WO2026008013A1 - 氧代杂芳基类化合物、其制备方法及其在医药上的应用 - Google Patents

氧代杂芳基类化合物、其制备方法及其在医药上的应用

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Publication number
WO2026008013A1
WO2026008013A1 PCT/CN2025/106834 CN2025106834W WO2026008013A1 WO 2026008013 A1 WO2026008013 A1 WO 2026008013A1 CN 2025106834 W CN2025106834 W CN 2025106834W WO 2026008013 A1 WO2026008013 A1 WO 2026008013A1
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WIPO (PCT)
Prior art keywords
alkyl
heterocyclic
cycloalkyl
compound
membered
Prior art date
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PCT/CN2025/106834
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English (en)
French (fr)
Inventor
李心
陈阳
徐国际
蔡国栋
贺峰
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Shanghai Hengrui Pharmaceutical Co Ltd
Jiangsu Hengrui Pharmaceutical Co Ltd
Original Assignee
Shanghai Hengrui Pharmaceutical Co Ltd
Jiangsu Hengrui Pharmaceutical Co Ltd
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Publication date
Application filed by Shanghai Hengrui Pharmaceutical Co Ltd, Jiangsu Hengrui Pharmaceutical Co Ltd filed Critical Shanghai Hengrui Pharmaceutical Co Ltd
Publication of WO2026008013A1 publication Critical patent/WO2026008013A1/zh
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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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
    • A61K31/435—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
    • A61K31/4353—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 ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4375—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 ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • 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
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • This disclosure pertains to the pharmaceutical field and relates to oxoheteroaryl compounds, their preparation methods, and their pharmaceutical applications.
  • this disclosure relates to oxoheteroaryl compounds of general formula (I), their preparation methods, pharmaceutical compositions containing such compounds, their use as Nav inhibitors, and their use in the preparation of medicaments for treating and/or alleviating pain and pain-related diseases.
  • Pain is a complex physiological and psychological activity and one of the most common clinical symptoms.
  • the International Association for the Study of Pain defines pain as "an unpleasant sensory and emotional experience associated with actual or potential tissue damage; it is a subjective feeling.” Pain can serve as a warning signal, alerting the body to potential dangers and playing an indispensable protective role in normal bodily functions.
  • Pain is also a common clinical symptom; after the external stimulus that triggered the pain disappears, intense or persistent pain can cause physiological dysfunction, severely impacting the quality of life.
  • Statistics show that approximately one-fifth of the world's population suffers from moderate to severe chronic pain.
  • action potentials nerve impulses
  • DRG dorsal root ganglion
  • the generation and conduction of action potentials in neurons depend on voltage-gated sodium channels (Nav) on the cell membrane. When the cell membrane depolarizes, sodium ion channels are activated, opening and causing an influx of sodium ions, further depolarizing the cell membrane and leading to the generation of action potentials. Therefore, inhibiting abnormal sodium ion channel activity can help treat and alleviate pain.
  • Nav voltage-gated sodium channels
  • Sodium channels are a class of transmembrane ion channel proteins. These proteins consist of an ⁇ subunit with a molecular weight of 260 kDa and a ⁇ subunit with a molecular weight of 30-40 kDa. Based on the different ⁇ subunits, they can be divided into nine subtypes, Nav1.1 to Nav1.9. Different subtypes exhibit different tissue distributions and electrophysiological and pharmacological characteristics. Based on their ability to be effectively inhibited by tetrodotoxin (TTX), sodium ion channels are classified into TTX-sensitive (TTX-S) and TTX-insensitive (TTX-R) types.
  • TTX-S TTX-sensitive
  • TTX-R TTX-insensitive
  • Nav1.1, Nav1.2, Nav1.3, and Nav1.7 are TTX-S type, with their encoding genes located on human chromosome 2q23-24, and they are highly expressed in neurons.
  • Nav1.5, Nav1.8, and Nav1.9 are TTX-R type, with their encoding genes located on human chromosome 3p21-24.
  • Nav1.5 is mainly found in cardiomyocytes, while Nav1.8 and Nav1.9 are present in the peripheral nervous system.
  • Nav1.4 and Nav1.6 are both TTX-S type, and are abundant in skeletal muscle and the central nervous system, respectively.
  • the local anesthetic lidocaine relieves pain by inhibiting Nav.
  • Non-selective Nav inhibitors such as lamotrigine, lacocillin, and mexiletine, have been successfully used to treat chronic pain.
  • Nav1.8 a TTX-R type gene encoded by SCN10A, is primarily found in trigeminal ganglion neurons and DRG neurons, exhibiting slow inactivation and rapid recovery electrophysiological characteristics. In neurons expressing Nav1.8, the rise in action potentials is mainly driven by Nav1.8 currents. In several models of neuropathic pain, nerve injury increases Nav1.8 expression levels in axons and neuronal cell bodies. Using Nav1.8 antisense oligonucleotides to reduce Nav1.8 expression significantly alleviates pain. Intraplasty of carrageenan in rat paws increased Nav1.8 expression in DRG neurons. Nav1.8 knockout mice do not exhibit normal visceral inflammatory pain.
  • Nav1.8 Functionally gain mutations in the human Nav1.8 gene lead to peripheral neuropathic pain. Based on a series of animal experiments and human genetic evidence, selective inhibition of Nav1.8 has the potential to become a novel analgesic therapy for treating various pain types, including inflammatory pain, neuropathic pain, postoperative pain, and cancer pain.
  • Nav1.8 is primarily distributed in the peripheral nervous system, so selective inhibition of Nav1.8 can effectively reduce side effects. Therefore, it is necessary to develop Nav1.8 inhibitors with higher activity, better selectivity, superior pharmacokinetic properties, and fewer side effects.
  • Nav1.8 inhibitor compounds include WO2023205463A1, WO2023205465A1, WO2023205468A1, and WO2023205778A1.
  • Ring A is aryl or heteroaryl; ring B is cycloalkyl or heterocyclic.
  • R15 and R16 may be the same or different, and each is independently selected from hydrogen, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxy, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl, cyano , NR11R12 , C(O) NR11R12 , C(O) R14 , OR14 , cycloalkyl, heterocyclic, aryl , and heteroaryl; wherein the alkyl, alkoxy, alkoxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl are each independently optionally substituted by one or more R01 ;
  • G is selected from N, N + O - and CR;
  • G1 is selected from N, N + O - and CR9 ;
  • G2 is selected from N, N + O - and CR1 ;
  • G3 is selected from N, N + O- and CR2 ;
  • G4 is selected from N, N + O- and CR3 ;
  • R11 , R12 , R13 , and R14 may be the same or different, and each is independently selected from hydrogen, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxy, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl, NR 30 R 31 , C(O)NR 30 R 31 , C(O)R 33 , OR 33 , S(O) v R 33 , cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkylalkyl, heterocyclic alkyl, arylalkyl, and heteroarylalkyl; wherein the alkyl, alkoxy, alkoxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkylalkyl, heterocyclic alkyl, arylalkyl, and heteroarylalkyl; wherein the alky
  • R 30 , R 31 and R 33 may be the same or different, and each is independently selected from hydrogen atom, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, alkoxyalkyl, alkylthio, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkylalkyl and heterocyclicalkyl;
  • n 0, 1, 2, 3, 4, 5, or 6;
  • Each v is the same or different, and each is independently 0, 1 or 2.
  • the compound represented by general formula (I') or a pharmaceutically acceptable salt thereof is a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof:
  • X1 is N or CR 8 ;
  • X2 is N or CR 4 ;
  • X3 is N or CR 5 ;
  • X4 is N or CR 6 ;
  • Rings B, G1 to G4 , R, RB , R7 , n, R11 to R14 , R02 , RA and v are as defined in general formula (I').
  • the compounds represented by general formulas (I) and (I') or their pharmaceutically acceptable salts are compounds represented by general formula (II) or their pharmaceutically acceptable salts:
  • Rings B, RB , X1 , G1 , R, R1 to R7 and n are as defined in general formula (I).
  • the compound represented by general formula (I), (I'), or (II), or a pharmaceutically acceptable salt thereof is a compound represented by general formula (III) or a pharmaceutically acceptable salt thereof:
  • U is N or CR 7a , R 7a is a hydrogen atom or R 7 ;
  • G1 , X1 , R1 to R7 , R11 , R12 , R15 and R16 are as defined in general formula (I).
  • the compounds represented by general formulas (I) to (III) or pharmaceutically acceptable salts thereof are compounds represented by general formula (IV) or pharmaceutically acceptable salts thereof:
  • G1 , X1 , R1 to R7 , R7a , R11 , R12 , R15 , R16 , s, r and q are as defined in general formula (III).
  • the compounds represented by general formulas (I) to (IV) or their pharmaceutically acceptable salts are compounds represented by general formulas (IV-1) or (IV-2) or their pharmaceutically acceptable salts:
  • R 7a is selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, hydroxy, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl, amino, NR 11 R 12 , C(O)NR 11 R 12 , C(O)R 14 , OR 14 , cycloalkyl and heterocyclic groups, wherein each of the alkyl, alkoxy, alkoxyalkyl, alkenyl, alkynyl, cycloalkyl and heterocyclic groups is independently optionally substituted by one or more R 03 ;
  • G1 , X1 , R1 to R7 , R11 , R12 , R14 , R15 , R16 , s, r and q are as defined in general formula (IV), and R03 is as defined in general formula (I').
  • the compound represented by general formula (I') or a pharmaceutically acceptable salt thereof wherein ring A is a 6- to 10-membered aryl or a 5- to 10-membered heteroaryl; in some embodiments, ring A is phenyl or a 5- or 6-membered heteroaryl; in some embodiments, ring A is phenyl or a 6-membered heteroaryl; in some embodiments, ring A is selected from phenyl, pyridyl, and pyrazolyl; in some embodiments, ring A is phenyl or pyridyl; in some embodiments, ring A is selected from... In some implementations, ring A is In some embodiments, ring A is a pyrazolyl group; in some embodiments, ring A is... *The end is connected to ring B. The end is connected to the ring containing NH.
  • R15 and R16 are the same or different and are each independently selected from hydrogen atoms, halogens, and C1-6 alkyl groups; in some embodiments, R15 and R16 are the same or different and are each independently hydrogen atoms or halogens; in some embodiments, R15 and R16 are the same or different and are each independently hydrogen atoms or F; in some embodiments, R15 and R16 are the same or different and are each independently halogens; in some embodiments, both R15 and R16 are F.
  • the compound represented by general formula (I') or a pharmaceutically acceptable salt thereof wherein for In some implementation schemes, for In some implementation schemes, for X1 , X2 , X3 and X4 are as defined in general formula (I); *the end is connected to ring B.
  • the compounds represented by general formulas (I) to (IV) or their pharmaceutically acceptable salts wherein Selected from X1 , X2 , X3 , X4 , R4 , R5 , and R6 are as defined in general formula (I); in some implementations, for In some implementation schemes, for X1 , X3 , R4 , R5 , R6 and R8 are as defined in general formula (I).
  • the compounds represented by general formulas (I) to (IV) or pharmaceutically acceptable salts thereof wherein X1 is N or CR8 , and R8 is selected from hydrogen atoms, halogens, C1-6 alkyl groups, and C1-6 haloalkyl groups; in some embodiments, X1 is CR8 , and R8 is as defined in general formula (I); in some embodiments, X1 is N or CH; in some embodiments, X1 is N; in some embodiments, X1 is CH.
  • the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof wherein X2 is N or CR4 , and R4 is selected from hydrogen atoms, halogens, C1-6 alkyl groups, C1-6 haloalkyl groups, and 3- to 6-membered cycloalkyl groups, wherein the 3- to 6-membered cycloalkyl groups are optionally substituted with one or more selected from halogens, C1-6 alkyl groups, and C1-6 haloalkyl groups; in some embodiments, X2 is CR4 , and R4 is as defined in general formula (I); in some embodiments, X2 is CH or C-methyl; in some embodiments, X2 is C-methyl.
  • the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof wherein X3 is N or CR5 , and R5 is selected from hydrogen atoms, halogens, C1-6 alkyl groups and C1-6 haloalkyl groups; in some embodiments, X3 is CR5 , and R5 is as defined in general formula (I); in some embodiments, X3 is N or CH; in some embodiments, X3 is CH.
  • the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof wherein X4 is N or CR6 , and R6 is selected from hydrogen, halogen, cyano, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, and 3- to 6-membered cycloalkyl, wherein the 3- to 6-membered cycloalkyl is optionally substituted by one or more selected from halogen, C1-6 alkyl, and C1-6 haloalkyl; in some embodiments, X4 is selected from N, CH, C-Cl, and C- CF3 ; in some embodiments, X4 is C-Cl or C- CF3 ; in some embodiments, X4 is C-Cl.
  • the compound represented by general formula (I) or its pharmaceutically acceptable salt wherein X1 is N or CR8 , X2 is N or CR4 , X3 is CR5 , X4 is CR6 , or X1 is N or CR8 , X2 is CR4 , X3 is N or CR5, X4 is CR6 , or X1 is N or CR8 , X2 is CR4, X3 is CR5 , X4 is N or CR6 ; in some embodiments, X1 is N or CR8 , X2 is CR4 , X3 is CR5, X4 is CR6 ; in some embodiments, X1 is CR8 , X2 is CR4 , X3 is N, X4 is CR6 ; in some embodiments, X1 is CR8, X2 is CR4 , X3 is CR8 , X1 is CR8, X2
  • X4 is CR6 ; R4 , R5 , R6 and R8 are as defined in general formula (I); in some embodiments, X1 is N or CH, X2 is CR4 , X3 is CR5 , X4 is CR6 , R4 , R5 and R6 are the same or different, and each is independently selected from hydrogen atoms, halogens, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy and 3 to 6 membered cycloalkyl.
  • the compounds represented by general formulas (I) to (IV) or pharmaceutically acceptable salts thereof wherein R8 is selected from hydrogen atoms, halogens, C1-6 alkyl groups and C1-6 haloalkyl groups; in some embodiments, R8 is a hydrogen atom.
  • R4 is selected from hydrogen, halogen, cyano, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, 3- to 6-membered cycloalkyl, and 3- to 6-membered heterocyclic groups, wherein each of the 3- to 6-membered cycloalkyl and 3- to 6-membered heterocyclic groups is independently optionally substituted by one or more selected from halogen, C1-6 alkyl , and C1-6 haloalkyl; in some embodiments, R4 is selected from hydrogen, halogen, C1-6 alkyl , C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, and 3- to 6 -membered cycloalkyl; in some embodiments, R4 is hydrogen or C1-6 alkyl; in some embodiments, R 4 is a hydrogen atom
  • R5 is selected from hydrogen, halogen, cyano, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, 3- to 6-membered cycloalkyl, and 3- to 6-membered heterocyclic groups; in some embodiments, R5 is selected from hydrogen, halogen, C1-6 alkyl, and C1-6 haloalkyl; in some embodiments, R5 is a hydrogen atom.
  • R6 is selected from hydrogen, halogen, cyano, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, 3- to 6-membered cycloalkyl, and 3- to 6-membered heterocyclic groups, wherein each of the 3- to 6-membered cycloalkyl and 3- to 6-membered heterocyclic groups is independently optionally substituted by one or more selected from halogen, C1-6 alkyl, and C1-6 haloalkyl; in some embodiments, R6 is selected from hydrogen, halogen, cyano, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, and 3- to 6-membered cycloalkyl; in some embodiments, R6 is selected from hydrogen, halogen, C1-6 alkyl, and C1-6 haloalkyl
  • the compounds represented by general formulas (I) to (IV) or their pharmaceutically acceptable salts wherein R4 , R5 , R6 , and R8 are the same or different, and each is independently selected from hydrogen, halogen, cyano, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, 3- to 6 - membered cycloalkyl, and 3- to 6-membered heterocyclic groups, wherein the 3- to 6-membered cycloalkyl and 3- to 6-membered heterocyclic groups are each independently optionally substituted by one or more R02 , R02 as defined in general formula (I); in some embodiments, R4, R5, R6, and R8 are the same or different, and each is independently selected from hydrogen, halogen, cyano, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, and 3- to 6-membered cycloalky
  • the compounds represented by general formulas (I) to (IV) or their pharmaceutically acceptable salts wherein R4 , R5 , and R6 are the same or different and are each independently selected from hydrogen atoms, halogens, C1-6 alkyl groups, and C1-6 haloalkyl groups; in some embodiments, R4 , R5 , and R6 are the same or different and are each independently selected from hydrogen atoms, F, C1, methyl, CF3 , and cyclopropyl groups.
  • ring B is a 3- to 10-membered cycloalkyl or a 3- to 10-membered heterocyclic group; in some embodiments, ring B is a 3- to 10-membered cycloalkyl; in some embodiments, ring B is a 4- to 7-membered cycloalkyl; in some embodiments, ring B is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, ...
  • ring B is selected from cyclobutyl, cyclopentyl and cyclohexyl; in some embodiments, ring B is cyclopentyl.
  • the compounds represented by general formulas (I'), (I), and (II) or their pharmaceutically acceptable salts wherein for U, R7 , R15 , R16 , s, t, r, and q are as defined in general formula (III); in some implementations, Selected from In some implementation schemes, for In some implementation schemes, for R7 , R7a , R15 , R16 , s, r, and q are as defined in general formulas (IV), (IV-1), or (IV-2); in some implementations, Selected from
  • the compound represented by general formula (III) or a pharmaceutically acceptable salt thereof wherein Selected from In some implementation schemes, for In some implementation schemes, for R7 , R7a , R15 , R16 , s, r and q are as defined in general formula (IV), (IV-1) or (IV-2).
  • each R7 is the same or different and is independently selected from halogens, C1-6 alkyl, C1-6 haloalkyl, and C1-6 alkoxy, or two R7s and the carbon atom attached thereto form a 3- to 6-membered cycloalkyl group, wherein the 3- to 6-membered cycloalkyl group is optionally substituted with one or more selected from halogens, C1-6 alkyl, and C1-6 haloalkyl; in some embodiments, each R7 is the same or different and is independently selected from halogens, C1-6 alkyl, and C1-6 haloalkyl; in some embodiments, each R7 is the same or different and is independently selected from C1-6 alkyl and C1-6 haloalkyl; in some embodiments, R7 is a C1-6 alkyl; in some embodiments, R7 is methyl or CF3
  • the compounds represented by general formulas (I) to (IV) or pharmaceutically acceptable salts thereof wherein the two R7s and the carbon atoms attached thereto form a spirocyclic, fused-ring, or bridged ring; in some embodiments, the two R7s and the carbon atoms attached thereto form a spirocyclic alkyl, fused-ring alkyl, or bridged-ring alkyl; in some embodiments, the two R7s and the carbon atoms attached thereto form a spirocyclic alkyl or fused-ring alkyl; the rings formed thereto may optionally be replaced by one or more R03s ; R03s are as defined in general formula (I').
  • the compounds represented by general formulas (III) to (IV) or their pharmaceutically acceptable salts are used, wherein q is 0, 1 or 2; in some embodiments, q is 0.
  • the compounds represented by general formulas (III) to (IV) or their pharmaceutically acceptable salts are used, wherein s is 0 or 1; in some embodiments, s is 1; and in some embodiments, s is 0.
  • the compounds represented by general formulas (III) to (IV) or their pharmaceutically acceptable salts are used, wherein r is 0 or 1; in some embodiments, r is 1; and in some embodiments, r is 0.
  • n 0, 1 or 2; in some embodiments, n is 1.
  • R 7a is selected from hydrogen atoms, halogens, C1-6 alkyl groups, C1-6 haloalkyl groups, C1-6 alkoxy groups, C1-6 haloalkoxy groups, 3- to 6-membered cycloalkyl groups, and 3- to 6-membered heterocyclic groups; in some embodiments, R 7a is selected from hydrogen atoms, halogens, C1-6 alkyl groups, and C1-6 haloalkyl groups; in some embodiments, R 7a is a hydrogen atom or a C1-6 alkyl group; in some embodiments, R 7a is a hydrogen atom.
  • R7a is selected from halogens, C1-6 alkyl groups, C1-6 haloalkyl groups, C1-6 alkoxy groups, C1-6 haloalkoxy groups, 3- to 6-membered cycloalkyl groups, and 3- to 6 -membered heterocyclic groups; in some embodiments, R7a is selected from halogens, C1-6 alkyl groups, and C1-6 haloalkyl groups; in some embodiments, R7a is a C1-6 alkyl group; in some embodiments, R7a is methyl or CF3 ; in some embodiments, R7a is methyl.
  • the compounds represented by general formulas (I) to (IV) or pharmaceutically acceptable salts thereof wherein G1 is N or CR9 ; in some embodiments, G1 is CR9 , and R9 is as defined in general formula (I'); in some embodiments, G1 is N or CR9 , and R9 is selected from hydrogen atoms, halogens, C1-6 alkyl groups, and C1-6 haloalkyl groups; in some embodiments, G1 is N or CH; in some embodiments, G1 is N; in some embodiments, G1 is CH.
  • the compounds represented by general formulas (I') and (I) or their pharmaceutically acceptable salts wherein G2 is N or CR1 ; in some embodiments, G2 is CR1 , and R1 is as defined in general formula (I'); in some embodiments, G2 is CR1 , and R1 is selected from hydrogen atoms, halogens, C1-6 alkyl groups, and C1-6 haloalkyl groups; in some embodiments, G2 is N or CH; in some embodiments, G2 is CH.
  • the compounds represented by general formulas (I') and (I) or their pharmaceutically acceptable salts wherein G3 is N or CR2 ; in some embodiments, G3 is CR2 , and R2 is as defined in general formula (I'); in some embodiments, G3 is CR2 , and R2 is selected from hydrogen atoms, halogens, C1-6 alkyl groups, and C1-6 haloalkyl groups; in some embodiments, G3 is N or CH; in some embodiments, G3 is CH.
  • the compounds represented by general formulas (I') and (I) or their pharmaceutically acceptable salts wherein G4 is N or CR3 ; in some embodiments, G4 is CR3 , and R3 is as defined in general formula (I'); in some embodiments, G4 is CR3 , and R3 is selected from hydrogen atoms, halogens, C1-6 alkyl groups, and C1-6 haloalkyl groups; in some embodiments, G4 is N or CH; in some embodiments, G4 is CH.
  • the compounds represented by general formulas (I) to (IV) or pharmaceutically acceptable salts thereof wherein R9 is selected from hydrogen atoms, halogens, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, and C1-6 haloalkoxy; in some embodiments, R9 is a hydrogen atom.
  • R1 is selected from hydrogen, halogen, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, 3- to 6-membered cycloalkyl, and 3- to 6-membered heterocyclic groups, wherein each of the 3- to 6-membered cycloalkyl and 3- to 6- membered heterocyclic groups is independently optionally substituted by one or more selected from halogen, C1-6 alkyl, and C1-6 haloalkyl; in some embodiments, R1 is hydrogen or halogen; in some embodiments, R1 is hydrogen, F, Cl, methyl, methoxy, CF3 , and cyclopropyl; in some embodiments, R1 is hydrogen or F; in some embodiments, R1 is hydrogen.
  • the compound represented by general formulas (I) to (IV) or a pharmaceutically acceptable salt thereof wherein R2 is selected from hydrogen, halogen, C1-6 alkyl, and C1-6 haloalkyl; in some embodiments, R2 is hydrogen or halogen; in some embodiments, R2 is selected from hydrogen, F, Cl, methyl, methoxy, CF3 , and cyclopropyl; in some embodiments, R2 is hydrogen.
  • R3 is selected from hydrogen, halogen, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, 3- to 6-membered cycloalkyl, and 3- to 6-membered heterocyclic groups, each of which is independently optionally substituted by one or more selected from halogen, C1-6 alkyl, and C1-6 haloalkyl ; in some embodiments, R3 is hydrogen or halogen; in some embodiments, R3 is selected from hydrogen, F, Cl , methyl, methoxy, CF3 , and cyclopropyl; in some embodiments, R3 is selected from hydrogen, F , and Cl; in some embodiments, R3 is hydrogen; in some embodiments, R3 is halogen.
  • the compounds represented by general formulas (I) to (IV) or their pharmaceutically acceptable salts wherein R1 , R2 , and R3 are the same or different, and each is independently selected from hydrogen, halogen, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, and C1-6 haloalkoxy; in some embodiments, R1 , R2 , and R3 are the same or different, and each is independently selected from hydrogen, halogen, C1-6 alkyl, and C1-6 haloalkyl; in some embodiments, R1 , R2 , and R3 are the same or different, and each is independently hydrogen or halogen; in some embodiments, R1 , R2 , and R3 are the same or different, and each is independently selected from hydrogen, F, Cl, methyl, methoxy, CF3 , and cyclopropyl; in some embodiments, R1 , R2 , and R3 are hydrogen atoms.
  • the compounds represented by general formulas (I) to (IV) or their pharmaceutically acceptable salts wherein R1 , R2 , R3 , and R9 are the same or different, and each is independently selected from hydrogen atoms, halogens, C1-6 alkyl groups, and C1-6 haloalkyl groups; in some embodiments, R1 , R2 , R3 , and R9 are the same or different, and each is independently a hydrogen atom or a halogen; in some embodiments, R1 , R2 , R3 , and R9 are hydrogen atoms.
  • the compound represented by the general formula (I’) or a pharmaceutically acceptable salt thereof wherein m is 0, 1, 2, 3 or 4; in some embodiments, m is 0, 1 or 2; in some embodiments, m is 2; in some embodiments, m is 1; in some embodiments, m is 0.
  • each RA is the same or different and is independently selected from halogen, hydroxyl, cyano, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C1-6 alkoxy- C1-6 alkyl, 3- to 6-membered cycloalkyl, and 3- to 6-membered heterocyclic groups, wherein each C1-6 alkyl, C1-6 alkoxy, 3- to 6-membered cycloalkyl, and 3- to 6-membered heterocyclic group is independently optionally substituted by one or more selected from halogen, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, and C1-6 haloalkoxy; in some embodiments, each RA is the same or different and is independently selected from halogen, C1-6 alkyl, and C1-6 haloalkyl; in some embodiments, each RA is the same or different and is independently selected from halogen, C1-6 alkyl, and C1-6 haloalkyl;
  • each R 01 is the same or different and is independently selected from oxo, halogen, hydroxyl, cyano, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C1-6 alkoxy-C1-6 alkyl and 3 to 6-membered cycloalkyl; in some embodiments, each R 01 is the same or different and is independently selected from halogen, C1-6 alkyl and C1-6 haloalkyl.
  • each RO2 is the same or different and is independently selected from oxo, halogen, hydroxyl, cyano, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C1-6 alkoxy-C1-6 alkyl and 3 to 6-membered cycloalkyl; in some embodiments, each RO2 is the same or different and is independently selected from halogen, C1-6 alkyl and C1-6 haloalkyl.
  • each RO3 is the same or different and is independently selected from oxo, halogen, hydroxyl, cyano, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C1-6 alkoxy-C1-6 alkyl , and 3 to 6-membered cycloalkyl; in some embodiments, each RO3 is the same or different and is independently selected from halogen, C1-6 alkyl, and C1-6 haloalkyl.
  • each R * is the same or different and is independently selected from oxo, halogen, hydroxyl, cyano, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C1-6 alkoxy- C1-6 alkyl, and 3 to 6-membered cycloalkyl; in some embodiments, each R * is the same or different and is independently selected from halogen, C1-6 alkyl, and C1-6 haloalkyl.
  • the compounds represented by general formulas (I) to (IV) or their pharmaceutically acceptable salts wherein R11 and R12 are the same or different and are each independently selected from hydrogen atoms, C1-6 alkyl groups, and 3- to 6-membered cycloalkyl groups; in some embodiments, R11 and R12 are the same or different and are each independently hydrogen atoms or C1-6 alkyl groups; in some embodiments, R11 and R12 are the same or different and are each independently hydrogen atoms or methyl groups; in some embodiments, both R11 and R12 are hydrogen atoms.
  • R 11 is a hydrogen atom or a C1-6 alkyl group; in some embodiments, R 11 is a hydrogen atom or a methyl group; in some embodiments, R 11 is a hydrogen atom.
  • R 12 is a hydrogen atom or a C1-6 alkyl group; in some embodiments, R 12 is a hydrogen atom or a methyl group; in some embodiments, R 12 is a hydrogen atom.
  • R 14 is selected from hydrogen atoms, C1-6 alkyl groups and 3- to 6-membered cycloalkyl groups; in some embodiments, R 14 is a hydrogen atom or a C1-6 alkyl group; in some embodiments, R 14 is a hydrogen atom or a methyl group; in some embodiments, R 14 is a hydrogen atom.
  • the compounds represented by general formulas (I) to (IV) or their pharmaceutically acceptable salts wherein R 30 and R 31 are the same or different and are each independently a hydrogen atom or a C1-6 alkyl group; in some embodiments, R 30 and R 31 are the same or different and are each independently a hydrogen atom or a methyl group; in some embodiments, both R 30 and R 31 are hydrogen atoms.
  • R 33 is a hydrogen atom or a C1-6 alkyl group; in some embodiments, R 33 is a hydrogen atom.
  • the compounds represented by general formulas (I) to (IV) or their pharmaceutically acceptable salts are used, wherein v is 2; in some embodiments, v is 1; and in some embodiments, v is 0.
  • formulas (I) through (IV) include formulas (I), (I’), (II), (III), (IV), (IV-1), and (IV-2); formulas (I) through (III) include formulas (I), (I’), (II), and (III).
  • the compound represented by general formula (III) or its pharmaceutically acceptable salt wherein R11 and R12 are hydrogen atoms; G1 is N or CH; R1 , R2 , and R3 are the same or different, and each is independently selected from hydrogen atoms, halogens, C1-6 alkyl, and C1-6 haloalkyl; X1 is N or CH; R4 , R5 , and R6 are the same or different, and each is independently selected from hydrogen atoms, halogens, C1-6 alkyl, and C1-6 haloalkyl; U is CR7a , R7a is a hydrogen atom or a C1-6 alkyl; q is 0; s is 0 or 1; r is 0 or 1; t is 0 or 1; R15 and R16 are the same or different, and each is independently a hydrogen atom or a halogen.
  • the compound represented by general formula (IV), (IV-1) or (IV-2) or its pharmaceutically acceptable salt wherein R11 and R12 are hydrogen atoms; G1 is N or CH; R1 , R2 and R3 are the same or different, and each is independently a hydrogen atom or a halogen; X1 is N or CH; R4 , R5 and R6 are the same or different, and each is independently selected from hydrogen atoms, halogens, C1-6 alkyl and C1-6 haloalkyl; R7a is C1-6 alkyl; q is 0; s is 0 or 1; r is 0 or 1; R15 and R16 are the same or different, and each is independently a halogen.
  • R11 and R12 are hydrogen atoms
  • G1 is N or CH
  • R1 , R2 and R3 are the same or different, and each is independently a hydrogen atom or a halogen
  • X1 is N or CH
  • R4 , R5 and R6
  • the compound represented by general formula (IV), (IV-1) or (IV-2) or its pharmaceutically acceptable salt wherein R11 and R12 are hydrogen atoms; G1 is N; R1 , R2 and R3 are hydrogen atoms; X1 is N or CH; R4 is C1-6 alkyl; R5 is hydrogen atom; R6 is halogen; R7a is C1-6 alkyl; q is 0; s is 1; r is 0; R15 and R16 may be the same or different, and each is independently a halogen.
  • the compound represented by general formula (IV), (IV-1) or (IV-2) or its pharmaceutically acceptable salt wherein R11 and R12 are hydrogen atoms; G1 is N; R1 , R2 and R3 are hydrogen atoms; X1 is CH; R4 is C1-6 alkyl; R5 is hydrogen atom; R6 is halogen; R7a is C1-6 alkyl; q is 0; s is 1; r is 0; R15 and R16 may be the same or different, and each is independently a halogen.
  • the compound represented by general formula (IV), (IV-1) or (IV-2) or its pharmaceutically acceptable salt wherein R11 and R12 are hydrogen atoms; G1 is N or CH; R1 , R2 and R3 are hydrogen atoms; X1 is N or CH; R4 is methyl; R5 is hydrogen atom; R6 is Cl or CF3 ; R7a is methyl; q is 0; s is 1; r is 0; R15 and R16 are F.
  • the compound represented by general formula (IV), (IV-1) or (IV-2) or its pharmaceutically acceptable salt wherein R11 and R12 are hydrogen atoms; G1 is N; R1 is a hydrogen atom; R2 is a hydrogen atom; R3 is a hydrogen atom or a halogen; X1 is CH; R4 is a C1-6 alkyl; R5 is a hydrogen atom; R6 is a halogen; R7a is a C1-6 alkyl; q is 0; s is 1; r is 0; R15 and R16 may be the same or different, and each is independently a halogen.
  • R11 and R12 are hydrogen atoms
  • G1 is N
  • R1 is a hydrogen atom
  • R2 is a hydrogen atom
  • R3 is a hydrogen atom or a halogen
  • X1 is CH
  • R4 is a C1-6 alkyl
  • R5 is a hydrogen atom
  • R6 is a halogen
  • Another aspect of this disclosure relates to compounds of general formula (I'A) or salts thereof.
  • RW is a hydrogen atom or a hydroxyl protecting group, and in some embodiments it is a benzyl group;
  • Rings A, RA , m, B, G to G4 , RB , R7 and n are as defined in general formula (I').
  • Another aspect of this disclosure relates to compounds of general formula (IA) or salts thereof.
  • R is a hydrogen atom or a hydroxyl protecting group, and in some embodiments it is a benzyl group; in some embodiments, R is a cyano group;
  • Rings B, X1 to X4 , G1 to G4 , R, RB , R7 and n are as defined in general formula (I).
  • Another aspect of this disclosure relates to compounds of general formulas (IIA) and (IIa) or salts thereof.
  • R is a hydrogen atom or a hydroxyl protecting group, and in some embodiments, it is a benzyl group; in some embodiments, R is a cyano group; X is selected from halogen, boric acid, or borate ester group; in some embodiments, X is Br or
  • Rings B, RB , X1 , G1 , R, R1 to R7 and n are as defined in general formula (II).
  • Another aspect of this disclosure relates to compounds of general formulas (IIIA) and (IIIa) or salts thereof.
  • RW is a hydrogen atom or a hydroxyl protecting group, and in some embodiments it is a benzyl group;
  • X is selected from halogen, boric acid, or borate ester groups; in some embodiments, X is Br or
  • Another aspect of this disclosure relates to compounds of general formula (IVA), (IV-1A) or (IV-2A) or salts thereof.
  • RW is a hydrogen atom or a hydroxyl protecting group, and in some embodiments it is a benzyl group;
  • G1 , X1 , R1 to R7 , R7a , R15 , R16 , s, r and q are as defined in general formula (IV), (IV-1) or (IV-2).
  • R is a cyano group
  • Table B lists typical intermediate compounds or salts thereof disclosed herein, including but not limited to:
  • Another aspect of this disclosure relates to a method for preparing a compound of the above general formula (I') or a pharmaceutically acceptable salt thereof, the method comprising:
  • RW is a hydroxyl protecting group, which is benzyl in some embodiments.
  • Rings A, RA , m, B, G to G4 , RB , R7 and n are as defined in general formula (I');
  • G in general formula (I'A) is CR and R is cyano
  • G in general formula (I') is CR and R is C(O)NH 2 .
  • Another aspect of this disclosure relates to a method for preparing the compound of the above general formula (I) or a pharmaceutically acceptable salt thereof, the method comprising:
  • RW is a hydroxyl protecting group, which is benzyl in some embodiments.
  • Rings B, X1 to X4 , G1 to G4 , R, RB , R7 and n are as defined in general formula (I);
  • R in general formula (IA) is a cyano group, and R in general formula (I) is C(O) NH2 ;
  • a compound of general formula (IA) with R being a cyano group or a salt thereof is hydrolyzed to give a compound of general formula (I) with R being C(O) NH2 or a pharmaceutically acceptable salt thereof.
  • Another aspect of this disclosure relates to a method for preparing the compound of the above general formula (II) or a pharmaceutically acceptable salt thereof, the method comprising:
  • a compound of general formula (IIA) or its salt thereof undergoes hydrolysis to yield a compound of general formula (II) or its pharmaceutically usable salt thereof; or a compound of general formula (II) or its salt thereof, in which R3 is a hydrogen atom, undergoes a halogenation reaction with a halogenating agent to yield a compound of general formula (II) or its pharmaceutically usable salt thereof, in which...
  • RW is a hydroxyl protecting group, which is benzyl in some embodiments.
  • Rings B, RB , X1 , G1 , R, R1 to R7 and n are as defined in general formula (II); in some embodiments, R in general formula (IIA) is cyano and R in general formula (II) is C(O) NH2 ;
  • a compound of general formula (IIA) with R being a cyano group or a salt thereof is hydrolyzed to give a compound of general formula (II) with R being C(O) NH2 or a pharmaceutically acceptable salt thereof.
  • Another aspect of this disclosure relates to a method for preparing the compound of the above general formula (III) or a pharmaceutically acceptable salt thereof, the method comprising:
  • a compound of general formula (IIIA) or a salt thereof undergoes hydrolysis to yield a compound of general formula (III) or a pharmaceutically usable salt thereof; or a compound of general formula (III) or a salt thereof in which R3 is a hydrogen atom undergoes a halogenation reaction with a halogenating agent to yield a compound of general formula (III) in which R3 is a halogen or a pharmaceutically usable salt thereof, wherein...
  • R ⁇ sub>W ⁇ /sub> is a hydroxyl protecting group, which is benzyl in some embodiments;
  • R ⁇ sub>11 ⁇ /sub> and R ⁇ sub>12 ⁇ /sub> are hydrogen atoms;
  • Another aspect of this disclosure relates to a method for preparing compounds of the above general formulas (IV), (IV-1), and (IV-2) or pharmaceutically acceptable salts thereof, the method comprising:
  • a compound of general formula (IVA) or its salt may undergo hydrolysis to yield a compound of general formula (IV) or its pharmaceutically usable salt, or a compound of general formula (IV) or its salt containing a hydrogen atom at R3 may undergo halogenation with a halogenating agent to yield a compound of general formula (IV) containing a halogen at R3 or its pharmaceutically usable salt.
  • a compound of general formula (IV-2A) or its salt thereof undergoes a hydrolysis reaction to yield a compound of general formula (IV-2) or its pharmaceutically usable salt thereof; or a compound of general formula (IV-2) or its salt thereof , in which R3 is a hydrogen atom, undergoes a halogenation reaction with a halogenating agent to yield a compound of general formula (IV-2) or its pharmaceutically usable salt thereof, in which R3 is a halogen.
  • R ⁇ sub>W ⁇ /sub> is a hydroxyl protecting group, which is benzyl in some embodiments;
  • R ⁇ sub>11 ⁇ /sub> and R ⁇ sub>12 ⁇ /sub> are hydrogen atoms;
  • G1 , X1 , R1 to R7 , R7a , R15 , R16 , s, r and q are as defined in general formula (IV), (IV-1) or (IV-2).
  • Another aspect of this disclosure relates to a method for preparing compounds of the above general formulas (IV-1) and (IV-2) or pharmaceutically acceptable salts thereof, the method comprising:
  • G1 , X1 , R1 to R7 , R7a , R11 , R12 , R15 , R16 , s, r and q are as defined in general formula (IV-1) or (IV-2).
  • the halogenating agent is selected from elemental iodine, Cl2 , Br2 , hydrohalic acids (hydrofluoric acid, hydrochloric acid, hydrobromic acid, etc.), thionyl chloride, phosphorus pentachloride, phosphorus trihalides (such as phosphorus trichloride), N-bromosuccinimide, N-chlorosuccinimide, and 1-chloromethyl-4-fluoro-1,4-diazidobicyclo[2.2.2]octane bis(tetrafluoroborate); in some embodiments, the halogenating agent is N-chlorosuccinimide or 1-chloromethyl-4-fluoro-1,4-diazidobicyclo[2.2.2]octane bis(tetrafluoroborate).
  • Another aspect of this disclosure relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I) to (IV) of this disclosure or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.
  • This disclosure further relates to the use of compounds of general formulas (I) to (IV) or shown in Table A, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising thereof, in the preparation of a medicament for inhibiting a voltage-gated sodium channel; in some embodiments, the voltage-gated sodium channel is Nav1.8.
  • This disclosure further relates to the use of compounds of general formulas (I) to (IV) or shown in Table A, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising thereof, in the preparation of medicaments for treating and/or preventing diseases or conditions mediated by voltage-gated sodium channels; in some embodiments, the voltage-gated sodium channel is Nav1.8.
  • This disclosure further relates to the use of compounds of general formulas (I) to (IV) or Table A, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising thereof, in the preparation of medicaments for treating and/or alleviating pain and pain-related disorders, multiple sclerosis, Sharma-Tutankhamun syndrome, incontinence, pathological cough, or arrhythmias;
  • the pain is selected from chronic pain, acute pain, inflammatory pain, cancer pain, postoperative pain, neuropathic pain, musculoskeletal pain, primary pain, intestinal pain, idiopathic pain, and visceral pain;
  • the postoperative pain is selected from pain following bunion excision, pain following hernia repair, and pain following abdominoplasty.
  • This disclosure further relates to a method of inhibiting voltage-gated sodium channels, comprising administering to a desired patient a compound of formula (I) to (IV) or Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising thereof.
  • This disclosure further relates to a method of treating and/or preventing diseases or conditions mediated by voltage-gated sodium channels, comprising administering to a desired patient a compound of formula (I) to (IV) or Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising thereof.
  • This disclosure further relates to a method of treating and/or preventing pain and pain-related disorders, multiple sclerosis, Sharma-Tutankhamun syndrome, incontinence, pathological cough, or arrhythmia, comprising administering to a desired patient a compound of formula (I) to (IV) or Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.
  • This disclosure further relates to a compound of general formula (I) to (IV) or Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising thereof, which is used as a drug; in some embodiments, it is used as a drug for inhibiting the activity of voltage-gated sodium channels; in some embodiments, it is used as a drug for inhibiting Nav1.8 activity.
  • This disclosure further relates to a compound of general formula (I) to (IV) or Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the thereof, for inhibiting voltage-gated sodium channel activity; in some embodiments, it is used to inhibit Nav1.8 activity.
  • This disclosure further relates to a compound of general formula (I) to (IV) or Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the thereof, which acts as a voltage-gated sodium channel inhibitor; in some embodiments, it acts as a Nav1.8 inhibitor.
  • This disclosure further relates to a compound of general formula (I) to (IV) or Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising thereof, which is used as a medicament for treating and/or preventing diseases or conditions mediated by voltage-gated sodium channels; in some embodiments, it is used as a medicament for treating and/or preventing diseases or conditions mediated by Nav1.8.
  • This disclosure further relates to a compound of general formula (I) to (IV) or Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising thereof, for the treatment and/or prevention of diseases or conditions mediated by voltage-gated sodium channels.
  • This disclosure further relates to a compound of formula (I) to (IV) or Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising thereof, for the treatment and/or prevention of pain and pain-related disorders, multiple sclerosis, Shama-Tutan syndrome, incontinence, pathological cough, or arrhythmia.
  • the diseases or conditions described in this disclosure are treated and/or prevented by inhibiting voltage-gated sodium channels.
  • the voltage-gated sodium channel described in this disclosure is Nav1.8.
  • the diseases or conditions mediated by voltage-gated sodium channels described in this disclosure are pain and pain-related diseases, multiple sclerosis, Sharma-Tutus syndrome, incontinence, pathological cough, or arrhythmia; in some embodiments, the pain is selected from chronic pain, acute pain, inflammatory pain, cancer pain, postoperative pain, neuropathic pain, musculoskeletal pain, primary pain, intestinal pain, idiopathic pain, and visceral pain; in some embodiments, the postoperative pain is selected from pain from bunion removal surgery, hernia repair surgery, and abdominoplasty.
  • the diseases or conditions mediated by voltage-gated sodium channels described in this disclosure are selected from painful peripheral neuropathy, painless peripheral neuropathy, anterior cutaneous nerve entrapment syndrome, chronic pain syndrome, and nerve entrapment syndrome.
  • Trigeminal neuralgia small fiber neuropathy, diabetic neuropathy, painful diabetic peripheral neuropathy, painful lumbosacral radiculopathy, postherpetic neuralgia, erythromelalgia, arthralgia, osteoarthritis and fibromyalgia, neuropathic pain, diabetic neuropathy.
  • the pain is selected from diabetic pain, osteoarthritis pain, and acute pain after surgical removal of impacted third molars.
  • the active compound can be formulated in a form suitable for administration via any appropriate route, in some embodiments of which the active compound is administered in a unit dose or in a manner that allows the patient to self-administer a single dose.
  • the unit dose of the disclosed compound or composition can be expressed as a tablet, capsule, sachet, bottled liquid, powder, granule, lozenge, suppository, regenerated powder, or liquid formulation.
  • a suitable unit dose can be 0.1–1000 mg.
  • the pharmaceutical compositions disclosed herein may contain one or more excipients selected from the following: fillers (diluents), binders, wetting agents, disintegrants, or excipients.
  • the composition may contain 0.1 to 99% by weight of the active compound.
  • the unit dose of the pharmaceutical composition is 0.001 mg to 1000 mg.
  • the pharmaceutical composition contains 0.01-99.99% of the aforementioned compound or its pharmaceutically acceptable salt or isotopic substitution, based on the total weight of the composition. In some embodiments, the pharmaceutical composition contains 0.1-99.9% of the aforementioned compound or its pharmaceutically acceptable salt or isotopic substitution. In some embodiments, the pharmaceutical composition contains 0.5%-99.5% of the aforementioned compound or its pharmaceutically acceptable salt or isotopic substitution. In some embodiments, the pharmaceutical composition contains 1%-99% of the aforementioned compound or its pharmaceutically acceptable salt or isotopic substitution. In some embodiments, the pharmaceutical composition contains 2%-98% of the aforementioned compound or its pharmaceutically acceptable salt or isotopic substitution.
  • the pharmaceutical composition contains 0.01% to 99.99% pharmaceutically acceptable excipients based on the total weight of the composition. In some embodiments, the pharmaceutical composition contains 0.1% to 99.9% pharmaceutically acceptable excipients. In some embodiments, the pharmaceutical composition contains 0.5% to 99.5% pharmaceutically acceptable excipients. In some embodiments, the pharmaceutical composition contains 1% to 99% pharmaceutically acceptable excipients. In some embodiments, the pharmaceutical composition contains 2% to 98% pharmaceutically acceptable excipients.
  • compositions containing an active ingredient can be in forms suitable for oral administration, such as tablets, sugar lozenges, tablets, aqueous 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, and such compositions may contain one or more ingredients selected from sweeteners, flavoring agents, coloring agents, and preservatives to provide an appealing and palatable pharmaceutical formulation.
  • Tablets contain an active ingredient and non-toxic, pharmaceutically acceptable excipients suitable for tablet preparation for mixing.
  • excipients may be inert excipients, granulating agents, disintegrants, binders, and lubricants. These tablets may be uncoated or coated using known techniques that mask the taste of the drug or delay disintegration and absorption in the gastrointestinal tract, thus providing sustained release over a longer period.
  • Oral formulations can also be provided using soft gelatin capsules in which the active ingredient is mixed with an inert solid diluent or in which the active ingredient is mixed with a water-soluble carrier or an oil solvent.
  • Aqueous suspensions contain active substances and excipients suitable for preparing aqueous suspensions for mixing. These 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 sweeteners.
  • Oil suspensions are formulated by suspending the active ingredient in vegetable or mineral oil.
  • Oil suspensions may contain thickeners. Sweeteners and flavoring agents mentioned above may be added to provide palatable formulations. These compositions may be preserved by adding antioxidants.
  • compositions disclosed herein may also be in the form of an oil-in-water emulsion.
  • the oil phase may be vegetable oil, 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 formulations may also contain modifiers, preservatives, colorants, and antioxidants.
  • the pharmaceutical compositions disclosed herein may be in the form of sterile injectable aqueous solutions.
  • Acceptable solvents or media that can be used include water, Ringer's solution, and isotonic sodium chloride solution.
  • the sterile injectable formulation may be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in the oil phase, which can be injected into the patient's bloodstream via local large-volume injection.
  • the solution and microemulsion are preferably administered in a manner that maintains a constant circulating concentration of the compounds disclosed herein.
  • a continuous intravenous delivery device may be used.
  • An example of such a device is the Deltec CADD-PLUSTM 5400 intravenous infusion pump.
  • compositions disclosed herein may be in the form of sterile injectable aqueous or oil suspensions for intramuscular and subcutaneous administration. These suspensions may be formulated using suitable dispersants or wetting agents and suspending agents according to known techniques.
  • the sterile injectable formulations may also be sterile injectable solutions or suspensions prepared in parenteral acceptable non-toxic diluents or solvents.
  • sterile fixative oils can be conveniently used as solvents or suspension media. Any blended fixative oil may be used for this purpose.
  • fatty acids may also be used to prepare injectable formulations.
  • the disclosed compounds can be administered in suppository form for rectal administration.
  • These pharmaceutical compositions can be prepared by mixing the drug with a suitable, non-irritating excipient that is solid at normal temperatures but liquid in the rectum, and thus dissolves in the rectum to release the drug.
  • the dosage of a drug depends on a variety of factors, including but not limited to: the activity of the specific compound used, the patient's age, the patient's weight, the patient's health status, the patient's behavior, the patient's diet, the timing of administration, the route of administration, the rate of excretion, the combination of drugs, the severity of the disease, etc.; in addition, the optimal treatment mode, such as the treatment pattern, the daily dosage of the compound, or the type of medicinal salt can be validated based on conventional treatment protocols.
  • alkyl refers to a saturated, straight-chain or branched aliphatic hydrocarbon group having 1 to 20 carbon atoms (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) (i.e., C1-20 alkyl).
  • the alkyl group is an alkyl group having 1 to 12 carbon atoms (i.e., C1-10 alkyl), and in some embodiments, it is an alkyl group having 1 to 6 carbon atoms (i.e., C1-6 alkyl).
  • 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-methylhexyl, 5-methylhexyl
  • Alkyl groups can be substituted or unsubstituted, and when substituted, they can be substituted at any usable connection point.
  • the substituents are selected from one or more of the following: D atom, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.
  • alkylene refers to a divalent alkyl group, wherein the alkyl group, as defined above, has 1 to 20 carbon atoms (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) (i.e., C1-20 alkylene ).
  • the alkylene group has 1 to 10 carbon atoms (i.e., C1-10 alkylene), in some embodiments it has 1 to 8 carbon atoms (i.e., C1-8 alkylene), in some embodiments it has 2 to 7 carbon atoms (i.e., C2-7 alkylene), or it has 1, 2, or 3 carbon atoms (i.e., C1-6 alkylene).
  • Non-limiting examples include: -CH2- , -CH( CH3 )-, -C(CH3) 2- , -CH2CH2-, -CH(CH2CH3)-, -CH2CH(CH3)-, -CH2C ( CH3 ) 2- , -CH2CH2CH2- , -CH2CH2CH2- , etc.
  • the alkylene group can be substituted or unsubstituted, and when substituted, it can be substituted at any usable linker.
  • the substituent is selected from one or more of the following : D atom, halogen , alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.
  • alkenyl refers to an alkyl group containing at least one carbon-carbon double bond in a molecule, wherein the alkyl group is defined as described above and has 2 to 12 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12) carbon atoms (i.e., C2-12 alkenyl). In some embodiments, the alkenyl group has 2 to 6 carbon atoms (i.e., C2-6 alkenyl).
  • Non-limiting examples include vinyl, propenyl, isopropenyl, butenyl, etc.
  • the alkenyl group can be substituted or unsubstituted, and when substituted, it can be substituted at any usable linker, with the substituent selected from one or more of the following: D atom, alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.
  • alkynyl refers to an alkyl group containing at least one carbon-carbon triple bond in a molecule, wherein the alkyl group is defined as described above and has 2 to 12 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12) carbon atoms (i.e., C2-12 alkynyl ). In some embodiments, the alkynyl group has 2 to 6 carbon atoms (i.e., C2-6 alkynyl). Non-limiting examples include: ethynyl, propynyl, butynyl, pentyynyl, hexynyl, etc.
  • the alkynyl group can be substituted or unsubstituted, and when substituted, it can be substituted at any usable linker, with the substituent selected from one or more of the following: D atom, alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.
  • alkoxy refers to -O-(alkyl), where alkyl is defined as described above. Non-limiting examples include methoxy, ethoxy, propoxy, and butoxy, etc. Alkoxy groups can be substituted or unsubstituted, and when substituted, they can be substituted at any usable linker. Substituents are selected from one or more of the following: D atom, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.
  • alkathio refers to -S-(alkyl), where alkyl is defined as described above. Non-limiting examples include methylthio, ethylthio, propanethio, and butylthio. Alkathio groups can be substituted or unsubstituted, and when substituted, they can be substituted at any usable linker. Substituents are selected from one or more of the following: D atom, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.
  • cycloalkyl refers to a saturated or partially unsaturated monocyclic all-carbon ring (i.e., monocyclic cycloalkyl) or polycyclic system (i.e., polycyclic cycloalkyl) having 3 to 20 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) ring atoms (i.e., 3 to 20 membered cycloalkyl).
  • the cycloalkyl group is a cycloalkyl group having 3 to 12 ring atoms (i.e., a 3 to 12-membered cycloalkyl group) or a cycloalkyl group having 3 to 10 ring atoms (i.e., a 3 to 10-membered cycloalkyl group); in some embodiments, it is a cycloalkyl group having 3 to 8 ring atoms (i.e., a 3 to 8-membered cycloalkyl group); in some embodiments, it is a cycloalkyl group having 3 to 6 ring atoms (i.e., a 3 to 6-membered cycloalkyl group), a cycloalkyl group having 4 to 7 ring atoms (i.e., a 4 to 7-membered cycloalkyl group), or a cycloalkyl group having 5 or 6 ring atoms (i.e.
  • Non-limiting examples of the monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclohepttrienyl, and cyclooctyl.
  • the polycyclic alkyl groups include: spirocyclic alkyl, fused cyclic alkyl, and bridged cyclic alkyl.
  • spirocycloalkyl refers to a polycyclic system in which rings share a single carbon atom (called a spiro atom), and the ring may contain one or more double bonds, or one or more heteroatoms selected from nitrogen, oxygen, and sulfur (the nitrogen may optionally be oxidized, i.e., to form nitrogen oxides; the sulfur may optionally be oxidized, i.e., to form sulfoxides or sulfones, but excluding -O-O-, -O-S-, or -S-S-), provided that it contains at least one full carbon ring with a bonding point on that full carbon ring, having 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., 5 to 20-membered spirocycloalkyl).
  • the spirocycloalkyl is a spirocycloalkyl having 6 to 14 ring atoms (i.e., 6 to 14-membered spirocycloalkyl), and in some embodiments, it is a spirocycloalkyl having 7 to 10 ring atoms (i.e., 7 to 10-membered spirocycloalkyl).
  • the spirocyclic alkyl group includes monospirocyclic alkyl and polyspirocyclic alkyl (such as bispirocyclic alkyl, etc.), and in some embodiments is a monospirocyclic alkyl or bispirocyclic alkyl group, and in some embodiments is a 3-membered/4-membered, 3-membered/5-membered, 3-membered/6-membered, 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/3-membered, 5-membered/4-membered, 5-membered/5-membered, 5-membered/6-membered, 5-membered/7-membered, 6-membered/3-membered, 6-membered/4-membered, 6-membered/5-membered, 6-membered/6-membered, 6-membered/7-membered, 6-membered/3-membered, 6-member
  • fused cycloalkyl refers to a polycyclic system in which two adjacent carbon atoms are shared between rings. This system is a monocyclic cycloalkyl group fused with one or more monocyclic cycloalkyl groups, or a monocyclic cycloalkyl group fused with one or more heterocyclic, aryl, or heteroaryl groups, wherein the bonding point is on the monocyclic cycloalkyl group, which may contain one or more double bonds and has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., 5 to 20-membered fused cycloalkyl).
  • the fused cycloalkyl group is a fused cycloalkyl group having 6 to 14 ring atoms (i.e., 6 to 14-membered fused cycloalkyl), and in some embodiments, it is a fused cycloalkyl group having 7 to 10 ring atoms (i.e., 7 to 10-membered fused cycloalkyl).
  • the fused cyclic alkyl group includes bicyclic fused cyclic alkyl groups and polycyclic fused cyclic alkyl groups (such as tricyclic fused cyclic alkyl groups, tetracyclic fused cyclic alkyl groups, etc.).
  • it is a bicyclic fused cyclic alkyl group or a tricyclic fused cyclic alkyl group.
  • it is a 3-membered/4-membered, 3-membered/5-membered, 3-membered/6-membered, 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/3-membered, 5-membered/4-membered, 5-membered/5-membered, 5-membered/6-membered, 5-membered/7-membered, 6-membered/3-membered, 6-membered/4-membered, 6-membered/5-membered, 6-membered/6-membered, 6-membered/7-membered, 7-membered/5-membered, or 7-membered/6-membered bicyclic fused cyclic alkyl group.
  • Non-limiting examples include:
  • connection point can be anywhere; wait.
  • bridged cycloalkyl refers to a fully carbon polycyclic system in which two non-directly connected carbon atoms are shared between rings, and the ring may contain one or more double bonds and have 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) carbon atoms (i.e., 5 to 20-membered bridged cycloalkyl).
  • the bridged cycloalkyl is a bridged cycloalkyl having 6 to 14 carbon atoms (i.e., 6 to 14-membered bridged cycloalkyl), and in some embodiments, it is a bridged cycloalkyl having 7 to 10 carbon atoms (i.e., 7 to 10-membered bridged cycloalkyl).
  • the bridged cycloalkyl includes bicyclic bridged cycloalkyl and polycyclic bridged cycloalkyl (e.g., tricyclic bridged cycloalkyl, tetracyclic bridged cycloalkyl, etc.), and in some embodiments, it is a bicyclic bridged cycloalkyl or a tricyclic bridged cycloalkyl.
  • Non-limiting examples include:
  • the cycloalkyl group can be substituted or unsubstituted. When substituted, it can be substituted at any usable connection point.
  • the substituent is selected from one or more of the following: D atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, oxo, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.
  • heterocyclic group refers to a saturated or partially unsaturated monocyclic heterocycle (i.e., monocyclic heterocyclic group) or polycyclic heterocyclic system (i.e., polycyclic heterocyclic group) containing at least one (e.g., 1, 2, 3 or 4) heteroatoms selected from nitrogen, oxygen and sulfur (the nitrogen may optionally be oxidized, i.e., to form nitrogen oxides; the sulfur may optionally be oxidized, i.e., to form sulfoxides or sulfones, but excluding -O-O-, -O-S- or -S-S-), and having 3 to 20 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) ring atoms (i.e., 3 to 20 membered heterocyclic groups).
  • monocyclic heterocyclic group i.e., monocyclic heterocyclic group
  • polycyclic heterocyclic system i.e., polycyclic
  • the heterocyclic group has heterocyclic groups with 3 to 12 ring atoms (i.e., 3 to 12-membered heterocyclic groups), heterocyclic groups with 3 to 10 ring atoms (i.e., 3 to 10-membered heterocyclic groups), and heterocyclic groups with 7 to 10 ring atoms (i.e., 7 to 10-membered heterocyclic groups); in some embodiments, it has heterocyclic groups with 3 to 8 ring atoms (i.e., 3 to 8-membered heterocyclic groups); in some embodiments, it has heterocyclic groups with 3 to 6 ring atoms (i.e., 3 to 6-membered heterocyclic groups), 4 to 7 ring atoms (i.e., 4 to 7-membered heterocyclic groups), or 5 or 6 ring atoms (i.e., 5 or 6-membered heterocyclic groups); in some embodiments, it has heterocyclic groups with 5 or 6 ring atoms.
  • Non-limiting examples of the monocyclic heterocyclic group include: pyrrolidinyl, tetrahydropyranyl, tetrahydrofuranyl, 1,2,3,6-tetrahydropyridyl, piperidinyl, piperazinyl, azacyclic butyl, morpholinyl, thiomorpholinyl, and homopiperazinyl, etc.
  • the polycyclic heterocyclic groups include spirocyclic heterocyclic groups, fused heterocyclic groups, and bridged heterocyclic groups.
  • spiroheterocyclic group refers to a polycyclic heterocyclic system in which rings share a single atom (called a spiro atom), which may contain one or more double bonds and at least one (e.g., 1, 2, 3, or 4) heteroatoms selected from nitrogen, oxygen, and sulfur (the nitrogen may optionally be oxidized to form nitrogen oxides; the sulfur may optionally be oxidized to form sulfoxides or sulfones, but excluding -O-O-, -O-S-, or -S-S-), provided that it contains at least one monocyclic heterocyclic group with a connecting point on the monocyclic heterocyclic group, which has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., 5 to 20 membered spiroheterocyclic groups).
  • a spiro atom polycyclic heterocyclic system in which rings share a single atom
  • the spiroheterocyclic group is a spiroheterocyclic group having 6 to 14 ring atoms (i.e., a 6 to 14-membered spiroheterocyclic group), and in some embodiments, it is a spiroheterocyclic group having 7 to 10 ring atoms (i.e., a 7 to 10-membered spiroheterocyclic group).
  • the spiroheterocyclic group includes mono-spiroheterocyclic groups and multi-spiroheterocyclic groups (such as bi-spiroheterocyclic groups), and in some embodiments, it is a mono-spiroheterocyclic group or a bi-spiroheterocyclic group.
  • it is a 3-membered/4-membered, 3-membered/5-membered, 3-membered/6-membered, 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/3-membered, 5-membered/4-membered, 5-membered/5-membered, 5-membered/6-membered, 5-membered/7-membered, 6-membered/3-membered, 6-membered/4-membered, 6-membered/5-membered, 6-membered/6-membered, 6-membered/7-membered, 7-membered/5-membered, or 7-membered/6-membered mono-spiroheterocyclic group.
  • Non-limiting examples include:
  • fused heterocyclic group refers to a polycyclic heterocyclic system in which two adjacent atoms are shared between the rings.
  • the rings may contain one or more double bonds and at least one (e.g., 1, 2, 3, or 4) heteroatom selected from nitrogen, oxygen, and sulfur (the nitrogen may optionally be oxidized to form nitrogen oxides; the sulfur may optionally be oxidized to form sulfoxides or sulfones, but excluding -O-O-, -O-S-, or -S-S-).
  • the fused heterocyclic group is a fused heterocyclic group having 6 to 14 ring atoms (i.e., a 6 to 14-membered fused heterocyclic group), and in some embodiments, it is a fused heterocyclic group having 7 to 10 ring atoms (i.e., a 7 to 10-membered fused heterocyclic group).
  • the fused heterocyclic group includes bicyclic and polycyclic fused heterocyclic groups (such as tricyclic fused heterocyclic groups, tetracyclic fused heterocyclic groups, etc.), and in some embodiments, it is a bicyclic or tricyclic fused heterocyclic group.
  • it is a 3-membered/4-membered, 3-membered/5-membered, 3-membered/6-membered, 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/3-membered, 5-membered/4-membered, 5-membered/5-membered, 5-membered/6-membered, 5-membered/7-membered, 6-membered/3-membered, 6-membered/4-membered, 6-membered/5-membered, 6-membered/6-membered, 6-membered/7-membered, 7-membered/5-membered, or 7-membered/6-membered bicyclic fused heterocyclic group.
  • Non-limiting examples include:
  • bridged heterocyclic group refers to a polycyclic heterocyclic system in which two non-directly bonded atoms are shared between the rings.
  • the rings may contain one or more double bonds and at least one (e.g., 1, 2, 3, or 4) heteroatoms selected from nitrogen, oxygen, and sulfur (the nitrogen may optionally be oxidized to form nitrogen oxides; the sulfur may optionally be oxidized to form sulfoxides or sulfones, but excluding -O-O-, -O-S-, or -S-S-), having 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., 5 to 20-membered bridged heterocyclic groups).
  • the bridged heterocyclic group has 6 to 14 ring atoms (i.e., 6 to 14-membered bridged heterocyclic groups), and in some embodiments, it has 7 to 10 ring atoms (i.e., 7 to 10-membered bridged heterocyclic groups).
  • heterocyclic groups can be classified into bicyclic bridged heterocyclic groups and multicyclic bridged heterocyclic groups (such as tricyclic bridged heterocyclic groups, tetracyclic bridged heterocyclic groups, etc.). In some embodiments, they are bicyclic bridged heterocyclic groups or tricyclic bridged heterocyclic groups.
  • Non-limiting examples include:
  • the heterocyclic group can be substituted or unsubstituted. When substituted, it can be substituted at any usable connection point.
  • the substituent is selected from one or more of the following: D atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, oxo, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.
  • aryl refers to a monocyclic all-carbon aromatic ring (i.e., monocyclic aryl) or a polycyclic aromatic ring system (i.e., polycyclic aryl) having a conjugated ⁇ -electron system, having 6 to 20 (e.g., 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., 6 to 20-membered aryl).
  • the aryl group has 6 to 14 ring atoms (i.e., 6 to 14-membered aryl), and in some embodiments, it has 6 to 10 ring atoms (i.e., 6 to 10-membered aryl).
  • Monocyclic aryl groups include, for example, phenyl.
  • Non-limiting examples of polycyclic aryl groups include naphthyl, anthracene, phenanthrene, etc.
  • the polycyclic aryl group further includes fusion of a phenyl group with one or more heterocyclic or cycloalkyl groups, or fusion of a naphthyl group with one or more heterocyclic or cycloalkyl groups, wherein the bonding site is on the phenyl or naphthyl group, and in this case, the number of ring atoms continues to represent the number of ring atoms in the polycyclic aromatic ring system, non-limiting examples including:
  • the aryl group can be substituted or unsubstituted. When substituted, it can be substituted at any usable connection point.
  • the substituent is selected from one or more of the following: D atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, oxo, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.
  • heteroaryl refers to a monocyclic heteroaryl ring (i.e., monocyclic heteroaryl) or a polycyclic heteroaryl ring system (i.e., polycyclic heteroaryl) having a conjugated ⁇ -electron system, containing at least one (e.g., 1, 2, 3 or 4) heteroatoms selected from nitrogen, oxygen and sulfur (the nitrogen may optionally be oxidized, i.e., to form nitrogen oxides; the sulfur may optionally be oxidized, i.e., to form sulfoxides or sulfones, but excluding -O-O-, -O-S- or -S-S-), having 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) ring atoms (i.e., 5 to 20 membered heteroaryl).
  • the heteroaryl group is a heteroaryl group having 5 to 14 ring atoms (i.e., a 5 to 14-membered heteroaryl group), in some embodiments it is a heteroaryl group having 5 to 10 ring atoms (i.e., a 5 to 10-membered heteroaryl group), and in some embodiments it is a heteroaryl group having 5 or 6 ring atoms (i.e., a 5 or 6-membered heteroaryl group).
  • Non-limiting examples of the aforementioned monocyclic heteroaryl groups include: furanyl, thiopheneyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, furazonyl, pyrroleyl, N-alkylpyrroleyl, pyridyl, pyrimidinyl, pyridoneyl, N-alkylpyridone (e.g.) (etc.), pyrazinyl, pyridazinyl, pyridine-1-oxide, etc.
  • Non-limiting examples of the polycyclic heteroaryl groups include: indolyl, indazole, quinolinyl, isoquinolinyl, quinoxalinyl, phthalazinyl, benzimidazolyl, benzothiophene, quinazolinyl, benzothiazolyl, carbazole, etc.
  • the polycyclic heteroaryl groups also include monocyclic heteroaryl groups fused with one or more aryl groups, wherein the connecting point is on the aromatic ring, and in this case, the number of ring atoms continues to represent the number of ring atoms in the polycyclic heteroaryl ring system.
  • the polycyclic heteroaryl groups also include monocyclic heteroaryl groups fused with one or more cycloalkyl or heterocyclic groups, wherein the connecting point is on the monocyclic heteroaryl ring, and in this case, the number of ring atoms continues to represent the number of ring atoms in the polycyclic heteroaryl ring system.
  • Non-limiting examples include:
  • the heteroaryl group can be substituted or unsubstituted. When substituted, it can be substituted at any usable connection point.
  • the substituent is selected from one or more of the following: D atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.
  • cycloalkyloxy refers to -O-cycloalkyl, where the cycloalkyl is as defined above.
  • heterocyclic oxy group refers to an -O-heterocyclic group, wherein the heterocyclic group is as defined above.
  • aryloxy group refers to -O-aryl, where the aryl group is as defined above.
  • heteroaryloxy refers to -O-heteroaryl, where the heteroaryl is as defined above.
  • cycloalkylalkyl refers to an alkyl group that is substituted by one or more cycloalkyl groups, wherein the cycloalkyl and alkyl groups are as defined above.
  • heterocyclic alkyl refers to an alkyl group that is substituted by one or more heterocyclic groups, wherein the heterocyclic group and the alkyl group are as defined above.
  • arylalkyl refers to an alkyl group that is substituted with one or more aryl groups, wherein the aryl and alkyl groups are as defined above.
  • heteroarylalkyl refers to an alkyl group that is substituted by one or more heteroaryl groups, wherein the heteroaryl and alkyl groups are as defined above.
  • halogenated alkyl refers to an alkyl group that has been substituted with one or more halogens, wherein the alkyl group is as defined above.
  • haloalkoxy refers to an alkoxy group that is substituted by one or more halogens, wherein the alkoxy group is as defined above.
  • hydroxyalkyl refers to an alkyl group that is replaced by one or more hydroxyl groups, wherein the alkyl group is as defined above.
  • hydroxyalkoxy refers to an alkoxy group that is substituted with one or more hydroxyl groups, where the alkoxy group is as defined above.
  • alkoxyalkyl refers to an alkyl group substituted with one or more alkoxy groups, wherein the alkyl and alkoxy groups are as defined above; in some embodiments, they are -alkyl-alkoxy groups; including but not limited to methoxymethyl, ethoxymethyl, and methoxyethyl.
  • halogen refers to fluorine, chlorine, bromine, or iodine.
  • hydroxyl group refers to -OH.
  • amino refers to -NH2 .
  • cyano refers to -CN.
  • nitro refers to -NO2 .
  • TBS refers to tert-butyldimethylsilyl.
  • hydroxyl protecting group refers to a hydroxyl derivative that is typically used to block or protect a hydroxyl group and react on other functional groups of a compound.
  • Non-limiting examples include: triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl (TBS), tert-butyldiphenylsilyl, methyl, tert-butyl, allyl, benzyl, methoxymethyl (MOM), tert-butyldiphenylsilyl (TBDPS), ethoxyethyl, 2-tetrahydropyranyl (THP), formyl, acetyl, benzoyl, and p-nitrobenzoyl, etc.; in some embodiments, benzyl is used.
  • stereoisomer refers to isomers with the same structure but different spatial arrangements of atoms. These include cis and trans (or Z and E) isomers, (-)- and (+)- isomers, (R)- and (S)- enantiomers, diastereomers, (D)- and (L)- isomers, tautomers, blocked isomers, conformational isomers, and mixtures thereof (such as racemic mixtures and mixtures of diastereomers). Substituents in the compounds disclosed herein may contain additional asymmetric atoms. All such stereoisomers and mixtures thereof are included within the scope of this disclosure.
  • Optically active (-)- and (+)- isomers, (R)- and (S)- enantiomers, and (D)- and (L)- isomers can be prepared by chiral synthesis, chiral reagents, or other conventional techniques.
  • This disclosure discloses an isomer of a compound, which can be prepared by asymmetric synthesis or with chiral auxiliaries, or, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), by forming a salt of the diastereomer with a suitable optically active acid or base, followed by diastereomer resolution using conventional methods known in the art to obtain the pure isomer. Furthermore, the separation of enantiomers and diastereomers is typically performed by chromatography.
  • the bonds... This indicates that the configuration is not specified; that is, if chiral isomers exist in the chemical structure, the bond... It can be Or simultaneously include Two configurations. For all carbon-carbon double bonds, even if only one configuration is named, both the Z-type and E-type are included.
  • the compounds disclosed herein may comprise all of their rotational isomers and conformationally restricted states. They also include transisomers, the term "transisomer" being a stereoisomer resulting from restricted rotation around a single bond, wherein an energy difference attributable to stereostrain or other contributing factors creates a sufficiently high rotational barrier to allow the separation of individual conformational isomers.
  • some of the compounds disclosed herein may exist as mixtures of transisomers (e.g., equal-proportion mixtures, mixtures enriched with one transisomer, etc.) or as a purified transisomer.
  • the compounds disclosed herein include all suitable isotopic derivatives thereof.
  • isotopic derivative refers to a compound in which at least one atom is replaced by an atom having the same atomic number but a different atomic mass.
  • isotopes that may be introduced into the compounds of this disclosure include stable and radioactive isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine, and iodine, such as 2H (deuterium, D), 3H ( tritium, T), 11C , 13C , 14C , 15N , 17O , 18O , 32p , 33p , 33S , 34S , 35S , 36S, 18F , 36Cl , 82Br , 123I , 124I, 125I , 129I , and 131I , and in some embodiments , deuterium.
  • deuterated drugs Compared to undeuterated drugs, deuterated drugs offer advantages such as reduced toxicity, increased drug stability, enhanced efficacy, and prolonged biological half-life. All isotopic variations of the compounds disclosed herein, regardless of radioactivity, are included within the scope of this disclosure.
  • Each available hydrogen atom bonded to a carbon atom can be independently replaced by a deuterium atom, wherein the deuterium substitution can be partial or complete; partial deuterium substitution refers to the replacement of at least one hydrogen atom with at least one deuterium atom.
  • the site When a site is specifically designated as deuterium D, the site should be understood as having a deuterium abundance of at least 1,000 times greater than the natural abundance of deuterium (which is 0.015%) (i.e., at least 15% deuterium incorporation).
  • the compounds in the examples having a natural abundance greater than deuterium can be at least 1000 times abundant deuterium (i.e., at least 15% deuterium doping), at least 2000 times abundant deuterium (i.e., at least 30% deuterium doping), at least 3000 times abundant deuterium (i.e., at least 45% deuterium doping), at least 3340 times abundant deuterium (i.e., at least 50.1% deuterium doping), at least 3500 times abundant deuterium (i.e., at least 52.5% deuterium doping), at least 4000 times abundant deuterium (i.e., at least 60% deuterium doping), or at least 4500 times abundant deuterium (i.e., at least 67.5% deuter
  • the abundance of deuterium is at least 5000 times (i.e., at least 75% deuterium doping), at least 5500 times (i.e., at least 82.5% deuterium doping), at least 6000 times (i.e., at least 90% deuterium doping), at least 6333.3 times (i.e., at least 95% deuterium doping), at least 6466.7 times (i.e., at least 97% deuterium doping), at least 6600 times (i.e., at least 99% deuterium doping), at least 6633.3 times (i.e., at least 99.5% deuterium doping), or higher.
  • Optional or “optional” means that the event or environment described below may but not necessarily occur, including both the occurrence and non-occurrence of the event or environment.
  • optionally substituted C1-6 alkyl groups with halogens or cyano groups includes cases where the alkyl group is substituted with halogens or cyano groups and cases where the alkyl group is not substituted with halogens or cyano groups.
  • substitution refers to one or more hydrogen atoms in a group, in some embodiments one, two, or three, and in some embodiments one to three hydrogen atoms are independently substituted by the corresponding number of substituents.
  • substitutions can determine possible or impossible substitutions without much effort (through experimentation or theory).
  • an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom having an unsaturated bond (such as an alkene).
  • “Pharmaceutical composition” means a mixture containing one or more of the compounds described herein or their pharmaceutically acceptable salts, along with other chemical components, such as pharmaceutically acceptable carriers and excipients.
  • the purpose of a pharmaceutical composition is to facilitate administration to a living organism, thereby promoting the absorption of the active ingredient and its biological activity.
  • “Pharmacologically acceptable salt” refers to the salt of the compounds disclosed herein, which may be selected from inorganic or organic salts. Such salts are safe and effective when used in mammals and possess the expected biological activity. They can be prepared separately during the final isolation and purification of the compound, or by reacting a suitable group with a suitable base or acid.
  • Bases commonly used to form pharmaceutically acceptable salts include inorganic bases, such as sodium hydroxide and potassium hydroxide, and organic bases, such as ammonia. Acids commonly used to form pharmaceutically acceptable salts include both inorganic and organic acids.
  • the term "pharmaceutically acceptable” means that these compounds, materials, compositions, and/or dosage forms are suitable for contact with patient tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, within reasonable medical judgment, have a reasonable benefit/risk ratio, and are effective for their intended use.
  • This disclosure provides a method for preparing a compound of general formula (I') or a pharmaceutically acceptable salt thereof, the method comprising:
  • RW is a hydroxyl protecting group, which is benzyl in some embodiments.
  • G is CR and R is cyano, and in general formula (I'), G is CR and R is C(O)NH 2 ;
  • Rings A, RA , m, B, G to G4 , RB , R7 and n are as defined in general formula (I').
  • This disclosure provides a method for preparing a compound of general formula (I) or a pharmaceutically acceptable salt thereof, the method comprising:
  • a compound of general formula (IA) or a salt thereof reacts under acidic conditions to give a compound of general formula (I) or a pharmaceutically acceptable salt thereof, wherein...
  • RW is a hydroxyl protecting group, which is benzyl in some embodiments.
  • R is a cyano group
  • R is C(O) NH2 .
  • Rings B, X1 to X4 , G1 to G4 , R, RB , R7 and n are as defined in general formula (I).
  • This disclosure provides a method for preparing a compound of general formula (II) or a pharmaceutically acceptable salt thereof, the method comprising:
  • a compound of general formula (IIA) or a salt thereof reacts under acidic conditions to give a compound of general formula (II) or a pharmaceutically usable salt thereof, wherein...
  • RW is a hydroxyl protecting group, which is benzyl in some embodiments.
  • R is a cyano group
  • R is C(O) NH2 .
  • Rings B, RB , X1 , G1 , R, R1 to R7 and n are as defined in general formula (II).
  • This disclosure provides a method for preparing a compound of formula (III) or a pharmaceutically acceptable salt thereof, the method comprising:
  • a compound of general formula (IIIA) or a salt thereof reacts under acidic conditions to give a compound of general formula (III) or a pharmaceutically acceptable salt thereof, wherein...
  • R ⁇ sub>W ⁇ /sub> is a hydroxyl protecting group, which is benzyl in some embodiments;
  • R ⁇ sub>11 ⁇ /sub> and R ⁇ sub>12 ⁇ /sub> are hydrogen atoms;
  • This disclosure provides a method for preparing compounds of general formulas (IV), (IV-1), and (IV-2) or pharmaceutically acceptable salts thereof, the method comprising:
  • the compound of general formula (IV-1A) or its salt reacts under acidic conditions to give the compound of general formula (IV-1) or its pharmaceutically usable salt.
  • R ⁇ sub>W ⁇ /sub> is a hydroxyl protecting group, which is benzyl in some embodiments;
  • R ⁇ sub>11 ⁇ /sub> and R ⁇ sub>12 ⁇ /sub> are hydrogen atoms;
  • G1 , X1 , R1 to R7 , R7a , R15 , R16 , s, r and q are as defined in general formula (IV), (IV-1) or (IV-2).
  • This disclosure provides a method for preparing compounds of general formulas (IV-1) and (IV-2) or pharmaceutically acceptable salts thereof, the method comprising:
  • G1 , X1 , R1 to R7 , R7a , R11 , R12 , R15 , R16 , s, r and q are as defined in general formula (IV-1) or (IV-2).
  • the reagents providing acidic conditions in the above schemes include, but are not limited to, hydrogen chloride, 1,4-dioxane solution of hydrogen chloride, 1,4-dioxane solution of hydrochloric acid, trifluoroacetic acid, formic acid, acetic acid, hydrochloric acid, concentrated sulfuric acid, methanesulfonic acid, nitric acid, phosphoric acid, p-benzenesulfonic acid, Me3SiCl , TMSOTf, ALCl3 , BBr3 , BF3, and ferric bromide; in some embodiments, trifluoroacetic acid is used.
  • the reactions described above can be carried out in a solvent, including but not limited to: pyridine, ethylene glycol dimethyl ether, acetic acid, methanol, ethanol, acetonitrile, n-butanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, dimethyl sulfoxide, 1,4-dioxane, water, N,N-dimethylformamide, N,N-dimethylacetamide, 1,2-dibromoethane, and mixtures thereof.
  • a solvent including but not limited to: pyridine, ethylene glycol dimethyl ether, acetic acid, methanol, ethanol, acetonitrile, n-butanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, dimethyl
  • NMR nuclear magnetic resonance
  • MS mass spectrometry
  • ⁇ NMR shifts ( ⁇ ) are given in units of 10 ⁇ 6 (ppm).
  • NMR measurements were performed using a Bruker AVANCE-400 NMR spectrometer or a Bruker AVANCE NEO 500M, with deuterated dimethyl sulfoxide (DMSO- d6 ), deuterated chloroform ( CDCl3 ), and deuterated methanol ( CD3OD ) as solvents, and tetramethylsilane (TMS) as the internal standard.
  • DMSO- d6 deuterated dimethyl sulfoxide
  • CDCl3 deuterated chloroform
  • CD3OD deuterated methanol
  • TMS tetramethylsilane
  • MS was determined using an Agilent 1200/1290DAD-6110/6120 Quadrupole MS liquid chromatography-mass spectrometry system (manufacturer: Agilent, MS model: 6110/6120 Quadrupole MS).
  • HPLC High-performance liquid chromatography
  • Chiral HPLC analysis was performed using an Agilent 1260DAD high-performance liquid chromatograph.
  • the CombiFlash rapid preparation system uses the CombiFlash Rf200 (TELEDYNE ISCO).
  • Thin-layer chromatography silica gel plates are Yantai Huanghai HSGF254 or Qingdao GF254.
  • the silica gel plates used in thin-layer chromatography (TLC) have a diameter of 0.15 mm to 0.2 mm, and the diameter of the silica gel plates used for thin-layer chromatography separation and purification products is 0.4 mm to 0.5 mm.
  • Silica gel column chromatography generally uses Yantai Huanghai silica gel with a mesh size of 200-300 as the carrier.
  • the average inhibition rate and IC50 value of the kinase were determined using a NovoStar microplate reader (BMG GmbH, Germany).
  • the known starting materials disclosed herein can be synthesized using or in accordance with methods known in the art, or can be purchased from companies such as ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc., and Darui Chemicals.
  • Argon or nitrogen atmosphere refers to a reaction flask connected to an argon or nitrogen gas balloon with a volume of approximately 1L.
  • a hydrogen atmosphere refers to a reaction vessel connected to a hydrogen balloon with a volume of approximately 1L.
  • the pressurized hydrogenation reaction was performed using a Parr 3916EKX hydrogenator and a Qinglan QL-500 hydrogen generator or an HC2-SS hydrogenator.
  • the hydrogenation reaction is usually carried out under vacuum, filled with hydrogen gas, and repeated 3 times.
  • the microwave reaction was performed using a CEM Discover-S 908860 microwave reactor.
  • solution refers to an aqueous solution.
  • reaction temperature is room temperature.
  • the reaction process in the examples was monitored using thin-layer chromatography (TLC).
  • TLC thin-layer chromatography
  • the volume ratio of the solvent was adjusted according to the polarity of the compounds, and small amounts of basic or acidic reagents such as triethylamine and acetic acid could also be added for adjustment.
  • the mixture was purified by preparative high-performance liquid chromatography (Waters-2545, column: Welch Ultimate C18, 30*150 mm, 5 ⁇ m; mobile phase: aqueous phase (10 mmol/L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 40%-60%, flow rate: 30 mL/min) to obtain the title compound (22 mg, yield: 40.8%).
  • the longer-retention compounds 1-p1 and 1-p2 (600 mg, 1.35 mmol) were dissolved in N,N-dimethylformamide (60 mL), and acetic acid (363 mg, 6.04 mmol) and N-chlorosuccinimide (271 mg, 2.03 mmol) were added. The mixture was stirred for 16 hours, water was added to the reaction solution, and the mixture was extracted with ethyl acetate (15 mL ⁇ 3).
  • Compounds 4-1 and 4-2 were prepared as control compounds according to Examples 4 and 84 of WO2023205778A1.
  • Test Example 1 Determination of the inhibitory activity of the disclosed compound against Nav1.8
  • the purpose of this experiment was to investigate the effect of a compound on the Nav1.8 ion channel in vitro.
  • the Nav1.8 ion channel is stably expressed in HEK293 cells.
  • the effect of the compound on the Nav1.8 ion channel can be determined.
  • the extracellular solution consisted of: NaCl, 137 g; KCl, 4 g; CaCl2 , 1.8 g; MgCl2 , 1 g; HEPES, 10 g; glucose, 10 g; pH 7.4 (NaOH titration).
  • the intracellular solution (mM) consisted of: aspartic acid, 140 g; MgCl2, 2 g; EGTA, 11 g; HEPES, 10 g; pH 7.2 (CsOH titration). All test compound solutions contained 1 ⁇ M TTX.
  • test compound was stored at a concentration of 9 mM and dissolved in dimethyl sulfoxide (DMSO). It was then dissolved in extracellular fluid on the day of testing to prepare the required concentration.
  • DMSO dimethyl sulfoxide
  • the data will be stored in a computer system for analysis. Data acquisition and analysis will be performed using pCLAMP 10 (Molecular Devices, Union City, CA).
  • the inhibitory activity of the disclosed compound against Nav1.8 was determined by the above experiments, and the measured IC50 values are shown in Table 1.
  • the plasma drug concentration at different time points after oral administration (i.g.) of the compound of the present invention was determined by LC-MS/MS to study the pharmacokinetic behavior of the compound in rats and evaluate its pharmacokinetic characteristics.
  • Dosage 2.0 mg/kg, administration volume: 10 mL/kg.
  • Blood samples of 0.2 mL were collected from the orbital cavity before administration and at 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 11.0, and 24.0 hours after administration.
  • the samples were placed in EDTA-K2 anticoagulant tubes and centrifuged at 10,000 rpm for 2 minutes (4°C). Plasma was separated within 1 hour and stored at -20°C or -80°C for later analysis. The entire process, from blood collection to centrifugation, was performed under ice bath conditions.
  • Determination of the content of the target compound in rat plasma after drug administration Take 50 ⁇ L of rat plasma samples at various time points after drug administration, add 450 ⁇ L of acetonitrile and 25 ⁇ L of camptothecin and tolbutamide, vortex mix for 5 min, and centrifuge at 3700 rpm for 10 min. Take the supernatant for LC-MS/MS analysis.

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Abstract

本公开涉及氧代杂芳基类化合物、其制备方法及其在医药上的应用。具体而言，本公开涉及一种通式(I')所示的氧代杂芳基类化合物、其制备方法及含有该类化合物的药物组合物以及其作为治疗剂的用途，特别是作为Nav抑制剂的用途和其在制备治疗和/或减轻疼痛和疼痛相关疾病的药物中的用途。其中通式(I')中各基团如说明书中所定义。

Description

氧代杂芳基类化合物、其制备方法及其在医药上的应用 技术领域
本公开属于医药领域，涉及氧代杂芳基类化合物、其制备方法及其在医药上的应用。特别地，本公开涉及通式(I)所示的氧代杂芳基类化合物、其制备方法及含有该类化合物的药物组合物，以及其作为Nav抑制剂的用途和其在制备治疗和/或减轻疼痛和疼痛相关疾病的药物中的用途。
背景技术
疼痛是一种复杂的生理心理活动，是临床上最常见的症状之一。国际疼痛研究协会将疼痛定义为“一种令人不快的感觉和情绪上的感受，伴有实质上的或潜在的组织损伤，它是一种主观感受。”疼痛可以作为一种警戒信号，提醒机体注意潜在的危险，对机体正常的生命活动具有不可或缺的保护作用。同时，疼痛也是一种常见的临床症状，在引发疼痛的外界刺激消失后，强烈或持久的疼痛会造成生理功能的紊乱，严重影响生命体的生活质量。统计数据显示，全世界约五分之一的人患有中度至重度慢性疼痛。
疼痛起源于周围神经系统的伤害感受器。这是一种游离的神经末梢，广泛分布于全身的皮肤、肌肉、关节和内脏组织中，它可以将感受到的热的、机械的或化学的刺激转化为神经冲动(动作电位)并经由传入神经纤维传递到其位于背根神经节(dorsal root ganglia，DRG)的胞体部分，最终传递到高级神经中枢，引起痛觉。而神经元中动作电位的产生和传导又依赖于细胞膜上的电压门控钠通道(voltage-gated sodium channels，Nav)。当细胞膜去极化时，钠离子通道激活，通道打开，引起钠离子内流，使细胞膜进一步去极化，导致动作电位的产生。因此，抑制异常的钠离子通道活动有助于疼痛的治疗、缓解。
Nav是一类跨膜离子通道蛋白。这些蛋白由分子量260kD的α亚基和分子量为30-40kD的β亚基组成。根据α亚基的不同可以分为9种亚型，Navl.l～Nav1.9。不同亚型表现出不同的组织分布和电生理、药理学特征。根据能否被纳摩尔河豚毒素(tetrodotoxin，TTX)有效抑制，钠离子通道被分为TTX敏感型(TTX-S)和TTX不敏感型(TTX-R)。其中，Nav1.1、Nav1.2、Nav1.3和Nav1.7为TTX-S型，编码基因位于人类染色体2q23-24，它们在神经元中大量表达。Nav1.5、Nav1.8和Nav1.9为TTX-R型，编码基因位于人类染色体3p21-24。其中，Nav1.5主要存在于心肌细胞中，Nav 1.8、Nav l.9存在于外周神经系统。Nav1.4和Nav1.6都为TTX-S型，分别在骨骼肌和中枢神经系统中大量存在。局部麻醉药利多卡因通过抑制Nav来止痛。而非选择性的Nav抑制剂，例如拉莫三嗪，拉科酰胺，美西律已经成功地用于治疗慢性疼痛。
Nav1.8为TTX-R型，编码基因为SCN10A，主要存在于三叉神经节神经元和DRG神经元中，具有慢速失活、迅速恢复的电生理特征。在表达Nav 1.8的神经元内，动作电位的上升主要由Nav1.8电流构成。在研究神经性疼痛的一些模型中，神经损伤会使Nav1.8在轴突和神经元胞体中的表达水平上升。使用Nav1.8反义寡核苷酸在降低Nav1.8表达的同时可以明显地缓解疼痛。大鼠爪内注射角叉菜胶(carrageenan)后，DRG神经元中Nav1.8的表达有所上升。Nav1.8敲除小鼠不能表现出正常的内脏炎症痛。人类的Nav1.8基因产生功能增益突变后，会导致外周神经痛。根据一系列动物实验以及人类基因证据，选择性抑制Nav1.8具有成为新型镇痛疗法的潜力，可以用于炎性疼痛，神经疼痛，手术后疼痛，癌痛等多种疼痛类型的治疗。
临床中使用的Nav抑制剂由于缺乏亚型选择性，能够抑制表达在心脏和中枢神经系统中的钠离子通道，因此治疗窗口较窄，应用范围受到限制。Nav1.8主要分布在外周神经系统，所以选择性地抑制Nav1.8可以有效地减少副作用。因此，有必要开发活性更高，选择性更好，药代动力学性质更佳，副作用更少的Nav1.8抑制剂。
已公开的Nav1.8抑制剂化合物的专利申请包括WO2023205463A1、WO2023205465A1、WO2023205468A1、WO2023205778A1等。
发明内容
本公开的目的在于提供一种通式(I’)所示的化合物或其可药用的盐：
其中：
环A为芳基或杂芳基；环B为环烷基或杂环基；
RB为＝CR15R16；
R15和R16相同或不同，且各自独立地选自氢原子、卤素、烷基、卤代烷基、烷氧基、卤代烷氧基、羟基、羟烷基、烷氧基烷基、烯基、炔基、氰基、NR11R12、C(O)NR11R12、C(O)R14、OR14、环烷基、杂环基、芳基和杂芳基；所述的烷基、烷氧基、烷氧基烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基各自独立地任选被一个或多个R01所取代；
G选自N、N+O-和CR；
G1选自N、N+O-和CR9；G2选自N、N+O-和CR1；
G3选自N、N+O-和CR2；G4选自N、N+O-和CR3；
R、R1、R2、R3和R9相同或不同，且各自独立地选自氢原子、卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、氰基、羟基、羟烷基、烷氧基烷基、烯基、炔基、氨基、NR11R12、C(O)NR11R12、NR13C(O)R14、NR13C(O)NR11R12、C(O)R14、C(O)OR14、S(O)vR14、S(O)vNR11R12、C(＝NR13)R14、S(＝NR13)R14、S(＝NR13)(O)R14、OR14、C(＝S)NR11R12、Si(烷基)3、环烷基、杂环基、芳基和杂芳基，其中所述的烷基、烷氧基、烷氧基烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基各自独立地任选被一个或多个R01所取代；
各个RA相同或不同，且各自独立地选自氧代基、＝S、卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、氰基、羟基、羟烷基、烷氧基烷基、烯基、炔基、氨基、NR11R12、C(O)NR11R12、NR13C(O)R14、NR13C(O)NR11R12、C(O)R14、C(O)OR14、S(O)vR14、S(O)vNR11R12、C(＝NR13)R14、S(＝NR13)R14、S(＝NR13)(O)R14、OR14、Si(烷基)3、环烷基、杂环基、芳基和杂芳基，其中所述的烷基、烷氧基、烷氧基烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基各自独立地任选被一个或多个R02所取代；
各个R7相同或不同，且各自独立地选自氧代基、＝S、卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、氰基、羟基、羟烷基、烷氧基烷基、烯基、炔基、氨基、NR11R12、C(O)NR11R12、NR13C(O)R14、NR13C(O)NR11R12、C(O)R14、C(O)OR14、OC(O)R14、S(O)vR14、S(O)vNR11R12、OR14、＝CR15R16、＝NR13、Si(烷基)3、环烷基、杂环基、芳基和杂芳基，其中所述的烷基、烷氧基、烷氧基烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基各自独立地任选被一个或多个R03所取代；或，两个R7及与其相连的原子一起形成环烷基或杂环基，所述环烷基和杂环基各自独立地任选被一个或多个R03所取代；
各个R01、R02和R03相同或不同，且各自独立地选自氧代基、＝S、卤素、烷基、卤代烷基、烷氧基、卤代烷氧基、羟基、羟烷基、烷氧基烷基、烯基、炔基、氰基、硝基、氨基、NR11R12、C(O)NR11R12、NR13C(O)R14、NR13C(O)NR11R12、C(O)R14、C(O)OR14、S(O)vR14、S(O)vOR14、S(O)vNR11R12、C(＝NR13)R14、S(＝NR13)R14、OR14、＝CR15R16、＝NR13、S(＝NR13)(O)R14、Si(烷基)3、环烷基、杂环基、芳基、杂芳基、环烷基烷基、杂环基烷基、芳基烷基和杂芳基烷基；所述的烷基、烷氧基、烷氧基烷基、烯基、炔基、环烷基、杂环基、芳基、杂芳基、环烷基烷基、杂环基烷基、芳基烷基和杂芳基烷基各自独立地任选被一个或多个R*所取代；
各个R11、R12、R13和R14相同或不同，且各自独立地选自氢原子、烷基、卤代烷基、烷氧基、卤代烷氧基、羟基、羟烷基、烷氧基烷基、烯基、炔基、NR30R31、C(O)NR30R31、C(O)R33、OR33、S(O)vR33、环烷基、杂环基、芳基、杂芳基、环烷基烷基、杂环基烷基、芳基烷基和杂芳基烷基；所述的烷基、烷氧基、烷氧基烷基、烯基、炔基、环烷基、杂环基、芳基、杂芳基、环烷基烷基、杂环基烷基、芳基烷基和杂芳基烷基各自独立地任选被一个或多个R*所取代；或R11、R12及与其相连的氮原子一起形成杂环基，所述杂环基任选被一个或多个R*所取代；
各个R*相同或不同，且各自独立地选自氧代基、＝S、卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、羟基、羟烷基、烷氧基烷基、氰基、烯基、炔基、烷硫基、NR30R31、C(O)NR30R31、亚烷基NR30R31、亚烷基C(O)NR30R31、C(O)R33、C(O)OR33、OR33、Si(烷基)3、硝基、环烷基、杂环基、芳基、杂芳基、环烷基烷基、杂环基烷基、芳基烷基和杂芳基烷基；
各个R30、R31和R33相同或不同，且各自独立地选自氢原子、烷基、烷氧基、卤代烷基、卤代烷氧基、羟基、羟烷基、烷氧基烷基、烷硫基、环烷基、杂环基、芳基、杂芳基、环烷基烷基和杂环基烷基；
m为0、1、2、3、4、5或6；n为0、1、2、3、4、5或6；且
各个v相同或不同，且各自独立地为0、1或2。
在本公开一些实施方案中，所述的通式(I’)所示的化合物或其可药用的盐，其为通式(I)所示的化合物或其可药用的盐：
其中：
X1为N或CR8；X2为N或CR4；X3为N或CR5；X4为N或CR6；
R4、R5、R6和R8相同或不同，且各自独立地选自氢原子、卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、氰基、羟基、羟烷基、烷氧基烷基、烯基、炔基、氨基、NR11R12、C(O)NR11R12、NR13C(O)R14、NR13C(O)NR11R12、C(O)R14、C(O)OR14、S(O)vR14、S(O)vNR11R12、C(＝NR13)R14、S(＝NR13)R14、S(＝NR13)(O)R14、OR14、Si(烷基)3、环烷基、杂环基、芳基和杂芳基，其中所述的烷基、烷氧基、烷氧基烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基各自独立地任选被一个或多个R02所取代；或R5、R6及与其相连的碳原子一起形成环烷基、杂环基、芳基或杂芳基，所述环烷基、杂环基、芳基和杂芳基各自独立地任选被一个或多个RA所取代；
环B、G1至G4、R、RB、R7、n、R11至R14、R02、RA和v如通式(I’)中所定义。
在本公开一些实施方案中，所述的通式(I)、(I’)所示的化合物或其可药用的盐，其为通式(II)所示的化合物或其可药用的盐：
其中，
环B、RB、X1、G1、R、R1至R7和n如通式(I)中所定义。
在本公开一些实施方案中，所述的通式(I)、(I’)或(II)所示的化合物或其可药用的盐，其为通式(III)所示的化合物或其可药用的盐：
其中：U为N或CR7a，R7a为氢原子或R7；
s为0、1或2；r为0、1或2；t为0或1；q为0、1、2、3或4；
G1、X1、R1至R7、R11、R12、R15和R16如通式(I)中所定义。
在本公开一些实施方案中，所述的通式(I)至(III)所示的化合物或其可药用的盐，其为通式(IV)所示的化合物或其可药用的盐：
其中，
G1、X1、R1至R7、R7a、R11、R12、R15、R16、s、r和q如通式(III)中所定义。
在本公开一些实施方案中，所述的通式(I)至(IV)所示的化合物或其可药用的盐，其为通式(IV-1)或(IV-2)所示的化合物或其可药用的盐：
其中，
R7a选自卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、氰基、羟基、羟烷基、烷氧基烷基、烯基、炔基、氨基、NR11R12、C(O)NR11R12、C(O)R14、OR14、环烷基和杂环基，其中所述的烷基、烷氧基、烷氧基烷基、烯基、炔基、环烷基和杂环基各自独立地任选被一个或多个R03所取代；
G1、X1、R1至R7、R11、R12、R14、R15、R16、s、r和q如通式(IV)中所定义，R03如通式(I’)中所定义。
在本公开一些实施方案中，所述的通式(I’)所示的化合物或其可药用的盐，其中环A为6至10元芳基或5至10元杂芳基；在一些实施方案中，环A为苯基或5或6元杂芳基；在一些实施方案中，环A为苯基或6元杂芳基；在一些实施方案中，环A选自苯基、吡啶基和吡唑基；在一些实施方案中，环A为苯基或吡啶基；在一些实施方案中，环A选自在一些实施方案中，环A为在一些实施方案中，环A为吡唑基；在一些实施方案中，环A为*端与环B连接，端与NH所在的环连接。
在本公开一些实施方案中，所述的通式(I)至(IV)所示的化合物或其可药用的盐，其中R15和R16相同或不同，且各自独立地选自氢原子、卤素和C1-6烷基；在一些实施方案中，R15和R16相同或不同，且各自独立地为氢原子或卤素；在一些实施方案中，R15和R16相同或不同，且各自独立地为氢原子或F；在一些实施方案中，R15和R16相同或不同，且各自独立地为卤素；在一些实施方案中，R15和R16均为F。
在本公开一些实施方案中，所述的通式(I’)所示的化合物或其可药用的盐，其中为在一些实施方案中，为在一些实施方案中，为X1、X2、X3和X4如通式(I)中所定义；*端与环B连接。
在本公开一些实施方案中，所述的通式(I)至(IV)所示的化合物或其可药用的盐，其中选自X1、X2、X3、X4、R4、R5和R6如通式(I)中所定义；在一些实施方案中，为 在一些实施方案中，为X1、X3、R4、R5、R6和R8如通式(I)中所定义。
在本公开一些实施方案中，所述的通式(I)至(IV)所示的化合物或其可药用的盐，其中X1为N或CR8，R8选自氢原子、卤素、C1-6烷基和C1-6卤代烷基；在一些实施方案中，X1为CR8，R8如通式(I)中所定义；在一些实施方案中，X1为N或CH；在一些实施方案中，X1为N；在一些实施方案中，X1为CH。
在本公开一些实施方案中，所述的通式(I)所示的化合物或其可药用的盐，其中X2为N或CR4，R4选自氢原子、卤素、C1-6烷基、C1-6卤代烷基和3至6元环烷基，所述3至6元环烷基任选被选自卤素、C1-6烷基和C1-6卤代烷基中的一个或多个所取代；在一些实施方案中，X2为CR4，R4如通式(I)中所定义；在一些实施方案中，X2为CH或C-甲基；在一些实施方案中，X2为C-甲基。
在本公开一些实施方案中，所述的通式(I)所示的化合物或其可药用的盐，其中X3为N或CR5，R5选自氢原子、卤素、C1-6烷基和C1-6卤代烷基；在一些实施方案中，X3为CR5，R5如通式(I)中所定义；在一些实施方案中，X3为N或CH；在一些实施方案中，X3为CH。
在本公开一些实施方案中，所述的通式(I)所示的化合物或其可药用的盐，其中X4为N或CR6，R6选自氢原子、卤素、氰基、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基和3至6元环烷基，所述3至6元环烷基任选被选自卤素、C1-6烷基和C1-6卤代烷基中的一个或多个所取代；在一些实施方案中，X4选自N、CH、C-Cl和C-CF3；在一些实施方案中，X4为C-Cl或C-CF3；在一些实施方案中，X4为C-Cl。
在本公开一些实施方案中，所述的通式(I)所示的化合物或其可药用的盐，其中X1为N或CR8，X2为N或CR4，X3为CR5，X4为CR6，或X1为N或CR8，X2为CR4，X3为N或CR5，X4为CR6，或X1为N或CR8，X2为CR4，X3为CR5，X4为N或CR6；在一些实施方案中，X1为N或CR8，X2为CR4，X3为CR5，X4为CR6；在一些实施方案中，X1为CR8，X2为CR4，X3为N，X4为CR6；在一些实施方案中，X1为CR8，X2为CR4，X3为CR5，X4为CR6；R4、R5、R6和R8如通式(I)中所定义；在一些实施方案中，X1为N或CH，X2为CR4，X3为CR5，X4为CR6，R4、R5和R6相同或不同，且各自独立地选自氢原子、卤素、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基和3至6元环烷基。
在本公开一些实施方案中，所述的通式(I)至(IV)所示的化合物或其可药用的盐，其中R8选自氢原子、卤素、C1-6烷基和C1-6卤代烷基；在一些实施方案中，R8为氢原子。
在本公开一些实施方案中，所述的通式(I)至(IV)所示的化合物或其可药用的盐，其中R4选自氢原子、卤素、氰基、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、3至6元环烷基和3至6元杂环基，所述3至6元环烷基和3至6元杂环基各自独立地任选被选自卤素、C1-6烷基和C1-6卤代烷基中的一个或多个所取代；在一些实施方案中，R4选自氢原子、卤素、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基和3至6元环烷基；在一些实施方案中，R4选自氢原子、卤素、C1-6烷基和C1-6卤代烷基；在一些实施方案中，R4为氢原子或C1-6烷基；在一些实施方案中，R4为氢原子或甲基；在一些实施方案中，R4为氢原子；在一些实施方案中，R4为C1-6烷基；在一些实施方案中，R4为甲基；在一些实施方案中，R4选自氢原子、F、Cl、甲基、CF3和环丙基。
在本公开一些实施方案中，所述的通式(I)至(IV)所示的化合物或其可药用的盐，其中R5选自氢原子、卤素、氰基、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、3至6元环烷基和3至6元杂环基；在一些实施方案中，R5选自氢原子、卤素、C1-6烷基和C1-6卤代烷基；在一些实施方案中，R5为氢原子。
在本公开一些实施方案中，所述的通式(I)至(IV)所示的化合物或其可药用的盐，其中R6选自氢原子、卤素、氰基、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、3至6元环烷基和3至6元杂环基，所述3至6元环烷基和3至6元杂环基各自独立地任选被选自卤素、C1-6烷基和C1-6卤代烷基中的一个或多个所取代；在一些实施方案中，R6选自氢原子、卤素、氰基、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基和3至6元环烷基；在一些实施方案中，R6选自氢原子、卤素、C1-6烷基和C1-6卤代烷基；在一些实施方案中，R6选自氢原子、F、Cl、甲基、CF3和环丙基；在一些实施方案中，R6为卤素或C1-6卤代烷基；在一些实施方案中，R6为Cl或CF3；在一些实施方案中，R6为Cl；在一些实施方案中，R6为CF3。
在本公开一些实施方案中，所述的通式(I)至(IV)所示的化合物或其可药用的盐，其中R4、R5、R6和R8相同或不同，且各自独立地选自氢原子、卤素、氰基、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、3至6元环烷基和3至6元杂环基，所述3至6元环烷基和3至6元杂环基各自独立地任选被一个或多个R02所取代，R02如通式(I)中所定义；在一些实施方案中，R4、R5、R6和R8相同或不同，且各自独立地选自氢原子、卤素、氰基、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基和3至6元环烷基，所述3至6元环烷基任选被选自卤素、C1-6烷基和C1-6卤代烷基中的一个或多个所取代，或R5、R6及与其相连的碳原子一起形成3至10元环烷基或3至10元杂环基；在一些实施方案中，R4、R5、R6和R8相同或不同，且各自独立地选自氢原子、卤素、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基和3至6元环烷基；在一些实施方案中，R4、R5、R6和R8相同或不同，且各自独立地选自氢原子、卤素、C1-6烷基和C1-6卤代烷基；在一些实施方案中，R4、R5、R6和R8相同或不同，且各自独立地选自氢原子、F、Cl、甲基、CF3和环丙基。
在本公开一些实施方案中，所述的通式(I)至(IV)所示的化合物或其可药用的盐，其中R4、R5和R6相同或不同，且各自独立地选自氢原子、卤素、C1-6烷基和C1-6卤代烷基；在一些实施方案中，R4、R5和R6相同或不同，且各自独立地选自氢原子、F、Cl、甲基、CF3和环丙基。
在本公开一些实施方案中，所述的通式(I’)、(I)和(II)所示的化合物或其可药用的盐，其中环B为3至10元环烷基或3至10元杂环基；在一些实施方案中，环B为3至10元环烷基；在一些实施方案中，环B为4至7元环烷基；在一些实施方案中，环B选自环丙基、环丁基、环戊基、环己基、 端与X1所在环连接；在一些实施方案中，环B选自环丁基、环戊基和环己基；在一些实施方案中，环B为环戊基。
在本公开一些实施方案中，所述的通式(I’)、(I)和(II)所示的化合物或其可药用的盐，其中为U、R7、R15、R16、s、t、r和q如通式(III)中所定义；在一些实施方案中，选自 在一些实施方案中，为在一些实施方案中，为R7、R7a、R15、R16、s、r和q如通式(IV)、(IV-1)或(IV-2)中所定义；在一些实施方案中，选自
在本公开一些实施方案中，所述的通式(III)所示的化合物或其可药用的盐，其中选自在一些实施方案中，为在一些实施方案中，为R7、R7a、R15、R16、s、r和q如通式(IV)、(IV-1)或(IV-2)中所定义。
在本公开一些实施方案中，所述的通式(I’)、(I)至(IV)所示的化合物或其可药用的盐，其中各个R7相同或不同，且各自独立地选自卤素、C1-6烷基、C1-6卤代烷基和C1-6烷氧基，或两个R7及与其相连的碳原子一起形成3至6元环烷基，所述3至6元环烷基任选被选自卤素、C1-6烷基和C1-6卤代烷基中的一个或多个所取代；在一些实施方案中，各个R7相同或不同，且各自独立地选自卤素、C1-6烷基和C1-6卤代烷基；在一些实施方案中，各个R7相同或不同，且各自独立地选自C1-6烷基和C1-6卤代烷基；在一些实施方案中，R7为C1-6烷基；在一些实施方案中，R7为甲基或CF3；在一些实施方案中，R7为甲基。
在本公开一些实施方案中，所述的通式(I)至(IV)所示的化合物或其可药用的盐，其中两个R7及与其相连的碳原子一起形成螺环、稠环或桥环；在一些实施方案中，两个R7及与其相连的碳原子一起形成螺环烷基、稠环烷基或桥环烷基；在一些实施方案中，两个R7及与其相连的碳原子一起形成螺环烷基或稠环烷基；上述形成的环任选被一个或多个R03所取代；R03如通式(I’)中所定义。
在本公开一些实施方案中，所述的通式(III)至(IV)所示的化合物或其可药用的盐，其中q为0、1或2；在一些实施方案中，q为0。
在本公开一些实施方案中，所述的通式(III)至(IV)所示的化合物或其可药用的盐，其中s为0或1；在一些实施方案中，s为1；在一些实施方案中，s为0。
在本公开一些实施方案中，所述的通式(III)至(IV)所示的化合物或其可药用的盐，其中r为0或1；在一些实施方案中，r为1；在一些实施方案中，r为0。
在本公开一些实施方案中，所述的通式(I’)、(I)和(II)所示的化合物或其可药用的盐，其中n为0、1或2；在一些实施方案中，n为1。
在本公开一些实施方案中，所述的通式(III)所示的化合物或其可药用的盐，其中t为0。
在本公开一些实施方案中，所述的通式(III)所示的化合物或其可药用的盐，其中U为CR7a，R7a如通式(III)中所定义；在一些实施方案中，U为N；在一些实施方案中，U为CR7a，R7a选自氢原子、卤素、C1-6烷基和C1-6卤代烷基；在一些实施方案中，U为CR7a，R7a为C1-6烷基或C1-6卤代烷基；在一些实施方案中，U为CR7a，R7a为甲基或CF3；在一些实施方案中，U为C-甲基。
在本公开一些实施方案中，所述的通式(III)至(IV)所示的化合物或其可药用的盐，其中R7a选自氢原子、卤素、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、3至6元环烷基和3至6元杂环基；在一些实施方案中，R7a选自氢原子、卤素、C1-6烷基和C1-6卤代烷基；在一些实施方案中，R7a为氢原子或C1-6烷基；在一些实施方案中，R7a为氢原子。
在本公开一些实施方案中，所述的通式(III)至(IV)所示的化合物或其可药用的盐，其中R7a选自卤素、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、3至6元环烷基和3至6元杂环基；在一些实施方案中，R7a选自卤素、C1-6烷基和C1-6卤代烷基；在一些实施方案中，R7a为C1-6烷基或C1-6卤代烷基；在一些实施方案中，R7a为C1-6烷基；在一些实施方案中，R7a为甲基或CF3；在一些实施方案中，R7a为甲基。
在本公开一些实施方案中，所述的通式(I’)所示的化合物或其可药用的盐，其中G为CR，R如通式(I’)中所定义；在一些实施方案中，G为C-C(O)NH2。
在本公开一些实施方案中，所述的通式(I)至(II)所示的化合物或其可药用的盐，其中R选自氰基、C1-6羟烷基、C(O)NR11R12、S(O)2NR11R12和S(＝NR13)(O)R14，R11、R12、R13和R14如通式(I)中所定义；在一些实施方案中，R为C(O)NR11R12，R11和R12如通式(I)中所定义；在一些实施方案中，R为C(O)NH2。
在本公开一些实施方案中，所述的通式(I)至(IV)所示的化合物或其可药用的盐，其中G1为N或CR9；在一些实施方案中，G1为CR9，R9如通式(I’)中所定义；在一些实施方案中，G1为N或CR9，R9选自氢原子、卤素、C1-6烷基和C1-6卤代烷基；在一些实施方案中，G1为N或CH；在一些实施方案中，G1为N；在一些实施方案中，G1为CH。
在本公开一些实施方案中，所述的通式(I’)和(I)所示的化合物或其可药用的盐，其中G2为N或CR1；在一些实施方案中，G2为CR1，R1如通式(I’)中所定义；在一些实施方案中，G2为CR1，R1选自氢原子、卤素、C1-6烷基和C1-6卤代烷基；在一些实施方案中，G2为N或CH；在一些实施方案中，G2为CH。
在本公开一些实施方案中，所述的通式(I’)和(I)所示的化合物或其可药用的盐，其中G3为N或CR2；在一些实施方案中，G3为CR2，R2如通式(I’)中所定义；在一些实施方案中，G3为CR2，R2选自氢原子、卤素、C1-6烷基和C1-6卤代烷基；在一些实施方案中，G3为N或CH；在一些实施方案中，G3为CH。
在本公开一些实施方案中，所述的通式(I’)和(I)所示的化合物或其可药用的盐，其中G4为N或CR3；在一些实施方案中，G4为CR3，R3如通式(I’)中所定义；在一些实施方案中，G4为CR3，R3选自氢原子、卤素、C1-6烷基和C1-6卤代烷基；在一些实施方案中，G4为N或CH；在一些实施方案中，G4为CH。
在本公开一些实施方案中，所述的通式(I)至(IV)所示的化合物或其可药用的盐，其中R9选自氢原子、卤素、C1-6烷基、C1-6卤代烷基、C1-6烷氧基和C1-6卤代烷氧基；在一些实施方案中，R9为氢原子。
在本公开一些实施方案中，所述的通式(I)至(IV)所示的化合物或其可药用的盐，其中R1选自氢原子、卤素、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、3至6元环烷基和3至6元杂环基，所述3至6元环烷基和3至6元杂环基各自独立地任选被选自卤素、C1-6烷基和C1-6卤代烷基中的一个或多个所取代；在一些实施方案中，R1选自氢原子、卤素、C1-6烷基和C1-6卤代烷基；在一些实施方案中，R1为氢原子或卤素；在一些实施方案中，R1选自氢原子、F、Cl、甲基、甲氧基、CF3和环丙基；在一些实施方案中，R1为氢原子或F；在一些实施方案中，R1为氢原子。
在本公开一些实施方案中，所述的通式(I)至(IV)所示的化合物或其可药用的盐，其中R2选自氢原子、卤素、C1-6烷基和C1-6卤代烷基；在一些实施方案中，R2为氢原子或卤素；在一些实施方案中，R2选自氢原子、F、Cl、甲基、甲氧基、CF3和环丙基；在一些实施方案中，R2为氢原子。
在本公开一些实施方案中，所述的通式(I)至(IV)所示的化合物或其可药用的盐，其中R3选自氢原子、卤素、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C1-6羟烷基、3至6元环烷基和3至6元杂环基，所述3至6元环烷基和3至6元杂环基各自独立地任选被选自卤素、C1-6烷基和C1-6卤代烷基中的一个或多个所取代；在一些实施方案中，R3选自氢原子、卤素、C1-6烷基和C1-6卤代烷基；在一些实施方案中，R3为氢原子或卤素；在一些实施方案中，R3选自氢原子、F、Cl、甲基、甲氧基、CF3和环丙基；在一些实施方案中，R3选自氢原子、F和Cl；在一些实施方案中，R3为氢原子；在一些实施方案中，R3为卤素。
在本公开一些实施方案中，所述的通式(I)至(IV)所示的化合物或其可药用的盐，其中R1、R2和R3相同或不同，且各自独立地选自氢原子、卤素、C1-6烷基、C1-6卤代烷基、C1-6烷氧基和C1-6卤代烷氧基；在一些实施方案中，R1、R2和R3相同或不同，且各自独立地选自氢原子、卤素、C1-6烷基和C1-6卤代烷基；在一些实施方案中，R1、R2和R3相同或不同，且各自独立地为氢原子或卤素；在一些实施方案中，R1、R2和R3相同或不同，且各自独立地选自氢原子、F、Cl、甲基、甲氧基、CF3和环丙基；在一些实施方案中，R1、R2和R3为氢原子。
在本公开一些实施方案中，所述的通式(I)至(IV)所示的化合物或其可药用的盐，其中R1、R2、R3和R9相同或不同，且各自独立地选自氢原子、卤素、C1-6烷基和C1-6卤代烷基；在一些实施方案中，R1、R2、R3和R9相同或不同，且各自独立地为氢原子或卤素；在一些实施方案中，R1、R2、R3和R9为氢原子。
在本公开一些实施方案中，所述的通式(I’)所示的化合物或其可药用的盐，其中m为0、1、2、3或4；在一些实施方案中，m为0、1或2；在一些实施方案中，m为2；在一些实施方案中，m为1；在一些实施方案中，m为0。
在本公开一些实施方案中，所述的通式(I’)所示的化合物或其可药用的盐，其中各个RA相同或不同，且各自独立地选自卤素、羟基、氰基、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C1-6烷氧基C1-6烷基、3至6元环烷基和3至6元杂环基，所述C1-6烷基、C1-6烷氧基、3至6元环烷基和3至6元杂环基各自独立地任选被选自卤素、C1-6烷基、C1-6烷氧基、C1-6卤代烷基和C1-6卤代烷氧基中的一个或多个所取代；在一些实施方案中，各个RA相同或不同，且各自独立地选自卤素、C1-6烷基和C1-6卤代烷基；在一些实施方案中，各个RA相同或不同，且各自独立地选自F、Cl、甲基、甲氧基、CF3和环丙基；在一些实施方案中，RA为Cl或甲基。
在本公开一些实施方案中，所述的通式(I)至(IV)所示的化合物或其可药用的盐，其中各个R01相同或不同，且各自独立地选自氧代基、卤素、羟基、氰基、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C1-6烷氧基C1-6烷基和3至6元环烷基；在一些实施方案中，各个R01相同或不同，且各自独立地选自卤素、C1-6烷基和C1-6卤代烷基。
在本公开一些实施方案中，所述的通式(I)至(IV)所示的化合物或其可药用的盐，其中各个R02相同或不同，且各自独立地选自氧代基、卤素、羟基、氰基、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C1-6烷氧基C1-6烷基和3至6元环烷基；在一些实施方案中，各个R02相同或不同，且各自独立地选自卤素、C1-6烷基和C1-6卤代烷基。
在本公开一些实施方案中，所述的通式(I)至(IV)所示的化合物或其可药用的盐，其中各个R03相同或不同，且各自独立地选自氧代基、卤素、羟基、氰基、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C1-6烷氧基C1-6烷基和3至6元环烷基；在一些实施方案中，各个R03相同或不同，且各自独立地选自卤素、C1-6烷基和C1-6卤代烷基。
在本公开一些实施方案中，所述的通式(I)至(IV)所示的化合物或其可药用的盐，其中各个R*相同或不同，且各自独立地选自氧代基、卤素、羟基、氰基、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C1-6烷氧基C1-6烷基和3至6元环烷基；在一些实施方案中，各个R*相同或不同，且各自独立地选自卤素、C1-6烷基和C1-6卤代烷基。
在本公开一些实施方案中，所述的通式(I)至(IV)所示的化合物或其可药用的盐，其中R11和R12相同或不同，且各自独立地选自氢原子、C1-6烷基和3至6元环烷基；在一些实施方案中，R11和R12相同或不同，且各自独立地为氢原子或C1-6烷基；在一些实施方案中，R11和R12相同或不同，且各自独立地为氢原子或甲基；在一些实施方案中，R11和R12均为氢原子。
在本公开一些实施方案中，所述的通式(I)至(IV)所示的化合物或其可药用的盐，其中R11为氢原子或C1-6烷基；在一些实施方案中，R11为氢原子或甲基；在一些实施方案中，R11为氢原子。
在本公开一些实施方案中，所述的通式(I)至(IV)所示的化合物或其可药用的盐，其中R12为氢原子或C1-6烷基；在一些实施方案中，R12为氢原子或甲基；在一些实施方案中，R12为氢原子。
在本公开一些实施方案中，所述的通式(I)至(IV)所示的化合物或其可药用的盐，其中R13为氢原子或C1-6烷基；在一些实施方案中，R13为氢原子。
在本公开一些实施方案中，所述的通式(I)至(IV)所示的化合物或其可药用的盐，其中R14选自氢原子、C1-6烷基和3至6元环烷基；在一些实施方案中，R14为氢原子或C1-6烷基；在一些实施方案中，R14为氢原子或甲基；在一些实施方案中，R14为氢原子。
在本公开一些实施方案中，所述的通式(I)至(IV)所示的化合物或其可药用的盐，其中R30和R31相同或不同，且各自独立地为氢原子或C1-6烷基；在一些实施方案中，R30和R31相同或不同，且各自独立地为氢原子或甲基；在一些实施方案中，R30和R31均为氢原子。
在本公开一些实施方案中，所述的通式(I)至(IV)所示的化合物或其可药用的盐，其中R33为氢原子或C1-6烷基；在一些实施方案中，R33为氢原子。
在本公开一些实施方案中，所述的通式(I)至(IV)所示的化合物或其可药用的盐，其中v为2；在一些实施方案中，v为1；在一些实施方案中，v为0。
在本公开文本中，通式(I)至(IV)包含通式(I)、(I’)、(II)、(III)、(IV)、(IV-1)和(IV-2)；通式(I)至(III)包含通式(I)、(I’)、(II)和(III)。
在本公开一些实施方案中，所述的通式(III)所示的化合物或其可药用的盐，其中R11和R12为氢原子；G1为N或CH；R1、R2和R3相同或不同，且各自独立地选自氢原子、卤素、C1-6烷基和C1-6卤代烷基；X1为N或CH；R4、R5和R6相同或不同，且各自独立地选自氢原子、卤素、C1-6烷基和C1-6卤代烷基；U为CR7a，R7a为氢原子或C1-6烷基；q为0；s为0或1；r为0或1；t为0或1；R15和R16相同或不同，且各自独立地为氢原子或卤素。
在本公开一些实施方案中，所述的通式(IV)、(IV-1)或(IV-2)所示的化合物或其可药用的盐，其中R11和R12为氢原子；G1为N或CH；R1、R2和R3相同或不同，且各自独立地为氢原子或卤素；X1为N或CH；R4、R5和R6相同或不同，且各自独立地选自氢原子、卤素、C1-6烷基和C1-6卤代烷基；R7a为C1-6烷基；q为0；s为0或1；r为0或1；R15和R16相同或不同，且各自独立地为卤素。
在本公开一些实施方案中，所述的通式(IV)、(IV-1)或(IV-2)所示的化合物或其可药用的盐，其中R11和R12为氢原子；G1为N；R1、R2和R3为氢原子；X1为N或CH；R4为C1-6烷基；R5为氢原子；R6为卤素；R7a为C1-6烷基；q为0；s为1；r为0；R15和R16相同或不同，且各自独立地为卤素。
在本公开一些实施方案中，所述的通式(IV)、(IV-1)或(IV-2)所示的化合物或其可药用的盐，其中R11和R12为氢原子；G1为N；R1、R2和R3为氢原子；X1为CH；R4为C1-6烷基；R5为氢原子；R6为卤素；R7a为C1-6烷基；q为0；s为1；r为0；R15和R16相同或不同，且各自独立地为卤素。
在本公开一些实施方案中，所述的通式(IV)、(IV-1)或(IV-2)所示的化合物或其可药用的盐，其中R11和R12为氢原子；G1为N或CH；R1、R2和R3为氢原子；X1为N或CH；R4为甲基；R5为氢原子；R6为Cl或CF3；R7a为甲基；q为0；s为1；r为0；R15和R16为F。
在本公开一些实施方案中，所述的通式(IV)、(IV-1)或(IV-2)所示的化合物或其可药用的盐，其中R11和R12为氢原子；G1为N；R1为氢原子；R2为氢原子；R3为氢原子或卤素；X1为CH；R4为C1-6烷基；R5为氢原子；R6为卤素；R7a为C1-6烷基；q为0；s为1；r为0；R15和R16相同或不同，且各自独立地为卤素。
在本公开一些实施方案中，所述的通式(IV)、(IV-1)或(IV-2)所示的化合物或其可药用的盐，其中R11和R12为氢原子；G1为N；R1为氢原子；R2为氢原子；R3为卤素；X1为CH；R4为C1-6烷基；R5为氢原子；R6为卤素；R7a为C1-6烷基；q为0；s为1；r为0；R15和R16相同或不同，且各自独立地为卤素。
表A本公开的典型化合物包括但不限于：


本公开的另一方面涉及通式(I’A)所示的化合物或其盐，
其中，RW为氢原子或羟基保护基，在一些实施方案中为苄基；
环A、RA、m、环B、G至G4、RB、R7和n如通式(I’)中所定义。
本公开的另一方面涉及通式(IA)所示的化合物或其盐，
其中，RW为氢原子或羟基保护基，在一些实施方案中为苄基；在一些实施方案中，R为氰基；
环B、X1至X4、G1至G4、R、RB、R7和n如通式(I)中所定义。
本公开的另一方面涉及通式(IIA)、(IIa)所示的化合物或其盐，
其中，RW为氢原子或羟基保护基，在一些实施方案中为苄基；在一些实施方案中，R为氰基；X选自卤素、硼酸或硼酸酯基；在一些实施方案中，X为Br或
环B、RB、X1、G1、R、R1至R7和n如通式(II)中所定义。
本公开的另一方面涉及通式(IIIA)、(IIIa)所示的化合物或其盐，
其中，RW为氢原子或羟基保护基，在一些实施方案中为苄基；
X选自卤素、硼酸或硼酸酯基；在一些实施方案中，X为Br或
U、X1、G1、R1至R7、R15、R16、q、t、r和s如通式(III)中所定义。
本公开的另一方面涉及通式(IVA)、(IV-1A)或(IV-2A)所示的化合物或其盐，
其中，RW为氢原子或羟基保护基，在一些实施方案中为苄基；
G1、X1、R1至R7、R7a、R15、R16、s、r和q如通式(IV)、(IV-1)或(IV-2)中所定义。
在本公开一些实施方案中，R为氰基。
表B本公开的典型中间体化合物或其盐包括但不限于：

本公开另一方面涉及一种制备上述通式(I’)所示的化合物或其可药用的盐的方法，该方法包括：
通式(I’A)所示的化合物或其盐经水解反应得到通式(I’)所示的化合物或其可药用的盐，其中
RW为羟基保护基，在一些实施方案中为苄基；
环A、RA、m、环B、G至G4、RB、R7和n如通式(I’)中所定义；
在一些实施方案中，通式(I’A)中G为CR，R为氰基，且通式(I’)中G为CR，R为C(O)NH2。
本公开另一方面涉及一种制备上述通式(I)所示的化合物或其可药用的盐的方法，该方法包括：
通式(IA)所示的化合物或其盐经水解反应得到通式(I)所示的化合物或其可药用的盐，其中
RW为羟基保护基，在一些实施方案中为苄基；
环B、X1至X4、G1至G4、R、RB、R7和n如通式(I)中所定义；
在一些实施方案中，通式(IA)中R为氰基，且通式(I)中R为C(O)NH2；
在一些实施方案中，R为氰基的通式(IA)所示的化合物或其盐经水解反应得到R为C(O)NH2的通式(I)所示的化合物或其可药用的盐。
本公开另一方面涉及一种制备上述通式(II)所示的化合物或其可药用的盐的方法，该方法包括：
通式(IIA)所示的化合物或其盐经水解反应得到通式(II)所示的化合物或其可药用的盐，或R3为氢原子的通式(II)所示的化合物或其盐与卤化试剂发生卤化反应得到R3为卤素的通式(II)所示的化合物或其可药用的盐，其中
RW为羟基保护基，在一些实施方案中为苄基；
环B、RB、X1、G1、R、R1至R7和n如通式(II)中所定义；在一些实施方案中，通式(IIA)中的R为氰基，且通式(II)中R为C(O)NH2；
在一些实施方案中，R为氰基的通式(IIA)所示的化合物或其盐经水解反应得到R为C(O)NH2的通式(II)所示的化合物或其可药用的盐。
本公开的另一方面涉及一种制备上述通式(III)所示的化合物或其可药用的盐的方法，该方法包括：
通式(IIIA)所示的化合物或其盐经水解反应得到通式(III)所示的化合物或其可药用的盐，或R3为氢原子的通式(III)所示的化合物或其盐与卤化试剂发生卤化反应得到R3为卤素的通式(III)所示的化合物或其可药用的盐，其中
RW为羟基保护基，在一些实施方案中为苄基；R11和R12为氢原子；
U、X1、G1、R1至R7、R15、R16、q、t、r和s如通式(III)中所定义。
本公开的另一方面涉及一种制备上述通式(IV)、(IV-1)和(IV-2)所示的化合物或其可药用的盐的方法，该方法包括：
通式(IVA)所示的化合物或其盐经水解反应得到通式(IV)所示的化合物或其可药用的盐，或R3为氢原子的通式(IV)所示的化合物或其盐与卤化试剂发生卤化反应得到R3为卤素的通式(IV)所示的化合物或其可药用的盐，
通式(IV-1A)所示的化合物或其盐反应得到通式(IV-1)所示的化合物或其可药用的盐，或R3为氢原子的通式(IV-1)所示的化合物或其盐与卤化试剂发生卤化反应得到R3为卤素的通式(IV-1)所示的化合物或其可药用的盐，
通式(IV-2A)所示的化合物或其盐经水解反应得到通式(IV-2)所示的化合物或其可药用的盐，或R3为氢原子的通式(IV-2)所示的化合物或其盐与卤化试剂发生卤化反应得到R3为卤素的通式(IV-2)所示的化合物或其可药用的盐，
RW为羟基保护基，在一些实施方案中为苄基；R11和R12为氢原子；
G1、X1、R1至R7、R7a、R15、R16、s、r和q如通式(IV)、(IV-1)或(IV-2)中所定义。
本公开的另一方面涉及一种制备上述通式(IV-1)和(IV-2)所示的化合物或其可药用的盐的方法，该方法包括：
通式(IV)所示的化合物或其盐拆分得到通式(IV-1)和(IV-2)所示的化合物或其可药用的盐，其中，
G1、X1、R1至R7、R7a、R11、R12、R15、R16、s、r和q如通式(IV-1)或(IV-2)中所定义。
在本公开一些实施方案中，所述卤化试剂选自碘单质、Cl2、Br2、氢卤酸(氢氟酸、氢氯酸、氢溴酸等)、氯化亚砜、五氯化磷、三卤化磷(如三氯化磷)、N-溴代丁二酰亚胺、N-氯代丁二酰亚胺和1-氯甲基-4-氟-1,4-二叠氮双环[2.2.2]辛烷双四氟硼酸盐；在一些实施方案中，所述卤化试剂为N-氯代丁二酰亚胺或1-氯甲基-4-氟-1,4-二叠氮双环[2.2.2]辛烷双四氟硼酸盐。
本公开的另一方面涉及一种药物组合物，所述药物组合物含有本公开通式(I)至(IV)或表A中所示的化合物或其可药用的盐，以及一种或多种药学上可接受的载体、稀释剂或赋形剂。
本公开进一步涉及通式(I)至(IV)或表A中所示的化合物或其可药用的盐、或包括其的药物组合物在制备抑制电压门控钠通道的药物中的用途；在一些实施方案中，所述电压门控钠通道为Nav1.8。
本公开进一步涉及通式(I)至(IV)或表A中所示的化合物或其可药用的盐、或包括其的药物组合物在制备用于治疗和/或预防由电压门控钠通道介导的疾病或病症的药物中的用途；在一些实施方案中，所述电压门控钠通道为Nav1.8。
本公开进一步涉及通式(I)至(IV)或表A中所示的化合物或其可药用的盐、或包括其的药物组合物在制备治疗和/或减轻疼痛和疼痛相关疾病、多发性硬化症、夏-马-图三氏综合症、失禁、病理咳嗽或心律失常的药物中的用途；在一些实施方案中，所述疼痛选自慢性疼痛、急性疼痛、炎性疼痛、癌症疼痛、术后疼痛、神经性疼痛、肌肉骨骼痛、原发性疼痛、肠痛、特发性疼痛和内脏痛；在一些实施方案中，所述术后疼痛选自拇囊炎切除术疼痛、疝修补术疼痛和腹部整形术疼痛。
本公开进一步涉及一种抑制电压门控钠通道的方法，其包括给予所需患者通式(I)至(IV)或表A所示的化合物或其可药用的盐、或包括其的药物组合物。
本公开进一步涉及一种治疗和/或预防由电压门控钠通道介导的疾病或病症的方法，其包括给予所需患者通式(I)至(IV)或表A所示的化合物或其可药用的盐、或包括其的药物组合物。
本公开进一步涉及一种治疗和/或预防疼痛和疼痛相关疾病、多发性硬化症、夏-马-图三氏综合症、失禁、病理咳嗽或心律失常的方法，其包括给予所需患者通式(I)至(IV)或表A所示的化合物或其可药用的盐、或包括其的药物组合物。
本公开进一步涉及一种通式(I)至(IV)或表A所示的化合物或其可药用的盐、或包括其的药物组合物，其用作药物；在一些实施方案中，其用作抑制电压门控钠通道活性的药物；在一些实施方案中，其用作抑制Nav1.8活性的药物。
本公开进一步涉及一种通式(I)至(IV)或表A所示的化合物或其可药用的盐、或包括其的药物组合物，其用于抑制电压门控钠通道活性；在一些实施方案中，其用于抑制Nav1.8活性。
本公开进一步涉及一种通式(I)至(IV)或表A所示的化合物或其可药用的盐、或包括其的药物组合物，其用作电压门控钠通道抑制剂；在一些实施方案中，其用作Nav1.8抑制剂。
本公开进一步涉及一种通式(I)至(IV)或表A所示的化合物或其可药用的盐、或包括其的药物组合物，其用作治疗和/或预防由电压门控钠通道介导的疾病或病症的药物；在一些实施方案中，其用作治疗和/或预防由Nav1.8介导的疾病或病症的药物。
本公开进一步涉及一种通式(I)至(IV)或表A所示的化合物或其可药用的盐、或包括其的药物组合物，其用于治疗和/或预防由电压门控钠通道介导的疾病或病症。
本公开进一步涉及一种通式(I)至(IV)或表A所示的化合物或其可药用的盐、或包括其的药物组合物，其用于治疗和/或预防疼痛和疼痛相关疾病、多发性硬化症、夏-马-图三氏综合症、失禁、病理咳嗽或心律失常。
本公开所述的疾病或病症是通过抑制电压门控钠通道来治疗和/或预防的疾病或病症。
在一些实施方案中，本公开所述的电压门控钠通道为Nav1.8。
在一些实施方案中，本公开所述的由电压门控钠通道介导的疾病或病症为疼痛和疼痛相关疾病、多发性硬化症、夏-马-图三氏综合症、失禁、病理咳嗽或心律失常；在一些实施方案中，所述疼痛选自慢性疼痛、急性疼痛、炎性疼痛、癌症疼痛、术后疼痛、神经性疼痛、肌肉骨骼痛、原发性疼痛、肠痛、特发性疼痛和内脏痛；在一些实施方案中，所述术后疼痛选自拇囊炎切除术疼痛、疝修补术疼痛和腹部整形术疼痛。
在一些实施方案中，本公开所述的由电压门控钠通道介导的疾病或病症选自疼痛性周围神经病变(Painful Peripheral Neuropathy)、无痛性周围神经病变(Painless Peripheral Neuropathy)、前皮神经卡压综合征(Anterior Cutaneous Nerve Entrapment Syndrome)、慢性疼痛综合征(Chronic Pain Syndrome)、神经卡压综合征(Nerve Entrapment Syndrome)、三叉神经痛(Trigeminal Neuralgia)、小纤维神经病(Small Fiber Neuropathy)、糖尿病周围神经病变(Diabetic Neuropathy Peripheral)、糖尿病周围神经痛(Painful Diabetic Peripheral Neuropathy)、疼痛性腰骶神经根病(Painful Lumbosacral Radiculopathy)、带状疱疹后神经痛、红斑性肢痛症、关节痛、骨性关节炎和纤维肌痛、神经疼痛、糖尿病神经疼痛。
在一些实施方案中，所述疼痛选自糖尿病疼痛、骨关节炎疼痛和手术拔除阻生第三磨牙后的急性疼痛(Acute Pain After Surgical Removal of Impacted Third Molars)。
可将活性化合物制成适合于通过任何适当途径给药的形式，在一些实施方案中活性化合物是以单位剂量的方式，或者是以患者可以以单剂自我给药的方式。本公开化合物或组合物的单位剂量的表达方式可以是片剂、胶囊、扁囊剂、瓶装药水、药粉、颗粒剂、锭剂、栓剂、再生药粉或液体制剂。
作为一般性指导，合适的单位剂量可以是0.1～1000mg。
本公开的药物组合物除活性化合物外，可含有一种或多种辅料，所述辅料选自以下成分：填充剂(稀释剂)、粘合剂、润湿剂、崩解剂或赋形剂等。根据给药方法的不同，组合物可含有0.1至99重量％的活性化合物。
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。
含活性成分的药物组合物可以是适用于口服的形式，例如片剂、糖锭剂、锭剂、水或油混悬液、可分散粉末或颗粒、乳液、硬或软胶囊，或糖浆剂或酏剂。可按照本领域任何已知制备药用组合物的方法制备口服组合物，此类组合物可含有一种或多种选自以下的成分：甜味剂、矫味剂、着色剂和防腐剂，以提供悦目和可口的药用制剂。片剂含有活性成分和用于混合的适宜制备片剂的无毒的可药用的赋形剂。这些赋形剂可以是惰性赋形剂、造粒剂、崩解剂、粘合剂和润滑剂。这些片剂可以不包衣或可通过掩盖药物的味道或在胃肠道中延迟崩解和吸收，因而在较长时间内提供缓释作用的已知技术将其包衣。
也可用其中活性成分与惰性固体稀释剂或其中活性成分与水溶性载体或油溶媒混合的软明胶胶囊提供口服制剂。
水混悬液含有活性物质和用于混合的适宜制备水混悬液的赋形剂。此类赋形剂是悬浮剂、分散剂或湿润剂。水混悬液也可以含有一种或多种防腐剂、一种或多种着色剂、一种或多种矫味剂和一种或多种甜味剂。
油混悬液可通过使活性成分悬浮于植物油或矿物油配制而成。油悬浮液可含有增稠剂。可加入上述的甜味剂和矫味剂，以提供可口的制剂。可通过加入抗氧化剂保存这些组合物。
本公开的药物组合物也可以是水包油乳剂的形式。油相可以是植物油、矿物油或其混合物。适宜的乳化剂可以是天然产生的磷脂，乳剂也可以含有甜味剂、矫味剂、防腐剂和抗氧剂。此类制剂也可含有缓和剂、防腐剂、着色剂和抗氧剂。
本公开的药物组合物可以是无菌注射水溶液形式。可以使用的可接受的溶媒或溶剂有水、林格氏液和等渗氯化钠溶液。无菌注射制剂可以是其中活性成分溶于油相的无菌注射水包油微乳，可通过局部大量注射将注射液或微乳注入患者的血流中。或者，最好按可保持本公开化合物恒定循环浓度的方式给予溶液和微乳。为保持这种恒定浓度，可使用连续静脉内递药装置。这种装置的实例是Deltec CADD-PLUS.TM.5400型静脉注射泵。
本公开的药物组合物可以是用于肌内和皮下给药的无菌注射水或油混悬液的形式。可按已知技术，用适宜的分散剂或湿润剂和悬浮剂配制该混悬液。无菌注射制剂也可以是在肠胃外可接受的无毒稀释剂或溶剂中制备的无菌注射溶液或混悬液。此外，可方便地用无菌固定油作为溶剂或悬浮介质。为此目的，可使用任何调和固定油。此外，脂肪酸也可以制备注射剂。
可按用于直肠给药的栓剂形式给予本公开化合物。可通过将药物与在普通温度下为固体但在直肠中为液体，因而在直肠中会溶化而释放药物的适宜的无刺激性赋形剂混合来制备这些药物组合物。
如本领域技术人员所熟知的，药物的给药剂量依赖于多种因素，包括但并非限定于以下因素：所用具体化合物的活性、患者的年龄、患者的体重、患者的健康状况、患者的行为、患者的饮食、给药时间、给药方式、排泄的速率、药物的组合、疾病的严重性等；另外，最佳的治疗方式如治疗的模式、化合物的日用量或可药用的盐的种类可以根据传统的治疗方案来验证。
术语说明
除非有相反陈述，在说明书和权利要求书中使用的术语具有下述含义。
术语“烷基”指饱和的直链或带有支链的脂肪族烃基，其具有1至20个(例如1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20个)碳原子(即C1-20烷基)。在一些实施方案中，所述烷基具有1至12个碳原子的烷基(即C1-10烷基)，在一些实施方案中具有1至6个碳原子的烷基(即C1-6烷基)。非限制性的实例包括：甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基、正庚基、2-甲基己基、3-甲基己基、4-甲基己基、5-甲基己基、2,3-二甲基戊基、2,4-二甲基戊基、2,2-二甲基戊基、3,3-二甲基戊基、2-乙基戊基、3-乙基戊基、正辛基、2,3-二甲基己基、2,4-二甲基己基、2,5-二甲基己基、2,2-二甲基己基、3,3-二甲基己基、4,4-二甲基己基、2-乙基己基、3-乙基己基、4-乙基己基、2-甲基-2-乙基戊基、2-甲基-3-乙基戊基、正壬基、2-甲基-2-乙基己基、2-甲基-3-乙基己基、2,2-二乙基戊基、正癸基、3,3-二乙基己基、2,2-二乙基己基，及其各种支链异构体等。烷基可以是取代的或非取代的，当被取代时，其可以在任何可使用的连接点被取代，在一些实施方案中取代基选自D原子、卤素、烷氧基、卤代烷基、卤代烷氧基、环烷基氧基、杂环基氧基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基中的一个或多个。
术语“亚烷基”指二价烷基，其中烷基如上所定义，其具有1至20个(例如1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20个)碳原子(即C1-20亚烷基)。在一些实施方案中，所述亚烷基具有1至10个碳原子的亚烷基(即C1-10亚烷基)，在一些实施方案中具有1至8个碳原子的亚烷基(即C1-8亚烷基)，在一些实施方案中具有2至7个碳原子的亚烷基(即C2-7亚烷基)或具有1、2或3个碳原子的亚烷基(即C1-6亚烷基)。非限制性的实例包括：-CH2-、-CH(CH3)-、-C(CH3)2-、-CH2CH2-、-CH(CH2CH3)-、-CH2CH(CH3)-、-CH2C(CH3)2-、-CH2CH2CH2-、-CH2CH2CH2CH2-等。亚烷基可以是取代的或非取代的，当被取代时，其可以在任何可使用的连接点被取代，取代基选自D原子、卤素、烷氧基、卤代烷基、卤代烷氧基、环烷基氧基、杂环基氧基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基中的一个或多个。
术语“烯基”指分子中含有至少一个碳碳双键的烷基，其中烷基的定义如上所述，其具有2至12个(例如2、3、4、5、6、7、8、9、10、11或12个)碳原子(即C2-12烯基)。在一些实施方案中，所述烯基具有2至6个碳原子的烯基(即C2-6烯基)。非限制性的实例包括：乙烯基、丙烯基、异丙烯基、丁烯基等。烯基可以是取代的或非取代的，当被取代时，其可以在任何可使用的连接点被取代，取代基选自D原子、烷氧基、卤素、卤代烷基、卤代烷氧基、环烷基氧基、杂环基氧基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基中的一个或多个。
术语“炔基”指分子中含有至少一个碳碳三键的烷基，其中烷基的定义如上所述，其具有2至12个(例如2、3、4、5、6、7、8、9、10、11或12个)碳原子(即C2-12炔基)。在一些实施方案中，所述炔基具有2至6个碳原子的炔基(即C2-6炔基)。非限制性的实例包括：乙炔基、丙炔基、丁炔基、戊炔基、己炔基等。炔基可以是取代的或非取代的，当被取代时，其可以在任何可使用的连接点被取代，取代基选自D原子、烷氧基、卤素、卤代烷基、卤代烷氧基、环烷基氧基、杂环基氧基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基中的一个或多个。
术语“烷氧基”指-O-(烷基)，其中烷基的定义如上所述。非限制性的实例包括：甲氧基、乙氧基、丙氧基和丁氧基等。烷氧基可以是取代的或非取代的，当被取代时，其可以在任何可使用的连接点被取代，取代基选自D原子、卤素、烷氧基、卤代烷基、卤代烷氧基、环烷基氧基、杂环基氧基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基中的一个或多个。
术语“烷硫基”指-S-(烷基)，其中烷基的定义如上所述。非限制性的实例包括：甲硫基、乙硫基、丙硫基和丁硫基等。烷硫基可以是取代的或非取代的，当被取代时，其可以在任何可使用的连接点被取代，取代基选自D原子、卤素、烷氧基、卤代烷基、卤代烷氧基、环烷基氧基、杂环基氧基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基中的一个或多个。
术语“环烷基”指饱和或部分不饱和的单环全碳环(即单环环烷基)或多环系统(即多环环烷基)，其具有3至20个(例如3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20个)环原子(即3至20元环烷基)。在一些实施方案中，所述环烷基具有3至12个环原子的环烷基(即3至12元环烷基)或3至10个环原子的环烷基(即3至10元环烷基)，在一些实施方案中具有3至8个环原子的环烷基(即3至8元环烷基)，在一些实施方案中具有3至6个环原子的环烷基(即3至6元环烷基)、4至7个环原子的环烷基(即4至7元环烷基)或5或6个环原子的环烷基(即5或6元环烷基)；在一些实施方案中具有5或6个环原子的环烷基。
所述的单环环烷基，非限制性的实例包括：环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环己二烯基、环庚基、环庚三烯基和环辛基等。
所述的多环环烷基包括：螺环烷基、稠环烷基和桥环烷基。
术语“螺环烷基”指环之间共用一个碳原子(称螺原子)的多环系统，其环内可以含有一个或多个双键，或其环内可以含有一个或多个选自氮、氧和硫的杂原子(所述的氮可任选被氧化，即形成氮氧化物；所述的硫可任选被氧代，即形成亚砜或砜，但不包括-O-O-、-O-S-或-S-S-)，条件是至少含有一个全碳环且连接点在该全碳环上，其具有5至20个(例如5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20个)环原子(即5至20元螺环烷基)。在一些实施方案中，所述螺环烷基具有6至14个环原子的螺环烷基(即6至14元螺环烷基)，在一些实施方案中具有7至10个环原子的螺环烷基(即7至10元螺环烷基)。所述螺环烷基包括单螺环烷基和多螺环烷基(如双螺环烷基等)，在一些实施方案中为单螺环烷基或双螺环烷基，在一些实施方案中为3元/4元、3元/5元、3元/6元、4元/4元、4元/5元、4元/6元、5元/3元、5元/4元、5元/5元、5元/6元、5元/7元、6元/3元、6元/4元、6元/5元、6元/6元、6元/7元、7元/5元或7元/6元单螺环烷基。非限制性的实例包括：
其连接点可在任意位置；
等。
术语“稠环烷基”指环之间共享毗邻的两个碳原子的多环系统，其为单环环烷基与一个或多个单环环烷基稠合，或者单环环烷基与杂环基、芳基或杂芳基中的一个或多个稠合，其中连接点在单环环烷基上，其环内可以含有一个或多个双键，且具有5至20个(例如5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20个)环原子(即5至20元稠环烷基)。在一些实施方案中，所述稠环烷基具有6至14个环原子的稠环烷基(即6至14元稠环烷基)，在一些实施方案中具有7至10个环原子的稠环烷基(即7至10元稠环烷基)。所述稠环烷基包括双环稠环烷基和多环稠环烷基(如三环稠环烷基、四环稠环烷基等)，在一些实施方案中为双环稠环烷基或三环稠环烷基，在一些实施方案中为3元/4元、3元/5元、3元/6元、4元/4元、4元/5元、4元/6元、5元/3元、5元/4元、5元/5元、5元/6元、5元/7元、6元/3元、6元/4元、6元/5元、6元/6元、6元/7元、7元/5元或7元/6元双环稠环烷基。非限制性的实例包括：
其连接点可在任意位置；等。
术语“桥环烷基”指环之间共用两个不直接连接的碳原子的全碳多环系统，其环内可以含有一个或多个双键，且具有5至20个(例如5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20个)碳原子(即5至20元桥环烷基)。在一些实施方案中，所述桥环烷基具有6至14个碳原子的桥环烷基(即6至14元桥环烷基)，在一些实施方案中具有7至10个碳原子的桥环烷基(即7至10元桥环烷基)。所述桥环烷基包括双环桥环烷基和多环桥环烷基(如三环桥环烷基、四环桥环烷基等)，在一些实施方案中为双环桥环烷基或三环桥环烷基。非限制性的实例包括：
其连接点可在任意位置。
环烷基可以是取代的或非取代的，当被取代时，其可以在任何可使用的连接点被取代，取代基选自D原子、卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、环烷基氧基、杂环基氧基、羟基、羟烷基、氧代基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基中的一个或多个。
术语“杂环基”指饱和或部分不饱和的单环杂环(即单环杂环基)或多环杂环系统(即多环杂环基)，其环内至少含有一个(例如1、2、3或4个)选自氮、氧和硫的杂原子(所述的氮可任选被氧化，即形成氮氧化物；所述的硫可任选被氧代，即形成亚砜或砜，但不包括-O-O-、-O-S-或-S-S-)，且具有3至20个(例如3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20个)环原子(即3至20元杂环基)。在一些实施方案中，所述杂环基具有3至12个环原子的杂环基(即3至12元杂环基)和3至10个环原子的杂环基(即3至10元杂环基)和7至10个环原子的杂环基(即7至10元杂环基)；在一些实施方案中具有3至8个环原子的杂环基(即3至8元杂环基)；在一些实施方案中具有3至6个环原子的杂环基(即3至6元杂环基)、4至7个环原子的杂环基(即4至7元杂环基)或5或6个环原子的杂环基(即5或6元杂环基)；在一些实施方案中具有5或6个环原子的杂环基。
所述的单环杂环基，非限制性的实例包括：吡咯烷基、四氢吡喃基、四氢呋喃基、1,2,3,6-四氢吡啶基、哌啶基、哌嗪基、氮杂环丁烷基、吗啉基、硫代吗啉基和高哌嗪基等。
所述的多环杂环基包括螺杂环基、稠杂环基和桥杂环基。
术语“螺杂环基”指环之间共用一个原子(称螺原子)的多环杂环系统，其环内可以含有一个或多个双键，且其环内至少含有一个(例如1、2、3或4个)选自氮、氧和硫的杂原子(所述的氮可任选被氧化，即形成氮氧化物；所述的硫可任选被氧代，即形成亚砜或砜，但不包括-O-O-、-O-S-或-S-S-)，条件是至少含有一个单环杂环基且连接点在该单环杂环基上，其具有5至20个(例如5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20个)环原子(即5至20元螺杂环基)。在一些实施方案中，所述螺杂环基具有6至14个环原子的螺杂环基(即6至14元螺杂环基)，在一些实施方案中具有7至10个环原子的螺杂环基(即7至10元螺杂环基)。所述螺杂环基包括单螺杂环基和多螺杂环基(如双螺杂环基等)，在一些实施方案中为单螺杂环基或双螺杂环基，在一些实施方案中为3元/4元、3元/5元、3元/6元、4元/4元、4元/5元、4元/6元、5元/3元、5元/4元、5元/5元、5元/6元、5元/7元、6元/3元、6元/4元、6元/5元、6元/6元、6元/7元、7元/5元或7元/6元单螺杂环基。非限制性的实例包括：
等。
术语“稠杂环基”指环之间共享毗邻的两个原子的多环杂环系统，其环内可以含有一个或多个双键，且其环内至少含有一个(例如1、2、3或4个)选自氮、氧和硫的杂原子(所述的氮可任选被氧化，即形成氮氧化物；所述的硫可任选被氧代，即形成亚砜或砜，但不包括-O-O-、-O-S-或-S-S-)，其为单环杂环基与一个或多个单环杂环基稠合，或者单环杂环基与环烷基、芳基或杂芳基中的一个或多个稠合，其中连接点在单环杂环基上，且具有5至20个(例如5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20个)环原子(即5至20元稠杂环基)。在一些实施方案中，所述稠杂环基具有6至14个环原子的稠杂环基(即6至14元稠杂环基)，在一些实施方案中具有7至10个环原子的稠杂环基(即7至10元稠杂环基)。所述稠杂环基包括双环和多环稠杂环基(如三环稠杂环基、四环稠杂环基等)，在一些实施方案中为双环稠杂环基或三环稠杂环基，在一些实施方案中为3元/4元、3元/5元、3元/6元、4元/4元、4元/5元、4元/6元、5元/3元、5元/4元、5元/5元、5元/6元、5元/7元、6元/3元、6元/4元、6元/5元、6元/6元、6元/7元、7元/5元或7元/6元双环稠杂环基。非限制性的实例包括：
等。
术语“桥杂环基”指环之间共用两个不直接连接的原子的多环杂环系统，其环内可以含有一个或多个双键，并且其环内至少含有一个(例如1、2、3或4个)选自氮、氧和硫的杂原子(所述的氮可任选被氧化，即形成氮氧化物；所述的硫可任选被氧代，即形成亚砜或砜，但不包括-O-O-、-O-S-或-S-S-)，其具有5至20个(例如5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20个)环原子(即5至20元桥杂环基)。在一些实施方案中，所述桥杂环基具有6至14个环原子的桥杂环基(即6至14元桥杂环基)，在一些实施方案中具有7至10个环原子的桥杂环基(即7至10元桥杂环基)。根据组成环的数目可以分为双环桥杂环基和多环桥杂环基(如三环桥杂环基、四环桥杂环基等)，在一些实施方案中为双环桥杂环基或三环桥杂环基。非限制性的实例包括：
等。
杂环基可以是取代的或非取代的，当被取代时，其可以在任何可使用的连接点被取代，取代基选自D原子、卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、环烷基氧基、杂环基氧基、羟基、羟烷基、氧代基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基中的一个或多个。
术语“芳基”指具有共轭的π电子体系的单环全碳芳环(即单环芳基)或多环芳环系统(即多环芳基)，其具有6至20个(例如6、7、8、9、10、11、12、13、14、15、16、17、18、19或20个)环原子(即6至20元芳基)。在一些实施方案中，所述芳基具有6至14个环原子的芳基(即6至14元芳基)，在一些实施方案中具有6至10个环原子的芳基(即6至10元芳基)。所述的单环芳基，例如苯基。所述的多环芳基，非限制性的实例包括：萘基、蒽基、菲基等。所述多环芳基还包括苯基与杂环基或环烷基中的一个或多个稠合，或萘基与杂环基或环烷基中的一个或多个稠合，其中连接点在苯基或萘基上，并且在这种情况下，环原子个数继续表示多环芳环系统中的环原子个数，非限制性的实例包括：
等。
芳基可以是取代的或非取代的，当被取代时，其可以在任何可使用的连接点被取代，取代基选自D原子、卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、环烷基氧基、杂环基氧基、羟基、羟烷基、氧代基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基中的一个或多个。
术语“杂芳基”指具有共轭的π电子体系的单环杂芳环(即单环杂芳基)或多环杂芳环系统(即多环杂芳基)，其环内至少含有一个(例如1、2、3或4个)选自氮、氧和硫的杂原子(所述的氮可任选被氧化，即形成氮氧化物；所述的硫可任选被氧代，即形成亚砜或砜，但不包括-O-O-、-O-S-或-S-S-)，其具有5至20个(例如5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20个)环原子(即5至20元杂芳基)。在一些实施方案中，所述杂芳基具有5至14个环原子的杂芳基(即5至14元杂芳基)，在一些实施方案中具有5至10个环原子的杂芳基(即5至10元杂芳基)，在一些实施方案中具有5或6个环原子的杂芳基(即5或6元杂芳基)。
所述的单环杂芳基，非限制性的实例包括：呋喃基、噻吩基、噻唑基、异噻唑基、噁唑基、异噁唑基、噁二唑基、噻二唑基、咪唑基、吡唑基、三唑基、四唑基、呋咱基、吡咯基、N-烷基吡咯基、吡啶基、嘧啶基、吡啶酮基、N-烷基吡啶酮(如等)、吡嗪基、哒嗪基、吡啶-1-氧化物基等。
所述的多环杂芳基，非限制性的实例包括：吲哚基、吲唑基、喹啉基、异喹啉基、喹喔啉基、酞嗪基、苯并咪唑基、苯并噻吩基、喹唑啉基、苯并噻唑基、咔唑基等。所述多环杂芳基还包括单环杂芳基与一个或多个芳基稠合，其中连接点在芳香环上，并且在这种情况下，环原子个数继续表示多环杂芳环系统中的环原子个数。所述多环杂芳基还包括单环杂芳基与环烷基或杂环基中的一个或多个稠合，其中连接点在单环杂芳环上，并且在这种情况下，环原子个数继续表示多环杂芳环系统中的环原子个数。非限制性的实例包括：
等。
杂芳基可以是取代的或非取代的，当被取代时，其可以在任何可使用的连接点被取代，取代基选自D原子、卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、环烷基氧基、杂环基氧基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基中的一个或多个。
术语“环烷基氧基”指-O-环烷基，其中环烷基如上所定义。
术语“杂环基氧基”指-O-杂环基，其中杂环基如上所定义。
术语“芳基氧基”指-O-芳基，其中芳基如上所定义。
术语“杂芳基氧基”指-O-杂芳基，其中杂芳基如上所定义。
术语“环烷基烷基”指烷基被一个或多个环烷基取代，其中环烷基、烷基如上所定义。
术语“杂环基烷基”指烷基被一个或多个杂环基取代，其中杂环基、烷基如上所定义。
术语“芳基烷基”指烷基被一个或多个芳基取代，其中芳基、烷基如上所定义。
术语“杂芳基烷基”指烷基被一个或多个杂芳基取代，其中杂芳基、烷基如上所定义。
术语“卤代烷基”指烷基被一个或多个卤素取代，其中烷基如上所定义。
术语“卤代烷氧基”指烷氧基被一个或多个卤素取代，其中烷氧基如上所定义。
术语“羟烷基”指烷基被一个或多个羟基取代，其中烷基如上所定义。
术语“羟烷氧基”指烷氧基被一个或多个羟基取代，其中烷氧基如上所定义。
术语“烷氧基烷基”指烷基被一个或多个烷氧基取代，其中烷基和烷氧基如上所定义；在一些实施方案中为-烷基-烷氧基；包括但不限于甲氧基甲基、乙氧基甲基、甲氧基乙基。
术语“卤素”指氟、氯、溴或碘。
术语“羟基”指-OH。
术语“氨基”指-NH2。
术语“氰基”指-CN。
术语“硝基”指-NO2。
术语“氧代”或“氧代基”指“＝O”。
术语“羰基”指C＝O。
TBS指叔丁基二甲基硅基。
术语“羟基保护基”是指通常用于阻断或保护羟基而反应在化合物的其它官能团上进行的羟基衍生物。非限制性实施例包含：三乙基硅基、三异丙基硅基、叔丁基二甲基硅基(TBS)、叔丁基二苯基硅基、甲基、叔丁基、烯丙基、苄基、甲氧基甲基(MOM)、叔丁基二苯基硅基(TBDPS)、乙氧基乙基、2-四氢吡喃基(THP)、甲酰基、乙酰基、苯甲酰基和对硝基苯甲酰基等；在一些实施方案中为苄基。
本公开化合物可以存在特定的立体异构体形式。术语“立体异构体”是指结构相同但原子在空间中的排列不同的异构体。其包括顺式和反式(或Z和E)异构体、(-)-和(+)-异构体、(R)-和(S)-对映异构体、非对映异构体、(D)-和(L)-异构体、互变异构体、阻转异构体、构象异构体及其混合物(如外消旋体、非对映异构体的混合物)。本公开化合物中的取代基可以存在另外的不对称原子。所有这些立体异构体以及它们的混合物，均包括在本公开的范围内。可以通过手性合成、手性试剂或者其他常规技术制备光学活性的(-)-和(+)-异构体、(R)-和(S)-对映异构体以及(D)-和(L)-异构体。本公开某化合物的一种异构体，可以通过不对称合成或者手性助剂来制备，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，得到纯的异构体。此外，对映异构体和非对映异构体的分离通常是通过色谱法完成。
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。对于所有的碳-碳双键，即使仅命名了一个构型，Z型和E型均包括在内。
本公开的化合物可包含其所有方式的旋转异构体和构象上受限的状态。还包括阻转异构体，术语“阻转异构体”为由于围绕单键的旋转受阻而产生的立体异构体，其中归因于立体应变或其他促成因素的能量差异形成足够高的旋转壁垒以允许个别构象异构体分离。例如，某些本公开化合物可以以阻转异构体的混合物的形式(如等比例混合物、富集一种阻转异构体的混合物等)或经纯化的一种阻转异构体的形式存在。
本公开的化合物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在本公开的范围内。术语“互变异构体”或“互变异构体形式”是指平衡存在并且容易从一种异构形式转化为另一种异构形式的结构异构体。其包括所有可能的互变异构体，即以单一异构体的形式或以所述互变异构体的任意比例的混合物的形式存在。非限制性的实例包括：酮-烯醇、亚胺-烯胺、内酰胺-内酰亚胺等。内酰胺-内酰亚胺平衡实例如下所示：
如当提及吡唑基时，应理解为包括如下两种结构中的任何一种或两种互变异构体的混合物：
所有的互变异构形式在本公开的范围内，且化合物的命名不排除任何互变异构体。
本公开的化合物包括其化合物的所有合适的同位素衍生物。术语“同位素衍生物”是指至少一个原子被具有相同原子序数但原子质量不同的原子替代的化合物。可引入到本公开化合物中的同位素的实例包括氢、碳、氮、氧、磷、硫、氟、氯、溴和碘等的稳定和放射性的同位素，例如分别为2H(氘，D)、3H(氚，T)、11C、13C、14C、15N、17O、18O、32p、33p、33S、34S、35S、36S、18F、36Cl、82Br、123I、124I、125I、129I和131I等，在一些实施方案中为氘。
相比于未氘代药物，氘代药物有降低毒副作用、增加药物稳定性、增强疗效、延长药物生物半衰期等优势。本公开的化合物的所有同位素组成的变换，无论放射性与否，都包括在本公开的范围之内。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，其中氘的替换可以是部分或完全的，部分氘的替换是指至少一个氢被至少一个氘替换。
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15％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(即至少15％的氘掺入)、至少2000倍的丰度的氘(即至少30％的氘掺入)、至少3000倍的丰度的氘(即至少45％的氘掺入)、至少3340倍的丰度的氘(即至少50.1％的氘掺入)、至少3500倍的丰度的氘(即至少52.5％的氘掺入)、至少4000倍的丰度的氘(即至少60％的氘掺入)、至少4500倍的丰度的氘(即至少67.5％的氘掺入)、至少5000倍的丰度的氘(即至少75％的氘掺入)、至少5500倍的丰度的氘(即至少82.5％的氘掺入)、至少6000倍的丰度的氘(即至少90％的氘掺入)、至少6333.3倍的丰度的氘(即至少95％的氘掺入)、至少6466.7倍的丰度的氘(即至少97％的氘掺入)、至少6600倍的丰度的氘(即至少99％的氘掺入)、至少6633.3倍的丰度的氘(即至少99.5％的氘掺入)或更高丰度的氘。
“任选的”或“任选”是指随后所描述的事件或环境可以但不必然发生，其包括该事件或环境发生或不发生两种情形。例如“任选被卤素或者氰基取代的C1-6烷基”包括烷基被卤素或者氰基取代的情形和烷基不被卤素或氰基取代的情形。
“取代”或“取代的”指基团中的一个或多个氢原子，在一些实施方案中为1、2或3个，在一些实施方案中为1至3个氢原子彼此独立地被相应数目的取代基取代。本领域技术人员能够在不付出过多努力的情况下(通过实验或理论)确定可能或不可能的取代。例如，具有游离氢的氨基或羟基与具有不饱和键的碳原子(如烯)结合时可能是不稳定的。
“药物组合物”表示含有一种或多种本文所述化合物或其可药用的盐与其他化学组分的混合物，以及其他组分例如药学上可接受的载体和赋形剂。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。
“可药用的盐”是指本公开化合物的盐，可选自无机盐或有机盐。这类盐用于哺乳动物体内时具有安全性和有效性，且具有应有的生物活性。可以在化合物的最终分离和纯化过程中，或通过使合适的基团与合适的碱或酸反应来单独制备。通常用于形成药学上可接受的盐的碱包括无机碱，例如氢氧化钠和氢氧化钾，以及有机碱，例如氨。通常用于形成药学上可接受的盐的酸包括无机酸以及有机酸。
本文所用的术语“药学上可接受的”是指这些化合物、材料、组合物和/或剂型，在合理的医学判断范围内，适用于与患者组织接触而没有过度毒性、刺激性、过敏反应或其他问题或并发症，具有合理的获益/风险比，并且对预期的用途是有效。
本文所使用的，单数形式的“一个”、“一种”和“该”包括复数引用，反之亦然，除非上下文另外明确指出。
当将术语“约”应用于诸如pH、浓度、温度等的参数时，表明该参数可以变化±10％，并且有时在±5％之内。如本领域技术人员将理解的，当参数不是关键时，通常仅出于说明目的给出数字，而不是限制。
本公开化合物的合成方法
为了完成本公开的目的，本公开采用如下技术方案：
方案一
本公开提供通式(I’)所示的化合物或其可药用的盐的制备方法，该方法包括：
通式(I’A)所示的化合物或其盐在酸性条件下反应得到通式(I’)所示的化合物或其可药用的盐，其中
RW为羟基保护基，在一些实施方案中为苄基；
通式(I’A)中的G为CR，R为氰基，且通式(I’)中G为CR，R为C(O)NH2；
环A、RA、m、环B、G至G4、RB、R7和n如通式(I’)中所定义。
方案二
本公开提供通式(I)所示的化合物或其可药用的盐的制备方法，该方法包括：
通式(IA)所示的化合物或其盐在酸性条件下反应得到通式(I)所示的化合物或其可药用的盐，其中
RW为羟基保护基，在一些实施方案中为苄基；
通式(IA)中的R为氰基，且通式(I)中R为C(O)NH2；
环B、X1至X4、G1至G4、R、RB、R7和n如通式(I)中所定义。
方案三
本公开提供通式(II)所示的化合物或其可药用的盐的制备方法，该方法包括：
通式(IIA)所示的化合物或其盐在酸性条件下反应得到通式(II)所示的化合物或其可药用的盐，其中
RW为羟基保护基，在一些实施方案中为苄基；
通式(IIA)中的R为氰基，且通式(II)中R为C(O)NH2；
环B、RB、X1、G1、R、R1至R7和n如通式(II)中所定义。
方案四
本公开提供通式(III)所示的化合物或其可药用的盐的制备方法，该方法包括：
通式(IIIA)所示的化合物或其盐在酸性条件下反应得到通式(III)所示的化合物或其可药用的盐，其中
RW为羟基保护基，在一些实施方案中为苄基；R11和R12为氢原子；
U、X1、G1、R1至R7、R15、R16、q、t、r和s如通式(III)中所定义。
方案五
本公开提供通式(IV)、(IV-1)和(IV-2)所示的化合物或其可药用的盐的制备方法，该方法包括：
通式(IVA)所示的化合物或其盐在酸性条件下反应得到通式(IV)所示的化合物或其可药用的盐，
通式(IV-1A)所示的化合物或其盐在酸性条件下反应得到通式(IV-1)所示的化合物或其可药用的盐，
通式(IV-2A)所示的化合物或其盐反应得到通式(IV-2)所示的化合物或其可药用的盐，
RW为羟基保护基，在一些实施方案中为苄基；R11和R12为氢原子；
G1、X1、R1至R7、R7a、R15、R16、s、r和q如通式(IV)、(IV-1)或(IV-2)中所定义。
方案五-2
本公开提供通式(IV-1)和(IV-2)所示的化合物或其可药用的盐的制备方法，该方法包括：
通式(IV)所示的化合物或其盐手性拆分得到通式(IV-1)和(IV-2)所示的化合物或其可药用的盐，
G1、X1、R1至R7、R7a、R11、R12、R15、R16、s、r和q如通式(IV-1)或(IV-2)中所定义。
上述方案中提供酸性条件的试剂包括但不限于氯化氢、氯化氢的1,4-二氧六环溶液、盐酸的1,4-二氧六环溶液、三氟醋酸、甲酸、乙酸、盐酸、浓硫酸、甲磺酸、硝酸、磷酸、对苯甲磺酸、Me3SiCl、TMSOTf、ALCl3、BBr3、BF3和溴化铁等；在一些实施方案中为三氟醋酸。
上述步骤的反应任选在溶剂中进行，所用的溶剂包括但不限于：吡啶、乙二醇二甲醚、醋酸、甲醇、乙醇、乙腈、正丁醇、甲苯、四氢呋喃、二氯甲烷、石油醚、乙酸乙酯、正己烷、二甲基亚砜、1,4-二氧六环、水、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、1,2-二溴乙烷及其混合物。
具体实施方式
以下结合实施例用于进一步描述本公开，但这些实施例并非限制着本公开的范围。
实施例
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核磁仪或Bruker AVANCE NEO 500M，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Agilent 1200/1290DAD-6110/6120Quadrupole MS液质联用仪(生产商：Agilent，MS型号：6110/6120Quadrupole MS)。
waters ACQuity UPLC-QD/SQD(生产商：waters，MS型号：waters ACQuity Qda Detector/waters SQ Detector)
THERMO Ultimate 3000-Q Exactive(生产商：THERMO，MS型号：THERMO Q Exactive)
高效液相色谱法(HPLC)分析使用Agilent HPLC 1200DAD、Agilent HPLC 1200VWD和Waters HPLC e2695-2489高效液相色谱仪。
手性HPLC分析测定使用Agilent 1260DAD高效液相色谱仪。
高效液相制备使用Waters 2545-2767、Waters 2767-SQ Detecor2、Shimadzu LC-20AP和Gilson GX-281制备型色谱仪。
手性制备使用Shimadzu LC-20AP制备型色谱仪。
CombiFlash快速制备仪使用Combiflash Rf200(TELEDYNE ISCO)。
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。
硅胶柱色谱法一般使用烟台黄海硅胶200～300目硅胶为载体。
激酶平均抑制率及IC50值的测定用NovoStar酶标仪(德国BMG公司)。
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，反应均能够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。
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包括：A：二氯甲烷/甲醇体系，B：正己烷/乙酸乙酯体系，C：石油醚/乙酸乙酯体系，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
2-(5-氯-4-(3-(二氟亚甲基)-1-甲基环戊基)-2-甲基苯基)-4-氧代-1,4-二氢-1,6-萘啶-5-甲酰胺1
(S)-2-(5-氯-4-(3-(二氟亚甲基)-1-甲基环戊基)-2-甲基苯基)-4-氧代-1,4-二氢-1,6-萘啶-5-甲酰胺1-p1
(R)-2-(5-氯-4-(3-(二氟亚甲基)-1-甲基环戊基)-2-甲基苯基)-4-氧代-1,4-二氢-1,6-萘啶-5-甲酰胺1-p2

第一步
1-溴-5-氯-4-(3-(二氟亚甲基)-1-甲基环戊基)-2-甲基苯1b
将3-(4-溴-2-氯-5-甲基苯基)-3-甲基环戊-1-酮1a(300mg，994.67μmol，采用专利申请“WO2023205778”中说明书第375页的中间体B-99公开的方法制备而得)和2-((二氟甲基)磺酰)吡啶(230mg，1.2mmol)溶于N,N-二甲基甲酰胺(9mL)，-40℃下加入1M叔丁醇钾的四氢呋喃溶液(1.5mL)，保持温度搅拌反应3.5小时，反应液中加入饱和氯化铵溶液，用乙酸乙酯(10mL×3)萃取，合并有机相，减压浓缩，残余物用硅胶柱色谱法以洗脱剂体系A纯化得到标题化合物1b(90mg，产率：27％)。
第二步
2-(5-氯-4-(3-(二氟亚甲基)-1-甲基环戊基)-2-甲基苯基)-4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷1c
将化合物1b(90mg，268.16μmol)，乙酸钾(52.6mg，536.32μmol)，联硼酸频那醇酯(204.3mg，804.5μmol)，1,1'-二(二苯膦基)二茂铁二氯化钯(II)二氯甲烷络合物(21.9mg，26.8μmol)溶于1,4二氧六环(1mL)中，氮气置换，升温至90℃反应16小时，反应液减压浓缩，残余物用硅胶柱色谱法以洗脱剂体系B纯化得到标题化合物1c(100mg，产率：97.4％)。
第三步
4-(苄氧基)-2-(5-氯-4-(3-(二氟亚甲基)-1-甲基环戊基)-2-甲基苯基)-1,6-萘啶-5-甲腈1e
将化合物1c(155.28mg，405.78μmol)，4-(苄氧基)-2-氯-1,6-萘啶-5-甲腈1d(100mg，338.18μmol，采用专利申请“WO2023205778”中说明书第212页的中间体A-1A公开的方法制备而得)，[1,1'-双(二叔丁基膦)二茂铁]二氯化钯(II)(44mg，67.6μmol)，磷酸钾(149.4mg，845.3μmol)溶于1,4二氧六环(1mL)中，氮气氛下，50℃反应1小时，反应液减压浓缩，残余物用硅胶柱色谱法以洗脱剂体系B纯化得到标题化合物1e(90mg，产率：51.5％)。
MS m/z(ESI):516.5[M+1]。
第四步
2-(5-氯-4-(3-(二氟亚甲基)-1-甲基环戊基)-2-甲基苯基)-4-氧代-1,4-二氢-1,6-萘啶-5-甲酰胺1
(S)-2-(5-氯-4-(3-(二氟亚甲基)-1-甲基环戊基)-2-甲基苯基)-4-氧代-1,4-二氢-1,6-萘啶-5-甲酰胺1-p1
(R)-2-(5-氯-4-(3-(二氟亚甲基)-1-甲基环戊基)-2-甲基苯基)-4-氧代-1,4-二氢-1,6-萘啶-5-甲酰胺1-p2
将化合物1e(90mg，174.4μmol)溶于甲苯(3mL)中，加入三氟醋酸(3mL)，氮气氛下，70℃反应6小时，反应液减压浓缩，残余物用高效液相制备色谱法纯化(Waters-2545，色谱柱：Welch Xtimate C18，30*150mm，5μm；流动相：水相(10mmol/L碳酸氢铵)和乙腈，梯度配比：乙腈40％-60％，流速：30mL/min)得到标题化合物1(35mg，产率：45.2％)。
MS m/z(ESI):444.3[M+1]。
1H NMR(500MHz,DMSO-d6):δ11.99(s,1H),8.50(d,1H),7.53(s,2H),7.46(s,1H),7.44(d,1H),7.31(s,1H),6.13(s,1H),2.97(d,1H),2.67–2.58(m,1H),2.31(s,4H),2.08(q,1H),2.02–1.96(m,1H),1.46(t,1H),1.34(s,3H)。
化合物1(50mg)经手性柱拆分(Waters SFC 150，色谱柱：30*250mm,10μm；流动相A：Supercritical CO2，流动相B：乙醇(含0.1％7M氨甲醇溶液)，梯度配比：A:B为85:15，流速：140mL/min)纯化得到标题化合物(15mg，产率：33.8％)，(15mg，产率：33.8％)。
单一构型化合物(较短保留时间)(15mg，产率：33.8％)
MS m/z(ESI):444.3[M+1]。
手性HPLC分析：保留时间5.471分钟，纯度：99％(色谱柱:3*100mm,3μm；流动相A：Supercritical CO2，流动相B：乙醇(含0.1％二乙胺)，梯度配比：A:B为85:15，流速：1.5mL/min)。
1H NMR(500MHz,DMSO-d6):δ12.18(s,1H),8.69(d,1H),7.72(s,2H),7.67–7.57(m,2H),7.50(s,1H),6.32(s,1H),3.16(d,1H),2.86–2.77(m,1H),2.66(s,1H),2.57–2.52(m,1H),2.50(s,3H),2.31–2.23(m,1H),2.22–2.14(m,1H),1.53(s,3H)。
单一构型化合物(较长保留时间)(15mg，产率：33.8％)
MS m/z(ESI):444.3[M+1]。
手性HPLC分析：保留时间7.049分钟，纯度：96.9％(色谱柱:3*100mm,3μm；流动相A：Supercritical CO2，流动相B：乙醇(含0.1％二乙胺)，梯度配比：A:B为85:15，流速：1.5mL/min)。
1H NMR(500MHz,DMSO-d6):δ11.99(s,1H),8.50(d,1H),7.52(s,2H),7.48–7.41(m,2H),7.31(s,1H),6.12(s,1H),2.96(d,1H),2.68–2.57(m,1H),2.45(d,1H),2.37–2.32(m,1H),2.30(s,3H),2.13–2.06(m,1H),2.05–1.89(m,1H),1.33(s,3H)。
实施例2-1
(S)-3-氯-2-(5-氯-4-(3-(二氟亚甲基)-1-甲基环戊基)-2-甲基苯基)-4-氧代-1,4-二氢-1,6-萘啶-5-甲酰胺2-1或
(R)-3-氯-2-(5-氯-4-(3-(二氟亚甲基)-1-甲基环戊基)-2-甲基苯基)-4-氧代-1,4-二氢-1,6-萘啶-5-甲酰胺2-2
将化合物1-p1，1-p2中保留时间较短的(50mg，112.6μmol)溶于N,N-二甲基甲酰胺(5mL)，加入乙酸(15mg，249.8μmol)和N-氯代丁二酰亚胺(30mg，224.6636μmol)，搅拌反应48小时，反应液中滴加几滴甲醇，用高效液相制备色谱法纯化(Waters-2545，色谱柱：Welch Xtimate C18，30*150mm，5μm；流动相：水相(10mmol/L碳酸氢铵)和乙腈，梯度配比：乙腈40％-60％，流速：30mL/min)得到标题化合物(22mg，产率：40.8％)。
MS m/z(ESI):478.1[M+1]。
1H NMR(500MHz,DMSO-d6):δ12.53(s,1H),8.52(d,1H),7.57(s,1H),7.54(s,1H),7.48(s,1H),7.44(d,1H),7.37(s,1H),3.00-2.92(m,1H),2.65-2.58(m,1H),2.50-2.41(m,2H),2.39-2.30(m,1H),2.18(s,3H),2.11-2.04(m,1H),1.33(s,3H)。
实施例2-2
(R)-3-氯-2-(5-氯-4-(3-(二氟亚甲基)-1-甲基环戊基)-2-甲基苯基)-4-氧代-1,4-二氢-1,6-萘啶-5-甲酰胺2-2或
(S)-3-氯-2-(5-氯-4-(3-(二氟亚甲基)-1-甲基环戊基)-2-甲基苯基)-4-氧代-1,4-二氢-1,6-萘啶-5-甲酰胺2-1
将化合物1-p1，1-p2中保留时间较长的(600mg，1.35mmol)溶于N,N-二甲基甲酰胺(60mL)，加入乙酸(363mg，6.04mmol)和N-氯代丁二酰亚胺(271mg，2.03mmol)，搅拌反应16小时，反应液中加入水，用乙酸乙酯(15mL×3)萃取，合并有机相，减压浓缩，残余物用高效液相制备色谱法纯化(Waters-2545，色谱柱：Welch Xtimate C18，30*150mm，5μm；流动相：水相(10mmol/L碳酸氢铵)和乙腈，梯度配比：乙腈40％-60％，流速：30mL/min)得到标题化合物(340mg，产率：52.5％)。
MS m/z(ESI):478.1[M+1]。
1H NMR(500MHz,DMSO-d6):δ12.53(s,1H),8.52(d,1H),7.57(s,1H),7.54(s,1H),7.48(s,1H),7.44(d,1H),7.37(s,1H),3.00-2.92(m,1H),2.65-2.58(m,1H),2.50-2.41(m,2H),2.39-2.30(m,1H),2.18(s,3H),2.11-2.04(m,1H),1.33(s,3H)。
实施例3
2-(5-氯-4-(3-(二氟亚甲基)-1-甲基环戊基)-2-甲基苯基)-3-氟-4-氧代-1,4-二氢-1,6-萘啶-5-甲酰胺3
将化合物1(30mg，67.6μmol)溶于乙腈(9mL)，加入1-氯甲基-4-氟-1,4-二叠氮双环[2.2.2]辛烷双四氟硼酸盐(26mg，73.4μmol)，氮气置换，搅拌反应16小时，反应液中加入水，用乙酸乙酯(5mL×3)萃取，合并有机相，减压浓缩，残余物用高效液相制备色谱法纯化(Waters-2545，色谱柱：Welch Xtimate C18，30*150mm，5μm；流动相：水相(10mmol/L碳酸氢铵)和乙腈，梯度配比：乙腈40％-60％，流速：30mL/min)得到标题化合物3(4mg，产率：12.8％)。
MS m/z(ESI):462.1[M+1]。
1H NMR(500MHz,DMSO-d6):δ12.27(s,1H),8.49(d,1H),7.61(s,1H),7.57(s,1H),7.49(s,1H),7.45(d,1H),7.38(s,1H),2.97(d,1H),2.67-2.59(m,1H),2.50-2.42(m,2H),2.38-2.31(m,1H),2.24(s,3H),2.12-2.05(m,1H),1.34(s,3H)。
实施例4(对照)
参照WO2023205778A1实施例4和84制备得到化合物4-1和4-2作为对照化合物。
生物学评价
测试例1、本公开化合物对Nav1.8抑制活性的测定
实验目的是为了检测化合物在体外实验中对Nav1.8离子通道的影响。Nav1.8离子通道稳定地表达在HEK293细胞上。在Nav1.8电流稳定后，比较化合物处理前后Nav1.8电流的大小，可以得到化合物对Nav1.8离子通道的影响。
1实验材料及仪器
1)膜片钳放大器：patch clamp PC-505B(WARNER instruments)
2)数模转换器：Digidata 1440A(Axon instruments)
3)微操控仪：MP-225(SUTTER instrument)
4)倒置显微镜：TL4(Olympus)
5)玻璃微电极拉制仪：PC-10(NARISHIGE)
6)微电极玻璃毛细管：B12024F(武汉微探科学仪器有限公司)
7)二甲基亚砜(DMSO)(Sigma-Aldrich,D2650)
8)TTX(Affix Scientific,AF3014)
2实验步骤
2.1化合物配制
配制细胞内外液的化合物除用于酸碱滴定的NaOH和KOH外，均从Sigma公司购买。细胞外液(mM)为：NaCl，137；KCl，4；CaCl2，1.8；MgCl2，1；HEPES，10；葡萄糖，10；pH 7.4(NaOH滴定)。细胞内液(mM)为：天冬氨酸，140；MgCl2，2；EGTA，11；HEPES，10；pH 7.2(CsOH滴定)。所有测试化合物溶液均含1μM TTX。
测试化合物的保存浓度为9mM，溶于二甲基亚砜(DMSO)。测试当天再溶于细胞外液，配制成要求浓度。
2.2手动膜片钳测试过程
1)化合物配制成指定浓度的溶液后，按浓度从低到高顺序将药液依次加入各个管道，并对各个管道进行标记。
2)将细胞转移到灌流槽中，电极内施加正压，将电极尖端接触到细胞，抽气装置三通阀调成三通状态，然后对电极施加负压，使得电极与细胞形成高阻封接。继续施加负压，使得细胞膜破裂，形成电流通路。
3)待细胞破膜电流稳定后，依次进行不同的浓度的灌注。若电流稳定至少一分钟即可换下一个浓度进行灌流。每个浓度灌流时间不超过五分钟。
4)清洗灌流槽。按药液浓度从高到低进行冲洗，每个浓度药液冲洗20s。最后用细胞外液冲洗1min。
2.3测试电压方程
将细胞钳制在-80mV，然后用持续10毫秒方波去极化到10mV，以得到Nav1.8电流。这一程序每5秒重复一次。检测方波引发的最大电流，待其稳定后，灌流测试化合物，当反应稳定后，计算抑制的强度。
3.数据分析
资料将存于计算机系统做分析。资料采集和分析使用pCLAMP 10(Molecular Devices,Union City,CA)。
本公开化合物对Nav1.8的抑制活性通过以上实验进行测定，测得的IC50值见表1。
表1、本公开化合物对Nav1.8通道活性抑制的IC50
结论：本公开中的化合物对Nav1.8通道活性具有明显的抑制效果。
测试例2、大鼠药代动力学评价
1、摘要
以SD大鼠为受试动物，应用LC-MS/MS法测定了大鼠灌胃(i.g.)给予实施例化合物后不同时刻血浆中的药物浓度，研究本公开化合物在大鼠体内的药代动力学行为，评价其药动学特征。
2、试验方案
2.1、试验药品
化合物2-1和2-2。
2.2、试验动物
大鼠8只，由维通利华实验动物技术有限公司提供，生产许可证SCXK(京)2021-0006。
2.3、药物配制
分别称取一定量的受试化合物，加5％DMSO+5％吐温80+90％生理盐水，配制成0.2mg/mL无色澄明溶液。
2.4、给药
给药剂量:2.0mg/kg，给药体积:10mL/kg。
3、操作
于给药前及给药后0.25、0.5、1.0、2.0、4.0、6.0、8.0、11.0、24.0小时，由眼眶采血0.2mL，置EDTA-K2抗凝试管中，10000rpm离心2分钟(4℃)，1小时内分离血浆，-20℃或-80℃保存待测。采血至离心过程在冰浴条件下操作。
测定给药后大鼠血浆中的待测化合物含量：取给药后各时刻的大鼠血浆样品50μL，加入450μL乙腈和25μL喜树碱,甲苯磺丁脲，涡旋混合5min，并在3700rpm下离心10分钟。取上清液进行LC-MS/MS分析。
4、药代动力学参数结果
表2、本公开化合物在大鼠体内的药代动力学参数
结论：本公开化合物在大鼠体内血药浓度高，暴露量高，具有药代动力学优势。

Claims (16)

  1. 一种通式(I’)所示的化合物或其可药用的盐：
    其中：
    环A为芳基或杂芳基；环B为环烷基或杂环基；
    RB为＝CR15R16；
    R15和R16相同或不同，且各自独立地选自氢原子、卤素、烷基、卤代烷基、烷氧基、卤代烷氧基、羟基、羟烷基、烷氧基烷基、烯基、炔基、氰基、NR11R12、C(O)NR11R12、C(O)R14、OR14、环烷基、杂环基、芳基和杂芳基；所述的烷基、烷氧基、烷氧基烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基各自独立地任选被一个或多个R01所取代；
    G选自N、N+O-和CR；
    G1选自N、N+O-和CR9；G2选自N、N+O-和CR1；
    G3选自N、N+O-和CR2；G4选自N、N+O-和CR3；
    R、R1、R2、R3和R9相同或不同，且各自独立地选自氢原子、卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、氰基、羟基、羟烷基、烷氧基烷基、烯基、炔基、氨基、NR11R12、C(O)NR11R12、NR13C(O)R14、NR13C(O)NR11R12、C(O)R14、C(O)OR14、S(O)vR14、S(O)vNR11R12、C(＝NR13)R14、S(＝NR13)R14、S(＝NR13)(O)R14、OR14、C(＝S)NR11R12、Si(烷基)3、环烷基、杂环基、芳基和杂芳基，其中所述的烷基、烷氧基、烷氧基烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基各自独立地任选被一个或多个R01所取代；
    各个RA相同或不同，且各自独立地选自氧代基、＝S、卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、氰基、羟基、羟烷基、烷氧基烷基、烯基、炔基、氨基、NR11R12、C(O)NR11R12、NR13C(O)R14、NR13C(O)NR11R12、C(O)R14、C(O)OR14、S(O)vR14、S(O)vNR11R12、C(＝NR13)R14、S(＝NR13)R14、S(＝NR13)(O)R14、OR14、Si(烷基)3、环烷基、杂环基、芳基和杂芳基，其中所述的烷基、烷氧基、烷氧基烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基各自独立地任选被一个或多个R02所取代；
    各个R7相同或不同，且各自独立地选自氧代基、＝S、卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、氰基、羟基、羟烷基、烷氧基烷基、烯基、炔基、氨基、NR11R12、C(O)NR11R12、NR13C(O)R14、NR13C(O)NR11R12、C(O)R14、C(O)OR14、OC(O)R14、S(O)vR14、S(O)vNR11R12、OR14、＝CR15R16、＝NR13、Si(烷基)3、环烷基、杂环基、芳基和杂芳基，其中所述的烷基、烷氧基、烷氧基烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基各自独立地任选被一个或多个R03所取代；或，两个R7及与其相连的原子一起形成环烷基或杂环基，所述环烷基和杂环基各自独立地任选被一个或多个R03所取代；
    各个R01、R02和R03相同或不同，且各自独立地选自氧代基、＝S、卤素、烷基、卤代烷基、烷氧基、卤代烷氧基、羟基、羟烷基、烷氧基烷基、烯基、炔基、氰基、硝基、氨基、NR11R12、C(O)NR11R12、NR13C(O)R14、NR13C(O)NR11R12、C(O)R14、C(O)OR14、S(O)vR14、S(O)vOR14、S(O)vNR11R12、C(＝NR13)R14、S(＝NR13)R14、OR14、＝CR15R16、＝NR13、S(＝NR13)(O)R14、Si(烷基)3、环烷基、杂环基、芳基、杂芳基、环烷基烷基、杂环基烷基、芳基烷基和杂芳基烷基；所述的烷基、烷氧基、烷氧基烷基、烯基、炔基、环烷基、杂环基、芳基、杂芳基、环烷基烷基、杂环基烷基、芳基烷基和杂芳基烷基各自独立地任选被一个或多个R*所取代；
    各个R11、R12、R13和R14相同或不同，且各自独立地选自氢原子、烷基、卤代烷基、烷氧基、卤代烷氧基、羟基、羟烷基、烷氧基烷基、烯基、炔基、NR30R31、C(O)NR30R31、C(O)R33、OR33、S(O)vR33、环烷基、杂环基、芳基、杂芳基、环烷基烷基、杂环基烷基、芳基烷基和杂芳基烷基；所述的烷基、烷氧基、烷氧基烷基、烯基、炔基、环烷基、杂环基、芳基、杂芳基、环烷基烷基、杂环基烷基、芳基烷基和杂芳基烷基各自独立地任选被一个或多个R*所取代；或R11、R12及与其相连的氮原子一起形成杂环基，所述杂环基任选被一个或多个R*所取代；
    各个R*相同或不同，且各自独立地选自氧代基、＝S、卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、羟基、羟烷基、烷氧基烷基、氰基、烯基、炔基、烷硫基、NR30R31、C(O)NR30R31、亚烷基NR30R31、亚烷基C(O)NR30R31、C(O)R33、C(O)OR33、OR33、Si(烷基)3、硝基、环烷基、杂环基、芳基、杂芳基、环烷基烷基、杂环基烷基、芳基烷基和杂芳基烷基；
    各个R30、R31和R33相同或不同，且各自独立地选自氢原子、烷基、烷氧基、卤代烷基、卤代烷氧基、羟基、羟烷基、烷氧基烷基、烷硫基、环烷基、杂环基、芳基、杂芳基、环烷基烷基和杂环基烷基；
    m为0、1、2、3、4、5或6；n为0、1、2、3、4、5或6；且
    各个v相同或不同，且各自独立地为0、1或2。
  2. 根据权利要求1所述的化合物或其可药用的盐，其为通式(I)所示的化合物或其可药用的盐：
    其中，
    X1为N或CR8；X2为N或CR4；X3为N或CR5；X4为N或CR6；
    R4、R5、R6和R8相同或不同，且各自独立地选自氢原子、卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、氰基、羟基、羟烷基、烷氧基烷基、烯基、炔基、氨基、NR11R12、C(O)NR11R12、NR13C(O)R14、NR13C(O)NR11R12、C(O)R14、C(O)OR14、S(O)vR14、S(O)vNR11R12、C(＝NR13)R14、S(＝NR13)R14、S(＝NR13)(O)R14、OR14、Si(烷基)3、环烷基、杂环基、芳基和杂芳基，其中所述的烷基、烷氧基、烷氧基烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基各自独立地任选被一个或多个R02所取代；或R5、R6及与其相连的碳原子一起形成环烷基、杂环基、芳基或杂芳基，所述环烷基、杂环基、芳基和杂芳基各自独立地任选被一个或多个RA所取代；
    环B、G1至G4、R、RB、R7、n、R11至R14、R02、RA和v如权利要求1中所定义。
  3. 根据权利要求1或2所述的化合物或其可药用的盐，其为通式(III)所示的化合物或其可药用的盐：
    其中：U为N或CR7a，R7a为氢原子或R7；
    s为0、1或2；r为0、1或2；t为0或1；q为0、1、2、3或4；
    G1、X1、R1至R7、R11、R12、R15和R16如权利要求2中所定义。
  4. 根据权利要求1至3中任一项所述的化合物或其可药用的盐，其中R15和R16相同或不同，且各自独立地为氢原子或卤素；优选地，R15和R16相同或不同，且各自独立地为卤素。
  5. 根据权利要求2至4中任一项所述的化合物或其可药用的盐，其中R4、R5、R6和R8相同或不同，且各自独立地选自氢原子、卤素、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基和3至6元环烷基；优选地，R4、R5、R6和R8相同或不同，且各自独立地选自氢原子、卤素、C1-6烷基和C1-6卤代烷基。
  6. 根据权利要求1至5中任一项所述的化合物或其可药用的盐，其中G1为N或CH。
  7. 根据权利要求1至6中任一项所述的化合物或其可药用的盐，其中R1、R2和R3相同或不同，且各自独立地选自氢原子、卤素、C1-6烷基和C1-6卤代烷基；优选地，R1、R2和R3相同或不同，且各自独立地为氢原子或卤素。
  8. 根据权利要求1至7中任一项所述的化合物或其可药用的盐，其中R11和R12相同或不同，且各自独立地为氢原子或C1-6烷基；优选地，R11和R12为氢原子。
  9. 根据权利要求3至8中任一项所述的化合物或其可药用的盐，其中R7a选自氢原子、卤素、C1-6烷基和C1-6卤代烷基；优选地，R7a为C1-6烷基。
  10. 根据权利要求1至9中任一项所述的化合物或其可药用的盐，其选自如下化合物：
  11. 一种通式(IA)所示的化合物或其盐：
    其中，RW为氢原子或羟基保护基，优选为苄基；
    环B、X1至X4、G1至G4、R、RB、R7和n如权利要求2中所定义；R优选为氰基。
  12. 化合物或其盐，其选自如下化合物：
  13. 一种制备通式(I)所示的化合物或其可药用的盐的方法，该方法包括：
    通式(IIIA)所示的化合物或其盐经水解反应得到通式(III)所示的化合物或其可药用的盐，或R3为氢原子的通式(III)所示的化合物或其盐与卤化试剂发生卤化反应得到R3为卤素的通式(III)所示的化合物或其可药用的盐，其中
    RW为羟基保护基，优选为苄基；R11和R12为氢原子；
    U、X1、G1、R1至R7、R15、R16、q、t、r和s如权利要求3中所定义。
  14. 一种药物组合物，所述药物组合物含有根据权利要求1至10中任一项所述的化合物或其可药用的盐，以及一种或多种药学上可接受的载体、稀释剂或赋形剂。
  15. 根据权利要求1至10中任一项所述的化合物或其可药用的盐或根据权利要求14所述的药物组合物在制备抑制电压门控钠通道的药物中的用途；优选地，所述电压门控钠通道为Nav1.8。
  16. 根据权利要求1至10中任一项所述的化合物或其可药用的盐或根据权利要求14所述的药物组合物在制备治疗和/或减轻疼痛和疼痛相关疾病、多发性硬化症、夏-马-图三氏综合症、失禁、病理咳嗽或心律失常的药物中的用途；优选地，所述疼痛选自慢性疼痛、急性疼痛、炎性疼痛、癌症疼痛、术后疼痛、神经性疼痛、肌肉骨骼痛、原发性疼痛、肠痛、特发性疼痛和内脏痛。
PCT/CN2025/106834 2024-07-03 2025-07-03 氧代杂芳基类化合物、其制备方法及其在医药上的应用 Pending WO2026008013A1 (zh)

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CN112390745A (zh) * 2019-08-19 2021-02-23 江苏恒瑞医药股份有限公司 吡啶烟酰胺类衍生物、其制备方法及其在医药上的应用
WO2023205463A1 (en) * 2022-04-22 2023-10-26 Vertex Pharmaceuticals Incorporated Heteroaryl compounds for the treatment of pain
WO2023205778A1 (en) * 2022-04-22 2023-10-26 Vertex Pharmaceuticals Incorporated Heteroaryl compounds for the treatment of pain

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WO2020151728A1 (zh) * 2019-01-25 2020-07-30 江苏恒瑞医药股份有限公司 2-氧代-1,2-二氢吡啶类衍生物、其制备方法及其在医药上的应用
CN112390745A (zh) * 2019-08-19 2021-02-23 江苏恒瑞医药股份有限公司 吡啶烟酰胺类衍生物、其制备方法及其在医药上的应用
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