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WO2021032074A1 - Dérivé cyclicque aromatique condensé de benzamide, son procédé de préparation et son utilisation en médecine - Google Patents

Dérivé cyclicque aromatique condensé de benzamide, son procédé de préparation et son utilisation en médecine Download PDF

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Publication number
WO2021032074A1
WO2021032074A1 PCT/CN2020/109692 CN2020109692W WO2021032074A1 WO 2021032074 A1 WO2021032074 A1 WO 2021032074A1 CN 2020109692 W CN2020109692 W CN 2020109692W WO 2021032074 A1 WO2021032074 A1 WO 2021032074A1
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Prior art keywords
general formula
tautomer
pharmaceutically acceptable
racemate
enantiomer
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English (en)
Chinese (zh)
Inventor
杨方龙
郁楠
王伟民
刘志伟
贺峰
陶维康
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Jiangsu Hengrui Medicine Co Ltd
Shanghai Hengrui Pharmaceutical Co Ltd
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Jiangsu Hengrui Medicine Co Ltd
Shanghai Hengrui Pharmaceutical Co Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
    • C07D237/02—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings
    • C07D237/06—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D237/10—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D237/14—Oxygen atoms

Definitions

  • the present disclosure belongs to the field of medicine, and relates to a benzamide fused aromatic ring derivative represented by the general formula (I), a preparation method thereof, a pharmaceutical composition containing the derivative, and its use as a therapeutic agent, especially The use as a Na V inhibitor and its use in preparing medicines for treating and/or reducing pain and pain-related diseases.
  • Pain is a complex physical and psychological activity and one of the most common symptoms in clinical practice.
  • the International Association for Pain Research defines pain as "an unpleasant feeling and emotional feeling accompanied by substantial or potential tissue damage. It is a subjective feeling.” Pain can be used as a warning signal to remind The body pays attention to potential dangers and has an indispensable protective effect on the body's normal life activities. At the same time, pain is also a common clinical symptom. After the external stimulus that caused the pain disappears, strong or long-lasting pain can cause disorders of physiological functions and seriously affect the quality of life of the living body. Statistics show that about one-fifth of people in the world suffer from moderate to severe chronic pain.
  • action potentials nerve impulses
  • DRG dorsal root ganglia
  • the generation and conduction of action potentials in neurons relies on voltage-gated sodium channels (Na V ) on the cell membrane. When the cell membrane is depolarized, the sodium ion channel is activated and the channel opens, causing the influx of sodium ions, further depolarizing the cell membrane, leading to the generation of action potentials. Therefore, inhibiting abnormal sodium ion channel activity is helpful for the treatment and relief of pain.
  • Na V voltage-gated sodium channels
  • Na V is a type of transmembrane ion channel protein. These proteins consist of an alpha subunit with a molecular weight of 260kD and a beta subunit with a molecular weight of 30-40kD. According to the different ⁇ subunits, it can be divided into 9 subtypes, Na V ll ⁇ Na V 1.9. Different subtypes show different tissue distribution and electrophysiological and pharmacological characteristics. According to whether it can be effectively inhibited by nanomolar tetrodotoxin (TTX), sodium ion channels are classified into TTX sensitive (TTX-S) and TTX insensitive (TTX-R).
  • TTX-S TTX sensitive
  • TTX-R TTX insensitive
  • Na V 1.1, Na V 1.2, Na V 1.3, and Na V 1.7 are TTX-S type, and the coding genes are located in human chromosome 2q23-24, and they are expressed in large amounts in neurons.
  • Na V 1.5, Na V 1.8 and Na V 1.9 are TTX-R type, and the coding gene is located on human chromosome 3p21-24.
  • Na V 1.5 is mainly present in cardiomyocytes
  • Na V 1.8 and Na V 1. 9 are present in the peripheral nervous system.
  • Both Na V 1.4 and Na V 1.6 are TTX-S type, which are abundant in skeletal muscle and central nervous system respectively.
  • Non-selective Na V inhibitors such as lamotrigine, lacosamide, and mexiletine have been successfully used to treat chronic pain.
  • Na V 1.8 is of TTX-R type, and the coding gene is SCN10A. It mainly exists in trigeminal ganglion neurons and DRG neurons, and has electrophysiological characteristics of slow inactivation and rapid recovery. In neurons expressing Na V 1.8, the rise of action potential is mainly composed of Na V 1.8 current. In some models of neuropathic pain, nerve damage will increase the expression level of Na V 1.8 in axons and neuron cell bodies. The use of Na V 1.8 antisense oligonucleotides can significantly relieve pain while reducing the expression of Na V 1.8. After carrageenan was injected into the paws of rats, the expression of Na V 1.8 in DRG neurons increased.
  • Na V 1.8 knockout mice cannot show normal visceral inflammation pain. After the human Na V 1.8 gene has a functional gain mutation, it will cause peripheral neuralgia. Based on a series of animal experiments and human genetic evidence, selective inhibition of Na V 1.8 has the potential to become a new type of analgesic therapy, which can be used for the treatment of inflammatory pain, nerve pain, postoperative pain, cancer pain and other types of pain.
  • Na V inhibitors Due to the lack of subtype selectivity in clinical use of Na V inhibitors, it can inhibit sodium channels expressed in the heart and central nervous system, so the therapeutic window is narrow and the scope of application is limited.
  • Na V 1.8 is mainly distributed in the peripheral nervous system, so selective inhibition of Na V 1.8 can effectively reduce side effects. Necessary to develop higher activity, better selectivity, better pharmacokinetic properties, fewer side effects of inhibitors of Na V 1.8.
  • the purpose of the present disclosure is to provide a compound represented by general formula (I), or its tautomer, meso, racemate, enantiomer, diastereomer, or Its mixture form or its pharmaceutically acceptable salt:
  • X is selected from CH, C atom and N atom
  • Y is selected from CH, C atom and N atom
  • M is selected from H 2 , NH, O atom and S atom;
  • Ring A is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl;
  • R 1 are the same or different, and are each independently selected from hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, hetero Cyclic and heterocyclylalkyl;
  • R 2 is selected from hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, -CH 2 OR w , cycloalkyl and heterocyclic group;
  • R w is selected from hydrogen atom, alkyl group, -S (O) 2 OH, -S (O) 2 O - Q +, -PO (OH) 2, -PO (O -) 2 Q + 2 ,, - PO (OH) O - Q + and -PO (O -) 2 W 2+ ;
  • Q + is a monovalent pharmaceutically acceptable cation;
  • W 2+ cation is a pharmaceutically acceptable divalent;
  • R 3 are the same or different, and are each independently selected from hydrogen, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, hetero Cyclic and heterocyclylalkyl;
  • R 4 are the same or different, and are each independently selected from hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, hetero Cyclic and heterocyclylalkyl;
  • R 5 are the same or different, and are each independently selected from hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, hetero Cyclic and heterocyclylalkyl;
  • n 0, 1, 2, 3, 4 or 5;
  • n 0, 1, 2 or 3;
  • s 0, 1, 2 or 3;
  • t 0, 1, 2, or 3.
  • the compound represented by the general formula (I), or its tautomer, meso, racemate, enantiomer, or diastereomer The structure, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the X is CH.
  • the compound represented by the general formula (I), or its tautomer, meso, racemate, enantiomer, or diastereomer The structure, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the Y is CH.
  • the compound represented by the general formula (I), or its tautomer, meso, racemate, enantiomer, or diastereomer The structure, or the form of a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the M is an O atom.
  • the compound represented by the general formula (I), or its tautomer, meso, racemate, enantiomer, or diastereomer The structure, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the ring A is selected from cycloalkyl, heterocyclic and aryl, preferably cycloalkyl, more preferably cyclopentyl.
  • the compound represented by the general formula (I), or its tautomer, meso, racemate, enantiomer, or diastereomer The structure, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the R 1 is the same or different, and each independently is a hydrogen atom or an alkyl group, preferably a hydrogen atom.
  • the compound represented by the general formula (I), or its tautomer, meso, racemate, enantiomer, or diastereomer The structure, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the R 2 is selected from hydrogen atom, halogen, alkyl group and -CH 2 OR w ; R w is -PO(OH) 2 .
  • the compound represented by the general formula (I), or its tautomer, meso, racemate, enantiomer, or diastereomer The structure, or the form of a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the R 3 is the same or different, and each is independently selected from a hydrogen atom, a halogen and an alkyl group, preferably a halogen.
  • the compound represented by the general formula (I), or its tautomer, meso, racemate, enantiomer, or diastereomer The structure, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the R 4 is the same or different, and each is independently selected from a hydrogen atom, a halogen, an alkyl group and a halogenated alkyl group, preferably a halogen or a halogenated alkyl group, and more Preferably, it is a Cl atom or a trifluoromethyl group.
  • the compound represented by the general formula (I), or its tautomer, meso, racemate, enantiomer, or diastereomer The structure, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the R 5 is the same or different, and are each independently selected from a hydrogen atom, an alkyl group, a hydroxyl group and a halogen, preferably a hydrogen atom or an alkyl group, and more Preferably it is a hydrogen atom.
  • the compound represented by the general formula (I), or its tautomer, meso, racemate, enantiomer, or diastereomer The structure, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the n is 2.
  • the compound represented by the general formula (I), or its tautomer, meso, racemate, enantiomer, or diastereomer In the form of a construct, or a mixture thereof, or a pharmaceutically acceptable salt thereof, the s is 1 or 2, preferably 1.
  • the compound represented by the general formula (I), or its tautomer, meso, racemate, enantiomer, or diastereomer Conformer, or its mixture form or its pharmaceutically acceptable salt which is a compound represented by general formula (II), or its tautomer, meso, racemate, enantiomer , Diastereomers, or mixtures or pharmaceutically acceptable salts thereof:
  • the compound represented by the general formula (I), or its tautomer, meso, racemate, enantiomer, or diastereomer Conformer, or its mixture form or its pharmaceutically acceptable salt which is a compound represented by general formula (III), or its tautomer, meso, racemate, enantiomer , Diastereomers, or mixtures or pharmaceutically acceptable salts thereof:
  • the compound represented by the general formula (I), or its tautomer, meso, racemate, enantiomer, or diastereomer Conformer, or its mixture form or its pharmaceutically acceptable salt which is the compound represented by the general formula (IV), or its tautomer, meso, racemate, enantiomer , Diastereomers, or mixtures or pharmaceutically acceptable salts thereof:
  • R 1 , R 2 , R 3 , R 4 , R 5 , m, n, s, and t are as defined in the general formula (I).
  • the compound represented by the general formula (I), or its tautomer, meso, racemate, enantiomer, or diastereomer Structure, or its mixture form or its pharmaceutically acceptable salt which is a compound represented by general formula (IVB) or (IVD), or its tautomer, meso, racemate, or Enantiomers, diastereomers, or mixtures thereof or their pharmaceutically acceptable salts:
  • R 1 , R 3 , R 4 , R 5 , m, n, s and t are as defined in the general formula (I).
  • the compound represented by the general formula (I), or its tautomer, meso, racemate, enantiomer, or diastereomer Conformer, or its mixture form or its pharmaceutically acceptable salt which is a compound represented by the general formula (V), or its tautomer, meso, racemate, enantiomer , Diastereomers, or mixtures or pharmaceutically acceptable salts thereof:
  • R 4a or R 4b are the same or different, and are each independently selected from hydrogen atom, halogen, alkyl, alkoxy, halogenated alkyl, halogenated alkoxy, hydroxy, hydroxyalkyl, cyano, amino, nitro Group, cycloalkyl, heterocyclyl and heterocyclylalkyl;
  • R 1 , R 2 , R 3 and m are as defined in the general formula (I).
  • the compound represented by the general formula (I), or its tautomer, meso, racemate, enantiomer, or diastereomer is a compound represented by the general formula (VB) or (IVD), or its tautomer, meso, racemate, or pair Enantiomers, diastereomers, or mixtures thereof or their pharmaceutically acceptable salts:
  • R 4a or R 4b are the same or different, and are each independently selected from hydrogen atom, halogen, alkyl, alkoxy, halogenated alkyl, halogenated alkoxy, hydroxy, hydroxyalkyl, cyano, amino, nitro Group, cycloalkyl, heterocyclyl and heterocyclylalkyl;
  • R 1 , R 3 and m are as defined in the general formula (I).
  • the compound represented by the general formula (I), or its tautomer, meso, racemate, enantiomer, or diastereomer Conformer, or its mixture form or its pharmaceutically acceptable salt which is the compound represented by the general formula (VI), or its tautomer, meso, racemate, enantiomer , Diastereomers, or mixtures or pharmaceutically acceptable salts thereof:
  • R 4c or R 4d are the same or different, and are each independently selected from hydrogen atom, halogen, alkyl, alkoxy, halogenated alkyl, halogenated alkoxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro Group, cycloalkyl, heterocyclyl and heterocyclylalkyl;
  • the X, Y, ring A, M, R 1 , R 2 , R 3 , R 5 , m, s and t are as defined in the general formula (I).
  • the compound represented by the general formula (VI), or its tautomer, meso, racemate, enantiomer, or diastereomer The structure, or the form of a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein said R 4c is halogen, preferably a Cl atom.
  • the compound represented by the general formula (VI), or its tautomer, meso, racemate, enantiomer, or diastereomer The structure, or a mixture thereof or a pharmaceutically acceptable salt thereof, wherein said R 4d is a haloalkyl group, preferably a trifluoromethyl group.
  • Typical compounds of the present disclosure include but are not limited to:
  • Another aspect of the present disclosure relates to the compound represented by the general formula (IIA) or its tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof Form or its pharmaceutically acceptable salt:
  • Ra is an alkyl group, preferably a methyl group
  • the X, Y, M, ring A, R 1 , R 3 , R 4 , R 5 , m, n, s and t are as defined in the general formula (I).
  • Another aspect of the present disclosure relates to a compound represented by general formula (IVA) or its tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof Form or its pharmaceutically acceptable salt:
  • Ra is an alkyl group, preferably a methyl group
  • R 1 , R 3 , R 4 , R 5 , m, n, s and t are as defined in the general formula (IV).
  • Another aspect of the present disclosure relates to a compound represented by the general formula (VA) or a tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof Form or its pharmaceutically acceptable salt:
  • Ra is an alkyl group, preferably a methyl group
  • R 1 , R 3 , R 4a , R 4b and m are as defined in the general formula (V).
  • Another aspect of the present disclosure relates to the compound represented by the general formula (VIA) or its tautomer, mesoisomer, racemate, enantiomer, diastereomer, or mixture thereof Form or its pharmaceutically acceptable salt:
  • R 4c is halogen, R 4d is halogenated alkyl or R 4d is halogen, R 4c is halogenated alkyl;
  • the X, Y, R 1 and m are as defined in the general formula (VI).
  • Another aspect of the present disclosure relates to a preparation of a compound represented by general formula (II) or its tautomer, meso, racemate, enantiomer, diastereomer, Or a method in the form of a mixture or a pharmaceutically acceptable salt thereof, the method comprising:
  • the compound of the general formula (IIA) or its tautomer, meso, racemate, enantiomer, diastereomer, or mixture form or pharmaceutically acceptable salt thereof Under acidic conditions, the compound of general formula (II) or its tautomer, mesoisomer, racemate, enantiomer, diastereomer, or its mixture form or its combination Medicinal salt,
  • said Ra is an alkyl group, preferably a methyl group
  • the X, Y, M, ring A, R 1 , R 3 , R 4 , R 5 , m, n, s and t are as defined in the general formula (I).
  • Another aspect of the present disclosure relates to a method for preparing a compound represented by the general formula (IVB) or its tautomer, meso, racemate, enantiomer, diastereomer, Or a method in the form of a mixture or a pharmaceutically acceptable salt thereof, the method comprising:
  • the Ra is an alkyl group, preferably a methyl group; the R 1 , R 3 , R 4 , R 5 , m, n, s and t are as defined in the general formula (I).
  • Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (VB) or its tautomer, meso, racemate, enantiomer, diastereomer, Or a method in the form of a mixture or a pharmaceutically acceptable salt thereof, the method comprising:
  • the compound of general formula (VB) or its tautomer, mesoisomer, racemate, enantiomer, diastereomer, or its mixture form or its alternative Medicinal salt Under acidic conditions, the compound of general formula (VB) or its tautomer, mesoisomer, racemate, enantiomer, diastereomer, or its mixture form or its alternative Medicinal salt,
  • the Ra is an alkyl group, preferably a methyl group; the R 4a , R 4b , R 1 , R 3 , and m are as defined in the general formula (V).
  • the present disclosure relates to the preparation of compounds represented by general formula (II), (IVB) or (VB) or tautomers, mesosomes, racemates, enantiomers, diastereomers
  • the acid is preferably pyridine hydrobromide.
  • Another aspect of the present disclosure relates to the compound represented by the general formula (IVC) or its tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof Form or its pharmaceutically acceptable salt:
  • R 1 , R 3 , R 4 , R 5 , m, n, s, and t are as defined in the general formula (IV).
  • Another aspect of the present disclosure relates to the compound represented by the general formula (VC) or its tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof Form or its pharmaceutically acceptable salt:
  • R 1 , R 3 , R 4a , R 4b and m are as defined in the general formula (V).
  • Another aspect of the present disclosure relates to a preparation of a compound represented by the general formula (IVD) or its tautomer, meso, racemate, enantiomer, diastereomer, Or a method in the form of a mixture or a pharmaceutically acceptable salt thereof, the method comprising:
  • the compound of general formula (IVC) or its tautomer, meso, racemate, enantiomer, diastereomer, or its mixture form or its pharmaceutically acceptable salt Heating reaction under acidic conditions to obtain the compound of general formula (IVD) or its tautomer, meso, racemate, enantiomer, diastereomer, or its mixture form or Medicinal salt,
  • R 1 , R 3 , R 4 , R 5 , m, n, s and t are as defined in the general formula (I).
  • Another aspect of the present disclosure relates to a preparation of a compound represented by the general formula (VD) or its tautomer, meso, racemate, enantiomer, diastereomer, Or a method in the form of a mixture or a pharmaceutically acceptable salt thereof, the method comprising:
  • the compound of general formula (VC) or its tautomer, meso, racemate, enantiomer, diastereomer, or its mixture form or its pharmaceutically acceptable salt Heating reaction under acidic conditions to obtain the compound of general formula (VD) or its tautomer, meso, racemate, enantiomer, diastereomer, or its mixture form or Medicinal salt,
  • R 4a , R 4b , R 1 , R 3 and m are as defined in the general formula (V).
  • the present disclosure relates to the preparation of compounds represented by the general formula (IVD) or (VD) or tautomers, mesosomes, racemates, enantiomers, diastereomers, or
  • the reagent for providing acidic conditions includes, but is not limited to, pyridine hydrobromide, trifluoroacetic acid, formic acid, acetic acid, hydrochloric acid, sulfuric acid or methanesulfonic acid, preferably Acetic acid; the heating reaction temperature is preferably 80°C.
  • Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (VI) or its tautomer, mesoisomer, racemate, enantiomer, diastereomer, Or a method in the form of a mixture or a pharmaceutically acceptable salt thereof, the method comprising:
  • the compound of general formula (VIB) is reacted to obtain a compound of general formula (VI) or its tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof Form or its pharmaceutically acceptable salt,
  • said Z is halogen
  • M is S atom or O atom
  • the X, Y, ring A, R 1 , R 3 , R 5 , m, s, and t are as defined in the general formula (VI).
  • the present disclosure relates to the preparation of intermediate compounds of the general formula (I) including but not limited to:
  • Another aspect of the present disclosure relates to a pharmaceutical composition containing a therapeutically effective amount of the compound represented by the general formula (I) of the present disclosure or its tautomer, mesosome, racemic Isomers, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.
  • a pharmaceutical composition containing a therapeutically effective amount of the compound represented by the general formula (I) of the present disclosure or its tautomer, mesosome, racemic Isomers, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.
  • the present disclosure also relates to a compound represented by the general formula (I) as described above or its tautomer, mesoisomer, racemate, enantiomer, diastereomer, Or the use of a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described above in the preparation of a medicament for inhibiting voltage-gated sodium channels in a subject.
  • the voltage-gated sodium channel is preferably Na V 1.8.
  • the present disclosure also relates to a compound represented by the general formula (I) as described above or its tautomer, mesoisomer, racemate, enantiomer, diastereomer, Or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described above in preparation for the treatment and/or alleviation of pain and pain-related diseases, multiple sclerosis, and Char-Martin-Tusan syndrome , Incontinence or arrhythmia drugs.
  • the pain is selected from chronic pain, acute pain, inflammatory pain, cancer pain, neuropathic pain, musculoskeletal pain, primary pain, intestinal pain and idiopathic pain.
  • the present disclosure also relates to a method for inhibiting a voltage-gated sodium channel in a subject, the method comprising administering to a patient in need thereof the compound represented by the general formula (I) of the present disclosure or its tautomer, The meso, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described above.
  • the voltage-gated sodium channel is preferably Na V 1.8.
  • the present disclosure also relates to a method of treating and/or alleviating pain and pain-related diseases, multiple sclerosis, Char-Martin-Tuson syndrome, incontinence, or arrhythmia, the method comprising administering to a patient in need thereof
  • the pain is selected from chronic pain, acute pain, inflammatory pain, cancer pain, neuropathic pain, musculoskeletal pain, primary pain, intestinal pain and idiopathic pain.
  • the present disclosure also relates to a compound represented by the general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer or mixture thereof, Or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described above, for use as a medicine.
  • the present disclosure also relates to a compound represented by the general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer or mixture thereof, Or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described above, which is used to inhibit voltage-gated sodium channels in a subject.
  • the voltage-gated sodium channel is preferably Na V 1.8.
  • the present disclosure also relates to a compound represented by the general formula (I) as described above or its tautomer, mesoisomer, racemate, enantiomer, diastereomer, Or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described above, which is used for the treatment and/or alleviation of pain and pain-related diseases, multiple sclerosis, and Charma-Martin syndrome , Incontinence or arrhythmia.
  • the pain is selected from chronic pain, acute pain, inflammatory pain, cancer pain, neuropathic pain, musculoskeletal pain, primary pain, intestinal pain and idiopathic pain.
  • the neuropathic pain described in the present disclosure is preferably selected from the group consisting of trigeminal neuralgia, postherpetic neuralgia, diabetic neuralgia, painful HIV-related sensory neuralgia, burn syndrome, post-amputation pain, pain after spinal cord injury, phantom Pain, painful neuroma, traumatic neuroma, Morton neuroma, nerve crush injury, spinal stenosis, carpal tunnel syndrome, nerve root pain, sciatica, nerve avulsion, brachial plexus avulsion Injuries, complex regional pain syndrome, neuralgia caused by drug therapy, neuralgia caused by cancer chemotherapy, neuralgia caused by antiretroviral therapy, primary small fiber neuropathy, primary sensory neuralgia, and trigeminal Autonomic headache.
  • the musculoskeletal pain described in the present disclosure is preferably selected from osteoarthritis pain, back pain, cold pain, burning pain and toothache.
  • the intestinal pain described in the present disclosure is preferably selected from inflammatory bowel disease pain, Crohn's disease pain or interstitial cystitis pain.
  • the inflammatory pain described in the present disclosure is preferably selected from rheumatoid arthritis pain and vulvar pain.
  • the idiopathic pain described in the present disclosure is preferably fibromyalgia.
  • the active compound can be prepared in a form suitable for administration by any appropriate route, and the active compound is preferably in a unit dose form, or a form in which the patient can self-administer in a single dose.
  • the expression mode of the unit dose of the compound or composition of the present disclosure can be tablet, capsule, cachet, bottled syrup, powder, granule, lozenge, suppository, regenerating powder or liquid preparation.
  • the dosage of the compound or composition used in the treatment methods of the present disclosure will generally vary with the severity of the disease, the weight of the patient, and the relative efficacy of the compound.
  • a suitable unit dose can be 0.1-1000 mg.
  • the pharmaceutical composition of the present disclosure may contain one or more auxiliary materials selected from the following ingredients: fillers (diluents), binders, wetting agents, disintegrants or excipients Wait.
  • auxiliary materials selected from the following ingredients: fillers (diluents), binders, wetting agents, disintegrants or excipients Wait.
  • the composition may contain 0.1 to 99% by weight of the active compound.
  • the pharmaceutical composition containing the active ingredient may be in a form suitable for oral administration, such as tablets, dragees, lozenges, water or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or Elixirs.
  • Oral compositions can be prepared according to any method known in the art for preparing pharmaceutical compositions. Such compositions can contain one or more ingredients selected from the group consisting of sweeteners, flavoring agents, coloring agents and preservatives, In order to provide pleasing and delicious medicinal preparations.
  • the tablet contains the active ingredient and non-toxic pharmaceutically acceptable excipients suitable for the preparation of tablets for mixing.
  • excipients can be inert excipients, granulating agents, disintegrating agents, binders and lubricants. These tablets may be uncoated or may be coated by known techniques that mask the taste of the drug or delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained release effect over a longer period of time.
  • Oral preparations can also be provided in soft gelatin capsules in which the active ingredient is mixed with an inert solid diluent or the active ingredient is mixed with a water-soluble carrier or oil vehicle.
  • Aqueous suspensions contain the active substance and excipients suitable for the preparation of aqueous suspensions for mixing. Such excipients are suspending agents, dispersing agents or wetting agents. Aqueous suspensions may also contain one or more preservatives, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents.
  • Oil suspensions can be formulated by suspending the active ingredients in vegetable oil or mineral oil.
  • the oil suspension may contain thickening agents.
  • the above-mentioned sweeteners and flavoring agents can be added to provide a palatable preparation. These compositions can be preserved by adding antioxidants.
  • dispersible powders and granules suitable for preparing water suspensions can be provided with active ingredients and dispersing or wetting agents for mixing, suspending agents or one or more preservatives. Suitable dispersing or wetting agents and suspending agents can illustrate the above examples. Other excipients such as sweetening agents, flavoring agents and coloring agents may also be added. These compositions are preserved by adding antioxidants such as ascorbic acid.
  • the pharmaceutical composition of the present disclosure may also be in the form of an oil-in-water emulsion.
  • the oil phase can be vegetable oil, or mineral oil or a mixture thereof.
  • Suitable emulsifiers may be naturally occurring phospholipids, and the emulsion may also contain sweeteners, flavoring agents, preservatives and antioxidants.
  • Such preparations may also contain a demulcent, a preservative, a coloring agent and an antioxidant.
  • the pharmaceutical composition of the present disclosure may be in the form of a sterile injectable aqueous solution.
  • the acceptable solvents or solvents that can be used include water, Ringer's solution and isotonic sodium chloride solution.
  • the sterile injection preparation may be a sterile injection oil-in-water microemulsion in which the active ingredient is dissolved in the oil phase.
  • the injection or microemulsion can be injected into the patient's bloodstream by local mass injection. Alternatively, it is best to administer the solution and microemulsion in a manner that maintains a constant circulating concentration of the compound of the present disclosure.
  • a continuous intravenous delivery device can be used. An example of such a device is the Deltec CADD-PLUS.TM. 5400 intravenous pump.
  • the pharmaceutical composition of the present disclosure may be in the form of a sterile injection water or oil suspension for intramuscular and subcutaneous administration.
  • the suspension can be formulated according to known techniques using those suitable dispersing or wetting agents and suspending agents mentioned above.
  • the sterile injection preparation may also be a sterile injection solution or suspension prepared in a parenterally acceptable non-toxic diluent or solvent.
  • sterile fixed oil can be conveniently used as a solvent or suspension medium. For this purpose, any blended fixed oil can be used.
  • fatty acids can also be used to prepare injections.
  • the compounds of the present disclosure can be administered in the form of suppositories for rectal administration.
  • These pharmaceutical compositions can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at ordinary temperatures but liquid in the rectum and thus will melt in the rectum to release the drug.
  • the dosage of the drug depends on many factors, including but not limited to the following factors: the activity of the specific compound used, the age of the patient, the weight of the patient, the health of the patient, and the behavior of the patient , The patient’s diet, time of administration, mode of administration, rate of excretion, combination of drugs, etc.; in addition, the best mode of treatment such as the mode of treatment, the daily dosage of compound (I) or the amount of pharmaceutically acceptable salt
  • the type can be verified according to the traditional treatment plan.
  • alkyl refers to a saturated aliphatic hydrocarbon group, which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 12 carbon atoms, more preferably containing 1 to 6 carbon atoms An alkyl group of carbon atoms.
  • Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1 ,2-Dimethylpropyl, 2,2-Dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2- Methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3 -Dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2 -Methylhexyl, 3-methylhexyl, 4-methylhe
  • a lower alkyl group containing 1 to 6 carbon atoms non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl Group, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethyl Butyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl Group, 2,3-dimethylbutyl, etc.
  • Alkyl groups may be substituted or unsubstituted. When substituted, the substituents may be substituted at any available attachment point.
  • the substituents are preferably independently selected from H atom, D atom, halogen, and alkane. Is substituted by one or more substituents in the group, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.
  • alkoxy refers to -O- (alkyl) and -O- (unsubstituted cycloalkyl), where alkyl is defined as described above.
  • alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy.
  • the alkoxy group may be optionally substituted or unsubstituted.
  • the substituent is preferably one or more of the following groups, which are independently selected from H atom, D atom, halogen, alkyl, and alkoxy , Haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl substituted by one or more substituents.
  • alkylene refers to a saturated linear or branched aliphatic hydrocarbon group, which has 2 residues derived from the removal of two hydrogen atoms from the same carbon atom or two different carbon atoms of the parent alkane, which is A straight or branched chain group containing 1 to 20 carbon atoms, preferably containing 1 to 12 carbon atoms, more preferably an alkylene group containing 1 to 6 carbon atoms.
  • Non-limiting examples of alkylene groups include, but are not limited to, methylene (-CH 2 -), 1,1-ethylene (-CH(CH 3 )-), 1,2-ethylene (-CH 2 -) CH 2 )-, 1,1-propylene (-CH(CH 2 CH 3 )-), 1,2-propylene (-CH 2 CH(CH 3 )-), 1,3-propylene (-CH 2 CH 2 CH 2 -), 1,4-butylene (-CH 2 CH 2 CH 2 CH 2 -), etc.
  • the alkylene group may be substituted or unsubstituted. When substituted, the substituent may be substituted at any available point of attachment.
  • the substituent is preferably independently optionally selected from alkyl, alkenyl, alkynyl , Alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxyl, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy Substituted by one or more substituents in the group, cycloalkylthio, heterocycloalkylthio and oxo.
  • alkenyl refers to an alkyl compound containing a carbon-carbon double bond in the molecule, wherein the definition of the alkyl group is as described above.
  • the alkenyl group may be substituted or unsubstituted.
  • the substituent is preferably one or more of the following groups, which are independently selected from hydrogen atoms, alkyl groups, alkoxy groups, halogens, halogenated alkyl groups, hydroxyl groups, It is substituted by one or more substituents among hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl and heteroaryl.
  • alkynyl refers to an alkyl compound containing a carbon-carbon triple bond in the molecule, wherein the definition of the alkyl group is as described above.
  • the alkynyl group may be substituted or unsubstituted.
  • the substituent is preferably one or more of the following groups, which are independently selected from hydrogen atoms, alkyl groups, alkoxy groups, halogens, halogenated alkyl groups, hydroxyl groups, It is substituted by one or more substituents among hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl and heteroaryl.
  • cycloalkyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent.
  • the cycloalkyl ring contains 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, preferably 3 to 8 The carbon atom more preferably contains 3 to 6 carbon atoms.
  • Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene Groups, cyclooctyl, etc.; polycyclic cycloalkyls include spiro, fused, and bridged cycloalkyls.
  • spirocycloalkyl refers to a polycyclic group that shares one carbon atom (called a spiro atom) between 5- to 20-membered monocyclic rings. It may contain one or more double bonds, but none of the rings have complete conjugate ⁇ electronic system. It is preferably 6 to 14 yuan, more preferably 7 to 10 yuan (for example, 7, 8, 9 or 10 yuan).
  • the spirocycloalkyl group is classified into a single spirocycloalkyl group, a bispirocycloalkyl group or a polyspirocycloalkyl group, preferably a single spirocycloalkyl group and a bispirocycloalkyl group. More preferably, it is a 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered, or 5-membered/6-membered monospirocycloalkyl.
  • spirocycloalkyl groups include:
  • fused cycloalkyl refers to a 5- to 20-membered all-carbon polycyclic group in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more rings may contain one or Multiple double bonds, but none of the rings have a fully conjugated ⁇ electron system. It is preferably 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of constituent rings, it can be classified into bicyclic, tricyclic, tetracyclic or polycyclic condensed cycloalkyls, preferably bicyclic or tricyclic, and more preferably 5-membered/5-membered or 5-membered/6-membered bicyclic alkyl.
  • fused cycloalkyl groups include:
  • bridged cycloalkyl refers to a 5- to 20-membered, all-carbon polycyclic group with any two rings sharing two carbon atoms that are not directly connected. It may contain one or more double bonds, but no ring has complete Conjugated ⁇ electron system. It is preferably 6 to 14 yuan, more preferably 7 to 10 yuan. It can be classified into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyls according to the number of constituent rings, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic.
  • bridged cycloalkyl groups include:
  • the cycloalkyl ring includes the cycloalkyl as described above (including monocyclic, spiro, fused, and bridged rings) fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein it is connected to the parent structure
  • the ring together is a cycloalkyl group, and non-limiting examples include indanyl, tetrahydronaphthyl, benzocycloheptyl, etc.; preferably phenylcyclopentyl, tetrahydronaphthyl.
  • Cycloalkyl groups can be substituted or unsubstituted. When substituted, the substituents can be substituted at any available attachment point.
  • the substituents are preferably independently optionally selected from hydrogen atoms, halogens, alkyl groups, Alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl are substituted by one or more substituents.
  • heterocyclyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent which contains 3 to 20 ring atoms, one or more of which is selected from nitrogen, oxygen or S(O) p (where p is an integer of 0 to 2) heteroatoms, but does not include the ring part of -OO-, -OS- or -SS-, and the remaining ring atoms are carbon.
  • Non-limiting examples of monocyclic heterocyclic groups include pyrrolidinyl, tetrahydropyranyl, 1,2.3.6-tetrahydropyridinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, Homopiperazinyl and so on.
  • Polycyclic heterocyclic groups include spiro, fused, and bridged heterocyclic groups.
  • spiroheterocyclic group refers to a polycyclic heterocyclic group sharing one atom (called a spiro atom) between monocyclic rings of 5 to 20 members, wherein one or more ring atoms are selected from nitrogen, oxygen or S(O ) p (where p is an integer of 0 to 2) heteroatoms, and the remaining ring atoms are carbon. It can contain one or more double bonds, but none of the rings have a fully conjugated ⁇ -electron system. It is preferably 6 to 14 yuan, more preferably 7 to 10 yuan.
  • the spiro heterocyclic group is classified into a single spiro heterocyclic group, a dispiro heterocyclic group or a polyspiro heterocyclic group, preferably a single spiro heterocyclic group and a dispiro heterocyclic group. More preferably, it is a 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered, or 5-membered/6-membered monospiro heterocyclic group.
  • spiroheterocyclic groups include:
  • fused heterocyclic group refers to a 5- to 20-membered polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with other rings in the system.
  • One or more rings may contain one or more Double bond, but none of the rings have a fully conjugated ⁇ -electron system, where one or more of the ring atoms are heteroatoms selected from nitrogen, oxygen or S(O) p (where p is an integer from 0 to 2), and the rest of the ring
  • the atom is carbon. It is preferably 6 to 14 yuan, more preferably 7 to 10 yuan.
  • fused heterocyclic groups include:
  • bridged heterocyclic group refers to a 5- to 14-membered polycyclic heterocyclic group with any two rings sharing two atoms that are not directly connected. It may contain one or more double bonds, but none of the rings has a complete common A conjugated ⁇ -electron system in which one or more ring atoms are heteroatoms selected from nitrogen, oxygen or S(O) p (where p is an integer of 0 to 2), and the remaining ring atoms are carbon. It is preferably 6 to 14 yuan, more preferably 7 to 10 yuan.
  • bridged heterocyclic groups include:
  • the heterocyclyl ring includes the heterocyclic group (including monocyclic, spiro heterocyclic, fused heterocyclic and bridged heterocyclic ring) as described above fused to an aryl, heteroaryl or cycloalkyl ring, wherein the group is
  • the structures linked together are heterocyclic groups, non-limiting examples of which include:
  • the heterocyclic group may be substituted or unsubstituted. When substituted, the substituent may be substituted at any available point of attachment.
  • the substituents are preferably independently optionally selected from hydrogen atoms, halogens, alkyl groups, Alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl are substituted by one or more substituents.
  • aryl refers to a 6 to 14-membered all-carbon monocyclic or fused polycyclic (that is, rings sharing adjacent pairs of carbon atoms) with a conjugated ⁇ -electron system, preferably 6 to 10 members, such as benzene Base and naphthyl.
  • the fused polycyclic aryl group is a fused aryl group, including the above-mentioned aryl ring fused to a heteroaryl, heterocyclic or cycloalkyl ring, wherein the ring connected to the parent structure Is an aryl ring, non-limiting examples include:
  • the aryl group may be substituted or unsubstituted. When substituted, the substituent may be substituted at any available point of attachment.
  • the substituents are preferably independently optionally selected from hydrogen atoms, halogens, alkyl groups, and alkyl groups.
  • One or more substituents of oxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl are substituted.
  • heteroaryl refers to a heteroaromatic system containing 1 to 4 heteroatoms and 5 to 14 ring atoms, where the heteroatoms are selected from oxygen, sulfur and nitrogen.
  • Heteroaryl groups are preferably 5 to 10 members, more preferably 5 members or 6 members, such as furyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, Imidazolyl, pyrazolyl, triazolyl, tetrazolyl and the like.
  • the heteroaryl ring includes the aforementioned heteroaryl group fused to an aryl, heterocyclic or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring, and non-limiting examples thereof include :
  • Heteroaryl groups can be substituted or unsubstituted. When substituted, the substituents can be substituted at any available attachment point.
  • the substituents are preferably independently optionally selected from hydrogen atoms, halogens, alkyl groups, Alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl are substituted by one or more substituents.
  • monovalent cation includes ammonium, alkali metal ions (such as sodium, lithium, and potassium ions), dicyclohexylamine ions, and N-methyl-D-reduced glucosamine ions.
  • Divalent cations include alkaline earth metal ions, such as calcium and magnesium ions, and divalent aluminum ions. It also includes amino acid cations, such as monovalent or divalent ions such as arginine, lysine, ornithine.
  • cycloalkyloxy refers to cycloalkyl-O-, where cycloalkyl is as defined above.
  • haloalkyl refers to an alkyl group substituted with one or more halogens, where the alkyl group is as defined above.
  • deuterated alkyl refers to an alkyl group substituted with one or more deuterium atoms, where the alkyl group is as defined above.
  • hydroxy refers to the -OH group.
  • hydroxyalkyl refers to an alkyl group substituted with a hydroxy group, where the alkyl group is as defined above.
  • halogen refers to fluorine, chlorine, bromine or iodine.
  • hydroxy refers to the -OH group.
  • amino refers to -NH 2 .
  • cyano refers to -CN.
  • nitro refers to -NO 2 .
  • carboxylate group refers to -C(O)O(alkyl) or -C(O)O(cycloalkyl), wherein alkyl and cycloalkyl are as defined above.
  • the present disclosure also includes compounds of formula (I) in various deuterated forms. Each available hydrogen atom connected to a carbon atom can be independently replaced by a deuterium atom. Those skilled in the art can synthesize the compound of formula (I) in deuterated form with reference to relevant literature. Commercially available deuterated starting materials can be used when preparing the deuterated form of the compound of formula (I), or they can be synthesized using conventional techniques using deuterated reagents. Deuterated reagents include but are not limited to deuterated borane and tri-deuterated. Borane tetrahydrofuran solution, deuterated lithium aluminum hydride, deuterated ethyl iodide and deuterated methyl iodide, etc.
  • heterocyclic group optionally substituted by an alkyl group means that an alkyl group may but need not be present, and the description includes the case where the heterocyclic group is substituted by an alkyl group and the case where the heterocyclic group is not substituted by an alkyl group .
  • Substituted refers to one or more hydrogen atoms in the group, preferably up to 5, more preferably 1 to 3 hydrogen atoms, independently of each other, substituted with a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art can determine (by experiment or theory) possible or impossible substitutions without too much effort. For example, an amino group or a hydroxyl group with free hydrogen may be unstable when combined with a carbon atom with an unsaturated (eg, olefinic) bond.
  • “Pharmaceutical composition” means a mixture containing one or more of the compounds described herein or their physiologically/pharmaceutically acceptable salts or prodrugs and other chemical components, and other components such as physiological/pharmaceutically acceptable carriers And excipients.
  • the purpose of the pharmaceutical composition is to promote the administration of the biological body, facilitate the absorption of the active ingredient and then develop the biological activity.
  • “Pharmaceutically acceptable salt” refers to the salt of the compound of the present disclosure. Such salt is safe and effective when used in the body of a mammal, and has due biological activity.
  • the compounds of the present disclosure may also include isotopic derivatives thereof.
  • isotopic derivatives refers to compounds that differ in structure only in the presence of one or more isotopically enriched atoms.
  • isotopic derivatives refers to compounds that differ in structure only in the presence of one or more isotopically enriched atoms.
  • in addition to using “deuterium” or “tritium” instead of hydrogen, or using 18 F-fluorine label ( 18 F isotope) instead of fluorine, or using 11 C-, 13 C-, or 14 C-rich Compounds in which a set of carbons ( 11 C-, 13 C-, or 14 C-carbon labels; 11 C-, 13 C-, or 14 C-isotopes) replace carbon atoms are within the scope of the present disclosure.
  • Such compounds can be used, for example, as analytical tools or probes in biological assays, or as tracers for in vivo diagnostic imaging of diseases, or as tracers for pharmacodynamics, pharmacokinetics, or receptor studies.
  • Deuterated compounds can generally retain activity comparable to that of non-deuterated compounds, and when deuterated at certain specific sites, they can achieve better metabolic stability, thereby obtaining certain therapeutic advantages (such as increased in vivo half-life or reduced dosage requirements) ).
  • the term "therapeutically effective amount” refers to a sufficient amount of a drug or agent that is non-toxic but can achieve the desired effect.
  • the determination of the effective amount varies from person to person, and depends on the age and general conditions of the recipient, as well as the specific active substance. The appropriate effective amount in a case can be determined by those skilled in the art according to routine experiments.
  • the preparation method of compound 1 of the present disclosure or its salt includes the following steps:
  • the reagent for providing acidic conditions includes, but is not limited to, pyridine hydrobromide, trifluoroacetic acid, formic acid, acetic acid, hydrochloric acid, sulfuric acid or methanesulfonic acid, preferably pyridine hydrobromide.
  • the preparation method of compound 2 of the present disclosure or its salt includes the following steps:
  • compound 1 undergoes an alkylation reaction in the presence of an alkylating reagent (preferably chloromethyl chloroformate) to obtain compound 2a.
  • an alkylating reagent preferably chloromethyl chloroformate
  • compound 2a is heated (preferably 80°C) under catalytic conditions (preferably tetrabutylammonium iodide) to perform phosphorylation reaction (preferably di-tert-butyl potassium phosphate) to obtain compound 2b,
  • catalytic conditions preferably tetrabutylammonium iodide
  • phosphorylation reaction preferably di-tert-butyl potassium phosphate
  • compound 2b is reacted under acidic conditions (acid reagent is preferably acetic acid) and heated (preferably 80°C) to obtain compound 2.
  • acid reagent is preferably acetic acid
  • the salt method used includes:
  • the compound of the general formula (IIA) or its tautomer, meso, racemate, enantiomer, diastereomer, or mixture form or pharmaceutically acceptable salt thereof Under acidic conditions, the compound of general formula (II) or its tautomer, mesoisomer, racemate, enantiomer, diastereomer, or its mixture form or its combination Medicinal salt,
  • said Ra is an alkyl group, preferably a methyl group
  • the X, Y, M, ring A, R 1 , R 3 , R 4 , R 5 , m, n, s and t are as defined in the general formula (I).
  • the compound represented by the general formula (IVB) of the present disclosure or its tautomer, meso, racemate, enantiomer, diastereomer, or a mixture of its form or its pharmacologically
  • the salt method used includes:
  • the Ra is an alkyl group, preferably a methyl group; the R 1 , R 3 , R 4 , R 5 , m, n, s and t are as defined in the general formula (I).
  • the salt method used includes:
  • the compound of general formula (VB) or its tautomer, mesoisomer, racemate, enantiomer, diastereomer, or its mixture form or its alternative Medicinal salt Under acidic conditions, the compound of general formula (VB) or its tautomer, mesoisomer, racemate, enantiomer, diastereomer, or its mixture form or its alternative Medicinal salt,
  • the Ra is an alkyl group, preferably a methyl group; the R 4a , R 4b , R 1 , R 3 , and m are as defined in the general formula (V).
  • the reagents for providing acidic conditions include but are not limited to pyridine hydrobromide, trifluoroacetic acid, formic acid, acetic acid, hydrochloric acid, sulfuric acid or methanesulfonic acid, preferably pyridine hydrobromide.
  • the salt method used includes:
  • the compound of general formula (IVC) or its tautomer, meso, racemate, enantiomer, diastereomer, or its mixture form or its pharmaceutically acceptable salt Heating reaction under acidic conditions to obtain the compound of general formula (IVD) or its tautomer, meso, racemate, enantiomer, diastereomer, or its mixture form or Medicinal salt,
  • the Ra is an alkyl group, preferably a methyl group; the R 1 , R 3 , R 4 , R 5 , m, n, s and t are as defined in the general formula (I).
  • the salt method used includes:
  • the compound of general formula (VC) or its tautomer, meso, racemate, enantiomer, diastereomer, or its mixture form or its pharmaceutically acceptable salt Heating reaction under acidic conditions to obtain the compound of general formula (VD) or its tautomer, meso, racemate, enantiomer, diastereomer, or its mixture form or Medicinal salt,
  • the Ra is an alkyl group, preferably a methyl group; the R 4a , R 4b , R 1 , R 3 , and m are as defined in the general formula (V).
  • the reagents that provide acidic conditions include, but are not limited to, pyridine hydrobromide, trifluoroacetic acid, formic acid, acetic acid, hydrochloric acid, sulfuric acid or methanesulfonic acid, preferably acetic acid; the heating reaction temperature is preferably 80°C.
  • the compound represented by the general formula (VI) of the present disclosure or its tautomer, meso, racemate, enantiomer, diastereomer, or a mixture of its form or its pharmacologically
  • the salt method used includes:
  • the compound of general formula (VIB) is reacted under basic conditions to obtain the compound of general formula (VI) or its tautomer, meso, racemate, enantiomer, diastereomer Structure, or its mixture form or its pharmaceutically acceptable salt,
  • said Z is halogen
  • the X, Y, ring A, R 1 , R 3 , R 5 , m, s, and t are as defined in the general formula (VI).
  • the reagents that provide basic conditions in the above synthesis scheme include organic bases and inorganic bases.
  • the organic bases include, but are not limited to, triethylamine, N,N-diisopropylethylamine, n-butyllithium, and diisopropylamine.
  • the inorganic bases include, but are not limited to, sodium hydride, potassium phosphate, sodium carbonate , Potassium carbonate, potassium acetate, cesium carbonate, sodium hydroxide and lithium hydroxide.
  • the above reaction is preferably carried out in a solvent.
  • the solvents used include but are not limited to: ethylene glycol dimethyl ether, acetic acid, methanol, ethanol, n-butanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, Dimethyl sulfoxide, 1,4-dioxane, water or N,N-dimethylformamide.
  • the structure of the compound is determined by nuclear magnetic resonance (NMR) or/and mass spectrometry (MS).
  • NMR shift ( ⁇ ) is given in units of 10 -6 (ppm).
  • NMR was measured with Bruker AVANCE-400 nuclear magnetic instrument, and the solvent was deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), deuterated methanol (CD 3 OD), and the internal standard was four Methylsilane (TMS).
  • HPLC High performance liquid chromatography analysis uses Agilent HPLC 1200DAD, Agilent HPLC 1200VWD and Waters HPLC e2695-2489 high pressure liquid chromatograph.
  • HPLC preparation uses Waters 2545-2767, Waters 2767-SQ Detecor2, Shimadzu LC-20AP and Gilson GX-281 preparative chromatographs.
  • CombiFlash rapid preparation instrument uses Combiflash Rf200 (TELEDYNE ISCO).
  • the thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate, the size of the silica gel plate used in thin layer chromatography (TLC) is 0.15mm ⁇ 0.2mm, and the size of thin layer chromatography separation and purification products is 0.4mm ⁇ 0.5mm.
  • Silica gel thin-layer chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier.
  • the known starting materials of the present disclosure can be synthesized by or according to 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.
  • reaction can all be carried out under an argon atmosphere or a nitrogen atmosphere.
  • the argon atmosphere or nitrogen atmosphere means that the reaction flask is connected to an argon or nitrogen balloon with a volume of about 1L.
  • the hydrogen atmosphere means that the reaction flask is connected to a hydrogen balloon with a volume of about 1L.
  • the pressure hydrogenation reaction uses Parr 3916EKX hydrogenator and Qinglan QL-500 hydrogen generator or HC2-SS hydrogenator.
  • the hydrogenation reaction is usually evacuated, filled with hydrogen, and repeated three times.
  • the microwave reaction uses the CEM Discover-S 908860 microwave reactor.
  • the solution refers to an aqueous solution.
  • reaction temperature is room temperature, which is 20°C to 30°C.
  • the monitoring of the reaction progress in the examples adopts thin-layer chromatography (TLC).
  • the developing reagent used in the reaction, the eluent system of column chromatography used in the purification of the compound and the developing reagent system of thin-layer chromatography include: A: Dichloromethane/methanol system; B: n-hexane/ethyl acetate system.
  • the volume ratio of the solvent is adjusted according to the polarity of the compound, and it can also be adjusted by adding a small amount of basic or acidic reagents such as triethylamine and acetic acid.
  • the crude compound 1c (8.60g, 32.98mmol) and 2-methoxypyridine-4-amine (4.90g, 39.5mmol, Shaoyuan Technology (Shanghai) Co., Ltd.) were dissolved in 80mL of dichloromethane, and pyridine (11g, 139mmol), react at room temperature for 16 hours.
  • the reaction solution was concentrated under reduced pressure, and purified by silica gel column chromatography with the developing solvent system A to obtain the title compound 1d (10 g), yield: 87%.
  • Compound 3b (6g, 27.2mmol) was mixed with aluminum trichloride (11g, 82.5mmol) uniformly, and reacted at 100°C for 15 minutes, and then heated to 170°C and reacted for 3 hours. Cool to room temperature, slowly add ice water and ethyl acetate, and crush the lumps with the help of an ultrasonic cleaner. It was filtered with Celite, the filtrate was concentrated under reduced pressure, and purified by silica gel column chromatography with the developing solvent system B to obtain the title compound 3c (2.7 g), yield: 54%.
  • the compound 7-bromo-4-fluorobenzofuran 6a (1.0g, 4.65mmol, Shaoyuan Technology (Shanghai) Co., Ltd.) was dissolved in ethanol, rhodium carbon (150mg, 1.46mmol) was added, and hydrogen was replaced three times. Reverse the atmosphere at room temperature overnight.
  • the crude product (1g) of title compound 6b was obtained by filtration and concentration, which was directly used in the next reaction.
  • the reaction was cooled, the reaction solution was concentrated, saturated sodium bicarbonate solution was added, extracted with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
  • the residue was dissolved in tetrahydrofuran, cooled to 0°C, and sodium hydroxide solution (1M, 2mL) and hydrogen peroxide (0.5mL) were added dropwise. It was naturally raised to room temperature and reacted for 2 hours. Saturated sodium thiosulfate solution was added dropwise to the reaction solution under ice bath.
  • the raw material 4d in the fifth step was replaced with compounds 13b and 13c to obtain the title compound 13 (220 mg) and the title compound 14 (90 mg).
  • Test Example 1 Determination of the inhibitory activity of the compound of the present disclosure on Nav1.8
  • the purpose of the experiment is to investigate the effect of the compound on the Na V 1.8 ion channel in an in vitro experiment, and the Na V 1.8 ion channel is stably expressed on HEK293 cells. After the Na V 1.8 current is stable, comparing the Na V 1.8 current before and after the compound application, the influence of the compound on the Na V 1.8 ion channel can be obtained.
  • Patch clamp amplifier patch clamp PC-505B (WARNER instruments)/MultiClamp 700A (Axon instrument)
  • Tetrodotoxin AF3014 (Affix Scientific)
  • the extracellular fluid (mM) is: NaCl, 137; KCl, 4; CaCl 2 , 1.8; MgCl 2 , 1; HEPES, 10; glucose 10; pH 7.4 (NaOH titration).
  • Intracellular fluid (mM) is aspartic acid, 140; MgCl 2 , 2; EGTA11; HEPES, 10; pH 7.2 (CsOH titration). All test compound and control compound solutions contained 1 ⁇ M TTX.
  • the storage concentration of the test compound is 9 mM, dissolved in dimethyl sulfoxide (DMSO). Re-dissolve in the extracellular fluid on the day of the test and prepare the required concentration.
  • DMSO dimethyl sulfoxide
  • the data will be stored in the computer system for analysis. Data collection and analysis will use pCLAMP 10 (Molecular Devices, Union City, CA), and management personnel will review the analysis results.
  • Current stability means that the current changes within a limited range over time. The magnitude of the current stabilized is used to calculate the effect of the compound's solubility.
  • the inhibitory activity of the compounds of the present disclosure on Nav1.8 was determined by the above test, and the measured IC 50 value is shown in Table 1.
  • Table 1 The IC 50 of the compounds of the present disclosure for inhibition of Nav1.8 channel activity

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Abstract

La présente divulgation concerne un dérivé cyclicque aromatique condensé de benzamide, son procédé de préparation et son utilisation en médecine. Plus particulièrement, la présente divulgation concerne un dérivé cyclique aromatique condensé de benzamide représenté par la formule générale (I), son procédé de préparation, une composition pharmaceutique comprenant le dérivé et son utilisation en tant qu'agent thérapeutique, ainsi que son utilisation en tant qu'inhibiteur de NaV1.8 et son utilisation dans la préparation d'un médicament pour le traitement et/ou la prévention de la douleur et de maladies associées à la douleur. Chaque substituant dans la formule générale (I) est le même que celui défini dans la description.
PCT/CN2020/109692 2019-08-19 2020-08-18 Dérivé cyclicque aromatique condensé de benzamide, son procédé de préparation et son utilisation en médecine Ceased WO2021032074A1 (fr)

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WO2022256708A1 (fr) 2021-06-04 2022-12-08 Vertex Pharmaceuticals Incorporated Formes galéniques solides et schémas posologiques comprenant du (2r,3s,4s,5r)-4-[[3-(3,4-difluoro-2-méthoxy-phényl)-4,5-diméthyl-5-(trifluorométhyl)tétrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide
WO2022256842A1 (fr) 2021-06-04 2022-12-08 Vertex Pharmaceuticals Incorporated Tétrahydrofuranes à substitution hydroxy et (halo)alkoxy utiles en tant que modulateurs de canaux sodiques
WO2022256676A1 (fr) 2021-06-04 2022-12-08 Vertex Pharmaceuticals Incorporated Analogues de tétrahydrofurane substitués utiles en tant que modulateurs de canaux sodiques
WO2022256622A1 (fr) 2021-06-04 2022-12-08 Vertex Pharmaceuticals Incorporated N-(hydroxyalkyl (hétéro)aryl) tétrahydrofuran carboxamides utilisés en tant que modulateurs de canaux sodiques
WO2022256679A1 (fr) 2021-06-04 2022-12-08 Vertex Pharmaceuticals Incorporated Analogues de n-(hydroxyalkyl(hétéro)aryl)tétrahydrofurane carboxamide en tant que modulateurs de canaux sodiques
WO2022256702A1 (fr) 2021-06-04 2022-12-08 Vertex Pharmaceuticals Incorporated Tétrahydrofuran-2-carboxamides substitués utiles en tant que modulateurs de canaux sodiques
WO2023205468A1 (fr) 2022-04-22 2023-10-26 Vertex Pharmaceuticals Incorporated Composés hétéroaryle pour le traitement de la douleur
WO2023205463A1 (fr) 2022-04-22 2023-10-26 Vertex Pharmaceuticals Incorporated Composés hétéroaryles pour le traitement de la douleur
WO2023205465A1 (fr) 2022-04-22 2023-10-26 Vertex Pharmaceuticals Incorporated Composés hétéroaryles pour le traitement de la douleur
WO2023205778A1 (fr) 2022-04-22 2023-10-26 Vertex Pharmaceuticals Incorporated Composés hétéroaryles pour le traitement de la douleur
CN116947713A (zh) * 2022-04-25 2023-10-27 中国科学院上海药物研究所 并环类化合物及其应用
WO2023211990A1 (fr) 2022-04-25 2023-11-02 Siteone Therapeutics, Inc. Inhibiteurs d'amides hétérocycliques bicycliques de na v1.8 pour le traitement de la douleur
CN117567257A (zh) * 2023-11-29 2024-02-20 江苏盈天环保科技有限公司 一种1-四氢萘酮的制备方法
WO2024123815A1 (fr) 2022-12-06 2024-06-13 Vertex Pharmaceuticals Incorporated Procédé de synthèse de modulateurs de tétrahydrofurane substitués de canaux sodiques
WO2025090480A1 (fr) 2023-10-23 2025-05-01 Vertex Pharmaceuticals Incorporated Composés hétéroaryles pour le traitement de la douleur
WO2025090465A1 (fr) 2023-10-23 2025-05-01 Vertex Pharmaceuticals Incorporated Composés hétéroaryle pour le traitement de la douleur
WO2025090511A1 (fr) 2023-10-23 2025-05-01 Vertex Pharmaceuticals Incorporated Procédés de préparation de modulateurs de canaux sodiques et formes solides de ceux-ci pour le traitement de la douleur
WO2025090516A1 (fr) 2023-10-23 2025-05-01 Vertex Pharmaceuticals Incorporated Procédés de préparation de composés pour le traitement de la douleur et de formes solides de ceux-ci
WO2025122953A1 (fr) 2023-12-07 2025-06-12 Vertex Pharmaceuticals Incorporated Schémas posologiques et formulations de suzétrigine pour le traitement des douleurs sévères et chroniques
WO2025160286A1 (fr) 2024-01-24 2025-07-31 Siteone Therapeutics, Inc. 2-aryl cycloalkyle et inhibiteurs d'hétérocycloalkyle de nav1.8 pour le traitement de la douleur
US12503439B2 (en) 2023-04-21 2025-12-23 Vertex Pharmaceuticals Incorporated Heteroaryl compounds for the treatment of pain

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022256708A1 (fr) 2021-06-04 2022-12-08 Vertex Pharmaceuticals Incorporated Formes galéniques solides et schémas posologiques comprenant du (2r,3s,4s,5r)-4-[[3-(3,4-difluoro-2-méthoxy-phényl)-4,5-diméthyl-5-(trifluorométhyl)tétrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide
WO2022256842A1 (fr) 2021-06-04 2022-12-08 Vertex Pharmaceuticals Incorporated Tétrahydrofuranes à substitution hydroxy et (halo)alkoxy utiles en tant que modulateurs de canaux sodiques
WO2022256676A1 (fr) 2021-06-04 2022-12-08 Vertex Pharmaceuticals Incorporated Analogues de tétrahydrofurane substitués utiles en tant que modulateurs de canaux sodiques
WO2022256622A1 (fr) 2021-06-04 2022-12-08 Vertex Pharmaceuticals Incorporated N-(hydroxyalkyl (hétéro)aryl) tétrahydrofuran carboxamides utilisés en tant que modulateurs de canaux sodiques
WO2022256679A1 (fr) 2021-06-04 2022-12-08 Vertex Pharmaceuticals Incorporated Analogues de n-(hydroxyalkyl(hétéro)aryl)tétrahydrofurane carboxamide en tant que modulateurs de canaux sodiques
WO2022256702A1 (fr) 2021-06-04 2022-12-08 Vertex Pharmaceuticals Incorporated Tétrahydrofuran-2-carboxamides substitués utiles en tant que modulateurs de canaux sodiques
US12258333B2 (en) 2021-06-04 2025-03-25 Vertex Pharmaceuticals Incorporated N-(hydroxyalkyl (hetero)aryl) tetrahydrofuran carboxamides as modulators of sodium channels
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WO2023205468A1 (fr) 2022-04-22 2023-10-26 Vertex Pharmaceuticals Incorporated Composés hétéroaryle pour le traitement de la douleur
WO2023205463A1 (fr) 2022-04-22 2023-10-26 Vertex Pharmaceuticals Incorporated Composés hétéroaryles pour le traitement de la douleur
WO2023205465A1 (fr) 2022-04-22 2023-10-26 Vertex Pharmaceuticals Incorporated Composés hétéroaryles pour le traitement de la douleur
WO2023205778A1 (fr) 2022-04-22 2023-10-26 Vertex Pharmaceuticals Incorporated Composés hétéroaryles pour le traitement de la douleur
WO2023207949A1 (fr) * 2022-04-25 2023-11-02 中国科学院上海药物研究所 Composé cyclique fusionné et son utilisation
WO2023211990A1 (fr) 2022-04-25 2023-11-02 Siteone Therapeutics, Inc. Inhibiteurs d'amides hétérocycliques bicycliques de na v1.8 pour le traitement de la douleur
CN116947713A (zh) * 2022-04-25 2023-10-27 中国科学院上海药物研究所 并环类化合物及其应用
WO2024123815A1 (fr) 2022-12-06 2024-06-13 Vertex Pharmaceuticals Incorporated Procédé de synthèse de modulateurs de tétrahydrofurane substitués de canaux sodiques
US12503439B2 (en) 2023-04-21 2025-12-23 Vertex Pharmaceuticals Incorporated Heteroaryl compounds for the treatment of pain
WO2025090480A1 (fr) 2023-10-23 2025-05-01 Vertex Pharmaceuticals Incorporated Composés hétéroaryles pour le traitement de la douleur
WO2025090465A1 (fr) 2023-10-23 2025-05-01 Vertex Pharmaceuticals Incorporated Composés hétéroaryle pour le traitement de la douleur
WO2025090511A1 (fr) 2023-10-23 2025-05-01 Vertex Pharmaceuticals Incorporated Procédés de préparation de modulateurs de canaux sodiques et formes solides de ceux-ci pour le traitement de la douleur
WO2025090516A1 (fr) 2023-10-23 2025-05-01 Vertex Pharmaceuticals Incorporated Procédés de préparation de composés pour le traitement de la douleur et de formes solides de ceux-ci
CN117567257A (zh) * 2023-11-29 2024-02-20 江苏盈天环保科技有限公司 一种1-四氢萘酮的制备方法
WO2025122953A1 (fr) 2023-12-07 2025-06-12 Vertex Pharmaceuticals Incorporated Schémas posologiques et formulations de suzétrigine pour le traitement des douleurs sévères et chroniques
WO2025160286A1 (fr) 2024-01-24 2025-07-31 Siteone Therapeutics, Inc. 2-aryl cycloalkyle et inhibiteurs d'hétérocycloalkyle de nav1.8 pour le traitement de la douleur

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