-、羟基、NR'(R”)、3至7元环烷基、3至7元杂环基；或者连接在相邻碳原子上的两个R5一起形成3至10元的环烷基或3至10元的杂环基；所述R5任选被一个或多个R5A取代；
R6各自独立地选自选氢、C1-6烷基、C1-6卤代烷基、C1-6羟烷基、-C(O)2R'、R'-(O)-亚烷基-、羟基、NR'(R”)、3至7元环烷基、3至7元杂环基；或者连接在相邻碳原子上的两个R6一起形成3至10元的环烷基或3至10元的杂环基；所述R6任选被一个或多个R6A取代；
环B选自5至12元的芳香基或5至12元的杂芳基；
R7各自独立地选自卤素、C1-6烷基、羟基、硝基、氰基、-C(O)2R'、NR'(R”)、R'-(O)-亚烷基-、3至7元环烷基、3至7元杂环基或且至少有一个为所述R7任选被一个或多个R7A取代；
R8为所述A+为一价或二价阳离子；
R5A、R6A、R7A各自独立地选自卤素、氰基、硝基、氨基、C1-6烷基或C1-6烷氧基；
R'和R”各自独立地选自氢、C1-6烷基、C1-6羟烷基、C1-6卤代烷基、3至7元环烷基、3至7元杂环基；
其中y和z各自独立地选自为1、2、3、4或5；
w选自1、2、3、4、5或6。
在一些实施方案中，本公开提供的式(II)所示的化合物或其可药用盐，其中，环B选自苯基或萘基。
在一些实施方案中，本公开提供的式(II)所示的化合物或其可药用盐，其中，环B为萘基。
在一些实施方案中，本公开提供的式(II)所示的化合物或其可药用盐，其为式(II-1)所示的化合物或其可药用盐，
其中，所述R5、R6、w、z、A+分别如式(II)所示的化合物中定义。
在一些实施方案中，本公开提供的式(II)所示的化合物或其可药用盐，其为式(II-2)所示的化合物或其可药用盐，
其中，所述R5、R6、w、z、A+分别如式(II)所示的化合物中定义。
在一些实施方案中，本公开提供的式(II)所示的化合物或其可药用盐，其为式(II-3)所示的化合物或其可药用盐，
其中，所述R5、R6、w、z、A+分别如式(II)所示的化合物中定义。
在一些实施方案中，本公开提供的式(II)、(II-1)、(II-2)、(II-3)所示的化合物或其可药用盐，所述R5各自独立地为C1-6烷基或C1-6卤代烷基。
在一些实施方案中，本公开提供的式(II)、(II-1)、(II-2)、(II-3)所示的化合物或其可药用盐，所述R5各自独立地为C1-3烷基。
在一些实施方案中，本公开提供的式(II)、(II-1)、(II-2)、(II-3)所示的化合物或其可药用盐，所述R5各自独立地为甲基。
在一些实施方案中，本公开提供的式(II)、(II-1)、(II-2)、(II-3)所示的化合物或其可药用盐，其中，所述R6各自独立地为氢。
在一些实施方案中，本公开提供的式(II)、(II-1)、(II-2)、(II-3)所示的化合物或其可药用盐，其中，A+选自一价阳离子，所述一价阳离子选自H+、Na+、K+、H4N+、Et3NH+、(HOCH2CH2)3NH+或乙二胺、哌嗪、三苯基甲基氨基甲烷的阳离子形式。
在一些实施方案中，本公开提供的式(II)、(II-1)、(II-2)、(II-3)所示的化合物或其可药用盐，其中，A+为一价阳离子，所述一价阳离子选自H+、Na+或K+。
在一些实施方案中，本公开提供的式(II)、(II-1)、(II-2)、(II-3)所示的化合物或其可药用盐，其中，A+为二价阳离子，所述二价阳离子选自Ca2+、Mg2+或Zn2+。
在一些实施方案中，本公开提供的式(II)、(II-1)、(II-2)、(II-3)所示的化合物或其可药用盐，其中，w各自独立地选自2、3或4。
在一些实施方案中，本公开提供的式(II)、(II-1)、(II-2)、(II-3)所示的化合物或其可药用盐，其中，w各自独立地为3。
在一些实施方案中，本公开提供的式(II)、(II-1)、(II-2)、(II-3)所示的化合物或其可药用盐，其中，z各自独立地选自2、3或4。
在一些实施方案中，本公开提供的式(II)、(II-1)、(II-2)、(II-3)所示的化合物或其可药用盐，其中，z各自独立地为2。
在一些实施方案中，本公开提供的式(II)、(II-1)、(II-2)、(II-3)所示的化合物或其可药用盐，其选自：

本公开另一方面提供一种式(Ⅲ)所示的化合物或其可药用盐，
其中：
XC1、X C2各自独立地选自O、S、-NH-；
RC2选自选氢、C1-6烷基、C1-6卤代烷基、C1-6羟烷基、-C(O)2R'、R'-(O)-亚烷基-、羟基、NR'(R”)、3至7元环烷基、3至7元杂环基；或者连接在相邻碳原子上的两个RC2一起形成3至10元的环烷基或3至10元的杂环基；所述RC2任选被一个或多个卤素、氰基、硝基、氨基、C1-6烷基或C1-6烷氧基取代；
环C选自6至18元的芳香基或5至18元的杂芳基；
RC3各自独立地为
RC4各自独立地为羧酸基、-羧酸根-阳离子、磷酸基、-磷酸根-阳离子、磺酸基、-磺酸根-阳离子；
L、L1、L2相同或不同，各自独立地为亚烷基或杂亚烷基，所述的亚烷基、杂亚烷基任选地被一个或多个卤素、氰基、硝基、氨基、C1-6烷基或C1-6烷氧基取代；
Rc各自独立地选自氢、卤素、氰基、硝基、氨基、C1-6烷基或C1-6烷氧基；
Ra、Rb相同或不同，各自独立地选自羧酸基、-羧酸根-阳离子、磷酸基、-磷酸根-阳离子、磺酸基、-磺酸根-阳离子；
R'、R”各自独立地选自氢、C1-6烷基、C1-6羟烷基、C1-6卤代烷基、3至7元环烷基、3至7元杂环基；
x选自1、2、3、4或5；
v各自独立地选自1、2、3、4或5；
q各自独立地选自1、2、3、4、5或6。
在一些实施方案中，本公开提供的式(Ⅲ)所示的化合物或其可药用盐，其中XC1、X C2相同且选自O、S、-NH-。在某些实施方案中，其中XC1、X C2均为O。
在一些实施方案中，本公开提供的式(Ⅲ)所示的化合物或其可药用盐，其 中L各自独立地为C1-6亚烷基。
在一些实施方案中，本公开提供的式(Ⅲ)所示的化合物或其可药用盐，其中环C选自苯环、萘环或蒽环，优选萘环或蒽环。
在一些实施方案中，本公开提供的式(Ⅲ)所示的化合物或其可药用盐，其选自式(Ⅲ-A)、式(Ⅲ-B)、式(Ⅲ-C)或式(Ⅲ-D)所示的化合物或其可药用盐，
其中：
RD各自独立地选自羧酸基、-羧酸根-阳离子、磷酸基、-磷酸根-阳离子；
RE各自独立地选自羧酸基、-羧酸根-阳离子、磷酸基、-磷酸根-阳离子、磺酸基、-磺酸根-阳离子；
r选自1、2、3；
RC2、q、x、L1、L2、Ra、Rb、Rc如前述中所定义。
在一些实施方案中，本公开提供的式(Ⅲ)、式(Ⅲ-A)、式(Ⅲ-B)、式(Ⅲ-C)或式(Ⅲ-D)所示的化合物或其可药用盐，其中L1、L2相同或不同，各自独立地为C1-6亚烷基。
在一些实施方案中，本公开提供的式(Ⅲ)、式(Ⅲ-A)、式(Ⅲ-B)、式(Ⅲ-C)或式(Ⅲ-D)所示的化合物或其可药用盐，其中RD各自独立地选自羧酸基、-羧酸根-阳离子。
在一些实施方案中，本公开提供的式(Ⅲ)、式(Ⅲ-A)、式(Ⅲ-B)、式(Ⅲ-C)或式(Ⅲ-D)所示的化合物或其可药用盐，其中RE各自独立地选自羧酸基、-羧酸根-阳离子、磺酸基、-磺酸根-阳离子。
在一些实施方案中，本公开提供的式(Ⅲ)、式(Ⅲ-A)、式(Ⅲ-B)、式(Ⅲ-C)或式(Ⅲ-D)所示的化合物或其可药用盐，其中Ra、Rb相同或不同，各自独立地选自羧酸基、-羧酸根-阳离子、磺酸基、-磺酸根-阳离子。
在一些实施方案中，本公开提供的式(Ⅲ)所示的化合物或其可药用盐，其选自式(Ⅲ-A-1)、式(Ⅲ-B-1)、式(Ⅲ-B-2)、式(Ⅲ-C-1)、式(Ⅲ-C-2)、式(Ⅲ-C-3)、式(Ⅲ-D-1)、式(Ⅲ-D-2)或式(Ⅲ-D-3)所示的化合物或其可药用盐，


其中：
a各自独立地选自1、2、3、4；
b选自1、2、3、4；
c选自1、2、3、4；
A1 +或A2 +相同或不同，各自独立地选自一价阳离子或二价阳离子；
当A1 +为一价阳离子时，s为4；
当A1 +为二价阳离子时，s为2；
当A2 +为一价阳离子时，t为8；
当A2 +为二价阳离子时，t为4；
RC2、q、x、r如前述中所定义。
在一些实施方案中，本公开提供的式(Ⅲ)、式(Ⅲ-A)、式(Ⅲ-B)、式(Ⅲ-C)、式(Ⅲ-D)、式(Ⅲ-A-1)、式(Ⅲ-B-1)、式(Ⅲ-B-2)、式(Ⅲ-C-1)、式(Ⅲ-C-2)、式(Ⅲ-C-3)、式(Ⅲ-D-1)、式(Ⅲ-D-2)或式(Ⅲ-D-3)所示的化合物或其可药用盐，其中RC2各自独立地为氢。
在一些实施方案中，本公开提供的式(Ⅲ)、式(Ⅲ-A)、式(Ⅲ-B)、式(Ⅲ-C)、式(Ⅲ-D)、式(Ⅲ-A-1)、式(Ⅲ-B-1)、式(Ⅲ-B-2)、式(Ⅲ-C-1)、式(Ⅲ-C-2)、式(Ⅲ-C-3)、式(Ⅲ-D-1)、式(Ⅲ-D-2)或式(Ⅲ-D-3)所示的化合物或其可药用盐，其中x选自2、3或4。在某些实施方案中，x选自2、3。在某些实施方案中，x为2。
在一些实施方案中，本公开提供的式(Ⅲ-A)、式(Ⅲ-B)、式(Ⅲ-C)、式(Ⅲ-D)、式(Ⅲ-A-1)、式(Ⅲ-B-1)、式(Ⅲ-B-2)、式(Ⅲ-C-1)、式(Ⅲ-C-2)、式(Ⅲ-C-3)、 式(Ⅲ-D-1)、式(Ⅲ-D-2)或式(Ⅲ-D-3)所示的化合物或其可药用盐，其中q各自独立地选自2、3或4。在某些实施方案中，q选自3、4。在某些实施方案中，q为3。
在一些实施方案中，本公开提供的式(Ⅲ-A)、式(Ⅲ-B)、式(Ⅲ-C)、式(Ⅲ-D)、式(Ⅲ-A-1)、式(Ⅲ-B-1)、式(Ⅲ-B-2)、式(Ⅲ-C-1)、式(Ⅲ-C-2)、式(Ⅲ-C-3)、式(Ⅲ-D-1)、式(Ⅲ-D-2)或式(Ⅲ-D-3)所示的化合物或其可药用盐，其中r选自2或3。在某些实施方案中，r为2。
在一些实施方案中，本公开提供的式(Ⅲ-A-1)、式(Ⅲ-B-1)、式(Ⅲ-B-2)、式(Ⅲ-C-1)、式(Ⅲ-C-2)、式(Ⅲ-C-3)、式(Ⅲ-D-1)、式(Ⅲ-D-2)或式(Ⅲ-D-3)所示的化合物或其可药用盐，其中a、b、c相同或不同，各自独立地选自1、2或3，优选地，a、b、c均为1。
在一些实施方案中，本公开提供的式(Ⅲ-A-1)、式(Ⅲ-B-1)、式(Ⅲ-B-2)、式(Ⅲ-C-1)、式(Ⅲ-C-2)、式(Ⅲ-C-3)、式(Ⅲ-D-1)、式(Ⅲ-D-2)或式(Ⅲ-D-3)所示的化合物或其可药用盐，其中A1 +、A2 +各自独立地为一价阳离子，所述一价阳离子选自H+、Na+、K+、H4N+、Et3NH+、(HOCH2CH2)3NH+或乙二胺、哌嗪、三苯基甲基氨基甲烷的阳离子形式。在某些实施方案中，所述一价阳离子选自H+、Na+或K+。在某些实施方案中，所述一价阳离子为Na+。
在一些实施方案中，本公开提供的式(Ⅲ-A-1)、式(Ⅲ-B-1)、式(Ⅲ-B-2)、式(Ⅲ-C-1)、式(Ⅲ-C-2)、式(Ⅲ-C-3)、式(Ⅲ-D-1)、式(Ⅲ-D-2)或式(Ⅲ-D-3)所示的化合物或其可药用盐，其中A1 +、A2 +各自独立地为二价阳离子，所述二价阳离子选自Ca2+、Mg2+或Zn2+。
在一些实施方案中，本公开提供的式(Ⅲ)、式(Ⅲ-A)、式(Ⅲ-B)、式(Ⅲ-C)、式(Ⅲ-D)、式(Ⅲ-A-1)、式(Ⅲ-B-1)、式(Ⅲ-B-2)、式(Ⅲ-C-1)、式(Ⅲ-C-2)、式(Ⅲ-C-3)、式(Ⅲ-D-1)、式(Ⅲ-D-2)或式(Ⅲ-D-3)所示的化合物或其可药用盐，其选自：


本公开另一方面提供一种式(Ⅳ)所示的化合物或其可药用盐，
其中，X4各自独立地选自O、S、NH；
X5各自独立地选自O、S、NH；
R9A各自独立地选自氢、卤素、氰基、硝基、氨基、羧基、巯基、C1-6烷基或C1-6烷氧基，所述的烷基、烷氧基任选地被一个或多个卤素、氰基、硝基、氨基、羧基、巯基取代；
R9B各自独立地选自氢、卤素、氰基、硝基、氨基、羧基、巯基、C1-6烷基或C1-6烷氧基，所述的烷基、烷氧基任选地被一个或多个卤素、氰基、硝基、氨基、羧基、巯基取代；
R10各自独立地选自氢、卤素、氰基、硝基、氨基、羧基、巯基、C1-6烷基或C1-6烷氧基，所述的烷基、烷氧基任选地被一个或多个卤素、氰基、硝基、氨基、羧基、巯基取代；
h各自独立地选自1、2、3、4；
R1A、d、e、f、g、p如前述中定义。
在一些实施方案中，X4同时为O。或者，在一些实施方案中，X4同时为S。或者，在一些实施方案中，X4同时为NH。
在一些实施方案中，X5同时为O。或者，在一些实施方案中，X5同时为S。 或者，在一些实施方案中，X5同时为NH。
在一些实施方案中，本公开提供的式(Ⅳ)所示的化合物或其可药用盐，其选自式(Ⅳ-A)、式(Ⅳ-B)或式(Ⅳ-C)所示的化合物或其可药用盐，
其中R9A、R9B、R10、h、p如前述中定义。
在一些实施方案中，R9A各自独立地选自氢、C1-6烷基或C1-6烷氧基。在某些具体的实施方案中，R9A各自独立地选自氢、甲基、乙基、甲氧基、乙氧基。
在一些实施方案中，R9B各自独立地选自氢、C1-6烷基或C1-6烷氧基。在某些具体的实施方案中，R9B各自独立地选自氢、甲基、乙基、甲氧基、乙氧基。
在一些实施方案中，R10各自独立地选自氢、C1-6烷基或C1-6烷氧基。在某些具体的实施方案中，R10各自独立地选自氢、甲基、乙基、甲氧基、乙氧基。
在一些实施方案中，本公开提供的式(Ⅳ)、式(Ⅳ-A)、式(Ⅳ-B)或式(Ⅳ-C)所示的化合物或其可药用盐，其选自：

本公开另一方面提供一种式(I-1)所示化合物或其可药用盐的制备方法，包括式(C)所示化合物与式(B)所示化合物酸性环境中反应的步骤，
本公开另一方面提供一种式(II-1)所示化合物或其可药用盐的制备方法，包括式(D)所示化合物与式(B)所示化合物酸性环境中反应的步骤，
本公开中提供酸性环境的试剂可选有机酸或无机酸，例如三氟乙酸。
本公开另一方面提供一种组合物，含式(I)、(I-1)、(II)、(II-1)、(II-2)、(II-3)、式(Ⅲ)、式(Ⅲ-A)、式(Ⅲ-B)、式(Ⅲ-C)、式(Ⅲ-D)、式(Ⅲ-A-1)、式(Ⅲ-B-1)、式(Ⅲ-B-2)、式(Ⅲ-C-1)、式(Ⅲ-C-2)、式(Ⅲ-C-3)、式(Ⅲ-D-1)、式(Ⅲ-D-2)或式(Ⅲ-D-3)所示的化合物或其可药用盐、同位素取代物及药学上可接受的赋形剂。
在一些实施方案中，所述的药物组合物的单位剂量为0.001mg-1000mg。
在某些实施方案中，基于组合物的总重量，所述的药物组合物含有0.01-99.99％ 的前述化合物或其可药用的盐或其同位素取代物。在某些实施方案中，所述的药物组合物含有0.1-99.9％的前述化合物或其可药用的盐或其同位素取代物。在某些实施方案中，所述的药物组合物含有0.5％-99.5％的前述化合物或其可药用的盐或其同位素取代物。在某些实施方案中，所述的药物组合物含有1％-99％的前述化合物或其可药用的盐或其同位素取代物。在某些实施方案中，所述的药物组合物含有2％-98％的前述化合物或其可药用的盐或其同位素取代物。
在某些实施方案中，基于组合物的总重量，所述的药物组合物含有0.01％-99.99％的药学上可接受的赋形剂。在某些实施方案中，所述的药物组合物含有0.1％-99.9％的药学上可接受的赋形剂。在某些实施方案中，所述的药物组合物含有0.5％-99.5％的药学上可接受的赋形剂。在某些实施方案中，所述的药物组合物含有1％-99％的药学上可接受的赋形剂。在某些实施方案中，所述的药物组合物含有2％-98％的药学上可接受的赋形剂。
本公开另一方面提供上述式(I)、式(I-1)、式(I-1-A)、式(I-1-B)、式(I-1-C)、式(I-1-D)、式(I-1-E)、式(II)、式(II-1)、式(II-2)、式(II-3)、式(Ⅲ)、式(Ⅲ-A)、式(Ⅲ-B)、式(Ⅲ-C)、式(Ⅲ-D)、式(Ⅲ-A-1)、式(Ⅲ-B-1)、式(Ⅲ-B-2)、式(Ⅲ-C-1)、式(Ⅲ-C-2)、式(Ⅲ-C-3)、式(Ⅲ-D-1)、式(Ⅲ-D-2)、式(Ⅲ-D-3)、式(Ⅳ)、式(Ⅳ-A)、式(Ⅳ-B)或式(Ⅳ-C)所示的化合物或其可药用盐、同位素取代物、组合物在制备治疗或预防疾病或病症的药物中的用途，所述的疾病或病症选自增殖性疾病、血液癌、心血管相关疾病或传染病。
本公开另一方面提供一种治疗或预防疾病或病症的方法，所述的疾病或病症选自增殖性疾病、血液癌、心血管相关疾病或传染病，给与患者上述式(I)、式(I-1)、式(I-1-A)、式(I-1-B)、式(I-1-C)、式(I-1-D)、式(I-1-E)、式(II)、式(II-1)、式(II-2)、式(II-3)、式(Ⅲ)、式(Ⅲ-A)、式(Ⅲ-B)、式(Ⅲ-C)、式(Ⅲ-D)、式(Ⅲ-A-1)、式(Ⅲ-B-1)、式(Ⅲ-B-2)、式(Ⅲ-C-1)、式(Ⅲ-C-2)、式(Ⅲ-C-3)、式(Ⅲ-D-1)、式(Ⅲ-D-2)、式(Ⅲ-D-3)、式(Ⅳ)、式(Ⅳ-A)、式(Ⅳ-B)或式(Ⅳ-C)所示的化合物或其可药用盐、同位素取代物、组合物。
本公开另一方面提供上述式(I)、式(I-1)、式(I-1-A)、式(I-1-B)、式(I-1-C)、式(I-1-D)、式(I-1-E)、式(II)、式(II-1)、式(II-2)、式(II-3)、式(Ⅲ)、式(Ⅲ-A)、式(Ⅲ-B)、式(Ⅲ-C)、式(Ⅲ-D)、式(Ⅲ-A-1)、式(Ⅲ-B-1)、式(Ⅲ-B-2)、式(Ⅲ-C-1)、式(Ⅲ-C-2)、式(Ⅲ-C-3)、式(Ⅲ-D-1)、式(Ⅲ-D-2)、式(Ⅲ-D-3)、式(Ⅳ)、式(Ⅳ-A)、式(Ⅳ-B)或式(Ⅳ-C)所示的化合物或其可药用盐、同位素取代物、组合物在制备逆转药物诱导的神经肌肉阻滞和/或麻醉的药物中的用途。
本公开另一方面提供一种逆转药物诱导的神经肌肉阻滞和/或麻醉的方法，给与患者上述式(I)、式(I-1)、式(I-1-A)、式(I-1-B)、式(I-1-C)、式(I-1-D)、式(I-1-E)、式(II)、式(II-1)、式(II-2)、式(II-3)、式(Ⅲ)、式(Ⅲ-A)、式 (Ⅲ-B)、式(Ⅲ-C)、式(Ⅲ-D)、式(Ⅲ-A-1)、式(Ⅲ-B-1)、式(Ⅲ-B-2)、式(Ⅲ-C-1)、式(Ⅲ-C-2)、式(Ⅲ-C-3)、式(Ⅲ-D-1)、式(Ⅲ-D-2)、式(Ⅲ-D-3)、式(Ⅳ)、式(Ⅳ-A)、式(Ⅳ-B)或式(Ⅳ-C)所示的化合物或其可药用盐、同位素取代物、组合物。
本公开中所述的增殖性疾病选自纤维肉瘤、粘肉肉瘤、脂肪肉瘤、软骨肉瘤、成骨肉瘤、脊索瘤、血管肉瘤、内皮肉瘤、淋巴管肉瘤、假性粘液瘤腹膜、淋巴管内膜鞘肉瘤、滑膜瘤、滑膜肉瘤、结肠肉瘤、间皮瘤、间皮瘤、乳腺癌、卵巢癌、前列腺癌、鳞状细胞癌、基底细胞癌、腺癌、头颈癌、汗腺癌、皮脂腺癌、乳头状癌、乳头状腺癌、囊状腺癌、髓样癌、支气管癌、肾细胞癌、肝癌、胆管癌、绒毛膜癌、精原细胞瘤、胚胎癌、威尔斯氏肿瘤、宫颈癌、睾丸肿瘤、肺癌、小细胞肺癌、膀胱癌、上皮癌、神经胶质瘤、星形细胞瘤、髓母细胞瘤、颅咽管瘤、室管膜瘤、松果体瘤、血管母细胞瘤尿瘤、少突胶质细胞瘤、脑膜瘤、黑色素瘤、神经母细胞瘤、视网膜母细胞瘤、白血病、淋巴瘤、多发性骨髓瘤、胸腺瘤、沃尔登斯特罗姆巨球蛋白血症和重链疾病。
本公开中所述的血液癌选自白血病、淋巴瘤和骨髓瘤。
本公开另一方面提供一种式(I)、式(I-1)、式(I-1-A)、式(I-1-B)、式(I-1-C)、式(I-1-D)、式(I-1-E)、式(II)、式(II-1)、式(II-2)、式(II-3)、式(Ⅲ)、式(Ⅲ-A)、式(Ⅲ-B)、式(Ⅲ-C)、式(Ⅲ-D)、式(Ⅲ-A-1)、式(Ⅲ-B-1)、式(Ⅲ-B-2)、式(Ⅲ-C-1)、式(Ⅲ-C-2)、式(Ⅲ-C-3)、式(Ⅲ-D-1)、式(Ⅲ-D-2)、式(Ⅲ-D-3)、式(Ⅳ)、式(Ⅳ-A)、式(Ⅳ-B)或式(Ⅳ-C)所示的化合物或其可药用盐、同位素取代物，或由前述方法制备获得化合物用做药物的用途。
本公开中所述化合物可药用盐可选自无机盐或有机盐，所述的无机盐包含但不限于Na+、K+、Ca2+、Mg2+、Zn2+；所述的有机盐包含但不限于H4N+、Et3NH+、(HOCH2CH2)3NH+或乙二胺、哌嗪、三苯基甲基氨基甲烷的阳离子形式。
本公开化合物可以存在特定的几何或立体异构体形式。本公开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公开的范围之内。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，均包括在本公开的范围之内。本公开的含有不对称碳原子的化合物可以以光学活性纯的形式或外消旋形式被分离出来。光学活性纯的形式可以从外消旋混合物拆分，或通过使用手性原料或手性试剂合成。
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。如果想得到本公开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)。
本公开所述化合物的化学结构中，键表示未指定构型，即如果化学结构中存在手性异构体，键可以为或者同时包含两种构型。
本公开的化合物和中间体还可以以不同的互变异构体形式存在，并且所有这样的形式包含于本公开的范围内。术语“互变异构体”或“互变异构体形式”是指可经由低能垒互变的不同能量的结构异构体。例如，质子互变异构体(也称为质子转移互变异构体)包括经由质子迁移的互变，如酮-烯醇及亚胺-烯胺、内酰胺-内酰亚胺异构化。内酰胺-内酰亚胺平衡实例是在如下所示的A和B之间。
本公开中的所有化合物可以被画成A型或B型。所有的互变异构形式在本发明的范围内。化合物的命名不排除任何互变异构体。
本公开还包括一些与本文中记载的那些相同的，但一个或多个原子被原子量或质量数不同于自然中通常发现的原子量或质量数的原子置换的同位素标记的本公开化合物。可结合到本公开化合物的同位素的实例包括氢、碳、氮、氧、磷、硫、氟、碘和氯的同位素，诸如分别为2H、3H、11C、13C、14C、13N、15N、15O、17O、18O、31P、32P、35S、18F、123I、125I和36Cl等。
除另有说明，当一个位置被特别地指定为氘(D)时，该位置应理解为具有大于氘的天然丰度(其为0.015％)至少1000倍的丰度的氘(即，至少10％的氘掺入)。示例中化合物的具有大于氘的天然丰度可以是至少1000倍的丰度的氘、至少2000倍的丰度的氘、至少3000倍的丰度的氘、至少4000倍的丰度的氘、至少5000倍的丰度的氘、至少6000倍的丰度的氘或更高丰度的氘。本公开还包括各种氘化形式的式(I)化合物。与碳原子连接的各个可用的氢原子可独立地被氘原子替换。本领域技术人员能够参考相关文献合成氘化形式的式(I)化合物。在制备氘代形式的式(I)化合物时可使用市售的氘代起始物质，或它们可使用常规技术采用氘代试剂合成，氘代试剂包括但不限于氘代硼烷、三氘代硼烷四氢呋喃溶液、氘代氢化锂铝、氘代碘乙烷和氘代碘甲烷等。
“任选地”或“任选”是指意味着随后所描述的事件或环境可以但不必发生，该说明包括该事件或环境发生或不发生的场合。例如“任选的被卤素或者氰基取代的 C1-6烷基”是指卤素或者氰基可以但不必须存在，该说明包括烷基被卤素或者氰基取代的情形和烷基不被卤素和氰基取代的情形。
术语解释：
“药物组合物”表示含有一种或多种本文所述化合物或其生理学上可药用的盐或前体药物与其他化学组分的混合物，以及其他组分例如生理学可药用的载体和赋形剂。药物组合物的目的是促进对生物体的给药，利于活性成分的吸收进而发挥生物活性。
“可药用赋形剂”包括但不限于任何已经被美国食品和药物管理局(FDA)批准对于人类或家畜动物使用可接受的任何助剂、载体、助流剂、甜味剂、稀释剂、防腐剂、染料/着色剂、增香剂、表面活性剂、润湿剂、分散剂、助悬剂、稳定剂、等渗剂、溶剂或乳化剂。
本公开中所述“有效量”或“有效治疗量”包含足以改善或预防医学病症的症状或病症的量。有效量还意指足以允许或促进诊断的量。用于特定患者或兽医学受试者的有效量可依据以下因素而变化：如待治疗的病症、患者的总体健康情况、给药的方法途径和剂量以及副作用严重性。有效量可以是避免显著副作用或毒性作用的最大剂量或给药方案。
前缀“Cu-v”表示后面的基团具有从u到v个碳原子。例如，“C1-6烷基”表示烷基具有1至6个碳原子，具体可以是具有1、2、3、4、5或6个碳原子的烷基。
术语“烷基”是指非支化或者支化的饱和烃链。本文中使用的烷基具有1至20个碳原子(即，C1-20烷基)、1至8个碳原子(即，C1-8烷基)、1至6个碳原子(即，C1-6烷基)，或者1至4个碳原子(即，C1-4烷基)。烷基的实例包括甲基、乙基、丙基、异丙基、正丁基、仲丁基、异丁基、叔丁基、戊基、2-戊基、异戊基、新戊基、己基、2-己基、3-己基，和3-甲基戊基。当具有特定碳原子数的烷基残基通过化学名称命名或由分子式确定时，可以包括具有该碳原子数目的所有位置的异构体；因此，例如，“丁基”包括正丁基(即，-(CH2)3CH3)、仲丁基(即，-CH(CH3)CH2CH3)、异丁基(即，-CH2CH(CH3)2)和叔丁基(即，-C(CH3)3)；以及“丙基”包括正丙基(即，-(CH2)2CH3)和异丙基(即，-CH(CH3)2)。
术语“环烷基”或“碳环”是指饱和的或者部分不饱和的环状烷基，其具有单环或者多环(包括稠合的、桥连的和螺环环系)。所述术语“环烷基”包括环烯基(即所述环状基团具有至少一个双键)。本文中使用的环状烷基具有3至20个环碳原子(即，C3-20环烷基)、3至12个环碳原子(即，C3-12环烷基)、3至10个环碳原子(即，C3-10环烷基)、3至8个环碳原子(即，C3-8环烷基)、或者3至7个环碳原子(即，C3-7环烷基)、或者3至6个环碳原子(即，C3-6环烷基)。环烷基的实例包括环丙基、环丁基、环戊基，和环己基、环己烯基、环己二烯基。所述环烷基环可以稠合于芳基或杂芳基环上，其中与母体结构连接在一起的环为环烷基，非限制性实例包括茚满基、四氢萘基、苯并环庚烷基等。
术语“杂环基”或“杂环烷基(Heterocycloalkyl)”指具有一个或多个独立地选自氮、氧、硫和磷的环杂原子的饱和或不饱和环烷基。术语“杂环基烷”包括杂环烯基(即具有至少一个双键的杂环基)、桥连杂环基、稠合杂环基和螺-杂环基。杂环基可以是单环或多环，其中多环可以是稠合的、桥连的或螺环的。含有至少一个杂原子的任何非芳族环都被认为是杂环基，与连接无关(即，可以通过碳原子或杂原子结合)。此外，术语杂环基旨在包含任何含有至少一个杂原子的非芳族环，所述环可以与芳基或杂芳基环稠合，而与分子其余部分的连接无关。本文中使用的杂环基具有3至20个环原子(即，3至20元杂环基)、3至12个环原子(即，3至12元杂环基)、3至10个环原子(即，3至10元杂环基)、3至8个环原子(即，3至8元杂环基)、3至7个环原子(即，3至7元杂环基)、3至6个环原子(即，3至6元杂环基)；具有1至5个环杂原子、1至4个环杂原子、1至3个环杂原子、1至2个环杂原子，或者1个环杂原子，所述环杂原子独立地选自氮、硫、磷或者氧。杂环基的实例包括吡咯烷基、咪唑烷基、氧杂环丁烷基、二氧戊环基、氮杂环丁烷基、四氢呋喃基、四氢呋喃基、四氢噻吩基、二氢咪唑基、二氢呋喃基、二氢吡唑基、二氢吡咯基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、高哌嗪基。
术语“杂芳基”指包含1至4个杂原子、5至14个环原子的杂芳族体系，其中杂原子选自氧、硫和氮。杂芳基优选为6至12元，更优选为5元或6元。例如。其非限制性实例包括：咪唑基、呋喃基、噻吩基、噻唑基、吡唑基、噁唑基、吡咯基、四唑基、吡啶基、嘧啶基、噻二唑、吡嗪，等等。
所述杂芳基环可以稠合于芳基、杂环基或环烷基环上，其中与母体结构连接在一起的环为杂芳基环，其非限制性实例包括：
术语“烷氧基”是指基团“烷基-O-”，其中烷基的定义如上所述。烷氧基的实例包括甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、叔丁氧基、仲丁氧基、正戊氧基、正己氧基，和1,2-二甲基丁氧基。
术语“卤代烷基”是指如上定义的无支链或支链的烷基，其中一个或多个氢原子被卤素代替。例如，当一个残基取代有多于一个卤素，其可通过使用对应于连接的卤素部分的数目的前缀来提及。二卤代烷基和三卤代烷基是指取代有两个或三个卤素基团的烷基，它们可为，但不必须为，相同的卤素。卤代烷基的实例包括二氟甲基(-CHF2)和三氟甲基(-CF3)。
术语“卤代烷氧基”是指如上所定义的烷氧基，其中一个或者多个氢原子被卤素替代。
术语“羟烷基”是指被一个或者多个羟基取代的烷基，烷基如上述定义。
“一价基团”是指一个化合物从“形式上”消除一个单价的原子或基团。“亚基”则是指化合物从“形式上”消除两个单价或一个双价形成的原子或原子团。
术语“亚烷基”表示烷烃分子中去除2个氢原子后余下的部分，包括1至20个碳原子的直链和支链亚基团。含有1至6个碳原子的亚烷基，非限制性实施例包括亚甲基(-CH2-)、亚乙基(如-CH2CH2-或-CH(CH3)-)。如无特殊说明，亚烷基可以是取代的或未取代的。在本文的任何上下文中使用的亚烷基任选以与烷基相同的方式被取代。
术语“杂亚烷基”指亚烷基中的一个或多个-CH2-被选自N、O和S的杂原子所替代；其中所述的亚烷基如上所定义；杂亚烷基可以是取代的或非取代的。如无特殊说明，杂亚烷基可以是取代的或未取代的。在本文的任何上下文中使用的杂亚烷基任选以与烷基相同的方式被取代。
术语“羟基”指-OH基团。
术语“卤素”指氟、氯、溴或碘。
术语“氰基”指-CN。
术语“硝基”指-NO2。
术语“氧代”指＝O取代基。
“取代的”指基团中的一个或多个氢原子，优选为最多5个，更优选为1～3个氢原子彼此独立地被相应数目的取代基取代。不言而喻，取代基仅处在它们的可能的化学位置，本领域技术人员能够在不付出过多努力的情况下确定(通过实验或理论)可能或不可能的取代。
附图说明
图1.顺阿曲库铵拮抗后给与拮抗剂的TOF0.9比较；
图2.化合物在20mpk时的TOF0.9比较。其中，*代表p＝0.05；
图3.顺阿曲库铵给与肌松药拮抗剂的TOF0.9时间，其中*p<0.05,**p<0.01,***p<0.001。
具体实施方式
以下结合实施例进一步描述本公开，但这些实施例并非限制着本公开的范围。
本公开实施例中未注明具体条件的实验方法，通常按照常规条件，或按照原料或商品制造厂商所建议的条件。未注明具体来源的试剂，为市场购买的常规试剂。
化合物的结构是通过核磁共振(NMR)或/和质谱(MS)来确定的。NMR位移(δ)以10-6(ppm)的单位给出。NMR的测定是用Bruker AVANCE-400核磁仪，测定溶 剂为氘代二甲基亚砜(DMSO-d6)，氘代氯仿(CDCl3)，氘代甲醇(CD3OD)，内标为四甲基硅烷(TMS)。
MS的测定用Shimadzu 2010Mass Spectrometer或Agilent 6110A MSD质谱仪。
HPLC的测定使用Shimadzu LC-20A systems、Shimadzu LC-2010HT series或安捷伦Agilent 1200LC高压液相色谱仪(Ultimate XB-C18 3.0*150mm色谱柱或Xtimate C18 2.1*30mm色谱柱)。
手性HPLC分析测定使用Chiralpak IC-3 100×4.6mm I.D.,3um、Chiralpak AD-3 150×4.6mm I.D.,3um、Chiralpak AD-3 50×4.6mm I.D.,3um、Chiralpak AS-3 150×4.6mm I.D.,3um、Chiralpak AS-3 100×4.6mm I.D.,3μm、ChiralCel OD-3 150×4.6mm I.D.,3um、Chiralcel OD-3 100×4.6mm I.D.,3μm、ChiralCel OJ-H 150×4.6mm I.D.,5um、Chiralcel OJ-3 150×4.6mm I.D.,3um色谱柱；
薄层层析硅胶板使用烟台黄海HSGF254或青岛GF254硅胶板，薄层色谱法(TLC)使用的硅胶板采用的规格是0.15mm～0.2mm，薄层层析分离纯化产品采用的规格是0.4mm～0.5mm。
柱层析一般使用烟台黄海硅胶100～200目、200～300目或300～400目硅胶为载体。
手性制备柱使用DAICEL CHIRALPAK IC(250mm*30mm,10um)或Phenomenex-Amylose-1(250mm*30mm,5um)。
CombiFlash快速制备仪使用Combiflash Rf150(TELEDYNE ISCO)。
本公开的已知的起始原料可以采用或按照本领域已知的方法来合成，或可购买自ABCR GmbH&Co.KG，Acros Organics，Aldrich Chemical Company，韶远化学科技(Accela ChemBio Inc)、达瑞化学品等公司。
实施例中无特殊说明，反应能够均在氩气氛或氮气氛下进行。
氩气氛或氮气氛是指反应瓶连接一个约1L容积的氩气或氮气气球。
氢气氛是指反应瓶连接一个约1L容积的氢气气球。
加压氢化反应使用Parr 3916EKX型氢化仪和清蓝QL-500型氢气发生器或HC2-SS型氢化仪。
氢化反应通常抽真空，充入氢气，反复操作3次。
微波反应使用CEM Discover-S 908860型微波反应器。
实施例中无特殊说明，溶液是指水溶液。
实施例中无特殊说明，反应的温度为室温，为20℃～30℃。
实施例中的反应进程的监测采用薄层色谱法(TLC)，反应所使用的展开剂，纯化化合物采用的柱层析的洗脱剂的体系和薄层色谱法的展开剂体系，溶剂的体积比根据化合物的极性不同而进行调节，也可以加入少量的三乙胺和醋酸等碱性或酸性试剂进行调节。
实施例1.化合物2的制备
步骤1：向500mL三口瓶中加入尿素(38.89g，647.46mmol)、0.3M的稀盐酸(80mL)和1,2-环己二酮2a(22.0g,196.20mmol)，加热至50℃搅拌16小时。反应冷却至室温，过滤，滤饼用100mL水淋洗，100mL无水乙醇淋洗，干燥，得化合物2b(浅黄色体，27.4g，产率：71％)。
MS m/z(ESI):197.1[M+1]+。
1H NMR(400MHz,DMSO-d6):δ7.02(s,4H),1.72-1.68(m,4H),1.42-1.35(m,4H)。
步骤2：向1L三口瓶中加入化合物2b(27.4g,139.65mmol)、140mL 9M的盐酸和多聚甲醛(20.9g，698.23mmol)，反应液室温搅拌24小时，向反应体系中加入500mL水，室温搅拌继续16小时，将反应液过滤，洗涤，干燥，得到化合物2c(白色固体，20.2g,收率：52％)。
MS(ESI):281.1[M+1]+。
1H NMR(400MHz,DMSO-d6):δ5.20(d,4H,J＝11.6),4.91(d,4H,J＝11.2),2.25-2.18(m,4H),1.56-1.50(m,4H)。
步骤3：将化合物2c(2.73g,9.73mmol)称入干燥三口烧瓶中，置换氩气， 加入甲磺酸(10mL)溶解，加入化合物1a(1g，3.24mmol，采用公知的方法“WO2012/051407A”制备而得)后室温搅拌反应24小时，将反应液慢慢加入100mL水中(冰水浴冷却)，加完后恢复到室温。过滤。干燥得粗品产物1.77g，将上述粗产物加热溶于TFA中(4mL)，然后加入16mL水，搅拌，过滤，真空干燥得到化合物2d(1.21g，产率：44.9％)。
MS(ESI):837.3[M+1]+。
1H NMR(400MHz,CDCl3):δ5.72～5.37(m,10H),5.15(d,4H),4.75(d,4H),4.15～4.11(m,6H),2.28(br,4H),2.05(br,4H),1.45(br,8H)。
步骤4：将化合物2d(1.06g,1.27mmol)称入干燥三口烧瓶中，置换氩气，加入TFA(10mL)溶解，然后加入化合物1b(1.42g,3.17mmol，采用公知的方法“WO2012/051407A”制备而得)。加完后将反应加热到60℃搅拌反应3小时。减压蒸掉TFA，向所得固体中加入20mL乙醇加热回流2小时，冷到室温，过滤。滤饼用乙醇洗涤，干燥，所得固体用10mL水加热溶解，然后加入30mL乙醇，，过滤，，接着滤饼用高效液相色谱法(色谱柱：SharpSil-T，30*150mm，5μm；流动相：水相和乙腈，梯度配比：水相25％-42％)纯化，最后用氢氧化钠成盐得到化合物2(0.27g，产率：12.6％)。
MS m/z(ESI):1605.2[M-4Na+5H]+。
1H NMR(400MHz,D2O):δ7.68～7.65(m,4H),7.07～7.05(m,4H),5.50～5.45(m,6H),5.26～5.16(m,8H),4.39(d,4H),4.17～4.05(m,8H),3.94～3.82(m,6H),3.20～3.04(m,8H),2.26～2.07(m,16H),1.46(br s,8H)。
实施例2.化合物3的制备

步骤1：将尿素(12g，0.2mol)溶于0.3M HCl(30mL)中，室温下加入化合物3a(6.97g，0.061mol)，随后室温搅拌24小时；过滤，洗涤，干燥得到标题产物3b(6.8g，产率：56.2％)。
步骤2：将底物3b(3.4g，17.2mmol)称入干燥三口烧瓶中，加入2.54克的多聚甲醛和9M HCl(15mL)，室温下搅拌24小时，反应在室温下继续搅拌24小时，过滤，洗涤，干燥得到标题产物3c(2.1g，产率：43.2％)。
MS m/z(ESI):283.1[M+1]+。
1H NMR(400MHz,DMSO-d6):δ5.21(d,4H),4.93(d,4H)，2.33(q,4H),0.91(d,6H)。
步骤3：将化合物3c(2.75g,，9.73mmol)用甲磺酸(10mL)溶解，加入化合物1a(1g，3.24mmol)后室温搅拌反应18小时，将反应液慢慢加入100mL水中(冰水浴冷却)，加完后恢复到室温。过滤。干燥得粗品产物1.67g。将上述粗产物加热溶于TFA中(4mL)，然后加入16mL水，下搅拌，过滤，真空干燥得到标题产物3d(类白色固体，1.56g，产率：57.3％)。
MS m/z(ESI):833.2[M+1]+。
1H NMR(400MHz,DMSO-d6):δ5.68(d,2H),5.53(t,6H)，5.38(d,2H),5.15(d,4H),4.77(d,4H),4.20～4.15(m,6H),2.35～2.32(m,4H),2.20～2.15(m,4H),0.88～0.80(m,12H)。
步骤4：将3d(0.89g,1.06mmol)称入干燥三口烧瓶中，置换氩气，加入TFA(10mL)溶解，然后加入化合物1b(1.19g，2.66mmol)，加完后将反应加热到70℃搅拌反应3小时，减压蒸掉TFA，向所得固体中加入20mL乙醇加热回流2小时，冷到室温，过滤，干燥。所得固体用6.6mL水加热溶解，然后加入19.8mL 乙醇，，过滤，洗涤，着滤饼用高效液相色谱法(色谱柱：SharpSil-T，30*150mm，5μm；流动相：水相和乙腈，梯度配比：水相25％-42％)纯化，最后用氢氧化钠成盐得到标题产物3(0.28g，产率：15.5％)。
MS(ESI):1607.4[M-4Na+3H]-。
1H NMR(400MHz,D2O):δ7.41～7.39(m,4H),6.81～6.80(m,4H),5.46(d,4H),5.38(d,2H),5.30(d,4H),5.20(d,2H),5.08(d,2H),4.38(d,4H),4.09～4.01(m,8H),3.84～3.76(m,6H),3.19～3.02(m,8H),2.36～2.18(m,16H),0.88(t,6H),0.82(t,6H)。
实施例3.化合物1的制备
实施例4.化合物4的制备

实施例5.化合物5的制备
实施例6.化合物6的制备

实施例7.化合物7的制备
实施例8.化合物8的制备

实施例9.化合物9的制备
实施例10.化合物10的制备

实施例11.化合物11的制备
步骤1：将1,4-二羟基萘(1g，6.24mmol)溶于10％的NaOH水溶液(8mL)中,氮气置换后滴加化合物11a(2.14g,15.6mmol)的二氧六环溶液(12mL)。反 应室温搅拌过夜。反应液旋干，反相制备纯化得白色固体化合物11b(0.8g，产率：26％)。
MS m/z(ESI):433.1[M-2Na+3H]+。
1H NMR(400MHz,DMSO-d6):δ8.12～8.10(m,2H),7.53～7.51(m,2H),6.84(s,2H),4.07(t,4H),2.55～2.49(m,4H),1.91～1.79(m,8H)。
步骤2：将化合物11b(520mg,1.09mmol)加入TFA(10mL)溶解，然后加入化合物2d(364mg,0.44mmol)。加完后将反应体系加热到70℃搅拌反应2小时。减压蒸掉TFA，所得固体过柱纯化(色谱柱：SharpSil-T，30×150mm，5μm；流动相：水相和乙腈，梯度配比：水相25％-42％)得到192mg白色固体，该固体用2mL水溶解，然后用0.5M氢氧化钠水溶液将体系pH值调为5～8，加入10mL乙醇，析出固体，过滤得白色固体化合物11(120mg，产率：16.5％)。
MS m/z(ESI):1678.3[(M-4Na+4H+18)]+。
1H NMR(400MHz,D2O):δ7.87～7.81(m,4H),7.44～7.36(m,4H),5.53～5.46(m,7H),5.31～5.23(m,9H),4.30(d,3H),4.12～3.94(m,9H),3.78～3.76(m,4H),2.87～2.82(m,8H),2.05～1.80(m,24H),1.38～1.25(m,8H)。
实施例12.化合物12的制备
步骤1：将化合物12a(10.85g，51.6mmol，采用与实施例1中化合物2b相同的制备方法制备而得)称入干燥三口烧瓶中，加入7.75克的多聚甲醛和9M HCl(45mL)，室温下搅拌24小时。补加163毫升的水，反应在室温下继续搅拌24小时；过滤，滤饼用水(60mL)和乙醇(60mL)洗涤，干燥得到10.84g米白色固体化合物12b(产率：71.4％)。
MS m/z(ESI):295.1[M+1]+。
1H NMR(400MHz,DMSO-d6):δ5.21(d,4H,J＝11.3Hz),4.93(d,4H,J＝11.3Hz)，2.34(br,4H),1.48(br,6H)。
步骤2：将化合物12b(2.00g,6.80mmol)称入干燥三口烧瓶中，置换氩气，加入甲磺酸(7mL)溶解；室温下(23℃)加入化合物1a(0.70g,2.27mmol,采用公知的方法“WO2012/051407A2”制备而得)。室温搅拌反应18小时后，将反应液慢慢加入70mL水中(冰水浴冷却)，加完后恢复到室温。过滤，滤饼用少量水洗。干燥得粗品产物1.97g。将上述粗产物溶于TFA中(6mL，23℃)，然后加入24mL水，23℃下搅拌30分钟。过滤，滤饼用少量水洗，真空干燥得到1.75g类白色固体化合物12c(产率：81.7％)。
MS m/z(ESI):861.3[M+1]+。
1H NMR(400MHz,DMSO-d6):δ5.50～5.41(m,10H),5.16(d,4H,J＝10.7Hz)，4.76(d,4H,J＝10.6Hz),4.22～4.15(m,6H),2.40(br,4H),2.22(br,4H),1.45～1.26(m,12H)。
步骤3：将化合物12c(1.00g,1.16mmol)称入干燥三口烧瓶中，置换氩气，加入TFA(10mL)溶解，然后加入化合物1b。加完后将反应加热到60℃搅拌反应3小时。减压蒸掉TFA，向所得固体中加入20mL乙醇加热回流2小时，冷到室温，过滤。滤饼用乙醇洗涤，干燥。所得固体用高效液相色谱法(流动相：水相和乙腈，梯度配比：水相25％-42％)纯化，最后用氢氧化钠成盐得到0.12g白色固体化合物12。
MS m/z(ESI):1649.1[M-4Na+4H+NH4]+。
1H NMR(400MHz,D2O):δ8.04(br,4H),7.64(br,4H),5.68～5.59(m,7H),5.42～5.39(m,4H),5.30～5.26(m,4H),4.44～4.39(m,3H),4.22～4.07(m,10H),3.93～3.91(m,4H),3.28～3.13(m,8H),2.44～2.22(m,16H),1.61～1.34(m,12H)。
实施例13.化合物13的制备

步骤1：在三口瓶里加入DMSO(50mL)，加入KOH(8.75g，156mmol)，超声混合液让KOH分散在DMSO中，然后用氮气置换其中的空气，然后室温搅拌一个小时。化合物13a(5g,31.25mmol)和化合物13b(24.3g,125mmol)分别慢慢地加到反应液里。反应加热至60℃搅拌2小时。等到反应冷却至室温，加入200mL水，用二氯甲烷萃取(50mL×3)。合并的有机相用饱和食盐水洗(100mL)，干燥，过滤，溶剂旋干。粗产品过柱(PE:EA＝5:1)得4.56g红色固体化合物13c(产率：38％)。
MS m/z(ESI):389.2[M+1]+。
1H NMR(400MHz,CDCl3):δ8.20(q,2H),7.49(q,2H),6.67(s,2H),4.18-4.12(m,8H),2.61(t,4H),2.27-2.20(m,4H),1.25(t,6H)。
步骤2：将化合物13c(3.50g,9.02mmol)称入干燥三口烧瓶中，置换氮气，加入TFA(20mL)溶解，然后加入化合物2d(3.00g,3.61mmol)和乙酸酐(918mg,9.02mmol)。加完后将反应加热到70℃搅拌反应4小时。减压蒸掉TFA，向所得固体中加入50mL甲基叔丁基醚，加热到50℃搅拌半小时，冷到室温，过滤。滤饼用甲基叔丁基醚洗涤，干燥得到4.2g棕色固体化合物13d。
MS m/z(ESI):1590.3[M+18]+。
步骤3：将化合物13d(2.0g,1.27mmol)加入50mL单口瓶中，加入甲醇和水(1：1，30mL)、LiOH.H2O(534mg,12.7mmol)使其溶解。加完后将反应加热到80℃搅拌反应3小时。减压蒸掉溶剂，加入乙醇和水(10:1,20mL)室温搅拌半小时，过滤。滤饼用乙醇洗涤，干燥。所得固体用水、NaOH(1M)使其溶解，然后用高效液相色谱法(流动相：水相和乙腈，梯度配比：水相25％-42％)纯化，最后用氢氧化钠成盐得到114mg白色固体化合物14(产率：6.15％)。
MS m/z(ESI):1478.2[M-4Na+4H+NH4]+。
1H NMR(400MHz,D2O):δ7.87(br,4H),7.46(br,4H),5.55～5.44(m,6H),5.29～5.13(m,8H),4.20-3.92(m,14H),3.69(br,4H),2.19～1.90(m,24H),1.34(br,8H)。
实施例14.化合物14的制备
步骤1：在三口瓶里加入化合物E1(25g,96mmol)和无水THF(70mL)，然后用氮气置换其中的空气，然后用干冰丙酮浴冷却至-78℃，接着慢慢滴加DIBAL-H(135mL,202mmol，1.5M甲苯),滴毕，升温到0℃，反应在0℃搅拌45分钟。然后在0℃下滴加HCl(1M,500mL)淬灭反应，加入200mL乙酸乙酯，用乙酸乙酯萃取(50mL×3)。合并的有机相用饱和食盐水洗(100mL)，干燥，过滤，溶剂旋干。粗产品过柱(PE:EA＝5:1)得15.8g淡黄色油状物化合物E2(产率：71.5％)。
1H NMR(400MHz,CDCl3):δ3.77-3.75(m,2H),3.62-3.53(m,4H),2.46(br,1H),2.29-2.22(m,1H)。
步骤2：将化合物E2(7g,30.4mmol)，化合物13a(1.62g,10.1mmol)和MeSO3H(1.4mL)称入干燥三口烧瓶中，置换氮气，将反应加热到100℃搅拌3小时。冷却到室温，然后将反应液倒入冰水中，用乙酸乙酯萃取(50mL×3),合并的有机相依次用NaHCO3溶液和饱和食盐水洗，干燥，过滤，溶剂旋干。粗产品过柱(PE:EA＝50:1)得2.74g淡黄色固体化合物E3(产率：46％)。
1H NMR(400MHz,CDCl3):δ8.16(q,2H),7.54(q,2H),6.74(s,2H),4.23(d,4H),3.81-3.71(m,8H),2.73-2.70(m,2H)。
步骤3：将化合物E3(5.0g,8.56mmol)称入干燥单口烧瓶中，置换氮气， 加入DMSO(60mL)溶解，然后加入NaCN(4.2g,85.6mmol)。加完后将反应加热到75℃搅拌反应1小时。把反应液倒入冰水中，大量固体析出，过滤。所得固体中加入乙酸乙酯，室温搅拌半小时，过滤，干燥得2.33g白色固体化合物E(产率：73.5％)。
MS m/z(ESI):390[M+18]+。
步骤4：将化合物E(2.1g,5.64mmol)称入一个封管中，加入HCl/EtOH(75mL,10M)没有完全溶解，将反应加热到90℃搅拌24小时。溶剂旋干。粗产品过柱(PE:EA＝5:1)得1.08g无色油状物化合物14a(产率：34.2％)。
MS m/z(ESI):561[M+1]+。
1H NMR(400MHz,CDCl3):δ8.16(q,2H)，7.50(q,2H)，6.67(s,2H)，4.16-4.11(m,12H)，3.00-2.95(m,2H)，2.72-2.54(m,8H)，1.23(t,12H)。
步骤5：将化合物14a(1.4g,2.50mmol)称入干燥三口烧瓶中，置换氮气，加入TFA(5mL)溶解，然后加入化合物2d(520mg,0.625mmol)和乙酸酐(5mL)。加完后将反应加热到90℃搅拌反应4小时。减压蒸掉TFA，向所得固体中加入50mL甲基叔丁基醚，加热到50℃搅拌半小时，冷到室温，过滤。滤饼用甲基叔丁基醚洗涤，干燥得到1.2g棕色固体。所得固体加入乙腈溶解。然后用高效液相色谱法(流动相：水相和乙腈，梯度配比：水相25％-42％)纯化，得到170mg白色固体化合物14b(产率：3.55％)。
MS m/z(ESI):1934[M+18]+。
步骤6：将化合物14b(150mg,0.078mmol)称入一个25mL单口瓶中，加入甲醇和水(1：1，10mL)不能溶解，然后加入LiOH.H2O(534mg,12.7mmol)。加完后将反应加热到80℃搅拌反应3小时。反应液用高效液相色谱法(流动相：水相和乙腈，梯度配比：水相25％-42％)纯化，最后用氢氧化钠成盐得到53mg白色固体化合物14(产率：40％)。
MS m/z(ESI):1710[M-8Na+8H+NH4]+。
1H NMR(400MHz,D2O):δ7.80-7.97(m,4H),7.39-7.38(m,4H),5.50-5.46(m,6H),5.34(s,4H),4.96(d,4H),4.50(d,4H),4.11-3.95(m,10H),3.69-3.67(m,4H),2.69-2.47(m,12H),2.37-2.32(m,8H),2.18(s,4H),1.94(s,4H),1.44(s,8H)。
实施例15.化合物15的制备

步骤1：向三口瓶中加入化合物E3(2.25g，3.83mmol)和亚硫酸钠(4.91g,38.9mmol),用氮气置换其中的空气，然后加入42mL异丙醇和42mL水。反应加热至100℃搅拌24小时。反应冷却至室温，浓缩得到粗品，再加入83mL甲醇，打浆搅拌1小时，过滤，收集所得固体，送HPLC制备，得1.62g白色固体化合物15a(产率：64％)。
MS m/z(ESI):331.8[M/2+1]+。
1H NMR(400MHz,D2O):δ8.23～8.22(m,2H),8.57～7.55(m,2H),6.90～6.88(m,2H),4.40～4.39(m,4H),3.33～3.31(m,8H),2.94～2.92(m,2H)。
步骤2：将化合物15a(1.57g,2.37mmol)称入干燥三口烧瓶中，置换氩气，加入TFA(15mL)溶解，然后加入化合物2d(0.79g,0.95mmol)。加完后将反应加热到70℃搅拌反应3小时。减压蒸掉TFA，向所得固体中加入40mL乙醇加热回流2小时，冷到室温，过滤。滤饼用乙醇洗涤，干燥。所得固体用12mL水溶解，然后用1M氢氧化钠水溶液将体系pH值调为约为7，加入50mL乙醇，析出粘稠物，倒掉上清液，残余物旋干，然后用高效液相色谱法(流动相：水相和乙腈，梯度配比：水相25％-42％)纯化，最后用氢氧化钠成盐得到299mg白色固体化合物15(产率：12％)。
MS m/z(ESI):990.6[(M-8Na+8H)/2]+。
1H NMR(400MHz,D2O):δ7.96～7.93(m,4H),7.32～7.33(m,4H),5.57～5.44(m,6H),5.35～5.31(m,4H),5.09～5.05(m,4H),4.54～4.50(m,4H),4.27～4.23(m,4H),4.10～4.01(m,10H),3.52～3.31(m,16H),2.98～2.92(m,4H),2.19～2.17(m,4H),2.01～1.98(m,4H),1.47～1.45(m,8H)。
实施例16.化合物16的制备
步骤1：将1,4-二羟基萘(2.00g,12.49mmol)，1,2-二溴乙烷(23.46g,124.87mmol,10.76mL)和18-冠-6(165.02mg,624.34μmol)溶于乙腈(40mL)。反应液置换氮气3次，加热至70℃反应2天。等反应液冷却到室温，过滤，滤液浓缩得到粗品，过柱(PE:PA＝50:1)纯化得到化合物16a(1.6g,产率:34.25％)。
1H NMR(400MHz,CDCl3):δ8.27～8.25(m,2H),7.55～7.52(m,2H),6.69(s,2H),4.42(t,4H),3.76(t,4H)。
步骤2：向三口瓶中加入化合物16a(800mg，2.14mmol)和亚硫酸钠(593mg,4.70mmol)，用氮气置换其中的空气，然后加入6mL DMF和6mL水。反应加热至100℃搅拌24小时。反应液冷到室温，过滤，滤液倒进60毫升的丙酮里，有沉淀析出，过滤得到880毫克淡黄色固体。粗品用2毫升水溶解，慢慢滴加乙醇(10毫升)，有大量固体析出，过滤，固体抽干得570mg白色固体化合物16b(产率：63％)。
MS m/z(ESI):393.8[M-2Na+2H+18]+。
步骤3：将化合物16b(570mg,1.36mmol)称入干燥三口烧瓶中，置换氩气，加入TFA/Ac2O(1:1,10mL)溶解，然后加入化合物2d(452mg,0.54mmol)。加完后将反应加热到70℃搅拌反应2小时。减压浓缩、过柱纯化(流动相：水相和乙腈，梯度配比：水相25％-42％)得到157毫克白色固体，用2mL水溶解，然后用0.5M氢氧化钠水溶液将体系pH值调为7左右，加入10mL乙醇，过滤得到116mg白色固体化合物16(产率：13.8％)。
MS m/z(ESI):774.4[M/2-4Na+5H]+。
1H NMR(400MHz,D2O):δ7.76～7.74(m,4H),7.01～6.99(m,4H),5.52～5.46(m, 6H),5.29～5.17(m,8H),4.48-4.36(m,8H),4.18～4.06(m,8H),3.95(d,2H),3.46(t,8H),2.15～2.07(m,8H),1.52～1.39(m,8H)。
实施例17.化合物17的制备
步骤1：于100mL三口瓶中依次加入锌粉(3.720g,56.9mmol)和乙酸(20ml)，氮气置换三次，随后一次性加入化合物17a(0.980g,5.69mmol)，室温搅拌5-10分钟。中控显示反应完毕，反应液过滤，滤饼用15mL乙酸淋洗，滤液减压浓缩，所得固体用50mL的乙酸乙酯溶解，用20ml饱和食盐水洗涤，无水硫酸钠干燥，过滤、浓缩得到0.982g化合物17b(收率：99％，纯度95.8％)。
MS-ESI:m/z 175.1[M+H]+。
步骤2：于50mL三口瓶中依次加入氢氧化钠(0.370g,9.24mmol)和水(3.3ml)，氮气置换三次，待搅拌溶解后加入化合物17b(0.7g,4.02mmol)，冰水浴冷却。然后滴加1,3-丙烷磺内酯(1.030g,9.24mmol)的二氧六环(8.4ml)溶液，滴毕恢复至室温继续搅拌19h。中控显示原料反应完全。反应液过滤，滤饼依次用二氧六环/水(5mL/1mL)混合溶剂和二氧六环(5mL)淋洗。然后滤饼经甲苯(15mL×3)浓缩，得到0.830g化合物17c(收率：44.6％，纯度：99.7％)。
MS-ESI:m/z 418.9[M-2Na+3H]+。
1H NMR(400MHz,D2O)：δ8.01(d,J＝8.4Hz,1H),7.89(s,1H),7.37-7.35(m, 1H),6.80-6.73(m,2H),4.16-4.13(m,4H),3.10-3.06(m,4H),2.42(s,3H)2.25-2.17(m,4H)。
步骤3：于50mL单口瓶中依次加入化合物17c(0.416g,0.9mmol)，TFA(6mL)和化合物2d(0.3g,0.36mmol)，氮气置换三次，油浴加热至70℃，反应3h。中控显示反应完毕，停止反应。反应液冷却至室温，浓缩得固体，加入15mL乙醇并搅拌10min，过滤，滤饼乙醇(10mL)淋洗，得到822mg粗品化合物17d(收率：35.7％，纯度：97.7％)。
MS-ESI:m/z 1650.4[M+18]+。
步骤4：于100mL单口瓶中依次加入化合物17d(0.210g,0.128mmol)，THF(4mL)，用0.5N的氢氧化钠水溶液调节溶液pH到7，随后滴加乙醇(12mL)，析出固体。过滤，滤饼用乙醇(5mL)淋洗，所得滤饼冻干得到0.153g化合物17(收率：69.2％，纯度：98.02％)。
MS-ESI:m/z 1650.3[M-4Na+18]+。
1H NMR(400MHz,DMSO-d6)：δ7.78-7.71(m,4H),7.53-7.52(m,2H),5.59-5.24(m,14H),4.33-3.72(m,18H),2.78-2.62(m,14H),2.44-1.86(m,17H),1.46-1.23(m,9H)。
实施例18.化合物18的制备
步骤1：将化合物18a(338mg,3.43mmol，采用公知方法制备而得，Journal of the American Chemical Society,1996,vol.118,#34,p.7946–7968)加入叔丁醇2mL搅拌溶解，接着加入N-甲基吗啡啉氧化物(803.4mg，6.86mmol)、锇酸钾二水合物(25.3mg，68.6μmol)，加完后室温反应16小时，中控显示反应完毕。加入亚硫酸钠水溶液5mL淬灭反应，乙酸乙酯萃取(20ml×5次)，合并有机相，无水硫酸钠干燥，过滤，浓缩后粗品用柱层析(PE:EA＝1:1)分离得到197mg化合物18b(收率：40％)。
1H NMR(400MHz,CDCl3):δ3.83(s,2H),2.89(s,2H),1.97～1.90(m,2H),1.77～1.72(m,2H),1.51～1.45(m,2H),0.87～0.82(m,6H)。
步骤2：向500mL三口反应瓶中加入DMSO(12.22g，156.41mmol)和DCM(310mL)，氮气保护，降温至-60℃，滴加三氟乙酸酐(29.15g，138.77mmol)，约25分钟滴加完毕，保温搅拌20分钟后加入化合物18b(5.1g，35.36mmol)的DCM(15mL)溶液，保温搅拌1.5小时后加入三乙胺(32.67g，322.86mmol)，-60℃搅拌1小时后升到室温搅拌。中控显示反应完毕，反应体系加入324mL 10％的盐酸，分液，水相用DCM(100mL×2)萃取，合并有机相，无水硫酸钠干燥，浓缩后粗品用柱层析(PE:EA＝10:1)分离得到3.715g化合物18c(收率：75％)。
MS m/z(ESI):141.1[M+H]+。
1H NMR(400MHz,CDCl3):δ6.06(d,1H),5.90(s,1H),2.65-2.57(m,1H),2.47-2.34(m,3H),1.06(d,3H),1.00(d,3H)。
步骤3：向100mL反应瓶中加入尿素(5.25g，87.35mmol)、0.3M的稀盐酸(13.4mL)和化合物18c(3.71g,26.47mmol)，加热至50℃搅拌16小时。反应冷却至室温，过滤，滤饼用10mL水淋洗，12mL无水乙醇淋洗，干燥，得到2.34g化合物18d(收率：39％)。
MS m/z(ESI):225.1[M+H]+。
1H NMR(400MHz,DMSO-d6):δ7.10(s,2H),7.02(s,2H),1.75-1.71(m,4H),1.57-1.51(m,2H),0.84(s,3H),0.82(s,3H)。
步骤4：向50mL反应瓶中加入化合物18d(1.12g,5.0mmol)、5mL 9M的盐酸和多聚甲醛(751mg,25.0mmol)，反应液室温搅拌24小时。向反应体系中加入18mL水，室温搅拌继续22小时，将反应液过滤，滤饼用5mL水淋洗，5mL乙醇淋洗，干燥，得到0.54g化合物18e(收率：35％)。
MS m/z(ESI):309.1[M+H]+。
1H NMR(400MHz,DMSO-d6):δ5.21-5.17(m,4H),,4.97-4.88(m,4H),2.64-2.60(m,2H),1.87-1.75(m,2H),1.66-1.56(m,2H),0.92(s,3H),0.90(s,3H)。
步骤5：将化合物18e(0.54g,1.75mmol)称入干燥反应瓶中，置换氩气，加入甲磺酸(1.8mL)溶解。室温下加入化合物1a(0.18g，0.584mmol)搅拌反应24小时，将反应液慢慢加入18mL水中(冰水浴冷却)，加完后恢复到室温搅拌10min。过滤，滤饼用少量水洗，粗品溶于TFA中(0.72mL)，然后加入2.88mL 水，室温下搅拌10min。过滤，滤饼用少量水洗，真空干燥得到0.518g化合物18f(收率：99％)。
MS m/z(ESI):889.3[M+H]+。
1H NMR(400MHz,DMSO-d6):δ5.74～5.35(m,10H),5.21-5.08(m,4H),4.86-4.69(m,4H),4.29-4.05(m,4H),1.80-1.43(m,10H),0.98-0.74(m,16H)。
步骤6：将化合物18f(502mg，0.565mmol)称入干燥三口烧瓶中，置换氩气，加入三氟乙酸(5mL)溶解，然后加入化合物1b(637mg，1.42mmol)。加完后将反应加热到70℃搅拌反应3小时。减压蒸掉TFA，向所得固体中加入7.5mL乙醇加热回流1小时，冷到室温，过滤。滤饼用乙醇洗涤，干燥。所得固体用高效液相色谱制备(流动相：水和乙腈，梯度配比：水相25％-42％)纯化，再用氢氧化钠成盐得到0.12g化合物18(收率：12％)。
MS m/z(ESI):1678.5[M-4Na+4H+18]+。
1H NMR(400MHz,DMSO-d6):δ8.00-7.89(m,4H),7.75-7.63(m,4H),7.35-6.99((m,7H),5.63-5.19(m,14H),4.42-4.00(m,12H),3.92-3.78(m,3H),2.88-2.77(m,7H),2.66-2.56(m,1H),2.19-1.94(m,8H),1.83-1.62(m,8H),1.01-0.82(m,12H)。
实施例19.化合物19的制备
步骤1：将化合物19a(4g，41.59mmol)加入到叔丁醇(1.4mL)搅拌溶解， 再加入N-甲基吗啡啉氧化物(5.43g，46.35mmol)、锇酸钾二水合物(172mg，467μmol)，加完后室温反应16小时，中控显示反应完毕，加入亚硫酸钠水溶液30mL淬灭，乙酸乙酯萃取(3×30ml)，合并有机相，硫酸钠干燥，过滤，浓缩得粗品柱层析(PE:EA＝1:1)分离得到3g化合物19b(收率：55％)。
1H NMR(400MHz,CDCl3):δ3.99-3.91(m,1H),3.66-3.54(m,1H),2.43-2.11(m,2H)，1.97-1.61(m,4H),1.50-1.09(m,3H),0.97-0.85(m,3H)。
步骤2：向500mL三口反应瓶中加入DMSO(9.82g,125.69mmol)和DCM(200mL)，氮气保护，降温至-60℃，滴加三氟乙酸酐(24.24g,115.40mmol)，20分钟滴加完毕，保温搅拌20分钟后，加入化合物19b(3g,23.04mmol)的DCM(8mL)溶液，保温搅拌1.5小时后加入三乙胺(26.50g，261.87mmol)，-60℃搅拌1小时后升到室温搅拌。中控显示反应完毕，反应体系加入约216mL 10％的盐酸，DCM(60mL×3)萃取，无水硫酸钠干燥，浓缩后粗品柱层析分离(PE:EA＝10:1)得到2.01g化合物19c(收率：69％)。
MS m/z(ESI):127.1[M+H]+。
1H NMR(400MHz,CDCl3):δ6.13-6.09(m,1H),2.64-2.37(m,3H),2.29-2.06(m,3H),1.09(d,3H)。
步骤3：向100mL反应瓶中加入尿素(3.17g，52.78mmol)、0.3M的稀盐酸(7.24mL)和化合物19c(2.01g,15.93mmol)，加热至50℃搅拌16小时。反应冷却至室温，过滤，滤饼用10mL水淋洗，10mL无水乙醇淋洗，干燥，得到1.52g化合物19d(收率：45％)。
MS m/z(ESI):211.1[M+H]+。
1H NMR(400MHz,DMSO-d6):δ7.11-6.98(m,4H),2.00-1.86(m,2H),1.59-1.44(m,3H),1.26-1.10(m,1H),1.00-0.86(m,4H)。
步骤4：向50mL反应瓶中加入化合物19d(1.02g，4.85mmol)、4.85mL 9M的盐酸和多聚甲醛(730mg，24.31mmol)，反应液室温搅拌24小时。反应液浓缩，残余物柱层析分离(二氯甲烷:乙腈＝10:1)得到191mg化合物19e(收率：13％)。
MS m/z(ESI):295.1[M+H]+。
1H NMR(400MHz,DMSO-d6):δ5.21-5.17(m,4H),,4.96-4.88(m,4H),2.62-2.57(m,1H),1.96-1.61(m,3H),1.25-1.17(m,3H),1.00(d,3H)。
步骤5：将化合物19e(66mg,0.21mmol)称入干燥三口烧瓶中，置换氩气，加入甲磺酸(0.5mL)溶解，室温下加入化合物1a(189mg,0.64mmol)。室温搅拌反应18小时后，将反应液慢慢加入5mL水中(冰水浴冷却)，加完后恢复到室温。过滤，滤饼用少量水洗，将干燥后粗品溶于TFA中(0.26mL)，然后加入1mL水，室温搅拌10分钟。过滤，滤饼用少量水洗，真空干燥得到185mg化合物19f(收率：100％)。
MS m/z(ESI):878.1[M+18]+。
1H NMR(400MHz,DMSO-d6):δ5.68～5.42(m,10H),5.16～5.14(m,4H), 4.80～4.74(m,4H),4.20～4.16(m,6H),2.08～1.99(m,2H),1.55～1.47(m,6H),1.24～0.97(m,12H)。
步骤6：将化合物19f(204mg，0.24mmol)称入干燥三口烧瓶中，置换氩气，加入TFA(2mL)溶解，然后加入化合物1b(266mg，0.59mmol)。加完后将反应加热到70℃搅拌反应3小时，减压蒸掉TFA，向所得固体中加入3mL乙醇加热回流(80℃)40min，冷到室温，过滤。滤饼用乙醇洗涤，干燥得到粗品用高效液相色谱制备(流动相：水和乙腈，梯度配比：水相25％-42％)纯化，再用氢氧化钠成盐得到0.15g化合物19(收率：36％)。
MS m/z(ESI):1650.4[M-4Na+4H+18]+。
1H NMR(400MHz,D2O):δ7.99～7.55(m,4H),7.47～7.04(m,4H),5.43～4.81(m,14H),4.20～3.52(m,18H),3.07～2.66(m,8H),2.20～0.90(m,28H)。
测试例1.本公开化合物对肌松药拮抗的效果测试
一、实验目的
测试本公开提供的化合物在大鼠神经肌肉模型中对腓肠肌的肌松药效逆转作用，评价起效时间、TOF等指标，并与CB2和新斯的明进行比较。
二、实验材料
SPF级SD雄性大鼠，BL-420A生物机能实验系统(主机、刺激器、张力换能器)，呼吸机，电子称，手术器械，注射器，剪毛器，电子秤，铁架台，泡沫板，氨基甲酸乙酯，氯化钠，CB2，化合物2，化合物3，顺阿曲库铵，琥珀酰胆碱，新斯的明，无菌水，95％酒精。
三、实验方法
取检疫合格的SPF级雄性SD大鼠，饲养环境为室温22±0.5℃，换气次数20-50/h，气流速度0.05-0.18m/s 12/12小时昼夜明暗交替。动物设施中适应3天以上，6只/笼饲养，待体重范围在220g～250g开始试验。
利用0.9％氯化钠复溶供试品。按含量折算后，称取所需量的供试品，用0.9％氯化钠注射液溶解后(30min以内)，再用涡旋混匀器混匀震荡。其中，CB2用纯净水复溶。
实际称药重量(mg)＝给药制剂浓度A(mg/mL)×溶媒体积(mL)/含量(％)
将大鼠随机分成CB2、化合物2、化合物3、新斯的明组，每组4只(以实际入组只数为准)，给药体积均为2mL/kg。
CB2(采用公知方法“WO2012051407A2”制备而得)，其结构如下所示：
大鼠麻醉后，分离坐骨神经和腓肠肌，刺激坐骨神经并通过张力换能器记录肌张力信号。气管插管通过小动物呼吸机给予机械通气。稳定记录肌张力信号一段时间后给予药物：首次给予2倍ED90剂量(0.8mg/kg)的肌松药(顺阿曲库铵)，此时肌张力曲线应当下降，给药30-60s后注射拮抗药(供试品和新斯的明)，待肌张力曲线恢复至95％以上后，给ED90剂量(0.9mg/kg)的肌松药(琥珀酰胆碱)，此时应观察到肌张力的下降，待肌张力自然恢复至95％以上即可停止实验。期间持续记录肌张力信号，统计分析起效时间和临床时效等指标，通过给药后肌张力信号的比较，判断并比较拮抗药的肌松逆转作用。
四、实验步骤
4.1大鼠称重、麻醉
将大鼠进行称重，待大鼠情绪稳定，将氨基甲酸乙酯配制成25％的乌拉坦，按照1mL/100g进行腹腔注射麻醉，待疼痛反射消失后将大鼠俯卧位固定于泡沫板上，对臀部和右大腿外侧区域脱毛处理。
4.2分离坐骨神经
在髋关节后，大腿中部股骨外缘切开皮肤，掀开皮肤、浅筋膜层，钝性分离肌肉，暴露坐骨神经。注意分离时使用玻璃分针，防止金属器械损伤神经。
4.3分离腓肠肌
从踝关节处剪开小腿皮肤，剪断踝关节前部韧带，分离腓肠肌，在踝部的腓肠肌肌腱处扎线，于结扎线远端切断肌腱。
4.4收集信号
将腓肠肌结扎线与张力换能器连接，刺激器与坐骨神经相连接。设定输入信号为张力，参数设定为方波，细电压，串刺激，延时0.05ms，波宽0.2ms，频率2Hz，强度0.225±0.025V，强度增量0，串长4，主周期12s，停止次数30000，记录肌肉收缩曲线。测量期间通过生理盐水始终保持肌肉神经处于湿润状态，每3-5分钟润湿一次。
4.5连接呼吸机，注射肌松药、拮抗药
酒精擦拭呼吸机管口，切开颈部皮肤，找到颈静脉和气管，将气管剪开，连接呼吸机，参数设定为潮气量6mL，呼吸时比5:4，呼吸频率80次/min。稳定5分钟左右经颈静脉给药，结合参考文献设定，首次给予2倍ED90剂量的肌松药(顺阿曲库铵)，此时肌张力曲线应当下降，给药30-60s后注射拮抗药(供试品或新 斯的明)，待肌张力曲线恢复至95％以上后，给予ED90剂量的肌松药(琥珀酰胆碱)，再次等待肌张力曲线恢复至95％以上后即可停止实验。期间持续记录肌张力曲线。
表1.
4.6时效指标统计
利用生物机能实验系统统计起效时间、二次肌松起效时间等指标，统计标准如下。
1)TOF恢复90％时间(TOF0.9)：TOF串刺激的T4/T1值恢复至90％左右的时间-拮抗剂给药时间
2)琥珀酰胆碱肌松作用时间：肌张力下降到最低值的时间-琥珀酰胆碱给药时间
五、实验结论
从图1及图2可知，化合物2和3在20mg/kg可达到新斯的明的药效水平，优于CB2。
测试例2.本公开化合物对肌松药体外结合活性的测试
一、试验目的：
通过等温滴定量热法(ITC)测试本公开化合物与肌松药的体外结合活性，评价结合的Kd值。
二、试验材料：
等温滴定量热仪(含电脑主机及配套软件)、CB2、化合物2、化合物3、化合物7、化合物12、化合物13、化合物15、顺阿曲库铵、去离子水。
三、试验方法与步骤：
利用预设的洗涤程序，使用去离子水洗涤等温滴定量热系统的管路、样品池与滴定针。配置顺阿曲库铵水溶液与待测化合物的水溶液，顺阿曲库铵：待测化合物＝10:1～20:1。以加样针将CB2与待测化合物加满样品池中，以加样程序将顺阿曲库铵吸取到滴定针中。将滴定针置入样品池中，启动搅拌，平衡系统5～10min。设置滴定参数：每滴样品2.5μL，共20滴，滴定间隔150s。开始滴定，记录热曲线。
滴定完毕后，通过热曲线计算待测化合物与顺阿曲库铵结合的Kd值，利用洗 涤程序洗涤管路、样品池与滴定针，进行下一个化合物的测试。
四、试验结果：
以ITC的方法检测了CB2、化合物2、化合物3、化合物7、化合物12、化合物13、化合物15在体外结合顺阿曲库铵的结合能力，其解离常数Kd值如表2所示，结果表明，化合物2、化合物13与化合物15体外结合顺阿曲库铵的能力强于CB2。
表2：待测化合物与顺阿曲库铵的体外结合力
测试例3.本公开化合物对肌松药拮抗的效果测试
一、实验目的
测试本公开提供的化合物在大鼠神经肌肉模型中对腓肠肌的肌松药效逆转作用，评价起效时间、TOF等指标，并与CB2和新斯的明进行比较。
二、实验材料
SPF级SD雄性大鼠，BL-420A生物机能实验系统(主机、刺激器、张力换能器)，呼吸机，电子称，手术器械，注射器，剪毛器，电子秤，铁架台，泡沫板，氨基甲酸乙酯，氯化钠，CB2，化合物2，化合物3，顺阿曲库铵，琥珀酰胆碱，新斯的明，无菌水，95％酒精。
三、实验方法
取检疫合格的SPF级雄性SD大鼠，饲养环境为室温22±0.5℃，换气次数20-50/h，气流速度0.05-0.18m/s 12/12小时昼夜明暗交替。动物设施中适应3天以上，6只/笼饲养，待体重范围在220g～250g开始试验。
利用0.9％氯化钠复溶供试品。按含量折算后，称取所需量的供试品，用0.9％氯化钠注射液溶解后(30min以内)，再用涡旋混匀器混匀震荡。其中，CB2用纯净水复溶。
实际称药重量(mg)＝给药制剂浓度A(mg/mL)×溶媒体积(mL)/含量(％)
将大鼠随机分成CB2、化合物2、化合物15、新斯的明组，每组5只(以实际入组只数为准)，给药体积均为2mL/kg。
CB2(采用公知方法“WO2012051407A2”制备而得)，其结构如下所示：
大鼠麻醉后，分离坐骨神经和腓肠肌，刺激坐骨神经并通过张力换能器记录肌张力信号。气管插管通过小动物呼吸机给予机械通气。稳定记录肌张力信号一段时间后给予药物：首次给予2倍ED90剂量(0.8mg/kg)的肌松药(顺阿曲库铵)，此时肌张力曲线应当下降，给药30-60s后注射拮抗药(供试品和新斯的明)，待肌张力曲线恢复至95％以上后，给ED90剂量(0.9mg/kg)的肌松药(琥珀酰胆碱)，此时应观察到肌张力的下降，待肌张力自然恢复至95％以上即可停止实验。期间持续记录肌张力信号，统计分析起效时间和临床时效等指标，通过给药后肌张力信号的比较，判断并比较拮抗药的肌松逆转作用。
四、实验步骤
4.1大鼠称重、麻醉
将大鼠进行称重，待大鼠情绪稳定，将氨基甲酸乙酯配制成25％的乌拉坦，按照1mL/100g进行腹腔注射麻醉，待疼痛反射消失后将大鼠俯卧位固定于泡沫板上，对臀部和右大腿外侧区域脱毛处理。
4.2分离坐骨神经
在髋关节后，大腿中部股骨外缘切开皮肤，掀开皮肤、浅筋膜层，钝性分离肌肉，暴露坐骨神经。注意分离时使用玻璃分针，防止金属器械损伤神经。
4.3分离腓肠肌
从踝关节处剪开小腿皮肤，剪断踝关节前部韧带，分离腓肠肌，在踝部的腓肠肌肌腱处扎线，于结扎线远端切断肌腱。
4.4收集信号
将腓肠肌结扎线与张力换能器连接，刺激器与坐骨神经相连接。设定输入信号为张力，参数设定为方波，细电压，串刺激，延时0.05ms，波宽0.2ms，频率2Hz，强度0.225±0.025V，强度增量0，串长4，主周期12s，停止次数30000，记录肌肉收缩曲线。测量期间通过生理盐水始终保持肌肉神经处于湿润状态，每3-5分钟润湿一次。
4.5连接呼吸机，注射肌松药、拮抗药
酒精擦拭呼吸机管口，切开颈部皮肤，找到颈静脉和气管，将气管剪开，连接呼吸机，参数设定为潮气量6mL，呼吸时比5:4，呼吸频率80次/min。稳定5分钟左右经颈静脉给药，结合参考文献设定，首次给予2倍ED90剂量的肌松药(顺阿曲库铵)，此时肌张力曲线应当下降，给药30-60s后注射拮抗药(供试品或新 斯的明)，待肌张力曲线恢复至95％以上后，给予ED90剂量的肌松药(琥珀酰胆碱)，再次等待肌张力曲线恢复至95％以上后即可停止实验。期间持续记录肌张力曲线。
表3.
4.6时效指标统计
利用生物机能实验系统统计起效时间、二次肌松起效时间等指标，统计标准如下。
1)TOF恢复90％时间(TOF0.9)：TOF串刺激的T4/T1值恢复至90％左右的时间-拮抗剂给药时间
2)琥珀酰胆碱肌松作用时间：肌张力下降到最低值的时间-琥珀酰胆碱给药时间
五、实验结论
由图3可知，化合物2和15在20mg/kg可达到新斯的明的药效水平，优于CB2。
测试例4.本公开化合物对肌松药体外结合活性的测试
一、试验目的：
通过等温滴定量热法(ITC)测试本公开化合物与肌松药的体外结合活性，评价结合的Kd值。
二、试验材料：
等温滴定量热仪(含电脑主机及配套软件)、CB2、化合物2、化合物11、化合物15、化合物16、顺阿曲库铵、去离子水。
三、试验方法与步骤：
利用预设的洗涤程序，使用去离子水洗涤等温滴定量热系统的管路、样品池与滴定针。配置顺阿曲库铵水溶液与待测化合物的水溶液，顺阿曲库铵：待测化合物＝10:1～20:1。以加样针将CB2与待测化合物加满样品池中，以加样程序将顺阿曲库铵吸取到滴定针中。将滴定针置入样品池中，启动搅拌，平衡系统5～10min。设置滴定参数：每滴样品2.5μL，共20滴，滴定间隔150s。开始滴定，记录热曲线。
滴定完毕后，通过热曲线计算待测化合物与顺阿曲库铵结合的Kd值，利用洗 涤程序洗涤管路、样品池与滴定针，进行下一个化合物的测试。
四、试验结果：
以ITC的方法检测了CB2、化合物2、化合物11、化合物15、化合物16在体外结合顺阿曲库铵的结合能力，其解离常数Kd值如表4所示，结果表明，化合物2、化合物11、化合物15和化合物16体外结合顺阿曲库铵的能力强于CB2。
表4：待测化合物与顺阿曲库铵的体外结合力

Claims (29)

  1. 一种式(I)所示的化合物或其可药用盐，
    其中，
    R1各自独立地选自C2-6烷基、C1-6卤代烷基、C1-6羟烷基、-C(O)2R'、R'-(O)-亚烷基-、羟基、NR'(R”)、3至7元环烷基、3至7元杂环基；或者连接在相邻碳原子上的两个R1一起形成3至10元的环烷基或3至10元的杂环基；所述R1任选被一个或多个R1A取代；
    R2各自独立地选自氢、C1-6烷基、C1-6卤代烷基、C1-6羟烷基、-C(O)2R'、R'-(O)-亚烷基-、羟基、NR'(R”)、3至7元环烷基、3至7元杂环基；或者连接在相邻碳原子上的两个R2一起形成3至10元的环烷基或3至10元的杂环基；所述R2任选被一个或多个R2A取代；
    环A各自独立地选自5至12元的芳香基或5至12元的杂芳基；
    R3各自独立地选自卤素、C1-6烷基、羟基、硝基、氰基、-C(O)2R'、NR'(R”)、R'-(O)-亚烷基-、3至7元环烷基、3至7元杂环基或且至少有一个为所述R3任选被一个或多个R3A取代；
    R4为A+为一价或二价阳离子；
    R1A、R2A、R3A各自独立地选自卤素、氰基、硝基、氨基、C1-6烷基或C1-6烷氧基；
    R'和R”各自独立地选自氢、C1-6烷基、C1-6羟烷基、C1-6卤代烷基、3至7元环烷基、3至7元杂环基；
    m和n各自独立地选自1、2、3、4或5；
    p各自独立地选自1、2、3、4、5或6。
  2. 根据权利要求1所述的式(I)所示的化合物或其可药用盐，其中，所述环A为苯基或萘基，优选萘基。
  3. 根据权利要求1或2所述的式(I)所示的化合物或其可药用盐，其为式(I-1)所示化合物或其可药用盐，
    其中，R1、R2、p、m和A+如权利要求1中定义。
  4. 根据权利要求1至3中任一项所述的式(I)所示的化合物或其可药用盐，其中，连接在相邻碳原子上的两个R1一起形成3至10元的环烷基或3至10元的杂环基；优选地，连接在相邻碳原子上的两个R1一起形成6元环烷基；更优选地，连接在相邻碳原子上的两个R1一起形成5至6元的杂环基，其中的杂原子选自氮或氧，优选为氧。
  5. 根据权利要求1至3中任一项所述的式(I)所示的化合物或其可药用盐，其中，R1各自独立地为C2-6烷基，优选乙基；或者，R1各自独立地为C1-6卤代烷基，优选C1-3卤代烷基，更优选一个或两个或三个氟取代的甲基；或者R1各自独立地为-C(O)2R'，所述R'各自独立地选自氢、C1-6烷基、C1-6卤代烷基，优选地，所述R'为H或C1-6烷基，更优选甲基或乙基；或者，R1各自独立地为C1-6羟烷基或C1-6烷基-O-C1-6亚烷基-，优选C1-3羟烷基或C1-3烷基-O-C1-3亚烷基-，更优选羟甲基或甲基-O-亚甲基-；或者，R1各自独立地为R'-(O)-亚烷基-，所述R'选自C1-6烷基、C1-6羟烷基、C1-6卤代烷基、3至7元环烷基、3至7元杂环基，优选地，所述R'为C1-6烷基或C1-6卤代烷基，更优选地，所述R'为C1-3烷基。
  6. 根据权利要求1至5中任一项所述的式(I)所示的化合物或其可药用盐，其中，R2各自独立地为氢。
  7. 根据权利要求1至6中任一项所述的式(I)所示的化合物或其可药用盐，A+为一价阳离子，所述一价阳离子选自H+、Na+、K+、H4N+、Et3NH+、(HOCH2CH2)3NH+或乙二胺、哌嗪、三苯基甲基氨基甲烷的阳离子形式，优选H+、Na+或K+，更优选Na+；或者，A+为二价阳离子，所述二价阳离子选自Ca2+、Mg2+或Zn2+。
  8. 根据权利要求1至7中任一项所述的式(I)所示的化合物或其可药用盐， 其中，p各自独立地选自2、3或4，优选3。
  9. 根据权利要求1至8中任一项所述的式(I)所示的化合物或其可药用盐，其中，m各自独立地选自2、3或4，优选2。
  10. 根据权利要求1至9中任一项所述的式(I)所示的化合物或其可药用盐，其选自：

  11. 一种式(Ⅲ)所示的化合物或其可药用盐，
    其中：
    XC1、XC2各自独立地选自O、S、-NH-；
    RC2各自独立选自选氢、C1-6烷基、C1-6卤代烷基、C1-6羟烷基、-C(O)2R'、R'-(O)-亚烷基-、羟基、NR'(R”)、3至7元环烷基、3至7元杂环基；或者连接在相邻碳原子上的两个RC2一起形成3至10元的环烷基或3至10元的杂环基；所述RC2任选被一个或多个卤素、氰基、硝基、氨基、C1-6烷基或C1-6烷氧基取代；
    环C选自6至18元的芳香基或5至18元的杂芳基；
    RC3各自独立地为
    RC4各自独立地为羧酸基、-羧酸根-阳离子、磷酸基、-磷酸根-阳离子、磺酸基、-磺酸根-阳离子；
    L、L1、L2相同或不同，各自独立地为亚烷基或杂亚烷基，所述的亚烷基、杂亚烷基任选地被一个或多个卤素、氰基、硝基、氨基、C1-6烷基或C1-6烷氧基取代；
    Rc各自独立地选自氢、卤素、氰基、硝基、氨基、C1-6烷基或C1-6烷氧基；
    Ra、Rb相同或不同，各自独立地选自羧酸基、-羧酸根-阳离子、磷酸基、-磷酸根-阳离子、磺酸基、-磺酸根-阳离子；
    R'、R”各自独立地选自氢、C1-6烷基、C1-6羟烷基、C1-6卤代烷基、3至7元环烷基、3至7元杂环基；
    x选自1、2、3、4或5；
    v各自独立地选自1、2、3、4或5；
    q各自独立地选自1、2、3、4、5或6。
  12. 根据权利要求11所述的式(Ⅲ)所示的化合物或其可药用盐，其中XC1、XC2相同且选自O、S、-NH-，优选O。
  13. 根据权利要求11或12所述的式(Ⅲ)所示的化合物或其可药用盐，其中L各自独立地为C1-6亚烷基。
  14. 根据权利要求11至13中任一项所述的式(Ⅲ)所示的化合物或其可药用盐，其中环C选自苯环、萘环或蒽环，优选萘环或蒽环。
  15. 根据权利要求11至14中任一项所述的式(Ⅲ)所示的化合物或其可药用盐，其选自式(Ⅲ-A)、式(Ⅲ-B)、式(Ⅲ-C)或式(Ⅲ-D)所示的化合物或其可药用盐，

    其中：
    RD各自独立地选自羧酸基、-羧酸根-阳离子、磷酸基、-磷酸根-阳离子；
    RE各自独立地选自羧酸基、-羧酸根-阳离子、磷酸基、-磷酸根-阳离子、磺酸基、-磺酸根-阳离子；
    r选自1、2、3；
    RC2、q、x、L1、L2、Ra、Rb、Rc如权利要求11中所定义。
  16. 根据权利要求11至15中任一项所述的式(Ⅲ)所示的化合物或其可药用盐，其中L1、L2相同或不同，各自独立地为C1-6亚烷基。
  17. 根据权利要求11至16中任一项所述的式(Ⅲ)所示的化合物或其可药用盐，其选自式(Ⅲ-A-1)、式(Ⅲ-B-1)、式(Ⅲ-B-2)、式(Ⅲ-C-1)、式(Ⅲ-C-2)、式(Ⅲ-C-3)、式(Ⅲ-D-1)、式(Ⅲ-D-2)或式(Ⅲ-D-3)所示的化合物或其可药用盐，

    其中：
    a各自独立地选自1、2、3、4；
    b各自独立地选自1、2、3、4；
    c各自独立地选自1、2、3、4；
    A1 +或A2 +相同或不同，各自独立地为一价阳离子或二价阳离子；
    当A1 +为一价阳离子时，s为4；
    当A1 +为二价阳离子时，s为2；
    当A2 +为一价阳离子时，t为8；
    当A2 +为二价阳离子时，t为4；
    RC2、q、x如权利要求11中所定义，r如权利要求15中所定义。
  18. 根据权利要求17所述的式(Ⅲ)所示的化合物或其可药用盐，其中RC2各自独立地为氢。
  19. 根据权利要求17或18所述的式(Ⅲ)所示的化合物或其可药用盐，其中r为2或3，优选2。
  20. 根据权利要求17至19中任一项所述的式(Ⅲ)所示的化合物或其可药用盐，其中a、b、c相同或不同，各自独立地选自1、2或3，优选地，a、b、c均为1。
  21. 根据权利要求17至20中任一项所述的式(Ⅲ)所示的化合物或其可药用盐，其中q各自独立地选自2、3或4，优选3、4，更优选3。
  22. 根据权利要求17至21中任一项所述的式(Ⅲ)所示的化合物或其可药用盐，其中x选自2、3或4，优选2、3，更优选2。
  23. 根据权利要求17至22中任一项所述的式(Ⅲ)所示的化合物或其可药用盐，其中A1 +、A2 +各自独立地为一价阳离子，所述一价阳离子选自H+、Na+、K+、H4N+、Et3NH+、(HOCH2CH2)3NH+或乙二胺、哌嗪、三苯基甲基氨基甲烷的阳离子形式，优选H+、Na+或K+，更优选Na+。
  24. 根据权利要求17至23中任一项所述的式(Ⅲ)所示的化合物或其可药用盐，其中A1 +、A2 +各自独立地为二价阳离子，所述二价阳离子选自Ca2+、Mg2+或Zn2+。
  25. 根据权利要求17至24中任一项所述的式(Ⅲ)所示的化合物或其可药用盐，其选自


  26. 一种根据权利要求1-25中任一项所述的化合物或其可药用的盐的同位素取代物，优选地，所述的同位素取代物为氘原子取代物。
  27. 一种药物组合物，包括至少一种治疗有效量的根据权利要求1-25中任一 项所述的化合物或其可药用的盐，根据权利要求26所述的同位素取代物以及药学上可接受的赋形剂。
  28. 根据权利要求1-25中任一项所述的化合物或其可药用的盐，根据权利要求26所述的同位素取代物或根据权利要求27所述的药物组合物在制备治疗或预防疾病或病症的药物中的用途，所述的疾病或病症选自增殖性疾病、心血管相关疾病或血液癌。
  29. 根据权利要求1-25中任一项所述的化合物或其可药用的盐，根据权利要求26所述的同位素取代物或根据权利要求27所述的药物组合物在制备逆转药物诱导的神经肌肉阻滞和/或麻醉的药物中的用途。
PCT/CN2023/131007 2022-11-11 2023-11-10 葫芦脲类化合物及其医药用途 WO2024099434A1 (zh)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
CN202211412397 2022-11-11
CN202211412397.6 2022-11-11
CN202310888540.7 2023-07-19
CN202310888540 2023-07-19

Publications (1)

Publication Number Publication Date
WO2024099434A1 true WO2024099434A1 (zh) 2024-05-16

Family

ID=91031981

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2023/131007 WO2024099434A1 (zh) 2022-11-11 2023-11-10 葫芦脲类化合物及其医药用途

Country Status (1)

Country Link
WO (1) WO2024099434A1 (zh)

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012051407A2 (en) * 2010-10-13 2012-04-19 University Of Maryland, College Park Molecular containers and methods of making and using same
US20150328334A1 (en) * 2010-10-13 2015-11-19 University Of Maryland, College Park Molecular containers and methods of making and using same
WO2016061571A1 (en) * 2014-10-18 2016-04-21 University Of Maryland, College Park Acyclic cucurbit(n)uril type molecular containers to treat intoxication and decrease relapse rate in substance abuse disorders
CN116925088A (zh) * 2023-07-21 2023-10-24 复旦大学 二芳并四甘脲八羧酸盐及其用途
CN116925087A (zh) * 2023-07-18 2023-10-24 复旦大学 一类二芳基四甘脲羧酸盐及其用途

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012051407A2 (en) * 2010-10-13 2012-04-19 University Of Maryland, College Park Molecular containers and methods of making and using same
US20150328334A1 (en) * 2010-10-13 2015-11-19 University Of Maryland, College Park Molecular containers and methods of making and using same
WO2016061571A1 (en) * 2014-10-18 2016-04-21 University Of Maryland, College Park Acyclic cucurbit(n)uril type molecular containers to treat intoxication and decrease relapse rate in substance abuse disorders
CN116925087A (zh) * 2023-07-18 2023-10-24 复旦大学 一类二芳基四甘脲羧酸盐及其用途
CN116925088A (zh) * 2023-07-21 2023-10-24 复旦大学 二芳并四甘脲八羧酸盐及其用途

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
DA MA, PETER Y. ZAVALIJ, LYLE ISAACS: "Acyclic Cucurbit[ n ]uril Congeners Are High Affinity Hosts", THE JOURNAL OF ORGANIC CHEMISTRY, AMERICAN CHEMICAL SOCIETY, vol. 75, no. 14, 16 July 2010 (2010-07-16), pages 4786 - 4795, XP055095701, ISSN: 00223263, DOI: 10.1021/jo100760g *

Similar Documents

Publication Publication Date Title
RU2625309C2 (ru) Замещенные диаминокарбоксамидные и диаминокарбонитрильные производные пиримидинов, их композиции и способы лечения с их помощью
EP3508476B1 (en) Amino mercaptan compound and preparation method therefor and use thereof in protection against radiation
JP2010513445A (ja) Ｇｌｋアクチベーターとして有用な新規結晶性化合物
MX2014013166A (es) Derivados de 2-amino-4-(bencilamino)fenilcarbamato fluorados.
JP5875863B2 (ja) マレイン酸オルブピタントの無水結晶形
JP2022553833A (ja) エストロゲン受容体調節薬の塩及び形態
WO2024099434A1 (zh) 葫芦脲类化合物及其医药用途
JPS59167564A (ja) スルホニウム化合物
TW202408503A (zh) 治療纖維化之方法
TW202421155A (zh) 葫蘆脲類化合物及其醫藥用途
JP6639651B2 (ja) 疼痛のための治療化合物及びその合成
ES2898774T3 (es) Cocristales farmacéuticos cristalinos de bromuro de glicopirronio con lactosa
TWI738162B (zh) 稠合三環氘代衍生物及其組合物和用途
CN117586204A (zh) 异硒唑酮类化合物、其合成方法及用途
WO2024082629A1 (zh) 哌嗪取代苯酚类衍生物及其用途
JP2023552672A (ja) ヌクレオシド類似体の塩及びその結晶形、医薬組成物並びに用途
WO2020072870A1 (en) Co-crystal forms of baricitinib
AU2015201030A1 (en) Substituted diaminocarboxamide and diaminocarbonitrile pyrimidines, compositions thereof, and methods of treatment therewith

Legal Events

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

Ref document number: 23888119

Country of ref document: EP

Kind code of ref document: A1