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WO2024046409A1 - Composé hétérocyclique, son procédé de préparation et son utilisation pharmaceutique - Google Patents

Composé hétérocyclique, son procédé de préparation et son utilisation pharmaceutique Download PDF

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Publication number
WO2024046409A1
WO2024046409A1 PCT/CN2023/116053 CN2023116053W WO2024046409A1 WO 2024046409 A1 WO2024046409 A1 WO 2024046409A1 CN 2023116053 W CN2023116053 W CN 2023116053W WO 2024046409 A1 WO2024046409 A1 WO 2024046409A1
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group
alkyl
pain
cycloalkyl
general formula
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PCT/CN2023/116053
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English (en)
Chinese (zh)
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李心
蔡国栋
陈阳
王斌
贺峰
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江苏恒瑞医药股份有限公司
上海恒瑞医药有限公司
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Publication of WO2024046409A1 publication Critical patent/WO2024046409A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/443—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with oxygen as a ring hetero atom
    • 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
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • 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
    • C07D471/08—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/08—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/052—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being six-membered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/08—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D521/00—Heterocyclic compounds containing unspecified hetero rings

Definitions

  • the present disclosure belongs to the field of medicine and relates to a heterocyclic compound, its preparation method and its application in medicine.
  • the present disclosure relates to heterocyclic compounds represented by general formula (I), their preparation methods and pharmaceutical compositions containing such compounds, as well as their use as Nav inhibitors and their preparation for treating and/or alleviating pain. and use in medicines for pain-related conditions.
  • 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 sensation associated with actual or potential tissue damage that is subjective.” Pain can serve as a warning signal and a reminder.
  • Pain can serve as a warning signal and a reminder.
  • the body's attention to potential dangers plays an indispensable protective role in the body's normal life activities.
  • pain is also a common clinical symptom. After the external stimulus that caused the pain disappears, strong or long-lasting pain will cause physiological function disorders and seriously affect the quality of life of the living body. Statistics show that approximately one in five people worldwide suffer from moderate to severe chronic pain.
  • DRG dorsal root ganglion
  • the generation and conduction of action potentials in neurons rely on voltage-gated sodium channels (Nav) on the cell membrane. When the cell membrane is depolarized, the sodium ion channel is activated and the channel opens, causing the influx of sodium ions, further depolarizing the cell membrane, resulting in the generation of an action potential. Therefore, inhibiting abnormal sodium ion channel activity contributes to the treatment and relief of pain.
  • Nav voltage-gated sodium channels
  • Nav is a type of transmembrane ion channel protein. These proteins are composed of an ⁇ subunit with a molecular weight of 260 kD and a ⁇ subunit with a molecular weight of 30-40 kD. According to the different ⁇ subunits, it can be divided into 9 subtypes, Navl.l ⁇ Nav1.9. Different subtypes show different tissue distribution and electrophysiological and pharmacological characteristics (Rush AM, et al. J. Physiol. 2007, 579, 1–14). According to whether they can be effectively inhibited by nanomolar tetrodotoxin (TTX), sodium ion channels are divided into TTX-sensitive (TTX-S) and TTX-insensitive (TTX-R).
  • TTX-S TTX-sensitive
  • TTX-R TTX-insensitive
  • Nav1.1, Nav1.2, Nav1.3 and Nav1.7 are TTX-S type, and the coding genes are located on human chromosome 2q23-24. They are abundantly expressed in neurons.
  • Nav1.5, Nav1.8 and Nav1.9 are TTX-R types, and the coding genes are located on human chromosome 3p21-24.
  • Nav1.5 mainly exists in cardiomyocytes
  • Nav 1.8 and Nav 1.9 exist in the peripheral nervous system (GoldinA.L., et al. Annu. Rev. Physiol. 2001, 63, 871-894).
  • Nav1.4 and Nav1.6 are TTX-S types, which are abundant in skeletal muscle and central nervous system respectively (Fozzard HA, et al. Physiol. Rev. 1996, 76, 887–926).
  • the local anesthetic lidocaine provides pain relief by inhibiting Nav.
  • Non-selective Nav inhibitors such as lamotrigine, lacosamide, and mexiletine, have been successfully used in treatment Chronic pain.
  • Nav1.8 is a TTX-R type, and the encoding gene is SCN10A. It mainly exists in trigeminal ganglion neurons and DRG neurons, and has electrophysiological characteristics of slow inactivation and rapid recovery (Dib-Hajj S.D., et al. Annu . Rev. Neurosci. 2010, 33, 325–347). In neurons expressing Nav 1.8, the rise in action potential is mainly composed of Nav1.8 currents. In some models of neuropathic pain, nerve injury increases the expression level of Nav1.8 in axons and neuronal cell bodies (Sleeper A.A., et al. J. Neurosci. 2000, 20, 7279–7289).
  • Nav1.8 antisense oligonucleotides can significantly relieve pain while reducing Nav1.8 expression (Yoshimura N., et al. J. Neurosci. 2001, 21, 8690-8696).
  • Nav1.8 antisense oligonucleotides After intrapaw injection of carrageenan in rats, the expression of Nav1.8 in DRG neurons increased (Tanaka M., et al. G. NeuroReport 1998, 9, 967-972).
  • Nav1.8 knockout mice do not exhibit normal visceral inflammatory pain (Kerr B.J., et al. NeuroReport 2001, 12, 3077–3080).
  • Gain-of-function mutations in the human Nav1.8 gene can cause peripheral neuralgia (Faber C.G., et al. Proc. Natl.
  • Nav inhibitors used clinically lack subtype selectivity and can inhibit sodium ion channels expressed in the heart and central nervous system. Therefore, the therapeutic window is narrow and the scope of application is limited.
  • Nav1.8 is mainly 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, better pharmacokinetic properties and fewer side effects.
  • Nav1.8 inhibitor compounds include WO2015089361A1, WO2021113627A1, WO2022129281 A1, WO2022121517A1, WO2019014352A1, WO2022256622A1, WO2022256676A1, WO2022256679 A1, WO2022256842A1 and WO2022256702A1.
  • Ring Cy is selected from polycyclic cycloalkyl, polycyclic heterocyclyl, polycyclic aryl and polycyclic heteroaryl;
  • Each R B is the same or different, and each is independently selected from halogen, hydroxyl, amino, cyano, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, alkenyl, cycloalkyl, heterocyclyl , aryl and heteroaryl;
  • R 3 , R 4 and R 5 are the same or different, and are each independently selected from hydrogen atom, alkyl group, alkoxy group, alkenyl group, alkynyl group, NR 20 R 21 , C(O)NR 20 R 21 , NR 22 C(O)R 23 , C(O)R 23 , C(O)OR 23 , OC(O)R 23 , S(O) v R 23 , S(O) v OR 23 , OS(O) v R 23 , S(O) v NR 20 R 21 , OR 23 , cycloalkyl, heterocyclyl, aryl and heteroaryl; wherein, the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; wherein, the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; wherein, the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl Each ary
  • R 3 , R 4 and the nitrogen atom connected to them together form a heterocyclic group; the heterocyclic group is optionally substituted by one or more R 01 ;
  • R 6 , R 7 and R 8 are the same or different, and are each independently selected from hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, NR 20 R 21 , C(O)NR 20 R 21 , NR 22 C(O)R 23 , C(O)R 23 , C(O)OR 23 , OC(O)R 23 , S(O) v R 23 , S (O) v OR 23 , OS(O) v R 23 , S(O) v NR 20 R 21 , OR 23 , cycloalkyl, heterocyclyl, aryl and heteroaryl;
  • Each R 01 is the same or different, and each is independently selected from halogen, hydroxyl, cyano, oxo, amino, -NH alkyl, -N (alkyl) 2 , acetyl, alkyl, alkenyl, alkynyl , alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;
  • R 20 , R 21 , R 22 and R 23 is the same or different, and each is independently selected from a hydrogen atom, an alkyl group, an alkoxy group, an alkenyl group, an alkynyl group, a cycloalkyl group, a heterocyclic group, an aryl group and a heterocyclic group.
  • Aryl the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are each independently selected from the group consisting of halogen, hydroxyl, cyano, amino, Substituted with one or more of alkyl, alkoxy, haloalkyl, haloalkoxy and hydroxyalkyl;
  • R' is selected from hydrogen atoms, alkyl groups, haloalkyl groups, hydroxyalkyl groups, cycloalkyl groups and heterocyclyl groups;
  • X is O or S
  • R a and R b are the same or different, and are each independently selected from hydrogen atom, halogen, hydroxyl, cyano, amino, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl , cycloalkyl, heterocyclyl, cycloalkyloxy and heterocyclyloxy; each group of the cycloalkyl, heterocyclyl, cycloalkyloxy and heterocyclyloxy is independently optionally Replaced by 1 or more R 02 ;
  • R c and R d are the same or different, and are each independently selected from hydrogen atom, halogen, hydroxyl, cyano, amino, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl , cycloalkyl, heterocyclyl, cycloalkyloxy and heterocyclyloxy; the cycloalkyl, heterocyclyl, cycloalkyloxy and heterocyclyloxy each The group is independently optionally replaced by 1 or more R 02 ;
  • R e is selected from hydrogen atoms, halogen, hydroxyl, cyano, amino, alkyl, alkoxy, haloalkyl, haloalkoxy and hydroxyalkyl;
  • Each R 02 is the same or different, and each is independently selected from halogen, hydroxyl, cyano, oxo, amino, amide, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxyl Alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;
  • X 1 is CR X1 or N
  • X 2 is CR X2 or N;
  • X 3 is CR X3 or N
  • X 4 is CR X4 or N
  • X 5 is CR X5 or N
  • the condition is that X 1 , X 2 , X 3 , X 4 and X 5 are not N at the same time;
  • RX1 , R _ _ alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, -O-(CH 2 ) n -cycloalkyl, -O-(CH 2 ) s -heterocyclyl, Aryl and heteroaryl; wherein, the cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted by one or more R 03 ;
  • Each R 03 is the same or different, and each is independently selected from halogen, hydroxyl, cyano, oxo, amino, amide, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxyl Alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;
  • v is selected from 0, 1 and 2;
  • n is selected from 0, 1, 2, 3, 4 and 5;
  • s is selected from 0, 1, 2, 3, 4 and 5;
  • r is selected from 0, 1, 2, 3, 4 and 5.
  • Ring Cy is selected from polycyclic cycloalkyl, polycyclic heterocyclyl, polycyclic aryl and polycyclic heteroaryl;
  • Each R B is the same or different, and each is independently selected from halogen, hydroxyl, amino, cyano, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, alkenyl, cycloalkyl, heterocyclyl , aryl and heteroaryl;
  • R 3 , R 4 and R 5 are the same or different, and are each independently selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group and a heteroaryl group; wherein, the alkyl group, cycloalkyl group , heterocyclyl, aryl and heteroaryl are each independently optionally substituted by 1 or more R 01 ;
  • R 3 , R 4 and the nitrogen atom connected to them together form a heterocyclic group; the heterocyclic group is optionally substituted by one or more R 01 ;
  • R 6 is selected from alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;
  • Each R 01 is the same or different, and each is independently selected from halogen, hydroxyl, cyano, oxo, amino, -NH alkyl, -N (alkyl) 2 , acetyl, alkyl, alkenyl, alkynyl , alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;
  • R' is selected from hydrogen atoms, alkyl groups, haloalkyl groups, hydroxyalkyl groups, cycloalkyl groups and heterocyclyl groups;
  • X is O or S
  • R a and R b are the same or different, and are each independently selected from hydrogen atom, halogen, hydroxyl, cyano, amino, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl , cycloalkyl, heterocyclyl, cycloalkyloxy and heterocyclyloxy; the cycloalkyl, heterocyclyl, cycloalkyloxy and heterocyclyloxy are optionally substituted by one or more Replaced by R 02 ;
  • R c and R d are the same or different, and are each independently selected from hydrogen atom, halogen, hydroxyl, cyano, amino, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl , cycloalkyl, heterocyclyl, cycloalkyloxy and heterocyclyloxy; the cycloalkyl, heterocyclyl, cycloalkyloxy and heterocyclyloxy are optionally substituted by one or more Replaced by R 02 ;
  • R e is selected from hydrogen atoms, halogen, hydroxyl, cyano, amino, alkyl, alkoxy, haloalkyl, haloalkoxy and hydroxyalkyl;
  • Each R 02 is the same or different, and each is independently selected from halogen, hydroxyl, cyano, oxo, amino, amide, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;
  • X 1 is CR X1 or N
  • X 2 is CR X2 or N;
  • X 3 is CR X3 or N
  • X 4 is CR X4 or N
  • X 5 is CR X5 or N
  • the condition is that X 1 , X 2 , X 3 , X 4 and X 5 are not N at the same time;
  • RX1 , R _ _ alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, -O-(CH 2 ) n -cycloalkyl, -O-(CH 2 ) s -heterocyclyl, Aryl and heteroaryl; wherein, the cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted by one or more R 03 ;
  • Each R 03 is the same or different, and each is independently selected from halogen, hydroxyl, cyano, oxo, amino, amide, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxyl Alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;
  • v is selected from 0, 1 and 2;
  • n is selected from 0, 1, 2, 3, 4 and 5;
  • s is selected from 0, 1, 2, 3, 4 and 5;
  • r is selected from 0, 1, 2, 3, 4 and 5.
  • the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof wherein X 1 is N, X 2 is CR X2 , X 3 is CR X3 , and X 4 is CR X4 , X5 is CR X5 ; or X2 is N, X1 is CR X1 , X3 is CR X3 , X4 is CR X4 , X5 is CR X5 ; or X3 is N, X1 is CR X1 , X 2 is CR X2 , X 4 is CR X4 , X 5 is CR X5 ; or X 1 is N , X 3 is N, X 2 is CR X2 , X 4 is CR is N, X 4 is N, X 1 is CR X1 , X 3 is CR X3 , X 5 is CR X5 ;
  • the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof is a compound represented by general formula (II) or a pharmaceutically acceptable salt thereof:
  • R a and R b are different and each is independently selected from hydrogen atom, halogen, hydroxyl, cyano group, amino group, C 1-6 alkyl group, C 2-6 alkenyl group, C 2-6 alkynyl group, C 1-6 Alkoxy, halogenated C 1-6 alkyl, halogenated C 1-6 alkoxy, C 1-6 hydroxyalkyl, 3 to 10 -membered cycloalkyl, 3 to 10-membered heterocyclyl, 3 to 10 3- to 10-membered cycloalkyloxy and 3 to 10-membered heterocyclyloxy; the 3 to 10-membered cycloalkyl, 3 to 10-membered heterocyclyl, 3 to 10-membered cycloalkyloxy and 3 to 10-membered
  • the heterocyclyloxy group is optionally substituted by 1 or more R 02 ;
  • R c and R d are different and each is independently selected from hydrogen atom, halogen, hydroxyl, cyano group, amino group, C 1-6 alkyl group, C 2-6 alkenyl group, C 2-6 alkynyl group, C 1-6 Alkoxy, halogenated C 1-6 alkyl, halogenated C 1-6 alkoxy, C 1-6 hydroxyalkyl, 3 to 10 -membered cycloalkyl, 3 to 10-membered heterocyclyl, 3 to 10 3- to 10-membered cycloalkyloxy and 3 to 10-membered heterocyclyloxy; the 3 to 10-membered cycloalkyl, 3 to 10-membered heterocyclyl, 3 to 10-membered cycloalkyloxy and 3 to 10-membered
  • the heterocyclyloxy group is optionally substituted by 1 or more R 02 ;
  • Rings Cy, RA , RB , R', X, RX1 , RX2 , RX3 , R02 and r are as defined in general formula (I).
  • the compound represented by general formula (I) or general formula (II) or a pharmaceutically acceptable salt thereof is a compound represented by general formula (II-1) or a pharmaceutically acceptable salt thereof.
  • Medicinal salt :
  • R', X, Ra, Rb , Rc , Rd, RX1 , RX2 and RX3 are as defined in the general formula (II ) .
  • the compound represented by general formula (I) or general formula (II) or a pharmaceutically acceptable salt thereof is a compound represented by general formula (III) or a pharmaceutically acceptable salt thereof. of salt:
  • ring A is phenyl or 5- or 6-membered heteroaryl
  • Q 1 is C or N
  • Q 2 is selected from CRA, N , NR” and C(O);
  • Q 3 is selected from CR aa , CHR aa , N, NR” and O;
  • Y is selected from CR aa , CHR aa , N, NR” and O;
  • R aa is the same or different, and each is independently selected from hydrogen atom, halogen, hydroxyl, amino, cyano, alkyl, alkoxy, haloalkyl, haloalkoxy, alkenyl, cycloalkyl, heterocyclyl, aromatic base and heteroaryl;
  • R are the same or different, and are each independently selected from a hydrogen atom, an alkyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a cycloalkyl group, a heterocyclyl group, an aryl group and a heteroaryl group;
  • the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof wherein Selected from Ra, Rb , Rc , Rd and X are as defined by general formula (I); preferably, Selected from X, Ra , Rb , Rc and Rd are as defined in general formula (II); further preferably, Selected from X is O or S, R a and R b are different, and each is independently selected from hydrogen atom, halogen, C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkyl, halogenated C 1-6 alkoxy and 3 to 10-membered cycloalkyl, R c and R d are different, and each is independently selected from hydrogen atom, halogen, C 1-6 alkyl, C 1-6 alkoxy, halogen Substituted C 1-6 alkyl, halogenated C 1-6 alkoxy and 3 to 10 membered cycloalkyl; most preferably,
  • R a and R b are the same or different, and are each independently selected from hydrogen atoms, halogens, C 1-6 alkyl groups, halogenated C 1-6 alkyl groups and 3 to 10-membered cycloalkyl groups;
  • R c and R d are different , and each is independently selected from hydrogen atoms, halogens, C 1-6 alkyl groups, halogenated C 1-6 alkyl groups and 3 to 10-membered cycloalkyl groups;
  • R a and R b are different, and each is independently selected from hydrogen atom, halogen, C 1-6 alkyl group, halogenated C 1-6 alkyl group and 3 to 10-membered cycloalkyl group;
  • R c and R d are the same or different , and each is independently selected from hydrogen atom, halogen, C 1-6 alkyl group, halogenated C 1-6 alkyl group and 3 to 10-membered cycloalkyl group.
  • the compound represented by general formula (I) or general formula (II) or a pharmaceutically acceptable salt thereof wherein ring Cy is selected from 5 to 20-membered fused cycloalkyl, 5 to 20-membered fused heterocyclyl, 8- to 14-membered polycyclic aryl, and 7- to 14-membered polycyclic heteroaryl; in some embodiments, ring Cy is an 8- to 14-membered polycyclic heteroaryl; preferably, ring Cy It is a 9 to 10 membered bicyclic heteroaryl group.
  • the compound represented by general formula (I) or general formula (II) or a pharmaceutically acceptable salt thereof wherein ring Cy is represented by Ring A and Ring B are the same or different, and are each independently selected from 3 to 12-membered cycloalkyl, 3 to 12-membered heterocyclyl, 6 to 10-membered aryl and 5 to 14-membered heteroaryl, and the * end is with - C(O)NR'-connection, R A and R B are connected to any position of ring A and ring B within the range allowed by the chemical valency; preferably, ring Cy is expressed as Ring A is phenyl or 5- or 6-membered heteroaryl, ring B is selected from 3 to 10-membered cycloalkyl, 3 to 10-membered heterocyclyl, phenyl and 5- or 6-membered heteroaryl, and the * end is with -C (O) NR'-connection, R A and R B are connected to any position of ring A and
  • Ring Cy is represented by Ring A is phenyl or 5- or 6-membered heteroaryl, ring B is 5- or 6-membered heteroaryl, the * end is connected to -C(O)NR'-, R A and R B are within the allowable range of the valence. Attached to any position of Ring A and Ring B; more preferably, Ring Cy is selected from The * end is connected to -C(O)NR'-, and R A and R B are connected to any position of ring Cy within the range allowed by the chemical valency; most preferably, ring Cy is selected from The * end is connected to -C(O)NR'-, and R A and R B are connected to any position of the ring Cy within the range allowed by the chemical valency.
  • the compound represented by general formula (I) or general formula (II) or a pharmaceutically acceptable salt thereof wherein ring Cy is Ring A is phenyl or 5- or 6-membered heteroaryl; Q 1 is C or N, Q 2 is selected from CH, CH 2 , N, NH and C(O); Q 3 is selected from CH, CH 2 , N, NH and O; Y is selected from CH, CH 2 , N, NH and O; --- is a single bond or a double bond; y is 0 or 1; the * end is connected to -C(O)NR'-, and the valency allows R A and R B are connected to any position of the ring Cy within the range.
  • Ring Cy is selected from The * end is connected to -C(O)NR'-, and R A and R B are connected to any position of the ring Cy within the range allowed by the valency; in some embodiments, the ring Cy is selected from The * end is connected to -C(O)NR'-, and R A and R B are connected to any position of the ring Cy within the range allowed by the valency; in some embodiments, the ring Cy is selected from
  • Ring Cy is selected from
  • Ring Cy is selected from In some embodiments, Cy is The * end is connected to -C(O)NR'-, and R A and R B are connected to any position of the ring Cy within the range allowed by the chemical valency.
  • the compound represented by general formula (I) or general formula (II) or a pharmaceutically acceptable salt thereof wherein ring Cy is represented by Ring A is a 5-membered heteroaryl group, Ring B is a 5- or 6-membered heterocyclyl group or a 5- or 6-membered heteroaryl group, the * end is connected to -C(O)NR'-, and R A is a hydroxyl or amino group.
  • the compound represented by general formula (I) or general formula (II) or a pharmaceutically acceptable salt thereof wherein the number of heteroatoms contained in ring Cy does not exceed 5, preferably does not exceed 4, more preferably no more than 3.
  • the compound represented by the general formula (I), (II) or (III) or a pharmaceutically acceptable salt thereof wherein R A is selected from hydrogen atoms, hydroxyl groups, C 1-6 Hydroxyalkyl, C 1-6 hydroxyalkoxy, -NR 3 R 4 , -C 1-6 alkylene -NR 3 R 4 , -OC 1-6 alkylene -NR 3 R 4 , 3 to 10 1-membered cycloalkyl, 3 to 10 membered heterocyclyl, 6 to 10 membered aryl, 5 to 14 membered heteroaryl, -OC 1-6 alkylene, -5 to 14 heteroaryl and -OC 1-6 Alkyl-3 to 10-membered heterocyclyl, wherein the C 1-6 alkylene group, 3 to 10-membered cycloalkyl group, 3 to 10-membered heterocyclyl group, 6 to 10-membered aryl group and 5 to 14-membered aryl group
  • R A is selected from hydrogen atoms,
  • RA is selected from hydrogen atom, hydroxyl group, C 1-6 hydroxyalkyl group, C 1-6 hydroxyalkoxy group, -NR 3 R 4 , -C 1-6 alkylene group -NR 3 R 4 and - OC 1-6 alkylene-NR 3 R 4 , the C 1-6 alkylene group is optionally substituted by one or more R 01 ; R 01 , R 3 and R 4 are as in the general formula (I) defined; further preferably, R A is selected from hydroxyl, amino, C 1-6 alkoxy, C 1-6 hydroxyalkyl and C 1-6 hydroxyalkoxy; more preferably, R A is hydroxyl or amino ; Most preferably, R A is hydroxyl;
  • each R B is the same or different, and each is independently selected from Halogen, hydroxyl, amino, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl and halo C 1-6 alkoxy; preferably, each R B is the same or different, And each is independently selected from halogen, hydroxyl, C 1-6 alkyl and halogenated C 1-6 alkyl;
  • each R B is the same or different, and each is independently selected from oxo, halogen, C 1-6 alkyl and halo C 1-6 alkyl; preferably, each R B is the same or different, and each is independently selected from oxo, halogen and C 1-6 alkyl; more preferably, each R B are the same or different, and each is independently selected from oxo, and C 1-6 alkyl; in some embodiments, each R B is the same or different, and each is independently selected from halogen, C 1-6 alkyl and haloC 1-6 alkyl; in some embodiments, each R B is the same or different, and each independently is halogen or C 1-6 alkyl.
  • the compound represented by the general formula (I), (II) or (III) or a pharmaceutically acceptable salt thereof wherein each R B is the same or different, and each is independently selected from Halogen, C 1-6 alkyl and halo C 1-6 alkyl, and r is selected from 0, 1 and 2.
  • the compound represented by general formula (I) or general formula (II) or a pharmaceutically acceptable salt thereof wherein Selected from W is N or CR W ; one of W 1 , W 2 and W 3 is CRA , and the remaining two are independently N or CR 1B ; one of W 4 and W 5 is CRA , and the other One is N or CR 2B ; W 6 is selected from O, S and NR 3B ; one of W 7 , W 8 , W 9 and W 10 is CRA , and the remaining three are each independently N or CR 4B , and at least one of W 7 , W 8 , W 9 and W 10 is N; W 11 and W 12 are the same or different, and each is independently N or CR 5B ; W 13 and W 14 are the same or different, and each Independently N or CR 6B ; one of W 17 , W 18 , W 19 and W 20 is CRA , the remaining three are each independently N or CR 7B ; W
  • Selected from W is N or CH;
  • One of W 1 , W 2 and W 3 is CRA , and the remaining two are independently N or CR 1B ;
  • one of W 4 and W 5 is CRA , and the other is N or CR 2B ;
  • W 6 is selected from O, S and NR 3B ;
  • W 13 and W 14 are the same or different, and each is independently N or CR 6B ;
  • W 15 is N or CR 8B , and W 16 is selected from O, S and NR 9B ;
  • One of W 17 , W 18 , W 19 and W 20 is CRA , and the remaining three are each independently N or CR 7B ;
  • each of R 1B , R 0 , R 2B , R 6B , R 7B and R 8B The same or different, and each is independently selected from hydrogen atom, halogen, C 1-6 alkyl and halogenated C 1-6 alkyl;
  • R 9B and R 3B are each
  • Selected from R A is as defined by general formula (I);
  • Selected from R A is as defined by general formula (I); most preferably, Selected from
  • the compound represented by general formula (I) or general formula (II) or a pharmaceutically acceptable salt thereof wherein Selected from W 21 and W 22 are each independently N or CR 5b ; W 23 is N or CR 6b ; W 24 is selected from O, S and NR 7b ; each of R 1b , R 2b , R 3b , R 4b , R 5b and R 6b same or different, and each Independently selected from hydrogen atom, halogen, C 1-6 alkyl and halogenated C 1-6 alkyl; R 7b is selected from hydrogen atom, C 1-6 alkyl and halogenated C 1-6 alkyl; t is selected from From 0, 1 and 2, p is selected from 0, 1 and 2, and t and p are not 0 at the same time; preferably, Selected from W 21 and W 22 are each independently N or CR 5b ; W 23 is N or CR 6b ; W 24 is selected from O, S and NR 7b ; each of R 1b , R
  • W 13 , W 14 , W 17 , W 18 , W 19 and W 20 are as defined in formula (C8), W 15 and W 16 are as defined in formula (C11), W 21 , W 22 , R 1b , W 2b , R 3b , W 4b , t and p As defined in formula (C13-3); preferably, Selected from Among them, W 13 , W 14 , W 17 , W 18 , W 19 and W 20 are as defined in formula (C8), W 15 and W 16 are as defined in formula (C11), W 21 , W 22 , R 1b , W 2b , R 3b , W 4b , t and p are as defined in formula (C13-3); more preferably, for Among them, W 13 , W 14 , W 17 ,
  • the compound represented by general formula (I) or (II) or a pharmaceutically acceptable salt thereof wherein for Ring A is phenyl or 5- or 6-membered heteroaryl; Q 1 is C or N; Q 2 is selected from CRA , N, NR” and C(O); Q 3 is selected from CR aa , CHR aa , N, NR” and O; Y is selected from CR aa , CHR aa , N, NR” and O; --- is a single bond or a double bond;
  • R aa is the same or different, and each is independently selected from hydrogen atom, halogen, hydroxyl, amino, cyano, alkyl, alkoxy, haloalkyl, haloalkoxy, alkenyl, cycloalkyl, heterocyclyl, aromatic base and heteroaryl;
  • R" is the same or different, and each is independently selected from a hydrogen atom, an alkyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a cycloalkyl group, a heterocyclyl group, an aryl group and a heteroaryl group;
  • the * terminal is connected to -C(O)NR'-, the # terminal is connected to Y, and the + terminal is connected to Q 2 .
  • the compound represented by general formula (I) or (II) or a pharmaceutically acceptable salt thereof wherein Selected from RC is a hydrogen atom or RB , and RA , RB and r are as defined in general formula (I);
  • Selected from R C is a hydrogen atom or R B , R A and R B are as defined in general formula (I);
  • Selected from RA is as defined in general formula (I); in some embodiments, Selected from
  • R A is selected from halogen, hydroxyl and -NR 3 R 4 , R 3 and R 4 are the same or different, and each is independently a hydrogen atom or a C 1-6 alkyl group; each R B is the same or different, and each Independently selected from halogen, C 1-6 alkyl and halogenated C 1-6 alkyl, and r is selected from 0, 1 and 2; * end is connected to -C(O)NR'-;
  • the compound represented by general formula (I) or (II) or a pharmaceutically acceptable salt thereof wherein Selected from R A is selected from hydrogen atom, hydroxyl group, amino group, C 1-6 alkoxy group, C 1-6 hydroxyalkyl group and C 1-6 hydroxyalkoxy group (preferably hydrogen atom, hydroxyl group or amino group), the * end is with - C(O)NR'-connection; preferably, Selected from R A is selected from hydrogen atom, hydroxyl group, amino group, C 1-6 alkoxy group, C 1-6 hydroxyalkyl group and C 1-6 hydroxyalkoxy group (preferably hydrogen atom, hydroxyl group or amino group), the * end is with - C(O)NR'-connection.
  • R A is selected from hydroxyl, amino, C 1-6 alkoxy, C 1-6 hydroxyalkyl and C 1-6 hydroxyalkoxy,
  • R 1B is selected from hydrogen atom, halogen and C 1 -6 alkyl; preferably, W 2 is CRA , W 1 and W 3 are both N; or, W 2 is CRA , W 1 is N, W 3 is CR 1B ; or, W 2 is CRA , W 3 is N, W 1 is CR 1B ;
  • R A is selected from hydroxyl, amino, C 1-6 hydroxyalkyl and C 1-6 hydroxyalkoxy, R 1B is hydrogen atom, halogen and C 1-6 alkyl ;
  • W 2 is CRA , W 1 and W 3 are both N;
  • R A is selected from
  • the compound represented by formula (C4) or (C5) or a pharmaceutically acceptable salt thereof wherein R 0 is selected from hydrogen atoms, halogens and C 1-6 alkyl groups, W 5 is CRA , W 4 is N, W 6 is NR 3B ; R A is selected from hydroxyl, amino, C 1-6 alkoxy, C 1-6 hydroxyalkyl and C 1-6 hydroxyalkoxy, R 3B is a hydrogen atom or a C 1-6 alkyl group; preferably, R 0 is a hydrogen atom, W 5 is CRA , W 4 is N, and W 6 is NH; RA is a hydroxyl group or an amino group.
  • the compound represented by formula (C8), (C9) or (C10) or a pharmaceutically acceptable salt thereof wherein W 13 is N, and W 14 is CR 6B ; or, W 14 is N, and W 13 is CR 6B ; or, W 13 and W 14 are both CR 6B , and R 6B is selected from hydrogen atoms, halogens and C 1-6 alkyl groups; preferably, W 13 is N, and W 14 is CR 6B ; R 6B is selected from hydrogen atom, halogen and C 1-6 alkyl group; more preferably, W 13 is N, and W 14 is CH.
  • the compound represented by formula (C8), (C9), (C10), (C11), (C11-1) or (C12) or a pharmaceutically acceptable salt thereof wherein One of W 17 , W 18 , W 19 and W 20 is CRA , one is N, the remaining two are CR 7B , R 7B is selected from hydrogen atoms, halogens and C 1-6 alkyl groups, R A is as defined by general formula (I); preferably, one of W 17 , W 18 , W 19 and W 20 is CRA , one is N, the remaining two are CH, and R A is selected from hydroxyl , amino, C 1-6 alkoxy, C 1-6 hydroxyalkyl and C 1-6 hydroxyalkoxy; preferably, one of W 17 , W 18 , W 19 and W 20 is CRA , One is N, the remaining two are CH, and R A is hydroxyl or amino.
  • the compound represented by formula (C8), (C9), (C10) or (C11-1) substance or a pharmaceutically acceptable salt thereof wherein W 17 is CRA , W 19 is CR 7B , one of W 18 and W 20 is N, the other is CR 7B , R A is selected from hydroxyl, amino, C 1-6 hydroxyalkyl and C 1-6 hydroxyalkoxy, R 7B is selected from hydrogen atom, halogen and C 1-6 alkyl; preferably, W 17 is CRA , W 18 is N, W 19 and W 20 are all CR 7B , RA is selected from hydroxyl, amino, C 1-6 hydroxyalkyl and C 1-6 hydroxyalkoxy, R 7B is selected from hydrogen atom, halogen and C 1-6 alkyl; more preferably , W 17 is CRA , W 18 is N, W 19 and W 20 are both CH, R A is selected from hydroxyl, amino, C 1-6 hydroxyalkyl and C 1-6
  • the compound represented by formula (C11) or (C12) or a pharmaceutically acceptable salt thereof wherein W 20 is CRA , W 19 is N, and W 17 and W 18 are both CR 7B , RA is selected from hydroxyl, amino, C 1-6 hydroxyalkyl and C 1-6 hydroxyalkoxy, R 7B is selected from hydrogen atom, halogen and C 1-6 alkyl; preferably, W 20 is CR A , W 19 is N, W 17 and W 18 are both CH, R A is selected from hydroxyl, amino, C 1-6 hydroxyalkyl and C 1-6 hydroxyalkoxy.
  • the compound represented by formula (C1) to (C12), (C11-1), (C11-2) or (C8-1) or a pharmaceutically acceptable salt thereof wherein
  • Each R 1B , R 2B , R 4B , R 5B , R 6B , R 7B , R 8B , R W , and R 0 is the same or different on each occurrence, and is each independently selected from a hydrogen atom, a halogen, or a C 1- 6 alkyl; preferably, R 1B , R 2B , R 4B , R 5B , R 6B , R 7B , R 8B , R W and R 0 are hydrogen atoms in each occurrence.
  • the compound represented by formula (C1) to (C12), (C11-1), (C11-2) or (C8-1) or a pharmaceutically acceptable salt thereof wherein R 3B and R 9B are the same or different each time they appear, and are each independently a hydrogen atom or a C 1-6 alkyl group; preferably, R 3B and R 9B are both hydrogen atoms each time they appear.
  • the compound represented by formula (C14-1) or (C14-2) or a pharmaceutically acceptable salt thereof wherein W 23 is N or CR 6b and W 24 is NR 7b , R 6b is selected from hydrogen atom, halogen and C 1-6 alkyl group, R 7b is a hydrogen atom or C 1-6 alkyl group; preferably, W 23 is N or CH, W 24 is NH; more preferably, W 23 is CH, W 24 is NH.
  • the compound represented by formula (C13-1), (C13-2), (C13-3), (C14-1) or (C14-2) or a pharmaceutically acceptable compound thereof A salt wherein each R 1b , R 2b , R 3b , R 4b , R 5b and R 6b is the same or different at each occurrence, and each is independently selected from hydrogen atoms, halogens and C 1-6 alkyl groups, R 7b is selected from hydrogen atoms, C 1-6 alkyl groups and halo C 1-6 alkyl groups; preferably, R 1b , R 2b , R 3b , R 4b , R 5b , R 6b and R 7b appear in each occurrence All are hydrogen atoms.
  • the compound represented by the general formula (I), (II), (II-1) or (III) or a pharmaceutically acceptable salt thereof wherein R a is selected from a hydrogen atom, Halogen, C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkyl, halogenated C 1-6 alkoxy, C 1-6 hydroxyalkyl, 3 to 10 -membered cycloalkyl group and a 3 to 10-membered heterocyclyl group; preferably, R a is selected from a hydrogen atom, a halogen, a C 1-6 alkyl group and a halogenated C 1-6 alkyl group; further preferably, R a is a C 1-6 alkyl group base or halo C 1-6 alkyl; most preferably, R a is CH 3 or CF 3 ;
  • Ra is C 1-6 alkyl; preferably, Ra is CH 3 .
  • the compound represented by the general formula (I), (II), (II-1) or (III) or a pharmaceutically acceptable salt thereof wherein R b is selected from a hydrogen atom, Halogen, C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkyl, halogenated C 1-6 alkoxy, C 1-6 hydroxyalkyl, 3 to 10 -membered cycloalkyl group and a 3 to 10-membered heterocyclic group; preferably, R b is selected from a hydrogen atom, a halogen, a C 1-6 alkyl group and a halogenated C 1-6 alkyl group; further preferably, R b is a C 1-6 alkyl group base or halo C 1-6 alkyl; most preferably, R b is CH 3 or CF 3 ;
  • R b is haloC 1-6 alkyl; preferably, R b is CF 3 .
  • the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof wherein Re is selected from hydrogen atoms, halogens, hydroxyl, cyano groups and C 1-6 alkyl groups; Preferably, Re is a hydrogen atom.
  • the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof wherein R a and R b are the same or different, and each is independently selected from hydrogen atoms, C 1- 6 alkyl and halogenated C 1-6 alkyl; preferred
  • R a and R b are the same or different, and each is independently C 1-6 alkyl or halo C 1-6 alkyl; further preferably, R a is C 1-6 alkyl, and R b is halogenated C 1-6 alkyl, most preferably, R a is CH 3 and R b is CF 3 .
  • the compound represented by the general formula (II), (II-1) or (III) or a pharmaceutically acceptable salt thereof wherein R a and R b are different, and each is independently Selected from hydrogen atoms, C 1-6 alkyl and halo C 1-6 alkyl; preferably, R a and R b are different, and each is independently C 1-6 alkyl or halo C 1-6 alkyl base; further preferably, R a is C 1-6 alkyl, and R b is halogenated C 1-6 alkyl, most preferably, R a is CH 3 , and R b is CF 3 ;
  • R a is haloC 1-6 alkyl
  • R b is C 1-6 alkyl; preferably, R a is CF 3 , and R b is CH 3 .
  • the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof wherein R a and R b are the same or different, and each is independently selected from hydrogen atoms, CH 3 and CF 3 ; in some embodiments, R a and R b are the same or different, and each independently is C 1-6 alkyl; in some embodiments, R a and R b are the same or different, and each independently is Halogenated C 1-6 alkyl.
  • the compound represented by the general formula (I), (II), (II-1) or (III) or a pharmaceutically acceptable salt thereof wherein R a is halogenated C 1 -6 alkyl, R b is a hydrogen atom; in some embodiments, R a is a hydrogen atom, and R b is a halogenated C 1-6 alkyl group; in some embodiments, R a is a hydrogen atom, and R b is C 1-6 alkyl; in some embodiments, R a is C 1-6 alkyl, and R b is a hydrogen atom.
  • the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof wherein R c and R d are the same or different, and each is independently selected from hydrogen atoms, C 1- 6 alkyl and 3 to 6-membered cycloalkyl; preferably, R c and R d are the same or different, and each is independently a hydrogen atom or a C 1-6 alkyl group; further preferably, R c is a hydrogen atom, and R d is C 1-6 alkyl; most preferably, R c is a hydrogen atom, and R d is CH 3 .
  • the compound represented by the general formula (II), (II-1) or (III) or a pharmaceutically acceptable salt thereof wherein R c and R d are different and each is independently Selected from hydrogen atoms, C 1-6 alkyl groups and 3 to 6-membered cycloalkyl groups; preferably, R c and R d are different, and each is independently a hydrogen atom or C 1-6 alkyl group; further preferably, R c is a hydrogen atom, and R d is a C 1-6 alkyl group; most preferably, R c is a hydrogen atom, and R d is CH 3 ; in some embodiments, R c and R d are different, and each is independently is a hydrogen atom or CH 3 .
  • the compound represented by the general formula (I), (II), (II-1) or (III) or a pharmaceutically acceptable salt thereof wherein R c is C 1-6 Alkyl, and Rd is a hydrogen atom; or Rc is CH3 , and Rd is a hydrogen atom; in some embodiments, Rc is a 3 to 10-membered cycloalkyl group (preferably cyclopropyl), Rd is a hydrogen atom; in some embodiments, R c is a hydrogen atom, and R d is a 3 to 10-membered cycloalkyl group (preferably cyclopropyl).
  • the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof wherein R c and R d are the same or different, and each is independently a hydrogen atom or CH 3 ; in In some embodiments, R c and R d are both hydrogen atoms.
  • the compound represented by the general formula (I), (II), (II-1) or (III) or a pharmaceutically acceptable salt thereof wherein R 3 and R 4 are the same or Different, and each is independently selected from hydrogen atom, C 1-6 alkyl, halogenated C 1-6 alkyl and C 1-6 hydroxyalkyl; preferably, R 3 and R 4 are the same or different, and each is independent R is a hydrogen atom or a C 1-6 alkyl group; further preferably, R 3 and R 4 are both hydrogen atoms.
  • the oxygen group and the 4- to 7-membered heterocyclyloxy group are each independently optionally substituted by 1 or more R 03 , each R 03 is the same or different, and each is independently selected from halogen, C 1-6 alkyl and Halogenated C
  • the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof wherein R X4 and R X5 are each independently selected from hydrogen atoms, halogens, C 1-6 alkyl groups , C 1-6 alkoxy group, halogenated C 1-6 alkyl group and halogenated C 1-6 alkoxy group; preferably, R X4 and R X5 are both hydrogen atoms.
  • r is selected from 0, 1 and 2; preferably, r is 0 or 1, most preferably r is 0.
  • v is 1 or 2; preferably , v is 2.
  • the compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof wherein R a is a C 1-6 alkyl group; R b is a halogenated C 1-6 alkyl group.
  • Base R c is a hydrogen atom; R d is a C 1-6 alkyl group; X is O;
  • R' is a hydrogen atom or C 1-6 alkyl group
  • ring Cy is The * end is connected to -C(O)NR'-, and R A and R B are connected to any position of ring Cy within the range allowed by the chemical valency
  • R A is a hydroxyl or amino group
  • R X1 is a C 1-6 alkoxy group
  • R X2 is halogen
  • R X3 is halogen
  • r is 0.
  • the compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof wherein R a is a C 1-6 alkyl group; R b is a halogenated C 1-6 alkyl group. base; R c is a hydrogen atom; R d is a C 1-6 alkyl group; X is O; R' is a hydrogen atom or a C 1-6 alkyl group; Selected from R A is a hydrogen atom, hydroxyl group or amino group, and the * end is connected to -C(O)NR'-; R X1 is a C 1-6 alkoxy group; R X2 is a halogen; R X3 is a halogen.
  • the compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof wherein R a is a C 1-6 alkyl group; R b is a halogenated C 1-6 alkyl group. base; R c is a hydrogen atom; R d is a C 1-6 alkyl group; R X1 is a C 1-6 alkoxy group; R X2 is a halogen; R X3 is a halogen; X is O; R' is a hydrogen atom or C 1-6 alkyl; Selected from R C is a hydrogen atom or R B , R A is selected from halogen, hydroxyl and -NR 3 R 4 , R 3 and R 4 are the same or different, and each is independently a hydrogen atom or a C 1-6 alkyl group; each R B The same or different, and each is independently selected from halogen, C 1-6 alkyl and halogenated C 1-6 alkyl, and r is
  • the compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof wherein R a is CH 3 ; R b is CF 3 ; R c is a hydrogen atom; R d is CH 3 ; R X1 is methoxy; R X2 is halogen; R X3 is halogen; X is O; R' is a hydrogen atom; Selected from
  • Typical compounds of the present disclosure include, but are not limited to:
  • Another aspect of the present disclosure relates to compounds represented by general formula (IA) or salts thereof,
  • R 9 is C 1-6 alkyl
  • Another aspect of the present disclosure relates to a compound represented by general formula (II-A) or a salt thereof,
  • R 9 is C 1-6 alkyl
  • Rings Cy, RB , R' , X, Ra, Rb, Rc, Rd, RX1, RX2 , RX3 and r are as defined in general formula (II).
  • Another aspect of the present disclosure relates to a compound represented by general formula (II-1A) or a salt thereof,
  • R 11 , R 12 and R 13 are all amino protecting groups, preferably Boc;
  • Typical intermediate compounds of the present disclosure include, but are not limited to:
  • Another aspect of the present disclosure relates to a method for preparing the compound represented by the above general formula (I) or a pharmaceutically acceptable salt thereof, which method includes:
  • the compound represented by the general formula (Ia) or a salt thereof is subjected to a condensation reaction with the compound represented by the general formula (Ib) or a salt thereof to obtain a compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, wherein,
  • R 10 is halogen (preferably chlorine atom) or OH;
  • Ring Cy, R A , R B , R', R a , R b , R c , R d , Re, X , X 1 , X 2 , X 3 , X 4 , X 5 and r are as in the general formula (I ) as defined in.
  • Another aspect of the present disclosure relates to a method for preparing the compound represented by the above general formula (I) or a pharmaceutically acceptable salt thereof, which method includes:
  • R A is hydroxyl or amino;
  • R 9 is C 1-6 alkyl;
  • Ring Cy, R B , R', R a , R b , R c , R d , Re , X, X 1 , X 2 , X 3 , X 4 , X 5 and r are as in the general formula (I) definition.
  • Another aspect of the present disclosure relates to a method for preparing the compound represented by the above general formula (II) or a pharmaceutically acceptable salt thereof, which method includes:
  • the compound represented by the general formula (IIa) or a salt thereof is subjected to a condensation reaction with the compound represented by the general formula (Ib) or a salt thereof to obtain a compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof, wherein,
  • R 10 is halogen (preferably chlorine atom) or OH;
  • Rings Cy, RA , RB , R' , Ra, Rb , Rc , Rd , X, RX1 , RX2 , RX3 and r are as defined in general formula (II).
  • Another aspect of the present disclosure relates to a method for preparing the compound represented by the above general formula (II) or a pharmaceutically acceptable salt thereof, which method includes:
  • R A is hydroxyl or amino;
  • R 9 is C 1-6 alkyl;
  • Rings Cy, RB , R' , X, Ra, Rb, Rc, Rd, RX1, RX2 , RX3 and r are as defined in general formula (II).
  • Another aspect of the present disclosure relates to a method for preparing the compound represented by the above general formula (II-1) or a pharmaceutically acceptable salt thereof, which method includes:
  • R 11 , R 12 and R 13 are all amino protecting groups, preferably Boc;
  • Another aspect of the present disclosure relates to a method for preparing the compound represented by the above general formula (III) or a pharmaceutically acceptable salt thereof, which method includes:
  • the compound represented by the general formula (IIa) or a salt thereof is subjected to a condensation reaction with the compound represented by the general formula (IIIb) or a salt thereof (preferably a hydrochloride or trifluoroacetate) to obtain a compound represented by the general formula (III) Compounds or pharmaceutically acceptable salts thereof, wherein,
  • R 10 is halogen (preferably chlorine atom) or OH;
  • R ', X , R a , R b , R c , R d , R X1 , R aa and y are as defined in general formula (III).
  • Another aspect of the present disclosure relates to a pharmaceutical composition containing a compound shown in the general formula (I), (II), (II-1), (III) or Table A of the present disclosure or a compound thereof. a pharmaceutically acceptable salt, and one or more pharmaceutically acceptable carriers, diluents or excipients.
  • the present disclosure further relates to compounds shown in general formula (I), (II), (II-1), (III) or Table A or pharmaceutically acceptable salts thereof, or pharmaceutical compositions including the same in the preparation of inhibitory voltage Use of gated sodium channels in drugs; preferably, the voltage-gated sodium channel is Nav1.8.
  • the present disclosure further relates to compounds shown in general formula (I), (II), (II-1), (III) or Table A or pharmaceutically acceptable salts thereof, or pharmaceutical compositions including the same in the preparation of Use in medicines for treating and/or preventing diseases or conditions mediated by voltage-gated sodium channels.
  • the voltage-gated sodium channel is Nav1.8.
  • the present disclosure further relates to compounds shown in general formula (I), (II), (II-1), (III) or Table A or pharmaceutically acceptable salts thereof, or pharmaceutical compositions including the same in the preparation of treatments and /or Use in medicines to relieve pain and pain-related diseases, multiple sclerosis, Schaumburg-Touche syndrome, incontinence, pathological cough or cardiac arrhythmias; preferred
  • the pain is selected from chronic pain, acute pain, inflammatory pain, cancer pain, postoperative pain, neuropathic pain, musculoskeletal pain, primary pain, intestinal pain and idiopathic pain; the postoperative pain
  • the pain is preferably selected from the group consisting of bunionectomy pain, hernia repair pain and abdominoplasty pain.
  • the present disclosure further relates to a method for inhibiting voltage-gated sodium channels, which includes administering to a patient in need a compound represented by general formula (I), (II), (II-1), (III) or Table A or a compound thereof.
  • the present disclosure further relates to a method of treating and/or preventing a disease or condition mediated by voltage-gated sodium channels, comprising administering to a patient in need thereof general formulas (I), (II), (II-1), (III) ) or a compound shown in Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition including the same; preferably, the voltage-gated sodium channel is Nav1.8.
  • the present disclosure further relates to a method of treating and/or alleviating pain and pain-related disorders, multiple sclerosis, Schaumburg-Touche syndrome, incontinence, pathological cough and cardiac arrhythmias, comprising administering to a patient in need thereof the general formula (I), (II), (II-1), (III) or a compound shown in Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition including the same; preferably, the pain is selected from chronic pain , acute pain, inflammatory pain, cancer pain, postoperative pain, neuropathic pain, musculoskeletal pain, primary pain, intestinal pain and idiopathic pain; the postoperative pain is preferably selected from bunionectomy pain , hernia repair pain and abdominoplasty pain.
  • the present disclosure further relates to a compound represented by general formula (I), (II), (II-1), (III) or Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition including the same, which is used For medicine.
  • the present disclosure further relates to a compound represented by general formula (I), (II), (II-1), (III) or Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition including the same, which is used For inhibiting voltage-gated sodium channels; preferably, the voltage-gated sodium channel is Nav1.8.
  • the present disclosure further relates to a compound represented by general formula (I), (II), (II-1), (III) or Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition including the same, which is used For treating and/or preventing diseases or conditions mediated by voltage-gated sodium channels; preferably, the voltage-gated sodium channel is Nav1.8.
  • the present disclosure further relates to a compound represented by general formula (I), (II), (II-1), (III) or Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition including the same, which is used
  • the pain is selected from chronic pain, acute pain, inflammation sexual pain, cancer pain, neuropathic pain, musculoskeletal pain, primary pain, intestinal pain and idiopathic pain
  • the postoperative pain is preferably selected from bunionectomy pain, hernia repair pain and abdominoplasty pain pain.
  • the disease or condition described in the present disclosure is a disease or condition that is treated and/or prevented by inhibiting voltage-gated sodium channels; preferably, the voltage-gated sodium channel is Nav1.8.
  • the disease or condition mediated by voltage-gated sodium channels according to the present disclosure is pain and pain-related diseases, multiple sclerosis, Schein-Marie-Touche syndrome, incontinence or cardiac arrhythmia; preferably, The pain is selected from chronic pain, acute pain, inflammatory pain, cancer pain, neuropathic pain, musculoskeletal pain, primary pain, intestinal pain and idiopathic pain.
  • the neuropathic pain described in the present disclosure is preferably selected from trigeminal neuralgia, post-herpetic neuralgia, diabetic neuralgia Neuralgia, painful HIV-related sensory neuralgia, burn syndrome, post-amputation pain, post-spinal cord injury pain, phantom pain, painful neuroma, traumatic neuroma, Morton's neuroma, nerve compression Injury, spinal stenosis, carpal tunnel syndrome, radicular pain, sciatica, nerve avulsion, brachial plexus avulsion, complex regional pain syndrome, drug-induced neuralgia, cancer chemotherapy-induced neuralgia , antiretroviral therapy-induced neuralgia, primary small fiber neuropathy, primary sensory neuralgia, and trigeminal autonomic headache.
  • the musculoskeletal pain described in this disclosure is preferably selected from the group consisting of osteoarthritis pain, back pain, cold pain, burning pain and toothache.
  • Intestinal pain described in the present disclosure is preferably selected from inflammatory bowel disease pain, Crohn's disease pain or interstitial cystitis pain.
  • the inflammatory pain described in this disclosure is preferably selected from the group consisting of rheumatoid arthritis pain and vulvodynia.
  • Idiopathic pain as described in this disclosure includes fibromyalgia.
  • Acute pain as used in this disclosure includes acute postoperative pain.
  • Postoperative pain as described in this disclosure includes joint replacement pain, soft tissue surgery pain, bunionectomy pain, hernia repair pain, and abdominoplasty pain; preferably selected from the group consisting of bunionectomy pain, hernia repair pain, and abdominal pain. Orthopedic pain.
  • the neuropathic pain is diabetic peripheral neuralgia or small fiber neuralgia.
  • the disease or condition described in the present disclosure is selected from acute pain, chronic pain, neuropathic pain, inflammatory pain, arthritis, migraine, cluster headache, trigeminal neuralgia, herpetic neuralgia, general neuralgia, epilepsy, Epilepsy disorders, neurodegenerative disorders, psychiatric disorders, anxiety disorders, depression, bipolar disorder, myotonia, cardiac arrhythmias, movement disorders, neuroendocrine disorders, ataxia, multiple sclerosis, irritable bowel syndrome, Incontinence, pathological cough, visceral pain, osteoarthritis pain, post-herpetic neuralgia, diabetic neuropathy, radicular pain, sciatica, back pain, headache, neck pain, severe pain, intractable pain, nociceptive pain, outbreaks Sexual pain, post-operative pain, cancer pain, stroke, cerebral ischemia, traumatic brain injury, amyotrophic lateral sclerosis, stress-induced angina, exercise-induced angina, heart palpitations, high blood pressure, or abnormal gastrointestinal motility
  • the pain and pain-related disorders described in this disclosure are selected from the group consisting of femoral cancer pain, non-malignant chronic bone pain, rheumatoid arthritis, osteoarthritis, spinal stenosis, neuropathic low back pain, myofascial pain syndrome, and fibromuscular pain.
  • temporomandibular joint pain chronic visceral pain, abdominal pain, pancreatic pain, IBS pain, chronic and acute headache, migraine, tension headache, cluster headache, chronic and acute neuropathic pain, post-herpetic neuralgia, diabetic Neuropathy, HIV-related neuropathy, trigeminal neuralgia, Chuck-Marie-Duse neuropathy, hereditary sensory neuropathy, peripheral nerve injury, painful neuroma, ectopic proximal and distal discharges, radiculopathy, chemotherapy induction Neuropathic pain, radiation therapy-induced neuropathic pain, postmastectomy pain, central pain, spinal cord injury pain, poststroke pain, thalamic pain, complex regional pain syndrome, phantom pain, phantom limb pain, intractable pain , acute pain, acute post-operative pain, acute musculoskeletal pain, joint pain, mechanical low back pain, neck pain, tendonitis, injury pain, movement pain, acute internal pain Visceral pain, pyelonephritis, appendicit
  • the disease or condition described in the present disclosure is selected from the group consisting of acute pain, subacute and chronic pain, nociceptive pain, neuropathic pain, inflammatory pain, nociceptive pain, arthritis, migraine, cluster headache, trigeminal neuralgia, herpes Neuralgia, general neuralgia, epilepsy, epileptic disorders, neurodegenerative disorders, psychiatric disorders, anxiety, depression, bipolar disorder, myotonia, arrhythmias, movement disorders, neurodegenerative diseases, endocrine disorders, ataxia, Central neuropathic pain in multiple sclerosis and irritable bowel syndrome, incontinence, pathological cough, visceral pain, osteoarthritis pain, postherpetic neuralgia, diabetic neuropathy, radicular pain, sciatica, back pain , non-specific chronic back pain, head pain, neck pain, moderate pain, severe pain, intractable pain, nociceptive pain, breakthrough pain, postoperative pain, cancer pain (including chronic cancer pain and breakthrough cancer pain ),
  • the active compounds may be prepared in a form suitable for administration by any appropriate route and the compositions of the present disclosure may be formulated by conventional means using one or more pharmaceutically acceptable carriers. Accordingly, the active compounds of the present disclosure may be formulated in various dosage forms for oral administration, injection (eg, intravenous, intramuscular or subcutaneous) administration, inhalation or insufflation administration. The compounds of the present disclosure may also be formulated in dosage forms such as tablets, hard or soft capsules, aqueous or oily suspensions, emulsions, injections, dispersible powders or granules, suppositories, lozenges, or syrups.
  • the active compounds of the present disclosure are preferably in unit dosage form, or in such form that a patient may self-administer a single dose.
  • the unit dosage form of a compound or composition of the present disclosure may be expressed as a tablet, capsule, cachet, bottled solution, powder, granule, lozenge, suppository, reconstituted powder or liquid preparation.
  • a suitable unit dose may be 0.1 to 1000 mg.
  • the pharmaceutical composition of the present disclosure may contain one or more auxiliary materials selected from the following ingredients: fillers (diluents), binders, wetting agents, disintegrants or excipients wait.
  • auxiliary materials selected from the following ingredients: fillers (diluents), binders, wetting agents, disintegrants or excipients wait.
  • the composition may contain from 0.1 to 99% by weight of active compound.
  • the unit dosage of the pharmaceutical composition is 0.001 mg-1000 mg.
  • the pharmaceutical composition contains 0.01-99.99% of the aforementioned compound or a pharmaceutically acceptable salt or isotope substitution thereof, based on the total weight of the composition. In certain embodiments, the pharmaceutical composition contains 0.1-99.9% of the aforementioned compound or a pharmaceutically acceptable salt or isotope substitution thereof. In certain embodiments, the pharmaceutical composition contains 0.5% to 99.5% of the aforementioned compound or a pharmaceutically acceptable salt or isotope substitution thereof. In certain embodiments, the pharmaceutical composition contains 1% to 99% of the aforementioned compound or a pharmaceutically acceptable salt or isotope substitution thereof. In certain embodiments, the pharmaceutical composition contains 2% to 98% of the aforementioned compound or a pharmaceutically acceptable salt or isotope substitution thereof.
  • the pharmaceutical composition contains 0.01% to 99.99% of pharmaceutically acceptable excipients, based on the total weight of the composition. In certain embodiments, the pharmaceutical composition contains 0.1% to 99.9% pharmaceutically acceptable excipients. In certain embodiments, the pharmaceutical composition contains 0.5% to 99.5% pharmaceutically acceptable excipients. In certain embodiments, the pharmaceutical composition contains 1% to 99% pharmaceutically acceptable excipients. In certain embodiments, the pharmaceutical composition contains 2% to 98% pharmaceutically acceptable excipients. Tablets contain the active ingredient in admixture with nontoxic pharmaceutically acceptable excipients suitable for the manufacture of tablets. These excipients may be inert excipients, granulating agents, disintegrating agents, binders and lubricants. These tablets may be uncoated or may be coated by known techniques to mask the taste of the drug or to delay disintegration and absorption in the gastrointestinal tract, thereby providing sustained release over an extended period of time.
  • Oral formulations may also be presented in 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 oil vehicle.
  • Aqueous suspensions contain the active substances and excipients suitable for the preparation of aqueous suspensions for mixing. Such excipients are suspending, dispersing or wetting agents. Aqueous suspensions may also contain one or more preservatives, one or more coloring agents, one or more flavoring agents and one or more sweetening agents.
  • Oil suspensions can be formulated by suspending the active ingredient in vegetable oil, or mineral oil. Oil suspensions may contain thickening agents. Sweetening and flavoring agents as described above may be added to provide a palatable preparation. These compositions can be preserved by adding antioxidants.
  • compositions of the present disclosure may also be in the form of oil-in-water emulsions.
  • the oil phase may be vegetable oil, or mineral oil or mixtures thereof.
  • Suitable emulsifiers may be naturally occurring phospholipids, and the emulsions may also contain sweeteners, flavoring agents, preservatives and antioxidants.
  • Such preparations may also contain demulcents, preservatives, coloring agents and antioxidants.
  • compositions of the present disclosure may be in the form of sterile injectable aqueous solutions.
  • Acceptable solvents that can be used Or solvents include water, Ringer's solution and isotonic sodium chloride solution.
  • Sterile injectable preparations may be sterile injectable oil-in-water microemulsions in which the active ingredient is dissolved in an oily phase.
  • injectable solutions or microemulsions may be injected into the patient's bloodstream by local mass injection.
  • solutions and microemulsions are preferably administered in a manner that maintains constant circulating concentrations of the compounds of the present disclosure.
  • continuous intravenous drug delivery devices can be used.
  • An example of such a device is the Deltec CADD-PLUS.TM. 5400 intravenous pump.
  • compositions of the present disclosure may be in the form of sterile injectable aqueous or oily suspensions for intramuscular and subcutaneous administration.
  • the suspension may be formulated according to known techniques using suitable dispersing or wetting agents and suspending agents such as those mentioned above.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension prepared in a nontoxic parenterally acceptable diluent or solvent.
  • sterile fixed oil can be conveniently used as the solvent or suspending medium. For this purpose, any blend of fixed oils can be used.
  • fatty acids are also prepared as injectables.
  • the compounds of the present disclosure may be administered in the form of suppositories for rectal administration.
  • These pharmaceutical compositions may be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid in the rectum and will therefore dissolve in the rectum to release the drug.
  • compositions of the present disclosure may be administered by adding water to prepare water-suspended dispersible powders and granules.
  • These pharmaceutical compositions may be prepared by mixing the active ingredient with a dispersing or wetting agent, a suspending agent, or one or more preservatives.
  • the dosage of a drug depends on a variety of factors, including, but not limited to, the activity of the specific compound used, the severity of the disease, the patient's age, the patient's weight, the patient's health condition, patient's behavior, patient's diet, administration time, administration method, excretion rate, drug combination, etc.; in addition, the optimal treatment method such as mode of treatment, daily dosage of compound or pharmaceutically acceptable salt Types can be verified based on traditional treatment regimens.
  • alkyl refers to a saturated linear or branched aliphatic hydrocarbon group having 1 to 20 (for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) carbon atoms (i.e. C 1-20 alkyl).
  • the alkyl group is preferably an alkyl group having 1 to 12 carbon atoms (ie, C 1-12 alkyl group), more preferably an alkyl group having 1 to 6 carbon atoms (ie, C 1-6 alkyl group).
  • 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
  • the alkyl group may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment.
  • the substituents are preferably selected from the group consisting of D atoms, halogen, alkoxy, haloalkyl, haloalkoxy, cyclic One or more of alkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.
  • alkylene refers to a divalent alkyl group, wherein the alkyl group is as defined above and has 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 , 13, 14, 15, 16, 17, 18, 19 or 20) carbon atoms (i.e., C 1-20 alkylene group).
  • the alkylene group is preferably an alkylene group having 1 to 12 carbon atoms (i.e., C 1-12 alkylene group), and more preferably an alkylene group having 1 to 6 carbon atoms (i.e., C 1-6 alkylene group ).
  • Non-limiting examples include: -CH 2 -, -CH(CH 3 )-, -C(CH 3 ) 2 -, -CH 2 CH 2 -, -CH(CH 2 CH 3 )-, -CH 2 CH (CH 3 )-, -CH 2 C(CH 3 ) 2 -, -CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 -, etc.
  • the alkylene group may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment.
  • the substituent is preferably selected from the group consisting of D atoms, halogen, alkoxy, haloalkyl, haloalkoxy, One or more of cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.
  • alkenyl refers to an alkyl group containing at least one carbon-carbon double bond in the molecule, where the alkyl group is as defined above and has 2 to 12 (for example, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12) carbon atoms (i.e. C 2-12 alkenyl).
  • the alkenyl group is preferably an alkenyl group having 2 to 6 carbon atoms (i.e., C 2-6 alkenyl group).
  • Non-limiting examples include: vinyl, propenyl, isopropenyl, butenyl, and the like.
  • the alkenyl group may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment.
  • the substituents are preferably selected from the group consisting of D atoms, alkoxy, halogen, haloalkyl, haloalkoxy, cyclic One or more of alkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.
  • alkynyl refers to an alkyl group containing at least one carbon-carbon triple bond in the molecule, where the alkyl group is as defined above and has 2 to 12 (for example, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12) carbon atoms (i.e. C 2-12 alkynyl).
  • the alkynyl group is preferably an alkynyl group having 2 to 6 carbon atoms (ie, C 2-6 alkynyl group).
  • Non-limiting examples include: ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like.
  • Alkynyl groups may be substituted or unsubstituted, and when substituted, they may be substituted at any available point of attachment.
  • the substituents are preferably selected from the group consisting of D atoms, alkoxy, halogen, haloalkyl, haloalkoxy, cyclic One or more of alkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.
  • alkoxy refers to -O-(alkyl), where alkyl is as defined above. Non-limiting examples include: methoxy, ethoxy, propoxy, butoxy, and the like. Alkoxy may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment.
  • the substituent is preferably selected from the group consisting of D atom, halogen, alkoxy, haloalkyl, haloalkoxy, Cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano One or more of base, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.
  • cycloalkyl refers to a saturated or partially unsaturated monocyclic all-carbon ring (i.e., monocyclic cycloalkyl) or polycyclic ring 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 preferably a cycloalkyl group having 3 to 12 ring atoms (i.e., a 3- to 12-membered cycloalkyl group), and more preferably a cycloalkyl group having 3 to 10 ring atoms (i.e., a 3- to 10-membered cycloalkyl group). ) or a cycloalkyl group having 3 to 8 ring atoms (i.e. a 3 to 8 membered cycloalkyl group), most preferably a cycloalkyl group having 3 to 6 ring atoms (i.e.
  • cycloalkyl group having 5 to 6 ring atoms Or cycloalkyl group with 6 ring atoms (i.e. 5 or 6 membered cycloalkyl group).
  • Non-limiting examples of the monocyclic cycloalkyl include: cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, and cycloheptyl , cycloheptatrienyl and cyclooctyl, etc.
  • the polycyclic cycloalkyl group includes: spirocycloalkyl group, fused cycloalkyl group and bridged cycloalkyl group.
  • spirocycloalkyl refers to a polycyclic system in which one carbon atom (called a spiro atom) is shared between the rings.
  • the ring may contain one or more double bonds, or the ring may contain one or more atoms selected from nitrogen, Heteroatoms of oxygen and sulfur (the nitrogen can be optionally oxidized, that is, to form nitrogen oxides; the sulfur can be optionally oxoated, that is, to form sulfoxide or sulfone, but does not include -O-O-, -O-S - or -S-S-), provided that it contains at least one all-carbon ring and the point of attachment is on the all-carbon ring, which has 5 to 20 (for example, 5, 6, 7, 8, 9, 10, 11, 12, 13 , 14, 15, 16, 17, 18, 19 or 20) ring atoms (i.e.
  • the spirocycloalkyl group is preferably a spirocycloalkyl group having 6 to 14 ring atoms (i.e., a 6- to 14-membered spirocycloalkyl group), and more preferably a spirocycloalkyl group having 7 to 10 ring atoms (i.e., a 7 to 10-membered spirocycloalkyl group). membered spirocycloalkyl).
  • the spirocycloalkyl group includes a single spirocycloalkyl group and a multi-spirocycloalkyl group (such as a double spirocycloalkyl group, etc.), preferably a single spirocycloalkyl group or a double spirocycloalkyl group, and more preferably a 3-membered/4-membered, 3-membered or 3-membered spirocycloalkyl group.
  • Non-limiting examples include:
  • connection point can be at any position
  • fused cycloalkyl refers to a polycyclic system in which two adjacent carbon atoms are shared between the rings, which is a monocyclic cycloalkyl group fused with one or more monocyclic cycloalkyl groups, or a monocyclic cycloalkyl group fused with a heterocyclic cycloalkyl group.
  • One or more of the cyclic groups, aryl groups or heteroaryl groups are condensed, wherein the point of attachment is on a single-ring cycloalkyl group, which may contain one or more double bonds in the ring, and has 5 to 20 (for example, 5 , 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) ring atoms (i.e.
  • the fused ring alkyl group is preferably a fused ring alkyl group having 6 to 14 ring atoms (ie, a 6 to 14-membered fused ring alkyl group), and more preferably a fused ring alkyl group having 7 to 10 ring atoms (ie, a 7 to 10 membered ring alkyl group). fused ring alkyl group).
  • the fused cycloalkyl group includes bicyclic fused cycloalkyl group and polycyclic fused cycloalkyl group.
  • Cycloalkyl (such as tricyclic fused cycloalkyl, tetracyclic fused cycloalkyl, etc.), preferably bicyclic fused cycloalkyl or tricyclic fused cycloalkyl, more preferably 3-membered/4-membered, 3-membered/5-membered, 3-membered Yuan/6 Yuan, 4 Yuan/4 Yuan, 4 Yuan/5 Yuan, 4 Yuan/6 Yuan, 5 Yuan/3 Yuan, 5 Yuan/4 Yuan, 5 Yuan/5 Yuan, 5 Yuan/6 Yuan, 5 Yuan/ 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 ring alkyl group.
  • Non-limiting examples include: Its connection point can be at
  • bridged cycloalkyl refers to an all-carbon polycyclic ring system that shares two carbon atoms that are not directly connected between the rings.
  • the ring may contain one or more double bonds and has 5 to 20 (for example, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) carbon atoms (ie, 5 to 20 membered bridged cycloalkyl).
  • the bridged cycloalkyl group is preferably a bridged cycloalkyl group having 6 to 14 carbon atoms (i.e., a 6- to 14-membered bridged cycloalkyl group), and more preferably a bridged cycloalkyl group having 7 to 10 carbon atoms (i.e., a 7 to 10-membered bridged cycloalkyl group). bridged cycloalkyl).
  • the bridged cycloalkyl group includes bicyclic bridged cycloalkyl and polycyclic bridged cycloalkyl (such as tricyclic bridged cycloalkyl, tetracyclic bridged cycloalkyl, etc.), preferably bicyclic bridged cycloalkyl or tricyclic bridged cycloalkyl .
  • Non-limiting examples include:
  • Cycloalkyl may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment.
  • the substituents are preferably selected from the group consisting of D atoms, halogen, alkyl, alkoxy, haloalkyl, haloalkyl
  • heterocyclyl refers to a saturated or partially unsaturated monocyclic heterocycle (i.e., monocyclic heterocyclyl) or a polycyclic heterocyclic system (i.e., polycyclic heterocyclyl), which contains at least one ring (such as 1, 2, 3 or 4) heteroatoms selected from nitrogen, oxygen and sulfur (the nitrogen can be optionally oxidized, that is, to form nitrogen oxides; the sulfur can be optionally oxogenated, that is, to form sulfoxide or sulfone, but not including -OO-, -OS-, or -SS-), 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.
  • the heterocyclyl group is preferably a heterocyclyl group having 3 to 12 ring atoms (i.e., a 3 to 12-membered heterocyclyl group) or a heterocyclyl group having 3 to 10 ring atoms (i.e., a 3 to 10-membered heterocyclyl group); Further preferred are heterocyclyl groups having 3 to 8 ring atoms (i.e. 3 to 8 membered heterocyclyl groups); more preferred are heterocyclyl groups having 4 to 7 ring atoms (i.e.
  • heterocyclyl groups 4 to 7 membered heterocyclyl groups); more preferred Heterocyclyl groups having 3 to 6 ring atoms (i.e., 3 to 6-membered heterocyclyl groups); most preferred are heterocyclyl groups having 5 or 6 ring atoms (i.e., 5- or 6-membered heterocyclyl groups).
  • Non-limiting examples of the monocyclic heterocyclyl include: pyrrolidinyl, tetrahydropyranyl, 1,2,3,6-tetrahydropyridyl, piperidinyl, piperazinyl, morpholinyl , thiomorpholinyl and homopiperazinyl, etc.
  • the polycyclic heterocyclyl group includes spiroheterocyclyl group, fused heterocyclyl group and bridged heterocyclyl group.
  • spiroheterocyclyl refers to a polycyclic heterocyclic system in which the rings share one atom (called a spiro atom).
  • the ring may contain one or more double bonds, and the ring contains at least one (for example, 1, 2, 3 or 4) heteroatoms selected from nitrogen, oxygen and sulfur (the nitrogen can be optionally oxidized, that is, to form nitrogen oxides; the sulfur can be optionally oxo-substituted, that is, to form sulfoxide or sulfone, But does not include -O-O-, -O-S- or -S-S-), provided that it contains at least one monocyclic heterocyclyl group and the point of attachment is on the monocyclic heterocyclyl group, which has 5 to 20 (for example, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) ring atoms (ie, 5 to 20 membered spiroheterocyclyl).
  • the spiroheterocyclyl group is preferably a spiroheterocyclyl group having 6 to 14 ring atoms (i.e., a 6- to 14-membered spiroheterocyclyl group), and more preferably a spiroheterocyclyl group having 7 to 10 ring atoms (i.e., a 7 to 10-membered spiroheterocyclyl group).
  • 1-membered spiroheterocyclyl 1-membered spiroheterocyclyl
  • the spiroheterocyclyl group includes a single spiroheterocyclyl group and a polyspiroheterocyclyl group (such as a double spiroheterocyclyl group, etc.), preferably a single spiroheterocyclyl group or a double spiroheterocyclyl group, more preferably 3-membered/4-membered, 3-membered or 3-membered spiroheterocyclyl.
  • Non-limiting examples include:
  • fused heterocyclyl refers to a polycyclic heterocyclic system in which two adjacent atoms are shared between the rings.
  • the ring may contain one or more double bonds, and the ring may contain at least one (such as 1, 2, 3 or 4) heteroatoms selected from nitrogen, oxygen and sulfur (the nitrogen can be optionally oxidized, that is, to form nitrogen oxides; the sulfur can be optionally oxo-substituted, that is, to form sulfoxide or sulfone, but not Including -OO-, -OS- or -SS-), which is a monocyclic heterocyclyl fused with one or more monocyclic heterocyclyl groups, or a monocyclic heterocyclyl group with a cycloalkyl, aryl or heteroaryl group.
  • the fused heterocyclyl group is preferably a fused heterocyclyl group having 6 to 14 ring atoms (i.e., a 6- to 14-membered fused heterocyclyl group), and more preferably a fused heterocyclyl group having 7 to 10 ring atoms (i.e., a 7 to 10-membered fused heterocyclyl group). fused heterocyclic group).
  • the fused heterocyclyl group includes bicyclic and polycyclic fused heterocyclyl groups (such as tricyclic fused heterocyclyl group, tetracyclic fused heterocyclyl group, etc.), preferably bicyclic fused heterocyclyl group or tricyclic fused heterocyclyl group, more preferably 3 Yuan/4 Yuan, 3 Yuan/5 Yuan, 3 Yuan/6 Yuan, 4 Yuan/4 Yuan, 4 Yuan/5 Yuan, 4 Yuan/6 Yuan, 5 Yuan/3 Yuan, 5 Yuan/4 Yuan, 5 Yuan/ 5 yuan, 5 yuan/6 yuan, 5 yuan/7 yuan, 6 yuan/3 yuan, 6 yuan/4 yuan, 6 yuan/5 yuan, 6 yuan/6 yuan, 6 yuan/7 yuan, 7 yuan/5 yuan Or 7-membered/6-membered bicyclic fused heterocyclyl
  • bridged heterocyclyl refers to a polycyclic heterocyclic system that shares two atoms that are not directly connected between the rings.
  • the ring may contain one or more double bonds, and the ring contains at least one (for example, 1, 2, 3 or 4) heteroatoms selected from nitrogen, oxygen and sulfur (the nitrogen can be optionally oxidized, that is, to form nitrogen oxides; the sulfur can be optionally oxo-substituted, that is, to form sulfoxide or sulfone, but not including -O-O-, -O-S- or -S-S-), which has 5 to 20 (such as 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) ring atoms (i.e.
  • the bridged heterocyclyl group is preferably a bridged heterocyclyl group having 6 to 14 ring atoms (i.e., a 6- to 14-membered bridged heterocyclyl group), and more preferably a bridged heterocyclyl group having 7 to 10 ring atoms (i.e., a 7 to 10-membered bridged heterocyclyl group). Yuan-bridged heterocyclyl).
  • bicyclic bridged heterocyclyl and polycyclic bridged heterocyclyl such as tricyclic bridged heterocyclyl, tetracyclic bridged heterocyclyl, etc.
  • bicyclic bridged heterocyclyl or tricyclic bridged heterocyclyl preferably bicyclic bridged heterocyclyl or tricyclic bridged heterocyclyl. base.
  • Non-limiting examples include:
  • Heterocyclyl may be substituted or unsubstituted. When substituted, it may be substituted at any available point of attachment.
  • the substituent is preferably selected from D atoms, halogen, alkyl, alkoxy, haloalkyl, haloalkyl.
  • aryl refers to a monocyclic all-carbon aromatic ring (i.e., a monocyclic aryl) or a polycyclic aromatic ring system (i.e., a polycyclic aryl) having a conjugated ⁇ electron system, having 6 to 14 (e.g., 6 , 7, 8, 9, 10, 11, 12, 13 or 14) ring atoms (i.e. 6 to 14 membered aryl group).
  • the aryl group is preferably an aryl group having 6 to 10 ring atoms (ie, 6 to 10 membered aryl group).
  • the monocyclic aryl group is, for example, phenyl.
  • the polycyclic aryl group is preferably an 8- to 14-membered polycyclic aryl group, and non-limiting examples include: naphthyl, anthracenyl, phenanthrenyl, etc.
  • the polycyclic aryl group also includes phenyl fused with one or more of heterocyclyl or cycloalkyl, or naphthyl fused with one or more of heterocyclyl or cycloalkyl, where the point of attachment on phenyl or naphthyl, and in this case, the number of ring atoms continues to mean the number of ring atoms in the polycyclic aromatic ring system, non-limiting examples include:
  • Aryl groups may be substituted or unsubstituted. When substituted, they may be substituted at any available point of attachment.
  • the substituents are preferably selected from D atoms, halogens, alkyl groups, alkoxy groups, haloalkyl groups, haloalkoxy groups. or Multiple.
  • heteroaryl refers to a monocyclic heteroaromatic ring (i.e., monocyclic heteroaryl) or a polycyclic heteroaromatic ring system (i.e., polycyclic heteroaryl) with a conjugated ⁇ electron system, which contains at least one (For example, 1, 2, 3 or 4) heteroatoms selected from nitrogen, oxygen and sulfur (the nitrogen may be optionally oxidized, i.e. to form nitrogen oxides; the sulfur may be optionally oxo-substituted, i.e.
  • the heteroaryl group is preferably a heteroaryl group having 5 to 10 ring atoms (i.e., a 5- to 10-membered heteroaryl group), and more preferably a heteroaryl group having 5 or 6 ring atoms (i.e., a 5- or 6-membered heteroaryl group).
  • Non-limiting examples of the monocyclic heteroaryl include: furyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, imidazolyl , pyrazolyl, triazolyl, tetrazolyl, furazyl, pyrrolyl, N-alkylpyrrolyl, pyridyl, pyrimidinyl, pyridonyl, N-alkylpyridone (such as etc.), pyrazinyl, pyridazinyl, etc.
  • the polycyclic heteroaryl group is preferably a 7 to 14 membered polycyclic heteroaryl group or an 8 to 14 membered polycyclic heteroaryl group, and more preferably a 9 to 10 membered bicyclic heteroaryl group; non-limiting examples include: indole base, indazolyl, quinolyl, isoquinolinyl, quinoxalinyl, phthalazinyl, benzimidazolyl, benzothienyl, quinazolinyl, benzothiazolyl, carbazolyl, etc.
  • the polycyclic heteroaryl also includes a monocyclic heteroaryl fused with one or more aryl groups, wherein the point of attachment is on the aromatic ring, and in this case, the number of ring atoms continues to represent a polycyclic heteroaryl ring The number of ring atoms in the system.
  • the polycyclic heteroaryl also includes a monocyclic heteroaryl fused to one or more of cycloalkyl or heterocyclyl, wherein the point of attachment is on the monocyclic heteroaromatic ring, and in this case, the ring The number of atoms continues to represent the number of ring atoms in the polycyclic heteroaromatic ring system.
  • Non-limiting examples include:
  • Heteroaryl groups may be substituted or unsubstituted. When substituted, they may be substituted at any available point of attachment.
  • the substituents are preferably selected from D atoms, halogens, alkyl groups, alkoxy groups, haloalkyl groups, haloalkyl groups.
  • amino protecting group refers to an easily removable group introduced on the amino group in order to keep the amino group unchanged when other parts of the molecule react.
  • Non-limiting examples include: (trimethylsilyl)ethoxymethyl, tetrahydropyranyl, tert-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), watmethoxycarbonyl (Fmoc), allyl Oxycarbonyl (Alloc), trimethylsilylethoxycarbonyl (Teoc), methoxycarbonyl, ethoxycarbonyl, phthalyl (Pht), p-toluenesulfonyl (Tos), trifluoroacetyl (Tfa), Trityl (Trt), 2,4-dimethoxybenzyl (DMB), p-methoxybenzyl (PMB), acetyl, benzyl, allyl, p-methoxybenzyl, etc.
  • hydroxyl protecting group refers to an easily removable group introduced on a hydroxyl group to block or protect the hydroxyl group for reactions on other functional groups of the compound.
  • Non-limiting examples include: trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), tert-butyldimethylsilyl (TBS), tert-butyl Dimethylsilyl (TBDMS), tert-butyldiphenylsilyl (TBDPS), methyl, tert-butyl, allyl, benzyl, methoxymethyl (MOM), ethoxyethyl, 2-Tetrahydropyranyl (THP), formyl, acetyl, benzoyl, p-nitrobenzoyl, etc.
  • alkynyl protecting group refers to an easily removable group introduced on an alkynyl group in order to keep the active hydrogen in acetylene or terminal alkynes unchanged when other parts of the molecule react.
  • Non-limiting examples include: trimethylsilyl (TMS), triethylsilyl (TES), tert-butyldimethylsilyl (TBS), triisopropylsilyl (TIPS), tert-butyl Dimethylsilyl (TBDMS), tert-butyldiphenylsilyl (TBDPS), methyl, tert-butyl, allyl, benzyl, methoxymethyl (MOM), ethoxyethyl, 2-Tetrahydropyranyl (THP), formyl, acetyl, benzoyl, p-nitrobenzoyl, etc.
  • cycloalkyloxy refers to cycloalkyl-O-, where cycloalkyl is as defined above.
  • heterocyclyloxy refers to heterocyclyl-O-, wherein heterocyclyl is as defined above.
  • aryloxy refers to aryl-O-, where aryl is as defined above.
  • heteroaryloxy refers to heteroaryl-O-, where heteroaryl is as defined above.
  • alkylthio refers to alkyl-S-, where alkyl is as defined above.
  • haloalkyl refers to an alkyl group substituted with one or more halogens, where alkyl is as defined above.
  • haloalkoxy refers to an alkoxy group substituted with one or more halogens, where alkoxy is as defined above.
  • deuterated alkyl refers to an alkyl group substituted with one or more deuterium atoms, wherein alkyl is as defined above.
  • hydroxyalkyl refers to an alkyl group substituted with one or more hydroxyl groups, where alkyl is as defined above.
  • hydroxyalkoxy refers to an alkoxy group substituted with one or more hydroxyl groups, where alkoxy is as defined above.
  • halogen refers to fluorine, chlorine, bromine or iodine.
  • hydroxy refers to -OH.
  • mercapto refers to -SH.
  • amino refers to -NH2 .
  • cyano refers to -CN.
  • nitro refers to -NO2 .
  • acetyl refers to -C(O) CH3 .
  • amide refers to -C(O) NH2 .
  • carboxylate refers to -C(O)O(alkyl), -C(O)O(cycloalkyl), (alkyl)C(O)O- or (cycloalkyl)C(O )O-, where alkyl and cycloalkyl are as defined above.
  • stereoisomer refers to isomers that have the same structure but different arrangements of atoms in space. It includes cis and trans (or Z and E) isomers, (-)- and (+)-isomers, (R)- and (S)-enantiomers, diastereomers isomers, (D)- and (L)-isomers, tautomers, atropisomers, conformational isomers and their mixtures (e.g. racemates, mixtures of diastereomers) . Additional asymmetric atoms may be present for substituents in the compounds of the present disclosure.
  • Optically active (-)- and (+)-isomers, (R)- and (S)-enantiomers, and (D)- and (L)-isomer Optically active (-)- and (+)-isomers, (R)- and (S)-enantiomers, and (D)- and (L)-isomer.
  • An isomer of a certain compound of the present disclosure can be prepared through asymmetric synthesis or chiral auxiliaries, or when the molecule contains basic functional groups (such as amino) or acidic functional groups (such as carboxyl), and appropriate optical Reactive acids or bases form diastereomeric salts, and then the diastereoisomers are resolved by conventional methods known in the art to obtain pure isomers. Furthermore, the separation of enantiomers and diastereomers is usually accomplished by chromatography.
  • the bond Indicates that the configuration is not specified, i.e. if there are chiral isomers in the chemical structure, the bond can be or both Two configurations.
  • the bond If the configuration is not specified, it can be either the Z configuration or the E configuration, or both. For all carbon-carbon double bonds, even if only one configuration is named, both the Z and E forms are included.
  • the bond to the stereogenic center of the compound like represents the relative configuration of the stereoisomeric center; wherein, the compound 1a of Example 1 is a mixture of 1b-1 and 1b-2.
  • tautomer or tautomeric form
  • tautomer refers to a structural isomer that exists in equilibrium and is readily converted from one isomeric form to another. It includes all possible tautomers, either as single isomers or as mixtures of said tautomers in any proportion.
  • Non-limiting examples include: keto-enol, imine-enamine, lactam-lactam, and the like.
  • An example of a lactam-lactam equilibrium is shown below:
  • the compounds of the present disclosure include all suitable isotopic derivatives of the compounds thereof.
  • isotopic derivative refers to a compound in which at least one atom is replaced by an atom with the same atomic number but a different atomic mass.
  • isotopes that may be incorporated into the compounds of the present disclosure include stable and radioactive isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine, iodine, and the like, such as 2 H (deuterium, D), respectively.
  • deuterated drugs Compared with non-deuterated drugs, deuterated drugs have the advantages of reducing side effects, increasing drug stability, enhancing efficacy, and extending the biological half-life of the drug. All variations in the isotopic composition of the compounds of the present disclosure, whether radioactive or not, are included within the scope of the present disclosure.
  • Each available hydrogen atom attached to a carbon atom can independently is replaced by a deuterium atom, where the replacement of deuterium can be partial or complete.
  • the replacement of partial deuterium means that at least one hydrogen is replaced by at least one deuterium.
  • a position when a position is specifically designated as “deuterium” or “D", that position is understood to have an abundance of deuterium that is at least 1000 times greater than the natural abundance of deuterium (which is 0.015%) (i.e. At least 15% deuterium incorporation).
  • the abundance of deuterium per designated deuterium atom is at least 1000 times greater than the natural abundance of deuterium (ie, at least 15% deuterium incorporation).
  • the abundance of deuterium per designated deuterium atom is at least 2000 times greater than the natural abundance of deuterium (ie, at least 30% deuterium incorporation).
  • the abundance of deuterium per designated deuterium atom is at least 3000 times greater than the natural abundance of deuterium (ie, at least 45% deuterium incorporation). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 3340 times greater than the natural abundance of deuterium (ie, at least 50.1% deuterium incorporation). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 3500 times greater than the natural abundance of deuterium (ie, at least 52.5% deuterium incorporation). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 4000 times greater than the natural abundance of deuterium (ie, at least 60% deuterium incorporation).
  • the abundance of deuterium per designated deuterium atom is at least 4500 times greater than the natural abundance of deuterium (ie, at least 67.5% deuterium incorporation). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 5000 times greater than the natural abundance of deuterium (ie, at least 75% deuterium incorporation). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 5500 times greater than the natural abundance of deuterium (ie, at least 82.5% deuterium incorporation). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 6000 times greater than the natural abundance of deuterium (ie, at least 90% deuterium incorporation).
  • the abundance of deuterium per designated deuterium atom is at least 6333.3 times greater than the natural abundance of deuterium (ie, at least 95% deuterium incorporation). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 6466.7 times greater than the natural abundance of deuterium (ie, at least 97% deuterium incorporation). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 6600 times greater than the natural abundance of deuterium (ie, at least 99% deuterium incorporation). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 6633.3 times greater than the natural abundance of deuterium (ie, at least 99.5% deuterium incorporation).
  • alkyl optionally substituted by halogen or cyano includes the case where the alkyl is substituted by halogen or cyano and the case where the alkyl is not substituted by halogen and cyano.
  • Substituted or “substituted” means that one or more hydrogen atoms in a group, preferably 1 to 6, more preferably 1 to 3 hydrogen atoms, are independently substituted with a corresponding number of substituents.
  • a person skilled in the art will be able to determine possible or impossible substitutions without undue effort (either experimentally or theoretically).
  • an amino or hydroxyl group with a free hydrogen may be unstable when combined with a carbon atom with an unsaturated bond, such as an alkene.
  • “Pharmaceutical composition” means a mixture containing one or more compounds described herein, or a pharmaceutically acceptable salt thereof, and other chemical components, as well as other ingredients such as pharmaceutically acceptable carriers and excipients.
  • the purpose of pharmaceutical compositions is to facilitate administration to living organisms and facilitate the absorption of active ingredients to exert biological activity.
  • “Pharmaceutically acceptable salts” refer to salts of compounds of the present disclosure, which may be selected from inorganic salts or organic salts. This type of salt is used It is safe and effective when in vivo in mammals, and has due biological activity. They can be prepared individually 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 inorganic acids as well as organic acids.
  • pharmaceutically acceptable refers to compounds, materials, compositions and/or dosage forms which, within the scope of reasonable medical judgment, are suitable for contact with patient tissue without undue toxicity, irritation, allergic reaction or other problems or complications, has a reasonable benefit/risk ratio, and is effective for the intended use.
  • the present disclosure provides a method for preparing a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, which method includes:
  • the compound represented by the general formula (Ia) or a salt thereof and the compound represented by the general formula (Ib) or a salt thereof are subjected to a condensation reaction under alkaline conditions to obtain a compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof ,
  • R 10 is halogen (preferably chlorine atom) or OH;
  • Ring Cy, R A , R B , R', R a , R b , R c , R d , Re, X , X 1 , X 2 , X 3 , X 4 , X 5 and r are as in the general formula (I ) as defined in.
  • the present disclosure provides a method for preparing a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, which method includes:
  • the compound represented by general formula (I-A) or a salt thereof undergoes an aminolysis reaction in the presence of an aminating agent to obtain a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, wherein,
  • R A is an amino group, and R 9 is a C 1-6 alkyl group; further, when the solvent contains water, the compound represented by the general formula (IA) or its salt also undergoes a hydrolysis reaction to obtain the compound represented by the general formula (I) or Its pharmaceutically acceptable salt, in which R A is hydroxyl or amino;
  • Ring Cy, R B , R', R a , R b , R c , R d , Re , X, X 1 , X 2 , X 3 , X 4 , X 5 and r are as in the general formula (I) definition.
  • the present disclosure provides a method for preparing a compound represented by general formula (II) or a pharmaceutically acceptable salt thereof, which method includes:
  • the compound represented by the general formula (IIa) or a salt thereof and the compound represented by the general formula (Ib) or a salt thereof are subjected to a condensation reaction under alkaline conditions to obtain a compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof ,in,
  • R 10 is halogen (preferably chlorine atom) or OH;
  • Rings Cy, RA , RB , R' , Ra, Rb , Rc , Rd , X, RX1 , RX2 , RX3 and r are as defined in general formula (II).
  • the present disclosure provides a method for preparing a compound represented by general formula (II) or a pharmaceutically acceptable salt thereof, which method includes:
  • R A is an amino group, and R 9 is a C 1-6 alkyl group; further, when the solvent contains water, the compound represented by the general formula (II-A) or its salt also undergoes a hydrolysis reaction to obtain the compound represented by the general formula (II).
  • Rings Cy, RB , R' , X, Ra, Rb, Rc, Rd, RX1, RX2 , RX3 and r are as defined in general formula (II).
  • the present disclosure provides a method for preparing a compound represented by general formula (II-1) or a pharmaceutically acceptable salt thereof, which method includes:
  • R 11 , R 12 and R 13 are all amino protecting groups, preferably Boc;
  • the present disclosure provides a method for preparing a compound represented by general formula (III) or a pharmaceutically acceptable salt thereof, which method includes:
  • R 10 is halogen (preferably chlorine atom) or OH;
  • R ', X , R a , R b , R c , R d , R X1 , R aa and y are as defined in general formula (III).
  • the condensation reaction when R 10 is halogen, the condensation reaction may be carried out in the presence of a catalyst.
  • the catalyst is preferably 4-dimethylaminopyridine.
  • the reagents that provide alkaline conditions in the above synthesis scheme include organic bases and inorganic bases.
  • the organic bases include but are not limited to triethylamine, N,N-diisopropylethylamine (DIPEA), n-butyllithium , lithium diisopropylamide, potassium acetate, sodium tert-butoxide, potassium tert-butoxide, tetrabutylammonium fluoride, tetrabutylammonium fluoride solution in tetrahydrofuran or 1,8-diazabicycloundecarbon -7-ene
  • the inorganic bases include but are not limited to sodium hydride, potassium phosphate, sodium carbonate, sodium acetate, potassium acetate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, ammonia, cesium fluoride and Potassium hydroxide.
  • the reagent that provides basic conditions is preferably triethylamine or N,N-diisopropylethylamine; when R 10 is OH, the reagent that provides basic conditions is preferably N,N- Diisopropylethylamine.
  • the reagent that provides alkaline conditions is the aqueous solution of the above-mentioned organic base and inorganic base, preferably an aqueous solution of DIPEA.
  • the condensing agent described in the above reaction includes but is not limited to 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, N,N'-dicyclohexylcarbodiimide, N ,N'-diisopropylcarbodiimide, O-benzotriazole-N,N,N',N'-tetramethylurea tetrafluoroborate, 1-hydroxybenzotriazole, 1-hydroxy-7-azobenzotriazole, O-benzotriazole-N,N,N',N'-tetramethylurea hexafluorophosphate, O-(7-azabenzotriazole Azol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate (HATU), 2-(7-benzotriazole oxide)-N,N,N', N'-tetramethylurea hexafluorophosphat
  • reagents that provide acidic conditions include but are not limited to hydrogen chloride, hydrogen chloride solution in 1,4-dioxane, hydrochloric acid solution in 1,4-dioxane, trifluoroacetic acid, formic acid, acetic acid, hydrochloric acid, Concentrated sulfuric acid, methanesulfonic acid, nitric acid, phosphoric acid, p-benzenesulfonic acid, Me 3 SiCl and TMSOTf, preferably trifluoroacetic acid.
  • the aminating agent described in the above reaction includes but is not limited to: liquid ammonia, ammonia water, urea, ammonium salt (source of NH 3 ), 1,4-dioxane of ammonia and organic amines; preferably 1,4-dioxane of ammonia. 4-Dioxane.
  • the reaction of the above steps is preferably carried out in a solvent.
  • the solvents used include but are not limited to: pyridine, 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-dibromo Ethane and its mixtures.
  • the structure of the compound is determined by nuclear magnetic resonance (NMR) or/and mass spectrometry (MS). NMR shifts ( ⁇ ) are given in units of 10 -6 (ppm). NMR is measured using Bruker AVANCE-400 nuclear magnetic instrument or Bruker AVANCE NEO 500M.
  • the measurement solvents are deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), and deuterated methanol (CD 3 OD).
  • the internal standard is tetramethylsilane (TMS).
  • MS was measured using Agilent 1200/1290 DAD-6110/6120 Quadrupole MS liquid mass spectrometer (manufacturer: Agilent, MS model: 6110/6120 Quadrupole MS), waters ACQuity UPLC-QD/SQD (manufacturer: waters, MS Model: waters ACQuity Qda Detector/waters SQ Detector), THERMO Ultimate 3000-Q Exactive (manufacturer: THERMO, MS model: THERMO Q Exactive).
  • HPLC High performance liquid chromatography
  • Chiral HPLC analysis was performed using an Agilent 1260 DAD high performance liquid chromatograph.
  • High-performance liquid phase preparation uses Waters 2545-2767, Waters 2767-SQ Detecor2, Shimadzu LC-20AP and Gilson GX-281 preparative chromatographs.
  • Chiral preparation uses Shimadzu LC-20AP preparative chromatograph.
  • CombiFlash rapid preparation instrument uses Combiflash Rf200 (TELEDYNE ISCO).
  • Thin layer chromatography silica gel plates use Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates.
  • the specifications of silica gel plates used in thin layer chromatography (TLC) are 0.15mm ⁇ 0.2mm.
  • the specifications used for thin layer chromatography separation and purification products are 0.4mm. ⁇ 0.5mm.
  • Silica gel column chromatography generally uses Yantai Huanghai Silica Gel 200 ⁇ 300 mesh silica gel as the carrier.
  • the average kinase inhibition rate and IC 50 value were measured using NovoStar microplate reader (BMG Company, Germany).
  • the known starting materials of the present disclosure can be synthesized by methods known in the art, or can be purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Shaoyuan Chemical Technology (Accela ChemBio Inc), Darui Chemical companies.
  • Argon atmosphere or nitrogen atmosphere means that the reaction bottle is connected to an argon or nitrogen balloon with a volume of about 1L.
  • the hydrogen atmosphere refers to the reaction bottle connected to a hydrogen balloon with a volume of about 1L.
  • the pressurized hydrogenation reaction uses Parr 3916EKX hydrogenator and Clear Blue QL-500 hydrogen generator or HC2-SS hydrogenator.
  • the hydrogenation reaction is usually evacuated, filled with hydrogen, and repeated three times.
  • the microwave reaction uses CEM Discover-S 908860 microwave reactor.
  • the solution refers to an aqueous solution.
  • the reaction temperature is room temperature, which is 20°C to 30°C.
  • the reaction progress in the embodiment is monitored by thin layer chromatography (TLC).
  • TLC thin layer chromatography
  • the developing agent used in the reaction, the column chromatography eluent system and the thin layer chromatography developing agent system used to purify the compound include: A: Dichloromethane/methanol system, B: n-hexane/ethyl acetate system, C: petroleum ether/ethyl acetate system, the volume ratio of the solvent is adjusted according to the polarity of the compound, a small amount of triethylamine and Adjust with alkaline or acidic reagents such as acetic acid.
  • Example 1-P1 and Example 1-P2 are Example 1-P1 and Example 1-P2
  • Chiral HPLC analysis retention time 2.414 minutes, purity: 99% (Column: DAICEL 100*3mm, 3 ⁇ m; mobile phase A: Supercritical CO 2 , mobile phase B: IPA (0.1% DEA)), gradient ratio: mobile phase A: 60%-95%, flow rate: 1.5mL/min).
  • Ethyl (E)-3-(dimethylamino)-2-(2-(methylthio)pyrimidin-4-yl)acrylate 1c (5g, 18.7mmol, was adopted from the literature "Journal of Chemical Information and Modeling, 2021 , vol.61, #1, p.467-480" prepared by the disclosed method) was dissolved in dichloromethane (50mL), and 2,4,6-trimethylbenzenesulfonylhydroxylamine was added dropwise in an ice bath for 1d ( 5.47g, 25.43mmol, Shanghai Hanhong) in dichloromethane (50mL), stir and react for 3 hours, add saturated sodium bicarbonate solution (50mL) to the reaction solution, extract with dichloromethane (50mL ⁇ 3), combine the organic The phase was dried with anhydrous sodium sulfate, filtered to remove the desiccant and concentrated under reduced pressure.
  • Dissolve compound 4d (40mg, 127 ⁇ mol) in 1mL methanol, add 0.2mL 4M hydrochloric acid 1,4-dioxane solution, stir and react for 1.5 hours, neutralize the reaction solution with saturated sodium bicarbonate solution and concentrate under reduced pressure, that is The crude title compound 4e (19 mg) was obtained, and the product was directly used in the next reaction without purification.
  • Dissolve compound 8k (14 mg, 44.4 ⁇ mol) in methanol (1 mL), add 0.3 mL of 4M hydrochloric acid 1,4-dioxane solution, stir and react for 2 hours, adjust the pH of the reaction solution to 8 with saturated sodium bicarbonate solution, and add acetic acid Extract with ethyl ester (5mL ⁇ 2), combine the organic phases, dry with anhydrous sodium sulfate, filter to remove the desiccant and concentrate under reduced pressure.
  • the crude title compound 8l (6 mg) was obtained, which was used directly in the next step without purification.
  • the title compound 9 (1 mg, yield: 9.35%) was obtained by using the eighth to twelfth steps of the synthetic route in Example 8, and replacing the raw material compound 8h in the eighth step with compound 9a.
  • Crude compound 12a (100 mg, 506.12 ⁇ mol) was dissolved in tetrahydrofuran (5 mL) and ethanol (5 mL). Add iron powder (300 mg, 5.37 mmol) and 2 mL saturated ammonium chloride solution, stir and react at 70°C for 2 hours, filter the reaction solution while it is hot, and concentrate the filtrate under reduced pressure to obtain the crude title compound 12b (50 mg), which can be used directly without purification. to the next step.
  • the crude compound 14e (800 mg, 3.18 mmol) was dissolved in 30 mL of 4M hydrochloric acid 1,4-dioxane solution. The reaction was stirred for 14 hours. The reaction solution was concentrated under reduced pressure to obtain the crude title compound 14f (410 mg). Without purification, the crude compound 14e (410 mg) was obtained. for the next step.
  • the reaction solution is purified by high performance liquid phase preparative chromatography (Waters-2545, chromatographic column: YMC Triart-Exrs C18, 30*150mm, 5 ⁇ m; mobile phase : aqueous phase (10 mmol/L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 35%-42%, flow rate: 30 mL/min) to obtain the title compound 16 (15 mg, yield: 22.8%).
  • HPLC analysis retention time 1.835 minutes, purity: 95% (column: HALO C18, 2.7 ⁇ m, 3.0*30mm; mobile phase: water (1 ⁇ formic acid), acetonitrile, gradient ratio: acetonitrile 10%-95%).
  • HPLC analysis retention time 2.057 minutes, purity: 98% (column: HALO C18, 2.7 ⁇ m, 3.0*30mm; mobile phase: water (1 ⁇ formic acid), acetonitrile, gradient ratio: acetonitrile 10%-95%).
  • HPLC analysis retention time 2.57 minutes, purity: 97% (Column: ACQUITY C18, 1.7 ⁇ m, 2.1*50mm; mobile phase: water (1 ⁇ formic acid), acetonitrile, gradient ratio: acetonitrile 10%-95%).
  • HPLC analysis retention time 2.62 minutes, purity: 94% (Column: ACQUITY C18, 1.7 ⁇ m, 2.1*50mm; mobile phase: water (1 ⁇ formic acid), acetonitrile, gradient ratio: acetonitrile 10%-95%).
  • Dissolve compound 19b (1.1g, 6.78mmol) in concentrated sulfuric acid (10mL), add potassium nitrate (686mg, 6.78mmol) in batches under ice bath, maintain the temperature for 2 hours, pour ice water into the reaction solution, and use 2M Adjust the pH to neutral with sodium hydroxide solution, extract with ethyl acetate (30 mL -2545, column: YMC Triart-Exrs C18, 30*150mm, 5 ⁇ m; mobile phase: aqueous phase (10mmol/L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 30%-40%, flow rate: 30mL/min ) to obtain the title compound 19c (300 mg, yield: 21.3%).
  • Test Example 1 Determination of Nav1.8 inhibitory activity of compounds of the present disclosure
  • Nav1.8 ion channels are stably expressed on HEK293 cells. After the Nav1.8 current is stabilized, the effect of the compound on the Nav1.8 ion channel can be obtained by comparing the magnitude of the Nav1.8 current before and after compound application.
  • Patch clamp amplifier patch clamp PC-505B (WARNER instruments)/MultiClamp700A (Axon instruments)
  • Extracellular fluid is: NaCl, 137; KCl, 4; CaCl 2 , 1.8; MgCl 2 , 1; HEPES, 10; Glucose, 10; pH 7.4 (NaOH titration).
  • the intracellular fluid (mM) is aspartic acid, 140; MgCl 2 , 2; EGTA, 11; HEPES, 10; pH 7.2 (CsOH titration). All test compound and control compound solutions contained 1 ⁇ M TTX.
  • Test compounds are stored at a concentration of 9mM in dimethyl sulfoxide (DMSO). On the day of testing, dissolve it in extracellular fluid and prepare it to the required concentration.
  • DMSO dimethyl sulfoxide
  • the data will be stored in a computer system for analysis. Data collection and analysis will use pCLAMP 10 (Molecular Devices, Union City, CA), and management will review the analysis results. Current stability means that the current changes within a limited range over time. The magnitude of the current after stabilization is used to calculate the effect of the compound on this solubility.
  • the LC/MS/MS method was used to measure the drug concentrations in the plasma of SD rats at different times after the compounds of the examples were administered intragastrically (i.g.). Study the pharmacokinetic behavior of the disclosed compound in SD rats and evaluate its pharmacokinetic characteristics.
  • the dosage is 2 mg/kg, and the dosage volume is 10.0 mL/kg.
  • the disclosed compound has high blood concentration, high exposure, and high bioavailability in SD rats, and has obvious pharmacokinetic advantages.
  • the LC/MS/MS method was used to measure the drug concentration in the plasma of CD-1 mice at different times after oral administration (i.g.) of the compounds of the examples. Study the pharmacokinetic behavior of the disclosed compound in CD-1 mice and evaluate its pharmacokinetic characteristics.
  • Example 5 and Example 1-P1 compounds were prepared.
  • Example 1-P1 white suspension
  • Example 5 Colorless slightly opaque solution
  • the dosage is 100 mg/kg, and the dosage volume is 10.0 mL/kg.
  • 0.1 mL of blood was collected from the orbit, placed in an EDTA-K2 anticoagulant test tube, and centrifuged at 10,000 rpm for 1 minute (4°C) , separate plasma within 1 hour, and store at -20°C for testing.
  • the process from blood collection to centrifugation is operated under ice bath conditions. Eat 2 hours after dosing.
  • Example 1-P1 Verapamil 100ng/ml
  • Example 5 Tolbutamide 100ng/ml
  • Example 1-P1 group took a mixture of 120 ⁇ L of supernatant and 50 ⁇ L of water, and took 3 ⁇ L of the supernatant for LC/MS/MS analysis.
  • the disclosed compound has high blood concentration, high exposure, and low clearance rate in CD-1 mice, and has obvious pharmacokinetic advantages.

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Abstract

La présente invention concerne un composé hétérocyclique, son procédé de préparation et son utilisation pharmaceutique. Plus particulièrement, la présente invention concerne un composé hétérocyclique tel que représenté dans la formule générale (I), son procédé de préparation, une composition pharmaceutique contenant le composé, et une utilisation du composé hétérocyclique en tant qu'agent thérapeutique, en particulier une utilisation en tant qu'inhibiteur de Nav et une utilisation dans la préparation de médicaments pour le traitement et/ou le soulagement de la douleur et de maladies associées à la douleur. Les groupes dans la formule (I) sont tels que définis dans la description.
PCT/CN2023/116053 2022-08-31 2023-08-31 Composé hétérocyclique, son procédé de préparation et son utilisation pharmaceutique WO2024046409A1 (fr)

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Cited By (1)

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WO2024217557A1 (fr) * 2023-04-19 2024-10-24 武汉人福创新药物研发中心有限公司 Tétrahydrofuranes substitués en tant qu'inhibiteurs de nav1.8

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CN102241621A (zh) * 2010-05-11 2011-11-16 江苏恒瑞医药股份有限公司 5,5-双取代-2-亚氨基吡咯烷类衍生物、其制备方法及其在医药上的应用
CN108349968A (zh) * 2015-07-28 2018-07-31 维奥梅生物科学私人有限公司 抗菌治疗剂和预防剂
US20180289706A1 (en) * 2017-04-06 2018-10-11 Janssen Pharmaceutica Nv 2,4-diaminopyrimidine derivatives as histamine h4 modulators
CN111065383A (zh) * 2017-07-11 2020-04-24 沃泰克斯药物股份有限公司 用作钠通道调节剂的羧酰胺
CN114945566A (zh) * 2019-12-06 2022-08-26 沃泰克斯药物股份有限公司 作为钠通道调节剂的取代四氢呋喃
WO2022256679A1 (fr) * 2021-06-04 2022-12-08 Vertex Pharmaceuticals Incorporated Analogues de n-(hydroxyalkyl(hétéro)aryl)tétrahydrofurane carboxamide en tant que modulateurs de canaux sodiques
WO2022256702A1 (fr) * 2021-06-04 2022-12-08 Vertex Pharmaceuticals Incorporated Tétrahydrofuran-2-carboxamides substitués utiles en tant que modulateurs de canaux sodiques

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5491152A (en) * 1994-03-23 1996-02-13 The Du Pont Merck Pharmaceutical Company Derivatives of cyclic ethers and sulfides for the treatment of atherosclerosis
CN102241621A (zh) * 2010-05-11 2011-11-16 江苏恒瑞医药股份有限公司 5,5-双取代-2-亚氨基吡咯烷类衍生物、其制备方法及其在医药上的应用
CN108349968A (zh) * 2015-07-28 2018-07-31 维奥梅生物科学私人有限公司 抗菌治疗剂和预防剂
US20180289706A1 (en) * 2017-04-06 2018-10-11 Janssen Pharmaceutica Nv 2,4-diaminopyrimidine derivatives as histamine h4 modulators
CN111065383A (zh) * 2017-07-11 2020-04-24 沃泰克斯药物股份有限公司 用作钠通道调节剂的羧酰胺
CN114945566A (zh) * 2019-12-06 2022-08-26 沃泰克斯药物股份有限公司 作为钠通道调节剂的取代四氢呋喃
WO2022256679A1 (fr) * 2021-06-04 2022-12-08 Vertex Pharmaceuticals Incorporated Analogues de n-(hydroxyalkyl(hétéro)aryl)tétrahydrofurane carboxamide en tant que modulateurs de canaux sodiques
WO2022256702A1 (fr) * 2021-06-04 2022-12-08 Vertex Pharmaceuticals Incorporated Tétrahydrofuran-2-carboxamides substitués utiles en tant que modulateurs de canaux sodiques

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2024217557A1 (fr) * 2023-04-19 2024-10-24 武汉人福创新药物研发中心有限公司 Tétrahydrofuranes substitués en tant qu'inhibiteurs de nav1.8

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